A general, convergent strategy for the construction of indolizidine alkaloids: Total syntheses of (-)-indolizidine 223AB and alkaloid (-)-205B

Article abstract of DOI:10.1021/jo052314g

N-Toluenesulfonyl aziridines comprise effective second electrophiles in the solvent controlled three-component linchpin union of silyl dithianes for the stereocontrolled convergent elaboration of protected 1,5-amino alcohols. This tactic, in conjunction w

Full text of DOI:10.1021/jo052314g

VOLUME 71, NUMBER 7
MARCH 31, 2006
© Copyright 2006 by the American Chemical Society
A General, Convergent Strategy for the Construction of Indolizidine
Alkaloids: Total Syntheses of (-)-Indolizidine 223AB and Alkaloid
(-)-205B†
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 NoVember 8, 2005
N-Toluenesulfonyl aziridines comprise effective second electrophiles in the solvent controlled three-
component linchpin union of silyl dithianes for the stereocontrolled convergent elaboration of protected
1,5-amino alcohols. This tactic, in conjunction with a one-flask sequential cyclization, constitutes an
effective general strategy for the construction of indolizidine and related alkaloids, illustrated here with
the total syntheses of (-)-indolizidine 223AB (1) and alkaloid (-)-205B (2).
Introduction
of 1,3-dithiane chemistry, specifically the use of silyl 1,3-
dithianes as a tactic for the one-flask multicomponent union of
diverse epoxides, exploiting a solvent controlled Brook rear-
rangement,5 to access differentially protected monosilyl 1,5-
diol moieties with precise stereocontrol (Scheme 1). Initially
In 1965, Corey and Seebach introduced the use of 1,3-
dithianes as important umpolung linchpins in organic synthesis.1
This tactic for over 40 years has become a mainstay for the
union of both simple and complex fragments.2 A wide range of
electrophiles, including alkyl halides, aldehydes, and epoxides,
react smoothly with the derived acylanion equivalents.3 In 1997,
on the basis of the precedent by Tietze,4 we reported a variant
(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. (g) Smith, A. B., III; Adams, C. M.
Acc. Chem. Res. 2004, 37, 365.
† This paper is dedicated to the memory of professor Kenji Koga (Tokyo
University), scholar, gentleman, and friend.
(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, 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.
(4) Tietze, L. F.; Geissler, H.; Gewert, J. A.; Jakobi, U. Synlett 1994,
511.
10.1021/jo052314g CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/27/2006
J. Org. Chem. 2006, 71, 2547-2557
2547

Smith and Kim
SCHEME 1
SCHEME 2
designed for the construction of the spiroketal segments of the
highly potent antitumor spongistatins, this multicomponent
coupling tactic has been employed for the gram-scale synthesis
of a number of valuable advanced synthetic intermediates in
several completed and ongoing synthetic ventures in our
laboratory.6
To advance further the utility of this chemistry, we recently
explored the use of nitrogen containing electrophiles, such as
N-Ts aziridines,7 as the second electrophile to access protected
1,5-amino alcohols (Scheme 2).8 We reasoned that the resulting
1,5-amino alcohols could be exploited as advanced intermediates
for the construction of 3,5-disubstituted indolizidine rings, via
subsequent intramolecular alkylation of the 1,5-amino alcohols,
wherein the nitrogen would act as a nucleophile, attacking
electrophilic carbons bearing activated oxygen substituents. The
dithiane moiety would also play a significant role in the
subsequent construction of the bicyclic indolizidine system by
inducing a conformation that would accelerate the cyclization
(i.e., Thorpe-Ingold effect).9 From the synthetic perspective,
this convergent synthetic strategy should hold considerable
promise, given the flexibility of both the structure and/or
absolute configurations of the epoxide and aziridine coupling
partners, thereby permitting the stereoselective synthesis of all
possible diastereomers, as well as numerous analogues of this
alkaloid class. Functionalization at C(6), C(7), or C(8) of the
indolizidine system would also be possible by employing the
reinstated C(7) carbonyl upon removal of the dithiane. This
strategy would thus take full advantage of the versatility of the
1,3-dithiane group: first, as a linchpin in the bisalkylation step;
second, as an auxiliary augmenting the cyclization step; and
third, as a carbonyl protecting group.
