Total Synthesis and Preliminary Biological Evaluation of cis-Solamin Isomers

Article abstract of DOI:10.1021/jo049909g

An efficient total synthesis of cis-solamin (1) has been achieved in 21% overall yield and with a longest linear sequence of just 11 steps from aldehyde 8. A key feature of the approach was the use of asymmetric permanganate-promoted oxidative cyclization

Full text of DOI:10.1021/jo049909g

Tota l Syn th esis a n d P r elim in a r y Biologica l Eva lu a tion of
cis-Sola m in Isom er s
Alex R. L. Cecil,† Yulai Hu,† Mar´ıa J . Vicent,‡ Ruth Duncan,‡ and Richard C. D. Brown*,†
Department of Chemistry, The University of Southampton, Highfield, Southampton SO17 1BJ , U.K., and
Center for Polymer Therapeutics, Welsh School of Pharmacy, King Edward VII Avenue,
Redwood Building, Cardiff University, Cardiff CF10 3XF, U.K.
rcb1@soton.ac.uk
Received J anuary 15, 2004
An efficient total synthesis of cis-solamin (1) has been achieved in 21% overall yield and with a
longest linear sequence of just 11 steps from aldehyde 8. A key feature of the approach was the use
of asymmetric permanganate-promoted oxidative cyclization to introduce four of the five required
stereocenters in a single step. The use of robust and chemoselective methodology meant that the
use of protecting groups could be avoided during the assembly of cis-solamin (1) from the three
fragments 23, 6, and 4. The methodology was also applied to the synthesis of three further cis-
solamin isomers 2, ent-1, and ent-2. Cytotoxicity and hemolytic properties of cis-solamin isomers
and synthetic intermediates are reported.
In tr od u ction
products containing trans-2,5-disubstituted THF rings.
In contrast, there has been relatively little published on
the stereoselective synthesis of the corresponding cis-
THF compounds.5,6
Annonaceous acetogenins, isolated from the species
Annonaceae (custard apple family), are waxy substances
usually characterized by the presence of one or more 2,5-
disubstituted tetrahydrofuran (THF) rings connected to
a butenolide via an alkyl spacer. Many examples of these
fascinating natural products have now been reported, and
their isolation, synthesis, and biological activities have
been reviewed.1,2 The annonaceous acetogenins have been
the subject of considerable interest, primarily due to their
potent cytotoxicity,1,3 although a variety of other impor-
tant properties including insecticidal activity have also
been described.1 Consequently, significant effort has been
devoted toward the synthesis of acetogenins, and a
number of total syntheses have appeared.2,4 Most syn-
thetic approaches to acetogenins have focused on natural
cis-Solamin (1, Figure 1) provides an example of a
mono-cis-THF acetogenin, originally isolated from the
roots of a tropical fruit tree Annona muricata (popularly
known as “sour sop” or “guanabana”).7 The relative
stereochemistry within the bis-hydroxyalkyl THF (THF-
diol) unit of cis-solamin was assigned as threo/ cis/ threo
(C15/C16, C16/C19, and C19/C20) on the basis of detailed
2D NMR data and correlation with NMR data from model
compounds with known configuration. The absolute con-
figuration of the THF-diol region present in cis-solamin
(4) For a selection of approaches to the total synthesis of Annona-
ceous acetogenins: (a) Hoye, T. R.; Hanson, P. R.; Kovelesky, A. C.;
Ocain, T. D.; Zhuang, Z. P. J . Am. Chem. Soc. 1991, 113, 9369-9371.
(b) Hoye, T. R.; Ye, Z. X. J . Am. Chem. Soc. 1996, 118, 1801-1802. (c)
Hoye, T. R.; Hanson, P. R. Tetrahedron Lett. 1993, 34, 5043-5046. (d)
Figadere, B.; Chaboche, C.; Peyrat, J . F.; Cave, A. Tetrahedron Lett.
1993, 34, 8093-8096. (e) Figade`re, B. Acc. Chem. Res. 1995, 28, 359-
365. (f) Rao, A. V. R.; Reddy, K. L. N.; Reddy, K. A. Ind. J . Chem. Sect.
B-Org. Chem. Inc. Med. Chem. 1993, 32, 1203-1208. (g) Baurle, S.;
Hoppen, S.; Koert, U. Angew. Chem., Int. Ed. 1999, 38, 1263-1266.
(h) Emde, U.; Koert, U. Eur. J . Org. Chem. 2000, 1889-1904. (i)
Marshall, J . A.; J iang, H. J . J . Org. Chem. 1998, 63, 7066-7071. (j)
Marshall, J . A.; Piettre, A.; Paige, M. A.; Valeriote, F. J . Org. Chem.
2003, 68, 1771-1779. (k) Sinha, S. C.; Sinha, A.; Sinha, S. C.; Keinan,
E. J . Am. Chem. Soc. 1998, 120, 4017-4018. (l) Avedissian, H.; Sinha,
S. C.; Yazbak, A.; Sinha, A.; Neogi, P.; Sinha, S. C.; Keinan, E. J . Org.
Chem. 2000, 65, 6035-6051. (m) Trost, B. M.; Calkins, T. L.; Bochet,
C. G. Angew. Chem., Int. Ed. 1997, 36, 2632-2635. (n) Hanessian, S.;
Grillo, T. A. J . Org. Chem. 1998, 63, 1049-1057. (o) Kuriyama, W.;
Ishigami, K.; Kitahara, T. Heterocycles 1999, 50, 981-988. (p) Yu, Q.;
Wu, Y. K.; Ding, H.; Wu, Y. L. J . Chem. Soc., Perkin Trans. 1 1999,
1183-1188. (q) Ruan, Z. M.; Dabideen, D.; Blumenstein, M.; Mootoo,
D. R. Tetrahedron 2000, 56, 9203-9211. (r) Zanardi, F.; Battistini, L.;
Rassu, G.; Auzzas, L.; Pinna, L.; Marzocchi, L.; Acquotti, D.; Casiraghi,
G. J . Org. Chem. 2000, 65, 2048-2064. (s) Hu, T. S.; Yu, Q.; Wu, Y.
L.; Wu, Y. K. J . Org. Chem. 2001, 66, 853-861. (t) Zhang, H. P.;
Dabideen, D.; Pushchinska, G.; Mootoo, D. R. J . Carbohydr. Chem.
2002, 21, 411-430. (u) Dixon, D. J .; Ley, S. V.; Reynolds, D. J . Chem.
Eur. J . 2002, 8, 1621-1636.
† University of Southampton.
‡ Welsh School of Pharmacy.
(1) (a) Rupprecht, J . K.; Hui, Y. H.; McLaughlin, J . L. J . Nat. Prod.
1990, 53, 237-278. (b) Cave´, A.; Cortes, D.; Figade`re, B.; Hocquemiller,
R.; Lapre´vote, O.; Laurens, A.; Leboeuf, M. In Recent Advances in
Phytochemistry; Downum, K. R., Ed.; Plenum Press: New York, 1993;
Vol. 27, pp 167-202. (c) Zafra-Polo, M. C.; Gonzalez, M. C.; Estornell,
E.; Sahpaz, S.; Cortes, D. Phytochemistry 1996, 42, 253-271. (d) Zeng,
L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z. M.; He, K.; McLaughlin, J .
