myers methods for ring contraction chem 115 -...
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Recent Reviews:
Matt Mitcheltree
Chiral-pool starting materials have been much used as substrates for the Favorskii reaction, affording functionalized, optically active cyclopentanes.
Chem 115Methods for Ring ContractionMyers
Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556.Silva, Jr. L. F. Tetrahedron 2002, 58, 9137–9161.
•
OCl
O OCH3NaOCH3
Et2O, 35 °C, 2 h
56–61%
O
CH3CH3
O
CH3
(+)-Pulegone
Br2
Et2O
CH3
O
Br CH3CH3
BrCH3 CH3
CO2CH3
CH3
O
CH3 H
H OO CH3
CH3CH3
CH3H
H
CH3CH3
CH3CH3
H
60–67% (2 steps)
(+)-Epoxydictymene (–)-Iridomyrmecin
CH3
(+)-Acoradiene
Common intermediate: Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel's Textbook of Practical Organic Chemistry. 5th ed. Longman: London, 1989.(+)-Epoxydictymene: Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353–4363.(–)-Iridomyrmecin: Wolinsky, J.; Gibson, T.; Chan, D.; Wolf, H. Tetrahedron 1965, 21, 1247–1261.(+)-Acoradiene: Kurosawa, S.; Bando, M.; Mori, K. Eur. J. Org. Chem. 2001, 4395–4399.
CH3
O
(–)-Carvone
OCH3
Cl
THPO
THPO
CH3 CO3CH3
CH3 CH3
80%
Lee, E.; Yoon, C. H. J. Chem. Soc., Chem. Commun. 1994, 479–481.
Anionic Ring ContractionsFavorskii Rearrangement
X
O
O O Nu
O Nu
OM ROR
Anionic
Carbenoid
CationicFor example, the ring contraction of a (+)-pulegone derivative has been used in the synthesis of several terpenoid natural products.
•
Ring contraction reactions can be grouped into three general categories based on mechanism:•
The Favorskii reaction leads to the rearrangement of an !-halo cycloalkanone upon treatment with base. This reaction proceeds through a cyclopropanone intermediate that is opened by nucleophilic attack.
•
NaOCH3
CH3OH
1. TMSCl
Nu:
Nu:
H2O2
NaOH
CH3
O
CH3
O2. DHP, p-TsOH
NaOCH3CH3OH
90% 81% (2 steps)
Cope, A. C.; Graham, E. S. J. Am. Chem. Soc. 1951, 73, 4702–4706.Loftfield, R. B. J. Am. Chem. Soc. 1951, 73, 4707–4714.
OCH3
Organic syntheses; Wiley & Sons: New York, 1963; Coll. Vol. No. 4, pp. 594.
In some cases, enolization is not possible, precluding cyclopropanone formation. An alternate mechanism involves formation of a tetrahedral intermediate that promotes alkyl migration.
•
O
H
Br
H
BrOHOH
Ag+CO2H
H71%
H2O, t-BuOH
AgNO3
O
HCH3
THPOCH3CH3
1
Quasi-Favorskii Rearrangement
Matt Mitcheltree
Chem 115Methods for Ring ContractionMyers
Also referred to as the negative-ion pinacol rearrangement, the quasi-Favorskii rearrangement involves an alkyl shift with concomitant nucleophilic displacement of an aligned leaving group.
•
CH3HOOTs KOt-Bu
THF
CH3O OCH3
90%, 89 : 11
+
Hamon, D. P. G.; Tuck, K. L. Chem. Commun. 1997, 941–942.
Br
OH
Br
OH H
CHO
H
OH
LAH
98%
Harmata, M.; Bohnert, G.; Kürti, L.; Barnes, C. L. Tetrahedron Lett. 2002, 43, 2347–2349.
HO OH
CH3
OMsO
CH3CH3
O
Marshall, J. A.; Brady, S. F. J. Org. Chem. 1970, 35, 4068–4077.