Indolizidine alkaloids, disubstituted at the C(3) and C(5)
positions, comprise the first in class to have been discovered,
principally as components in the skin extracts of neotropical
frogs.10 Possessing a multitude of interesting biological activities
such as blocking nicotinic receptor-channels, many alkaloids
in this class have become attractive synthetic targets. Among
these, (-)-indolizidine 223AB (1, Figure 1) has been constructed
10 times, and as such it serves as an excellent test case for any
new synthetic strategy.11
FIGURE 1. Structures of (-)-indolizidine 223AB (1) and alkaloid
(-)-205B (2).
Alkaloid (-)-205B (2), a structurally more complex alkaloid,
also isolated from the skin of a neotropical frog (Dendrobates
pumilo) endemic to Panama, possesses an unusual tricyclic 8b-
azaacenaphthylene ring system,12 which embodies a similar 3,5-
(5) (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.
(6) (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.
(7) For early examples of N-Ts aziridine ring opening reactions by
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.
(8) Prior to the work reported here, there was one report of an
intramolecular linchpin reaction between bis(methylthio)trimethylsilyl-
methane and 1,4-biselectrophile, 1,2-epimino-3,4-epoxy-(N-Ts)butane, in
which the aziridine moiety played the role as the second electrophile:
Harms, G.; Schaumann, E.; Adiwidjaja, G. Synthesis 2001, 577.
(9) (a) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224. (b)
Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915, 107, 1080.
(c) Ingold, C. K. J. Chem. Soc. 1921, 119, 305.
(10) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical
and Biological PerspectiVe; Pelletier, S. W., Ed.; Pergamon: New York,
1999; Vol. 13, p 1.
(11) (a) Daly, J. W.; Brown, G. B.; Mensah-Dwumah, M. M.; Meyers,
C. W. Taxicon 1978, 16, 163. (b) Tokuyama, T.; Nishimori, N.; Karle, I.
K.; Edwards, M. W.; Daly, J. W. Tetrahedron 1986, 42, 3453. For the
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.
2548 J. Org. Chem., Vol. 71, No. 7, 2006

Strategy for Indolizidine Alkaloid Syntheses
SCHEME 4
disubstituted indolizidine system encased within the skeleton.
To date, only one report on the synthesis of this more complex
alkaloid has appeared. Toyooka and co-workers in 2003 dis-
closed the synthesis of (+)-205B, the un-natural antipode, there-
by establishing the absolute configuration.13 A central feature
of the Toyooka synthesis involved a series of Michael-type
additions to enaminoesters; the longest linear sequence required
30 steps from known (S)-6-(tert-butyldiphenylsilyloxymethyl)-
piperidin-2-one. Although the biological properties of the
naturally occurring congener of 205B remain unknown, presum-
ably due to lack of material, the unnatural (+)-antipode was
reported recently to be a potent antagonist of the R7 nicotinic
receptor.14 In this, a full account, we present the total syntheses
of both (-)-indolizidine 223AB (1) and alkaloid (-)-205B (2).15
Results and Discussions
Total Synthesis of (-)-Indolizidine 223AB: Retrosynthetic
Analysis. Our synthetic approach for the prototype 3,5-
disubstituted indolizidine alkaloid 223AB (1) calls for the
construction of protected amino alcohol 3, via a solvent
controlled, three-component linchpin coupling of silyl dithiane
5 with epoxide 4 and known aziridine 6,16 followed by sequential
conversion to the indolizidine alkaloid (Scheme 3).
SCHEME 3
functionality as the TBS ether, followed by Sharpless asym-
metric dihydoxylation,20 furnished diol 12 as a diastereomeric
mixture (ca. 7.5:1), which proved quite difficult to separate,
either at this stage or at the stage of the corresponding epoxide.
