Multicomponent linchpin coupling of silyl dithianes employing an N-Ts aziridine as the second electrophile: Synthesis of (-)-indolizidine 223AB

Article abstract of DOI:10.1021/ol049601b

An efficient, stereocontrolled assembly of the indolizidine alkaloid, (-)-indolizidine 223AB, exploiting a three-component linchpin coupling employing an N-Ts aziridine as the second electrophile, followed by a one-pot sequential construction of the indol

Full text of DOI:10.1021/ol049601b

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1493-1495
Multicomponent Linchpin Coupling of
Silyl Dithianes Employing an N-Ts
Aziridine as the Second Electrophile:
Synthesis of (−)-Indolizidine 223AB
Amos B. Smith, III* and Dae-Shik Kim
Department of Chemistry, Monell Chemical Senses Center and Laboratory for
Research on the Structure of Matter, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received March 3, 2004
ABSTRACT
An efficient, stereocontrolled assembly of the indolizidine alkaloid, (−)-indolizidine 223AB, exploiting a three-component linchpin coupling
employing an N-Ts aziridine as the second electrophile, followed by a one-pot sequential construction of the indolizidine ring system, has
been achieved. The longest linear sequence was 10 steps, proceeding in 10% overall yield.
Dithianes, important umpolung linchpins in organic chem-
istry,1 are frequently employed both for the stereocontrolled
generation of protected aldol products2 and for the union of
advanced fragments in complex molecule synthesis.3 In 1997,
we introduced a variant of dithiane chemistry, specifically
the use of silyl dithianes for multicomponent linchpin
couplings of diverse epoxide electrophiles, exploiting a
solvent-controlled Brook rearrangement.4 This tactic now
comprises the central strategic element in several completed
and ongoing synthetic ventures in our laboratory.5 To
advance this synthetic tactic further we have recently
explored the use of nitrogen-containing electrophiles such
as N-Ts aziridines6 as the second electrophilic agent in the
(1) (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4,
1075. (b) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231.
(2) Reviews: (a) Seebach, D. Synthesis 1969, 1, 17. (b) Grobel, B. T.;
Seebach, D. Synthesis 1977, 357. (c) Page, P. C. B.; Van Niel, M. B.;
Prodger, J. C. Tetrahedron 1989, 45, 7643. (d) Kolb, M. In Encyclopedia
of Reagents for Organic Synthesis; Paquette, L. A., Ed.; John Wiley &
Sons: Chichester, 1995; Vol. 5, p 2983. (e) Yus, M.; Najera, C.; Foubelo,
F. Tetrahedron 2003, 59, 6147.
(3) (a) Smith, A. B., III; Condon, S. M.; McCauley, J. A. Acc. Chem.
Res. 1998, 31, 35 and references therein. (b) Smith, A. B., III; Lodise, S.
A. Org. Lett. 1999, 1, 1249. (c) Smith, A. B., III; Doughty, V. A.; Lin, Q.;
Zhuang, L.; McBriar, M. D.; Boldi, A. M.; Moser, W. H.; Murase, N.;
Nakayama, K.; Sobukawa, M. Angew. Chem., Int. Ed. 2001, 40, 191. (d)
Smith, A. B., III; Lin, Q.; Doughty, V. A.; Zhuang, L.; McBriar, M. D.;
Kerns, J. K.; Brook, C. S.; Murase, N.; Nakayama, K. Angew. Chem., Int.
Ed. 2001, 40, 196. (e) Smith, A. B., III; Adams, C. M.; Lodise Barbosa, S.
A.; Degnan, A. P. J. Am. Chem. Soc. 2003, 125, 350. (f) Smith, A. B., III;
Zhu, W.; Shirakami, S.; Sfouggatakis, C.; Doughty, V. A.; Bennett, C. S.;
Sakamoto, Y. Org. Lett. 2003, 5, 761.
