Synthesis of cis-Solamin using a permanganate-mediated oxidative cyclization

Article abstract of DOI:10.1021/ol026669n

(graph presented) cis-Solamin (1) and its diastereoisomer 14 have been synthesized in 13 steps using the diastereoselective permanganate-promoted oxidative cyclization of 1,5-dienes to create the tetrahydrofuran diol core. Notably, no protecting groups are required during the stages of fragment assembly.

Full text of DOI:10.1021/ol026669n

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3715-3718
Synthesis of cis-Solamin Using a
Permanganate-Mediated Oxidative
Cyclization
Alexander R. L. Cecil and Richard C. D. Brown*
Department of Chemistry, UniVersity of Southampton, Highfield,
Southampton SO17 1BJ, UK
rcb1@soton.ac.uk
Received August 5, 2002
ABSTRACT
cis-Solamin (1) and its diastereoisomer 14 have been synthesized in 13 steps using the diastereoselective permanganate-promoted oxidative
cyclization of 1,5-dienes to create the tetrahydrofuran diol core. Notably, no protecting groups are required during the stages of fragment
assembly.
Since the identification of the Annonaceous acetogenin
uvaracin,1 isolated from the roots of UVaria accuminata, as
an in vivo active antitumor agent, there has been significant
interest in the isolation and biological evaluation of aceto-
genins from Annonaceae (custard-apple family).2 In addition
to potent cytotoxic antitumor activity, Annonaceous aceto-
genins have also displayed a variety of other interesting
biological effects that include anthelmintic, antimalarial,
antimicrobial, antiprotazoal, and pesticidal activities.2 Con-
sequently, significant effort has been devoted toward their
synthesis and a number of total syntheses have appeared in
the literature.3-5 However, the vast majority of these synthetic
approaches have focused on the natural products containing
trans-2,5-disubstituted tetrahydrofuran (THF) rings. In con-
trast, there has been relatively little published on the
stereoselective synthesis of the corresponding cis-THF
compounds.4,5
Figure 1. Approach to the synthesis of mono-THF acetogenin cis-
solamin (1).
cis-Solamin (1), is a mono-THF acetogenin isolated from
the roots of a tropical fruit tree Annona muricata, which
possesses cis-2,5-disubstitution of the THF core (Figure 1).6
The relative stereochemical relationship of the THF-diol
portion of 1 was determined to be threo/cis/threo from
analysis of the NMR data, although the absolute stereochem-
istry of this part of the molecule could not be defined.
Recently, syntheses of 1 and its diastereoisomer 14 were
reported, and the structure of cis-solamin was assigned as 1
on the basis of the optical rotation data obtained.4c Here we
report the total synthesis of 1 and 14.
(1) Jolad, S. D.; Hoffmann, J. J.; Schram, K. H.; Cole, J. R.; Tempesta,
M. S.; Kriek, G. R.; Bates, R. B. J. Org. Chem. 1982, 47, 3151-3153.
(2) For a recent review, see: Alali, F. Q.; Liu, X. X.; McLaughlin, J. L.
J. Nat. Prod. 1999, 62, 504-540.
10.1021/ol026669n CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/27/2002