L. Nat. Prod. Rep. 1996, 13, 275-306. (e) Cave´, A.; Figade`re, B.;
Laurens, A.; Cortes, D. In Progress in the Chemistry of Organic Natural
Products; Herz, W., Kirby, G. W., Moore, R. E., Steglish, W., Tamm,
C., Eds.; Springer-Verlag: New York, 1997; Vol. 70, pp 81-288. (f)
Zafra-Polo, M. C.; Figadere, B.; Gallardo, T.; Tormo, J . R.; Cortes, D.
Phytochemistry 1998, 48, 1087-1117. (g) Alali, F. Q.; Liu, X. X.;
McLaughlin, J . L. J . Nat. Prod. 1999, 62, 504-540.
(2) For reviews of acetogenin synthesis up to 1998, see refs 1 and:
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B.; Cave´, A. In Studies in Natural Products Chemistry; Atta-ur-
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3151-3153.
10.1021/jo049909g CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/13/2004
3368
J . Org. Chem. 2004, 69, 3368-3374

Total Synthesis of cis-Solamin Isomers
SCHEME 1. Retr osyn th etic An a lysis of
cis-Sola m in (1)
F IGURE 1. Structures of threo/ cis/ threo (C15/C16, C16/C19,
and C19/C20) isomers of solamin.
could not be established from the available data, leading
the authors to conclude that its structure was either 1
or 2. Subsequently, total syntheses of 1 and 2 were
reported by Makabe et al.,5c and the structure of cis-
solamin was tentatively assigned as 1 on the basis of
optical rotation values. For the purpose of clarity we will
refer to the structure 1 as cis-solamin.
cis-Solamin analogues have considerable potential as
a new family of anticancer agents and may even be useful
as the bioactive in polymer therapeutics;8 therefore, it
was important to develop a synthetic approach to give
cis-solamin analogues and evaluate their biological prop-
erties in vitro (hemolysis and cytotoxicity). Here we
report the total synthesis of cis-solamin and three ste-
reoisomers along with preliminary in vitro cytotoxicity
and hemolytic activity data.5d
Starting from the aldehyde 8, addition of vinyl Grig-
nard afforded allylic alcohol 9, which underwent a
J ohnson-Claisen rearrangement to give enoate 10 in
excellent overall yield (Scheme 2).13,14 Elaboration of 10
to dienoate 12 was best achieved without isolation of the
intermediate aldehyde 11, in a one-pot reduction-olefi-
nation reaction,15 although care was required during the
Resu lts a n d Discu ssion
Our retrosynthetic analysis of cis-solamin (1) was
designed to take advantage of elegant ruthenium-
catalyzed methodology developed by Trost to introduce
the butenolide portion of the molecule (Scheme 1).4n,9
Strategically, the use of the highly chemoselective transi-
tion-metal-catalyzed Alder-ene reaction would minimize
the requirement for protecting groups during the final
stages of the synthesis.4n After disconnection of the
butenolide, it becomes apparent that the C3-C13 chain
could be introduced by copper-promoted opening of an
epoxide derived from the product 5 of permanganate
oxidative cyclization of a diene 7.10-12 Asymmetric induc-
tion would be provided by a chiral auxiliary present in
the 1,5-dienoate 7,10f-i prepared from a commercially
available aldehyde 8.
(10) For some examples of oxidative cyclization of 1,5-dienes using
KMnO4: (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. (i) Brown, R. C. D.; Bataille, C. J .; Hughes, R. M.; Kenney,
A.; Luker, T. J . J . Org. Chem. 2002, 67, 8079-8085.
(11) For examples of the oxidative cyclization of 1,5-dienes using
other metal-oxo species, see the following. Ruthenium: (a) Carlsen,
P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J . Org. Chem.
1981, 46, 3936-3938. (b) Piccialli, V.; Cavallo, N. Tetrahedron Lett.
2001, 42, 4695-4699. (c) Albarella, L.; Musumeci, D.; Sica, D. Eur. J .
Org. Chem. 2001, 997-1003. (d) Bifulco, G.; Caserta, T.; Gomez-
Paloma, L.; Piccialli, V. Tetrahedron Lett. 2003, 44, 3429-3429.
Osmium: (e) Donohoe, T. J .; Winter, J . J . G.; Helliwell, M.; Stemp, G.
Tetrahedron Lett. 2001, 42, 971-974. (f) de Champdore, M.; Lasalvia,
M.; Piccialli, V. Tetrahedron Lett. 1998, 39, 9781-9784. (g) Donohoe,
T. J .; Butterworth: S. Angew. Chem., Int. Ed. 2003, 42, 978-981.
(12) For related oxidative cyclizations of hydroxy olefins by metal-
oxo species, see refs 4l, 6c, and: (a) Walba, D. M.; Stoudt, G. S.
Tetrahedron Lett. 1982, 23, 727-730. (b) Tang, S. H.; Kennedy, R. M.
Tetrahedron Lett. 1992, 33, 5299-5302. (c) Tang, S. H.; Kennedy, R.
M. Tetrahedron Lett. 1992, 33, 5303-5306. (d) McDonald, F. E.; Towne,
T. B. J . Am. Chem. Soc. 1994, 116, 7921-7922. (e) McDonald, F. E.;
Towne, T. B. J . Org. Chem. 1995, 60, 5750-5751. (f) Towne, T. B.;
McDonald, F. E. J . Am. Chem. Soc. 1997, 119, 6022-6028. (g)
Morimoto, Y.; Iwai, T.; Kinoshita, T. J . Am. Chem. Soc. 1999, 121,
6792-6797. (h) Keinan, E.; Sinha, S. C. Pure Appl. Chem. 2002, 74,
93-105.
(5) For examples of the stereoselective synthesis of cis-mono-THF
Annonaceous 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. (d) For a preliminary communication of part of
this work: Cecil, A. R. L.; Brown, R. C. D. Org. Lett. 2002, 4, 3715-
3718.
(6) For syntheses of other acetogenins where one of the THF rings
is cis-2,5-disubstituted, see the following. J imenezin (revised struc-
ture): (a) Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett.
1999, 1, 2025-2028. Trilobin: (b) Marshall, J . A.; J iang, 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.
(13) J an, S.-T.; Li, K.; Vig, S.; Rudolph, A.; Uckun, F. M. Tetrahedron
Lett. 1999, 40, 193-196.
(7) Gleye, C.; Duret, P.; Laurens, A.; Hocquemiller, R.; Cave´, A. J .
Nat. Prod. 1998, 61, 576-579.
(8) Duncan, R. Nat. Rev. Drug Discov. 2003, 2, 347-360.
(9) Trost, B. M.; Mu¨ller, T. J . J .; Martinez, J . J . Am. Chem. Soc.
1995, 117, 1888-1899.
(14) Makabe, H.; Tanimoto, H.; Tanaka, A.; Oritani, T. Heterocycles,
1996, 43, 2229-2248.
