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Enantioselective Synthesis of AzameroneMatthew L. Landry, Grace M. McKenna, and Noah Z. Burns*Department of Chemistry, Stanford University, Stanford, California 94305, United States

*S Supporting Information

ABSTRACT: A concise and selective synthesis of thedichlorinated meroterpenoid azamerone is described. Thepaucity of tactics for the synthesis of natural-product-relevant chiral organochlorides motivated the develop-ment of unique strategies for accessing these motifs inenantioenriched forms. The route features a novelenantioselective chloroetheri!cation reaction, a Pd-cata-lyzed cross-coupling between a quinone diazide and aboronic hemiester, and a late-stage tetrazine [4+2]-cycloaddition/oxidation cascade.

The napyradiomycins are a diverse class of halogenatedmeroterpenoids that have been isolated from terrestrial

and marine actinomycetes (Figure 1A).1 Initial isolation e"ortswere driven by a desire to identify novel antibiotic sca"olds; thenapyradiomycins have since demonstrated potent inhibition ofgastric (H+-K+)-ATPase, nonsteroidal estrogen antagonism,cancer cell cytotoxicities, and activity against Gram-positivebacteria.1c!f Of the over 40 members within this class, onlynapyradiomycin A1 has succumbed to chemical synthesis (2,Figure 1A).2 Syntheses of more highly oxidized members of thenapyradiomycins (e.g., 1 and 3, Figure 1A), which featuredensely functionalized, chiral halocycle appendages, remainelusive, representing an exciting arena for synthetic develop-ment.Azamerone is structurally unique among the napyradiomy-

cins. It is the lone example of a phthalazinone-containing naturalproduct.3 Moore has postulated that this nitrogen!nitrogenbond-containing heterocycle arises from oxidative rearrange-ment of SF2415A1 (5) via intermediate 6 (Figure 1B).3a,b Inaddition to its unusual hetereocycle, azamerone’s highlyoxidized structure, diversity of heteroatoms, two stereogenictertiary alcohols, and two distinct chlorine-bearing stereogeniccenters pose signi!cant synthetic challenges. We envisaged thatazamerone could be retrosynthetically traced to a chlorobenzo-pyran, tetrazine, and chlorocyclohexane of general forms 7, 8,and 9 (Figure 1C). A challenging enantioselective chloroether-i!cation on prenyl-containing hydroxyquinone 10 (a reactionwith no enantioselective variants, Figure 1D), a hinderedcarbon!carbon bond formation between 9 and 7, and anelectronically mismatched late-stage tetrazine Diels!Alderreaction were thus identi!ed as key challenges for this chemicalsynthesis.Our synthetic approach !rst required the assembly of

enantioenriched chlorocycles 7 and 9. Biosynthetically, thechlorocycle motifs found in 7 and 9 are proposed to derive fromchloronium-initiated cyclizations of the prenyl and geranylfragments within 5 (Figure 1B,C).4 Neither of these trans-

formations have enantioselective, synthetic parallels (Figure1D).5 In fact, the use of enantioselective halogenation in naturalproduct synthesis has been limited thus far to the enantiose-lective bromochlorination and dichlorination of ole!ns.2b,6

Cognizant of these methodological gaps and the challenge ofchiral organochloride synthesis in general, we set out to developa new method for enantioselective chloroetheri!cation toproduce a benzochloropyran akin to 7 and to discover ameans for resolving the enantiomers of chlorocycle 9, which waspreviously made in racemic form (9, X = OAc, Figure 1C).9a

De novo development of an enantioselective chloroether-i!cation required the identi!cation of a substrate that not onlywas amenable to asymmetric halogenation but also could beparlayed into a synthesis of azamerone. Although considerableadvances have been made in the area of intramolecular catalytic,enantioselective chlorolactonization and chloroetheri!cation,high selectivity has been achieved only for styrenyl substrates;use of nonstabilized ole!ns is accompanied by a precipitous dropin enantioselectivity.5,7 After extensive investigation of potentialsubstrate structures and chiral catalysts, we discovered thatprenylated hydroxyquinone 11 could be chlorocyclized to abenzochloropyran by a TADDOL-ligated titanium complex andtert-butyl hypochlorite in modest yield and 10% ee (entry 1,Table 1). Application of other common systems forenantioselective chlorofunctionalization, including cinchonaalkaloids, returned racemic product.7 Unexpectedly, under theconditions of entry 1, ortho-quinone 12 was formed as the majorproduct. Signi!cant enol chlorination was observed withformation of a racemic !-chlorinated triketone byproduct.Initial formation of intermediate 13 is proposed, as this isconsistent with our hypothesis in a related dihalogenationsystem that a coordinatively saturated octahedral titaniumcomplex is necessary for high selectivity.6d Chloroether 12 likelyarises via trapping of the chloronium by the vinylogouscarboxylate carbonyl oxygen in 14; however, titanium is notnecessary for such regioselectivity, as the racemic product couldbe produced in 52% yield solely by the action of tert-butylhypochlorite (see Supporting Information). We anticipated that12 could be leveraged as a precursor to a para-quinoneintermediate for the synthesis of azamerone and, therefore,pursued optimization of this chloroetheri!cation.A survey of chiral ligands a"orded optimal TADDOL ligand