These fragmentations are generally accelerated by oxyanion formation.•
60% (2 steps)
2. KOt-Bu H
CH3
CH3
H
HO
CH3
CH3
(±)-Hinesol
A quasi-Favorskii ring contraction was employed by Harding in the synthesis of (±)-sirenin. The stereochemical outcome of this rearrangement suggests formation of a tetrahedral intermediate that undergoes alkyl shift with halide displacement, rather than cyclopropanone formation as in the classic Favorskii rearrangement.
•
OBn
O
CH3Cl
H
HAgNO3
CH3OH
CH3O
ClCH3H
OH
OBn
CH3
CH3O2C
OBnH
H
Ag+
OH
CH3
CH3HO H
H
(±)-Sirenin
53%
Harding, K. E.; Strickland, J. B.; Pommerville, J. J. Org. Chem. 1988, 53, 4877–4883.
CH3 HOBn
O
A common application of the quasi-Favorskii rearrangement is in the rearrangement of fused polycycles.
•
OTsHO
O
O
OHCH3
OO
H
CH3
OO
OTs
OHCH3
HO
O
O
OCH3
HCH3
O
O
87%
(±)-Confertin
LiOH
t-BuOH, 65 °C
Heathcock, C. H.; DelMar, E. G.; Graham, S. L. J. Am. Chem. Soc. 1982, 104, 1907–1917.
OTs
O
CH3
1. MsCl (1 equiv), pyr
2
Quasi-Favorskii Rearrangement
Matt Mitcheltree
Chem 115Methods for Ring ContractionMyers
Harmata has showcased the power of the quasi-Favorskii rearrangement in the synthesis of several terpenoid natural products.
•
Cl ClO O
HCHO
CH3
H CH3
H H
OH
CH3 CH3
O O
1. LAH2. KH
76% (2 steps)
Harmata, M.; Rashatasakhon, P. Org. Lett. 2001, 3, 2533–2535.
O
Br
HCH3CH3
1. LAH2. KH
91% (3 steps)
CH3CH3
OH
HCH3CH3
CH3
CH3
(±)-Sterpurene
Harmata, M.; Bohnert, G. J. Org. Lett. 2003, 5, 59–61.
Carbenoid Ring ContractionsWolff RearrangementReviews:
Kirmse, W. Eur. J. Org. Chem. 2002, 2193–2256.Meier, H.; Zeller, K.-P. Angew. Chem. Int. Ed. 1975, 14, 32–43.
The Wolff rearrangement involves the transformation of an !-diazo ketone via carbene or carbenoid to a ketene, which undergoes further transformation to form a stable adduct.
•
The Wolff rearrangement may be induced by heat, Ag(I) salts, or light.•
R1 R2O
N2R1 R2
O
R1 R2
Oh", #, or AgI Nu-H
R1 R2
O Nu
Nu = -OCH3, -OBn, -OH, -NR2, SR, etc.
ON2
O OCH3h", CH3OH
In the prototypical case depicted below, the Wolff rearrangement proceeds in higher yield relative to the analogous Favorskii system.
•
Tomioka, H.; Okuno, H.; Izawa, Y. J. Org. Chem. 1980, 45, 5278–5283.
> 99%
N2
O
CO2CH3
H
H
CO2CH3
h", CH3OH
92%, 88 : 12
+
Kirmse, W.; Wroblowsky, H.-J. Chem. Ber. 1983, 116, 1118–1131.
OCH3
OH
H+
The stereochemistry of the ! position can be kinetically controlled, determined by the relative rates of protonation of the enol or enolate intermediate.
•
(±)-Spatol
3. LAH
Stereochemistryestablished by X-ray
H+
3
Matt Mitcheltree
Chem 115Methods for Ring ContractionMyers
Ketene intermediates produced in the Wolff rearrangement can also be trapped in [2+2] cycloaddition reactions.
