Total synthesis of cis-solamin: Exploiting the RuO4-catalyzed oxidative cyclization of dienes

Article abstract of DOI:10.1021/ol060520k

An enantioselective total synthesis of cis-solamin has been accomplished using a highly diastereoselective ruthenium tetroxide catalyzed oxidative cyclization as a crucial transformation. Further key steps involved an enzymatic desymmetrization, a TPAP-catalyzed oxidative termini differentiation, and a ruthenium-catalyzed Alder-ene reaction. Thus, the total synthesis of cis-solamin was achieved in 11 steps with an overall yield of 7.5%.

Full text of DOI:10.1021/ol060520k

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3433-3436
Total Synthesis of cis-Solamin:
Exploiting the RuO4-Catalyzed Oxidative
Cyclization of Dienes†
Hu1lya Go1ksel and Christian B. W. Stark*
Institut fu¨r Chemie und Biochemie-Organische Chemie, Freie UniVersita¨t Berlin,
Takustrasse 3, 14195 Berlin, Germany
stark@chemie.fu-berlin.de
Received March 2, 2006
ABSTRACT
An enantioselective total synthesis of cis-solamin has been accomplished using a highly diastereoselective ruthenium tetroxide catalyzed
oxidative cyclization as a crucial transformation. Further key steps involved an enzymatic desymmetrization, a TPAP-catalyzed oxidative termini
differentiation, and a ruthenium-catalyzed Alder-ene reaction. Thus, the total synthesis of cis-solamin was achieved in 11 steps with an overall
yield of 7.5%.
The annonaceous acetogenins are a class of more than 400
natural products isolated exclusively from the tropical plant
family Annonaceae.1 This unique class of metabolites has
attracted particular attention as a result of their remarkable
range of biological effects. They exhibit high antitumor,
antimalarial, pesticidal, and immunosuppressive activity.2
Interaction with mitochondrial complex I of the respiratory
chain appears to be the molecular basis for at least some of
these effects.
Structurally, most acetogenins are characterized by a long
unbranched fatty acid chain (C32 or C34) with one, two, or
three central tetrahydrofuran (THF) rings and a terminal
butenolide segment (Figure 1). Usually the THF core is
Figure 1. General structure of annonaceous acetogenins and cis-
solamin (1).
† Dedicated to Professor S. V. Ley on occasion of his 60th birthday.
(1) For recent reviews, see: (a) 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., Steglich, W., Tamm, Ch., Eds.; Springer-
Verlag: Wien, 1997; Vol. 10, pp 81-288. (b) Alali, F. Q.; Liu, X.-X.;
McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504-540. (c) Bermejo, A.;
Figade`re, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.; Cortes, D.
Nat. Prod. Rep. 2005, 22, 269-303.
flanked by additional hydroxy groups. Most acetogenins
differ in the number of THF rings and the stereochemistry
of the densely oxygenated central unit. Consequently, most
synthetic efforts3,4 have focused on an efficient and stereo-
selective construction of this core.
(2) (a) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.
Nat. Prod. Rep. 1996, 13, 276-306. (b) Oberlies, N. H.; Croy, V. L.;
Harrison, M. L.; McLaughlin, J. L. Cancer Lett. 1997, 115, 73-79. (c)
Oberlies, N. H.; Chang, C.-J.; McLaughlin, J. L. J. Med. Chem. 1997, 40,
2102-2106. See also ref 1.
(3) For reviews, see: (a) Hoppe, R.; Scharf, H.-D. Synthesis 1995, 1447-
1464. (b) Figade`re, B. Acc. Chem. Res. 1995, 28, 359-365. (c) Marshall,
J. A.; Hinkle, K. W.; Hagedorn, C. E. Isr. J. Chem. 1997, 37, 97-107. (d)
Cassiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G.; Appendino, G.
Chemtracts: Org. Chem. 1998, 11, 803-827.
10.1021/ol060520k CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/15/2006

As part of our interest in oxidation catalysis we have
recently developed an efficient ruthenium tetroxide5 catalyzed
oxidative cyclization of 1,5-dienes.6,7 We here present the
first application of this method to natural product synthesis.
