recent approaches to the total synthesis of …chemicke-listy.cz/docs/full/2014_04_301-319.pdf ·...

Chem. Listy 108, 301–319 (2014) Referát

301

EMANUELA JAHNa, THIERRY DURAND

b, JEAN-MARIE GALANO

b, and ULLRICH JAHN

a

a Institute of Organic Chemistry and Biochemistry, Acade-my of Sciences of the Czech Republic, Flemingovo náměstí 2, 166 10 Prague, Czech Republic, b Institut des Bio-molécules Max Mousseron (IBMM), UMR CNRS 5247 – Universités de Montpellier I et II, Faculté de Pharmacie, ENSCM, 15 Av. Charles Flahault, BP 14491, 34093 Mont-pellier cedex 05, France [email protected]

Keywords: lipids, oxidative stress, phytoprostanes, isoprostanes, neuroprostanes, total synthesis

Contents 1. Introduction 2. PhytoP Total Syntheses 3. Total Syntheses of F2- and F3-IsoPs 4. Epoxy-Isoprostane Syntheses 5. Total Syntheses of NeuroP 6. Conclusions and Outlook 1. Introduction

All living organisms are subject to oxidative stress at

major classes of primary metabolites, such as DNA, RNA, proteins, and lipids1,2. Especially lipid peroxidation is a very prominent process in plants and animals3,4. It occurs predominately at polyunsaturated fatty acid (PUFA) groups bound in the phospholipids of membranes (R = acyl(phosphoryl)glyceryl) or at PUFA cholesteryl esters (R = cholesteryl) in low-density lipid proteins (LDL) (Scheme 1). The extent of peroxidation is dependent on the degree of unsaturation in the corresponding PUFA unit; the more unsaturated, the more prone to autoxidation it is5–7, increasing from -linolenic acid (ALA) Ia, via arachidonic acid (AA) Ib and eicosapentaenoic acid (EPA) Ic to docosahexaenoic acid (DHA) Id. Other factors con-tributing to the extent of peroxidation are the concentration of oxygen in the tissue, the presence of reducing equiva-lents in the cell (vitamins C, E, and glutathione) and the presence of radical initiating species, especially reactive oxygen species, generated by mitochondrial leakage, elec-tron transfer from transition metal compounds or radiation. Lipid peroxidation starts usually by hydrogen atom ab-

straction at a bisallylic position of the corresponding PUFA. Autoxidative hydrogen atom abstraction proceeds in contrast to the enzymatic formation of prostaglandins (PG)8–11, where the hydrogen atom in 13-position of free AA 1b is selectively abstracted by the cyclooxygenase enzyme to give radical A, with almost equal probability at all available bisallylic positions leading to radicals IIa-d, IIIa-d and IVa-d. Thus a much larger variety of reactive radicals are generated in parallel. The enzymatic PG and the autoxidative PhytoP, IsoP, and NeuroP formation pro-ceed by the same elementary steps, namely coupling of the pentadienyl radical A or IIa-d with oxygen, radical 5-exo cyclization of the resulting peroxyl radical B or Va-d to an available olefinic unit in the PUFA chain, radical 5-exo cyclization of the carbon radical C or VIa-d and VIIa-d to the diene unit and coupling of the resulting allylic radical to oxygen giving either PGG2 or the G-type PhytoP, IsoP or NeuroP derived from Ia-d5,7,12.

The major difference between the enzymatic and au-toxidative process consists of the stereoselectivity of the coupling of the initial radical with oxygen, which occurs for A with high enantioselectivity in the enzyme, but with-out for IIa-d on peroxidation, and in the diastereoselectivi-ty of the cyclopentane forming step. Under autoxidative conditions a kinetically controlled cyclization of Va-d prevails with high selectivity, which leads to a cis-orientation of the side chains forming VIa-d and VIIa-d, whereas the cyclooxygenase enzyme forces the side chains of C in a trans-orientation for radical cyclization. As a consequence of these two factors PGs are single enantio-mers with trans-configuration of the chains as shown for the first observable PGG2, whereas PhytoP, IsoP and Neu-roP occur in Nature as regioisomeric mixture of racemic isomers, however, with relative cis-configuration at the ring. Further processing of the G-type IsoP proceeds by reduction to the F-Type IsoP or reduction and Kornblum-DeLaMare rearrangement to the D- and E-type IsoP, from which A- and J-type IsoP result by dehydration. The latter can isomerize to the B- and L-type IsoP13.

These differences have important consequences for the biological activity of these compounds. Whereas PGs act mostly as local hormones8–11, PhytoP and IsoP have been shown to display wide-ranging biological activities. They were summarized recently in several reviews and the reader should consult them for further information5,12,14,15. Very recently discovered activities concern the vascular homeostasis, the modulatory role on excitatory neurotrans-mitter release, neuroprotection, and anti-arrhythmic prop-erties. Moreover especially the F-type IsoP and PhytoP serve as important biomarkers for oxidative lipid stress in vivo, since they can be quantified easily by a number of mass-spectrometric or immunological techniques16.

As a direct consequence of their formation, PhytoP,

RECENT APPROACHES TO THE TOTAL SYNTHESIS OF PHYTOPROSTANES, ISOPROSTANES AND NEUROPROSTANES AS IMPORTANT PRODUCTS OF LIPID OXIDATIVE STRESS AND BIOMARKERS OF DISEASE


302

CO2R -Linolenic acid (ALA) Ia

CO2R Arachidonic acid (AA) Ib

CO2R Eicosa-5,8,11,14,17-pentaenoic acid (EPA) Ic

Docosa-4,7,10,13,16,19-hexaenoic acid (DHA) IdCO2R

For Ia-d:ROS

m

CH3p

CO2Rn

IIa m=0, n=7, p=1IIb m=1, n=3, p=4IIc m=2, n=3, p=1IId m=3, n=2, p=1

m

CH3p

CO2Rn

OO CO2Rm

CH3p

n

O

O

OOH

CO2R

OO

CH3p

nm

m

CH3p

CO2Rn m

CH3p

CO2Rn

IIIa-d IVa-d

OO

CO2R

CH3

nm

pOO

O

O

OOH

CO2R

CH3p

nm

CH34

CO2H3

CH34

CO2H3

OO

CH343

O

O

OOH

CO2H

OO

CH34

3

CO2H

For Ib:Cyclooxygenase

A

B

C

PGG2

O

O

++

O

O

+

Va-d

VIa-d

VIIa-d

G1t-PhytoP from IaG2t-IsoP from IbG3t-IsoP from IcG4t-NeuroP from Id

G1c-PhytoP from IaG2c-IsoP from IbG3c-IsoP from IcG4c-NeuroP from Id

+

OOH

CO2R

CH3p

nm

HO

HOOOH

CO2R

CH3p

nm

O

HO OOH

CO2R

CH3p

nm

HO

O

OOH

CO2R

CH3p

nm

OOOH

CO2R

CH3p

nm

O

OOH

CO2R

CH3p

nm

O

OOH

CO2R

CH3p

nm

O

F-typeE-type D-type

A-type B-type L-type J-type

O2

similarly

O2

–H2O –H2O

similarly

O

H

H H

R =

OO

O

P

R'

O

O

O NMe3

O

R' = C15H31R' = C17H35

H13C6

R=H

Ring substitution patterns for PG, PhytoP, IsoP and NeuroP

Scheme 1. The similar, but contrasting formation of prostaglandins and isoprostanes. (Note that the ring substitution pattern is only shown for IsoP resulting from Gxt-metabolites. The same substitution patterns are also found in PG, and metabolites resulting from IIIa-d, IVa-d and Gxc-metabolites.)


303

IsoP and NeuroP are regio- and diastereomeric mixtures, which are essentially impossible to separate. Therefore, it is impossible to use the natural material for biological in-vestigations to draw meaningful conclusions. For this rea-son, the only way to investigate them is to rely on synthet-ic material. Only this will allow a deeper understanding of the biological properties of PhytoP, IsoP and NeuroP. We summarized the state of the art of the total syntheses of oxidatively formed lipid metabolites some time ago5. Since then a number of new synthetic approaches have been de-veloped, which will be analyzed here to provide a com-plete picture of the opportunities known to date. The or-ganization of the review is by metabolite class, PhytoP are treated first, followed by IsoP and NeuroP.

