The tandem intramolecular silylformylation-allylsilylation and tandem aldol-allylation: Stereoselective methods for the synthesis of natural product polyol motifs - PowerPoint PPT Presentation

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The tandem intramolecular silylformylation-allylsilylation and tandem aldol-allylation: Stereoselective methods for the synthesis of natural product polyol motifs

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Title: The tandem intramolecular silylformylation-allylsilylation and tandem aldol-allylation: Stereoselective methods for the synthesis of natural product polyol motifs


1
The tandem intramolecular silylformylation-allylsi
lylation and tandem aldol-allylation
Stereoselective methods for the synthesis of
natural product polyol motifs
Leighton. J. J. Am. Chem. Soc. 2000, 122,
8587-8588 Leighton. J. J. Am. Chem. Soc. 2002,
124, 10672-10673
  • Jean-Louis Brochu
  • Department of Chemistry
  • University of Ottawa

2
Overview
  • Introduction
  • The tandem intramolecular silylformylation-allylsi
    lylation reaction
  • The tandem aldol-allylation reaction
  • Application to total synthesis
  • Summary
  • Conclusion

3
Introduction
  • Interest in polyketide macrolide-derived natural
    products with the skipped polyol structural motif
    and the development of efficient stereocontrolled
    strategies for their synthesis

Dolabelide A
4
  • First strategy

Leightons rhodium-catalyzed intramolecular
Silylformylation of alkenes
-Efforts in olefin carbonylation reactions
-Focus on the homoallylic alcohol class of
substrates
J. Am. Chem. Soc. 1997, 119, 12416-12417
5
  • Allylsilanes are well-known aldehyde allylation
    agents
  • Is a tandem carbonylation-aldehyde allylation
    possible?
  • Potential variants
  • Dicrotylsilanes
  • Alkyne substrates

1,3,5-triol
J. Am. Chem. Soc. 2000, 122, 8587-8588
6
Second strategy
The tandem aldol-allylation reaction
  • Potential variants
  • Crotylsilanes
  • Enolcrotylsilanes

J. Am. Chem. Soc. 2002, 124, 10672-10673
7
Strain release Lewis acidity
  • Responsible for spontaneous allylation
  • Concept first described by Denmarks group
  • -Distortion of the tetrahedral geometry imparts a
    strain energy which is released upon coordination
    of a Lewis base, narrowing the internal angles to
    a trigonal-bipyramidal geometry.

Internal C-Si-O angle ?90o
Internal C-Si-O angle ?95o
Organometallics, 1990, 9(12), 3015-3019
8
The tandem intramolecular silylformylation-allylsi
lylation reaction
NMR of crude 14 confirms no aldehyde
9
Proposed mechanism of rhodium-catalyzed
intramolecular silylformylation
10
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11
Validation of an intramolecular reaction
12
  • -The diastereoselectivity of the allylation is
    quite high
  • Achiral substrate provides a useful benchmark
  • diastereoselectivity (937)

13
Alkyne substrates
  • Alkynes are also well known substrates for
    silylformylation
  • The silicon-substituted carbon is no longer
    stereogenic

-Diastereoselectivity in the allylation would
have to derive from the original propargylic
stereocenter. -Thus leading to remote
1,5-stereoinduction
Angew. Chem. Int. Ed. 2001, 40(15), 2915-2917
14
First Alkyne study
0.1 mol
-Upon tandem formylation-allylation, product was
submitted to protodesilylation and the
peracetylation. - Major product is the 1,5-anti
product, which is opposite to alkene substrates.
15
Proposed model
More highly Strained complex
Destabilizing steric interaction between the
2-propyl group and the allyl group. Apical
position not possible.
16
Substrate study
Increasing steric size of propargylic substituent


17
  • A key feature
  • Both diastereotopic allyl groups can transfer and
    each lead to a different product diastereomer.
  • Selective replacement
  • of either allyl group
  • with a nontransferable
  • group would lead to a
  • stereospecific reaction.

