Myers Methods for Ring Contraction Chem 115

Recent Reviews: • Chiral-pool starting materials have been much used as substrates for the Favorskii reaction,
affording functionalized, optically active cyclopentanes.
Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556.
O O O
Silva, Jr. L. F. Tetrahedron 2002, 58, 9137–9161. H2O2 Cl
CH3 CH3 1. TMSCl
CH3
• Ring contraction reactions can be grouped into three general categories based on mechanism: O
NaOH 2. DHP, p-TsOH
THPO
O O Nu CH3 90% CH3 81% (2 steps) CH3
X Nu:
(–)-Carvone NaOCH3
Anionic
CH3OH

O
O O Nu CH3 CO3CH3
CH3 H
Nu:
Carbenoid THPO CH3 80% CH3
THPO

M Lee, E.; Yoon, C. H. J. Chem. Soc., Chem. Commun. 1994, 479–481.

O O R
R • For example, the ring contraction of a (+)-pulegone derivative has been used in the synthesis of
Cationic several terpenoid natural products.

CH3 CH3 CH3

Anionic Ring Contractions Br2 NaOCH3
Favorskii Rearrangement CO2CH3
O Et2O O CH3OH
Br
• The Favorskii reaction leads to the rearrangement of an !-halo cycloalkanone upon treatment Br CH3 CH3 CH3
CH3 CH3
with base. This reaction proceeds through a cyclopropanone intermediate that is opened by CH3
60–67% (2 steps)
nucleophilic attack. (+)-Pulegone

O O O OCH3
NaOCH3 OCH3
Cl
Et2O, 35 °C, 2 h

56–61% CH3 CH3

CH3 CH3 H
H
Organic syntheses; Wiley & Sons: New York, 1963; Coll. Vol. No. 4, pp. 594. CH3 CH3 O H
O CH3 CH3
• In some cases, enolization is not possible, precluding cyclopropanone formation. An alternate O CH3
H H
mechanism involves formation of a tetrahedral intermediate that promotes alkyl migration. CH3
(+)-Epoxydictymene (–)-Iridomyrmecin (+)-Acoradiene
Br Ag+
Br CO2H
AgNO3 Common intermediate: Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel's
OH
O Textbook of Practical Organic Chemistry. 5th ed. Longman: London, 1989.
H2O, t-BuOH OH (+)-Epoxydictymene: Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem.
H H H
Soc. 1997, 119, 4353–4363.
71%
(–)-Iridomyrmecin: Wolinsky, J.; Gibson, T.; Chan, D.; Wolf, H. Tetrahedron 1965, 21, 1247–1261.
Cope, A. C.; Graham, E. S. J. Am. Chem. Soc. 1951, 73, 4702–4706. (+)-Acoradiene: Kurosawa, S.; Bando, M.; Mori, K. Eur. J. Org. Chem. 2001, 4395–4399.
Loftfield, R. B. J. Am. Chem. Soc. 1951, 73, 4707–4714. Matt Mitcheltree

1
Myers Methods for Ring Contraction Chem 115
Quasi-Favorskii Rearrangement
• A common application of the quasi-Favorskii rearrangement is in the rearrangement of fused
• Also referred to as the negative-ion pinacol rearrangement, the quasi-Favorskii rearrangement polycycles.
involves an alkyl shift with concomitant nucleophilic displacement of an aligned leaving group.
OH OMs O
• These fragmentations are generally accelerated by oxyanion formation. HO 1. MsCl (1 equiv), pyr
O
2. KOt-Bu CH3
H
CH3 CH3
HO CH3 O CH3 O
OTs KOt-Bu CH3 60% (2 steps)
+ CH3
OTs
THF
O
90%, 89 : 11
Hamon, D. P. G.; Tuck, K. L. Chem. Commun. 1997, 941–942.