2. PhytoP Total Syntheses Durand’s Syntheses

In 2008, the Durand group fully implemented their

previously developed furan-based strategy to B1-PhytoPs17,18 towards the more challenging synthesis of the ethyl ester of 9-D1t-PhytoP19 (called PPE type II20 in the original paper19; for the nomenclature of oxidatively formed cyclic lipid metabolites, see5,13) (Scheme 2). 15-E2-IsoP19, resulting from arachidonic acid, and later 4-F3t-NeuroP21, derived from -6 docosapentaenoic acid (DPA), were similarly synthesized by this approach. Intermediate 1, which is accessible in 6 steps in 13% yield19, was re-duced with L-Selectride with complete stereoselectivity followed by ethoxymethyl protection to give cyclopentene 2 with mandatory orthogonal protection of the two hy-droxy groups for the synthesis of E- and D-PhytoP as well as IsoP. Hydrogenation of the hindered tetrasubstituted double bond using in situ generated diimine permitted access to the trans-cis-trans-substituted cyclopentane 3 with complete control.

Introduction of the ethyl appendage of 9-D1t-PhytoP was accomplished from 3 in three steps by LiAlH4 reduc-tion of the methyl ester, protection of the resulting hydrox-yl group with TsCl and LiAlH4 reduction of the tosylate group in 73% overall yield. Mild deprotection of the acetal group with p-TsOH in acetone, followed by a Horner-Wadsworth-Emmons (HWE) reaction with dimethyl [9-(ethoxycarbonyl)-2-oxononyl]phosphonate in the pres-ence of NaHMDS afforded the trans-,-enone ester 4 in 70% yield after two steps. The diastereoselective reduction of the C15 keto group in 4 with the chiral reducing agent (S)-BINAL-H developed by Noyori et al.22 gave the 15(S) derivative which was protected with TBDPSCl in 57% yield for these two steps. Selective deprotection of the EOM group with BF3·OEt2 and Me2S was achieved in modest 49% yield, but provides the TBS ether 5. Dess-Martin oxidation led quantitatively to the corresponding ketone, which was used without purification in the next step. Desilylation with the HF•pyridine complex gave the desired 9-D1t-PhytoP ethyl ester 6 in an overall yield of 2.8% in 10 steps from 1.

Mikołajczyk’s Syntheses

16-B1-PhytoP, 9-B1-PhytoP and their 16- and 9-epi-mers respectively are formed via nonenzymatic autoxida-tive processes in plants and exhibit biological activities in humans. A very short total synthesis of 16-B1-PhytoP 11 and its 16-epimer 12 was published recently by Mikołajczyk et al. (Scheme 3)23. 3-[(Dimethoxyphospho-ryl)methyl]cyclopent-2-enone 7 served as a starting mate-rial, which is available in three steps in ca. 55% yield from cyclopentenone24. Alkylation of the dienolate of 7 with 8-bromooctanoate allowed the introduction of the -chain. The resulting product 8 was subjected to a Horner-Wadsworth-Emmons reaction with enantiopure -benzoyl-oxybutanals 9 under mild basic conditions providing the full chain methyl esters (E,S)-10 and (E,R)-10. Subsequent saponification furnished the enantiomeric 16-B1-PhytoP 11 and 16-epi-16-B1-PhytoP 12 in ca. 25% overall yield from 7.

Scheme 2. Durand’s total synthesis of 9-D1t-PhytoP ethyl ester


304

The methyl esters of 9-B1-PhytoP 17 and 9-epi-9-B1-PhytoP 18 were also synthesized in eight linear steps from commercially available aleuritic acid 13 using a similar strategy (Scheme 4)25. It was converted to allylic alcohol 14 in three steps in 47% yield by esterification, oxidative cleavage with sodium metaperiodate and addition of vinyl magnesium bromide to the resulting aldehyde. Kinetic resolution gave allylic alcohols (+)-(S)-14 and (–)-(R)-14 (ref.26) by enantioselective Sharpless epoxidation of the undesired enantiomer of 14. Subsequently (+)-(S)-14 and (–)-(R)-14 were protected and converted into aldehydes (–)-(S)-15 and (+)-(R)-15 by ozonolysis. Horner olefina-tion with phosphorylmethyl cyclopentenone 16, followed by desilylation provided 9-B1-PhytoP 17 and 9-epi-9-B1-PhytoP 18 in overall yields of 7.5% and 8.5%, respectively.

Riera’s Synthesis

The Riera group highlighted the applicability of the

Pauson-Khand reaction by completing total syntheses of enantiopure B1- and L1-PhytoP27,28, which they applied previously in a synthesis of deoxy-J1-PhytoPs29. Whereas the intramolecular Pauson-Khand reaction is famous to synthesize five-membered hydrocarbon cycles, the inter-molecular version using internal alkynes has scarcely been used, probably because of the lower reactivity as well as

the more difficult regioselectivity control. They reasoned that the electronegativity of a si-

lyloxymethyl group, although low, would be enough to control the regioselectivity (Scheme 5)30. Alkyne precursor 19a was obtained by alkylation of propargyl alcohol with the corresponding -bromo acid, subsequent esterification and TBS protection in excellent yield, while 19b was syn-thesized by silylation from commercially available 2-pentynol. Alkynes 19a,b were treated with a stoichio-metric amount of Co2(CO)8 to give, after filtration through alumina, the corresponding hexacarbonylcobalt complexes 20a,b. They were used directly in the intermolecular PKR under 6 bar ethylene gas using anhydrous N-methyl-morpholine N-oxide (NMO) as the promoter in the pres-ence of molecular sieves. The corresponding cyclopente-nones 21a,b were obtained in satisfactory yields and with complete regioselectivity. Pauson-Khand adducts 21a,b were transformed to aldehydes 22a,b by a sequence of deprotection using the pyridine·HF complex and a Swern oxidation. Introduction of the side chain of the different PhytoPs was accomplished using the Julia-Kocienski ole-

O

P(OMe)2

O

71) NaH, DMSO2) Br(CH2)7CO2Me

O

P(OMe)2

O

8 45%

(CH2)7CO2Me

DBU-LiClO4OHC

OBz(+)-(R)-9

DBU-LiClO4OHC

OBz (–)-(S)-9

O(CH2)7CO2Me

OBz

(E,R)-10 78%

O(CH2)7CO2Me

OBz

(E,S)-10 80%

K2CO3,MeOH

K2CO3,MeOH

O(CH2)7CO2H

OH16-B1-PhytoP 11 70%

O(CH2)7CO2H

OH16-epi-16-B1-PhytoP 12 75%

Scheme 3. Mikołajczyk’s synthesis of B1-PhytoP

Scheme 4. The synthesis of 9-B1-PhytoP


305

fination with sulfones 23a,b giving exclusively the (E)- isomers 24a,b in all cases, whereas (E/Z)-mixtures resulted under Barbier-type conditions with TBS-protected sul-fones. Deprotection of the tert-butyl ethers in 24a,b re-quired much experimentation and using five equiv. of p-toluenesulfonic acid in acetonitrile gave the desired me-thyl ester of 16-B1-PhytoP 25 in 63% yield after purifica-tion by chromatography. These conditions were not suita-ble for the deprotection of 24b, however, the use of BF3·OEt2 in CH2Cl2 at 0 °C for a few minutes allowed the isolation of the methyl ester of 9-L1-PhytoP 26 (ref.13) in a very good 81% yield.

3. Total Syntheses of F2- and F3-IsoPs The Galano-Durand Syntheses

In 2008, the Durand group disclosed a novel strategy

based on a completely different way of securing the de-sired trans-cis-trans stereochemistry of the cyclopentane ring (Scheme 6)31. They relied on the use of a bicyclo[3.3.0]octene skeleton, which served not only to lock the side-chain stereochemistry, but also solved the inherent problem of introducing cis-1,3-hydroxy groups on the cy-clopentane ring system. Monoepoxidation of commercially available 1,3-cyclooctadiene 27 by peracetic acid followed by transannular C-H insertion of the lithium carbenoid generated by lithiation with Et2NLi in Et2O gave access to approx. 40 g of desired bicyclic alcohol 28. Enzymatic resolution of 20 g of 28 using amano AK lipase and suc-cinic anhydride as the acylating agent furnished both enan-tiomers by the means of a simple liquid-liquid extraction procedure. Compound (–)-28 was then oxidized to the corresponding enone 30 with IBX in hot DMSO. Stereose-lective epoxidation with tert-BuOOH and catalytic DBU proceeded as expected at the convex face yielding the keto epoxide 31.

