Synthesis of pyragonicin

Article abstract of DOI:10.1021/ol050997g

(Chemical Equation Presented) A stereocontrolled convergent synthesis of the annonaceous acetogenin pyragonicin (1) is presented. The key intermediates were accessed using asymmetric Horner-Wadsworth-Emmons (HWE) methodology. A reagent controlled zinc-med

Full text of DOI:10.1021/ol050997g

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2779-2781
Synthesis of Pyragonicin
Daniel Strand† and Tobias Rein*,†,‡
KTH Chemistry, Organic Chemistry, SE-100 44 Stockholm, Sweden, and AstraZeneca
R&D, DiscoVery Chemistry, SE-15185 So¨derta¨lje, Sweden
tobias.rein@astrazeneca.com
Received May 2, 2005
ABSTRACT
A stereocontrolled convergent synthesis of the annonaceous acetogenin pyragonicin (1) is presented. The key intermediates were accessed
using asymmetric Horner Wadsworth Emmons (HWE) methodology. A reagent controlled zinc-mediated stereoselective coupling, joining the
two highly functionalized intermediates 3 and 4, then provided the core structure.
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The annonaceous acetogonins class of natural products
constitutes a growing number of about 400 isolated members
that has attracted much attention from both chemists and
biologists in recent years.1 This interest emanates from the
structural diversity and potent biological effects exhibited
by these structures, including antimicrobial, pesticidal, and
more importantly cytotoxic properties. Pyragonicin was
isolated in 1998 by McLaughlin et al. and was proposed to
have the structure 1.2 Structurally it belongs to the nonclas-
sical subgroup of acetogenins together with, e.g., pyranicin
(2),2 mucocin,3 and muconin.4 As part of our continuing
studies of the acetogenins, we wished to develop a synthetic
route to pyragonicin to provide material for structural
comparison purposes and for further investigation of activity.
two fragments: the butenolide fragment 4, which is identical
to that used in our recent synthesis of pyranicin (2),5a and a
tetrahydropyran (THP) fragment 3, similar to an intermediate
in the pyranicin synthesis but differing in the length of the
aliphatic chain. As illustrated in Scheme 1, we planned to
obtain THP 3 from the simpler THP derivative 5, which in
turn is accessed from meso-dialdehyde 86 via an asymmetric
Horner-Wadsworth-Emmons (HWE) desymmetrization (5
steps, 62% overall). Butenolide 4 is constructed from rac-6
by a parallel kinetic HWE resolution and a subsequent
reaction sequence involving a stereoconvergent Pd-catalyzed
substitution. We envisioned the coupling of fragments 3 and
4, with a concomitant installation of the C13 stereocenter,
using the reagent-controlled, zinc-mediated addition of
alkynes to aldehydes developed by Carreira and co-workers.7
(1) For reviews, see: Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat.
Prod. 1999, 62, 504-540. (b) Zafra-Polo, M. C.; Figadere, B.; Gallardo,
T.; Tormo, J. R.; Cortes, D. Phytochemistry 1998, 48, 1087-1117. (c)
Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G.; Appendino, G.
Chemtracts 1998, 11, 803-827.
(2) Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L. Tetrahedron
1998, 54, 5833-5844.
(3) Shi, G.; Alfonso, D.; Fatope, M. O.; Zeng, L.; Gu, Z.-m.; Zhao, G.-
x.; He, K.; MacDougal, J. M.; McLaughlin, J. L. J. Am. Chem. Soc. 1995,
117, 10409-10410.
(4) Shi, G.; Kozlowski, J. F.; Schwedler, J. T.; Wood, K. V.; MacDougal,
J. M.; McLaughlin, J. L. J. Org. Chem. 1996, 61, 7988-7989.
(5) (a) Strand, D.; Rein, T. Org. Lett. 2005, 7, 199-202. For another
synthesis of 2, see: (b) Takahashi, S.; Kubota, A.; Nakata, T. Org. Lett.
2003, 5, 1353-1356.
(6) Available in 5 steps (57% overall) from cyclohexadiene; for details,
see: Vares, L.; Rein, T. J. Org. Chem. 2002, 67, 7226-7237.
(7) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4, 2605-
2606 and references therein.
In our retrosynthetic analysis of pyragonicin (Scheme 1),
we identified a key disconnection at C12/C13 resulting in
† KTH.
‡ AstraZeneca.
10.1021/ol050997g CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/02/2005