•
O O
O ON2
CH3 CH3
O O
CH3 CH3
OO
h!, THF R' R'
R
R' R'
ROO
O
CH3 CH3
O[2+2]
R R' Yield
H H 84%CH3 CH3 64%
CH3 H 76%
H 54%Ph
Stevens, R. V.; Bisacchi, G. S.; Goldsmith, L.; Strouse, C. E. J. Org. Chem. 1980, 45, 2708–2709.
Livinghouse, T.; Stevens, R. V. J. Am. Chem. Soc. 1978, 100, 6479–6482.
Danheiser and Helgason used such a strategy in the synthesis of salvilenone. The [2+2] cycloadduct in this case underwent retro-[2+2] ring opening followed by electrocyclization.
•
BrN2 O
CH3
h!, DCE
Br
HO OTIPSi-Pr
OTIPS
i-Pr+
O
i-Pr
OTIPS
CH3
Br
CH3
OTIPSi-Pr
OBr
Oi-Pr
O
CH3
CH3
CH3CH3
retro[2+2]
Danheiser, R. L.; Helgason, A. L. J. Am. Chem. Soc. 1994, 116, 9471–9479.
Salvilenone 61–71%
80 °C
Wolff Rearrangement Synthesis of diazo ketones
Compounds such as 1,3-dicarbonyls can be diazotized directly using arenesulfonyl azide reagents.•
In the absence of a " activating group, #-diazo ketones can be formed by formylation-diazotization-deformylation, in a procedure known as Regitz diazo transfer.
•
Similarly, in the Danheiser procedure, reversible #$trifluoroacetylation activates the substrate toward diazotization.
•
O
R
O
R H
OH
NaH
O
ORH N3SO2Ar
R3N
O
RN2
O
R
O
R CF3
OH
LiHMDS
N3SO2Ar
R3N
O
RN2
CF3
O
O
CF3
Danheiser, R. L.; Miller, R. F.; Brisbois, R. B.; Org. Synth. 1996, 73, 134–143.Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959–1964.
ReviewDoyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds. Wiley-Interscience, New York, 1998, pp. 1–60.
See course handout "C–O Bond-Forming Reactions" for further discussion of the synthesis of diazo compounds.
Regitz, M.; Maas, G. Diazo Compounds, Academic Press, New York, 1986, pp. 199–543.Regitz, M. in: The Chemistry of Diazonium and Diazo Groups, Part 2 (Ed.: Patai, S.), Wiley-Interscience, Chichester, 1978, pp. 751–820.
Direct Diazotization
R R'
O O N3SO2ArR R'
O O
N2Et3N
4
Matt Mitcheltree
Chem 115Methods for Ring ContractionMyersSynthesis of diazo ketones
NaHHCO2Et
O HOH
N3TfEt2NH
h!CH3OH
85% 95% 60%
t-BuOOH160 °C
45%Eaton, P. E.; Nyi, K. J. Am. Chem. Soc. 1971, 93, 2786–2788.
Sequential Regitz diazotization–Wolff rearrangement was applied by Eaton and Nyi in their synthesis of [3.2.2]propellane. Thermolytic decarboxylation of a tert-butyl perester provides the final product after ring contraction.
•
O O N2 CO2CH3
OO O
N2
CO2HO
H(CH2)7CO2CH3
+h!
1. NaHMDS, HCO2Et2. N3Ts, Et3N
1. h!, CH3OH2. LiOH
78% 62% (2 steps)
HCHO
1. Regitz2. h!, CH3OH
3. DIBAL-H4. Swern
43% (4 steps) 86% (2 steps)
Pentacycloannamoxic acid methyl ester
Mascitti, V.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 3118–3119.
Similarly, Corey and Mascitti use two Regitz diazotization–Wolff rearrangement reactions in sequence in their enantioselective synthesis of pentacycloannamoxic acid methyl ester.