(4) (a) Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc. 1997, 119,
6925. Also see: (b) Smith, A. B., III; Pitram, S. M.; Boldi, A. M.; Gaunt,
M. J.; Sfouggatakis, C.; Moser, W. H. J. Am. Chem. Soc. 2003, 125, 14435.
(5) (a) Smith, A. B., III; Zhuang, L.; Brook, C. S.; Boldi, A. M.; McBriar,
M. D.; Moser, W. H.; Murase, N.; Nakayama, K.; Verhoest, P. R.; Lin, Q.
Tetrahedron Lett. 1997, 38, 8667. (b) Smith, A. B., III; Zhuang, L.; Brook,
C. S.; Lin, Q.; Moser, W. H.; Trout, R. E. L.; Boldi, A. M. Tetrahedron
Lett. 1997, 38, 8671. (c) Smith, A. B., III; Lin, Q.; Nakayama, K.; Boldi,
A. M.; Brook, C. S.; McBriar, M. D.; Moser, W. H.; Sobukawa, M.; Zhuang,
L. Tetrahedron Lett. 1997, 38, 8675. (d) Smith, A. B., III; Pitram, S. M.
Org. Lett. 1999, 1, 2001. (e) Smith, A. B., III; Doughty V. A.; Sfouggatakis,
C.; Bennett, C. S.; Koyanagi J.; Takeuchi, M. Org. Lett. 2002, 4, 783. (f)
Smith, A. B., III; Pitram, S. M.; Fuertes, M. J. Org. Lett. 2003, 5, 2751. (g)
Smith, A. B., III; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.; Sfouggatakis,
C.; Moser, W. H. J. Am. Chem. Soc. 2003, 125, 14435.
10.1021/ol049601b CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/31/2004

multicomponent linchpin protocol for accessing protected
1,5-amino alcohols in a stereocontrolled fashion (Scheme
1).7
Scheme 3
Scheme 1
In this Letter, we report application of this tactic for the
efficient construction of (-)-indolizidine 223AB (1), a
representative alkaloid isolated from the skin of the neotro-
pical dart-poison frogs belonging to the genus Dendrobates
(Scheme 2).8 Our synthetic approach calls for the construc-
Scheme 2
via the Carreira protocol, using the Jiang chiral ligand (-)-
7.13 Protection of the hydroxyl functionality as the TBS ether,
followed in turn by nonstereoselective epoxidation with
m-CPBA and complete hydrogenation of the triple bond,
furnished (+)-3 and 2-epi-(+)-3, as a diastereomeric mixture
(8) (a) Daly, J. W.; Brown, G. B.; Mensah-Dwumah, M. M.; Meyers,
C. W. Toxicon 1978, 16, 163. (b) Tokuyama, T.; Nishimori, N.; Karle, I.
K.; Edwards, M. W.; Daly, J. W. Tetrahedron 1986, 42, 3453. For synthesis
of (-)-indolizidine 223AB, see: (c) Royer, J.; Husson, H. P. Tetrahedron
Lett. 1985, 26, 1515. (d) Taber, D. F.; Deker, P. B.; Silverberg, L. J. J.
Org. Chem. 1992, 57, 5990. (e) Machinaga, N.; Kibayashi, C. J. Org. Chem.
1992, 57, 5178. (f) Fleurant, A.; Ce´le´rier, J. P.; Lhommet, G. Tetrahedron:
Asymmetry 1993, 4, 1429. (g) Muraoka, O.; Okumura, K.; Maeda, T.;
Tanabe, G.; Momose, T. Tetrahedron: Asymmetry 1994, 5, 317. (h) Pilli,
R. A.; Dias, L. C.; Maldaner, A. O. J. Org. Chem. 1995, 60, 717. (i) Takahat,
H.; Bandoh, H.; Momose, T. Heterocycles 1995, 41, 1797. (j) Momose,
T.; Toshima, M.; Koike, Y.; Toyooka, N.; Hirai, Y. J. Chem. Soc., Perkin
Trans. 1 1997, 9, 1315. (k) Ce´lime`ne, C.; Dhimane, H.; Lhommet, G.
