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Paul Hanson Research Group
Friday Problem Set
Pradip K Maity
(02-01-13)
Semipinacol Rearrangement in Natural
Product Synthesis
2 Definition of Semipinacol Rearrangement
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Scheme1: Classical Pinacol Rearrangement
Scheme 2: Original Definition of Semipinacol Rearrangement
Pinacol rearrangement is the acid-catalyzed
transformation of 1,2-diols to ketones or
aldehydes by 1,2-migration of a C–C or C–H
bond toward the vicinal carbocation.
The term “semipinacol” was first coined by
Tiffeneau in 1923. It is a special type of
pinacol rearrangement in which the tertiary-secondary 1,2-diol undergoes an unusual
1,2-migration toward the secondary center,
rather than the tertiary one.
Zhen-Lei Song, Chun-An Fan, Yong-Qiang Tu Chem. Rev. 2011, 111, 7523–7556.
3 Different Types of Semipinacol Rearrangement
Scheme 3: Type I Rearrangement
Scheme 4: Type II Rearrangement
Zhen-Lei Song, Chun-An Fan, Yong-Qiang Tu, Chem. Rev. 2011, 111, 7523–7556.
Semipinacol rearrangement are categorized into
four types based on electrophilic carbon center.
Type I:
• Rearrangement of 2-heterosubstituted alcohols
and their derivatives.
• Good leaving groups such as OMs, OTs, Cl, Br, I,
N2, SR, and SeR are usually attached to the
electrophilic carbon center.
• 1,2-migration is facilitated by the loss of the
leaving group under either acidic or basic
conditions.
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Type II:
Rearrangements of allylic alcohols and their
derivatives.
• The electrophilic carbon center generated by the
addition of an electrophile to a C=C bond.
• Intermolecular rearrangements by initiate
halogeniums, selenium cations, and Brønsted and
Lewis acids electrophiles.
• Electrophiles such as oxocarbeniums,
thiocarbeniums, and iminiums mainly undergo
intramolecular rearrangements, known as the
Prins pinacol rearrangement.
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4 Different Types of Semipinacol Rearrangement
Scheme 6: Type III Rearrangement
Scheme 7: Type IV Rearrangement
Zhen-Lei Song, Chun-An Fan, Yong-Qiang Tu, Chem. Rev. 2011, 111, 7523–7556.
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Q uic k T im e ™ a nd a d e c o m p re s s o ra re ne e d e d to s e e th is p ic ture .Q uic k T im e ™ a nd a d e c o m p re s s o ra re ne e d e d to s e e th is p ic ture .
R4 C2
3,2-migration
R3 C3
2,3-migration
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Type III:
• Rrearrangement of 2,3-epoxy alcohols and their derivatives (Scheme 6).
• The electrophilic carbon center corresponds to either carbon of the oxirane, and the
migration is driven by acid-promoted epoxide ring-opening.
• Rearrangement can proceed via 1,2-, 2,3-, or 3,2-migration, depending on the structural
features of the substrate and on reaction conditions.
Type IV: Rearrangements of tertiary R-hydroxy
ketones and imines (Scheme 7).
• This reaction is also known as the “acyloin
rearrangement”. Because an enolization/protonation
is impossible for tertiary-hydroxy ketones and imines.
• Rearrangements occurs by 1,2-migration of the C-C
bond toward the electrophilic carbon center of the
carbonyl or imine group.
5 Rearrangements of 2-Heterosubstituted Alcohols
Sulfonates as Leaving Group :
Corey, E. J.; Ohno, M.; Mitra, R. B.; Vatakencherry, P. A. J. Am. Chem. Soc. 1964, 86, 478.
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2N HCl
100 ºC, 24 hQuickTime™ and a
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O
O
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(CH2OH)2, Et3N
225 ºC, 24 h
O
O
O
L-proline
DMSO
Wieland–Miescher ketone
(Hajos-Parrish reaction)
6 Hart’s Total Synthesis of RP 65479
Halide as Leaving Group :
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PhCO2H, DCCI
CH2Cl2/Py
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Hart, T. W.; Guillochon, D.; Perrier, G.; Sharp, B. W.; Vacher, B. Tetrahedron Lett. 1992, 33, 5117.
N
CHO"Wittig"
N
NBS, H2SO4
1. t-BuOK, MeNCS
2. KBH4, EtOH
DEAD, TPPTHF
DEAD, TPPHgBr2, THF
N
N
S
Me
N
S
N
Me
RP 65497, A novel, potent Potassium
Channel Opener.
Potassium channel openers have
therapeutic potential in a number of
disease states such as hypertension,
irritable bladder syndrome and asthma.
7 Harding’s Total Synthesis of (±) Sirenin
(a) Harding, K. E.; Trotter, J. W. J. Org. Chem. 1977, 42, 4157.