Our strategy for the synthesis of cis-solamin was centered
around the permanganate-promoted oxidative cyclization of
a 1,5-diene to introduce all the stereochemistry into the THF-
diol fragment 2 in a single step (Figure 1).7 A number of
elegant approaches to the butenolide portion of the aceto-
genins had already been devised, and we chose to employ
one of them, Trost’s ruthenium-catalyzed Alder-ene reaction,
in our synthesis.3c,8
72% yield to afford an allylic alcohol, which underwent a
Johnson-Claisen rearrangement to afford enoate 5 in excel-
lent yield (Scheme 1). Conversion of 5 to the known dienoate
6 was best achieved without isolation of the intermediate
aldehyde, in a one-pot reduction-olefination reaction.10 The
synthesis of precursor 7 for the oxidative cyclization reaction
Scheme 2a
Scheme 1a
a Reagents and conditions: (a) KMnO4 (1.4 equiv), AcOH (8
equiv), Adogen 464 (0.1 equiv), EtOAc, from -30 to 0 °C.
a Reagents and conditions: (a) CH2dCHMgBr/THF; (b) CH3C-
(OEt)3, 135 °C; (c) DIBAL-H; toluene, -60 °C, then added to
(EtO)2POCH2CO2Et, NaH, THF, from -60 °C to room temperature;
(d) NaOH, NaHCO3, MeOH-H2O; (e) (COCl)2, DMF; (f) (2S)-
10,2-camphorsultam, n-BuLi, THF.
was completed by hydrolysis of 6 and activation of the
resulting unsaturated acid as the acid chloride followed by
reaction with lithiated (2S)-10,2-camphorsultam.
The synthesis of diene 6, required for the key oxidative
cyclization, started from commercially available aldehyde 4
and followed a modification of a published procedure.9
Addition of vinyl Grignard to 4 proceeded in an unoptimized
(3) For lead references, see ref 2. For a recent review on the synthesis
of Annonaceous acetogenins covering the period from 1996-1997, see:
(a) Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G.; Appendino, G.
Chemtracts: Org. Chem. 1998, 11, 803-827. For a selection of recent
approaches to the total synthesis of Annonaceous acetogenins, see: (b) Hoye,
T. R.; Ye, Z. J. Am. Chem. Soc. 1996, 118, 1801-1802. (c) Trost, B. M.;
Calkins, T. L.; Bochet, C. G. Angew. Chem., Int. Ed. 1997, 36, 2632-
2635. (d) Neogi, P.; Doundoulakis, T.; Yazbak, A.; Sinha, S. C.; Sinha, S.
C.; Keinan, E. J. Am. Chem. Soc. 1998, 120, 11279-11284. (e) Makabe,
H.; Tanaka, A.; Oritani, T. Tetrahedron 1998, 54, 6329-6340. (f) Yu, Q.;
Wu, Y. K.; Ding, H.; Wu, Y. L. J. Chem. Soc., Perkin Trans. 1 1999, 1183-
1188. (g) Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett. 1999,
1, 2025-2028. (h) Kuriyama, W.; Ishigami, K.; Kitahara, T. Heterocycles
1999, 50, 981-988. (i) Marshall, J. A.; Jiang, H. J. J. Org. Chem. 1999,
64, 971-975. (j) Ruan, Z. M.; Mootoo, D. R. Tetrahedron Lett. 1999, 40,
49-52. (k) Hoppen, S.; Baurle, S.; Koert, U. Chem.-Eur. J. 2000, 6, 2382-
2396. (l) Wang, Z. M.; Tian, S. K.; Shi, M. Eur. J. Org. Chem. 2000, 349-
356. (m) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem. Soc.
ReV. 2000, 29, 109-118. (n) Dixon, D. J.; Ley, S. V.; Reynolds, D. J.
Angew. Chem., Int. Ed. 2000, 39, 3622-3626. (o) Avedissian, H.; Sinha,
S. C.; Yazbak, A.; Sinha, A.; Neogi, P.; Sinha, S. C.; Keinan, E. J. Org.
Chem. 2000, 65, 6035-6051. (p) Ruan, Z. M.; Dabideen, D.; Blumenstein,
