Myers
Chem 115
Methods for Ring Contraction
• Chiral-pool starting materials have been much used as substrates for the Favorskii reaction,
affording functionalized, optically active cyclopentanes.
Recent Reviews:
Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556.
O
Silva, Jr. L. F. Tetrahedron 2002, 58, 9137–9161.
O
H2O2
CH3
• Ring contraction reactions can be grouped into three general categories based on mechanism:
O
O
X
NaOH
Nu:
O
O
Nu
CO3CH3
CH3
Carbenoid
O
R
CH3
THPO
Lee, E.; Yoon, C. H. J. Chem. Soc., Chem. Commun. 1994, 479–481.
• For example, the ring contraction of a (+)-pulegone derivative has been used in the synthesis of
several terpenoid natural products.
CH3
CH3
CH3
Br2
Anionic Ring Contractions
Favorskii Rearrangement
O
• 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.
O
O
Cl
80%
R
Cationic
O
H
CH3
CH3
THPO
O
CH3
NaOCH3
CH3OH
Nu:
M
THPO
81% (2 steps)
CH3
(–)-Carvone
Anionic
O
2. DHP, p-TsOH
90%
CH3
Nu
O
Cl
CH3
1. TMSCl
CH3
O
CH3
Br
Br
O
CO2CH3
CH3OH
CH3
CH3
CH3
CH3
60–67% (2 steps)
(+)-Pulegone
OCH3
OCH3
NaOCH3
CH3
Et2O
NaOCH3
Et2O, 35 °C, 2 h
56–61%
Organic syntheses; Wiley & Sons: New York, 1963; Coll. Vol. No. 4, pp. 594.
AgNO3
Br
H2O, t-BuOH
OH
H
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.
H
O
H
71%
CH3
CH3 H
H
CH3
CH3
(+)-Epoxydictymene
CO2H
OH
O
H
Ag+
CH3
CH3
• In some cases, enolization is not possible, precluding cyclopropanone formation. An alternate
mechanism involves formation of a tetrahedral intermediate that promotes alkyl migration.
Br
CH3
O
H
H
O
CH3
CH3
CH3
(–)-Iridomyrmecin
(+)-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.
Matt Mitcheltree
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Chem 115
Methods for Ring Contraction
Quasi-Favorskii Rearrangement
• 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.
• A common application of the quasi-Favorskii rearrangement is in the rearrangement of fused
polycycles.
OH
HO
• These fragmentations are generally accelerated by oxyanion formation.
OMs
1. MsCl (1 equiv), pyr
CH3
2. KOt-Bu
HO CH3
OTs
KOt-Bu
CH3
THF
O
CH3
H
CH3
CH3
O
60% (2 steps)
CH3
+
OTs
O
O
O
90%, 89 : 11
Hamon, D. P. G.; Tuck, K. L. Chem. Commun. 1997, 941–942.
OH
Br
LAH
O
H
CH3
CH3 H
CHO
Br
O
H
CH3
HO
H
(±)-Hinesol
Marshall, J. A.; Brady, S. F. J. Org. Chem. 1970, 35, 4068–4077.
H
CH3
98%
Harmata, M.; Bohnert, G.; Kürti, L.; Barnes, C. L. Tetrahedron Lett. 2002, 43, 2347–2349.
CH3
OH
LiOH
• 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.
O
H
AgNO3
Cl
CH3 H
CH3OH
OBn
CH3O
Cl
Ag+
OH
O
O
HO
t-BuOH, 65 °C
OTs
CH3 OH
CH3
O
O
O H
O
O
O
O
OTs
H
87%
H
CH3
CH3 H
CH3O2C
OBn
H
OBn
53%
CH3 O
O
O
H
CH3
O
(±)-Confertin
H
CH3
CH3
H
OBn
Heathcock, C. H.; DelMar, E. G.; Graham, S. L. J. Am. Chem. Soc. 1982, 104, 1907–1917.
CH3
HO
H
OH
(±)-Sirenin
Harding, K. E.; Strickland, J. B.; Pommerville, J. J. Org. Chem. 1988, 53, 4877–4883.
