Myers Methods for Ring Contraction Chem 115...Myers Methods for Ring Contraction Chem 115 Ketene...
Transcript of Myers Methods for Ring Contraction Chem 115...Myers Methods for Ring Contraction Chem 115 Ketene...
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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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
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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.
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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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