paul hanson research group friday problem set … paul hanson research group friday problem set...

1

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.



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.



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.







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



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.





2N HCl

100 ºC, 24 hQuickTime™ and a

decompressorare needed to see this picture.





O

O



(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 :






are needed to see this picture.QuickTime™ and a


PhCO2H, DCCI

CH2Cl2/Py



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.









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 :





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



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




are needed to see this picture.QuickTime™ and a




(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



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



(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



13 Tsuchihashi and Suzuki’s Total Syntheses of

Avenaciolide and Isoavenaciolide






(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




Nemoto, H; Ishibashi, H.; Nagamochi, M.; Fukumoto, K. J. Org. Chem. 1992, 57, 1707.

15 Rearrangement of -Hydroxy Imines



(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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