CH3
OH HO
CHO CH3
Br LAH Br
CH3 H
CH3
O O
H H Marshall, J. A.; Brady, S. F. J. Org. Chem. 1970, 35, 4068–4077. (±)-Hinesol
H H

98%

Harmata, M.; Bohnert, G.; Kürti, L.; Barnes, C. L. Tetrahedron Lett. 2002, 43, 2347–2349.
OH CH3 CH3 OH
CH3 O
LiOH O
• A quasi-Favorskii ring contraction was employed by Harding in the synthesis of (±)-sirenin. The O O O H
O
stereochemical outcome of this rearrangement suggests formation of a tetrahedral intermediate t-BuOH, 65 °C O H
O HO O
that undergoes alkyl shift with halide displacement, rather than cyclopropanone formation as in OTs OTs
the classic Favorskii rearrangement. 87%

O H CH3O OH H
AgNO3 CH3
Cl CH3OH Cl OBn CH3O2C
CH3 H CH3 H H
OBn Ag+ OBn
O CH3 O
53%
O

H
CH3
O
H (±)-Confertin
CH3
OBn Heathcock, C. H.; DelMar, E. G.; Graham, S. L. J. Am. Chem. Soc. 1982, 104, 1907–1917.
CH3 H CH3
HO H
OH
(±)-Sirenin

Harding, K. E.; Strickland, J. B.; Pommerville, J. J. Org. Chem. 1988, 53, 4877–4883. Matt Mitcheltree

2
Myers Methods for Ring Contraction Chem 115
Quasi-Favorskii Rearrangement Carbenoid Ring Contractions
• Harmata has showcased the power of the quasi-Favorskii rearrangement in the synthesis of Wolff Rearrangement
several terpenoid natural products. Reviews:

Kirmse, W. Eur. J. Org. Chem. 2002, 2193–2256.

1. LAH
Meier, H.; Zeller, K.-P. Angew. Chem. Int. Ed. 1975, 14, 32–43.
2. KH
H
Cl O Cl O CHO • 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.
Stereochemistry 76% (2 steps)
established by X-ray • The Wolff rearrangement may be induced by heat, Ag(I) salts, or light.

h", #,
O O O Nu
or AgI O Nu-H
R2
R1 R2
R1
N2 R1 R2 R1 R2
CH3
H H Nu = -OCH3, -OBn, -OH, -NR2, SR, etc.
H CH3
OH
• In the prototypical case depicted below, the Wolff rearrangement proceeds in higher yield relative
to the analogous Favorskii system.
O O
CH3 CH3 O O OCH3
h", CH3OH
N2
(±)-Spatol

> 99%
Harmata, M.; Rashatasakhon, P. Org. Lett. 2001, 3, 2533–2535.
Tomioka, H.; Okuno, H.; Izawa, Y. J. Org. Chem. 1980, 45, 5278–5283.

• The stereochemistry of the ! position can be kinetically controlled, determined by the relative
rates of protonation of the enol or enolate intermediate.
H 1. LAH CH3
H
2. KH
CH3 CH3 CH3 H+
O
CH3 3. LAH CH3 CH3 O h", CH3OH
Br CH3 OH H + CO2CH3
OH
N2 OCH3
91% (3 steps) (±)-Sterpurene CO2CH3 H
H+
92%, 88 : 12

Kirmse, W.; Wroblowsky, H.-J. Chem. Ber. 1983, 116, 1118–1131.

Harmata, M.; Bohnert, G. J. Org. Lett. 2003, 5, 59–61.

Matt Mitcheltree

3
Myers Methods for Ring Contraction Chem 115
Wolff Rearrangement Synthesis of diazo ketones

• Ketene intermediates produced in the Wolff rearrangement can also be trapped in [2+2] Review
cycloaddition reactions. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
R Compounds. Wiley-Interscience, New York, 1998, pp. 1–60.
CH3 CH3
N2 O See course handout "C–O Bond-Forming Reactions" for further discussion of the synthesis of diazo
O O O R
O O h!, THF R' R' compounds.

O O O O [2+2] O
O Direct Diazotization
CH3 CH3 CH3 CH3 R' R'
• Compounds such as 1,3-dicarbonyls can be diazotized directly using arenesulfonyl azide reagents.
R R' Yield

Stevens, R. V.; Bisacchi, G. S.; Goldsmith, L.; Strouse, H H 84% N3SO2Ar O O

O O
C. E. J. Org. Chem. 1980, 45, 2708–2709. CH3 CH3 64% R R'
R R' Et3N
CH3 H 76% N2
Livinghouse, T.; Stevens, R. V. J. Am. Chem. Soc.
1978, 100, 6479–6482. Ph H 54%
• In the absence of a " activating group, #-diazo ketones can be formed by formylation-diazotization-
deformylation, in a procedure known as Regitz diazo transfer.
• 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.