•
In the Mandler procedure, enolized ketones are diazotized without the assistance of an activating group. These reactions are generally run under phase-transfer conditions, and are therefore not ideal for substrates sensitive to aqueous base (e.g., esters).
•
Lombardo, L.; Mandler, L. N. Synthesis 1980, 368–369.
R
O
R
ON2
1:1 H2O–C6H6
N3SO2Mes(n-Bu)4NBr, KOH, 18-cr-6
N
NN
N
NH2
OTBSO
O
BOTBSO
O
BOTBSO
ON2(CH3)2N
N(CH3)2
HCH3OCH3O
80%
N3Tf
72%
ON
OH
HO
N
N N
NH2
OxetanocinNorbeck, D. W.; Kramer, J. B. J. Am. Chem. Soc. 1988, 110, 7217–7218.
Mild conditions to activate cyclic ketones using dimethylformamide dimethyl acetal have been developed. The resulting enamine intermediates undergo diazotization with electron-poor diazo transfer reagents such as triflyl azide (N3SO2CF3). This approach was used in the synthesis of oxetanocin, a bacterial isolate with anti-HIV activity.
•
Wolff Rearrangement – Applications in target-oriented synthesis
5
Matt Mitcheltree
Chem 115Methods for Ring ContractionMyersWolff Rearrangement – Applications in target-oriented synthesis
O
HOCH3
H
H
CH3 CH3 CO2CH3H
HHOCH3
CH3 CH3H
HHOCH3
CH3 CH3
!9(12)-Capnellene
CH3CH3
CH3OCH3
CH3CH3H H
CH3
CH3CH3
H
CH3
48%
83% Pentalenene
CH3O2C
Ihara, M.; Katogi, M.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1 1988, 2963–2970.
Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1 1992, 865–873.
The Wolff rearrangement has been employed in the construction of the fused 5,5,5-tricyclic cores of sesquiterpenes.
•
N
O OBn
H
BocHN
N
CO2CH3
BocHN
HOBn
N
HNO
(±)-Meloscine
Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598–2610.Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Org. Chem. 1989, 54, 1236–1238.
Where other methods failed, the Mandler procedure enabled Overman and co-workers to diazotize a ketone en route to (±)-meloscine.
•
Cation-type rearrangementsPinacol Rearrangement
ReviewsSong, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556.Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143–7157.Overman, L. E. Acc. Chem. Res. 1992, 25, 352–359.
Vicinal diols, when treated with acid, generate a transient cation that may undergo alkyl shift coupled with carbonyl formation.
•
OHOH
OHCH3
CH3
CH3CH3
CH3OCH3H+
Pavlik, C.; Morton, M. D.; Smith, M. B. Synlett 2011, 2191–2194.68–72%
H
CH3OHO
CH3
CH3
BF3•OEt2
C6H6, refluxH
HOCH3
CH3 CH3CH3
O HCH3O
HF3B
Cationic rearrangements can proceed through concerted mechanisms as well, particularly when the migrating bond is aligned with the leaving group.
•
Hariprakasha, H. K.; SubbaRao, G. S. R. Tetradron Lett. 1997, 38, 5343–5346.
90%
–H2O –H+
HO OTs
CH3H
H
CH3 CH3
CH3
HO
CH3 CH3
HH
Al2O3
100%
CH3
H
CH3 CH3
HH
53%(–)-Aromadendrene
Ph3P CH2
Büchi, G.; Hofheinz, W.; Paukstelis, J. V. J. Am. Chem. Soc. 1969, 91, 6473–6478.
Halogens and sulfonate esters can also be used, as demonstrated below.•
H2O
3. h", CH3OH
1. NaH, HCO2Et2. N3Ts, Et3N
3. h", CH3OH
1. NaH, HCO2Et2. N3Ts, Et3N
1:1 C6H6–H2O35 °C, 1h
98%
N
O OBn
H
BocHN
N2
h", CH3OH
95%
N3SO2Ar(n-Bu)4NBr, 18-cr-6, KOH
Ar = 2,4,6-triisopropylphenyl
6
LA
Matt Mitcheltree
Chem 115Methods for Ring ContractionMyersPInacol Rearrangement
Schreiber's synthesis of the bicyclic core of calicheamicin relied on a pinacol rearrangement. Tautomerization of the resulting !-hydroxy ketone gave the enone product shown.
