23 Sigma Tropic Seminario Org III

8/3/2019 23 Sigma Tropic Seminario Org III

1/19

2,3-Sigmatropic Rearrangements in Organic Synthesis

October 25, 2006

Matt Haley

Crimmins Group


2/19

Sigmatropic Rearrangements-concerted pericyclic reactions traditionally thought to be governed by orbital symmetry

-a group attached by a sigma bond migrates to the terminus of an adjacent pi-electron system

2,3-sigmatropic rearrangements:

-can be defined as a thermal isomerization that proceeds through a six-electron, five-membered

cyclic transition state

-thermally allowed sigmatropic process according to the Woodward-Hoffman Rule*

XY

XY Y

X

5-membered cyclic transition state

2,3-sigmatropic rearrangements discussed:

-2,3-Wittig rearrangements

-Mislow-Evans rearrangement

-Additional 2,3 rearrangements

*Chem. Rev. 1986, 86, 885-902


3/19

2,3-Wittig Rearrangement(anionic)

O O O

O

G

Me

G = C CH

C Me

n-BuLi

THF, -85 CGHO

Me

99% ee99% ee

O

G

G = Ph

C CH

C TMS

n-BuLi

THF, -85 CGHO

Me

95~98% ee100% ee100% ee

Me

Chem. Rev. 1986, 86, 885-902

erythro

threo

A general trend is observed that E-alkenes

show threo selection and Z-alkenes show

Erythro selection. Exceptions include

Substrates where G = CO2H and Ph

-regiospecific carbon-carbon bond formation and allylic transposition of oxygen function

-generation of specific olefin geometries

-stereoselective creation of vicinal chiral centers

-transfer of chirality

-competition is seen with 1,2-shift, dependent on substrate structure and rxn

temperatureDiastereoselection Study


4/19

O

G

Me

O

G

Me

GHO

Me

GHO

Me

O

H

H

GMe

H

O

H

G

HMe

H

O

H

G

HH

Me

O

H

H

GH

Me

threoerythro

Diastereoselectivity:Proposed Transition States

Chem. Rev. 1986, 86, 885-902

Nakai and Mikami Marshall, Houk, and Wu

J. Org. Chem.1990, 55, 1421-1423

endo exo

Transition structure based onMP2/6-31+G computations:

sterics place substituents

preferentially in the exo position-acceptors like carbonyls

and electropositive groups

like silyl ethers prefer endo

position

Cation plays large role


5/19

Piers, et al. Organic Letters,2000, 2, 1407-1410

Me

OH

H

Me

Me KH, Bu3SnCH2I

Me

O

H

Me

Me

SnBu3

-diterpenoid from the cyathane family

-characterized by Ayer and Taube in 1972

-anti-fungal and promotes synthesis of nerve growth factor

M e

HO

1. Me 2NNH 22. CSA (equil.)

71% (2 s teps)

Me

HN

N

1 . K D A ,

2. AcOH, NaOAc, H 2O

69% (2 steps)

M e3Ge

Me

HO

Me 3GeI

1 . Na O M e , 6 6 %2. LDA, MeI, 85%

3 . N IS ,9 0 %4. BuLi, 86%

Me

OH

H Me

CHO

O

Me

HO

Me

H

Sarcodonin G

Me


6/19

Piers, et al. Organic Letters,2000, 2, 1407-1410

Me

O

H

Me

Me BuLi

88% (2 steps)

H

Me

O

H

Me

Me

Me

O

H

Me

Me

Me

H

Me

Mequench

HOH H


7/19


8/19

Mislow-Evans(neutral)

Acc. Chem. Res.1974, 7, 147-155

SO

SO O

S

R RR

R3P:

O

-it is proposed that the rearrangement proceeds exclusively through a concerted mechanism

-equilibrium lies largely to the left, sulfonate not detectable by NMR

-increased heating can result in 1,3-shift of sulfoxide:

S Ph

O

!

Ph S

O


9/19

J. Org. Chem.1989, 54, 2779-2780

There is a very high E-olefin selectivity when there issubstitution to the sulfoxide (substitution at R1)

