Total synthesis of jerangolid D

Article abstract of DOI:10.1021/ja0691728

A short and convergent synthesis of jerangolid D is described. As key steps, a Blaise reaction is employed to construct the lactone ring, a diastereoselective multicomponent Sakurai condensation leads to the dihydropyran ring, and the skipped diene is ass

Full text of DOI:10.1021/ja0691728

Published on Web 02/23/2007
Total Synthesis of Jerangolid D
Jirˇ´ı Posp´ısˇil and Istva´n E. Marko´*
De´partement de Chimie, Baˆtiment LaVoisier, UniVersite´ catholique de LouVain, Place Louis Pasteur 1,
B-1348 LouVain-la-NeuVe, Belgium
Received January 4, 2007; E-mail: marko@chim.ucl.ac.be
Scheme 1. Synthesis of Lactone 6
Jerangolids A, B, D, E, and H (Figure 1) are secondary
metabolites produced by the myxobacterium Sorangium cellulosum
(strain So ce 307), a myxobacterium isolated in 1987 in the soil of
Jerusalem.1 In vitro tests suggested that jerangolid A (1) and D (2)
might be potential antifungal agents (other jerangolid derivatives
were not tested), since they exhibit interesting activities against
the developing cells of Hansenula anomala and Mucor hiemalis
(∼70 ng/mL), Pichia membranaefaciens, Debaryomyces hansenii,
and Trichosporon terrestre (0.1-0.4 µg/mL), and Trichoderma
hamata, Botritis cinerea, and Candida albicans (4-7 µg/mL). The
mechanism of their action is believed to be similar to that of
ambruticin,2 another well-known myxobacterium isolate. However,
even in the case of ambruticin, its mode of the action is not clear.
Despite their promising antifungal properties, no total synthesis of
any member of this class of natural products has been disclosed so
far.3
Scheme 2. Synthesis of Pyran 8
Figure 1. Members of the jerangolid natural products family.
Herein we report a short and convergent total synthesis of
jerangolid D. At the onset of this project, it was decided that our
approach to 2 should be easily adaptable to the synthesis of various
structural analogues of 2. Hence, it was envisioned that jerangolid
D would derive from three fragments: lactone 6, sulfone 7, and
dihydropyran 8 (Figure 2). These fragments would then be
ultimately connected via a modified Julia and a Kociensky-Julia
olefination.4
â-hydroxynitrile 10, which was reacted with methyl bromoacetate
in the presence of activated zinc dust.6 To our delight, the Blaise
reaction proceeded smoothly and furnished the desired â-ketoester
11 in 78% yield. Interestingly, the free hydroxyl group was tolerated
under the reaction’s conditions.7 The Lewis acid mediated one-pot
cyclization/enol ether formation8 furnished lactone 12 in 84% yield.
Finally, FeCl3-promoted deprotection of the benzyl group9 com-
pleted the synthesis of the left-hand fragment 6.
The construction of the right-hand portion 8 was based upon
the diastereoselective three-component Sakurai condensation pro-
tocol10 recently developed in our laboratory (Scheme 2). Accord-
ingly, the readily available ether 1511 and aldehyde 17 were mixed
with allyltrimethylsilane at -78 °C and a catalytic amount of
Figure 2. Retrosynthesis of jerangolid D.
The synthesis of lactone 6 is described in Scheme 1. Thus,
Et2AlCN mediated epoxide 9 opening5 gave an easy access to the
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10.1021/ja0691728 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Synthesis of Sulfone 7 and First Julia Coupling
aldehyde 26. Finally, fragments 25 and 26 were reacted under the
standard Kociensky-Julia olefination conditions14 yielding jerangol-
id D 2 in 54% yield and >95:1 E/Z selectivity.
In summary, we have accomplished the first total synthesis of
jerangolid D in 22 steps (12 steps in the longest linear sequence)
and 6.1% overall yield (14.5% in the longest linear sequence)
starting from the commercially available epoxide 9, Roche ester
20, methacrylate 13, and ethyl lactate 16. While the synthesis of
the left-hand fragment 6 was based upon a Blaise reaction (four
steps, 46.7% overall yield), the Eastern ketone 8 was assembled
using a diastereoselective multicomponent Sakurai condensation
(eight steps, 51.2% overall yield). The synthesis of jerangolid D
analogues as well as other members of the jerangolid family is
currently in progress in our laboratory.
Acknowledgment. We are grateful to Dr. P. Washausen
(Helmholtz Zentrum fu¨r Infektionsforschung) for kindly supplying
us with spectral data of jerangolid D and with a sample of the
natural product itself. Financial support of this work by the
Universite´ catholique de Louvain, Rhodia Ltd. (studentship to J.P.)
and SHIMADZU Benelux (financial support for the acquisition of
a FTIR-8400S spectrometer) is gratefully acknowledged.
TMSOTf was added. The syn-syn adduct 18 was obtained as a
single stereoisomer in 80% yield. Ring closing metathesis followed
by TBS removal and oxidation of the resulting alcohol then
accomplished the synthesis of the right-hand subunit 8. The C7-
C9 remnant 7 was prepared from the Roche ester 20 in four steps
and 97% overall yield (Scheme 3).
Having established an easy access to all three fragments, we then
focused our efforts on their union, and a Julia olefination reaction
between sulfone 7 and ketone 8 was selected (Scheme 3). It was
envisioned that the stereoselective formation of the trisubstituted
C9-C10 olefin could be accomplished via the SmI2-mediated
reductive elimination12 of the â-benzoyloxysulfones 22. Initially,
a one-pot condensation between 7 and 8 followed by the in situ
benzoylation of the generated adducts was attempted. Surprisingly,
this sequence proved to be irreproducible and therefore a two-steps
procedure had to be used.13 The SmI2-mediated reductive elimina-
tion of the sulfones 22 then furnished the desired olefin 23 in good
yield and excellent E/Z selectivity.
Note Added after ASAP Publication: After this paper was
published ASAP on February 23, 2007, the Supporting Information
was updated with additional (and corrected) experimental details
for 21A and 23A and NMR spectra for 19A and 23. Typographical
errors and proton misassignments were also corrected. The revised
Supporting Information was published March 7, 2007.
Supporting Information Available: Characterization data for all
new compounds and experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Scheme 4. Completion of the Total Synthesis of Jerangolid D
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