•
MsO
OHOH
H
TBSO
O
OH
HH
TBSO
H
TBSO
OHO
H
Et2AlCl
65%
CH2Cl2
H
O
OHO
H
HN OCH3
O
SSCH3S
O
OHO
HNCH3
O
CH3OEtHN
O
OH
CH3S
OCH3I
OCH3OCH3
O
O
OHCH3OHOCH3
Calicheamicin "1
HO
CH3CH3
OCH3
OOMs O
CH3
CH3
OCH3
OH
(+)-Taxusin
Et2AlCl
CH2Cl2–Hexane–78 # –15 °C
96%
Similarly, Paquette employed a pinacol rearrangement to produce the (+)-taxusin skeleton.•
Paquette, L. A.; Zhao, M. J. Am. Chem. Soc. 1998, 120, 5203–5212.
The reaction of epoxides with Lewis acids can provide ring-contracted products by a pinacol-type mechanism.
•
OLiBr, Al2O3
PhCH3
CHO
Suga, H.; Miyake, H. Synthesis 1988, 394–395.
n
n
1
2
3
Yield
77%
42%
30%
O
OCH3
CH3CH3
BF3•OEt2O
CH3CH3
CHOCH3
93%
Kunisch, F.; Hobert, K.; Weizel, P. Tetrahedron Lett. 1985, 26, 6039–6042.
i-PrOTBS
OCH3
i-Pr
OTBSCHOCH3
82%
Yamamoto and co-workers have described an epoxide-opening ring contraction utilizing a methylaluminum diphenoxide Lewis acid that outperforms boron trifluoride in difficult ring contractions.
•
MABR
t-Bu
t-Bu
BrAr =
Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111, 6431–6432.
i-PrOTBS
OCH3
i-Pr
OTBSOHC CH3
88%
CH2Cl2, –78 °C
CH2Cl2, –78 °C
MABR = CH3Al(OAr)2
MABR
Schoenen, F. J.; Porco, J. A.; Schreiber, S. L. Tetrahedron Lett. 1989, 30, 3765–3768.
O
CH3
CH3
CH3
HAcO
CH3
OAcAcO
n
7
Matt Mitcheltree
Chem 115Methods for Ring ContractionMyersPinacol Rearrangement
CH3CH3CH3
O
OTIPSOCH3
OHO
OTIPSCH3O
HOCH3
CH3CH3
O
HO
CH3
CH3CH3
CH3
HOHO OH
Ingenol
Kuwajima and Baran both used pinacol-type rearrangements in their syntheses of ingenol.•
Al(CH3)3
CH2Cl2
76%
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498–1500.Jørgensen, L.; McKerall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S. Science 2013, 341, 878–882.A tandem pinacol–Schmidt rearrangement was used to synthesize the core of (±)-stemonamine.•
TMSOCH3
N3O
O O
Cl2Ti
CH3
N3
N
CH3
OH
ON
(±)-Stemonamine
Zhao, Y. M.; Gu, P. M.; Tu, Y. Q.; Fan, C. A.; Zhang, Q. W. Org. Lett. 2008, 10, 1763–1766.
68%
TiCl4
CH2Cl2–78 ! 0 °C
After cationic rearrangement, the resulting cation may be intercepted by elimination of an adjacent proton:
•
TsO CH3
CH3 CH3HH
AcOH, AcOK
Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746–1757.76%
CH3
CH3
CH3H CH3
CH3
CH3H
80 °C, 8 h
"-bulneseneOHO
CH3
CH3
CH3H
OCH3
HOTIPS
Al(CH3)3
NN2
CH3
OO
Cl2Ti
CH3
OH O N3
By elimination of a #-silyl group:•
Hwu, J. R.; Wetzel, J. M. J. Org. Chem. 1992, 57, 922–928.
