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Dihydropyran and oxetane formation via a transannular oxa- conjugate addition Steve Houghton Christopher Boddy Syracuse University Department of Chemistry June 15, 2007

Dihydropyran and oxetane formation via a transannular oxa-conjugate addition

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Dihydropyran and oxetane formation via a transannular oxa-conjugate addition. Steve Houghton Christopher Boddy Syracuse University Department of Chemistry June 15, 2007. Laulimalide. Cytotoxic marine polyketide Potential anticancer agent, similar to Taxol Stabilizes microtubules - PowerPoint PPT Presentation

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Dihydropyran and oxetane formation via a transannular

oxa-conjugate addition

Steve Houghton

Christopher Boddy

Syracuse University

Department of Chemistry

June 15, 2007

Laulimalide

Cytotoxic marine polyketide Potential anticancer agent, similar to Taxol Stabilizes microtubules Isolated from sponge in trace amounts Insufficient material for clinical development

HOO

O

OHO

O

OHH

HH

H

Pacific marine sponge Cacospongia mycofijiensis

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

HOO

O

OH

O

O

OHH

H

H

H

R

O

R

O

R

R

OH

fermentation chemical synthesis

Proposal for biosynthetic origin of dihydropyran

scytophycin Claulimalide

HOO

O

OH

O

O

OHH

H

H

H

O OH

O

O

MeOMeO

OMe

OH

O OMe

NCHO

Me

Pyran and cis olefin may form via a non-enzymatic method

OHR

O

OHR

O

OR

O

H Helimination

oxa-conjugate addition

OH

Hypothesis tested using model system

Can we form dihydropyrans via transannular oxa-conjugate addition in 20-membered rings?

Is oxa-conjugate addition a stereoselective reaction?

Kinetic or thermodynamically controlled?

O

OH

OH

O

O

OH

O

O O

OHH

oxa-conjugate additionelimination

O O

OH6,7-E

67

6,7-Z6

7

8.2 kcal/mol more stable

Energy calculations: DFT B3LYP/6-G31 d p level

Model System synthesis

Br

OH

Br

O

PCC

NaOAC, Celite

Br

OH

AllylMgBr

Et2O

Br

OTBS

TBSCl

Imidazole

Br

OTBSdioxane/H2O

O

AllylMgBr

Et2O

Br

OTBS

OH

TBSCl

Imidazole

Br

OTBS

OTBS

OsO4, NaIO4

Dioxane/H2O

Br

OTBSO

OTBS

Br

OTBS

OTBS

CO2EtP

EtOEtO

O

CO2Et

KOH, THF

Br

OTBS

OTBS

CO2HLiOH CsCO3

DMF

O

OTBS

OTBS

O

83% 91% 91%

64% 86% 99%

76%93%71%

52%

dr 1:1

OsO4, NaIO4

1,3-Diols are separable

Deprotection revealed 2 spots on TLC Characterized by Rychnovshky method by

preparing acetonides

O

OH

OH

O

TsOH

EtOH

O

OH

OH

O

+

75%

O

OTBS

OTBS

O

dr 1:1anti syn

Oxa-conjugate addition unexpected product

Highly strained trans oxetane is formed Under basic conditions diols are not reactive

O

OH

OH

O ClCH2CH2ClAmberlyst 15 H+

80oC

O O

O

H

H

63 %

Single diastereomer

Confirmed by COSY, HSQC, HMBC, NOESY

syn diastereomer

Energy calculations: DFT B3LYP/6-G31 d p level

14.2 kcal/mol higher energy than dihydropyran

Two possible mechanisms for oxetane formation

SN2 displacement Elimination/addition If SN2, anti diastereomer must produce cis oxetane

O

OH

OH2

O

H

O

O

O

H

H

O

OH

O

conjugate additionelimination

trans oxetaneKinetic Product

stereochemistry unknown, intermediate not observed

SN2 displacement

Anti diastereomer also produces trans oxetane

Since inversion of stereochemisty is not observed cannot be SN2 displacement

Mechanism must be elimination, oxa-conjugate addition

anti diastereomer 14.2 kcal/mol

O

OH

OH

OAmberlyst 15 H+

ClCH2CH2Cl

80oC

O

O

O

H

H

cis_oxetane

O

O

O

H

H

trans_oxetane

not observed

42%

13.3 kcal/mol

Energy calculations: DFT B3LYP/6-G31 d p level

higher energy than dihydropyran

E1cB-like mechanism

Elimination is likely rate determining Not reversible mechanism Intermediate is not observed

O

OH

OH2

O O

O

O

H

H

O

OH

Oconjugate addition

FAST

elimination RDS

trans oxetaneKinetic Product

stereochemistry unknown, intermediate not observed

H

Cis triene may access dihydropyrans

Olefin geometry may play role in oxetane formation

O

OH

OH2

O

H

O O

OH

O

OH

O

O

O

O

H

H

O O

OHH

elimination

elimination

E,E,E triene

E,E,Z triene

oxa-conjugate addition

oxa-conjugate addition

oxetane

trans intermediate can only give oxetane

cis intermediate may

access dihydropyran

dihydropyran

11.7 kcal/mol

3.5 kcal/mol

14.2 kcal/mol

0 kcal/mol

63% from diol

75% from carbonate

Energy calculations: DFT B3LYP/6-G31 d p level

Cyclic carbonate produces cis triene

Cis triene is generated under basic conditions from both syn and anti diastereomers

O

OH

ODBU

THF, 45 oC

O

OH

OH

O

THF, Et3N

N N

O

N N O O

O O

O

O

OH

ODBU

THF, 45 oC

O

OH

OH

O

THF, Et3N

N N

O

N N O O

O O

O

75% over 2 steps

84%

92%

cis triene via 1H NMR coupling constants

purification in progress

syn

anti

Cis triene produces new compound

Amberlyst conditions yields a new compound as shown by LC-MS

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.5 35.00.00

0.25

0.50

0.75

1.00

1.25

(x10,000,000)

329.00 (1.00)307.00 (1.00)

O

O

O

H

H

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.50.00

0.25

0.50

0.75

1.00

(x10,000,000)

329.00 (1.00)307.00 (1.00)

O

OH

O

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.50.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

(x1,000,000)

329.00 (1.00)307.00 (1.00)

trans oxetane

cis triene

uncharacterized new compound

4 hrs

Conclusions

Transannular oxa-conjugate addition can occur

High energy oxetane favored over low energy dihydropyran

Unusual regioselectivity of acid catalyzed oxa-conjugate 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