R1 X

H

R3R2

SOR4

R1

R2

X

H

OsR4

R3

R1 > R2

R1 OSR4

X

R3

R2

Olefin Geometry


10/19

Synthesis of the Imine Ring System of Pinnatoxins

OO

OH

Me

N

Me

OHO M e

H

R

Me

Pinnatoxins: A: R = CO2H C: R =

B: R =CO2

-

NH3+

CO2-

NH3+

-pinnatoxins structurally elucidated by Uemura et al. in 1995

-structurally unique cyclic imine, stable to aqueous acids

Organic Letters, 2005, 7, 1629-1631

O

OPMBO

OAc

N

Me

Me

O O

O

PivO

PMBO

SO

O

O

O

PMBO

PivO Me

Me

OH

cascade Claisen-Mislow-Evans


11/19

Construction of Cascade Reaction Precursor

Organic Letters, 2005, 7, 1629-1631

from ascorbic acid

O

HO

OHO

1. LAH, 98%

2. NaH, PivCl3. I2, Ph3P, ImH, 74% (2 steps) PivO

IA

O

O

O

TIP S O

MgBr1. , 9 3 %

2. OsO4, N a I O43. TP AP, N MO, 68% (2 s teps)

O O

OOTIPS

O

1. LDA; Et2Zn ;A , DMPU

2. PhNTf2, KHMDS

80% (2 steps )O O

OOTIPS

TfO

PivO

1. P MBOCH2C H 2C H 2ZnX, Pd0

, 7 5 %

2. TBAF, 91%

3. Swern

4. (S)-methyl p-tolyl sulfoxide, LDA

5. TMSCl, KHMDS

6. LDA, 65% (4 steps)

O O

OOTIPS

TfO

Piv O

O O

O

Piv O

PMBO

SO


12/19


13/19

O

Me

HO H

O

O

O

H

OMe

H

Me

MeH

M e

M eH

TBDPSO

O

HO

Me

H

Me

MeH

M e

M eH

Ph3

PO

H

OH

O TMS

O

OTBS

TIPSO

H

Me

H

+

(+)-Milbemycin D

-milbemycins first reported in 1975 by Mishima

-among the most potent antiparasitic and insecticidal agents known

-notable synthetic challenges include spiroketal moiety and hexahydrobenzofuran

Crimmins et al. J. Am. Chem. Soc.1996, 118, 7513-7528

Additional 2,3-Sigmatropic RearrangementsSynthesis of (+)-Milbemycin D


14/19

O

1. P h3P=CHCO2Et, 98%2. LAH

3. TB SCl, 95% (2 steps)

TBSO

H C C C H O1 . , 9 8 %2 . LA H , 9 8 %

M e

OTBS

Me

O TBSOH OH

+

1. SAE

2. Swern3. MeMgCl

4. Swern

73% (4 steps)Me

O TBS

M e

OTBSO O

+O O

1.5 : 1

M e

OTBSO

O

LD A , T M S C l

M e

OTBSOTMS

TMSO

mC P B A

60% (2 steps)

M e

OTBSO

TMSO

HO PhSeCl, 7 8%O

OR

H

OH

H

M e

SePh

OTBS

Preparation of 2,3-Rearrangement Precursor

Crimmins et al. J. Am. Chem. Soc.1996, 118, 7513-7528


15/19


16/19

O

MeMe

H

O

Bakkenolide A

Additional 2,3-Sigmatropic Rearrangements ContdSynthesis of Bakkenolide A

-Approximately 50 bakkanes isolated from plants to date

-they are sesquiterpenoids possessing a cis-hydrindane skeleton

with two quat. centers

-biological activities include selective cytotoxicity, antifeedant effectsand inhibition of platelet aggregation

Organic Letters, 2004, 6, 3345

J. Am. Chem. Soc.1977, 99, 5453


17/19

Me

Me

O

CHSnC 4H9

Cl

KotBu84%

Me

O

CHSnC4H 9

Me

KOH

78%

M e

O

M eM e

O

M e

+

OsO4, NaIO4

46 %

only syn pdt

taken on

M e

O

OM e

Me

O

O

Me 1. K O t Bu , 6 3 %

2. H 2/ Pd - C , 9 3 %O

H

Me

M e

L i

H

Me

M e

HO60%

PB r3

H

Me

M eBr

Synthesis of Bakkenolide A

H

MeMe

Br S

O

O

HN HN C

S

SCH3

NaH

75% (2 steps) H

Me

Me

SSCH3

NNHTs

J. Am. Chem. Soc.1977, 99, 5453


18/19

H

Me

Me

SSCH 3

NNHTs

H

Me

Me

SSCH3

N

TsN

H

Me

Me

S

N

T sN

SCH 3H

Me

Me

S

N

Ts N

SCH 3 H

Me

Me

SCH3

S

NaH

62%

2,3-Sigmatropic RearrangementSynthesis of Bakkenolinde A

H

MeMe

SCH 3

S

HgO, HgCl2, H 2O

H

MeMe

SCH 3

O

H2SeO3 O

MeMe

H

O


19/19

Additional Interesting 2,3 Rearrangements

SeAr*

Ar=

Fe

NMe2

Me

N

OMe

Ts

mCPBA or

Ti(OiPr)2, DIPT Me O H

Ph SeR

NHTs

*

R = OH , tBuOCl, then TsNHLi 90% ee

Angew. Chem. Int. Ed.2000, 39, 3740

NN2

O

( )m

( )n Cu(acac)2

C6H6, refluxN

H

O( )m

( )n

NO

N2

Cu(acac)2

C6H6, refluxN

O

H

J. Chem. Soc., Perkin Trans. 1.2001, 3325

23 Sigma Tropic Seminario Org III

Documents

Transcript of 23 Sigma Tropic Seminario Org III