As a target compound, cis-solamin, a representative mono-
THF acetogenin isolated in 1998,8 was chosen (Figure 1).
To date two total syntheses9 and one formal synthesis10 have
been reported.11
Scheme 1. Retrosynthetic Analysis
Our retrosynthetic analysis is outlined in Scheme 1. It takes
advantage of the inherent symmetry of the central THF diol
unit of cis-solamin by disconnection between C12-C13 and
C22-C23. The strategy is centered on the single-step
construction of the core THF unit by oxidative cyclization
of an appropriate diene precursor (6). Crucial to the success
of this approach is both the efficiency of the oxidative
cyclization and the feasibility of a subsequent desymmetri-
zation of the Cs-symmetric cyclization product.
(4) Representative acetogenin total syntheses: (a) Marshall, J. A.; Jiang,
H. J. Org. Chem. 1999, 64, 971-975. (b) Ba¨urle, S.; Hoppen, S.; Koert,
U. Angew. Chem. 1999, 111, 1341-1344; Angew. Chem., Int. Ed. 1999,
38, 1263-1266. (c) Sinha, A.; Sinha, S. C.; Sinha, S. C.; Keinan, E. J.
Org. Chem. 1999, 64, 2381-2386. (d) Hoppen, S.; Ba¨urle, S.; Koert, U.
Chem. Eur. J. 2000, 6, 2382-2396. (e) Dixon, D. J.; Ley, S. V.; Reynolds,
D. J. Angew. Chem. 2000, 112, 3768-3772; Angew. Chem., Int. Ed. 2000,
39, 3622-3626. (f) Harcken, C.; Bru¨ckner, R. New J. Chem. 2001, 25,
40-54. (g) Hu, T.-S.; Yu, Q.; Wu, Y.-L.; Wu, Y. J. Org. Chem. 2001, 66,
853-861. (h) Burke, S. D.; Jiang, L. Org. Lett. 2001, 3, 1953-1955. (i)
Takahashi, S.; Kubota, A.; Nakata, T. Angew. Chem. 2002, 114, 4945-
4948; Angew. Chem., Int. Ed. 2002, 41, 4751-4754. (j) Zhu, L.; Mootoo,
D. R. Org. Lett. 2003, 5, 3475-3478. (k) Zhang, Q.; Lu, H.; Richard, C.;
Curran, D. P. J. Am. Chem. Soc. 2004, 126, 36-37. (l) Crimmins, M. T.;
She, J. J. Am. Chem. Soc. 2004, 126, 12790-12791. (m) Nattrass, G. L.;
Diez, E.; McLachlan, M. M.; Dixon, D. J.; Ley, S. V. Angew. Chem. 2005,
117, 586-590; Angew. Chem., Int. Ed. 2005, 44, 580-584. (n) Hanessian,
S.; Giroux, S.; Buffat, M. Org. Lett. 2005, 7, 3989-3992. (o) Tinsley, J.
M.; Mertz, E.; Chong, P. Y.; Rarig, R.-A. F.; Roush, W. R. Org. Lett. 2005,
7, 4245-4248. See also refs 9-11.
The synthesis of the cyclization precursor is summarized
in Scheme 2. Commercially available (E,E,E)-1,5,9-cy-
Scheme 2. Synthesis of the Cyclization Precursor
(5) For a recent review on ruthenium tetroxide catalyzed oxidations,
see: Plietker, B. Synthesis 2005, 2453-2472.
(6) Roth, S.; Go¨hler, S.; Cheng, H.; Stark, C. B. W. Eur. J. Org. Chem.
2005, 4109-4118.
(7) Representative references for the oxidative cyclization of 1,5-dienes.
With ruthenium tetroxide: (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.;
Sharpless, K. B. J. Org. Chem. 1981, 46, 3936-3938. (b) Albarella, L.;
Musumeci, D.; Sica, D. Eur. J. Org. Chem. 2001, 997-1003. (c) Piccialli,
V.; Cavallo, N. Tetrahedron Lett. 2001, 42, 4695-4699. See also ref 6.