We therefore turned to the Jacobsen hydrolytic kinetic resolution
(HKR)21 to obtain pure epoxide (+)-4 for the coupling protocol.
Epoxidation of (+)-11 without stereocontrol employing m-
CPBA, followed by complete hydrogenation of the triple bond,
furnished (+)-4 and 2-epi-(+)-4, as a diastereomeric mixture
(ca. 1:1). Jacobsen-HKR employing (R,R)-13‚OAc as the
catalyst readily led to the desired epoxide (+)-4, along with
Epoxide 4. We began this venture with the construction of
epoxide 4 (Scheme 4). Toward this end, propargylic alcohol
(-)-817 was prepared from commercially available 4-pentenal
7 via the Carreira protocol.18 Using (+)-N-methylephedrine (9)
as a chiral ligand, we obtained (-)-8 in 44% isolated yield and
96% ee (chiral HPLC). Better results were obtained by employ-
ing the Jiang chiral ligand (-)-10.19 In this case, (-)-8 was
obtained in 83% yield and 99% ee. Protection of the hydroxyl
1
diol (+)-14, both diastereomerically pure (e.g., H and 13C
NMR).22 After separation by flash chromatography, diol (+)-
14 was transformed to (+)-4 by chemoselective pivaloylation,
followed in turn by mesylation of the secondary alcohol and
ring closure employing potassium carbonate.
The Solvent Controlled, Three-Component Linchpin
Union. With epoxide (+)-4 and known aziridine (-)-6 available,
the latter readily prepared from (D)-norvaline in 2 steps,16a we
(12) (a) Tokuyama, T.; Nishimori, N.; Shimada, A.; Edwards, M. W.;
Daly, J. W. Tetrahedron 1987, 43, 643. (b) Tokuyama, T.; Garraffo, H.
M.; Spande, T. F.; Daly, J. W. An. Asoc. Quim. Argent. 1998, 86, 291.
(13) (a) Toyooka, N.; Fukutome, A.; Shinoda, H.; Nemoto, H. Angew.
Chem., Int. Ed. 2003, 42, 3808. (b) Toyooka, N.; Fukutome, A.; Shinoda,
H.; Nemoto, H. Tetrahedron 2004, 60, 6197.
(14) Tsuneki, H.; You, Y.; Toyooka, N.; Kagawa, S.; Kobayashi, S.;
Sasaoka, T.; Nemoto, H.; Kimura, I.; Dani, J. A. Mol. Pharmacol. 2004,
66, 1061.
(19) (a) Jiang, B.; Chen, Z.; Xiong, W. Chem. Commun. 2002, 1524.
For preparation of (-)-10, see: (b) Jiang, B.; Chen, Z.; Tang, X. Org. Lett.
2002, 4, 3451.
(15) For our initial disclosure on this work, see: Smith, A. B., III; Kim,
D.-S. Org. Lett. 2004, 6, 1493; 2005, 7, 3247.
(16) (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.
(17) The 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.
(18) (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.
(20) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(21) (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.
(22) The relative and absolute configurations were confirmed by Kak-
isawa analysis of the Mosher esters of diol (+)-14; see ref 17.
J. Org. Chem, Vol. 71, No. 7, 2006 2549

Smith and Kim
SCHEME 5
SCHEME 7
proceeded with the multicomponent union. Pleasingly, lithiation
of dithiane 5 in Et2O (-78 °C), followed in turn by addition of
epoxide (+)-4, warming to -25 °C over a period of 1 h, stirring
for an additional 4 h at -25 °C, and then addition of aziridine
(-)-6 in Et2O containing HMPA (0.65 equiv) to effect the
solvent controlled Brook rearrangement furnished (-)-3 in 56%
isolated yield, accompanied by dithiane (-)-15 (24%), the latter
not having undergone reaction with aziridine (-)-6 (Scheme
5). Best results were obtained employing rapid warming to 0
°C after addition of aziridine (-)-6. Slower warming over 1-2
h resulted in capricious behavior (ca. 30-50%), in conjunction
with formation of large amounts of (-)-15. The structure of
indolizidine (-)-17 however proved ineffective; at best (-)-17
was isolated in 13% yield. Removal of the dithiane prior to
cyclization did not improve this transformation.