The stereoselective reduction of the ketone group was accomplished with LiAlH4 at –78 °C. The trajectory of the attack was directed by the epoxide to the concave face furnishing cis-epoxy alcohol 33 after protection. The re-ductive ring opening of the epoxide proved also to be regi-oselective and occurred at the more accessible remote car-bon from the ring fusion providing access to 1,3-diol 32 when allowing the temperature to rise slowly to room tem-perature. Remarkably, derivatives 32 or 33 are the first intermediates to be purified by silica gel chromatography and up to 4 g of 32 or 8 g of 34 can be prepared in one batch from 8 g of (–)-28. An interesting feature of this approach is the chemoselective ketone reduction of 31 in the presence of the epoxide allowing orthogonal protection leading to compound 34, from which either the E- or the D-series of IsoPs can be approached.

This strategy was initially validated by providing 15-F2t-IsoP and its 15-epimer (not shown)31. It proved more valuable to access 5-F3t-IsoP (Scheme 7)32. Starting point was the enantiomer of 32 derived from (+)-28. Its exhaustive TBS protection and subsequent ozonolysis with reductive workup produced diol 35, which was oxidized regioselectively to lactone 37 in 91% yield in a 98:2 ratio by using iridium catalyst 36 (ref.33). Dibal-H reduction to the corresponding lactol followed by introduction of the -chain by a Wittig reaction with phosphonium salt 38 and t-BuOK in THF gave dienylcyclopentane 39 in 64% yield. The -chain was appended in 85% yield by a two-step sequence of Dess-Martin oxidation and a HWE reaction with -ketophosphonate 40. Diastereoselective reduction of the enone 41 using Noyori’s (S)-BINAL-H reagent pro-vided a mixture of the corresponding allylic alcohol and the 1,5-lactone (not shown) in a 1:1 ratio with good dia-stereomeric ratio for both (d.r. >95%). Deprotection of the

TBSO

R1

19a: R1 = -(CH2)7CO2Me19b: R1 = -C2H5

(OC)3Co Co(CO)3

R1TBSO

6 bar H2C=CH2,DCM, NMO, MS R1

O

21a 69%21b 67%

1) HF•py2) Swern oxidation

20a20b

R1O

S

NS

OO

R2

OtBu

23a R2 = -C2H523b R2 = -C7H14CO2Me

KHMDS, THF, –78 °C to r.t.

R1O

R2

OtBu

22a 87%22b 78%

24a 61% R2 = -CH2CH324b 65% R2 = -(CH2)7CO2Me

p-TsOH, MeCN,35 °C

BF3·OEt2,DCM,0 °C, 5 min

(CH2)7CO2MeO

OH16-B1-PhytoPmethyl ester 25 63%

O

(CH2)7CO2Me

OH9-L1-PhytoP methyl ester 26 81%

Co2(CO)8

OTBS

CHO

Scheme 5. Riera’s synthesis of enone PhytoP via a Pauson-Khand strategy


306

TBS groups under acidic conditions and subsequent basic hydrolysis of the methyl ester and lactone units gave 5-F3t-IsoP 42 in poor 6% yield because the final steps were not optimized. 5-F3t-IsoP can be obtained in a higher overall yield (vide infra), however, this synthesis permitted to clarify the absolute stereochemistry at C5 for the first time.

A drawback of the bicyclic approach became clear, when confronted with the introduction of more complex and sensitive side chains. The rather poor reactivity of the lactol derived from 37 did not permit to use complex skipped diene or diyne phosphonium salts for the introduc-tion of the -chain in the Wittig reaction.

1) CH3CO3H

OHH

Hrac-28 72%

OH

H

HO H

H

+ O

CO2H

(+)-29 47%>98% ee

2) Et2NLi Et2O, 30 °C

Amano AK lipase,succinic anhydride,

(–)-28 48%>98% ee

S R

IBX

O H

H

O

O

H

H

tBuOOH, 15 mol% DBU

(–)-28

30 65% 31 82%

LiAlH4, THF –78 °C to r.t.

(d.r. = 95/5)

HO H

HHO

1) LiAlH4, –78 °C

2) , PPTS

O

O

H

H33 80%

O

*

*

EEO H

HTBSO

1) LiAlH4, THF

2) TBSCl

*O

O

sites ofattack

32 75%

34 81%

thenliquid-liquid extraction

27

DMSO, 90 °C CH2Cl2, 12 h, r.t.

EtO

Scheme 6. Access to bicyclo[3.3.0]octendiol intermediates on large scale

Scheme 7. Access to 5-F3t-IsoP based on bicyclo[3.3.0]octendiol


307

In order to overcome this limitation, a novel method-ology for the enzymatic monoprotection of unsymmetrical primary 1,5-diols using Candida antarctica lipase (CALB) was found, which proceeded with high selectivity and complete regiocontrol (Scheme 8)34. For example, mono-acetate 44 obtained in 98% from diol ent-35 served well to introduce complex side chains bearing skipped dienes or diynes (vide infra, Scheme 24). The orthogonally protected acetate intermediate 45 was similarly obtained from diol 43 and allowed access to the challenging first syntheses of 15-D2t-IsoP 46 together with 15-epi-15-E2-IsoP 47 (Figure 1)35. This methodology was also used in a synthesis of 17-F2t-dihomo-IsoP 48 and ent-7-epi-7-F2t-dihomo-IsoP 49 derived from adrenic acid (AdA)32,36.

Helmchen’s Synthesis

Helmchen et al. described a short diastereoselective

synthesis of all-cis-Corey lactone and employed it for the total syntheses of ent-5-F2c-IsoP and ent-5-epi-5-F2c-IsoP (Scheme 9)37. A seven step sequence starting with a Diels-Alder reaction of chiral fumarate 50 and cyclopentadiene followed by an iodolactonization provided lactone 51, which was transformed to enantiopure carboxylic acid 52 (ref.38) in 53% overall yield. exo-Chloronorbornane deriva-tive 53 was prepared by selective cyclopropane ring open-ing of 52 by treatment with HCl, from which two pathways

for the synthesis of bicyclic lactone 56 were explored. On path A lactone 54 was obtained by a Baeyer-Villiger oxi-dation of 53, which was converted to 56 by a chemoselec-tive reduction of the carboxylic acid via a mixed anhydride and translactonization. Alternatively, on route B the order of reduction and rearrangement was reversed. The mixed anhydride obtained from carboxylic acid 53 and ethyl chloroformate was chemoselectively reduced with zinc borohydride, giving alcohol 55 in 85% yield. Subsequent Baeyer-Villiger oxidation afforded lactone 56. The second-ary alcohol function was protected as a PMB-ether 57 by treatment with p-methoxybenzyl trichloroacetimidate in

OR1

OTBS

OH

OH

R1O

TBSO

OH

OAc

CandidaAntarcticalipase B,

vinyl acetate, THF, r.t.

44 R1 = TBS 98%45 R1 = EE 88%

ent-35 R1 = TBS43 R1 = EE

Scheme 8. Regioselective lipase-catalyzed monoacetylation of unsymmetrical primary 1,5-diols

C5H11

OHHO

O15-epi-15-E2-IsoP 47

HO

HO

C5H11

CO2H

OH17-F2t-dihomo-IsoP 48

HOCO2H

C5H11

ent-7-epi-7-F2t-dihomo-IsoP 49

OH

HO

O

C5H11

OH

HO

CO2H

15-D2-IsoP 46

CO2H3

5

3

5

C22

C20

Fig. 1. IsoPs obtained from Durand’s bicyclo[3.3.0]octene precursors

O

CO2H

O

ClCOOH

O

ClCOOH

O

AcOH, AcONa, H2O2,

60 °C, 6 h

conc. HCl

O

Cl OH

O

Cl

HO

OAcOH, AcONa, H2O2,

60 °C, 3 h

1) ClCO2Et, NEt3, THF, 0 °C, 0.5 h2) Zn(BH4)2, THF, 0 °C, 0.5-1 h

COOR*

R*OOC

R* = (S)-OCH(CH3)COOC2H5

1)

2) LiOH3) KI3

ICOOH

OO

1) NaOH2)

3) NaOH4) cat. RuO4/NaIO4

52 53% (7 steps)

50 51

53 82%, >99% ee 54 88%

55 85% 56

66%

63%

Path A

Path B

O CCl3

NH

p-MeOC6H4

Ph3C+BF4–, THF, r.t., 18 h O

Cl

PMBO

O

57 87%

LiOH, H2O2

OO

PMBO OH58 82%

THF/H2O, r.t., 24 h

Scheme 9. Helmchen’s synthesis of all-cis-Corey lactone 58


308

the presence of a catalytic amount of triphenylmethyl tetra-fluoroborate. Lactone saponification and subsequent nucle-ophilic substitution yielded 82% of Corey lactone isomer 58 (ref.39,40).