(15) Takacs, J . M.; Helle, M. A.; Seely, F. L. Tetrahedron Lett. 1986,
27, 1257-1260.
J . Org. Chem, Vol. 69, No. 10, 2004 3369

Cecil et al.
SCHEME 2 a
SCHEME 3 a
a
Reagents and conditions: (a) KMnO4, AcOH, solvent, additive
(see Table 1).
a
Reagents and conditions: (a) CH2dCHMgBr/THF; (b) CH3C-
TABLE 1. Resu lts fr om th e Oxid a tive Cycliza tion of
Dien oa te 7 (See Sch em e 3)
(OEt)3, 145 °C, xylene; (c) DIBAL-H; toluene, -60 °C; (d) DIBAL-
H; toluene, -60 °C then add to (EtO)2POCH2CO2Et, NaH, THF,
-40 °C to rt; (e) NaOH, NaHCO3, MeOH-H2O; (f) (COCl)2, DMF,
CH2Cl2; (g) (2S)-10,2-camphorsultam, n-BuLi, THF; (h) NaH,
CH2Cl2, 0 °C to rt, then 11.
AcOH
(equiv)
5/16a (%)
entry
solvent
(dr)b
1
acetone/H2O/ pH 6.5 buffer
3
8
8
8
21 (6:1)
31 (6:1)
50 (nd)
55 (6:1)
62 (6:1)
75 (6:1)e
2c
3c
4c
5c
6c
CH2Cl2
toluene
EtOAc
acetone
acetone
reduction step as any remaining ester 10 coeluted with
the desired dienoate 12. The synthesis of the oxidative
cyclization precursor 7 was originally completed by
hydrolysis of 12 and activation of the resulting unsatur-
ated acid 13 as its pentafluorophenol ester prior to
substitution with the lithiated (2S)-10,2-camphorsultam.
On a larger scale, the byproduct from acylation, pen-
tafluorophenol, proved inconvenient to separate from 7
leading to the use of acid chloride 14 as the acylating
agent. The sequence used to introduce the auxiliary
proceeded in satisfactory yield, but at the expense of
three extra synthetic steps in the overall linear sequence.
Therefore a more convergent route from aldehyde 11 to
1,5-diene 7 was subsequently developed by making use
of phosphonate 15 already carrying the sultam auxil-
iary.16
16
cosolventd
a
b
Combined isolated yield of THF diols 5 and 16. Ratio of 5/16
estimated from 1H NMR. c Reaction carried out with the addition
of 10 mol % adogen 464. Acetone/AcOH (3:2). e Reaction carried
d
out without adogen 464 gave similar results.
SCHEME 4 a
a
Reagents and conditions: (a) KMnO4 (aq, 1.6 equiv), AcOH
(3 equiv), acetone, pH 6.5 buffer, -20 °C.
Prior to this work, the asymmetric oxidative cyclization
of dienoates had been shown to provide an effective tool
for the synthesis of polyether antibiotic fragments, where
the starting olefins were trisubstituted.10e-i However,
other reports on the permanganate-promoted oxidative
cyclization of dienes containing mono- and disubstituted
olefins were far less encouraging in terms of isolated
yields (5-33%).17 In fact, our first attempts to effect the
oxidative cyclization of 7 gave similarly disappointing
results (Scheme 3), isolating the desired product 5 in only
18% yield along with a major component that arose from
mono-oxidation of the enoate olefin (entry 1, Table 1).18
Other minor products included the diastereoisomeric
THF-diol 16 and acid 18 that probably resulted from
oxidative cleavage of the enol tautomer of 17. The
previously successful oxidative cyclization of a model
dienoate 19 led us to speculate that the reluctance of 7
to undergo the cyclization reaction was related to poor
solvation of the hydrophobic C21-C32 alkyl chain in
acetone/water, causing aggregation in an aqueous envi-
ronment (Scheme 4).19
To improve the solubility of the diene 7, the oxidative
cyclization reaction was investigated under phase-
transfer conditions in a variety of solvents (Table 1,
entries 2-5).20 Improved yields of the desired THF
product 5 were realized, with the best results occurring
in acetone or EtOAc using adogen 464 as phase-transfer
catalysts (entries 4 and 5). However, we ultimately found
that addition of powdered KMnO4 (1.3 equiv) to the
substrate 7 dissolved in a mixed solvent system of
acetone/AcOH (3:2) provided the conditions of choice for
the oxidative cyclization of dienoate systems of this type.
Furthermore, both the substrate and the oxidant were
(16) Oppolzer, W.; Dupuis, D.; Poli, G.; Raynham, T. M.; Bernar-
dinelli, G. Tetrahedron Lett. 1988, 29, 5885-5888.
(17) (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.
(18) The stereochemistry of the major diastereoisomer was assigned
on the basis of literature precedent for the oxidative cyclization of
closely related substrates (see ref 10f,i).
(19) 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/Thyaga-
rajan/BT-336D/336d.pdf).
(20) Brown, R. C. D.; Keily, J . F. Angew. Chem., Int. Ed. 2001, 40,
4496-4498.
3370 J . Org. Chem., Vol. 69, No. 10, 2004

Total Synthesis of cis-Solamin Isomers
SCHEME 5 a
F IGURE 2. Diastereoselective oxidation of dienoyl sultam by
-
MnO4
.
soluble in acetone/AcOH (3:2), avoiding the need for any
phase-transfer agents.
Little change in diastereoselectivity was observed
under the various conditions investigated, with a dr
estimated as 6:1 in favor of 5.21 Considering the consis-
tent dr values obtained from reactions run in solvents of
very different polarity, it seems unlikely that chelation
control is involved in determining the facial selectivity
of the initial attack upon the enoate olefin.22 Dipolar
organization of the carbonyl and SO2 groups and an s-cis-
arrangement of the CdO and C(R)-C(â) bonds would give
a conformer where approach of MnO4- from the C(â) Re-
face would be favored (Figure 2).23
Following separation of the diastereoisomeric THF-
diols 5 and 16 by column chromatography, the sultam
was removed by reduction of 5 using NaBH4 to afford
diol 21 and the recovered auxiliary (Scheme 5). Closure
of the epoxide 23 was carried out by DBU treatment of
tosylate 22, obtained by direct mono-tosylation of 21 or
more efficiently via a stannylene derivative of the 1,2-
diol. As anticipated, cuprate addition to epoxide 23
proceeded without the need for protection of the C20
hydroxyl group, affording the C3-C32 fragment 3 of cis-
solamin in 89% yield. Formal Alder-ene reaction of the
terminal olefin 3 with alkyne 4 was carried out by
refluxing the reactants and a catalytic amount of the
Ru(II) complex 26 in MeOH for 3 h,4m,9 delivering a 6:1
(NMR) mixture of products derived from addition to
either end of the alkyne. As noted previously by Trost,
the undesired minor regioisomeric adduct 25 is reluctant
to cyclize to the corresponding butenolide due to develop-
ing A1,2 strain, facilitating chromatographic separation
of the two products.
