Total synthesis of pyranicin

Article abstract of DOI:10.1021/ol0479242

(Chemical Equation Presented) A stereocontrolled convergent synthesis of the annonaceous acetogenin pyranicin (1) is presented. Asymmetric Horner-Wadsworth-Emmons (HWE) reactions were used to access key intermediates. The tetrahydropyran derivative 2 was

Full text of DOI:10.1021/ol0479242

ORGANIC
LETTERS
2005
Vol. 7, No. 2
199-202
Total Synthesis of Pyranicin
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 October 8, 2004
ABSTRACT
A stereocontrolled convergent synthesis of the annonaceous acetogenin pyranicin (1) is presented. Asymmetric Horner−Wadsworth−Emmons
(HWE) reactions were used to access key intermediates. The tetrahydropyran derivative 2 was obtained via an asymmetric desymmetrization
of the meso-dialdehyde 6, and the butenolide fragment was constructed using a stereoconvergent reaction sequence involving a parallel
kinetic HWE resolution followed by a Pd-catalyzed allylic substitution. The C10/C15 1,6-diol motif was installed using Carreira’s asymmetric
acetylide addition methodology.
In recent years, the annonaceous acetogenin group of natural
products has been the focus of extensive synthetic efforts1
as a result of the interesting biological properties exhibited
by these compounds.2 Pyranicin (1) was first isolated from
the stem bark of Goniothalamus giganteus by McLaughlin
et al.3 Structurally, it belongs to the nonclassical subgroup
of annonaceous acetogenins together with other tetrahydro-
pyran (THP) acetogenins such as mucocin, pyragonicin, and
jimenicin. Interesting structural features include a unique
absolute and relative configuration of the THP stereocenters.
A previous synthesis of 1 has been reported by Takahasi et
al.1c We herein report a convergent total synthesis of 1
employing asymmetric Horner-Wadsworth-Emmons (HWE)
reactions4 as well as a stereoconvergent reaction sequence5
to install key stereocenters.
Retrosynthetically, we planned to access the substituted
THP intermediate 2 via an asymmetric HWE desymmetri-
zation of dialdehyde 6 (Scheme 1), through a strategy related
to our previously reported synthesis of the THP subunit of
mucocin.6 We planned to control the C4 stereocenter via a
parallel kinetic resolution of racemic acrolein dimer.5b In
conjunction with a Pd(0)-catalyzed stereoconvergent allylic
substitution, both enantiomers of rac-7 would overall give
the exact same intermediate 5, with simultaneous incorpora-
tion of a protective group suitable for last-step global
deprotection. The butenolide would be constructed via
condensation with a lactaldehyde derivative as described
previously.7 The C10 and C15 stereocenters would be
installed using Carreira’s stereoselective addition of TMS-
acetylene to aldehydes.8
Our synthesis began with the desymmetrization of meso-
dialdehyde 6a (readily available in five steps from cyclo-
† KTH Chemistry.
‡ AstraZeneca R&D.
(1) For recent examples, see: (a) Evans, P. A.; Cui, J.; Gharpure, S. J.;
Polosukhin, A.; Zhang, H.-R. J. Am. Chem. Soc. 2003, 125, 14702-14703.
(b) Takahashi, S.; Kubota, A.; Nakata, T. Angew. Chem., Int. Ed. 2002,
41, 4751-4754. (c) Takahashi, S.; Kubota, A.; Nakata, T. Org. Lett. 2003,
5, 1353-1356.
(4) Rein, T.; Pedersen, T. M. Synthesis 2002, 579-594.
(5) (a) Pedersen, T. M.; Hansen, E. L.; Kane, J.; Rein, T.; Helquist, P.;
Norrby, P.-O.; Tanner, D. J. Am. Chem. Soc. 2001, 123, 9738-9743. (b)
Pedersen, T. M.; Jensen, J. F.; Humble, R. E.; Rein, T.; Tanner, D.;
Bodmann, K.; Reiser, O. Org. Lett. 2000, 2, 535-538.
(2) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62,
504-540 and references therein.
(6) Vares, L.; Rein, T. J. Org. Chem. 2002, 67, 7226-7237.
(7) Marshall, J. A.; Jiang, H. J. Nat. Prod. 1999, 62, 1123-1127.
(8) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4, 2605-
2606 and references therein. NME ) N-methylephedrine.
(3) Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L. Tetrahedron
1998, 54, 5833-5844.
10.1021/ol0479242 CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/22/2004