Our initial failure to achieve an effective one-flask cyclization
led us to explore a stepwise scenario (Scheme 7). Pleasingly,
monocycle (+)-19 could be obtained in excellent yield (94%)
upon removal of the TBS groups and in turn bismesylation and
treatment of the resultant bismesylate with potassium carbonate
in MeOH. Equally encouraging, treatment of (+)-19 with 5%
Na-Hg led selectively to removal of the N-Ts group in the
presence of both the dithiane and O-mesylate moiety to furnish
20, which in turn underwent the requisite second cyclization to
furnish indolizidine (-)-17 in 60% yield.
Crucial for efficient cyclization was the dithiane moiety (i.e.,
Thorpe-Ingold effect).9 Without the dithiane, cyclization of (+)-
21 proved extremely slow (40 h), furnishing (-)-22 at best in
55% yield (Scheme 8), compared to the similar two step
sequence of (-)-18 to (+)-19 (Scheme 7), which proceeded in
94% yield.
1
(-)-3 was secured by H and 13C NMR analysis.
Development of a One-Flask Sequential Construction of
the 3,5-Disubstituted Indolizidine Skeleton. Having achieved
elaboration of the carbon backbone of (-)-indolizidine 223AB
(1), we now faced the task of generating the bicyclic indolizidine
ring. Toward this end, aminodiol (-)-16, obtained after removal
of the Ts group (Na/NH3) and the TBS groups (TBAF), was
subjected to Mitsunobu or related protocols (Scheme 6).23
Unfortunately, all attempts to convert (-)-16 directly to
SCHEME 6
SCHEME 8
Careful additional experimentation revealed that sequential
cyclization sequence could be conducted in a highly efficient
manner in a single flask (Scheme 9). For example, bismesylation
(23) (a) Stoilvoa, V.; Trifonov, L. S.; Orahovats, A. S. Synthesis 1979,
105. (b) Mereyala, H. B.; Gaddam, B. R. J. Chem. Soc., Perkin Trans. 1
1994, 2187. (c) Bernotas, R. C.; Cube, R. V. Tetrahedron Lett. 1991, 32,
161.
2550 J. Org. Chem., Vol. 71, No. 7, 2006

Strategy for Indolizidine Alkaloid Syntheses
SCHEME 9
SCHEME 11
axial methyl, removing the dithiane, and incorporating of the
3,4-trisubstituted olefin. The latter transformation was employed
by Toyooka et al. in their synthesis of the un-natural enantiomer
of alkaloid 205B (2).13 That introduction of the C(6) axial methyl
substituent might prove problematic was clearly recognized (vide
infra).
Construction of Linchpin Components: Aziridine 26 and
Epoxide 27. We initiated the synthesis of alkaloid (-)-205B
(2) with construction of aziridine 26 (Scheme 11). Tosylation
of the nitrogen of commercially available serine methyl ester
hydrochloride (-)-28, followed by Mitsunobu ring closure,
furnished aziridine (+)-29,25 which upon treatment with MeMgCl
led to tertiary alcohol (+)-30. Dehydration with Martin sul-
furane26 afforded aziridine (+)-26; the overall yield for the four-
step sequence was 66%.