TMS
CH3OH
CH3
CH3H
O
TMSCH3 CH3
CH3
TMSCH3
HCH3
CH3
FeBr3
–60 °C
CH3
HCH3
CH3
54%
CH3
HCH3
CH3
71%
O
(–)-Solavetivone
t-BuOH
CrO2Cl2
LA
Or by attack with an endogenous nucleophile.•
CH3OMs
CH3CH3HTMSO
CH3CH3
H
CH3
TMSO
H
MgI2HN(TMS)2
CH3
CH3
CH3
O
82%
CH3
CH3
CH3
OHCH
H
H
HOHC
(+)-Isovelleral
Bell, R. P. L.; Wjnberg, J. B. P. A.; de Groot, A. J. Org. Chem. 2001, 66, 2350–2357.
CH3
HOO
OO
CH3
O TMS
CH3
CH3
CH3
OTBS
O
CH3
CH3
CH3CH3
CH3
OTBSOOO
BF3•OEt2
80%
Kuwajima
Baran
CH2Cl2
O
OCH3
CH3
OCH3
8
Matt Mitcheltree
Chem 115Methods for Ring ContractionMyersLead-promoted ring contractions
Lead(IV) salts have been shown to promote ring contractions of ketones and enol ethers. However, these reactions sometimes provide significant amounts of !-acetoxy ketone side-products.
•
OCH3 O
O
CH3
HCH3
HO
CH3 OO
CH3
HCH3
HAcO
OO
CH3
HCH3
H
CH3
CH3O
O+
67% 30%
Pb(OAc)4BF3•OEt2
Miura, H.; Fujimoto, Y.; Tatsuno, T. Synthesis 1979, 898–899.
!-Santonin
HC(OEt)3NH4ClEtOH
EtOCH3 O
O
CH3
HCH3
H
Pb(OAc)4BF3•OEt2, EtOH
C6H6O
O
CH3
HCH3
H
CH3
EtO
O
80%
This reaction is believed to involve Pb–C bond formation followed by pinacol-type rearrangement.•
O O OAc
Pb(OAc)3
O H
OAc
OOAc
OAc
Pb(OAc)4
–Pb(OAc)3–
Norman, R. O. C.; Thomas, T. B. J. Chem. Soc. B. 1967, 604–611.
Lead(IV)-promoted ring contractions have been employed to modify !-santonin. Improved yields were achieved by first converting the substrate to the corresponding ethyl-enol ether.
•
100%
CH3OHCH2Cl2CH3 CH3
CH3
H
CH3
O CH3
OROCH3 CH3
CH3
H
CH3
CHOCH3
ORO
CH3 CH3
CH3
H
CH3
CHOCH3
HO
C6H6
96%
(–)-Hyrtiosal
R = (S)-mandeloyl
The Imamura synthesis of (–)-hyrtiosal employed an epoxide-opening rearrangement that is proposed to mimic the biosynthetic route to the natural product.
•
Lunardi, I.; Santiago, G. M. P.; Imamura, P. M. Tetrahedron Lett. 2002, 43, 3609–3611.
O
BF3•OEt2
An example of a pinacol rearrangement initiated by an endogenous electrophile was demonstrated by Oltra:
•
CH3HO
CH3O
O
OCH3
O
H
OO
HO CH3CH3
TMSO
O
CH3O
O
CH3H
OOHCH3
CH3
O
> 72%
TMSCl,NaI
Rosales, A.; Estévez, R. E.; Cuerva, J. M.; Oltra, J. E. Angew. Chem., Int. Ed. 2005, 44, 319–322.