of regioisomer 9.10 A Mitsunobu reaction followed by basic
hydrolysis of the chloroacetate then gave the inverted product
10 together with minor amounts of regioisomer 11. In the
subsequent hetero-Michael cyclization, the desired cis-cis-
THP 12 was formed with 96:4 stereoselectivity. On the basis
of work by Mart´ın and co-workers,11 we expected the (Z)-
olefin to give the trans-trans-THP 13 as the kinetically
favored product. However, we were pleased to find that
although 13 was formed initially, it rapidly equilibrated under
the reaction conditions to give the desired 12. Using toluene
as a solvent, we could also achieve tandem protective group
migration and cyclization, resulting in an essentially quan-
titative yield of 12 from a mixture of 10 and 11. The full
relative configurations of the THP rings in 12 and 13 were
unambiguously determined by 1H NOESY correlations. This
stereoselective approach to 12 is complementary to our
previous work6 in that a different relative configuration of
the THP stereocenters is obtained.
Scheme 1. Retrosynthetic Analysis
The aliphatic side chain was added via a one-pot DIBAL
reduction/Wittig olefination to give 14 (Scheme 3). Selective
P ) protective group; R* ) chiral auxiliary.
Scheme 3. Synthesis of the THP Fragment (Continued)
hexadiene6) through an asymmetric HWE olefination (Scheme
2).9 Reduction with NaBH4 in tandem with partial protective
group migration of the TBDPS group to the primary position
gave the secondary alcohol 4a together with minor amounts
Scheme 2. Synthesis of the THP Fragment
P1 ) TBDPS; P2 ) TBS.
deprotection, by treatment with activated alumina,12 followed
by Dess-Martin oxidation of the resulting primary alcohol
15, gave the corresponding aldehyde 16. The zinc-mediated
asymmetric addition of acetylides to aldehydes as published
by Carreira et al. has previously been exploited in the
stereocontrolled synthesis of chiral tetrahydrofuran deriva-
(9) For use of nor-8-phenylmenthol containing phosphonates, see:
Vaulont, I.; Gais, H.-J.; Reuter, N.; Schmitz, E.; Ossenkamp, R. K. L. Eur.
J. Org. Chem. 1998, 805-826.
(10) Initially, a 9:1 mixture of 4a and 9 was obtained, from which pure
4a was isolated in 70% yield. The remaining mixture could be reequilibrated
(DMAP, EtOH, ∆, 70%) to increase the overall yield of 4a.
(11) (a) Betancort, J. M.; Mart´ın, V. S.; Padro´n, J. M.; Palazo´n, J. M.;
Ram´ırez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570-4583.
(12) Feixas, J.; Capdevila, A.; Guerrero, A. Tetrahedron 1994, 50, 8539-
8550.
P1 ) TBDPS; R′ ) nor-8-phenylmentyl.
200
Org. Lett., Vol. 7, No. 2, 2005

selectivity.14 Subsequently, a one-pot procedure served to
first protect the propargylic hydroxyl group and then to
deprotect the TMS group to afford 18. Hydrozirconation of
the acetylene using Schwartz reagent followed by addition
of elemental iodine then gave the desired vinyl iodide 2a.
Scheme 4. Synthesis of the Butenolide Fragment
Our synthesis of the butenolide subunit began with a
parallel kinetic resolution of racemic acrolein dimer using
phosponate 19, which afforded the desired mixture of
(2E,4R)-20 and (2Z,4S)-21 as product with high stereo-
selectivity (Scheme 4). A subsequent acid-catalyzed addition
of water to the vinyl ethers gave the corresponding hemi-
acetals, the open chain forms of which could then be trapped
in an HWE reaction to give 22 and 23. Careful optimization
of the HWE conditions was required due to the predisposition
of the (2Z,4S)-alkene 23 to lactonize under basic conditions.
Activation of the secondary alcohols through formation of
phosphinate esters 24/25 then provided substrates suitable
for the stereoconvergent Pd(0)-catalyzed allylic substitution.
In this step, the (2Z)-olefin undergoes a π-σ-π rearrange-
ment resulting in a net inversion of both the alkene geometry
and the configuration at C4, while the (2E)-olefin reacts with
overall retention at both stereogenic units. The conditions
previously developed for an analogous case5a gave unsatis-
factory results due to slow reaction and extensive â-elimina-
tion. We were, however, pleased to find that use of
neocuproine as a ligand in combination with a 1:1 mixture
of CH2Cl2/nucleophile15 as a solvent almost completely
suppressed the undesired elimination (e10%) and also
increased the reaction rate significantly. It should be em-
phasized that separation of 20/21, 22/23, and 24/25, respec-
tively, was not necessary since 24 and 25 are both trans-
formed to 5a.
tives.13 However, good levels of stereocontrol have not
previously been achieved in direct formation of syn products
from 2-formyl-THP derivatives analogous to 16. We were
delighted to find that employment of the Carreira methodol-
ogy in a stereoselective addition of TMS-acetylene to 16 gave
the propargylic alcohol 17 in good yield and diastereo-
In this context, it could be noted that although TMS-
(CH2)2- is well established as a protective group for
carboxylic acids, it has been used only sparingly as a
protective group for alcohols.16
Hydrogenation/hydrogenolysis of 5a using Pd/C in hex-
anes followed by reduction with BH3‚DMS and Dess-Martin
Scheme 5. Synthesis of the Butenolide Fragment (Continued)
Org. Lett., Vol. 7, No. 2, 2005
201