B,8 which produced chloropyran 11 in increased yield but withsimilarly low enantioselectivity (entry 2, Table 1). Althoughcomparable to ligand A under the conditions of entries 1 and 2,acyclic ligand B proved to be more selective and higher yieldingacross a broader range of conditions and was selected for further

Received: November 22, 2018Published: February 1, 2019

Communication

pubs.acs.org/JACSCite This: J. Am. Chem. Soc. 2019, 141, 2867!2871

© 2019 American Chemical Society 2867 DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871

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racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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Why amazerone?

• Highly oxidized structure• Diversity of heteroatoms• Two stereogenic tertiary alcohols• Two chlorine in the structure• 5 chiral center

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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optimization e!orts. Screening of reaction solvents revealed that2-methyltetrahydrofuran increased the selectivity of thechloroetheri"cation to 57% ee (entries 3!8, Table 1). Use ofother electrophilic chlorine sources led to a reduction in theyield or enantioselectivity of the process (entries 9!11, Table1). Hypothesizing that adventitious acid could be promoting aracemic background reaction, we found that inclusion ofheterocyclic base additives, such as pyridine and quinoline,increased the enantioselectivity of chlorocyclization (entries 12,13, Table 1); the precise role of these additives is unclear, butthey could serve as general bases, activating agents for transfer ofelectrophilic chlorine, or ligands on titanium. Employing astoichiometric amount of titanium and chiral ligand deliveredonly amodest increase in selectivity but a dramatic improvementin yield (entry 14, Table 1). Increasing the amount of tert-butylhypochlorite to 1.3 equiv provided an improvement in yieldwhen using 25 mol % titanium and ligand (entry 15, Table 1).

Gratifyingly, performing the reaction on 4 g scale under theseconditions resulted in an isolated 40% yield (entry 16, Table 1),which was deemed su#cient for completing the synthesis.With an enantioselective chloroetheri"cation in hand, we

commenced our synthesis of azamerone. Prenylquinone 11,which can be made in two steps from commercially availablematerials, was cyclized to chloropyran 12 using our optimizedconditions (Scheme 1). Treatment of this ortho-quinone withaqueous acid induced hydrolysis and isomerization to anintermediate 2-hydroxy-para-quinone, which was smoothlyconverted to its corresponding ortho-chloro-para-quinone 15with oxalyl chloride and dimethylformamide (DMF). Pyrano-quinone 15 is embedded within nearly all members of thenapyradiomycins (e.g., 1!4, Figure 1).Our synthesis of the chlorocyclohexane of azamerone focused

on "rst establishing a means to resolve racemic 16 (Scheme 1).In 2010, the Snyder group reported the direct chlorocyclizationof geranyl acetate with chlorodiethylsulfonium hexachloroan-timonate (see Scheme S2 in the Supporting Information).9a

This reaction provides the primary acetate of diol 16 in racemicform. Important recent work by Gulder,9b along with a protocolused here by Snyder9c on a mercury-based two-step mimic forhalopolyene cyclizations, provided strategies for accessing

Figure 1. (A) Representative napyradiomycin meroterpenoids. (B)Proposed biosynthesis of azamerone. (C) Retrosynthetic analysis ofazamerone. (D) Methodological gap.

Table 1. Enantioselective Chloroetheri!cation Optimization

aReactions were conducted on a 0.035!0.176 mmol scale, and 1HNMR yields are reported based on 1,4-dinitrobenzene as internalstandard. b100 mol % ClTi(Oi-Pr)3, 100 mol % B. c1.3 equiv of t-BuOCl. dReaction conducted on 4.0 g of 11. eIsolated yield.

