Transcript Total Synthesis of Spiculoic Acid A

SPICULOIC ACID A
Understanding its Biogenesis through its Biomimetic Total Synthesis
Atahualpa Pinto and Christopher N. Boddy
Department of Chemistry, Syracuse University, Syracuse, NY 13244
Biomimetic Synthesis of Route 2 Linear Precursor
Abstract
Spiculoic Acid A, a polyketide natural product, was recently isolated from the marine sponge Plakortis angulospiculatus.
The specific objective of our research is to investigate the mode of action of dehydratase (DH) domains in
polyketide biosynthesis. Two conceivable routes may be hypothesized concerning Spiculoic Acid A's biosynthesis.
One containing an unusual dehydration mechanism has been proposed that leads to a β,γ-unsaturated thioester
intermediate. A more appealing alternative involves a dehydration intermediate that would resemble the normal
enzyme catalyzed product. To examine the latter's viability as a biosynthetic precursor its biomimetic synthesis is
being carried out.
Introduction
H
O
H
HO
O
Spiculoic Acid A
RETROSYNTHESIS
Diels-Alder
H
OTMS
OTMS
O
H
HO
OEt
O
O
O
OEt
Extended Enolate Precursor
Spiculoic Acid A
SYNTHESIS
•
•
•
•
Marine polyketide from the sponge Plakortis angulospiculatus.
Anticancer activity.
Highly congested ring system. 2 quaternary carbons.
Biosynthesis likely occurs in 2 stages:
•Linear chain via Polyketide Synthase (PKS).
•Cyclic core via post-PKS tailoring – Diels-Alder reaction.
O
i
ii
O
83%
OH
iii
O
81%
O
E/Z = 17 : 1
Ph 3P
i
O
• Linear chain extension in PKS is analogous to fatty acid biosynthesis:
O
i
1
iv
O
iii
O
OH
ii
O
O
O
ii
Ph 3P
O
O
2
OH
2 Potential Polyketide Synthase Pathways
ROUTE 1
O
iii
Reagents: (i) 1, toluene, 120oC, overnight; (ii) DIBAL-H, CH2Cl2, -78oC, 1hr; (iii) IBX; (iv) 2.
INITIALLY PROPOSED
• Abnormal dehydration product.
• 2 stereocenters in product.
RO
O
v
O
O
RO
O
O
vi
N
OR'
vii
N
O
O
Bn
viii
R=H
R = TBS
ix
Bn
R' = H
R' = TFA
R = TBS
R=H
3
x
OTMS
OTMS
O
xiii
xi
OR
O
ROUTE 2
xii
xiv
WE PROPOSE
• Normal dehydration product.
• Extended enolate is linear precursor to
cyclization product.
• 1 stereocenter in product.
• Favorable electronics for Diels-Alder reaction.
Each PKS route leads to different Diels-Alder substrates.
OTMS
OTFA
R =TFA
R=H
O
O
xv
H
O
O
O
O
HO
H
O
Spiculoic Acid A
Reagents: (v) 3; (vi) TBSCl, Imidazole; (vii) DIBAL-H; (viii) (CF3CO)2, Pyr; (ix) TBAF; (x) LDA; (xi) TMSCl,
Imidazole; (xii) LiOH (aq); (xiii) IBX; (xiv) 1; (xv) TBAF, D.