oxidation gave the corresponding aldehyde 27 in good yield
(Scheme 5). We intended to again utilize the Carreira
addition of TMS-acetylene to install the C10-stereocenter.
As indicated by literature precedence,17 this proved to be
difficult, and standard conditions gave only trace amounts
of product. However, use of excess acetylide at 60 °C in a
sealed vessel afforded the desired propargylic alcohol 28 in
good yield and with excellent diastereoselectivity.18 Con-
struction of the butenolide proceeded as expected, beginning
with a one-pot aldol addition of aldehyde 3119 followed by
removal of the TMS group with K2CO3/MeOH to give 29.
Subsequent lactonization under acidic conditions gave the
desired lactone as a diastereomeric mixture. Activation and
in situ elimination of the C33-hydroxy group was ac-
complished via formation of the bis-trichloroacetate 30,
which spontaneously gave the desired butenolide under the
reaction conditions. Finally, the propargylic alcohol could
be released upon mild hydrolytic workup without compro-
mising the integrity of the butenolide stereocenter to afford
3a.
Scheme 6. Endgame
P1 ) TBDPS; P2 ) TBS.
The complete pyranicin framework was assembled through
a Sonogashira coupling20 of 2a and 3a, giving ene-yne 32.
Finally, a selective diimide reduction followed by global
deprotection using HF in MeCN afforded pyranicin (1) in
good yield (Scheme 6). Spectroscopic properties of our
synthetic material were in all respects identical to those
reported by Takahashi.1c,21 In addition, we used Figade`re’s
method22 to confirm that, within limits of detection, no
epimerization of the C34 stereocenter had occurred.
In summary, we have developed a stereoselective and
convergent total synthesis of pyranicin (1). The longest linear
sequence comprises 19 isolated intermediates starting from
cyclohexadiene (14 from 6a), with an overall yield of 6.3%
(11.0% from 6a). Key features of the synthesis are (i)
extension and application of our strategies based on asym-
metric HWE reactions and (ii) use of Carreira’s zinc-
mediated asymmetric acetylide addition to install key
stereocenters. Further studies directed toward the synthesis
of related acetogenins as well as evaluation of biological
properties will be reported in due course.
(13) (a) Kojima, N.; Maezaki, N.; Tominaga, H.; Yanai, M.; Urabe, D.;
Tanaka, T. Chem. Eur. J. 2004, 10, 672-680.
(14) Since intermediates 14-18, 2a, and 32 were carried through the
synthesis as ∼1:10 (E):(Z) mixtures, an exact quantification of the selectivity
of the TMS-acetylide addition has not been performed. However, 1H NMR
analysis indicates g95:5 diastereoselectivity. The relative configuration was
assigned by analogy with the literature.8
(15) TMS(CH2)2OH could be recovered through bulb-to-bulb distillation
of the crude product in 80% yield.
(16) Burke, S. D.; Pacofsky, G. J. Tetrahedron Lett. 1986, 27, 445-
448.
Acknowledgment. We thank AstraZeneca R&D So¨der-
ta¨lje for financial support, Susanne Olofsson and Ulla
Jacobsson for providing NMR expertise, professor Shunya
Takahashi for kindly sharing copies of NMR spectra, and
professor Paul Helquist for stimulating discussions.
(17) Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2003, 5, 3197-3199.
(18) Diastereomeric ratio of 28 was determined by 1H and 19F NMR
analysis of the corresponding (+)- and (-)-MTPA derivatives. The relative
configuration was assigned by analogy with literature.8
Supporting Information Available: Characterization
data and experimental procedures for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima, S.
Tetrahedron 1989, 45, 5767-5790.
(20) Marshall, J. A.; Piettre, A.; Paige, M. A.; Valeriote, F. J. Org. Chem.
2003, 68, 1771-1779.
(21) Takahashi et al.1c confirmed McLaughlin’s original assignment3 of
the relative and absolute configuration of pyranicin. There is, however, a
strong discrepancy in the optical rotation reported for the natural product
and that of synthetic material: natural material, [R]D23 -9.7 (c 0.01, CHCl3);
synthetic material (Takahashi), [R]D23 +19.5 (c 0.55, CHCl3); our synthetic
OL0479242
(22) Latypov, S.; Franck, X.; Jullian, J.-C.; Hocquemiller, R.; Figade`re,
B. Chem. Eur. J. 2002, 8, 5662-5666.
23
material, [R]D +21.1 (c ) 0.24, CHCl3).
202
Org. Lett., Vol. 7, No. 2, 2005