With potassium permanganate: (d) Klein, E.; Rojahn, W. Tetrahedron 1965,
21, 2353-2358. (e) Walba, D. M.; Wand, M. D.; Wilkes, M. C. J. Am.
Chem. Soc. 1979, 101, 4396-4397. (f) Baldwin, J. E.; Crossley, M. J.;
Lehtonen, E.-M. M. J. Chem. Soc., Chem. Commun. 1979, 918-920 (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.; Keily, J.
F. Angew. Chem. 2001, 113, 4628-4630; Angew. Chem., Int. Ed. 2001,
40, 4496-4498. See also ref 9b and 9c. With osmium tetroxide: (i) de
Champdore´, M.; Lasalvia, M.; Piccialli, V. Tetrahedron Lett. 1998, 39,
9781-9784. (j) Donohoe, T. J.; Butterworth: S. Angew. Chem. 2003, 115,
978-981; Angew. Chem., Int. Ed. 2003, 42, 948-951.
clododecatriene 7 was readily converted into diene 8 via
monodihydroxylation, glycol cleavage, and subsequent boro-
hydride reduction.12 Standard silyl protection of diol 8
afforded the cyclization precursor 6 in excellent overall yield
(65% over 4 steps). It is worth noting that these four steps
can be carried out on a multigram scale without purification
of intermediates.
We next turned our attention to the ruthenium tetroxide
catalyzed oxidative cyclization.6 Treatment of diene 6 with
0.2 mol % ruthenium(III) chloride (as a precatalyst for the
ruthenium tetroxide generated in situ) in the presence of
sodium periodate on wet silica6,13 (in THF14 at 0 °C) resulted
(8) Gleye, C.; Duret, P.; Laurens, A.; Hocquemiller, R.; Cave´, A. J. Nat.
Prod. 1998, 61, 576-579.
(9) (a) Makabe, H.; Hattori, Y.; Tanaka, A.; Oritani, T. Org. Lett. 2002,
4, 1083-1085. (b) Cecil, A. R. L.; Brown, R. C. D. Org. Lett. 2002, 4,
3715-3718. (c) Cecil, A. R. L.; Hu, Y. L.; Vicent, M. J.; Duncan, R.;
Brown, R. C. D. J. Org. Chem. 2004, 69, 3368-3374.
(10) Donohoe, T. J.; Butterworth: S. Angew. Chem. 2005, 117, 4844-
4867; Angew. Chem., Int. Ed. 2005, 44, 4766-4768.
(11) For syntheses of the natural isomer trans-solamin, see: (a) Sinha,
S. C.; Keinan, E. J. Am. Chem. Soc. 1993, 115, 4891-4892. (b) Trost, B.
M.; Shi, Z. P. J. Am. Chem. Soc. 1994, 116, 7459-7460. (c) Makabe, H.;
Tanaka, A.; Oritani, T. J. Chem. Soc., Perkin Trans. 1 1994, 1975-1981.
(d) Kuriyama, W.; Ishigami, K.; Kitahara, T. Heterocycles 1999, 50, 981-
988. (e) Prestat, G.; Baylon, C.; Heck, M.-P.; Grasa, G. A.; Nolan, S. P.;
Mioskowski, C. J. Org. Chem. 2004, 69, 5770-5773. For a semi-synthesis
of cis- and trans-solamin from Diepomuricanin A, see: Gleye, C.; Franck,
X.; Hocquemiller, R.; Laurens, A.; Laprevote, O.; de Barros, S.; Figade`re,
B. Eur. J. Org. Chem. 2001, 3161-3164.
(12) The first two steps of this sequence have previously been described,
cf.: Neogi, P.; Doundoulakis, T.; Yazbak, A.; Sinha, S. C.; Sinha, S. C.;
Keinan, E. J. Am. Chem. Soc. 1998, 120, 11279-11284.