M.; Mootoo, D. R. Tetrahedron 2000, 56, 9203-9211. (q) Albarella, L.;
Musumeci, D.; Sica, D. Eur. J. Org. Chem. 2001, 997-1003. (r) Hu, T. S.;
Yu, Q.; Wu, Y. L.; Wu, Y. K. J. Org. Chem. 2001, 66, 853-861.
(4) For stereoselective syntheses of cis-mono-THF acetogenins, see the
following. 15,20-Di-epi-cis-solamin: (a) Makabe, H.; Tanaka, A.; Oritani,
T. J. Chem. Soc., Perkin Trans. 1 1994, 1975-1981. Muricatetrocin A:
(b) Ba¨urle, S.; Peters, U.; Friedrich, T.; Koert, U. Eur. J. Org. Chem. 2000,
65, 2207-2217. cis-Solamin: (c) Makabe, H.; Hattori, Y.; Tanaka, A.;
Oritani, T. Org. Lett. 2002, 4, 1083-1085.
Figure 2. Byproducts from the KMnO4 oxidation of diene 7.
The key oxidative cyclization reaction proved to be
somewhat more problematic than we had anticipated on the
(7) (a) Klein, E.; Rojahn, W. Tetrahedron 1979, 21, 2353-2358. (b)
Baldwin, J. E.; Crossley, M. J.; Lehtonen, E.-M. M. J. Chem. Soc., Chem.
Commun. 1979, 918-919. (c) Walba, D. M.; Wand, M. D.; Wilkes, M. C.
J. Am. Chem. Soc. 1979, 101, 4396-4397. (d) Walba, D. M.; Edwards, P.
D. Tetrahedron Lett. 1980, 21, 3531-3534. (e) Spino, C.; Weiler, L.
Tetrahedron Lett. 1987, 28, 731-734. (f) Walba, D. M.; Przybyla, C. A.;
Walker, C. B. J. J. Am. Chem. Soc. 1990, 112, 5624-5625. (g) Kocienski,
P. J.; Brown, R. C. D.; Pommier, A.; Procter, M.; Schmidt, B. J. Chem.
Soc., Perkin Trans. 1 1998, 9-39. (h) Brown, R. C. D.; Hughes, R. M.;
Keily, J.; Kenney, A. Chem. Commun. 2000, 1735-1736. For oxidative
cyclizations of 1,5-dienes using other metal-oxo species, see: (i) Carlsen,
P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981,
46, 3937-3938. (j) de Champdore, M.; Lasalvia, M.; Piccialli, V.
Tetrahedron Lett. 1998, 39, 9781-9784. (k) Piccialli, V.; Cavallo, N.
Tetrahedron Lett. 2001, 42, 4695-4699. (l) Donohoe, T. J.; Winter, J. J.
G.; Helliwell, M.; Stemp, G. Tetrahedron Lett. 2001, 42, 971-974. For
related oxidative cyclizations of hydroxy olefins, see: (m) Walba, D. M.;
Stoudt, G. S. Tetrahedron Lett. 1982, 23, 727-730. (n) Tang, S. H.;
Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5299-5302. (o) Tang, S. H.;
Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5303-5306. (p) McDonald,
F. E.; Towne, T. B. J. Am. Chem. Soc. 1994, 116, 7921-7922. (q)
McDonald, F. E.; Towne, T. B. J. Org. Chem. 1995, 60, 5750-5751.
(8) Trost, B. M.; Muller, T. J. J.; Martinez, J. J. Am. Chem. Soc. 1995,
117, 1888-1899.
(5) For syntheses of other acetogenins where one of the THF rings is
cis-2,5-disubstituted, see the following. Jimenezin (revised structure): (a)
Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett. 1999, 1, 2025-
2028. Trilobin: (b) Marshall, J. A.; Jiang, H. J. J. Org. Chem. 1999, 64,
971-975. Rollidecins C and D: (c) D’Souza, L. J.; Sinha, S. C.; Lu, S. F.;
Keinan, E.; Sinha, S. C. Tetrahedron 2001, 57, 5255-5262.
(9) Jan, S.-T.; Li, K. Q.; Vig, S.; Rudolph, A.; Uckun, F. M. Tetrahedron
Lett. 1999, 40, 193-196.
(10) Takacs, J. M.; Helle, M. A.; Seely, F. L. Tetrahedron Lett. 1986,
27, 1257-1260.
(6) Gleye, C.; Duret, P.; Laurens, A.; Hocquemiller, R.; Cave´, A. J. Nat.
Prod. 1998, 61, 576-579.
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Org. Lett., Vol. 4, No. 21, 2002

