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Matt Mitcheltree
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.
Silva, Jr. L. F. Tetrahedron 2002 , 58 , 9137–9161.
O
Cl
O OCH 3
NaOCH (^3)
Et 2 O, 35 °C, 2 h
56–61%
O
CH 3 CH 3
O
CH 3
(+)-Pulegone
Br (^2)
Et 2 O
CH 3
O
Br (^) CH 3
CH 3
Br CH 3 CH (^3)
CO 2 CH 3
CH 3
O
CH 3 H
H O
O CH^3
CH 3 CH^3
CH 3
H
H
CH 3
CH 3
CH 3
CH 3
H
60–67% (2 steps)
(+)-Epoxydictymene (–)-Iridomyrmecin
CH 3
(+)-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.
CH 3
O
(–)-Carvone
O
CH 3
Cl
THPO
THPO
CH 3 CO^3 CH^3
CH 3 CH 3
Lee, E.; Yoon, C. H. J. Chem. Soc., Chem. Commun. 1994 , 479–481.
Anionic Ring Contractions
Favorskii Rearrangement
X
O
O (^) O Nu
O Nu
O
M O R
R
Anionic
Carbenoid
Cationic
For 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.
NaOCH (^3)
CH 3 OH
- TMSCl
Nu :
Nu :
H 2 O 2
NaOH
CH 3
O
CH 3
O
- DHP, p -TsOH
NaOCH (^3) CH 3 OH
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.
OCH 3
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
Br OH OH
Ag + CO 2 H
H
H 2 O, t -BuOH
AgNO (^3)
O
CH 3 H
THPO
CH 3 CH 3
Quasi-Favorskii Rearrangement
Matt Mitcheltree
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.
HO CH 3
OTs KO t -Bu
THF
O CH 3 O
CH 3
Hamon, D. P. G.; Tuck, K. L. Chem. Commun. 1997 , 941–942.
Br
H O
Br
H O
H
CHO
H
OH
LAH
Harmata, M.; Bohnert, G.; Kürti, L.; Barnes, C. L. Tetrahedron Lett. 2002 , 43 , 2347–2349.
HO
OH
CH 3
OMs O CH (^3) CH (^3)
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)
- KO t -Bu (^) H
CH 3
CH 3
H
HO
CH 3
CH 3
(±)-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
CH 3
Cl H
H
AgNO (^3)
CH 3 OH
CH 3 O
Cl CH 3 H
OH
OBn
CH 3
CH 3 O 2 C
OBn
H
H
Ag +
OH
CH 3
CH 3
HO H
H
(±)-Sirenin
Harding, K. E.; Strickland, J. B.; Pommerville, J. J. Org. Chem. 1988 , 53 , 4877–4883.
CH (^3) H OBn
O
A common application of the quasi-Favorskii rearrangement is in the rearrangement of fused polycycles.
OTs
HO
O
O
CH OH
3 O
O
H
CH 3
O
O
OTs
CH 3 OH
H
O
O
O
CH 3 O
H
CH 3
O
O
(±)-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
CH 3
- MsCl (1 equiv), pyr
Matt Mitcheltree
Ketene intermediates produced in the Wolff rearrangement can also be trapped in [2+2] cycloaddition reactions.
O O
O O
N 2
CH 3 CH 3
O O
CH 3 CH 3
O
O
h!, THF (^) R' R'
R
R' R'
O OR
O
CH 3 CH^3
[2+2] O
R R' Yield
H H 84% CH 3 CH 3 64% CH 3 H 76% Ph H 54%
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.
Br
N 2 O
CH 3
h!, DCE
Br
HO OTIPS
i -Pr
OTIPS
i -Pr
O
i -Pr
OTIPS
CH 3
Br
CH 3
OTIPS
i -Pr
BrO
O
i -Pr O CH (^3)
CH 3
CH 3 CH 3
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
H OR N 3 SO 2 Ar
R 3 N
O
R
N 2
O
R
O
R
CF 3
OH
LiHMDS
N 3 SO 2 Ar
R 3 N
O
R
CF 3 N 2
O
O
CF 3
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.
Review 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.
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 N^3 SO^2 Ar R R'
O O
Et 3 N N (^2)
Matt Mitcheltree
Synthesis of diazo ketones
NaH HCO 2 Et
O HO
H
N 3 Tf Et 2 NH
h! CH 3 OH
t -BuOOH 160 °C
Eaton, P. E.; Nyi, K. J. Am. Chem. Soc. 1971 , 93 , 2786–2788. 45%
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 N^2 CO 2 CH 3
O
O O
N 2
CO 2 H
O
H
(CH 2 ) 7 CO 2 CH 3
h!