3434
Org. Lett., Vol. 8, No. 16, 2006

in a smooth conversion of the starting material. The
cyclization product was obtained in high yield (83%) and
as a single diastereoisomer (>98:2 dr). The excellent
diastereoselectivity of this transformation is believed to result
from a double syn specific [3 + 2]-cycloaddition with a
conformationally constrained second intramolecular addition
process (Scheme 3).6
Scheme 4. Enzymatic Desymmetrization
Scheme 3. RuO4-Catalyzed Oxidative Cyclization
ingly, TPAP (tetrapropylammonium perruthenate)18 catalyzed
oxidation of triol (+)-10 in the presence of an excess of
NMO (N-methyl-morpholine-N-oxide) co-oxidant furnished
the desired lactone aldehyde (-)-11 in 55% yield (3 oxidation
For the desymmetrization of meso-diol 2 we envisaged
enzymatic methodology.15 To avoid an additional acetylation
step (followed by lipase-catalyzed hydrolysis), an enzymatic
esterification was considered.16,17 After extensive investiga-
tion of a variety of lipases under different conditions we
found that lipase Amano AK provided best results concerning
both conversion and enantioselectivity. Under optimized
conditions in hexane at 60 °C using vinyl acetate as the
acylating agent, enantiomerically pure (>99% ee) acetate
(+)-9 was obtained in 81% yield. The absolute configuration
of (+)-9 was assigned by the use of Mosher esters. Fluoride-
induced deprotection furnished triol (+)-10 in 98% yield. It
is important to note that although this compound ((+)-10)
is enantiomerically pure, termini differentiation is required
for appropriate side chain attachment. We planned to achieve
this differentiation by oxidative means (Scheme 5). Pleas-
Scheme 5. Termini Differentiation
(13) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622-
2624.
(14) In a general procedure the addition 10 vol % CH2Cl2 has previously
been suggested to suppress unwanted overoxidation (ref 6). In the case of
substrate 6 the addition of this cosolvent proved not necessary.
(15) For reviews, see: (a) Theil, F. Chem. ReV. 1995, 95, 2203-2227.
(b) Schoffers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52,
3769-3826. (c) Schmid, R. D.; Verger, R. Angew. Chem. 1998, 110, 1694-
1720 Angew. Chem., Int. Ed. 1998, 37, 1608-1633. For a review on
nonenzymatic desymmetrizations of meso-compounds, see: Willis, M. C.
J. Chem. Soc., Perkin Trans. 1 1999, 1765-1784. For a general review on
meso-compounds in stereoselective synthesis, see: Hoffmann, R. W. Angew.
Chem. 2003, 115, 1128-1142; Angew. Chem., Int. Ed. 2003, 42, 1096-
1109.
events). Through this oxidation reaction both the termini
differentiation and the establishment of a functional group
required for C-C bond coupling were achieved. Subsequent
olefination provided the C12-C32 fragment in 81% yield.
Notably, the oxidation-olefination sequence could be carried
out as a one-pot procedure19 with an almost identical overall
yield (Scheme 5).
(16) Enzymatic desymmetrizations of THF diols using, e.g., Candida
antarctica, Candida rugosa, and Mucor jaVanicus lipases have been reported
previously (ref 17). However, in case of diol 2, these enzymes did not
provide substantial amounts of product.
The next crucial step involved the C9-extension to
introduce the C3-C11 linear carbon chain (Scheme 6). Thus,
(17) For enzymatic desymmetrizations of THF diols, see: (a) Estermann,
H.; Prasad, K.; Shapiro, M. Tetrahedron Lett. 1990, 31, 445-448. (b)
Naemura, K.; Fukada, R.; Takahashi, N.; Konishi, M.; Hirose, Y.
Tetrahedron: Asymmetry 1993, 4, 911-918. (c) Hegemann, K.; Schimanski,
H.; Ho¨weler, U.; Haufe, G. Tetrahedron Lett. 2003, 44, 2225-2229. (d)
Hegemann, K.; Fro¨hlich, R.; Haufe, G. Eur. J. Org. Chem. 2004, 2181-
2192.
