pubs.acs.org/joc
Total Synthesis and Absolute Stereochemistry of
Integric Acid
Dennis C. J. Waalboer, Henri A. van Kalkeren,
Mark C. Schaapman, Floris L. van Delft, and
Floris P. J. T. Rutjes*
Institute for Molecules and Materials, Radboud University
Nijmegen, Heyendaalseweg 135, NL-6525 AJ Nijmegen,
The Netherlands
Received August 26, 2009
FIGURE 1. Structures of integric acid (1), eremoxylarins A (2b)
and B (2a), 07H239-A (3), and xylarenals A (4a) and B (4b).
xylarenal A,7 no total syntheses have been developed to
access this valuable compound class. In addition, the abso-
lute configuration of integric acid was determined by the
synthesis of the corresponding PGME amides. However, the
stereochemistry of the chiral center at C40 in the side chain
could not be assigned. Basic hydrolysis of the ester afforded
(E)-2,4-dimethyloct-2-enoic acid (8) with an optical rotation
of [R]2D2 þ9.5 (c 0.42, MeOH), which is only indicative of
(S)-stereochemistry at C40.8
Preliminary structure-activity relationship (SAR) studies
through chemical modification of the natural product itself
have been reported, but these efforts were severely hampered
by the instability of the R,β-unsaturated aldehyde.9 Clearly, a
total synthesis of integric acid, which allows for the incorpora-
tion of the unsaturated aldehyde moiety at a late stage, would
give access to more relevant derivatives of 1 for biological
studies. Herein we describe a total synthesis of integric acid
and the determination of the absolute stereochemistry at C40.
Inspired by the synthesis of xylarenal A by Bonjoch and
co-workers,7 we envisioned to synthesize integric acid (1)
as shown in Scheme 1. Cleavage of the ester bond, protection
of the carboxylic acid as the dioxolane, and masking of the
R,β-unsaturated aldehyde moiety as an allyl group reveal the
advanced intermediates 6 and 8. To unambiguously assign
the side chain stereochemistry, both C40 diastereoisomers of
1 had to be synthesized and consequently both enantiomers
of 8 starting from hexanal. Intermediate 6 can be traced back
to the Wieland-Miescher ketone (7) via oxidation of the
corresponding dienyl acetate, a Wittig homologation, and
allylation as the key steps.
An efficient total synthesis of integric acid is described
starting from the Wieland-Miescher ketone. Key steps
involve a one-step orthogonal deprotection/protection
strategy of a thioacetal/aldehyde and the selective oxida-
tive cleavage of a prenyl group in the presence of two
other unsaturated moieties. The synthesis of both C40
diastereoisomers of integric acid delivered unambiguous
evidence for (S)-stereochemistry at the C40 position.
In 1999 integric acid (1) was isolated from the fermenta-
tion broth of Xylaria sp.1 It inhibits 30-end processing, strand
transfer, and disintegration reactions catalyzed by HIV-1
integrase with IC50 values of 3-10 μM. The interest for HIV-
1 integrase inhibitors has steadily increased over the past few
years and efforts in this field have recently been rewarded
with FDA approval of the first HIV-1 integrase inhibitor
Raltegravir (2007).2,3 The eremophilane sesquiterpenoid
structure of 1 is also encountered in natural products such
as the NPY receptor inhibitors xylarenals A (4a) and B (4b),4
the cytotoxic 07H239-A (3),5 and eremoxylarins A (2b) and B
(2a) showing antimicrobial activity (Figure 1).6 Except for
The enantiomers of 8 were prepared in five steps from
hexanal (Scheme 2).10 The RAMP-hydrazone of hexanal
was diastereoselectively alkylated with MeI yielding 9, which
was subsequently converted to the aldehyde by oxidative
(1) Singh, S. B.; Zink, D.; Polishook, J.; Valentino, D.; Shafiee, A.;
Silverman, K.; Felock, P.; Teran, A.; Vilella, D.; Hazuda, D. J.; Lingham,
R. B. Tetrahedron Lett. 1999, 40, 8775–8779.
(2) (a) Flexner, C. Nat. Rev. Drug Discovery 2007, 6, 959–966. (b) Craigie,
R. J. Biol. Chem. 2001, 276, 23213–23216.
(3) Deeks, S. G.; Kar, S.; Gubernick, S. I.; Kirkpatrick, P. Nat. Rev. Drug
Discovery 2008, 7, 117–118.
(7) Diaz, S.; Gonzalez, A.; Bradshaw, B.; Cuesta, J.; Bonjoch, J. J. Org.
Chem. 2005, 70, 3749–3752.
(4) Smith, C. J.; Morin, N. R.; Bills, G. F.; Dombrowski, A. W.; Salituro,
G. M.; Smith, S. K.; Zhao, A.; MacNeil, D. J. J. Org. Chem. 2002, 67, 5001–
5004.
(5) McDonald, L. A.; Barbieri, L. R.; Bernan, V. S.; Janso, J.; Lassota, P.;
Carter, G. T. J. Nat. Prod. 2004, 67, 1565–1567.
(6) Shiono, Y.; Murayama, T. Z. Naturforsch. 2005, 60b, 885–890.
(8) (S)-(8), [R]D þ37.6 (c 1.0, CHCl3); see: Alcaraz, L.; Macdonald, G.;
Ragot, J.; Lewis, N. J.; Taylor, R. J. K. Tetrahedron 1999, 55, 3707–3716.
(9) Singh, S. B.; Felock, P.; Hazuda, D. J. Bioorg. Med. Chem. Lett. 2000,
10, 235–238.
(10) For an enantioselective synthesis of 8 with Evans’ chiral oxazolidi-
none methodology, see ref 8.
8878 J. Org. Chem. 2009, 74, 8878–8881
Published on Web 10/27/2009
DOI: 10.1021/jo901845r
r
2009 American Chemical Society