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
Lisa Johnstone @ Wipf Group 2 2/17/2008
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
Lisa Johnstone @ Wipf Group 3 2/17/2008
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
Lisa Johnstone @ Wipf Group 4 2/17/2008
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
Lisa Johnstone @ Wipf Group 5 2/17/2008
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
Lisa Johnstone @ Wipf Group 6 2/17/2008
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
Lisa Johnstone @ Wipf Group 7 2/17/2008
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 %
Lisa Johnstone @ Wipf Group 8 2/17/2008
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 %
Lisa Johnstone @ Wipf Group 9 2/17/2008
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
Lisa Johnstone @ Wipf Group 10 2/17/2008
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 %
Lisa Johnstone @ Wipf Group 11 2/17/2008
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
Lisa Johnstone @ Wipf Group 12 2/17/2008
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
Lisa Johnstone @ Wipf Group 13 2/17/2008
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
Lisa Johnstone @ Wipf Group 14 2/17/2008
Lisa Johnstone @ Wipf Group 15 2/17/2008
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
Lisa Johnstone @ Wipf Group 16 2/17/2008
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
Lisa Johnstone @ Wipf Group 17 2/17/2008