(b) Harding, K. E.; Strickland, J. B.; Pommerville, J. J. Org. Chem. 1988, 53, 4877.
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CO2Et
1. LAH, AlCl3
2. NaH, BnBr
OBn
CH3CHClCOCl
Et3N
1. LAH, THF
2. PCC, CH2Cl2 OHC
MeH
HOBn
Halide as Leaving Group :
8 Greene’s Total Synthesis of (+)-Hirsutic Acid C
N2 as Leaving Group :
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Greene, A. E.; Luche, M. J.; Serra, A. A. J. Org. Chem. 1985, 50, 3957.
H
H
CO2Et
O
MeO2C
DME, H2O,
H
H
O
MeO2C
H
H
Me
MeO2C
CH3MgBr
HClO4, H2O
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CCl3COCl, POCl3Zn-Cu, CH2N2
Me
H
H
H
Me
MeO2C
Cl Cl
O
9 Tu’s Total Synthesis of (±)-Lycoramine and
(±)-Galanthamine
Rearrangement of Allylic Alcohol: Induced by Halonium Ions
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(a) Wang, B. M.; Song, Z. L.; Fan, C. A.; Tu, Y. Q.; Chen, W. M. Synlett 2003, 10, 1497. (b) Fan, C. A.; Tu, Y. Q.; Song, Z. L.;
Zhang, E.; Shi, L.; Wang, M.; Wang, B. M.; Zhang, S. Y. Org. Lett. 2004, 6, 4691. (c) Hu, X. D.; Tu, Y. Q.; Zhang, E.; Gao, S.
H.; Wang, S. H.; Wang, A. X.; Fan, C. A.; Wang, M. Org. Lett. 2006, 8, 1823.
NNHTs
OTBS
n-BuLi, TMEDA
OTBS
OMeOHC
OR2
R1 OMe
H
O H1. MeOCH=PPh3
2. Hg(OCOCF3)2
THF/H2O, KI OR2
R1 OMe
H
OHC
DBU, DMSO
(±)-Lycoramine (R1 = OH, R2 = H)
(±)-Galanthamine (R1 = H, R2 = OH)
OR1
R2 OMe
H
N
Me
10 Trost’s Total Syntheses of Plumericin
and Allamandin
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Rearrangement of Allylic Alcohol: Induced by Selenium Ions
(a) Trost, B. M.; Mao, M. K. T.; Balkovec, J. M.; Buhlmayer, P. J. Am. Chem. Soc. 1986, 108, 4965.
(b) Trost, B. M.; Balkovec, J. M.; Mao, M. K. T. J. Am. Chem. Soc. 1986, 108, 4974.
11 Stereocontrolled Synthesis of
Spiro Oxabicycles via Prins-Pinacol Annulation
Prins-Pinacol Rearrangement
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(a) Liebeskind, L. S.; Mitchell, D.; Foster, B. S. J. Am. Chem. Soc. 1987, 109, 7908.
(b) Mitchell, D.; Liebeskind, L. S. J. Am. Chem. Soc. 1990, 112, 291
12 Rearrangement of Epoxide
Rearrangement of Epoxide: 1,2-Migration
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13 Tsuchihashi and Suzuki’s Total Syntheses of
Avenaciolide and Isoavenaciolide
Rearrangement of Epoxide: 1,2-Migration
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(a) Suzuki, K.; Miyazawa, M.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 3515.
(b) Shimazaki, M.; Hara, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 5891.
14 Nemoto and Fukumoto’s Tandem Asymmetric
Epoxidation/Ring-Expansion Process
Rearrangement of Epoxide: 3,2-Migration
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Nemoto, H; Ishibashi, H.; Nagamochi, M.; Fukumoto, K. J. Org. Chem. 1992, 57, 1707.
15 Rearrangement of -Hydroxy Imines
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(a) Liu, Y. H.; McWhorter, W. W., Jr. J. Org. Chem. 2003, 68, 2618.
b) Liu, Y. H.; McWhorter, W. W., Jr. J. Am. Chem. Soc. 2003, 125, 4240.
16
(a) Wang, B. M.; Song, Z. L.; Fan, C. A.; Tu, Y. Q.; Chen, W. M. Synlett 2003, 10, 1497. (b) Fan, C. A.; Tu, Y. Q.; Song, Z. L.;
Zhang, E.; Shi, L.; Wang, M.; Wang, B. M.; Zhang, S. Y. Org. Lett. 2004, 6, 4691. (c) Hu, X. D.; Tu, Y. Q.; Zhang, E.; Gao, S.
H.; Wang, S. H.; Wang, A. X.; Fan, C. A.; Wang, M. Org. Lett. 2006, 8, 1823.
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