Tetrahedron 1998, 54, 10457. (l) Lee, E.; Jeong, E. J.; Min, S. J.; Hong,
S.; Lim, J.; Kim, S. K.; Kim, H. J.; Choi, B. G.; Koo, K. C. Org. Lett.
2000, 2, 2169.
(9) (a) Oppolzer, W.; Flaskamp, E.; Bieber, L. W. HelV. Chim. Acta 2001,
84, 141. (b) Oka, T.; Yasusa, T.; Ando, T.; Watanabe, M.; Yoneda, F.;
Ishida, T.; Knoll, J. Bioorg. Med. Chem. 2001, 9, 1213.
(10) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc.
2001, 123, 9687.
(11) (a) Annis, D. A.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121,
4147. (b) Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J. Org. Chem.
1998, 63, 6776. (c) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga,
M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307.
(12) Absolute configuration was established by Kakisawa analysis of
the Mosher esters of (-)-8: Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa,
H. J. Am. Chem. Soc. 1991, 113, 4092.
tion of 2, via a three-component linchpin coupling of silyl
dithiane 4 with epoxide 3 and known aziridine 5,9 followed
by sequential conversion to the indolizidine alkaloid.
We began this venture with the ready construction of
scalemic epoxide 3, exploiting Carreira alkyne methodol-
ogy,10 in conjunction with a Jacobsen hydrolytic kinetic
resolution (HKR)11 (Scheme 3). Toward this end, propargylic
alcohol (-)-812 (Scheme 3) was prepared from commercially
available 4-pentenal 6 both in high yield and with excellent
enantioselectivity (>99% ee determined by chiral HPLC)
(6) For N-Ts aziridine ring-opening reactions of lithiated dithiane anions,
see: (a) Bates, G. S. J. Chem. Soc., Chem. Commun. 1979, 161. (b) Howson,
W.; Osborn, H. M. I.; Sweeney, J. J. Chem. Soc., Perkin Trans. 1 1995,
2439. (c) Mao, H.; Joly, G. J.; Peeters, K.; Hoornaert, G. J.; Compernolle,
F. Tetrahedron 2001, 57, 6955. (d) Reich, H. J.; Sanders, A. W.; Fiedler,
A. T.; Bevan, M. J. J. Am. Chem. Soc. 2002, 124, 13386.
(7) There is one report of an intramolecular linchpin reaction between a
dithiane and the 1,4-biselectrophile, 1,2-epimino-3,4-epoxy-(N-Ts)butane,
in which the aziridine moiety played a role as the second electrophile;
Harms, G.; Schaumann, E.; Adiwidjaja, G. Synthesis 2001, 4, 577.
(13) (a) Jiang, B.; Chen, Z.; Xiong, W. Chem. Commun. 2002, 1524.
Using (+)-N-methyl ephedrine as a chiral ligand, we obtained (-)-8 in 44
% isolated yield and 96 % ee. For preparation of (-)-7, see: (b) Jiang, B.;
Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451.
1494
Org. Lett., Vol. 6, No. 9, 2004

Scheme 4
Scheme 5
(ca. 1:1). Jacobsen-HKR employing 1011 as the catalyst led
to the desired epoxide (+)-3 along with diol (+)-11, both
diastereomerically pure (e.g., H and 13C NMR).14 After
1
tion.17 Reductive removal of the dithiane with Raney Ni then
separation by flash chromatography, diol (+)-11 was trans-
formed to (+)-3 by chemoselective pivaloylation, followed
by mesylation of the secondary alcohol and ring closure
employing potassium carbonate.15 In this way, the mixture
of (+)-3 and 2-epi-(+)-3 was transformed into pure (+)-3,
with an overall efficiency of 81%.
completed the synthesis of (-)-indolizidine 223AB (1),18
1
which possessed spectral data (e.g., 500 MHz H and 125
Hz 13C) identical in all respects to the spectral data of
authentic synthetic (-)-indolizidine 223AB (1)8l provided
by Professor Eun Lee (Seoul National University).