a
Reagents and conditions: (a) NaBH4, THF, H2O; (b) Bu2SnO,
C6H6 then TsCl, TBAB; (c) DBU, CH2Cl2; (d) CH2dCH(CH2)9MgBr,
CuI, THF, -60 to -20 °C; (e) 4, CpRu(cod)Cl (26), MeOH, reflux;
(f) TsNHNH2, NaOAc, THF-H2O, 60 °C.
catalyst.2 Initial attempts conducted on a small scale led
to some over reduction of the butenolide ring, and
although we were able to achieve separation of cis-solmin
(1) from the mixture by preparative HPLC, we were
concerned to observe complete epimerisation of the C34
stereocenter in one of our synthetic samples.24 We
subsequently found that diimide reduction provided a
convenient and reliable means of reducing 24 to cis-
solamin, without any detectable epimerization at C34.25
Due to our interest in the relative cytotoxicity of cis-
solamin diastereoisomers and the uncertainty regarding
the absolute stereochemistry of the THF-diol unit
present in the natural product, we also prepared the
enantiomeric C3-C32 fragment ent-3 either using the
enantiomeric chiral auxiliary or from the minor diaste-
reoisomer 16 obtained in the oxidative cyclization of
dienoate 7 (Scheme 6). The enantiomers of 1 and 2 were
also synthesized by combination of the (R)-alkyne ent-4
with intermediates ent-3 and 3, respectively.26
The four synthetic solamin isomers were indistinguish-
able from each other and natural cis-solamin on the basis
of their IR, MS, H NMR, and 13C NMR spectra, due to
1
the length and flexiblity of the chain connecting the
THF-diol and butenolide regions. Optical rotation values
obtained for each of the pairs of diastereoisomers were
also very similar and consistent with previous observa-
tions that the contribution from the butenolide ring
dominates that from a pseudosymmetrical THF region
in acetogenins.27 Although all four isomers could be
The final step in the synthesis required selective
reduction of the C4-C5 double bond, a transformation
that was well precedented in the literature using careful
catalytic hydrogenation in the presence of Wilkinson’s
(21) Diastereoselectivity was estimated by integration of the H15
and H16 signals from the major and minor diastereoisomers in the 1H
NMR spectrum of the crude reaction mixture. Determination of an
accurate dr was complicated due to the incomplete resolution of the
H16minor signal from the H15/H16major signals, leading us to initially
report a higher value of 10:1. The dr value of 6:1 was confirmed from
the isolated yields of 5 and 16.
(22) The diastereofacial selectivity observed for the oxidative cy-
clization of enantiomerically enriched N-enoyl oxazolidinones was
previously explained by dipolar organization of the substrate (see ref
10f).
(24) Evidence for epimerization of the C34 stereocentre was provided
by chiral HPLC on a Chiralcel OD-H HPLC column, eluting with
i-PrOH/hexane (5:95), which gave two peaks with a ratio of 1:1. The
same sample only showed one set of signals in its 1H and 13C NMR
spectra.
(25) Marshall, J . A.; Chen, M. J . Org. Chem. 1997, 62, 5996-6000.
(26) ent-4 was prepared from (R)-methyl lactate using the method
(23) Reiser, O. In Organic Synthesis Highlights IV; Schmalz, H.-
G., Ed.; Wiley-VCH: Weinheim, 2000; pp 11-16.
described for the synthesis of 4 (see ref 9). [R]24 ) +27.2 (c 0.85,
D
CHCl3).
J . Org. Chem, Vol. 69, No. 10, 2004 3371

Cecil et al.
SCHEME 6 a
TABLE 2. In Vitr o Cytotoxicity a n d Hem olytic
P r op er ties of Acetogen in Der iva tives
a
entry
compd
IC50 (µM)
Hbb(% control)
1
2
3
4
5
6
7
8
9
24
27
ent-27
ent-24
1
0.27 ( 0.01
3.0 ( 0.8
2.2 ( 0.4
5.5 ( 0.8
2.8 ( 0.2
7.0 ( 1.6
23.2 ( 0.1
6.4 ( 0.8
>447
84.0 ( 1.2
20.4 ( 5.0
24.7 ( 4.8
92.1 ( 1.7
7.0 ( 0.8
3.6 ( 0.7
2.9 ( 0.8
5.6 ( 0.5
1.5 ( 0.4
1.0 ( 0.6
2
ent-1
ent-2
3
10
25
>336
a
IC50 values against B16F10 murine melanoma cell line (seed-
ing density 5 × 104 cells/mL, 3% DMSO in medium) (n ) 3, mean
b
( SD). Hemolysis (% control 1% Triton X-100) at compound
concentration of 0.3 mg/mL, 3% DMSO in PBS (n ) 3, mean (
SE).
a
Reagents and conditions: (a) 4, CpRu(cod)Cl (26), MeOH,
reflux; (b) TsNHNH2, NaOAc, THF-H2O, 60 °C.
separated by chiral HPLC and were shown to be isomeri-
cally pure,28 we were unable to determine whether cis-
solamin had the structure 1 or 2 due to the lack of an
authentic sample of the natural product.
Biologica l Activity of cis-Sola m in An a logu es. To
study the relative influence of the structural and stere-
ochemical features on biological activity, the hemolytic
activity and cytotoxicity were evaluated. Understanding
the structure-activity relationship of these properties is
important in relation to the selection of a potential
candidate(s) for further development as anticancer agent-
(s). Cytotoxicity gives an indication of antitumor activity,
and the hemolysis model relates to mechanism of action
and also the potential for later intravenous administra-
tion.
In vitro cytotoxicity of acetogenin derivatives was
evaluated using an MTT assay (72 h incubation) against
B16F10 murine melanoma cell line.29 Results are ex-
pressed as a percentage of viability of cells grown in the
absence of drug, but also with 3% DMSO medium (Table
2 and Figure 3).
All acetogenin derivatives were active at µM concen-
trations except 3 and 25 (IC50 > 447 and 336 µM,
respectively). These results are consistent with the
previous observation that the terminal lactone ring is one
of the main requirements for antitumoral activity in
acetogenins.1 The unsaturated precursor 24 to cis-sola-
min (1) was most potent (IC50 ) 0.27 ( 0.01 µM). In fact,
24 was at least 10 times more active than the rest of the
acetogenins described and even 100 times more active
than ent-1 (IC50 ) 23.2 ( 0.1 µM).
F IGURE 3. Structures of acetogenin derivatives for in vitro
cytotoxicity and haemolysis studies.
(Table 2). For instance, comparison of the compounds
containing C4-C5 unsaturation (entries 1-4, Table 2)
with the corresponding saturated spacer compounds
(entries 5-8, Table 2) shows that the presence of the
double bond (reduced flexibility) leads to a marked
increase in hemolysis. In addition, comparison of 24/ent-
24 with the diastereoisomers 27/ent-27, which display
differences in the relative chirality between the central
THF-diol and butenolide units, showed a decrease in
hemolysis (going from 84 to 92% to approximately 20%).
Further studies using other models are required to better
understand structure-activity relationships of mem-
brane interactions, but these are the first to investigate
such membrane properties.
Hemolytic properties of the acetogenin derivatives
studied were also related to their chemical structures
(27) 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. Tetra-
hedron Lett. 1997, 38, 8849-8852.