Matt Mitcheltree
2
Myers
Chem 115
Methods for Ring Contraction
Quasi-Favorskii Rearrangement
Carbenoid Ring Contractions
• Harmata has showcased the power of the quasi-Favorskii rearrangement in the synthesis of
several terpenoid natural products.
Wolff Rearrangement
Reviews:
Kirmse, W. Eur. J. Org. Chem. 2002, 2193–2256.
1. LAH
2. KH
Meier, H.; Zeller, K.-P. Angew. Chem. Int. Ed. 1975, 14, 32–43.
H
Cl O
CHO
Cl O
• 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.
76% (2 steps)
Stereochemistry
established by X-ray
• The Wolff rearrangement may be induced by heat, Ag(I) salts, or light.
O
R2
R1
h", #,
or AgI
H
H
R1
H
CH3
CH3
O
Nu
R2
R1
R2
Nu = -OCH3, -OBn, -OH, -NR2, SR, etc.
OH
O
Nu-H
R2
R1
N2
CH3
O
O
• In the prototypical case depicted below, the Wolff rearrangement proceeds in higher yield relative
to the analogous Favorskii system.
O
CH3
O
O
N2
(±)-Spatol
h", CH3OH
OCH3
> 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
CH3
CH3
1. LAH
2. KH
O
3. LAH
CH3
H
CH3
CH3
H+
CH3
CH3
Br
OH
91% (3 steps)
CH3
(±)-Sterpurene
O
h", CH3OH
OH
OCH3
N2
H+
H
+
CO2CH3
CO2CH3
H
92%, 88 : 12
Harmata, M.; Bohnert, G. J. Org. Lett. 2003, 5, 59–61.
Kirmse, W.; Wroblowsky, H.-J. Chem. Ber. 1983, 116, 1118–1131.
Matt Mitcheltree
3
Myers
Chem 115
Methods for Ring Contraction
Wolff Rearrangement
Synthesis of diazo ketones
• Ketene intermediates produced in the Wolff rearrangement can also be trapped in [2+2]
cycloaddition reactions.
R
CH3 CH3
O
N2
O R
O
O
O
O h!, THF
R' R'
Review
O
O
O
O
O
[2+2]
CH3 CH3
CH3 CH3
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.
O
Doyle, 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.
Direct Diazotization
R' R'
• Compounds such as 1,3-dicarbonyls can be diazotized directly using arenesulfonyl azide reagents.
R
R'
Yield
H
H
84%
CH3
CH3
64%
CH3
H
76%
Ph
H
54%
O
R'
R
O
N3SO2Ar
O
O
R
Et3N
R'
N2
• In the absence of a " activating group, #-diazo ketones can be formed by formylation-diazotizationdeformylation, 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.
N2
Br
i-Pr
O
i-Pr
h!, DCE
O
+
CH3
H
OTIPS
80 °C
CH3
CH3
O
HO
CH3
Salvilenone
N2
R
R3N
NaH
OTIPS
OTIPS
Br
Br
O
N3SO2Ar
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.), WileyInterscience, Chichester, 1978, pp. 751–820.
i-Pr
i-Pr
O
OH
H
R
retro
[2+2]
CH3
i-Pr
O
OR
R
Br
OTIPS
O
O
• Similarly, in the Danheiser procedure, reversible #$trifluoroacetylation activates the substrate toward
diazotization.
O
CH3
CH3
Danheiser, R. L.; Helgason, A. L. J. Am. Chem. Soc. 1994, 116, 9471–9479.
CF3
O
O
61–71%
CF3
O
OH
O
R
R
LiHMDS
CF3
O
N3SO2Ar
N2
R
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
Chem 115
Methods for Ring Contraction
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
group. These reactions are generally run under phase-transfer conditions, and are therefore not
ideal for substrates sensitive to aqueous base (e.g., esters).
• 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
N3SO2Mes
(n-Bu)4NBr, KOH, 18-cr-6
R
N3Tf
Et2NH
NaH
HCO2Et
O
N2
R
1:1 H2O–C6H6
O
O
H
O
HO
85%
Lombardo, L.; Mandler, L. N. Synthesis 1980, 368–369.
h!