Aldehyde 59 was prepared by a Dess-Martin oxida-tion of lactone 58 and submitted crude to a HWE olefina-tion with -keto phosphonate 60 using the Masamune-Roush protocol41 providing lactone 61 in 86% yield and 16:1 E/Z-selectivity (Scheme 10). Luche reduction of 61 gave a mixture of diastereomeric alcohols, which were separated by preparative HPLC. Their esterification with (S)-or (R)-O-methylmandelic acids, respectively, and anal-ysis of the 1H NMR spectra of the resulting esters allowed

the unambiguous assignment of the C5-configuration (not shown). The hydroxy group at C5 was protected as a TBS ether and the PMB group was oxidatively deprotected with DDQ affording diastereomers -62 and -62. The intro-duction of the C14-C20 unit was accomplished in two steps consisting of mild reduction of the lactone to the lactol, and subsequent Wittig olefination with phosphoni-um salt 63. Finally, the TBS-groups in -64 and -64 were deprotected and the ester units were saponified providing the diastereomeric ent-5-F2c-IsoP -65 and ent-5-epi-5-F2c-IsoP -65 after 12 linear steps in an overall yield of 4% for each from carboxylic acid 52.

Jahn’s Syntheses

Jahn et al. reported a new strategy, comprising an

oxidative radical anion cyclization/oxygenation methodol-ogy and the introduction of the -chain by linking C6-C7 via an acetylide alkylation reaction42. The total syntheses started with a vinylogous aldol addition of methyl aceto-acetate 66 and (E,E)-decadienal 67 (Scheme 11). The al-most quantitatively isolated product 68 was syn-selectively reduced and the resulting diol was regioselectively protect-ed giving cyclization substrate 69 in good yield. The dian-ion of 69 was generated under diverse deprotonation con-

58DMP O

O

CHO

OPMB 59

CH2Cl2,r.t.

O(MeO)2P CO2tBu

3

O

iPr2NEt, LiCl, MeCN, r.t.

O

O

OPMB O

CO2tBu

60

61 86%, d.r. 16:1

1) NaBH4, CeCl3, MeOH, 0 °C, then HPLC separation

2) TBSCl, imid.,CH2Cl2, r.t.3) DDQ, CH2Cl2, phosphate buffer, r.t.

O

O

OHCO2tBu

62 42% R1 = OTBS, R2 = H62 30% R1 = H, R2 = OTBS

R1 R2

1) Dibal-H, THF, 78 °C

2) Br– Ph3P+(CH2)5CH3, KHMDS, THF, 45 - 25 °C

HO

HOCO2tBu

R1 R2

C5H11 1) TBAF, THF, r.t.

2) KOH, MeOH, r.t.

HO

ent-5-F2c-IsoP 65 65%ent-5-epi-5-F2c-IsoP 65 77%

R1 R2

HO

3

3

3

CO2H

63

64 47% R1 = OTBS, R2 = H64 60% R1 = H, R2 = OTBS

(3 steps)

Scheme 10. Total synthesis of ent-5-F2c-IsoP and its 5-epimer

OH

OTBS

CO2Me

C5H11

O

O

CO2MeOHC

C5H11

2

O

HO

CO2Me

C5H11

NaH, BuLi, THF/HMPA,

1) Et2BOMe, NaBH4, THF

HO

TBSO

CO2Me

C5H11

2) TBSOTf, 2,6-lutidine, CH2Cl2

66

68 94%

69 64% (79% brsm)

67

Base, THF/HMPA, then

HO

TBSO

CO2R

C5H11

OT

+

NFe+ PF6

–

O 70 71

72 73

2.5 equiv. LDA, 7 equiv. LiCl 71%, 1.4:12.5 equiv. LDA, 15 equiv. LiCl 62%, 1.7:11.5 equiv. tBuMgCl/2.2 equiv. LDA 41%, 1:4.1

N

= TMP

PG configuration

MP

Scheme 11. Jahn’s oxidative cyclization to cyclopentanecar-boxylates


309

ditions and submitted to tandem oxidative 5-exo cycliza-tion/oxygenation triggered by single-electron oxidation by ferrocenium hexafluorophosphate 71 and subsequent oxy-genation by TEMPO 70. The cyclization was stereodiver-gent depending on the deprotonation conditions, giving a moderate excess of either cyclopentanecarboxylate 72 with IsoP configuration or 73 with PG configuration, which were separable by flash chromatography.

Methyl cyclopentanecarboxylate 72 was reduced with LiAlH4 and the resulting diol 74 was converted to the tri-

flate 75 by a one-pot O-triflation and TES protection (Scheme 12). The -chain was appended subsequently by alkylation of an excess orthoester lithium acetylide 76 with 75, affording the full C20 skeletons 77 and 78 in 76% combined yield. Methyl ester 79 was obtained almost quantitatively from this mixture by a sequence of deprotec-tion of the silyl groups, hydrolysis of the orthoester, sapon-ification and esterification. The tetramethylpiperidinyl group was subsequently oxidatively removed with mCPBA leading to a keto function in 15-position, which was re-duced by Yamamoto’s reagent 80 to a mixture of 15/-81 in a 1.7:1 ratio. After separation by flash chromatography, a quantitative Lindlar hydrogenation in ethanol/ethyl ace-tate gave 15-F2t-IsoP 82 and 15-epi-15-F2t-IsoP 83, respec-tively, in an overall yield of 14% over 12 steps for the sum of both diastereomers.

This methodology was adapted for the synthesis of potential metabolites of 15-E2-IsoP, 13,14-dehydro-15-oxo-E2-IsoP and 13,14-dehydro-15-oxo-PGE2 (ref.43). Here, the -chain was introduced in high yield by alkylation of lithi-um acetylide 84 with triflate 75 (Scheme 13). With the C20 precursor 85 in hand, the functional groups were ad-justed as follows: both triethylsilyloxy groups were oxi-dized under Swern conditions to an intermediate keto alde-hyde44, which was subjected to a Pinnick oxidation to the corresponding keto acid and transformed into the methyl ester. Mild deprotection of the TBS group by the pyri-dine•HF complex gave cyclopentanone esters 86 and 87 with little epimerization at the very sensitive 8-position. Oxidative removal of the tetramethylpiperidinyl group with mCPBA afforded enones 88, 89 and 90 in 75% yield in a 9:4:1 ratio. Considerable epimerization occurred at 8-position, and little also at the 12-position. The total syn-thesis of 91 and 92 was accomplished by Lindlar hydro-genation of the mixture of 88–90, during which further epimerization at the 8-position occurred. Metabolites 13,14-dehydro-15-oxo-E2-IsoP 91 and 13,14-dehydro-15-oxo-PGE2 92 were isolated in a 1.5:1 ratio. The synthesis re-vealed the high susceptibility of 15-E2-IsoP derivatives towards epimerization under slightly acidic or basic condi-tions, suggesting a common pathway of 15-E2-IsoP and PGE2 metabolism. Metabolites 91 and 92 were obtained in 11 steps and 1.4% overall yield.

Rokach’s Syntheses

In 2008, Rokach et al. complemented their impressive

number of IsoP and NeuroP metabolites by synthesizing the major metabolites of EPA, 5-F3c-IsoP and its C5 epimer45. They previously showed that 5-F3t-IsoP is stable in vivo and does not significantly metabolize46. In this new report they showed that both epimers of the all-cis-series are the most abundant F3-IsoP metabolites in urine. The synthesis of 5-epi-5-F3c-IsoP started from their central precursor, the dihydroxy lactone 93 (Scheme 14)47. After exhaustive TES protection of the alcohol units, the primary TES ether was selectively deprotected to lactone 94 in excellent yield using their Rh-catalyzed catechol borane

OH

OTBS

C5H11

OT

OH

OTBS

CO2Me

C5H11

OT

TESO

TBSO

C5H11

OT

Tf2O, 2,6-lutidine,then TESOTf

THF

72

OH

CH2Cl2, 78 °C

OTf

74 89%

75 81%

RO

TBSO

C5H11

OTMP77 50% R = TES78 26% R = H

OO

O

Li OO

O3

76 (3 equiv.)