O
N2 i-Pr O O OH O
O i-Pr H OR
Br h!, DCE N3SO2Ar N2
O OTIPS H
+ Br R R R
NaH R3N
80 °C retro
OTIPS [2+2]
CH3
CH3
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.
i-Pr i-Pr i-Pr
O O HO OTIPS OTIPS
CH3 O • Similarly, in the Danheiser procedure, reversible #$trifluoroacetylation activates the substrate toward
CH3 Br Br diazotization.

CH3 CH3 CH3 O CF3

Salvilenone 61–71% O O OH O
CF3 O N3SO2Ar N2
CF3
R R R
Danheiser, R. L.; Helgason, A. L. J. Am. Chem. Soc. 1994, 116, 9471–9479.
LiHMDS R3N

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.
Matt Mitcheltree

4
Myers Methods for Ring Contraction Chem 115
Synthesis of diazo ketones Wolff Rearrangement – Applications in target-oriented synthesis

• In the Mandler procedure, enolized ketones are diazotized without the assistance of an activating • Sequential Regitz diazotization–Wolff rearrangement was applied by Eaton and Nyi in their
group. These reactions are generally run under phase-transfer conditions, and are therefore not synthesis of [3.2.2]propellane. Thermolytic decarboxylation of a tert-butyl perester provides the
ideal for substrates sensitive to aqueous base (e.g., esters). final product after ring contraction.
NaH N3Tf h!
O N3SO2Mes O
HCO2Et Et2NH CH3OH
(n-Bu)4NBr, KOH, 18-cr-6 N2
R R
1:1 H2O–C6H6 H N2
O O O CO2CH3
HO
Lombardo, L.; Mandler, L. N. Synthesis 1980, 368–369. 85% 95% 60%

t-BuOOH
160 °C
• 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.

NH2 Eaton, P. E.; Nyi, K. J. Am. Chem. Soc. 1971, 93, 2786–2788. 45%
N(CH3)2
N N CH3O TBSO
H B TBSO • Similarly, Corey and Mascitti use two Regitz diazotization–Wolff rearrangement reactions in
TBSO CH3O O N3Tf B
N N O sequence in their enantioselective synthesis of pentacycloannamoxic acid methyl ester.
O
(CH3)2N O 1. NaHMDS, HCO2Et
N2 O O
O h! O 2. N3Ts, Et3N O
80% 72% +
N2
78% 62% (2 steps)

1. h!, CH3OH
O N 2. LiOH
N NH2
HO 1. Regitz
N N 2. h!, CH3OH
OH O
CHO CO2H
3. DIBAL-H
Oxetanocin H
4. Swern
Norbeck, D. W.; Kramer, J. B. J. Am. Chem. Soc. 1988, 110, 7217–7218. 43% (4 steps) 86% (2 steps)

(CH2)7CO2CH3 Pentacycloannamoxic acid methyl ester

H

Mascitti, V.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 3118–3119. Matt Mitcheltree

5
Myers Methods for Ring Contraction Chem 115
Wolff Rearrangement – Applications in target-oriented synthesis Cation-type rearrangements
• The Wolff rearrangement has been employed in the construction of the fused 5,5,5-tricyclic cores Pinacol Rearrangement
of sesquiterpenes.
Reviews
CH3 CH Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556.
3
CH3 CH CH3 CH
O 1. NaH, HCO2Et 3 3 Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143–7157.
H H CO2CH3 H
2. N3Ts, Et3N Overman, L. E. Acc. Chem. Res. 1992, 25, 352–359.

CH3 3. h", CH3OH CH3 CH3 • Vicinal diols, when treated with acid, generate a transient cation that may undergo alkyl shift
HO H H H
HO HO coupled with carbonyl formation.

48% !9(12)-Capnellene
OH OH O CH3
Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1 CH3 CH3
OH H+ CH3 CH3
1992, 865–873.
CH3
–H2O –H+
1. NaH, HCO2Et
CH3 CH3O2C CH3
O 2. N3Ts, Et3N 68–72%
CH3 CH3 CH3 Pavlik, C.; Morton, M. D.; Smith, M. B. Synlett 2011, 2191–2194.
CH3 3. h", CH3OH
H CH3 H CH3
H CH3 CH3
83% Pentalenene • Cationic rearrangements can proceed through concerted mechanisms as well, particularly when
the migrating bond is aligned with the leaving group.
Ihara, M.; Katogi, M.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1 1988, 2963–2970.