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racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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S4

3. Azamerone Synthesis Scheme

Scheme S1. Full synthesis of azamerone

PhOO

OO

MeMeCl

aq. HClO477%

O

OO

Cl

MeMe

Cl

O MeMe

ClO

N2

ClTf2Othen DBU

80%

BH3ŎSMe2

71%

BOOH

Me

MeMe

Cl

MeMe

Cl

OHMe

MeMe

Cl

OHMe OH

90% ee

O

OH

MeMe

ClCl

MeHO

MeMe

Cl

+

SPhos-Pd G3

K3PO4

NN

O

O

MeMe

Cl

MeO

Me

MeMe

Cl

H

TBSO OH

H H

H

O

O

MeMe

Cl

MeTBSO

MeMe

Cl

OH

H

SPhos-Pd G3K2CO3, i-PrOH

56%

34%overall

TsNHNH2then NaOH

46%

12

15

ClTi(Oi-Pr)3 (25 mol %)lig. B (25 mol %)

t-BuOCl (1.3 equiv)

quinoline (1.0 equiv)2-Me-THF, -78 ˚C

40%, 84% ee[4 grams]11

17(–)-16 18

19

2021

1-TBS

OH

OPhO

OOMe

OH

OMe

PhOO

O

(COCl)293%

S4

S1S3

OHHORef. 1

OMeOMe

BBr3;

air, CuSO496%

Proton Sponge®

64%I

Me

Me

S2

PhMgBr

99%

MeMe

Cl

OHMe O

H

OPh

OMe

MeMe

Cl

OHMe OAc

H

MeMe

HgCl

OHMe OAc

H

MeMe

Me OAc

Cl2, LiCl64%

S5

S6

MeMe

Cl

OHMe OH

H

(±)-16

K2CO3MeOH

82%

(+)-S7

Cl

OPh

OMe

HO

OPh

OMe

pyridine33%

K2CO3MeOH

95%

S9

O

OH

MeMe

Cl

MeHO

MeMe

Cl

H

S8

PhI(OTFA)242%

TBSOTf;NaOH87%

O

OH

MeMe

Cl

MeTBSO

MeMe

Cl

H

NN N

N

MeHO

MeOMe

NH•HCl

OHNH•HOAcH2N

1. H2NNH2•H2O

2.

3. NaNO2, HCl 5%22

BBMe

Me

NN

23

110 ˚C

NN

O

O

MeMe

Cl

MeO

Me

MeMe

Cl

H

HO OH

1: azamerone

NN

O

O

MeMe

Cl

MeHO

Me

MeMe

Cl

H

TBSO OH

S10

O

OO

Cl

MeMe

HOPhO

O

OOH

Me

Me

HCl

commercially availableHg(OTFA)2then NaCl

(COCl)2DMF

commercially available

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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2869

Starting materials:

Chem. Ber. 1968, 101, 3744-3752.

OH

OH

MeOH, MeONa O

O

MeO

MeOS2

Br92.4 mmol

NaI(1.1 equiv)

Iacetone, air

O

O

OH

Ar Ar

OH

Ar

Ar + ClTi(Oi-Pr)3O

O

O

Ar Ar

O

Ar

Ar Ti O-iPrO-iPr

3.52 mmol

hexane, 10 min0.25 equiv

O

NH

OHH Cl H2N NH2

H O H+

1 equiv2.5 equiv

MeOH, 0 oC, 1 h

NHH2NO

OH2.5 equiv

rt, 2 h

NN N

N

HO

22

NaNO28 equiv

0 oC, 30 min5%

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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2869

Step 1:

OH

OH

MeOH, MeONa O

O

MeO

MeOS2

356 mmol

THF, -78oC

Br

2.5 equivMg

2.6 equivTHF, -78oC, 1h

rt, 12hOMe

OMe

OHPhO

S199%

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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2869

Proposed mechanism:

OH

OH

MeOH, MeONa

O2

O

OH

O O O

OHO-O

O

O

OMe

MeO O

O

O O O

O

MeOH

MeO O

O

O

O

MeO

MeOS2

356 mmol

OMeOMe

OHPhO

S199%

MgBr

OMeOMe

OMgBrPhO

Step 2:

OMeOMe

OHPhO

S1353 mmol

DCM, -78oC, 30 min

BBr32.2 equiv

rt, 1h

OHO

OPhO

S396%

CuSO4

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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Proposed mechanism:

OMeOMe

OHPhO

S1353 mmol

DCM, -78oC, 30 min

BBr3

rt, 1hOMeBBr3

OMe

OHPhO

MeBrOBBr2

OMe

OHPhO

+

OBBr2OBBr2

OHPhO CuSO4

OHO

OPhO

Step 3, 4:

OHO

OPhO

S323.1 mmol

dioxane, rt, until dissolved

Proton SpongeI

(2 equiv)

24 h OHO

OPhO

1164%

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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2869

Step 5, 6:

OHO

OPhO

1114.07 mmol

OTi

OO-iPrO-iPr

ArAr

Ar Ar

O

O

2-Me-THF, rt, 10 min

(0.25 equiv)

N(1 equiv)

OO

OPhO

1240%, 80%ee

Cl

t-butyl-hypochlorite(1.3 equiv)

hexane, -78oC, 16 hrt, 1 h

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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2869

OCl

Proposed mechanism:

J. Org. Chem. 1995, 60, 6847-6851

optimization e!orts. Screening of reaction solvents revealed that2-methyltetrahydrofuran increased the selectivity of thechloroetheri"cation to 57% ee (entries 3!8, Table 1). Use ofother electrophilic chlorine sources led to a reduction in theyield or enantioselectivity of the process (entries 9!11, Table1). Hypothesizing that adventitious acid could be promoting aracemic background reaction, we found that inclusion ofheterocyclic base additives, such as pyridine and quinoline,increased the enantioselectivity of chlorocyclization (entries 12,13, Table 1); the precise role of these additives is unclear, butthey could serve as general bases, activating agents for transfer ofelectrophilic chlorine, or ligands on titanium. Employing astoichiometric amount of titanium and chiral ligand deliveredonly amodest increase in selectivity but a dramatic improvementin yield (entry 14, Table 1). Increasing the amount of tert-butylhypochlorite to 1.3 equiv provided an improvement in yieldwhen using 25 mol % titanium and ligand (entry 15, Table 1).

Gratifyingly, performing the reaction on 4 g scale under theseconditions resulted in an isolated 40% yield (entry 16, Table 1),which was deemed su#cient for completing the synthesis.With an enantioselective chloroetheri"cation in hand, we

commenced our synthesis of azamerone. Prenylquinone 11,which can be made in two steps from commercially availablematerials, was cyclized to chloropyran 12 using our optimizedconditions (Scheme 1). Treatment of this ortho-quinone withaqueous acid induced hydrolysis and isomerization to anintermediate 2-hydroxy-para-quinone, which was smoothlyconverted to its corresponding ortho-chloro-para-quinone 15with oxalyl chloride and dimethylformamide (DMF). Pyrano-quinone 15 is embedded within nearly all members of thenapyradiomycins (e.g., 1!4, Figure 1).Our synthesis of the chlorocyclohexane of azamerone focused

on "rst establishing a means to resolve racemic 16 (Scheme 1).In 2010, the Snyder group reported the direct chlorocyclizationof geranyl acetate with chlorodiethylsulfonium hexachloroan-timonate (see Scheme S2 in the Supporting Information).9a

This reaction provides the primary acetate of diol 16 in racemicform. Important recent work by Gulder,9b along with a protocolused here by Snyder9c on a mercury-based two-step mimic forhalopolyene cyclizations, provided strategies for accessing

Figure 1. (A) Representative napyradiomycin meroterpenoids. (B)Proposed biosynthesis of azamerone. (C) Retrosynthetic analysis ofazamerone. (D) Methodological gap.

Table 1. Enantioselective Chloroetheri!cation Optimization

aReactions were conducted on a 0.035!0.176 mmol scale, and 1HNMR yields are reported based on 1,4-dinitrobenzene as internalstandard. b100 mol % ClTi(Oi-Pr)3, 100 mol % B. c1.3 equiv of t-BuOCl. dReaction conducted on 4.0 g of 11. eIsolated yield.