(28) Each of the four isomers (1, ent-1, 2, and ent-2) gave a separate
and single peak on a Chiral CD-Ph HPLC column, eluting with i-PrOH/
hexane (15:85). Retention times: 1 (14.5 min), 2 (17.3 min), ent-1 (18.7
min), ent-2 (15.7 min). See the Supporting Information for an HPLC
trace for a mixed sample of 1 and 2.
In summary, we have completed a short and efficient
synthesis of cis-solamin (1) using an asymmetric oxida-
tive cyclization of a 1,5-diene as the key step. It has been
shown for the first time that permanganate-promoted
oxidations of substrates containing disubstituted olefins
can be achieved in high yield. The cytotoxicity and
hemolytic activity of several isomers of cis-solamin
indicated their potential for further investigation as
antitumor agents.
(29) Sgouras, D.; Duncan, R. J . Mater. Sci.: Mater. Med. 1990, 1,
61-68.
3372 J . Org. Chem., Vol. 69, No. 10, 2004

Total Synthesis of cis-Solamin Isomers
for com p ou n d 17: (obtained as a 5:1 inseparable mixture of
diastereoisomers, spectroscopic data for major isomer only) mp
66-69 °C; IR νmax (neat) 3524, 1699, 1467, 1304, 1295, 1214,
1131, 1106 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.44 (1H, td, J
) 6.5, 15.0 Hz), 5.35 (1H, td, 6.3, 15.3 Hz), 5.35 (1H, d, 7.5
Hz), 3.95 (1H, dd, J ) 5.0, 7.5 Hz), 3.92 (1H, d, J ) 7.5 Hz),
3.52 (1H, d, J ) 13.6 Hz), 3.45 (1H, d, J ) 13.6 Hz), 2.80 (1H,
td, J ) 7.3, 17.5 Hz), 2.64 (1H, td, J ) 7.2, 17.5 Hz), 2.29 (2H,
q, J ) 6.8 Hz), 2.21-2.01 (2H, m), 1.94-1.86 (5H, m), 1.49-
1.20 (22H, m), 1.16 (3H, s), 0.98 (3H, s), 0.89 (3H, t, J ) 6.8
Hz); 13C NMR (100 MHz, CDCl3) δ 203.3, 168.3, 132.1, 127.6,
76.6, 65.2, 53.0, 49.2, 48.0, 44.7, 39.4, 37.9, 32.9, 32.6, 32.0,
29.8, 29.7, 29.6, 29.5, 29.3, 26.6, 26.2, 22.8, 20.6, 20.1, 14.2;
LRMS (ES+) m/z 1069 (100, [2M + Na]+), 546 (50, [M + Na]+).
Anal. Calcd for C29H49NO5S: C, 66.50; H, 9.43; N, 2.67.
Found: C, 66.23; H, 9.27; N, 2.55.
Exp er im en ta l Section
(2S)-N-((2E,6E)-2,6-Non a d eca d ien oyl)ca m p h or -10,2-
su lta m (7). To a solution of phosphonate 1516 (409 mg 1.04
mmol) in CH2Cl2 (25 mL) at 0 °C was added in one batch NaH
(42 mg of a 60% dispersion in mineral oil, 1.04 mmol). The
reaction was allowed to warm to rt and was stirred for 20 min.
The solution was then cooled to 0 °C, and a solution of aldehyde
11 (250 mg, 0.99 mmol) in CH2Cl2 (5 mL) was added dropwise.
After 16 h, a saturated aqueous solution of NH4Cl (10 mL)
was added, and the organic layer was separated, re-extracting
with CH2Cl2 (2 × 10 mL). The combined organic solution was
dried (MgSO4) and concentrated in vacuo to give a yellow oil.
Purification by column chromatography (SiO2) eluting with
Et2O/hexane (1:9 then 1:4) gave diene 7 (389 mg, 0.79 mmol,
80%) as a white solid. A sample was recrystallized from hexane
to give colorless prisms: mp 41-44 °C; [R]24 +62.0 (CHCl3, c
D
(R)-1-[(2R,5S)-5-((S)-1-H yd r oxyt r id ecyl)t et r a h yd r o-
fu r a n -2-yl]eth a n e-1,2-d iol (21). To a solution of the acyl-
sultam 5 (1.39 g, 3.57 mmol) in a 3:1 mixture of THF/H2O (40
mL) at -10 °C was added NaBH4 (0.54 g, 14.3 mmol) in several
batches. The mixture was allowed to warm to 0 °C over 2 h,
whereupon HCl (2M, 10 mL) and EtOAc (20 mL) were added.
The organic phase was separated, re-extracting the aqueous
with EtOAc (2 × 20 mL). The combined organic phase was
dried (MgSO4) and concentrated in vacuo to give a colorless
oil. Purification by column chromatography (SiO2) eluting with
MeOH/CH2Cl2 (3:97 then 5:95) gave triol 21 (0.771 g, 2.33
mmol, 91%) as a white solid: mp 47-48 °C; [R]25D -9.1 (CHCl3,
c 0.76); IR νmax (neat) 3238 (br), 1460, 1415, 1327, 1118, 1078,
1056 cm-1; 1H NMR (400 MHz, MeOH-d4) δ 4.02 (1H, dt, J )
3.7, 6.7 Hz), 3.84 (1H, br q, J ) 6.0 Hz), 3.66 (1H, dd, J ) 5.3,
11.0 Hz), 3.62 (1H, dd, J ) 6.3, 11.0 Hz), 3.54 (1H, br q, J )
5.5 Hz), 3.45 (1H, br q, J ) 5.3 Hz), 2.04-1.77 (4H, m), 1.58-
0.77); IR νmax (neat) 1671, 1630, 1334, 1294, 1215, 1133 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.09 (1H, dt, J ) 15.1, 7.0 Hz),
6.56 (1H, dt, J ) 15.1, 1.5 Hz), 5.46 (1H, dt, J ) 15.3, 6.3 Hz),
5.38 (1H, dt, J ) 15.3, 6.3 Hz), 3.93 (1H, dd, J ) 5.0, 7.5 Hz),
3.51 (1H, d, J ) 13.6 Hz), 3.44 (1H, d, J ) 13.6 Hz), 2.31 (2H,
q, J ) 7.0 Hz), 2.20-2.05 (4H, m), 2.00-1.84 (5H, m), 1.46-
1.26 (22H, m), 1.18 (3H, s), 0.98 (3H, s), 0.89 (3H, t, J ) 6.8
Hz); 13C NMR (100 MHz, CDCl3) δ 164.2, 150.5, 132.0, 128.3,
121.1, 65.3, 53.3, 48.5, 47.9, 44.8, 38.6, 33.0, 32.7, 32.6, 32.0,
31.1, 29.8, 29.6, 29.5, 29.3, 26.6, 22.8, 21.0, 20.0, 14.3; LRMS
(ES+) m/z 515 (100, [M + Na]+). Anal. Calcd for C29H49
NO3S: C, 70.83; H, 10.01; N, 2.85. Found: C, 70.71; H, 9.96;
N, 2.79.