- NaHMDS, HCO 2 Et
- N 3 Ts, Et 3 N
- h!, CH 3 OH
- LiOH
78% 62% (2 steps)
H
CHO
- Regitz
- h!, CH 3 OH
- DIBAL-H
- 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
O
N 2
1:1 H 2 O–C 6 H 6
N 3 SO 2 Mes ( n -Bu) 4 NBr, KOH, 18-cr-
N
N N
N
NH 2
O
TBSO
O
OB
TBSO
O
TBSO OB
N 2 O
(CH 3 ) 2 N
N(CH 3 ) 2
CHCH 3 O H
3 O
N 3 Tf
O
N
OH
HO
N
N N
NH 2
Oxetanocin Norbeck, 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 (N 3 SO 2 CF 3 ). This approach was used in the synthesis of oxetanocin, a bacterial isolate with anti-HIV activity.
Wolff Rearrangement – Applications in target-oriented synthesis
LA
Matt Mitcheltree
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
OH
OH
H
TBSO
O
OH
H
H
TBSO
H
TBSO
OH
O
H
Et 2 AlCl
CH 2 Cl (^2)
H
O
OH
O
H
HN OCH 3
O
S
S
CH 3 S
O
O
HO
HN
CH 3
O
CH 3 O
EtHN
O
OH
CH 3
S
CH 3 O
I
OCH 3
OCH 3
O
O
CH 3 O OH
HO
CH 3
Calicheamicin " 1
HO
CH 3
CH 3
O
CH 3
OMs O O
CH 3
CH 3
O
CH 3
O
H
(+)-Taxusin
Et 2 AlCl
CH 2 Cl 2 –Hexane –78 # –15 °C
- 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.
O
LiBr, Al 2 O (^3)
PhCH (^3)
CHO
Suga, H.; Miyake, H. Synthesis 1988 , 394–395.
n
n 1 2 3
Yield 77% 42% 30%
O
O
CH 3
CH 3
CH 3
BF 3 •OEt (^2)
O
CH 3
CH 3
CHO
CH 3
Kunisch, F.; Hobert, K.; Weizel, P. Tetrahedron Lett. 1985 , 26 , 6039–6042.
i -Pr
OTBS
O
CH 3
i -Pr
OTBS
CH 3 CHO
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
Ar = Br
Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989 , 111 , 6431–6432.
i -Pr
OTBS
O
CH 3
i -Pr
OTBS
OHC CH 3
CH 2 Cl 2 , –78 °C
CH 2 Cl 2 , –78 °C
MABR = CH 3 Al(OAr) (^2)
MABR
Schoenen, F. J.; Porco, J. A.; Schreiber, S. L. Tetrahedron Lett. 1989 , 30 , 3765–3768.
O
CH 3
CH 3
CH 3
AcO H
CH 3
AcO OAc
n
Matt Mitcheltree
Pinacol Rearrangement
CH 3
CH 3
CH 3
O
OTIPS
OCH 3
OH
O
OTIPS
CH 3 O
HO
CH 3
CH 3
CH 3
O
HO
CH 3
CH 3
CH 3
CH 3
HO
HO OH
Ingenol
- Kuwajima and Baran both used pinacol-type rearrangements in their syntheses of ingenol.
Al(CH 3 ) (^3)
CH 2 Cl (^2)
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.
TMSO
CH 3
O N^3
O O
Cl (^2) Ti
CH 3
N 3
N
CH 3
OH
O
N
(±)-Stemonamine Zhao, Y. M.; Gu, P. M.; Tu, Y. Q.; Fan, C. A.; Zhang, Q. W. Org. Lett. 2008 , 10 , 1763–1766.
TiCl (^4)
CH 2 Cl (^2) –78! 0 °C
After cationic rearrangement, the resulting cation may be intercepted by elimination of an adjacent proton:
TsO (^) CH 3
CH 3 CH^3
H H
AcOH, AcOK
Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971 , 93 , 1746–1757.