CH3OH
N2
95%
NH2
TBSO
O
N
N
N
Eaton, P. E.; Nyi, K. J. Am. Chem. Soc. 1971, 93, 2786–2788.
N(CH3)2
CH3O
CH3O
H
TBSO
O
(CH3)2N
B
N3Tf
TBSO
O
O
O
O
72%
80%
h!
O
+
1. NaHMDS, HCO2Et
2. N3Ts, Et3N
1. h!, CH3OH
2. LiOH
N
N
NH2
HO
OH
N
Oxetanocin
Norbeck, D. W.; Kramer, J. B. J. Am. Chem. Soc. 1988, 110, 7217–7218.
O
N2
62% (2 steps)
78%
O
45%
• Similarly, Corey and Mascitti use two Regitz diazotization–Wolff rearrangement reactions in
sequence in their enantioselective synthesis of pentacycloannamoxic acid methyl ester.
B
N2
O
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.
N
CO2CH3
1. Regitz
2. h!, CH3OH
N
CHO
H
43% (4 steps)
O
3. DIBAL-H
4. Swern
(CH2)7CO2CH3
CO2H
86% (2 steps)
Pentacycloannamoxic acid methyl ester
H
Mascitti, V.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 3118–3119.
Matt Mitcheltree
5
Myers
Chem 115
Methods for Ring Contraction
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
of sesquiterpenes.
Pinacol Rearrangement
CH3 CH
3
H
CH3
O
CH3 CH
3
H CO2CH3
CH3
3. h", CH3OH
H
HO
CH3 CH
1. NaH, HCO2Et
2. N3Ts, Et3N
HO
Reviews
Song, 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.
3
H
CH3
H
• Vicinal diols, when treated with acid, generate a transient cation that may undergo alkyl shift
coupled with carbonyl formation.
H
HO
!9(12)-Capnellene
48%
Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1
1992, 865–873.
CH3
CH3
CH3
O
H
1. NaH, HCO2Et
2. N3Ts, Et3N
CH3O2C
OH
OH
CH3
H+
CH3
OH
O
H
CH3
CH3
CH3
–H+
–H2O
CH3
68–72%
CH3
3. h", CH3OH
CH3
CH3
CH3
CH3
Pentalenene
83%
Pavlik, C.; Morton, M. D.; Smith, M. B. Synlett 2011, 2191–2194.
CH3
CH3
H
• 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.
• Where other methods failed, the Mandler procedure enabled Overman and co-workers to
diazotize a ketone en route to (±)-meloscine.
N3SO2Ar
(n-Bu)4NBr, 18-cr-6, KOH
N
BocHN
BocHN
1:1 C6H6–H2O
35 °C, 1h
OBn
N2
98%
N
H
CH3 CH3
• Halogens and sulfonate esters can also be used, as demonstrated below.
OBn
H
HO
CO2CH3
CH3
O
OTs
Ph3P CH2
H
CH3
H
H
H
Al2O3
H
N
BocHN
(±)-Meloscine
H
O
OBn
h", CH3OH
O
H2O
Hariprakasha, H. K.; SubbaRao, G. S. R. Tetradron Lett. 1997, 38, 5343–5346.
O
Ar = 2,4,6-triisopropylphenyl
HN
C6H6, reflux
CH3O CH3
HO
CH3
H
F3B
90%
H
H
O
N
BF3•OEt2
CH3O CH3
HO
CH3
H
CH3
H
CH3 CH
3
100%
CH3
H
CH3 CH
H
CH3
3
53%
(–)-Aromadendrene
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
Chem 115
Methods for Ring Contraction
PInacol 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
TBSO
LA
H
H
OH
OH
H
H
O
OH
O
H
Et2AlCl
TBSO
• The reaction of epoxides with Lewis acids can provide ring-contracted products by a pinacol-type
mechanism.
n
Yield
CHO
LiBr, Al2O3
1
77%
O
2
42%
PhCH3
n
n
3
30%
TBSO
OH
CH2Cl2
Suga, H.; Miyake, H. Synthesis 1988, 394–395.
O
O
65%
BF3•OEt2
Schoenen, F. J.; Porco, J. A.; Schreiber, S. L. Tetrahedron Lett. 1989, 30, 3765–3768.
