Application of enantioselective radical reactions: Synthesis of (+)-ricciocarpins A and B

Article abstract of DOI:10.1021/ol0495772

Matrix presented. Enantioselective synthesis of (+)-ricciocarpins A and B has been achieved in 41 and 45% overall yields, respectively, starting from a β-substituted oxazolidinone. The key steps in the strategy are an enantioselective conjugate radical ad

Full text of DOI:10.1021/ol0495772

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1749-1752
Application of Enantioselective Radical
Reactions: Synthesis of
(+)-Ricciocarpins A and B
Mukund P. Sibi* and Liwen He
Department of Chemistry, North Dakota State UniVersity,
Fargo, North Dakota 58105-5516
mukund.sibi@ndsu.nodak.edu
Received March 7, 2004
ABSTRACT
Enantioselective synthesis of (+)-ricciocarpins A and B has been achieved in 41 and 45% overall yields, respectively, starting from a â-substituted
oxazolidinone. The key steps in the strategy are an enantioselective conjugate radical addition and the addition of a furyl organometallic to
a key aldehyde intermediate.
In the past decade, we have witnessed a rapid growth in
stereoselective free radical chemistry.1 In this context,
methods for enantioselective bond construction using free
radical intermediates have begun to emerge.2 The use of
enantioselective radical reactions at the strategy level in the
synthesis of natural products is yet to be demonstrated in a
routine fashion. Our group and others have reported several
novel methods for carbon-carbon bond construction using
enantioselective conjugate radical additions.3 In this work,
we highlight the application of enantioselective radical
chemistry in the synthesis of two novel sesquiterpene
lactones.
Ricciocarpin A, a furanosesquiterpene lactone, has been
isolated from an axenic culture of the European liverwort,
Ricciocarpos natas (Ricciaceae). The natural product exhibits
high molluscicidal activity against the water snail Biomphalar-
ia glabtata, a vector of schistosomiasis.4 Ricciocarpin B,
which differs from ricciocarpin A in the oxidation state of
the furan ring, has also been isolated from liverwort. Several
racemic syntheses of ricciocarpin A have been reported.5
Metz and co-workers have reported the only enantioselective
synthesis of ricciocarpin A.6 The conversion of ricciocarpin
A to ricciocarpin B has also been reported by Metz.6 In this
work, we report a short and efficient synthesis of both
ricciocarpins A and B in enantiomerically pure form.
(1) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, 2001; Vols. 1 and 2.
(2) For recent reviews see: (a) Sibi, M. P.; Manyem, S.; Zimmerman,
J. Chem. ReV. 2003, 103, 3263. (b) Bar, G.; Parsons, A. F. Chem. Soc.
ReV. 2003, 32, 251. (c) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999,
32, 163. (d) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8303.
(3) (a) Sibi, M. P.; Ji, J. G.; Wu, J. H.; Gurtler, S.; Porter, N. A. J. Am.
Chem. Soc. 1996, 118, 9200. (b) Sibi, M. P.; Ji, J. G. J. Org. Chem. 1997,
62, 3800. (c) Sibi, M. P.; Shay, J. J.; Ji, J. G. Tetrahedron Lett. 1997, 38,
5955. (d) Sibi, M. P.; Chen, J. J. Am. Chem. Soc. 2001, 123, 9472. (e)
Sibi, M. P.; Manyem, S. Org. Lett. 2002, 4, 2929. (f) Sibi, M. P.; Petrovic,
G. Tetrahedron: Asymmetry 2003, 15, 2879. (g) Sibi, M. P.; Zimmerman,
J.; Rheault, T. R. Angew. Chem., Int. Ed. 2003, 42, 4521. (h) Iserloh, U.;
Curran, D. P.; Kanemasa, S. Tetrahedron: Asymmetry 1999, 10, 2417. (i)
Murakata, M.; Tsutsui, H.; Hoshino, O. Org. Lett. 2001, 3, 299.
Our strategy for the synthesis of ricciocarpins A and B is
shown in Scheme 1. Our plan was to prepare a key aldehyde
intermediate 3 and optimize the addition of furan organo-
10.1021/ol0495772 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/01/2004