THF/HMPA, 78 °C

1) TBAF, THF, 0 °C2) NaHSO4, DME/H2O,

79 98%

HO

HO

C5H11

OT

CO2Me

then LiOH, THF/H2O,then TMSCHN2, THF/MeOH

1) mCPBA, CH2Cl2

HO

HO

C5H11

OH

CO2Me

tBu

tBu

OAliBu2

2)

toluene, 78 °C

81 86%, 15/15 1.7:1

Separation, thenLindlar cat., 1 bar H2,EtOH/EtOAc/Py, r.t.

HO

HO

CO2Me

X Y15-F2t-IsoP 82 96%, X = H, Y = OH15-epi-15-F2t-IsoP 83 99%, X = OH, Y = H

3

3

80

MP MP

MP

MP

LiAlH4,

Scheme 12. Completion of the total synthesis of 15-F2t-IsoP and its 15-epimer


310

procedure48. Two further steps, namely a Mitsunobu-type substitution followed by an S-oxidation afforded the de-sired 1-phenyl-1H-tetrazol-5-yl sulfone 95 in 94% yield, which was coupled via the Kocienski-modified Julia ole-fination with enantiopure aldehyde 96. Lactone 97 was obtained in 52% yield after separation of the initial 2:1 (E/Z)-mixture.

Compound 97 was subsequently transformed in four steps to the C20 derivative 99. These included reduction of the lactone to the corresponding diol, bis-TES protection,

a concomitant selective deprotection of the primary TES ether function and Swern oxidation. The obtained aldehyde was coupled with the (Z)-3-hexenyl Wittig reagent giving 99 in 49% yield. Complete deprotection of the silyl ethers with TBAF and saponification yielded 5-epi-5-F3c-IsoP 100 in 93% yield over two steps. This total synthesis pro-ceeded in 11 steps and 20% overall yield starting from 93, which was obtained in gram quantity in 8 additional steps.

Recently, the group described a significant improve-ment49 of a previous access50 to tetradeuterated 5-F3c-IsoP derivatives. It started from the propargyl tetrahydropyranyl ether 101 (Scheme 15), which was treated with deuterium gas in the presence of Wilkinson’s catalyst to generate the tetradeuterated THP ether, from which the low-boiling volatile three-carbon alcohol was liberated on treatment with Me2AlCl. The crude alcohol was treated with TsCl to generate the stable and high-boiling tosylate 102. Treat-ment with triphenylphosphine in CH3CN generated the

93

1) TESCl, NEt3, DMAP, CH2Cl2, r.t.

HO

O

OH OTES

O

O

OH

94 90%

, PPh3, DIAD, THFOTES

O

O

S

95 94%

O

ONPh

NNN

OHCCO2Me

OTBDPS

KHMDS, DME,

OTES

O

O

OTBDPS

CO2Me

9697 52%E/Z 63:37

4) LiHMDS, THF, then

OTES

OTES

OTBDPS

CO2Me

Et

HO

HO

OH

CO2H

5-epi-5-F3c-IsoP 100 93%

99 49% (4 steps)

1) TBAF, THF2) LiOH, iPrOH/H2O

OBH

O2) cat. (Ph3P)3RhCl,

, THF

HS NPh

NNN

2) mCPBA, CH2Cl2

1)

O

3

3

3

1) NaBH4, Et2O/MeOH2) TESCl, NEt3, DMAP3) Swern oxidation

Ph3P+ EtI–

98

(HBcat)

Scheme 14. Rokach’s approach to 5-epi-5-F3c-IsoP

75

85 71%

84 (3 equiv.)

THF/HMPA, 78 °C

mCPBA, CH2Cl2,0 °C, 13 min

Lindlar cat., 1 bar H2,EtOH/EtOAc/Py, r.t.

O

HO

CO2Me

13,14-Dihydro-15-oxo-E2-IsoP 91

1) DMSO, (COCl)2, NEt3, CH2Cl2,78 °C2) NaClO2, NaH2PO4, tBuOH/H2O, 2-methyl-2-butene, then Me3SiCHN2, THF/MeOH3) HF•py, MeCN

TESO

TBSO

C5H11

OT

45%, d.r. 9:1

O

OH

C5H11

OT

CO2Me8

12

O

OH

C5H11

O

CO2MeO

OH

C5H11

O

CO2Me

88 : 89 : 90 75%, d.r. 9 : 4 : 188 8,12-cis, 89 8,12-trans 90

O

HO

CO2Me

13,14-Dihydro-15-oxo-PGE2 92O

O

OH

C5H11

OT

CO2Me8

12

+

+

86 87

O

OTES

90%, d.r. 91 : 92 1.5:1

Li4

4

3 3

3 3

8

12

+

OTES

MP

MP MP

Scheme 13. Synthesis of potential 15-E2-IsoP metabolites


311

corresponding phosphonium tosylate. An anion exchange to the corresponding phosphonium iodide with NaI was necessary to obtain a better yield in the following Wittig reaction with aldehyde 103 (85% yield compared to 22–38% yield with the tosylate). (Z)-Olefinic deuterated silyl ether 104 was transformed to phosphonium iodide 105 via deprotection of TBS group, tosylation, reaction with tri-phenylphosphine and another anion exchange with NaI in 75% yield over 4 steps. The synthesis of 19,20-d4-5-F3c-IsoP 107 was achieved by coupling 105 and aldehyde 106, which was obtained as described before (cf. Scheme 14), TBS deprotection and saponification.

Snapper’s Synthesis

Snapper et al. developed a stereodivergent route to

a library of all eight enantiomerically enriched 5-F2-IsoPs 108 (Fig. 2)51. The approach is based on previous total syntheses of 15-F2t-IsoP isomers52–55.

The relative ring stereochemistry was set by exo- and endo-4-(tert-butyldimethylsilyloxy)bicyclo[3.2.0]hept-7-ene-2-ols exo-109a and endo-109b (Scheme 16). They

were subjected individually to a ring-opening metathesis applying the Grubbs I catalyst 110 in the presence of eth-ylene. The resulting racemic divinylcyclopentane 111 and its all-cis-diastereomer (not shown) underwent cross-metatheses with enone 113 using the Hoveyda-Grubbs II catalyst 112 affording dienones 114 or 115 with the entire -chain.

The secondary alcohol in (±)-114 was temporarily protected as a TMS ether and the resulting enone was en-antioselectively reduced by the (R)-CBS catalyst (R)-116 in the presence of catechol borane, providing diastere-omers (+)-117a and (+)-117d, which were separated by chromatography (Scheme 17). Employing the (S)-CBS catalyst (S)-116, diastereomers (–)-117b and (–)-117c were similarly prepared.

For the obtained diastereomers 117a-d the secondary alcohol functions were protected as TBS ethers as exem-plified for (+)-117a (Scheme 18). Hydroboration/oxidation of the terminal olefin afforded the primary alcohol, which was subjected to a one-pot oxidation/Wittig reaction with hexylphosphonium ylide. Global deprotection with TBAF and saponification yielded 5-F2t-IsoP 108a in 4.3% overall yield from bicyclo[3.2.0]heptene exo-109a. The 5-F2c-IsoP precursor (±)-115 was converted similarly, thus all eight 5-F2-IsoPs 108a-h were accessed in a stereodivergent man-ner from exo- or endo-109 in 7–8 steps in overall yields of 4.3–13%.

OTES

OTES

OTBS

O

19,20-d4-5-F3c-IsoP 107 68%

106

2) TBAF, THF3) LiOH, iPrOH/H2O

TsODD

D

D

1) PPh3, MeCN, 70 °C2) NaI, MeCN, r.t.