-
(2S)-N-[(S)-2-Hyd r oxy-2-[(2R,5S)-5-((S)-1-h yd r oxytr id e-
cyl)t e t r a h yd r o-2-fu r a n yl)e t h a n oyl]ca m p h or -10,2-su l-
ta m (5). To a rapidly stirred solution of diene 7 (500 mg, 1.0
mmol) and adogen 464 (10 mol %, 40 mg, 0.01 mmol) in AcOH/
acetone (25 mL 2:3) at -30 °C was added powdered KMnO4
(221 mg, 1.4 mmol) in one batch. The reaction mixture was
allowed to warm to -10 °C over 1 h, whereupon an ice-cold
solution of Na2S2O5 (20 mL of satd aq) was added. The
resulting aqueous mixture was extracted with EtOAc (3 × 20
mL). The combined organic solution was dried (MgSO4) and
concentrated in vacuo to give a yellow oil (600 mg). Purification
by column chromatography (SiO2) eluting with Et2O/hexane
(gradient 3:7 to 6:4) gave three main fractions: major THF
diastereoisomer 5 (355 mg, 0.63 mmol, 65%) as a gummy oil,
minor THF diastereoisomer 16 as a white solid (58 mg, 0.11
mmol, 11%), and hydroxyketoester 17 (5 mg, 0.01 mmol, 10%)
1.47 (2H, m), 1.45-1.26 (20H, m), 0.94 (3H, t, J ) 7.0 Hz); 13
C
NMR (100 MHz, MeO-d4) δ 83.8, 80.9, 75.3, 74.9, 65.2, 35.2,
33.1, 30.8, 30.5, 28.9, 28.6, 27.0, 23.8, 14.7; LRMS (ES+) m/z
684 (40, [2M + Na]+), 353 (100, [M + Na]+); HRMS (ES+) calcd
for C26H44O4Na+ m/z 330.2770, found 330.2768. Anal. Calcd
for C19H38O4: C, 69.05; H, 11.59. Found: C, 68.82; H, 11.41.
(R)-2-Hyd r oxy-2-[(2R,5S)-5-((S)-1-h yd r oxytr id ecyl)tet-
r a h yd r ofu r a n -2-yl]eth yl 4-Meth ylben zen esu lfon a te (22).
To a solution of the triol 21 (200 mg, 0.61 mmol) in benzene
(12 mL) was added Bu2SnO (181 mg, 0.73 mmol). The reaction
mixture was heated at reflux for 3 h and then cooled to rt.
TsCl (127 mg, 0.66 mmol) was added followed by TBAB (98
mg, 0.3 mmol). After 30 min, the reaction mixture was
concentrated in vacuo. Purification by column chromatography
(SiO2) eluting with EtOAc/hexane (1:4 then 2:3) afforded the
title tosylate 22 (293 mg, 0.61 mmol, 99%) as a white solid:
mp 70-72 °C; [R]25D -10.4 (CHCl3, c 0.40); IR νmax (neat) 3425,
as a yellow solid. Da ta for 5: [R]20 +40.0 (CHCl3, c 0.44); IR
D
νvmax (neat) 3524, 1699, 1467, 1304, 1295, 1214, 1131, 1106
1
cm-1; H NMR (400 MHz, CDCl3) δ 4.60-4.55 (2H, m), 3.96
(1H, dd, J ) 5.0, 7.5 Hz), 3.87 (1H, dt, J ) 4.5, 7.3 Hz), 3.52
(1H, d, J ) 13.8 Hz), 3.48-3.43 (1H, m), 3.45 (1H, d, J ) 13.8
Hz), 2.29-2.21 (3H, m), 2.13-2.03 (6H, m), 1.55-1.20 (24H,
m), 1.16 (3H, s), 0.98 (3H, s), 0.89 (3H, t, J ) 6.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 171.8, 83.3, 78.7, 74.1, 73.7, 65.9, 53.2,
49.1, 48.0, 44.7, 38.4, 34.7, 33.0, 32.0, 29.8, 29.7, 29.5, 28.5,
28.3, 26.5, 25.9 22.8, 21.0, 20.0, 14.2; LRMS (ES+) m/z 1106
(5, [2M + Na]+), 564 (100, [M + Na]+), 542 (5, [M + H]+);
HRMS (ES+) calcd for C29H51NO6SNa+ m/z 564.3329, found
564.3326. Anal. Calcd for C29H51NO6S: C, 64.29; H, 9.49; N,
2.58. Found: C, 64.24; H, 9.55; N, 2.56. Da ta for com p ou n d
16: mp 95-97 °C; [R]24D +102.8 (MeOH, c 0.38); 1H NMR (400
MHz, CDCl3) δ 4.67 (1H, br s), 4.51 (1H, ddd, J ) 2.3, 5.0, 7.5
Hz), 3.96 (1H, t, J ) 6.5 Hz), 3.77 (1H, dt, J ) 4.5, 7.3 Hz),
3.65 (1H, br), 3.50 (1H, d, J ) 13.7 Hz), 3.49-3.39 (1H, m),
3.45 (1H, d, J ) 13.7 Hz), 2.25-2.14 (1H, m), 2.10-1.83 (8H,
m), 1.60 (1H, br), 1.51-1.20 (24H, m), 1.16 (3H, s), 0.98 (3H,
s), 0.89 (3H, t, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 173.3,
83.1, 80.3, 74.3, 73.8, 65.0, 53.1, 49.1, 48.1, 44.6, 37.8, 34.7,
32.7, 32.1, 29.9, 29.8, 29.7, 29.5, 28.3, 27.9, 26.7, 25.8 22.8,
20.5, 20.0, 14.2; LRMS (ES+) m/z 564 (100, [M + Na]+), 542
(5, [M + H]+); HRMS (ES+) calcd for C29H51NO6SNa+ m/z
564.3329, found 564.3328. Anal. Calcd for C29H51NO6S: C,
64.29; H, 9.49; N, 2.58. Found: C, 64.20; H, 9.61; N, 2.57. Da ta
1
3309 (br), 1596, 1469, 1365, 1171, 1114 cm-1; H NMR (400
MHz, CDCl3) δ 7.80 (2H, d, J ) 8.3 Hz), 7.34 (2H, d, J ) 8.3
Hz), 4.09 (2H, d, J ) 6.0 Hz), 4.00 (1H, dt, J ) 2.7, 6.8 Hz),
3.84 (1H, dt, J ) 4.0, 7.0 Hz), 3.74 (1H, dt, J ) 2.7, 6.0 Hz),
3.44-3.40 (1H, m), 2.78 (2H, br), 2.45 (3H, s), 2.02-1.81 (4H,
m), 1.47-1.40 (2H, m), 1.34-1.20 (20H, m), 0.88 (3H, t, J )
7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 145.0, 132.9, 130.0,
128.1, 82.7, 78.6, 74.2, 71.8, 71.6, 34.6, 32.0, 29.8, 29.5, 28.2,
27.9, 25.9, 22.8, 21.8, 14.2; LRMS (ES+) m/z 991 (60, [2M +
Na]+), 507 (100, [M + Na]+), 485 (30, [M + H]+). Anal. Calcd
for C26H44O6S: C, 64.43; H, 9.15. Found: C, 64.39; H, 9.08.