1,5 syn
1,5 anti
18
Crotylsilylation
-Investigation of the spontaneous allylation with
dicrotylsilanes
Propionate unit
-Synthesis of di-cis-crotylsilane and
di-trans-crotylsilane were required.
J. Am. Chem. Soc. 2002, 124, 7890-7891
19
-Focused on catalytic dihydrosilane alcoholysis
as an efficient method for the silylation of the
substrate alcohols.
anti-propionate
20
Tandem silylformylation-crotylsilylation on
alkyne substrates
1,5-anti diol
anti-propionates
syn proprionate Propargylic alcohol
Highly diastereoselective
21
Transition state of the crotylsilylation on
alkene substrates
di-cis-crotylsilane
The alkyl chain of the aldehyde occupy a
pseudoaxial position
Transition state of the crotylsilylation on
alkyne substrates
di-cis-crotylsilane
22
-All attempts to prepare di-trans-crotylsilanes
have failed although trans-crotyl-phenylsilane
has been synthesized
Achiral alcohol
syn-propionate
23
Applying Evans and Brown chemistry
Pure App. 1987, 59, 879 J. Am. Chem. Soc. 1979,
101, 6120-6123
24
Rapid synthesis of a polyketide-like fragment
Separated from mixture of acetonides
5 steps from starting alcohol 31 overall yield 8
stereogenic centers
25
The tandem aldol-allylation reaction
J. Am. Chem. Soc. 2002, 124, 10672-10673
26
Polyketide chains
Envisioned the metal (MLn) would bear the desired
number of enolate fragments as well as an allyl
group. Upon completion of the aldol cascade,
intramolecular allylation of the terminal
aldehyde would halt the chain propagation. The
silicon, constrained in a five-membered ring,
possesses Lewis acidity to distort tetrahedral
geometry to tbp.
27
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28
-The strain induced in the silacycle by the
1,2-diol is essential for the reaction.
-To expand the scope of the process, cis and
trans-crotylsilanes were prepared, 55 and 56.
29
trans
syn propionate
cis
anti propionate
lt 5 simple aldehyde crotylation
Creation of 3 stereocenters.
30
-To further expand the scope of the process, (E)
and (Z)-crotylenolsilanes were prepared, 59 and
60.
61 38 yield
Z
15 simple aldehyde crotylation
30 simple aldehyde crotylation
E
Aldol reaction of 59 and 60 proceed through
boat-like transition states. Creation of 3
stereocenters.
31
Boat-like transition state through tpb orientation
Z
favored
E
favored
Computational modeling of similar transition
states done by
Denmark, S.E. J. Am. Chem. Soc. 1994, 116,
7026-7043
32
Possibility of creating 4 stereocenters in one
reaction
(Z)-enol-(Z)-crotyl silane
(Z)-enol-(E)-crotyl silane
Improved stereoselectivity
- Focus on (Z)-enol silanes due to poor results
with 60.
33
Propenol units can lead to tertiary carbinols,
found in important natural product.
lt2 direct allylation of aldehyde
cis
syn diols
trans
J. Am. Chem. Soc. 2005, 127, 12806-12807
34
lt19 direct allylation product
syn diols
35
Application in total synthesis
R Ac Dolabelide A R H Dolabelide B
Approach to the synthesis of Dolabelide A and B
Fragment synthesis by tandem silylformylation-crot
ylsilylation
Org. Lett. 2003, 5(19), 3535-3537
R Ac Dolabelide C R H Dolabelide D
Total synthesis of Dolabelide D
J. Am. Chem. Soc. 2006, accepted for publication
36
Divergent synthesis of complex polyketide-like
macrolides from a simple polyol fragment
7 chiral centers
8 chiral centers















Natural product-like macrolides
Org. Lett. 2005, 7(24), 5525-5527
37
Efficient asymmetric synthesis of ()-SCH 351448
Stereochemically-enrich with 14 chiral centers
28-membered bis-lactone Natural product
Features a new protodesilylative version of the
tandem silylformylation-allylsilylation reaction,
which provides an efficient synthesis of
1,5-syn-diols.
38
-Isolated in 2000 by researchers at the
Schering-Plough Research institute -Microbial
metabolite, Micromonospora sp -Unique ability to
specifically activate transcription of a report
construct under control of the LDL lipoprotein
receptor promoter. -Selective activators of
LDL-R transcription may be able to decrease serum
LDL levels by increasing LDL uptake by the LDL-R.
-Prevention and treatment of coronary heart
disease. -ED-50 of 25uM
39
Retrosynthetic analysis
40
Org. Lett. 2004, 6(23), 4375-4377
41
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42
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43
Summary
The tandem intramolecular silylformylation-allylsi
lylation reaction
  • Potential variants
  • Dicrotylsilanes
  • Alkyne substrates

1,3,5-triol
44
Summary
anti-propionate
5 steps from starting alcohol 31 overall yield 8
stereogenic centers
45
Summary
The tandem aldol-allylation reaction
46
Summary
(Z)-enol-(Z)-crotyl silane
(Z)-enol-(E)-crotyl silane
47
Conclusion
These operationally simple tandem reactions
provide remarkably efficient access to complex
structures with relevance to biologically
important polyketide natural products. Leighton
and co-workers continue to develop new
stereocontrolled strategies and applies them in
the synthesis of important natural products.
J. Am. Chem. Soc. 2005, 127, 12806-12807
48
Acknowledgements
Group Members Dr. Prabhat Arya Dr. Polepally
Reddy Dr. Ayub Reayi
Dr. Michaël Prakesch Dr. Stuti
Srivastava Dr. Jyoti Nandy
Dr. Ravi Naga Prasad Dr.
Deogratias Ntirampebura Michael Barnes (TO)
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