followed in turn without purification by treatment with potas-
sium carbonate in MeOH for 3 h, and then addition of excess
sodium amalgam (5%) directly to the reaction mixture furnished
(-)-17 in excellent yield (95%). Reductive removal of the
dithiane with Raney Ni completed the synthesis of (-)-
indolizidine 223AB (1), identical in all respects (e.g., 500 MHz
1H, 125 Hz 13C NMR, IR, HRMS, and optical rotation) with
the spectra derived from synthetic (-)-indolizidine (1).24
Total Synthesis of Alkaloid (-)-205B: An Initial Synthetic
Plan. Given the successful completion of (-)-indolizidine
223AB, we envisioned a similar approach to the structurally
more complex tricyclic alkaloid (-)-205B (2); a three compo-
nent linchpin coupling of TBS dithiane 5 with epoxide 27 and
aziridine 26, followed by our recently devised one-flask
sequential cyclization of 25, would deliver the requisite 3,5-
disubstituted indolizidine ring embedded in alkaloid (-)-205B
(Scheme 10). A successful ring closing metathesis (RCM) would
To construct epoxide 27, we turned to Brown asymmetric
crotylation27 of known aldehyde (-)-3128 employing (Z)-
crotylborane 32 to provide homoallylic alcohol 33 in good yield
(80%), albeit as an inseparable diastereomeric mixture (5.6:1)
of secondary alcohols (Scheme 12). With the enantiomeric
SCHEME 12
SCHEME 10
aldehyde (+)-31, a similar diastereoselectivity (ca. 6:1) was
observed under the same reaction conditions, suggesting that
we were not dealing with a mismatched case. To eliminate the
then secure the 8b-azaacenaphthylene skeleton. To complete the
synthesis, we would next face the task of introducing the C(6)
J. Org. Chem, Vol. 71, No. 7, 2006 2551

Smith and Kim
TABLE 1. Solvent Controlled Three-Component Linchpin Union
with Aziridine (+)-26
SCHEME 13
yield (%)
entry
1
conditions in step C
(-)-25
(+)-37
Et2O, HMPA (3 equiv)
10 min at -60 °C
then 0 °C to rt over 12 h
THF, HMPA (0.8 equiv)
10 min at -78 °C
then, 14 h at -25 °C
THF, 10 min at -78 °C
then, 5 h at 0 °C
15
40
disubstituted indolizidine ring, embedded in the 8b-azaacenaph-
thylene tricyclic ring of alkaloid (-)-2, was next achieved in
good yield (70%) via the previously devised sequential cycliza-
tion protocol (Scheme 13). Equally pleasing, RCM with the
second generation Grubbs catalyst 3832 proved highly efficient,
furnishing tricyclic amine (-)-23 in near quantitative yield.
Installation of the Axial Methyl Group at C(6): A Difficult
Transformation. From the outset, we recognized that reduction
of the trisubstituted olefin in (+)-39 derived from (-)-23
(Scheme 14) would at best be difficult, given that molecular
modeling of the ketone suggested a concave/convex conforma-
tion (39A) in favor of the more plane conformation (39B) by
ca. 5 kcal/mol (Figure 2).
2
3
12
33
63
46
possibility of chelation with the existing chiral center,29 we
replaced the acetonide with TBS groups. Pleasingly, Brown
crotylation of known aldehyde (-)-3430 with (Z)-crotylborane
32 furnished a significantly improved diastereomeric mixture
(ca. 11:1). Protection of the resulting secondary alcohol (-)-
35 as BPS ether, followed by removal of the TBS groups, next
led to diol (-)-36. Completion of epoxide (-)-27 was then
achieved via an efficient one-flask Fraser-Reid diol to epoxide
transformation.31
The Solvent Controlled Three-Component Linchpin Union.
With aziridine (+)-26 and epoxide (-)-27 in hand, we executed
the multicomponent union (Table 1). In this case, use of HMPA
resulted at best in low yields (entries 1 and 2). Somewhat better
results were obtained with THF as the cosolvent to trigger the
Brook rearrangement. However, the yield of coupling product
(-)-25 remained moderate (33%), accompanied by a significant
amount of dithiane (+)-37 (entry 3). Notwithstanding the
moderate yield of (-)-25, we continued with the synthesis. We
will return to this linchpin union in our second-generation
approach (vide infra).