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Step 7, 8:

O Cl

OO

PhO

122.98 mmol

Et2O, rt, 1 h

HClO4(1.3 equiv)

O Cl

O

O

S477%

OH

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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O Cl

O

O

1593%

ClDMF

(1.4 equiv)

+Cl

Cl

O

O(1.1 equiv)

acetonitrile, 0oC, 10 min

O Cl

O

O

S4 OH

DCM

Step 9-11:

Hg(CF3COO)2

O

O+

1.1 equiv 1 equiv MeNO2, -15 oC, 3 hOAc

HgCl

HHO

OAc

HgCl

HHO

S5

S567 g crude mass

LiCl3 equivCl2, Ar

Pyridine, -40 oC

OAc

Cl

HHO

S664%

K2CO32 equiv

92 mmol

MeOH, 50 oC, 30 min

OH

Cl

HHO

(+)1682%

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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Step 12, 13:

DMF

(1.4 equiv)

+Cl

Cl

O

O(1.1 equiv)

acetonirle, 0oC, 10 min

O OH

O

Cl

OPh

OMe

OH

Cl

HHO

(+)1653 mmol

pyridine, 20 min

O

Cl

HHO

(+)S733%

OPh

OMe

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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Step 14:

O

Cl

HHO

(+)S714 mmol

OPh

OMe

K2CO3(2 equiv)

MeOH, 50 oCOH

Cl

HHO

(-)1695%, 90%ee

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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Step 15-18:

OH

Cl

HHO

(-)1626.1 mmol

N

(1.2 equiv)

DCM, -78 oC

(1.05 equiv)

DCM, -78 oC

Tf2O DBU(2.5 equiv)rt, 12 h

Cl

HO

1780%

Cl

HO

174.36 mmol

(1.4 equiv)

THF, 0 oC, 5 min

BH3.SMe2

rt, 18 h

O

Cl1871%

BOH

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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Step 19, 20:

O Cl

O

O

150.126 mmol

Cl

S O

O NHNH2

(1.1 equiv)

MeOH, rt, 30 min O

O

N2

Cl Cl

19

NaOH

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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Step 21:

O

O

N2

Cl Cl

19

O

Cl181.1 equiv

BOH

+

crude

(SPhos)Pd-G30.1 equivK3PO4

1.3 equivDioxane, 60 oC, 30 min

OH

Cl

O

OHCl

Cl

2046%

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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Step 22, 23:

OH

Cl

O

OHCl

Cl

20

0.36 mmol

(SPhos)Pd-G30.1 equivK2CO3

2 equiv

90 oC, 50 min

i-Propanol

OH

Cl

O

OH

Cl

56%S8

OH

Cl

O

OH

Cl

0.2 mmolS8

TBSOTf3 equiv

i-Pr2NEt4 equiv

DCM, rt, 18 h

NaOHOSBT

Cl

O

OH

Cl

87%S9

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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Step 24:

OSBT

Cl

O

OH

Cl

0.027 equivS9

CH3CN/H2O(10:3), 30 s

PhI(OTFA)21.1 equiv OSBT

Cl

O

OH

Cl

42%21

OH

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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Step 25:

O

NH

OHH Cl H2N NH2

H O H+

1 equiv2.5 equiv

MeOH, 0 oC, 1 h

NHH2NO

OH2.5 equiv

rt, 2 h

NN N

N

HO

22

NaNO28 equiv

0 oC, 30 min5%

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

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Proposed mechanism:

ON

O

HHO

NO

HH2O

NO N O

O

NH2

OHH2N NH2

+

NH2H2N

ONH2

OHH2N

NH2

NH

NH

OH

NH2

HNHN

OH

NH2H2N NH2

HNH2N

OH

NH2HN NH2

H2N NH2

HNH2N

OH

NH2HN NH2

NH2NH2

NN N

N

HONO

Step 26, 27:

NN N

N

HO

225 equiv

OSBT

Cl

O

OH

Cl

0.018 mmol21

OH+ +

NN

HS

S

23 CF3Ph, 110 oC, 2 d

NN

O

OHO

Cl

TBSO

Cl

101 equiv

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

Journal of the American Chemical Society Communication

DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871

2869

NN N

N

HO

225 equiv

++NN

HS

S

23 1 equiv CF3Ph, 110 oC, 2 d

NN

O

OO

Cl

TBSO

Cl

1-TBS

NN

O

OHO

Cl

TBSO

Cl

10 34%

Step 28:

racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an

appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor

diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12

Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp

3!Csp2 bond formation between sterically hindered boronic

hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp

3 nucleophile.13

Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was

Scheme 1. Short Enantioselective Synthesis of Azameronea

aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.

Journal of the American Chemical Society Communication

DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871

2869

NN

O

OO

Cl

TBSO

Cl

1-TBS

0.0072 mmol

HCl (12 M)

MeOH/DCM, 5 h

NN

O

OO

Cl

HO

Cl

Azamerone

84%