basis of results previously obtained in our group for related
oxidations.11 The conventional acetone-water system re-
turned the desired THF diol 2 in a disappointing 18% yield,
with the major isolated product being R-hydroxy-â-ketoester
9 (Figure 2). Similarly poor yields have been observed by
others for the oxidative cyclization of 1,5-diene substrates
where the olefins were either mono- or disubstituted.7b,12
final selective reduction of the 4,5-double bond could be
achieved according to the literature method by hydrogenation
over Wilkinson’s catalyst,3-5 although great care had to be
exercised in order to avoid over reduction of the butenolide
ring. We found that diimide reduction was easier to control14
and ultimately used this method to complete the synthesis
of 1.15
Due to uncertainties relating to the exact stereochemical
assignment of cis-solamin, we also synthesized diastereo-
isomeric structure 14 following the route described above
but using the (2R)-10,2-camphorsultam (Figure 3). As
Fortunately, conducting the oxidation under phase-transfer
conditions13 led to an improved yield (55%) for this pivotal
transformation that introduces the C15, C16, C19, and C20
stereocenters present in cis-solamin in one step. A small
amount of the diastereoisomeric THF-diol 8 was also
produced in the oxidation (2:8 ) 10:1 as estimated from
crude 1H NMR spectrum). We were pleased to discover that
the minor isomer was readily separated from 2 by column
chromatography. The major byproduct isolated from the
phase-transfer oxidative cyclization was the cleavage product
10 (Figure 2), which probably arose from further oxidation
of R-hydroxy-â-ketoester 9, or rather its enol tautomer.
Figure 3. Structure of compound 14.
Scheme 3a
reported by Makabe et al., the NMR spectra of diastereo-
isomers 1 and 14 were not distinguishable from each other
and data reported for cis-solamin.4c However, in contrast to
the results of Makabe, we also found that the optical rotations
of the two synthetic compounds were quite similar,16,17
although the data for 1 more closely matched the reported
value for the natural product. Therefore, we believe that
structure 1 probably corresponds to the natural product cis-
solamin; however, it is not possible to unambiguously
confirm the assignment on the basis of the optical rotation
data alone.
In summary, concise total syntheses of two cis-diastereo-
isomers of solamin 1 and 14 have been achieved, both giving
spectroscopic data consistent with that of the natural product
cis-solamin. The key step in the syntheses involved oxidative
cyclization of a 1,5-diene 7 or ent-7 using permanganate
under phase-transfer conditions. Hydroxyl protecting groups
were not required during the final assembly of the fragments.
Our current efforts are extending the oxidative cyclization
methodology to the synthesis of adjacent and nonadjacent
bis-THF acetogenins.
a Reagents and conditions: (a) NaBH4, THF, H2O; (b) TsCl,
Et3N, CH2Cl2; (c) DBU, CH2Cl2; (d) CH2dCH(CH2)9MgBr, CuI,
THF, -60 °C; (e) 3, CpRu(cod)Cl, MeOH, reflux; (f) TsNHNH2,
NaOAc, THF-H2O, 60 °C.
We found that the auxiliary was best removed from 2 by
reduction using NaBH4, whereas LiAlH4 surprisingly gave
a complex mixture of products (Scheme 3). The resulting
diol was taken forward by conversion to the epoxide 11, prior
to addition of the C3-C13 fragment in a copper-catalyzed
Grignard reaction. Notably, there was no need for protection
of the C20 hydroxyl group. The butenolide ring in 4,5-
dehydro-cis-solamin (13) was put in place using a ruthenium-
catalyzed Alder-ene reaction, which was also tolerant of the
free hydroxyl groups present in the starting materials. The
(14) Marshall, J. A.; Chen, M. J. Org. Chem. 1997, 62, 5996-6000.
(15) It is interesting to note that one of our samples of 14, prepared by
hydrogenation over Wilkinson’s catalyst, displayed two peaks in a 1:1 ratio
when run down a Chiralcel OD-H HPLC column, eluting with 5:95 i-PrOH/
hexane. The same sample only showed one set of signals in the 13C NMR
spectrum. We concluded that the new peak corresponded to a C34 epimer
of 14 (ent-1). Epimerization of C34 has previously been reported to occur
under basic conditions (see ref 17).
(16) Optical rotation was measured on an Optical Activity, Ltd.,
Automatic Polarimeter. Compound 1: [R]24D +22.6 (c 0.12, MeOH) (lit.4c
[R]21D +26 (c 0.45, MeOH)). Compound 14: [R]24D +14 (c 0.19, MeOH)
(lit.4c [R]21 +42.0 (c 0.50, MeOH)). The optical rotation for a natural
D
(11) For the synthesis of a model compound, see: Cecil, A. R. L.; Brown,
R. C. D. ArkiVoc 2001, Part (xi): Commemorative Issue in Honor of Prof.
B. S. Thyagarajan, ms. BT-336D. http://www.Arkat-usa.org/ark/journal/
Volume2/Part3/Thyagarajan/BT-336D/336d.pdf.
sample of cis-solamin was reported as +22 (c 0.55, MeOH).6 Both of our
samples of 1 and 14, for which the optical rotation data are reported, gave
single peaks by chiral HPLC under the conditions given above (see ref
15).
(12) (a) Gale, J. B.; Yu, J.-G.; Hu, X. E.; Khare, A.; Ho, D. K.; Cassady,
J. M. Tetrahedron Lett. 1993, 34, 5847-5850. (b) Bertrand, P.; Gesson, J.
P. Tetrahedron Lett. 1992, 33, 5177-5180.
(13) Brown, R. C. D.; Keily, J. F. Angew. Chem., Int. Ed. 2001, 40,
4496-4498.
(17) It has previously been observed that the optical rotation value of
acetogenins is largely due to the stereochemistry of the butenolide and, to
a lesser extent, due to the stereochemistry of the THF diol portion: Duret,
P.; Figade`re, B.; Hocquemiller, R.; Cave´, A. Tetrahedron Lett. 1997, 38,
8849-8852.
Org. Lett., Vol. 4, No. 21, 2002
3717

1
Acknowledgment. We thank the Royal Society for a
University Fellowship (R.C.D.B.). Merck Sharp & Dohme,
Syngenta, and Pfizer Central Research are also gratefully
acknowledged for unrestricted grants.
Supporting Information Available: Copies of H and
13C NMR for 1, 2, 8, and 12-14. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL026669N
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Org. Lett., Vol. 4, No. 21, 2002