DDD

D

Ph3P+I–

105 75%

1) LiHMDS, THF, –78 °C, then 105

HO

HO

OHCO2H

101 102 73%

TBSOCHO

3) KHMDS, THF, DDD

D

TBSO

104 79%103

1) HCl, THF2) TsCl, Py

1) cat. (PPh3)3RhCl, D2, C6H62) Me2AlCl, –20 °C, CH2Cl2

DDD

D

THPO3) TsCl, py, CH2Cl2

–90 °C to r.t.

3) PPh3, MeCN4) NaI, MeCN

CO2Me

Scheme 15. Rokach’s improved synthesis of deuterated 5-F3c-IsoP derivatives

CO2HHO

HO

OH

3

5-F2t-Isoprostane 108a

4

CO2HHO

HO

OH

3

ent-5-F2t-Isoprostane 108b

4

CO2HHO

HO

OH

3

5-epi-F2t-Isoprostane 108c

4

CO2HHO

HO

OH

3

ent-5-epi-F2t-Isoprostane108d

4

CO2HHO

HO

OH

3

5-F2c-Isoprostane 108e

4

CO2HHO

HO

OH

3

ent-5-F2c-Isoprostane 108f

4

CO2HHO

HO

OH

3

5-epi-F2c-Isoprostane 108g

4

CO2HHO

HO

OH

3

ent-5-epi-F2c-Isoprostane108h

4

Fig. 2. The eight diastereomeric 5-F2-IsoP


312

4. Epoxy-Isoprostane Syntheses Jung’s Synthesis

E2-Epoxyisoprostane phospholipid (PEIPC) 127 has

important biological activities related to atherosclerosis (Scheme 19). The total synthesis of 127 was initially achieved in 2005 (ref.56), but was recently significantly improved57. Chiral pivalate 119 was prepared from meso-diacetate 118 by enzymatic deacetylation with electric eel acetylcholine esterase (EEAC), protection with pivaloyl chloride and saponification of the remaining acetyl group in 67% yield58. Pivalate 119 was converted uneventfully to 2-bromocyclopentenone 120 in 41% yield in four steps, namely protection of the free alcohol as a PMB ether, re-ductive deprotection of the pivalate, oxidation of the alco-hol to the ketone by PCC, and -bromination. The intro-duction of the C12-C13 unit was accomplished by a 1,4-addition of vinylcopper to enone 120 in the presence of TBSCl to afford an inseparable 2:1 trans/cis mixture of enol ethers 121. Hydroboration/oxidation of the terminal olefin afforded a separable mixture of terminal alcohols, which were individually converted to the aldehydes by a Dess-Martin oxidation. The -chain was attached by a Wittig reaction, affording the C8–C20 subunit 122. The introduction of the -chain was accomplished by a lithium-halogen exchange in 122, followed by the nucleophilic addition to chiral aldehyde 123 furnishing the C20 com-pound 124. A one-pot deprotection of the silyl enol ether and subsequent dehydration at the C7–C8 position, fol-lowed by a two-step oxidation of the terminal alcohol gave epoxy acid 125. Treatment of the free acid with commer-cially available 1-lysophosphatidylcholine 126 as previ-ously described56 and subsequent oxidative deprotection of the PMB group gave 1-palmitoyl-2-(5,6-epoxy-7,8-

Scheme 16. Approach to the 5-F2t- and 5-F2c cyclopentane cores

OH

OTBS

CO2Me

O

(±)-114

N BO

1) TMSCl, Et3N2) HBcat, NaOH, MeOH,

H PhPh

HO

TBSO

CO2Me

OH

(+)-117d 40%

HO

TBSO

CO2Me

OH

(+)-117a 40%

HO

TBSO

CO2Me

OH

()-117c 40%

HO

TBSO

CO2Me

OH

()-117b 40%

1) TMSCl, Et3N2) HBcat, NaOH, MeOH,

N BO

H PhPh

3

3

3

3

3

10 mol%

(R)-116

(S)-116

10 mol%

+

+

Scheme 17. Enantiodivergent reduction of racemic enone 114

HO

TBSO

OH

(+)-117a(similarly for diastereomers 117b-d)

1) TBSCl, Et3N, DMAP, CH2Cl22) (Cy)2BH, THF, then NaOOH3) TPAP, NMO, CH2Cl2, then CH3(CH2)4CH=PPh34) TBAF, THF, then LiOH, THF/H2O

CO2Me

HO

HO

OH

5-F2t-IsoP 108a 14% (4 steps)

CO2H

Scheme 18. Completion of the total syntheses of the diastereo-meric 5-F2-IsoPs 108

HO

TBSO

H

H(±)-exo-109a

Entry to 5-F2t-isoprostanes

Ru

Cy3P

PCy3

Cl

Cl Ph

1105 mol%

H2C=CH2

HO

TBSO

10 mol%

O

CO2Me

HO

TBSO

CO2Me

O

(±)-111

(±)-114 77%113

Ru

O

Cl

Cl112

iPr

NN MesMes

3

3

TBSO

TBSO

H

H(±)-endo-109b

Entry to 5-F2c-isoprostanes

TBSO

TBSO

CO2Me

O

(±)-115 68%

3

sameas above


313

dehydro-E2-IsoP)-sn-glycero-3-phosphocholine 127 after 17 linear steps in 0.8% overall yield from meso-diacetate 118.

Kobayashi’s Synthesis

Kobayashi et al. reported the total synthesis of 12,13-

dehydro-14,15-epoxy-J2-IsoP palmitoylphosphatidyl cho-line 136 (ref.59), which started with the ZnBr2-catalyzed

formation of propargylic Grignard reagents such as 129 from TMS-protected propargylic bromide 128 (Scheme 20)60. A copper-promoted allylic substitution of enantiopure monoester (1S)-130 gave acetylene 131. The alcohol was subsequently protected as a TBS ether, the trimethylsilyl group at the alkyne was cleaved by K2CO3 and the free alkyne was after deprotonation alkylated with the corresponding benzyloxybutyl bromide furnishing substituted silyloxy cyclopentene 132 with the complete C1–C7 alkyl chain. A Lindlar hydrogenation of the alkyne unit, deprotection of the silyl ether group and oxidation of the free alcohol set the stage for the crucial aldol addition, which was performed by kinetic deprotonation of the cy-clopentenone by LDA and addition of epoxy aldehyde 133. The resulting aldol adduct 134 was obtained as a 2:1 anti/syn mixture at the newly formed stereocenters in 55%

O

PMBO

Br CuTBSCl

HMPA

TBSO

PMBO

Br

PivO

HO

120 41%

1) 9-BBN, NaOOH, separation of alcohols

121 94%, d.r. 2:1

BrOTBS

OPMB122 41%

2) Dess-Martin oxidation3) NaHMDS, H13C6P+Ph3 Br–

tBuLi, Et2O, 78 °C

OHC OTBSO

C5H11

TBSO

PMBO

HO OOTBS

1) aq. THF, HCO2H2) Dess Martin oxidation

3) NaClO2 C5H11

O

PMBO

OCO2H

124 66%

125 60%

123

C5H11

O

HO

O

1-Palmitoyl-2-(7,8-dehydro-5,6-epoxy-E2-IsoP)-sn-glycero-3-phosphocholine 127 29%

O

OO P

O–

O

O

O2CC15H31

NMe3

1) 2,4,6-C6H2Cl3COCl, DMAP

2) DDQ, 0 °C

HOO P

O–

OO

O2CC15H31

NMe3

OAc

OAc118

1) EEAC, pH 6.9, 98% ee

119 67%

1) NaH, PMBBr2) LiAlH4

3) PCC4) Br2, Et3N

2) PivCl, DMAP3) K2CO3, MeOH

4

4

3

3

C5H11

126

Scheme 19. Jung’s total synthesis of 5,6-epoxy-E2-IsoP

1) TBSCl, imid.2) K2CO3, MeOH

131 80%

3) nBuLi, then PMBO(CH2)4Br

OTBS

(CH2)4OPMB132 80%

1) H2, Pd/BaSO4, quinoline2) TBAF

3) PCC4) LDA, then

OHCC5H11

O

O

OPMB

OHO

134 55%, anti/syn 2:1

1) MsCl, Et3N2) Al2O33) DDQ

O

CO2H

O135 67%

4) SO3•Py5) NaClO2, Me2C=CHMe

lyso-phosphatidylcholine 1262,4,6-Cl3C6H2COCl, DMAP, Et3N

O

COO

O1-Palmitoyl-2-(12,13-dehydro-14,15-epoxy-J2-IsoP)-sn-glycerophosphatidylcholine 136 50%

OP

O

O ONMe3

133

O2CtBu

OH

(1S)-130

TMSBr

TMSMgBr

128

129

CuCN, MgCl2

Mg/ZnBr2 (cat.)

