fundamentally different transition metal-catalyzed reac-
tions to assemble the molecule. The chemoselectivity and
rapid introduction of complexity resulted in an enantio-
selective synthesis of clinprost that is 9 total steps from
commercially available materials, which makes this synthe-
sis at least 6 fewer steps compared to other reports.
appended alkene, a diene-ene [2þ2þ1] reaction9 was envi-
sioned with in situ reduction of the resultant ketone from
the convex face of the bicycle.9b The requisite tetraene (7)
for this reaction, although simplistic in appearance, is
complicated by the methylene adjacent to the two con-
jugated dienes. After multiple routes to synthesize tetraene
7 were unsuccessful, a palladium(0)-catalyzed decarbox-
ylation with concomitant allylic transposition was de-
signed. If successful, this excision of carbon dioxide
would be a rare report of a metal-catalyzed decarboxyla-
tion of either a bis-allylic ester or of an ester without an
anion-stabilizing group attached. Importantly, this decar-
boxylation with isomerization of the diene provides for a
major simplification of the starting material to ester 8. We
envisioned that dienoate 8 could be easily accessed via
esterification using divinyl carbinol (11) and a subsequent
aldol condensation with acrolein (9).
Scheme 1. Retrosynthesis of Clinprost
Figure 1. Structure of prostacyclin, clinprost, and analogues.
The approach we took for synthesizing clinprost (5)
takes advantage of attaching the allylic alcohol side chain,
or ω-side chain, at a late stage using a cross-metathesis
reaction (Scheme 1). This cross-metathesis approach has
been previously reported; however, in our synthesis, the
bicyclic core and upper side chain map directly onto the
target and require no further modifications. Due to the
broad range of available primary alkenes, this design will
enable facile access to analogues that explore the activity of
compounds with diverse ω-side chains in future studies. To
rapidly assemble the bicyclo[3.3.0]octene core with an
The synthesis commenced with monoesterification of
pimelic acid (12) with divinyl carbinol (11) using excess of
the inexpensive diacid starting material (Scheme 2). The
resultant monoester (13) was treated with at least two
equivalents of base to initially deprotonate the remaining
carboxylic acid and subsequently form the ester enolate.
Thedianionwas added toacroleinatꢀ78°C andquenched
cold to yield alcohol 14 as a mixture of diastereomers that
were carried forward without separation. Methylation of
the carboxylic acid of 14 using TMS-diazomethane in
methanol and dehydration via the mesylate yielded desired
diester 15 as an ∼1:1 mixture of E/Z diastereomers. The
E-isomer is formed more rapidly in this elimination, so if
this diastereomer is desired, the reaction can be stopped
after 40 min and a 10:1 ratio of E:Z isomers is isolated. The
remaining mesylate intermediate can then be subsequently
eliminated to yield a 7:3 ratio of Z:E isomers. For the sake of
this synthesis, both isomers reacted similarly in the subse-
quent step so the reaction was run to completion to form a
diastereoisomeric mixture that required no separation.
With ester 15 in hand, conditions for the decarboxylation
were examined (Table 1). We envisioned that this reaction
might be successful since metal-catalyzed rearrangements10
and substitutions11 of bis-allylic systems were known.
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