BF3•OEt2 H2O
• Where other methods failed, the Mandler procedure enabled Overman and co-workers to CH3O CH3 CH3O CH3
diazotize a ketone en route to (±)-meloscine. O H
HO HO
CH3 C6H6, reflux CH3
H F3B H H
N N3SO2Ar N CH3 CH3
BocHN BocHN
(n-Bu)4NBr, 18-cr-6, KOH 90%
H H
1:1 C6H6–H2O Hariprakasha, H. K.; SubbaRao, G. S. R. Tetradron Lett. 1997, 38, 5343–5346.
O O
OBn 35 °C, 1h OBn
N2
Ar = 2,4,6-triisopropylphenyl 98% • Halogens and sulfonate esters can also be used, as demonstrated below.

h", CH3OH O
OTs H H
HO
Al2O3 Ph3P CH2
N H
N H H
BocHN H CH3 H CH3
CH3 H CH3
CH3 CH3 CH CH3 CH
OBn 3 3
HN H
CO2CH3 100% 53%
O (–)-Aromadendrene
(±)-Meloscine 95%
Büchi, G.; Hofheinz, W.; Paukstelis, J. V. J. Am. Chem. Soc. 1969, 91, 6473–6478.
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. Matt Mitcheltree

6
Myers Methods for Ring Contraction Chem 115
PInacol Rearrangement

• Schreiber's synthesis of the bicyclic core of calicheamicin relied on a pinacol rearrangement. • The reaction of epoxides with Lewis acids can provide ring-contracted products by a pinacol-type
Tautomerization of the resulting !-hydroxy ketone gave the enone product shown. mechanism.
n Yield
CHO
LiBr, Al2O3
1 77%
LA O
MsO H H H
O PhCH3 2 42%
H OH n n
H
Et2AlCl O 3 30%
TBSO OH TBSO
OH TBSO OH
CH2Cl2 Suga, H.; Miyake, H. Synthesis 1988, 394–395.

O O
65% BF3•OEt2 CHO

Schoenen, F. J.; Porco, J. A.; Schreiber, S. L. Tetrahedron Lett. 1989, 30, 3765–3768. CH3 O CH3
CH3
CH3 CH3 CH3

93%

CH3S H H
S Kunisch, F.; Hobert, K.; Weizel, P. Tetrahedron Lett. 1985, 26, 6039–6042.
OH
CH3 O S
CH3 CH3 O
I O HN O
S O HN OCH3 • Yamamoto and co-workers have described an epoxide-opening ring contraction utilizing a
O HO
O methylaluminum diphenoxide Lewis acid that outperforms boron trifluoride in difficult ring
O OCH3 OH O
CH3 OCH3 contractions.
O EtHN
HO CH3O
CH3O
OH
CH3 CH3 CHO
Calicheamicin "1 O MABR
OTBS

CH2Cl2, –78 °C MABR = CH3Al(OAr)2

OTBS i-Pr
i-Pr
• Similarly, Paquette employed a pinacol rearrangement to produce the (+)-taxusin skeleton. 82% t-Bu

OHC CH3 Ar = Br
CH3
O MABR
O O OTBS t-Bu
AcO OAc
CH3 CH3 CH3
CH3 Et2AlCl CH3 CH2Cl2, –78 °C
CH3 CH3 OTBS i-Pr
CH3
CH2Cl2–Hexane CH3 i-Pr
H CH3 88%
–78 # –15 °C O AcO H
HO OMs O
O O
96% (+)-Taxusin
Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111, 6431–6432.

Paquette, L. A.; Zhao, M. J. Am. Chem. Soc. 1998, 120, 5203–5212.

Matt Mitcheltree

7
Myers Methods for Ring Contraction Chem 115
Pinacol Rearrangement • After cationic rearrangement, the resulting cation may be intercepted by elimination of an
adjacent proton:
• Kuwajima and Baran both used pinacol-type rearrangements in their syntheses of ingenol.

