acid catalysed rearrangement of fused alkylideneoxetanolsccc.chem.pitt.edu/wipf/current...

Acid Catalysed Rearrangement of FusedAlkylideneoxetanols

Paul J Hickford, James R. Baker, Ian Bruce and KevinI. Booker-Milburn

Organic Letters 2007, 9 (23), 4681

Lisa Johnstone @ Wipf Group 1 2/17/2008

Abstract

• Synthesis of complex aza fused tricyclic lactones– Maleimide [5+2] cycloaddition/Norrish II cascade– Acid catalysed rearrangement of 3-oxetanol

N

H3COO

O

N

O

HO

OH

O N

O

HPhOCO

hv

MeCN

PhCO2H

PhMe, MgSO4


Norrish Type II

• Photochemical intramolecular abstraction of a γ-hydrogen by theexcited carbonyl compound to produce a 1,4-biradical as a primaryphotoproduct– Intramolecular recombination – cyclobutanes– Fragmentation – enol and alkene


Initial Work

• Extensively studied intermolecular [2+2] reaction oftetrahydrophthalic anhydride (X = O) and imides (X = NH, NMe) withalkenols– Extremely efficient– High yielding– Excellent stereoselectivity

• Natural progression of methodology – intramolecular variant

X

O

O

X = O, NH, NMe

OH

hv, MeCN

1-2 h, 90 -100 %

X O

O

HO

H

Booker-Milburn et al Eur. J. Org. Chem. 2001, 1473


High-Stereoselectivity - Explained

• High Stereoselectivity in favour of exo-isomer• Formation of 1,4 biradical adduct

– Exsist as two conformers (17 a and 17 b)– Interconverable by free rotation– Electrostatic replusion of oxygen lone pairs in 17 b favours 17 a

• Exo isomer – major product


Initial Work

• Exclusive formation of tricyclic azepine

• First example of formal [5+2] cycloaddition reaction of non-arylimides– Could be used in rapid construction of perhydroazaazules

N

O

O

hv, MeCN

1.5 h, 92 %

X O

OX

N

O

O


Mechanism

• Direct [2+2] onto excited amideresonance structure to give azwitterionic intermediate

• Spontaneous fragmentation toyield the product– Alkene geometry supports this

mechanism– stepwise process would allow

bond rotations and give epimericproducts

N

O

O

N+

O

O-

N+

O

-O

N

O

O

H

Fragmentation

[2+2]

hv


Application of Methodology to Total Synthesis- I

• Model Studies towards homoerythrinan alkaloids eg robustine

• Unexpected result – favours [2+2] addition– [5+2] TS less favourable– Require molecular modelling to help elucidate factors controlling the

switch in mode of cycloaddition

O

O N

MeO

N

O

O

N

O

O

H

NO

OH

1:3.75

20 % 75 %


Application of Methodology to Total Synthesis- II

• Synthesis of CDE skeleton of (-)-Cephalotaxine• Derivatives in Phase III for treatment of chronic myelogenous leukaemia• Formal [5+2] maleimide photocycloaddition sequence

O

ON

RO

OCH3

H

R = H, (-)-CephalotaxineR=

OOH

OH

Homoharringtonine

N

RO

OCH3

H

O

O

N

O

O

RO

N

O

O

H

RO

HO

HO

Br

TBDPSO

OH

i) TBDPSCl, Im, DMAP

ii)a) tBuLi, b)oxetane, BF3.Et2O

N

O

O

TBDPSO

N

TBDPSO

OCH3

H

O

ODEAD, PPh3

NH

O

O

i) TBAFii) hv, MeCN

3.5:166 %78 %72 %


Application of Methodology to Total Synthesis

• ABCD Tetracyclic Core of Neotuberostemonine– Human cough remedies and antihelminthics– [5+2] cycloaddition as key step to synthesise ABC ring system

N

H

HH

OO

H

H

H

O

H

O

A

B

C

D

E

N

H

HH

OCH3

H

H

O

H

O

H

O

H

O

NO O

N

H

H

H

H

O

H

O

OO

H

O

H

O

CO2H

H

O

H

O

O

O

H

H

Booker-Milburn et al ACIE, 2003, 42, 1642


Application of Methodology to Total Synthesis

HO

H

O

NO O

NH

H

H

HO

H

O

OO

HO

H

O

CO2H

HO

H

O

OO

H

H

OH

OH

O

CN

CN

O

CO2H

CO2H

O

HO

H

O

OH

NH

H

H

HO

H

O

OO

Cl Cl

Cl Cl

i) MsClii) KCN KOH, EtOH pTSA

EtMgBr, CuBr.DMS

i) EtOCOCl

ii) NaBH4 DIAD, PPh3

hv Zn, AcOH

75 % 85 % 93 %

63 %84%89 %

60 % 86 %


Second Iteration – Substituted Maleimides

N

R

R

O

O

N+

-O

OR

R

N

R

R

O

O

N

H3CO

Cl

O

O

NCl

O

N

Cl

H3CO

O

O

OOH

H

N

H3CO

Cl

O

O

N

O

Cl

O

O.

.N

O

Cl

O

HO..

H

hv, pyrex

hv, 40 mins

hv, 10 mins

hv, 2 h

95 %

95 %

84 %

3.5:1

Methoxymaleimide [5+2]/Norrish II Cascade

Excitation of X togive Y whichundergoes 1, 5 Habstraction to givediradical

Recombinationgives Z

Recombination of theradicals occurs form theleast hindered,CONVEX face of theazelene system – verystereoselective


Title Paper – Unexpected Rearrangements• Investigating further reactivity

of oxetane dervatives– Unusual behaviour observed

• Reduction/dechlorination canbe carried out with Zn/AcOH– OAc ester initially proposed– coupling constants

• oxetanol J = 6Hz• Product J = 12 Hz

– Acid cat. Rearrangement

• Nucleophillic ring opening ofoxetane ring– Followed by transannular

amide cleavage– Rationalised by Relief of ring

strain

N

Cl

Cl

O

ON

O

O

Cl

Cl

N

O

O

66 % 90 %

Zn, AcOHhv, MeCN

N

O

OOH

H

O N

O

HAcO

N

O

OOAc

H

N

O

O+OH

HH

AcO-

N

O

OH

H

AcO

OO

NH

O

O

AcO

Zn, AcOH

60 %

X


Reaction Scope

• Continuous flow reactor– Gram quantities of oxetanes to be

obtained

• Initial ring opening occurs mainlyby SN2 (minor diastereomer fromcompeting SN1 pathway)

• Inversion of stereochemistry ofreacting centre (confirmed by X-ray crystallography of 11)

• pTSA gave incorporation of OTs


Ring Opening of Oxetanes

• Alternative nucleophiles– Enabled isolation of initial oxetane

ring opened product to aidmechanism and structureelucidation

• Cl anion from LiCl sufficientlynucleophilic for ring opening

• 2-substituted (R = CH3) oxetanesdo not undergo ring openingreactions (cf with acid cat.opening)– Nucleophilic attack at 2Y oxetane

centre is severely restricted –SN2mechanism under non-acidicconditions


Summary

• Concerted [5+2]/Norrish II photocycloaddition sequence of simple alkoxymaleimide derivatives to provide oxetane/azepine fused system– Excellent yields and stereoselctivity

• Novel acid catalysed rearrangement of oxetane-fused azepines to complexlactone fused azatricycles


acid catalysed rearrangement of fused alkylideneoxetanolsccc.chem.pitt.edu/wipf/current...

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