(18) For reviews, see: (a) Ley, S. V.; Norman, J.; Griffith, W. P.;
Marsden, S. P. Synthesis 1994, 639-666. (b) Langer, P. J. Prakt. Chem.
2000, 342, 728-730. For an early publication on the oxidative lactonization
of diols using TPAP, see: Bloch, R.; Brillet, C. Synlett 1991, 829-830.
(19) MacCoss, R. N.; Balskus; E. P.; Ley, S. V. Tetrahedron Lett. 2003,
44, 7779-7781.
Org. Lett., Vol. 8, No. 16, 2006
3435

equimolar mixture of (-)-13 and known alkyne 521 with a
catalytic amount of CpRu(MeCN)3PF6 afforded the coupled
product with excellent chemoselectivity (in favor of the
terminal olefin) and in high yield (90%). Final diimide
reduction of the ∆4,11,23-triene in the presence of the R,â-
unsaturated lactone furnished cis-solamin (1) as a colorless
powder in 90% yield. Spectroscopic data for this compound
were identical to those reported for cis-solamin isolated from
natural sources.8 In addition, these data22 were in accord with
the absolute stereochemical assignment reported by Makabe
and co-workers.9a
Scheme 6. Final Steps of the Total Synthesis
In conclusion, our total synthesis of cis-solamin demon-
strates the potential of ruthenium tetroxide catalyzed oxida-
tive cyclizations. It represents the first application of this
method to natural product synthesis, and four of the five
stereogenic centers of cis-solamin were established through
this pivotal transformation. Other key steps involved an
enzymatic desymmetrization, a TPAP-catalyzed oxidative
termini differentiation, and a ruthenium-catalyzed Alder-ene
reaction. It is also worth mentioning that our strategy makes
minimal use of protecting groups and exploits the inherent
Cs-symmetry of the central THF diol unit. Thus, the total
synthesis of cis-solamin was achieved in 11 steps with an
overall yield of 7.5%.
lactone (-)-12 was reduced with 1 equiv of DIBALH
followed by addition of the separately generated Wittig ylide
derived from phosphonium salt 4. Under these conditions a
competing reduction of the C20 acetate protecting group
could not be prevented, resulting in diminished yields of the
desired coupling product and a significant amount of
recovered starting material. After some experimentation, it
was found that addition of 2 equiv of DIBALH (at -78 °C
in toluene) followed by addition of an excess of Wittig
reagent yielded the coupled and reductively deprotected
product (-)-13 (Scheme 6). With compound (-)-13 in hand,
the final sequence for the solamin synthesis was performed
as shown in Scheme 6. The butenolide segment was
introduced using a ruthenium(II)-catalyzed Alder-ene reaction
developed by Trost and co-workers.20 Thus, treatment of an
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (STA-634/1-1) and the
Fonds der Chemischen Industrie. We thank Prof. U. T.
Bornscheuer (Universita¨t Greifswald, Germany) for valuable
suggestions regarding the enzymatic desymmetrization. We
are also grateful to Prof. H.-U. Reissig (Freie Universita¨t
Berlin, Germany) for helpful discussions and generous
support.
Supporting Information Available: Experimental pro-
cedures for key reactions and full spectroscopic data for
compounds 2, 6, 10, 12, 13, and 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL060520K
(20) (a) Trost, B. M.; Toste, F. D. Tetrahedron Lett. 1999, 40, 7739-
7743. (b) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001,
101, 2067-2096. (c) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew.
Chem. 2005, 117, 6788-6825; Angew. Chem., Int. Ed. 2005, 44, 6630-
6666.
(21) Trost, B. M.; Mu¨ller, T. J. J.; Martinez, J. J. Am. Chem. Soc. 1995,
117, 1888-1899.
(22) Optical rotations. Synthetic cis-solamin 1: [R]24 ) +20.6 (c )
D
0.1 in MeOH). Natural cis-solamin [R]D ) +22 (c ) 0.55 in MeOH); see
ref 8. For details see also Supporting Information.
3436
Org. Lett., Vol. 8, No. 16, 2006