HO

TMS

C15H31CO2

Scheme 20. Kobayashi’s synthesis of epoxy-J2-IsoP


314

yield over the four steps. The functionality of the C20 pre-cursor was subsequently adjusted by dehydration at the C12–C13 positions, oxidative deprotection of the PMB group with DDQ, and a two-step oxidation of the terminal alcohol providing free 12,13-dehydro-14,15-epoxy-J2-IsoP 135. A Yamaguchi esterification with commercially avail-able lyso-1-palmitoyl-phosphatidylcholine furnished the desired target molecule 136 over 14 steps in 12% yield from cyclopentenol 130.

Carreira’s Synthesis

Carreira published most recently total syntheses of 7,8-

dehydro-5,6-epoxy-A2-IsoP, 7,8-dehydro-5,6-epoxy-E2-IsoP

and their phosphatidylcholine esters61. The synthesis com-menced with the preparation of -lactone 139 from (Z)-4-decenal 137 by an asymmetric [2+2] ketene-aldehyde cy-cloaddition catalyzed by modified cinchona catalyst 138 under Nelson conditions62. A Claisen condensation with methyl acetate yielded a -hydroxy--ketoester, which was subjected to diazo transfer with p-acetamidobenzene-sulfonyl azide (ABSA) and protection of the hydroxy group giving diazo ester 140 in 73% yield. A 1,5-C-H in-sertion catalyzed by [Rh2(S-PTAD)4] 141 afforded cyclo-pentanone carboxylates 144 and 145 in 71% yield with 9:1 11,12-cis:trans selectivity. (For the application of Rh-catalyzed intramolecular cyclopropanations of -diazo-ketones in the total syntheses of IsoP see ref.5).

The diastereoselectivity of the C-H insertion can be rationalized by a preferred transition state 142, in which the bulky rhodium catalyst and the alkyl chain are in a favorable trans-orientation as supposed to the minor isomer, which may arise via transition state 143. The ini-tially 8,11-cis-oriented methyl cyclopentanone carboxylate epimerized at the 8-position, giving the thermodynamically more stable cyclopentanone carboxylates 144 or 145. Cy-clopentenone 146 with full -chain was prepared by Krap-cho decarboxylation to the corresponding -silyloxy cyclo-pentanone, which allowed separation of the C11-C12 cis- and trans-diastereomers, and subsequent elimination of the silanol group by DBU.

The assembly of the C1-C8-chain was accomplished by a modified Kobayashi approach63 using a base-mediated aldol addition of 146 with 2,3-epoxyaldehyde

H

O

2

MeO2C

N2

OSiEt3

C5H11

O

2

137

140 73%

CH2Cl2, reflux

O

OTES

CO2Me

C5H11

144

OSiEt3

HR

H

CO2Me

RhH

O

LiClO4,12 mol%

OO

iPr2NEt, AcCl139 62%, 92% ee

1) LDA, MeOAc, THF, 78 °C

2) p-ABSA, Et3N, MeCN, 0 °C-r.t.3) Et3SiCl, imid., DMF, 0 °C-r.t.

O

C5H11

146 19% from 137

1) NaCl, DMSO, 140 °C, then separation

2) DBU, CH2Cl2, 0 °C

N

O

O

1-Ad H

O

O Rh

Rh

4141

N

H3CO

TMSO N

H

H

OSiEt3

HH

R

CO2Me

RhH

O

vs.

71%, 144:145 9:1

O

TESO

CO2Me

C5H11

145

+

H11C5

1-Ad = 1-Adamantyl

2

H11C5138

1 mol%

142 143

Scheme 21. Carreira’s synthesis of the epoxy-IsoP C8-C20 subunit 146

Scheme 22. Completion of the total synthesis of 7,8-dehydro-5,6-A2-IsoP phosphatidylcholine

147

2) MsCl, Et3N, then Al2O3, CH2Cl2

Novozyme,buffer pH 7/THF

lyso-PC 126,2,4,6-Cl3C6H2COCl

OP

O

O O–NMe3

146

1) LiN(SiMe3)2, THF, –78 °C

OHCO

CO2Me3

O

C5H11

CO2MeO

O

C5H11

7,8-Dehydro-5,6-epoxy-A2-IsoP 149 70%

OCO2H

O

C5H11

O O

O

1-Palmitoyl-2-(7,8-dehydro-5,6-epoxy-A2-IsoP)-sn-glycero-phosphatidylcholine 150 69%

O

C5H11

148 64%

3

DMAP, CHCl3

O2CC15H31


315

147 (Scheme 22). Dehydration of the C7-C8 position pro-vided epoxy-A2-IsoP methyl ester 148. Its enzymatic hy-drolysis gave the free 7,8-dehydro-5,6-epoxy-A2-IsoP 149, which was transformed to 1-palmitoyl-2-(7,8-dehydro-5,6-epoxy-A2-IsoP)-sn-glycero-phosphatidylcholine 150 by treatment with lyso-PC 126 under Yamaguchi esterifica-tion conditions. Hence, 149 was synthesized over 10 linear steps in 7.8% yield from (Z)-4-decenal 137, whereas 150 was assembled in 11 linear steps and 5.4% yield.

The epoxidation of the ring double bond of 148 in the presence of the exocyclic double bond using tert-butyl hydroperoxide and DBU occurred selectively, giving di-epoxide 151 as a single diastereomer in 74% yield. Reduc-tive opening with SmI2 furnished the -hydroxy cyclopen-tanone regioselectively in 54% yield. Subsequent enzymatic ester hydrolysis afforded 7,8-dehydro-5,6-epoxy-E2-IsoP 152, which was prepared in 12 linear steps and 2.7% yield from 137. In contrast, initial ester hydrolysis of 151 fol-lowed by esterification with lyso-PC 126 and subsequent reduction of the epoxide with SmI2 gave 1-palmitoyl-2-(7,8-dehydro-5,6-epoxy-E2-IsoP)-sn-glycero-phosphatidyl-choline 153 in 22% yield for the three steps. Hence the total synthesis of 153 was accomplished in 13 linear steps and 1.8% overall yield.

5. Total Syntheses of NeuroP The Galano-Durand Syntheses

The convenient enzymatic access to monoprotected

diols (vide supra, Scheme 8) permitted the total synthesis of more challenging isoprostanoids having skipped triene or triyne side chains as illustrated by a synthesis of (4R/S)-4-F4t-NeuroP 160 and its deuterated analog 161 (ref.64). Starting from diol 35, the enzymatic monoacetylation pro-vided monoacetate 154 in excellent yield. A Dess-Martin oxidation and a HWE olefination with -keto phosphonate 155, using the conditions developed by Paterson et al.65, afforded enone 156 in 60% yield. A Luche reduction of 156 gave a mixture of diastereomeric alcohols, which were protected as TBS derivatives. Compound 157 was isolated in 60% yield over 2 steps. Saponification of the acetate group with K2CO3 in MeOH, followed by oxidation of the resulting alcohol and Wittig olefination using diynyl phos-phonium salt 158 in the presence of NaHMDS at –78 °C gave the skipped enediyne precursor 159 in 45% yield over 3 steps. The crucial hydrogenation or deuteration of the skipped diyne unit was best performed by using P2-Ni (generated from Ni(OAc)2•4H2O, NaBH4, NH2CH2CH2NH2)

66 in order to avoid overreduction67 and afforded the desired target molecules, (4R/S)-4-F4t-NeuroP 160 and its tetradeuterated derivative 161, after final deprotection of the silyl groups and saponification in 71% and 57% yield over 3 steps. Despite that the synthesis of (4R/S)-4-F4t-NeuroP 160 required up to 20 steps in the longest linear sequence, the ease and scale-up options of this synthesis allowed to synthesize approx. 50 mg in one batch.

Compared to NeuroP partially reduced 7-F2t-Dihomo-IsoP and 17-F2t-dihomo-IsoP metabolites of adrenic acid (AdA) 48 and 49 were similarly synthesized (cf. Fig. 1)32,36. Other NeuroP derivatives have been very recently synthe-sized via this bicyclic strategy68 because of the newly dis-covered anti-arrhythmic activity of 4(R/S)-4-F4t-NeuroP, which will be published in due course.