CH3
CH3
CHO
O
CH3
CH3
CH3
CH3
93%
CH3S
CH3 O
I
O
CH3
O
HO
CH3O
OH
CH3
S
OCH3 OH
OCH3
HN
O HO
O
CH3
S
S
O
H
O
H
Kunisch, F.; Hobert, K.; Weizel, P. Tetrahedron Lett. 1985, 26, 6039–6042.
OH
O
HN
O
OCH3
• 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.
O
EtHN
CH3O
CH3
Calicheamicin "1
CH3 CHO
O
MABR
OTBS
• Similarly, Paquette employed a pinacol rearrangement to produce the (+)-taxusin skeleton.
O
CH3
CH3
CH3
HO
OMs O
Et2AlCl
CH2Cl2–Hexane
–78 # –15 °C
AcO
CH3
CH3
CH3
CH3
H
O
O
96%
AcO
CH3
OAc
CH3
CH3
i-Pr
MABR = CH3Al(OAr)2
82%
OHC
O
CH2Cl2, –78 °C
t-Bu
CH3
MABR
OTBS
i-Pr
H
CH2Cl2, –78 °C
i-Pr
CH3
O
OTBS
Ar =
OTBS
Br
t-Bu
i-Pr
88%
O
(+)-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
• After cationic rearrangement, the resulting cation may be intercepted by elimination of an
adjacent proton:
Pinacol Rearrangement
• Kuwajima and Baran both used pinacol-type rearrangements in their syntheses of ingenol.
TsO
Kuwajima
CH3
CH3
CH3
O
CH3
CH3
H
Al(CH3)3
OH
CH2Cl2
CH3 H
OTIPS
OCH3
OCH3
OTIPS
O OH
HO
CH3
CH3
CH3
O
CH3O
Baran
CH3
CH3
CH3
CH3
TMS
OTBS
O
O
O
O
CH3
BF3•OEt2 CH3
CH3
CH3
O
CH3
CH3
O
80%
CH3
FeBr3
H
LA
CH3
CH3
O
CH3
CH3
CH3
OH
Ingenol
CH3
O
CH3
CrO2Cl2
CH3
• A tandem pinacol–Schmidt rearrangement was used to synthesize the core of (±)-stemonamine.
(–)-Solavetivone 71%
TiCl4
TMSO
N3
O
OH
O
O
N3
N3
CH2Cl2
–78 ! 0 °C
CH3
CH3
CH3
O
N
O
Cl2
Ti O
N2
N
CH3
O
OH
CH3
CH3
(±)-Stemonamine
MgI2
HN(TMS)2
OMs
CH3
O
OCH3
CH3
H
CH3
54%
• Or by attack with an endogenous nucleophile.
TMSO
N
t-BuOH
H
CH3
Hwu, J. R.; Wetzel, J. M. J. Org. Chem. 1992, 57, 922–928.
Cl2
Ti
O
H
CH3
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.
CH3
CH3
TMS
OH
CH3
HO HO
HO
CH3
H
76%
"-bulnesene
OTBS
O
O
H
CH
TMS 3
–60 °C
CH3
CH2Cl2
CH3
CH3
Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746–1757.
TMS
CH3
H
• By elimination of a #-silyl group:
CH3
CH3
O
CH3
CH3
AcOH, AcOK
80 °C, 8 h
OTIPS
Al(CH3)3
CH3
CH3
H
CH3
76%
HO
Chem 115
Methods for Ring Contraction
H
CH3
CH3
CH3
H
CH3
CH3
TMSO
H
CH3
OHC
CH3
CH3
H
OHC
CH3
H
(+)-Isovelleral
CH3
CH3
H
O
H
82%
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
Chem 115
Methods for Ring Contraction
Lead-promoted ring contractions
• An example of a pinacol rearrangement initiated by an endogenous electrophile was
demonstrated by Oltra:
O
HO
CH3
O
CH3 O
TMSCl,
NaI
H
HO CH3
O
• This reaction is believed to involve Pb–C bond formation followed by pinacol-type rearrangement.
CH3
CH3
O
CH3
• 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 sideproducts.