(S)-1-[(2S,5R)-5-((R)-Oxir a n -2-yl)tetr a h yd r ofu r a n -2-yl]-
tr id eca n -1-ol (23). To a solution of tosylate 22 (95 mg, 0.20
mmol) in CH2Cl2 (6 mL) at 0 °C was added dropwise DBU (64
µL, 0.4 mmol). The solution was allowed to warm to rt, and
after 2 h the solution was concentrated in vacuo to give a
yellow oil that was purified by column chromatography (SiO2)
eluting with EtOAc/hexane (2:3) to give the title epoxide 23
(59 mg, 0.19 mmol, 96%) as a white solid: mp 36-40 °C; [R]24
D
-10.1 (CHCl3, c 0.40); IR νmax (neat) 3320 (br), 1465, 1418,
1
1321, 1122 cm-1; H NMR (300 MHz, MeOH-d4) δ 4.06 (1H,
dt, J ) 3.1, 6.6 Hz), 3.88 (1H, dt, J ) 4.2, 7.2 Hz), 3.45-3.29
J . Org. Chem, Vol. 69, No. 10, 2004 3373

Cecil et al.
(1H, m), 3.03 (1H, td, J ) 3.1, 4.0 Hz), 2.82 (1H, dd, J ) 2.9,
5.1 Hz), 2.80 (1H, br), 2.78 (1H, dd, J ) 4.0, 5.1 Hz), 2.20-
74.5, 70.8, 60.0, 34.3, 32.9, 32.6, 32.1, 29.8, 29.7, 29.6, 29.5,
29.2, 25.8, 22.8, 22.4, 14.4, 14.2; LRMS (ES+) m/z 631 (100,
[M + Na]+), 609 (100, [M + H]+); HRMS (ES+) C37H69O6+ calcd
609.5089, found 609.5085.
1.80 (4H, m), 1.57-1.12 (22H, m), 0.88 (3H, t, J ) 7.0 Hz); 13
C
NMR (75 MHz, CDCl3) δ 83.1, 77.2, 74.3, 54.7, 44.5, 34.8, 32.1,
29.8, 29.5, 29.4, 28.2, 26.0, 22.8, 14.3; LRMS (ES+) m/z 647
(100, [2M + Na]+), 335 (10, [M + Na]+). Anal. Calcd for
cis-Sola m in (1). A solution of 4,5-dihydro-cis-solamin (24)
(20 mg, 0.036 mmol), TsNHNH2 (40 mg, 0.22 mmol), and
NaOAc (18 mg, 0.22 mmol) in THF-H2O) (2 mL of 1:1) was
heated at 80 °C for 18 h. K2CO3 (satd aq, 2 mL) was added
and the mixture stirred for 1 h. The mixture was extracted
with CH2Cl2 (2 × 5 mL), and the combined organic phase was
dried (MgSO4) and concentrated in vacuo to give a white solid.
Purification by column chromatography (SiO2) eluting with
EtOAc/hexane (2:3) afforded cis-solamin (1) (19 mg, 0.034
mmol, 94%) as a white solid: mp 67-69 °C (lit.7 mp 63-66
C
19H36O3: C, 73.03; H, 11.61. Found: C, 72.95; H, 11.55.
(1R)-1-[(2R,5S)-5-((1S)-1-Hyd r oxytr id ecyl)tetr a h yd r o-
fu r a n -2-yl]-12-tr id ecen -1-ol (3). To a rapidly stirring sus-
pension of CuI (350 mg, 1.85 mmol) in THF (20 mL) at -60
°C was added dropwise a solution of undec-10-enylmagnesium
bromide (9.2 mL of 0.4 M in THF, 3.65 mmol). The mixture
was warmed to -30 °C, and after 20 min the resulting gray
suspension was cooled to -60 °C whereupon a solution of
epoxide 23 (228 mg, 0.73 mmol) in THF (5 mL) was added
dropwise. The mixture was allowed to warm to -20 °C over 1
h before an aqueous solution of NH4Cl/NH3 (9:1, 15 mL) was
added. The resulting mixture was extracted with EtOAc (3 ×
20 mL), and the combined organic phase was dried (MgSO4)
and concentrated in vacuo to give a colorless oil. Purification
by column chromatography (SiO2) eluting with EtOAc/hexane
(1:9 then 3:17) afforded the title olefin 3 (304 mg, 0.65 mmol,
°C, lit.5c mp 66-68 °C); [R]24D +11.3 (MeOH, c 0.87) [lit.5c [R]21
D
+26 (MeOH, c 0.45), lit.7 [R]D +22 (MeOH, c 0.55)]; IR νmax
(neat) 3390 (br), 1760, 1464, 1367, 1169, 1118, 1080 cm-1; 1H
NMR (400 MHz, CDCl3) δ 6.99 (1H, d, J ) 1.8 Hz), 5.00 (1H,
dq, J ) 1.8, 6.8 Hz), 3.87-3.83 (2H, m), 3.47-3.39 (2H, m),
2.26 (2H, t, J ) 7.1), 2.00-1.88 (2H, m), 1.81-1.71 (2H, m),
1.62-1.10 (44H, m), 1.42 (3H, d, J ) 6.8 Hz), 0.89 (3H, t, J )
7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 174.0, 148.9, 134.5, 82.8,
77.6, 74.5, 34.2, 32.1, 29.8, 29.7, 29.6, 29.5, 29.4, 28.3, 25.9,
25.2, 22.8, 19.3, 14.2; LRMS (ES+) m/z 1152 (20, [2M + Na]+),
1130 (10, [2M + H]+), 587 (80, [M + Na]+), 565 (100, [M +
H]+); HRMS (ES+) C35H65O5+ calcd 565.4827, found 565.4821.
Anal. Calcd for C34H64O5: C, 73.86; H, 11.67. Found: C, 73.72;
H, 11.53.
89%) as a white solid: mp 55-57 °C; [R]25 -0.9 (CHCl3, c
D
1.1); IR νmax (neat) 3380 (br), 1462, 1367, 1169, 1117 cm-1; 1H
NMR (400 MHz, CDCl3) δ 5.81 (1H, tdd, J ) 6.8, 10.2, 17.0
Hz), 4.99 (1H, dd, J ) 1.3, 17.0 Hz), 4.93 (1H, dd, J ) 1.3,
10.2 Hz), 3.84-3.80 (2H, m), 3.42 (2H, br q, J ) 5.5 Hz), 2.58
(2H, br s), 2.04 (2H, q, J ) 7.2 Hz), 1.99-1.86 (2H, m), 1.81-
1.69 (2H, m) 1.56-1.18 (40H, m), 0.88 (3H, t, J ) 7.0 Hz); 13
C
en t-cis-Sola m in (en t-1). Following the procedure for the
preparation of cis-solamin (1): compound ent-24 (24 mg, 0.04
mmol) was reduced to afford the title compound ent-1 (23 mg,
0.04, 92%) as a white solid: mp 71-72 °C; [R]24D -11.7 (MeOH,
c 1.02). Anal. Calcd for C34H64O5: C, 73.86; H, 11.67. Found:
NMR (100 MHz, CDCl3) δ 139.3, 114.2, 82.9, 74.5, 34.2, 33.9,
32.0, 29.8, 29.7, 29.6, 29.5, 29.3, 28.2, 25.8, 22.8, 14.2; LRMS
(ES+) m/z 955 (90, [2M + Na]+), 489 (100, [M + Na]+). Anal.