Scheme 1. Retrosyntetic Analysis of Pyragonicin
Scheme 3. Endgame
The butenolide moiety of annonaceous acetogenins is known
to be prone to base-induced epimerization.10 However, in
aprotic solvents at ambient temperature, Et3N has been shown
not to cause epimerization of the butenolide stereocenter.11
With this precedent at hand, we used the Carreira
conditions for the coupling. Pleasingly, the reaction pro-
ceeded cleanly, albeit to 40% conversion based on 4,12 using
an excess of reagents,13 1.5 equiv of aldehyde 3, and 1.0
equiv of acetylene 4. It should be noted that both unreacted
3 and 4 could potentially be recovered from the reaction
mixture, but 4 is difficult to separate from the desired product
11, which makes the recycling of 4 less practical than 3.
Instead, the separation was effected at a later point (see
below). An exact quantification of the stereoselectivity could
not be achieved because of the ∼1:10 mixture of alkene
isomers and the presence of 4, but at no point in the
remaining steps of the synthesis could we detect any minor
stereoisomer attributed to C13, indicating a selectivity of 13R:
13S g 95:5.14
This reaction has previously been shown to proceed in the
presence of unprotected propargylic alcohols.8
In the synthetic direction, ester 55a was subjected to a
one-pot DIBAL reduction/Wittig reaction, providing the
olefinated product 9 in good yield with moderate E:Z
selectivity (∼1:10) (Scheme 2). Selective deprotection of the
Scheme 2. Synthesis of the Pyragonicin THP-fragment
The final steps then proceeded as expected (Scheme 3).
Diimide reduction of a mixture of 11 and 4 gave an
inseparable mixture of the corresponding reduced products.
Global deprotection using aqueous HF afforded pyragonicin
(1) in 34% yield over three steps, along with readily separated
(10) Mild conditions such as TBDMSOTf, pyridine, and 4-DMAP have
been shown to cause partial epimerisation: (a) Latypov, S.; Franck, X.;
Jullian, J.-C.; Hocquemiller, R.; Figadere, B. Chem. Eur. J. 2002, 8, 5662-
5666. See also: (b) Yu, Q.; Wu, Y.; Wu, Y.-L.; Xia, L.-J.; Tang, M.-H.
Chirality 2000, 12, 127-129. (c) Duret, P.; Figadere, B.; Hocquemiller,
R.; Cave, A. Tetrahedron Lett. 1997, 38, 8849-8852.
(11) Marshall, J. A.; Jiang, H. J. Org. Chem. 1999, 64, 971-975.
(12) As determinded by 1H NMR analysis after filtration through a short
plug of silica.
primary silyl ether 9 by treatment with activated alumina9
followed by a Dess-Martin oxidation gave the desired
pyragonicin THP-fragment 3 in good yield.
A key step in the synthesis is the stereoselective joining
of THP-fragment 3 and butenolide fragment 4 (Scheme 3).
(13) Because of the small scale, an excess of reagents were used:
Zn(OTf)2, 2.0 equiv; (-)-NME, 3.0 equiv; and Et3N, 5.0 equiv.
(14) The C13 stereocenter was assigned by analogy with a similar
transformation5a and similar syntheses of 1,4-dihydroxy-2-alkynes using the
Carreira methodology.8
(8) Amador, M.; Ariza, X.; Garcia, J.; Ortiz, J. Tetrahedron Lett. 2002,
43, 2691-2694.
(9) Feixas, J.; Capdevila, A.; Guerrero, A. Tetrahedron 1994, 50, 8539-
8550.
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Org. Lett., Vol. 7, No. 13, 2005

butenolide 12 (51%), thus accounting for 85% of the total
amount of the butenolide fragment 4 used in the coupling
with 3.
intermediates from rac-acrolein dimer (6) (overall yield
5.5%). A key feature of the synthesis is a mild, stereoselec-
tive coupling reaction using Carreira’s asymmetric acetylide
addition with a substrate bearing an adjacent unprotected
hydroxyl group and a base-sensitive butenolide moiety. The
Carreira addition should be of general use for late stage
fragment coupling in syntheses of annonaceaous acetogenins
containing a 1,4-diol subunit.
The spectroscopic data of 1 (IR, 1H and 13C NMR) were,
within the normal error limits for such data, identical to those
reported by McLaughlin. However, there was a strong
discrepancy in the optical rotation;15 this discrepancy is
similar to what has been found for pyranicin (2).5a,b An
authentic sample of pyragonicin was not available to us for
purposes of direct comparison. To ensure that the C34
stereocenter was not epimerized in the coupling step, we
employed Figade`re’s method10a to confirm that, within limits
of detection, no epimerization had occurred.16
Full details of this study, as well as studies directed toward
the synthesis of related acetogenins, will be reported in due
course.
Acknowledgment. We thank AstraZeneca R&D So¨der-
ta¨lje for financial support, Ulla Jacobsson for NMR expertise,
and Professor Paul Helquist for helpful suggestions regarding
the manuscript, as well as stimulating discussions.
In conclusion, we have developed a stereoselective syn-
thesis of the proposed structure of pyragonicin with the
longest linear sequence comprising 16 isolated intermediates
from cyclohexadiene (overall yield 6.4%) and 16 isolated
Supporting Information Available: Characterization
data and experimental procedures for all new materials (1,
3, 9, 10, and 12). This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) Our synthetic material: [R]25 +10.5 (c 0.125, CHCl3); natural 1
D
25
[R]D -25.6 (c 0.008, CHCl3).2 In this context, it should be noted that a
large variation has been noted for the optical rotation of natural jimenizin,
a structurally related annonaceous acetogenin.
(16) See Supporting Information for further details.
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