Kuwajima TsO CH3 CH3

CH3 CH3
CH3 CH3 AcOH, AcOK
CH3
CH3 H CH3 HO O
CH3 OCH3 CH3 80 °C, 8 h
Al(CH3)3 OTIPS
O OH H H CH3 CH3
CH3 H H
CH3
CH2Cl2 CH3 H CH3 CH3
O OH CH3O 76%
OTIPS
OCH3 Al(CH3)3 OTIPS Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746–1757. "-bulnesene

76% • By elimination of a #-silyl group:

TMS
Baran TMS
CH3 CH3 CH CH3
CH3 FeBr3 TMS 3 CH3
CH3 CH3 CH3 CH3
CH3 CH3 O O O
CH3 –60 °C LA
CH3 CH3 CH3 H
HO BF3•OEt2 CH3 CH3 OH H
O TMS CH3 CH3
O OTBS OTBS CH3
CH2Cl2 O
O HO HO
O CH3 O CH3
O HO OH
80% Ingenol O CH3 CH3
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. CrO2Cl2
Am. Chem. Soc. 2003, 125, 1498–1500.
Jørgensen, L.; McKerall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S. Science CH3 H t-BuOH CH3 H
2013, 341, 878–882. CH3 CH3
• A tandem pinacol–Schmidt rearrangement was used to synthesize the core of (±)-stemonamine. (–)-Solavetivone 71% 54%
Hwu, J. R.; Wetzel, J. M. J. Org. Chem. 1992, 57, 922–928.
Cl2
CH3 Ti O • Or by attack with an endogenous nucleophile.
TMSO TiCl4 OH N3
O O
N3 MgI2
N3 CH2Cl2 OMs CH3
O CH3 HN(TMS)2
–78 ! 0 °C CH3 CH3 CH3
CH3 H
CH3
TMSO CH3
H TMSO H

O Cl2
N Ti O CH3 CH3
N N2
OCH3 O
N OHC CH3 CH3
CH3 H H
CH3 CH3
O OH OHC O
CH3 CH3 H H
O
CH3 (+)-Isovelleral 82%
(±)-Stemonamine 68%

Zhao, Y. M.; Gu, P. M.; Tu, Y. Q.; Fan, C. A.; Zhang, Q. W. Org. Lett. 2008, 10, 1763–1766. Bell, R. P. L.; Wjnberg, J. B. P. A.; de Groot, A. J. Org. Chem. 2001, 66, 2350–2357. Matt Mitcheltree

8
Myers Methods for Ring Contraction Chem 115
Lead-promoted ring contractions
• An example of a pinacol rearrangement initiated by an endogenous electrophile was • Lead(IV) salts have been shown to promote ring contractions of ketones and enol ethers.
demonstrated by Oltra: However, these reactions sometimes provide significant amounts of !-acetoxy ketone side-
products.

O HO CH3 O
TMSCl, • This reaction is believed to involve Pb–C bond formation followed by pinacol-type rearrangement.
CH3 CH3
NaI H CH
HO CH3 H O 3
O OAc
CH3 CH3 O Pb(OAc)4 O OAc OAc
O O O
CH3 O TMS CH3 O O O H O
O OH – OAc
O Pb(OAc)3 –Pb(OAc)3
> 72%

Rosales, A.; Estévez, R. E.; Cuerva, J. M.; Oltra, J. E. Angew. Chem., Int. Ed. 2005, 44, 319–322. Norman, R. O. C.; Thomas, T. B. J. Chem. Soc. B. 1967, 604–611.

• The Imamura synthesis of (–)-hyrtiosal employed an epoxide-opening rearrangement that is • Lead(IV)-promoted ring contractions have been employed to modify !-santonin. Improved yields
proposed to mimic the biosynthetic route to the natural product. were achieved by first converting the substrate to the corresponding ethyl-enol ether.