CH 3
CH 3
CH 3
H CH^3
CH 3
HCH 3
80 °C, 8 h
"-bulnesene
OOH
CH 3
CH 3
CH 3
H
OCH 3
H
OTIPS
Al(CH 3 ) (^3)
N
N 2
CH 3
O
O
Cl (^2) Ti
CH 3
OH O^ N^3
- By elimination of a #-silyl group:
Hwu, J. R.; Wetzel, J. M. J. Org. Chem. 1992 , 57 , 922–928.
TMS
OH CH 3
CH 3
CH 3 H
O
TMSCH^3 CH 3
CH 3
TMS
CH 3
H
CH 3
CH 3
FeBr (^3)
–60 °C
CH 3
H
CH 3
CH 3
CH 3
H
CH 3
CH 3
O
(–)-Solavetivone
t -BuOH
CrO 2 Cl (^2)
LA
- Or by attack with an endogenous nucleophile.
CH 3 OMs
CH (^3) TMSO H CH (^3)
CH 3
CH 3
H
CH 3
TMSO
H
MgI (^2) HN(TMS) (^2)
CH 3
CH 3
CH 3
O
CH 3
CH 3
CH 3
OHC
H
H
H
H
OHC
(+)-Isovelleral
Bell, R. P. L.; Wjnberg, J. B. P. A.; de Groot, A. J. Org. Chem. 2001 , 66 , 2350–2357.
CH 3
HO
O
O O
CH 3
O TMS
CH 3
CH 3
CH 3
OTBS
O
CH 3
CH 3
CH 3
CH 3
CH 3
O OTBS
O O
BF 3 •OEt (^2)
Kuwajima
Baran
CH 2 Cl (^2)
O
OCH 3
CH 3
CH 3 O
Matt Mitcheltree
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.
While both triflyl azide (N 3 Tf) and nonaflyl azide (N 3 Nf; N 3 SO 2 n -C 4 F 9 ) 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.
OSiR (^3)
R
R 3 SiO
R
N
Nf R^3 SiO^ N Nf R
O HN
Nf R
H H
N 3 SO 2 C 4 F 9 H 2 O
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
O
NHNf
O
NHNf
O
NHNf
Substrate Product Yield
OTIPS
O
O
CH 3
CH 3
CH 3
O O
CH 3 CH 3
CH 3
O (^) NHNf
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
CH 3
OTMS
CH 3
OTMS
CH 3
N 3 Nf
N 3 Nf
N 3 Nf
O NHNf
CH 3
O NHNf
O NHNf
CH 3
NNf
TMSO
CH (^3) single diastereomer
d.r. = 67 : 33
d.r. = 55 : 45
- The resulting N -acyl sulfonamide can be converted to alcohol, ester, or carboxamide products.
O
NH
SO 2 C 4 F 9
OH
OCH 3
NH 2
O
O
LAH
Et 2 O, 0!23 °C, 20 min
HCl (0.3 M)
20% CH 3 OH–PhCH (^3) 110 °C, 3 h
SmI (^2) THF, 23 °C, 30 min
Mitcheltree, M. J.; Konst, Z. A.; Herzon, S. B. Tetrahedron 2013 , 69 , 5634–5639.
–N 2
CH 3 CN
–N 2
CH 3 CH 3
Matt Mitcheltree
Synthesis of regiodefined silyl-enol ethers
Silyl-enol ethers are appealing substrates for ring contractions because they can be synthesized regioselectively.
O
CH 3
OTMS
CH 3 CH 3
OTMS
Conditions Yield A : B
A B
LDA, TMSCl 74 99 : 1
Et 3 N, 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.
Conditions
- Silyl-enol ethers can also be formed by 1,4-addition to !,"-unsaturated carbonyls.
O
OTBS
CH 3
CH 3
CH 3
MgBr
CuBr•S(CH 3 ) (^2) TMEDA, TMSCl (^) TBSO
CH 3
CH 3
CH 3
OTMS
Nozawa, D.; Takikawa, H.; Mori, K. J. Chem. Soc. Perkin Trans. 1 , 2000 , 2043–2046.
OTES
i -Pr
OTES
i -Pr 90%
Li, NH (^3)
t -BuOH, THF
Macdonald, T. L. J. Org. Chem. 1978 , 18 , 3621–3624.
TIPSO CH 3 CH 3
Br
O
O
N BO
Ph Ph
o -Tol
H
TIPSO CH
3
H O
O
CH 3
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.
HNTf (^2) –78 °C 96%, 97% e.e.
Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004 , 126 , 4800–4802.