Taber’s synthesis

Taber et al. described a novel approach toward the

synthesis of the four enantiomerically pure diastereomers of 13-F4t-NeuroP (Scheme 25)69. The key step consisted of a thermal diastereoselective ene cyclization of 1,6-dienes to the 1,2-cis-cyclopentane skeleton based on the original discovery by Sarkar70. Starting from the well-known 2-cyclopentene-1,4-diaceate precursor 118 ozonolysis and a double Wittig homologation of the intermediate dialde-hyde resulted in a clean conversion to the desired 1,6-diene 162 in 63% yield. A series of steps including deprotection of the acetate, silylation with TBDPSCl, monoepoxidation with mCPBA, oxidative epoxide cleavage, and a Horner-Wadsworth-Emmons reaction with phosphonoacetate fur-nished the precursor 163 for the ene reaction in a good 37% overall yield.

Scheme 23. Epoxy-E2-IsoP from epoxy-A2-IsoP

OP

O

O O–NMe3

148

O

C5H11

O O

O

1-Palmitoyl-2-(7,8-dehydro-5,6-epoxy-E2-IsoP)-sn-glycero-phosphatidylcholine 153 22%

1) SmI2, THF/MeOH, –90 °C2) Novozyme, buffer pH 7/THF

O

7,8-Dehydro-5,6-epoxy-E2-IsoP 152 32%

O

HO

CO2H

1) Novozyme, buffer pH 7/THF2) lyso-PC 126, 2,4,6-Cl3C6H2COCl, DMAP, CHCl33) SmI2, THF/MeOH, –90 °C

OH

O

C5H11151 74%

CO2MeO

t-BuOOH, DBU,THF, 0 °C

O12% from 137

3

O2CC15H31


316

154 96%

1) Dess-Martin oxidation2) Ba(OH)2, THF, r.t.,

MeOPO

MeOO

CO2Me

1) CeCl3•7H2O, NaBH4, MeOH

2) TBSCl, Imid., DMAP

156 60%

I–

Ph3P+

1) K2CO3, MeOH2) Dess-Martin oxidation3) NaHMDS, THF, –78 °C,

157 60%

159 45%

(4R/S)-4-F4t-NeuroP 160 71%, R = H16, 17, 19, 20-d4-(4R/S)-4-F4t-NeuroP 161 57%, R = D

1) P2-Ni, H2 or D22) TBAF, THF/H2O

155

158

OH

TBSO

TBSOOAc

TBSO

TBSO

O

CO2Me

OAc

TBSO

TBSO

OTBS

CO2Me

TBSO

TBSO

OTBS

CO2Me

HO

HO

OH

CO2H

R

R R

R

TBSO

TBSOOH OAc35

OHsee

Scheme 8

CALB

3) LiOH, THF/H2O

Scheme 24. Durand’s total synthesis of (4R/S)-4-F4t-NeuroP and its deuterated analog

Whereas the Lewis acid catalyzed variant of the ene reaction of 163 led to a mixture of cis- and trans-substituted cyclopentane isomers, the thermal ene reaction gave as predicted exclusively the cis-diastereoisomer 164 in 86% yield. Three further steps, namely benzyl ether deprotection, Dess-Martin oxidation and nucleophilic pro-pargylation, provided the separable diastereoisomers 165 and 166. An enzymatic resolution was carried out to access the four individual enantiomers, which served subsequent-ly as central intermediates for the total syntheses of the individual 13-F4t-NeuroP isomers. The further steps are illustrated for (S)-167. Three transformations served to reduce the ester function to the ethylcyclopentane (S)-168 in 44% yield. Coupling of (S)-168 with allylic bromide 169 provided the skipped 1,4,7-enediyne substrate (S)-170 in 51% yield in a 3:1 ratio with the corresponding SN2′ adduct (not shown). Semihydrogenation using P2-Ni af-forded the desired (Z,Z,Z)-triene in 64% yield accompa-nied by a minimal trace of over-reduced products, which were easily separated. Interestingly, an analogous P2-Ni reduction with the corresponding triyne compound resulted in a complex mixture of products. Deprotection of the TBS ether and saponification of the ester unit by LiOH fur-nished ent-13-epi-13-F4t-NeuroP 171 in 19 steps and 0.8% overall yield from 118. The other three diastereoisomers were also obtained using this strategy, which is like Du-rand’s limited to obtaining natural products with the trans-cis-trans ring stereochemistry, but furthermore so far also to F-type IsoPs and NeuroPs.

6. Conclusions and Outlook The current review shows that the field of total syn-

thesis of isoprostanes developed significantly over the last few years, since twenty diverse total syntheses were re-ported. A common trend is the increasing application of transition metal and enzymatically catalyzed key steps to provide enantiomerically enriched compounds. Many of the reported strategies involve new methodology to synthe-size the cyclopentane ring selectively and with a desired ring substitution pattern. One or both side chains are ap-pended subsequently by olefination or nucleophilic addi-tion reactions. Many of the reported syntheses approach IsoP derivatives, but an increasing number of publications dealt with the synthesis of the least investigated class of oxidatively formed lipid metabolites, the neuroprostanes. For the future, it will be important to concentrate on more diversity-oriented synthetic strategies, which will allow the total synthesis of multiple ring-substituted IsoP classes by late-stage diversification of common precursors with the full C18, C20, and C22 skeletons. This will streamline the access to the available metabolites for biological studies even more.


317

AcO

AcO

1) O3, PPh3

2) BnOCH2CH2CH=PPh3

AcO

AcO

OBn

OBn

1) Na2CO3, MeOH2) TBDPSCl, imid.

TBDPSO

TBDPSO

OBn

200 °C,

OTBDPS

OTBDPS

1) 88% HCO2H2) Dess-Martin oxidation

Br, Zn

61%, 1 : 1

+

The racemic diastereomers were at this stage separated. Both were resolved using Amano AK lipase in the

presence of vinyl acetate at 40% conversion to >99% ee.

118 162 63%163 37%

164 86%

(S)-167

1) LiAlH4

(S)-168 44%

NaI, CuI, K2CO3

169

1) P2-Ni, H22) TBAF

ent-13-epi-13-F4t-NeuroP 171 48%(S)-170 51%

3) mCPBA4) H5IO65) (EtO)2P(O)CH2CO2Et, NaH

CO2Et

BnO

CO2Et24 h, toluene

OTBDPS

OTBDPS165 (racemic)

OH

CO2Et

OTBDPS

OTBDPS166 (racemic)

OH

CO2Et3)

TBDPSO

TBDPSO

OH

CO2Et

TBDPSO

TBDPSO

OH

2) TsCl, Et3N3) LiEt3BH

Br

EtO2C

3) LiOH

TBDPSO

TBDPSO

OH

EtO2C

HO

HO

OH

HO2C

Scheme 25. Taber’s diastereoselective thermal intramolecular ene approach to NeuroP

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E. Jahna, T. Durandb, J.-M. Galanob, and U. Jahna

(a Institute of Organic Chemistry and Biochemistry, Acade-my of Sciences of the Czech Republic, Prague, Czech Re-public, b Institut des Biomolécules Max Mousseron, CNRS 5247, Faculté de Pharmacie, Universités de Montpellier I et II ENSCM, Montpellier, France): Recent Approaches to the Total Synthesis of Phytoprostanes, Isoprostanes and Neuroprostanes as Important Products of Lipid Oxidative Stress and Biomarkers of Disease

Isoprostanes (IsoP) are important biologically active

metabolites of arachidonic and eicosapentaenoic acids in mammals and humans. IsoPs are becoming the gold-standard biomarkers for monitoring oxidative stress. Their in-vivo detected amounts can be correlated with a number of diseases. Similarly, phytoprostanes derived from -linolenic acid and neuroprostanes from docosahexaenoic acid are other tools for the determination of oxidative stress in plants and the human brain, respectively. To fur-ther develop the field, it becomes more and more im-portant to develop total syntheses of these metabolites since this is the only way of obtaining reasonable amounts of pure compounds to study their biological effects and to quantify lipid oxidative stress. In this review, new synthet-ic strategies, developed in 2008–2013 are summarized, showing the significant advancement in the field.

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