O
O
TMS
O
H CH
3
O
CH3
CH3
O
OH
O
O
O
Pb(OAc)4
OAc
OAc
O
O
OAc
O
H
–
Pb(OAc)3 –Pb(OAc)3
OAc
> 72%
Rosales, A.; Estévez, R. E.; Cuerva, J. M.; Oltra, J. E. Angew. Chem., Int. Ed. 2005, 44, 319–322.
• The Imamura synthesis of (–)-hyrtiosal employed an epoxide-opening rearrangement that is
proposed to mimic the biosynthetic route to the natural product.
O
CH3 CH3
RO
CH3 CH3
R = (S)-mandeloyl
• 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.
CHO
CH3
CH3
H
Norman, R. O. C.; Thomas, T. B. J. Chem. Soc. B. 1967, 604–611.
BF3•OEt2
O
C6H6
H
RO
Pb(OAc)4
BF3•OEt2
CH3
CH3 CH3
H
O
O
CH3
CH3 CH3
O
O
CH3OH
CH2Cl2
CH3O
CH3 H O
CH3
H
CH3
O
O
Pb(OAc)4
BF3•OEt2, EtOH
CH3
CH3 CH3
O
30%
CH3
O
H
H
HO
H
O
HC(OEt)3
NH4Cl
EtOH
CHO
CH3
H
CH3
+
CH3
67%
!-Santonin
96%
AcO
H
CH3
H
CH3
O
O
CH3 CH3
(–)-Hyrtiosal
Lunardi, I.; Santiago, G. M. P.; Imamura, P. M. Tetrahedron Lett. 2002, 43, 3609–3611.
EtO
CH3
H
CH3
O
C6H6
EtO
O
O
100%
CH3
CH3 H O
80%
Miura, H.; Fujimoto, Y.; Tatsuno, T. Synthesis 1979, 898–899.
Matt Mitcheltree
9
Myers
Chem 115
Methods for Ring Contraction
Ring 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.
• 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.
• 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.
N3Nf
CH3
OSiR3
R3SiO
N3SO2C4F9
R
R3SiO
Nf
N
H
R
CH3CN
–N2
O
N
Nf
H2O
H
N
H
• 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.
Product
OTMS
CH3
CH3
O
N3Nf
single
diastereomer
NHNf
d.r. = 67 : 33
Yield
OTMS
O
N3Nf
O
NHNf
CH3
CH3
OTMS
Substrate
CH3
O
NNf
–N2
Nf
R
R
TMSO
OTMS
NHNf
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
OTMS
NHNf
O
78%
SO2C4F9
NH
Et2O, 0!23 °C, 20 min
O
OCH3
HCl (0.3 M)
75%
O
OTMS
20% CH3OH–PhCH3
110 °C, 3 h
NHNf
87%
O
NH2
SmI2
OTIPS
96%
THF, 23 °C, 30 min
O
NHNf
H
CH3
CH3
CH3
O
O
CH3
65%
O
Mitcheltree, M. J.; Konst, Z. A.; Herzon, S. B. Tetrahedron 2013, 69, 5634–5639.
O
CH3 CH
3
Mitcheltree, M. J.; Konst, Z. A.; Herzon, S. B. Tetrahedron 2013, 69, 5634–5639.
Matt Mitcheltree
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Myers
Chem 115
Methods for Ring Contraction
Synthesis of regiodefined silyl-enol ethers
• Silyl-enol ethers are appealing substrates for ring contractions because they can be synthesized
regioselectively.
O
OTMS
CH3
Conditions
CH3
• Silyl-enol ethers can be formed by enantioselective, catalytic Diels–Alder reactions.
H Ph
O
OTMS
CH3
Br
+
TIPSO
A
Conditions
Yield
A:B
LDA, TMSCl
74
99 : 1
Et3N, TMSCl, NaI
92
10 : 90
CH3
H
N B
o-Tol
CH3
O
B
Ph
O
TIPSO
HNTf2
–78 °C
CH3
O
Br
CH3
O
96%, 97% e.e.
Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800–4802.
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.
CH3
O
CH3
CH3
OTBS
OTMS
MgBr
CH3
CuBr•S(CH3)2
TMEDA, TMSCl
TBSO
CH3
CH3
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.
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