9
Matt Mitcheltree
Chem 115Methods for Ring ContractionMyersRing contractions of silyl-enol ethers
Cyclic silyl-enol ethers undergo ring contraction upon treatment with electron-deficient sulfonyl azides to give trialkylsilyl imidates, which are readily hydrolyzed to N-acyl sulfonamides.
•
While both triflyl azide (N3Tf) and nonaflyl azide (N3Nf; N3SO2n-C4F9) may be used in the ring contraction of silyl-enol ethers, the latter has the advantage of being a bench-stable, non-volatile liquid that does not detonate spontaneously upon concentration.
•
OSiR3
R
R3SiO
R
NNf R3SiO
NNf
R
O HN
NfR
H HN3SO2C4F9 H2O
Alkyl, vinyl, and aryl migrations are all possible. While 6!5 and 7!6 ring contractions are possible, this method does not permit cyclobutane synthesis.
•
OTMS
OTMS
NHNf
O
OTMS
OTMS
ONHNf
ONHNf
ONHNf
Substrate Product Yield
97%
67%
78%
87%
OTIPS
OO
CH3
CH3CH3
O OCH3 CH3
CH3
O NHNf
65%
Mitcheltree, M. J.; Konst, Z. A.; Herzon, S. B. Tetrahedron 2013, 69, 5634–5639.
H
Because alkyl migration is stereospecific, the stereochemistry of the product is determined by the facial selectivity of sulfonyl-azide addition. Lesser facial differentiation leads to lower diastereomeric ratios, as the following series demonstrates.
•
OTMS
CH3
OTMS
CH3
OTMS
CH3
N3Nf
N3Nf
N3Nf
NHNfO
CH3
NHNfO
NHNfO
CH3
NNfTMSO
CH3 singlediastereomer
d.r. = 67 : 33
d.r. = 55 : 45
The resulting N-acyl sulfonamide can be converted to alcohol, ester, or carboxamide products.•
ONHSO2C4F9
OH
OCH3
NH2
O
O
LAH
Et2O, 0!23 °C, 20 min
HCl (0.3 M)
20% CH3OH–PhCH3110 °C, 3 h
SmI2
THF, 23 °C, 30 min
85%
75%
96%
Mitcheltree, M. J.; Konst, Z. A.; Herzon, S. B. Tetrahedron 2013, 69, 5634–5639.
–N2
CH3CN–N2
CH3 CH3
10
Matt Mitcheltree
Chem 115Methods for Ring ContractionMyersSynthesis of regiodefined silyl-enol ethers
Silyl-enol ethers are appealing substrates for ring contractions because they can be synthesized regioselectively.
•
OCH3
OTMSCH3CH3
OTMS
Conditions Yield A : B
A B
LDA, TMSCl 74 99 : 1
Et3N, TMSCl, NaI 10 : 9092
Negishi, E.-I.; Chatterjee, S. Tetrahedron Lett. 1983, 24, 1341–1344.House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org. Chem. 1969, 34, 2324–2336.
Conditions+
Silyl-enol ethers can also be formed by 1,4-addition to !,"-unsaturated carbonyls.•
O
OTBSCH3
CH3
CH3MgBr
CuBr•S(CH3)2TMEDA, TMSCl TBSO
CH3
CH3CH3
OTMS
100%
Nozawa, D.; Takikawa, H.; Mori, K. J. Chem. Soc. Perkin Trans. 1, 2000, 2043–2046.
OTES
i-Pr
OTES
i-Pr
90%
Li, NH3
t-BuOH, THF
Macdonald, T. L. J. Org. Chem. 1978, 18, 3621–3624.
TIPSO CH3 CH3
BrO
O
N BO
PhPh
o-Tol
H
TIPSO CH3
H O
OCH3
Br
Birch reduction of substituted silyloxy aryl ethers gives regiodefined substrates for ring contraction.
•
Silyl-enol ethers can be formed by enantioselective, catalytic Diels–Alder reactions.•
HNTf2–78 °C
96%, 97% e.e.
Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800–4802.
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