Scheme 1
Scheme 2a
metallics leading to the two targets.7 The aldehyde 3 would
be accessed through a stereoselective cyclization of 4.
Enantioselective conjugate addition of a functionalized
radical 6 to enoate 5, followed by routine functional group
manipulations, would furnish the intermediate 4.
Our work began with the identification of an optimal
substrate for enantioselective conjugate addition with a
functionalized radical (Scheme 2). On the basis of our prior
work, we chose to investigate pyrrolidinone and oxazolidi-
none substrates 7-10.8 The functionalized radical precursor
12 was prepared by a two-step sequence starting with the
commercially available 5-chloro-2-pentanone.9 We have
previously shown that a chiral Lewis acid derived from
magnesium salts and bisoxazoline 11 is very effective in
enantioselective conjugate radical additions. Reactions of
7-10 with the tertiary radical derived from 12 using 100
mol % of the chiral Lewis acid gave products 13-16 (entries
1-4). The efficiency of the reaction was dependent on the
template and the oxygen protecting group. Substrate 10 with
an O-benzyl protecting group gave the highest yield and
enantioselectivity (entry 4).10 Reactions with lower catalyst
loading (50 mol %, entry 5; 30 mol %, entry 6) gave the
a For reaction conditions, see Supporting Information. bIsolated
yield after column purification. cDetermined by chiral HPLC.
e
dPerformed with 100 mol % of the chiral Lewis acid. Performed
with 50 mol % of the chiral Lewis acid. fPerformed with 30 mol %
of the chiral Lewis acid.
desired product 16 in lower yields but with similar levels of
selectivity.
With the desired conjugate addition product 16 in hand,
we set out to prepare the key aldehyde intermediate 3
(Scheme 3). The oxazolidinone 16 was converted to the
methyl ester 17 in excellent yield using a protocol developed
by Otera.11 Halogen interchange under Finkelstein conditions
produced the iodoester 18 in high yield. The crucial six-
membered ring construction12 was carried out using LHMDS
as the base yielding 19 as a single trans isomer.13 De-
benzylation under carefully controlled conditions,14 followed
(4) (a) Wurzel, G.; Becker, H.; Eicher, T.; Tiefensee, K. Planta Med.
1990, 56, 444. (b) Wurzel, G.; Becker, H. Phytochemistry 1990, 29, 2565.
(c) Zinsmeister, H. D.; Becker, H.; Eicher, T. Angew. Chem., Int. Ed. Engl.
1991, 30, 130. (d) Thiel, R.; Adam, K. P.; Zapp, J.; Becker, H. Pharm.
Pharmacol. Lett. 1997, 7, 103.
(5) Racemic synthesis: (a) Agapiou, K.; Krische, M. J. Org. Lett. 2003,
5, 1737. (b) Takeda, K.; Ohkawa, N.; Hori, K.; Koizumi, T.; Yoshii, E.
Heterocycles 1998, 47, 277. (c) Ihara, M.; Suzuki, S.; Taniguchi, N.;
Fukumoto, K. J. Chem., Soc., Perkin Trans. 1 1993, 2251. (d) Ihara, M.;
Suzuki, S.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Chem. Commun.
1993, 755. (e) Eicher, T.; Massonne, K.; Herrmann, M. Synthesis 1991,
1173.
Scheme 3
(6) (a) Held, C.; Frohlich, R.; Metz, P. AdV. Synth. Catal. 2002, 344,
720. (b) Held, C.; Frohlich, R.; Metz, P. Angew. Chem., Int. Ed. 2001, 40,
1058.
(7) A similar disconnection has been applied in the racemic synthesis of
1 starting with 3 (or a slight variant) and 3-furyllithium (see refs 5b-e).
The yield for this transformation has been <30%.
(8) These compounds were prepared in a straightforward fashion using
well-established literature procedures. See Supporting Information for
details.
(9) See Supporting Information for details.
(10) Stereochemical outcome in tert-butyl radical additions to oxazoli-
dinone crotonates or cinnamates using ligand 11 and MgI2 has been
previously shown to provide products with R configuration. We initially
assigned the stereochemistry for 16 on the basis of the above precedents,
which was later confirmed by the synthesis of the natural product.
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Org. Lett., Vol. 6, No. 11, 2004