With epoxide (+)-3 and known aziridine (-)-5 available,9
the latter readily prepared from D-norvaline in two steps,9a
we executed the multicomponent linchpin coupling. Pleas-
ingly, lithiation of dithiane 4 in Et2O (-78 °C), followed in
turn by addition of epoxide (+)-3, warming to -25 °C over
a period of 1 h, stirring the reaction mixture for an additional
4 h at -25 °C, and then adding aziridine (-)-5 in Et2O
containing HMPA (0.6 equiv) and warming to 0 °C,
furnished (-)-2 in 56% isolated yield, accompanied by
dithiane (-)-12 (24%) not having undergone reaction with
aziridine (-)-5 (Scheme 4).16 The structure of (-)-2 was
In summary, an efficient, highly stereocontrolled synthesis
of (-)-indolizidine 223 AB (1) has been achieved. Highlights
of the synthesis include the three-component linchpin
coupling of (+)-3, 4, and (-)-5, followed by a one-pot
sequential cyclization to construct the indolizidine ring. The
longest linear sequence from 4-pentenal (6) to (-)-1,
proceeding in an overall yield of 10%, was 10 steps.
Importantly, the synthetic strategy holds promise for the
construction of a wide variety of indolizidine, quinolizidine,
and quinolizine alkaloids, simply by altering the epoxide and
aziridine of the three-component linchpin coupling protocol.
Studies both to employ this tactic for alkaloid synthesis and
to exploit other nitrogen-containing electrophiles are under-
way in our laboratory and will be reported in due course.
1
secured by careful H and 13C NMR experiments.
Having arrived at the carbon backbone of (-)-indolizidine
223AB (1), we now faced the task of constructing the
indolizidine ring system (Scheme 5). Toward this end,
removal of the TBS groups in (-)-2 (TBAF/THF) furnished
diol (-)-13 in high yield. Mesylation (MsCl, TEA, DCM, 1
h), followed without purification of the bismesylate by
treatment with potassium carbonate in MeOH for 3 h and
then addition of excess sodium amalgam (5%) directly to
the reaction mixture to liberate the secondary amine, led to
(-)-14, the product of double cyclization. The yield for this
sequential construction of the indolizidine ring system was
excellent (95%). Importantly, the dithiane moiety proved to
be critical (i.e., reactive rotamer effect) in this transforma-
Acknowledgment. Financial support was provided by the
National Institutes of Health (Institute of General Medical
Sciences) through Grant GM-29028. We also thank Professor
Eun Lee, Seoul National University, for kindly providing
the 300 MHz 1H and 75 MHz 13C NMR of (-)-indolizidine
223AB.
Supporting Information Available: Spectroscopic and
analytical data and selected experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL049601B
(14) Relative and absolute configurations were confirmed by Kakisawa
analysis12 of the Mosher esters of diol 11.
(17) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224. Without
the dithiane moiety, the first cyclization was very slow (40 h), resulting in
low yield (55% for mesylation and the first cyclization).
(18) Optical rotations in two solvents were [R]D -43° (c 0.47, n-hexane)
(lit.8b -44° (c 1.0, n-hexane)) and [R]D -85° (c 0.42, MeOH) (lit.8h -88°
(c 0.50, MeOH)).
(15) Chang, J.; Paquette, L. A. Org. Lett. 2002, 4, 253.
(16) In step C, rapid warming to 0 °C after addition of aziridine (-)-5
proved to be more consistent and furnished better yields. Slow warming
over 1-2 h resulted in capricious behavior (ca. 30∼50%), in conjunction
with large amounts of (-)-12.
Org. Lett., Vol. 6, No. 9, 2004
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