Laulimalide Model System
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Transcript Laulimalide Model System
Dihydropyran and oxetane
formation via a transannular
oxa-conjugate addition
Steve Houghton
Christopher Boddy
Syracuse University
Department of Chemistry
June 15, 2007
Laulimalide
H
HO
O
H
O
H
O
OH
H
O
O
H
Pacific marine sponge Cacospongia mycofijiensis
Cytotoxic marine polyketide
Potential anticancer agent, similar to Taxol
Stabilizes microtubules
Isolated from sponge in trace amounts
Insufficient material for clinical development
Microtubules (green) during cell division
Producing laulimalide
Engineering of a recombinant biosynthetic pathway
Produce macrocyclic precursors by fermentation
Several synthetic transformations will have to be validated
• install the transannular dihydropyran
• 2,3-Z olefin.
Provides new rapid and efficient strategy for total synthesis
Proposal for biosynthetic origin of
dihydropyran
O
H
HO
O
H
O
H
O
OH
H
MeO MeO
O
O
OMe
H
O
O
OH
scytophycin C
O
OH
OH
O
laulimalide
R
OMe
O
elimination R
OH
O
oxa-conjugate
addition
R
H
O
H
OH
Pyran and cis olefin may form via a non-enzymatic method
Me
N
CHO
Hypothesis tested using model system
O
O
8.2 kcal/mol
more stable
OH
O
O
6
6,7-Z
7
elimination
O
OH
O
oxa-conjugate
addition
O
H
O
O
H
OH
6
7
6,7-E
OH
Can we form dihydropyrans via transannular oxa-conjugate
addition in 20-membered rings?
Is oxa-conjugate addition a stereoselective reaction?
Kinetic or thermodynamically controlled?
Energy calculations: DFT B3LYP/6-G31 d p level
Model System synthesis
Br
Br
PCC
Et2O
NaOAC, Celite
O
83%
OH
OTBS
64%
Br
Br
Et2O
OTBS
CO2Et
EtO
EtO
Imidazole
OTBS
99%
Br
OTBS
LiOH
KOH, THF
OTBS
OTBSO
OTBS
O
CO2H
CsCO3
OTBS
71%
DMF
OTBS
93%
76%
OTBS
Dioxane/H2O
52%
Br
CO2Et
Br
OsO4, NaIO4
OH
dr 1:1
O
P
OTBS
TBSCl
86%
O
91%
OH
91%
AllylMgBr
dioxane/H2O
Br
TBSCl
Imidazole
Br
OsO4, NaIO4
Br
AllylMgBr
OTBS
OTBS
O
1,3-Diols are separable
O
O
O
TsOH
OTBS
EtOH
O
O
O
+
OH
OH
75%
OTBS
OH
anti
dr 1:1
OH
syn
Deprotection revealed 2 spots on TLC
Characterized by Rychnovshky method by
preparing acetonides
Oxa-conjugate addition unexpected
product
O
O
Amberlyst 15 H+
ClCH2CH2Cl
O
O
80oC
63 %
OH
H
O
OH
H
syn diastereomer
Single diastereomer
Confirmed by COSY,
HSQC, HMBC, NOESY
14.2 kcal/mol
higher energy
than dihydropyran
Highly strained trans oxetane is formed
Under basic conditions diols are not reactive
Energy calculations: DFT B3LYP/6-G31 d p level
Two possible mechanisms for
oxetane formation
O
O
O
O
SN2 displacement
OH
conjugate
addition
elimination
H
O
H
O
O
H
OH2
OH
trans oxetane
Kinetic Product
stereochemistry unknown,
intermediate not observed
SN2 displacement
Elimination/addition
If SN2, anti diastereomer must produce cis oxetane
Anti diastereomer also produces
trans oxetane
not observed
O
O
O
O
O
O
+
Amberlyst 15 H
OH
ClCH2CH2Cl
80oC
42%
OH
H
O
H
trans_oxetane
anti diastereomer
14.2 kcal/mol
H
O
H
cis_oxetane
13.3 kcal/mol
higher energy than dihydropyran
Since inversion of stereochemisty is not observed cannot be
SN2 displacement
Mechanism must be elimination, oxa-conjugate addition
Energy calculations: DFT B3LYP/6-G31 d p level
E1cB-like mechanism
O
O
O
elimination
RDS
OH
O
O
OH
conjugate
addition
FAST
H
O
H
OH2
stereochemistry unknown,
intermediate not observed
H
trans oxetane
Kinetic Product
Elimination is likely rate determining
Not reversible mechanism
Intermediate is not observed
O
Cis triene may access dihydropyrans
O
O
O
oxa-conjugate
addition
elimination
O
trans
intermediate can
only give oxetane
H
O
O
O
OH
11.7 kcal/mol
63% from diol
14.2 kcal/mol
H
oxetane
E,E,E triene
OH
H
O
OH2
elimination
O
O
oxa-conjugate
addition
H
OH
O
H
3.5 kcal/mol
E,E,Z triene
O
cis
intermediate may
access dihydropyran
0 kcal/mol
dihydropyran
75% from carbonate
Olefin geometry may play role in oxetane formation
Energy calculations: DFT B3LYP/6-G31 d p level
Cyclic carbonate produces cis triene
O
O
O
N
N
N
O
N
O
THF, 45 oC
75% over
2 steps
84%
syn
OH
O
O
O
OH
O
N
N
OH
cis triene via 1H NMR
coupling constants
O
O
N
O
N
O
O
DBU
THF, 45 oC
THF, Et3N
OH
92%
anti
OH
O
O
purification in
progress
O
O
DBU
THF, Et3N
OH
O
Cis triene is generated under basic conditions
from both syn and anti diastereomers
O
Cis triene produces new compound
Amberlyst
conditions
yields a new
compound
as shown by
LC-MS
trans oxetane
O
O
O
O
H
O
H
cis triene
OH
4 hrs
uncharacterized
new compound
Conclusions
Transannular oxa-conjugate addition can occur
High energy oxetane favored over low energy
dihydropyran
Unusual regioselectivity of acid catalyzed oxaconjugate addition
Regioselectivity could be attributed to olefin
geometry of elimination (triene intermediate)
Acknowledgements
Dr. Christopher Boddy
The Boddy lab members
Deborah Kerwood
Department of Chemistry
Syracuse University