by immediate oxidation, provided the key aldehyde inter-
mediate 3 in good overall yield over two steps.
improvements in either the yield or the diastereoselectivity
favoring the target. Boukouvalas and co-workers in their
synthesis of dysidiolide have shown that furyl titanium
reagents18 add efficiently to aliphatic aldehydes. On the basis
of this precedent, we evaluated the addition of the 3-titanyl-
oxyfuran reagent to 3 (entries 5 and 6). These reactions were
very rewarding, and we obtained the highest chemical yield
for the lactone products with the desired natural ricciocarpin
1 as the major product. The two diastereomers could be
separated using preparative HPLC. The spectral and analyti-
cal characteristics of synthetic (+)-ricciocarpin A were
identical to those reported in the literature. The overall yield
for 1 starting from 10 is 41.5%.
The conversion of aldehyde 3 to racemic ricciocarpin A
has been reported in the literature. In this transformation,
3-lithiofuran was used as the nucleophile. The average yield
for the addition was <30%, and the diastereoselectivity in
general was modest.15 However, Takeda and co-workers have
reported that 1 can be obtained as the sole isomer in 29%
yield. The low yield and selectivity in the addition of
3-lithiofuran to 3 led us to examine this transformation in
some detail (Scheme 4). Addition of 3-lithiofuran to 3 in
Metz and co-workers have reported the conversion of
ricciocarpin A to B.6a The ready availability of the aldehyde
3 and the known chemistry of 2-alkoxy-4-lithio (or titanyl-
oxy) reagent led us to explore the synthesis of ricciocarpin
B (Scheme 5). The required 4-bromo-2-silyloxyfuran was
Scheme 4a
Scheme 5
synthesized following a literature procedure.19 The titanium
organometallic 21 was prepared according to the protocol
previously described by Boukouvalas.18a The reagent 21 was
prepared at room temperature and added to a solution of the
aldehyde 3 at -78 °C. The crude reaction mixture was treated
with dilute hydrochloric acid and stirred at room temperature
for 12 h. This resulted in silyl group deprotection and
cyclization to furnish ricciocarpin B 2 as a single isomer in
78% yield. The spectral and analytical characteristics of 2
were in complete agreement with those reported in the
literature.4a,6a
a For reaction conditions, see Supporting Information. b Isolated
yield after column purification. c Determined by NMR. d Pseudo-
ephedrine was used as a ligand.
either THF or ether as a solvent gave a mixture of
diastereomeric lactones 1 and 20 in modest yields. We did
not obtain 1 as the major isomer as had been reported in the
literature (entries 1 and 2). The use of the Grignard reagent
(entry 3)16 or the zinc reagent (entry 4)17 did not lead to
In conclusion, we have developed an efficient synthesis
of ricciocarpin A and B that highlights the use of enantio-
selective conjugate radical addition methodology. The syn-
(11) (a) Orita, A.; Nagano, Y.; Hirano, J.; Otera, J. Synlett 2001, 637.
(b) Also see: Sibi, M. P.; Hasegawa, H.; Ghorpade, S. R. Org. Lett. 2002,
4, 3343.
(12) Attempts to form the six-membered ring with an acyl-oxazolidinone
(instead of the methyl ester) gave complex product mixtures.
(13) Relative stereochemistry was established by coupling constant
analysis. The proton at C-1 resonates at δ 2.31 ppm (dt, Jt ) 12.0 Hz, Jd
) 3.6 Hz, 1H). The 12 Hz coupling constant clearly establishes the relative
stereochemistry at the ring as trans.
(16) For the addition of 3-furylmagnesium bromide to imines, see: (a)
Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303. (b)
Oppolzer, W.; Froelich, O.; Wiaux-Zamar, C.; Bernardinelli, G. Tetrahedron
Lett. 1997, 37, 2825.
(14) Temperature of the reaction is important to avoid the premature
formation of the lactone.
(17) Preparation of 3-furylzinc reagent: Negishi, E.-i.; Takahashi, T.;
King, A. O. Org. Synth. 1988, 66, 67. Difuryl zinc reagents: Xue, S.; Han,
K.-Z.; He, L.; Guo, Q.-X. Synlett 2003, 870.
(18) (a) Boukouvalas, J.; Cheng, Y.-X.; Robichaud, J. J. Org. Chem.
1998, 63, 228. For a recent review, see: (b) Cossy, J.; BouzBouz, S.;
Pradaux, F.; Willis, C.; Bellosta, V. Synlett 2002, 1595.
(19) Kanoh, N.; Ishihara, J.; Yamamoto, Y.; Murai, A. Synthesis 2000,
1878.
(15) For the addition of 3-furyllithium to aliphatic aldehydes, see: (a)
Corey, E. J.; Roberts, B. E. J. Am. Chem. Soc. 1997, 119, 12425. (b)
Demeke. D.; Forsyth, C. J. Org. Lett. 2000, 2, 3177. (c) Takahashi, M.;
Dodo, K.; Hashimoto, Y.; Shirai, R. Tetrahedron Lett. 2000, 41, 2111. (d)
Liu, H.-J.; Zhu, J.-L.; Chen, I.-C.; Jankowska, R.; Han, Y.; Shia, K.-S.
Angew. Chem., Int. Ed. 2003, 42, 1851.
Org. Lett., Vol. 6, No. 11, 2004
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thesis of other sesquiterpenes with biological activity, which
feature enantioselective radical chemistry, is underway in
our laboratory.
Supporting Information Available: Characterization
data for compounds 1-3 and 7-20 and experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank NIH GM-54656 for finan-
cial support. We also express our gratitude to Dr. Ruzhou
Zhang for preliminary experimental assistance.
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