O CHO
CH3 CH3 CH3 Pb(OAc)4 CH3 CH3
CH3 CH3 CH3 CH3 BF3•OEt2 O AcO
BF3•OEt2 H H + H
H H O CH3 CH3OH CH3O CH3 O CH3
O C6H6 O H
RO RO CH3 O CH2Cl2 CH3 H O CH3
H
O
CH3 CH3 CH3 CH3 O O O
!-Santonin 67% 30%
R = (S)-mandeloyl 96%

HC(OEt)3
NH4Cl
EtOH
CHO
CH3 Pb(OAc)4
CH3 CH3 CH3 CH3
BF3•OEt2, EtOH O
H H H
O EtO CH3 C6H6 EtO CH3
HO
CH3 CH3 CH3
H
O CH3 H O
O O
(–)-Hyrtiosal 100% 80%

Lunardi, I.; Santiago, G. M. P.; Imamura, P. M. Tetrahedron Lett. 2002, 43, 3609–3611.
Miura, H.; Fujimoto, Y.; Tatsuno, T. Synthesis 1979, 898–899.

Matt Mitcheltree

9
Myers Methods for Ring Contraction Chem 115
Ring contractions of silyl-enol ethers
• Cyclic silyl-enol ethers undergo ring contraction upon treatment with electron-deficient sulfonyl • Because alkyl migration is stereospecific, the stereochemistry of the product is determined by
azides to give trialkylsilyl imidates, which are readily hydrolyzed to N-acyl sulfonamides. the facial selectivity of sulfonyl-azide addition. Lesser facial differentiation leads to lower
diastereomeric ratios, as the following series demonstrates.
• 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. OTMS TMSO O
NHNf
NNf
CH3 N3Nf CH3 CH3
OSiR3 Nf R3SiO O H
R3SiO N N
N3SO2C4F9 N H2O –N2 CH3
Nf Nf
R H H CH3 CH3
R single
CH3CN R R diastereomer
–N2
OTMS O
N3Nf NHNf
• Alkyl, vinyl, and aryl migrations are all possible. While 6!5 and 7!6 ring contractions are d.r. = 67 : 33
possible, this method does not permit cyclobutane synthesis.

Substrate Product Yield

OTMS O
N3Nf NHNf
OTMS O d.r. = 55 : 45
NHNf
97% CH3
CH3

• The resulting N-acyl sulfonamide can be converted to alcohol, ester, or carboxamide products.
OTMS O

NHNf 67% OH
LAH
85%
O Et2O, 0!23 °C, 20 min
OTMS NHNf SO2C4F9
O
NH O
78% OCH3
HCl (0.3 M)
75%
O 20% CH3OH–PhCH3
OTMS NHNf 110 °C, 3 h
O
87% NH2
SmI2
96%
THF, 23 °C, 30 min
OTIPS O
NHNf
H
Mitcheltree, M. J.; Konst, Z. A.; Herzon, S. B. Tetrahedron 2013, 69, 5634–5639.
CH3 65%
O CH3
O
O O
CH3
CH3 CH3 CH
3

Mitcheltree, M. J.; Konst, Z. A.; Herzon, S. B. Tetrahedron 2013, 69, 5634–5639. Matt Mitcheltree

10
Myers Methods for Ring Contraction Chem 115
Synthesis of regiodefined silyl-enol ethers
• Silyl-enol ethers are appealing substrates for ring contractions because they can be synthesized • Silyl-enol ethers can be formed by enantioselective, catalytic Diels–Alder reactions.
regioselectively.
H Ph
Ph
O OTMS OTMS O O
O H
CH3 Conditions CH3 CH3 Br N B Br
+ o-Tol
TIPSO CH3 CH3 TIPSO CH3
CH3
A B O HNTf2 O
–78 °C
Conditions Yield A:B
96%, 97% e.e.
LDA, TMSCl 74 99 : 1
Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800–4802.
Et3N, TMSCl, NaI 92 10 : 90

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.

• Silyl-enol ethers can also be formed by 1,4-addition to !,"-unsaturated carbonyls.

O CH3
OTMS
MgBr
CH3
CH3
CH3 CuBr•S(CH3)2 CH3
TMEDA, TMSCl CH3
OTBS TBSO
100%

Nozawa, D.; Takikawa, H.; Mori, K. J. Chem. Soc. Perkin Trans. 1, 2000, 2043–2046.

• Birch reduction of substituted silyloxy aryl ethers gives regiodefined substrates for ring
contraction.

OTES OTES
Li, NH3

i-Pr t-BuOH, THF i-Pr

90%
Macdonald, T. L. J. Org. Chem. 1978, 18, 3621–3624.

Matt Mitcheltree

11