Calcd for C30H58O3: C, 77.19; H, 12.52. Found: C, 77.15; H,
12.37.
1
C, 73.68; H, 11.47. The H NMR, 13C NMR, IR, and MS data
(4E)-4,5-Did eh yd r o-cis-sola m in (24). To a stirred solution
of olefin 3 (200 mg, 0.43 mmol) and alkyne 49 (93 mg, 0.65
mmol) in degassed CH3OH (4 mL) was added a bright orange
solution of CpRu(COD)Cl9 (26, 7 mg, 0.023 mmol) in degassed
CH3OH (2 mL) under an atmosphere of argon. The solution
was heated at reflux for 3 h before cooling to rt and diluted
with ether (10 mL). The solution was then concentrated in
vacuo to give an orange gum which was filtered through a plug
of SiO2 eluting with acetone/hexane (2:5). Purification by
column chromatography (SiO2) eluting with MeOH/CH2Cl2 (1:
99 then 2:98) afforded the title butenolide 24 (169 mg, 0.30
mmol, 70%) as a white solid and the enoate 25 (39 mg, 0.064
for compound ent-1 were indistiguishable from that of cis-
solamin (1).
(S)-3-((S)-13-Hyd r oxy-13-[(2S,5R)-5-((R)-1-h yd r oxytr i-
d e cyl)t e t r a h yd r ofu r a n -2-yl)t r id e cyl]-5-m e t h yl-2,5-d i-
h yd r ofu r a n -2(5H)-on e (2). Following the procedure for the
preparation of cis-solamin (1): compound 27 (24 mg, 0.04
mmol) was reduced to afford the title compound 2 (23 mg, 0.04
mmol, 91%) as a white solid: mp 69-70 °C [lit.5c mp 61-63
°C]; [R]24 +11.8 (MeOH, c 0.85) [lit.5c [R]21 +42 (MeOH, c
D
D
0.50)]. Anal. Calcd for C34H64O5: C, 73.86; H, 11.67. Found:
1
C, 73.80; H, 11.63. The H NMR, 13C NMR, IR, and MS data
for compound 2 were indistiguishable from that of cis-solamin
(1).
mmol, 15%) as a white solid. Da ta for 24: mp 60-62 °C; [R]20
D
+10.5 (MeOH, c 0.76); IR vmax (neat) 3350 (br), 1758, 1462,
(R)-3-((R)-13-Hyd r oxy-13-[(2R,5S)-5-((S)-1-h yd r oxytr i-
d e cyl)t e t r a h yd r ofu r a n -2-yl)t r id e cyl]-5-m e t h yl-2,5-d i-
h yd r ofu r a n -2(5H)-on e (en t-2). Following the procedure for
the preparation of cis-solamin (1): compound ent-27 (24 mg,
0.04 mmol) was reduced to afford the title compound ent-2 (23
1365, 1171, 1115, 1078 cm-1 1H NMR (400 MHz, CDCl3) δ
;
6.99 (1H, d, J ) 1.8 Hz), 5.57 (1H, dt, J ) 15.3, 6.5 Hz), 5.47
(1H, dt, J ) 15.3, 6.5 Hz), 5.03 (1H, qq, J ) 1.8, 6.8 Hz), 3.87-
3.83 (2H, m), 3.47-3.39 (2H, m), 2.96 (2H, d, J ) 6.5), 2.50
(2H, br s), 2.03 (2H, q, J ) 7.1 Hz), 1.98-1.89 (2H, m), 1.81-
1.71 (2H, m), 1.54-1.22 (38H, m), 1.42 (3H, d, J ) 6.8 Hz),
0.89 (3H, t, J ) 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 173.6,
149.5, 134.3, 133.7, 124.4, 82.8, 77.7, 74.5 34.3, 32.6, 32.1, 29.8,
29.7, 29.6, 29.5, 29.4, 29.3, 25.9, 22.8, 19.3, 14.2; LRMS (ES+)
m/z 1148 (20, [2M + Na]+), 1126 (10, [2M + H]+), 586 (100,
[M + Na]+), 564 (100, [M + H]+); HRMS (ES+) C35H63O5+ calcd
563.4670, found 563.4662. Anal. Calcd for C35H62O5: C, 74.68;
H, 11.10. Found: C, 74.65; H, 11.09. Da ta for (2Z,5E,16R)-
16-h yd r oxy-3-((1S)-1-h yd r oxyeth yl)-16-[(2R,5S)-5-((1S)-1-
h yd r oxytr id ecyl)tetr a h yd r ofu r a n -2-yl]h exa d eca -2,5-d i-
en oic a cid et h yl est er (25): mp 32-34 °C; IR νmax (neat)
3333, 1730, 1462, 1365, 1171, 1115 cm-1; 1H NMR (400 MHz,
CDCl3) δ 6.01 (1H, d, J ) 1.1 Hz), 5.51 (1H, dt, J ) 15.3, 6.5
Hz), 5.43 (1H, dt, J ) 15.3, 6.5 Hz), 4.34 (1H, dq, J ) 1.1, 6.5
Hz), 4.18 (2H, q, J ) 7.0 Hz), 3.86-3.78 (2H, m), 3.56 (1H, dd,
J ) 6.0, 13.8 Hz), 3.47-3.38 (2H, m), 3.07 (1H, dd, J ) 6.7,
13.8 Hz), 2.39 (1H, br s), 2.02-1.89 (4H, m), 1.82-1.70 (2H,
m), 1.53-1.19 (44H, m), 0.89 (3H, t, J ) 7.0 Hz); 13C NMR
(100 MHz, CDCl3) δ 166.7, 163.4, 133.1, 126.7, 114.2, 82.8,
mg, 0.04, 90%) as a white solid: mp 68-70 °C; [R]24 -11.3
D
(MeOH, c 0.68). Anal. Calcd for C34H64O5: C, 73.86; H, 11.67.
Found: C, 73.78; H, 11.61. The 1H NMR, 13C NMR, IR, and
MS data for compound ent-2 were indistiguishable from that
of cis-solamin (1).
Ack n ow led gm en t. We thank The Royal Society for
a University Research Fellowship (R.C.D.B.) and the
Leverhulme Trust for a Postdoctoral Fellowship (Y.H.).
We also thank Merck Sharp & Dohme, Syngenta, and
Pfizer for general financial support.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 1, 5, 16, and 25. Experimental proce-
dures and characterization data for ent-3, 7, ent-7, 11, 12, 13,
15, ent-21, ent-22, ent-23, ent-24, 27, and ent-27. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O049909G
3374 J . Org. Chem., Vol. 69, No. 10, 2004