Elaboration of the 8b-Azaacenaphthylene Ring System.
Sequential closure of the two rings that comprise the 3,5-
FIGURE 2. Comparison of two conformations of the hydrogenation
substrate (+)-39 (Monte Carlo conformational search, 1000 steps,
chloroform GB/SA solvation model).
(24) We thank Professor Eun Lee, Seoul National University, for kindly
providing the 300 MHz 1H and 75 MHz 13C NMR spectra of synthetic
(-)-indolizidine 223AB.
(25) (a) Baldwin, J.; Spivey, A. C.; Schofield, C. J.; Sweeney, J. B.
Tetrahedron 1993, 49, 6309. (b) Bergmeier, S. C.; Seth, P. P. J. Org. Chem.
1997, 62, 2671. (c) Fujii, N.; Nakai, K.; Tamamura, H.; Otaka, A.; Mimura,
N.; Miwa, Y.; Taga, T.; Yamamoto, Y.; Ibuka, T. J. Chem. Soc., Perkin
Trans. 1 1995, 1359.
(26) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003.
(27) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(28) Schmidt, U.; Lieberknecht, A.; Kazmaier, U.; Griesser, H.; Jung,
G.; Metzger, J. Synthesis 1991, 49.
(30) (a) Shimizu, A.; Nishiyama, S. Tetrahedron Lett. 1997, 38, 6011.
(b) Chattopadhyay, S.; Mamdapur, V. R.; Chadha, M. S. Tetrahedron 1990,
46, 3667. Aldehyde (-)-34 was prepared in 4 steps and 95% overall yield
from commercially available ethyl (S)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-
2-propenoate (i): See Supporting Information for details.
(29) Berninger, J.; Koert, U.; Eisenberg- Ho¨hl, C.; Knochel, P. Chem.
Ber. 1995, 128, 1021.
2552 J. Org. Chem., Vol. 71, No. 7, 2006

Strategy for Indolizidine Alkaloid Syntheses
SCHEME 15
We nonetheless felt compelled to explore the hydrogenation
scenario. Removal of the dithiane moiety in (-)-23 employing
the Stork protocol33 [e.g., bis(trifluoroacetoxy)-iodobenzene]
furnished ketone (+)-39, which was subjected to hydrogenation
(Scheme 14). Not surprisingly, the undesired epimer (-)-40 was
obtained as the major product (ca. 4.5:1).
SCHEME 14
ketone 45, the latter available again exploiting our three-
component linchpin union, now employing aziridine 47, fol-
lowed by an effective one-flask sequential cyclization.
Aziridine 47 proved readily available from the previously
prepared (+)-29, via treatment with MeLi (1.05 equiv) at -78
°C to furnish ketone (+)-48 in excellent yield (92%); protection
of the carbonyl as the ethylene ketal employing the Noyori
protocol35 then led to (+)-47 (Scheme 16).
SCHEME 16
We also explored hydroiodination34 of (-)-23 with PI3
followed by stereoselective reduction of the corresponding
iodide (-)-42 as a possible scenario to access (-)-41; unfor-
tunately, none of the desired axial product was obtained. The
structure and absolute configuration of iodide (-)-42 were
confirmed by X-ray crystallographic analysis.
A Second Generation Approach. Given that vinyl aziridine
(+)-26 proved less than an optimal second electrophile in the
three-component linchpin union (Table 1), in conjunction with
the inherent difficulty in installing the axial methyl group, we
revised our synthetic plan. In particular, we envisioned that the
C(6) axial methyl group might be installed employing ketone
44 given the anticipated attack from the less encumbered convex
surface (Scheme 15). Ketone 44 in turn would be obtained via
RCM of the corresponding kinetic enol ether derived from
The Three-Component Linchpin Union with Aziridine
(+)-47. As in the case of aziridine (+)-26, use of HMPA or
DMPU to trigger the Brook rearrangement resulted only in poor
yields (Table 2; entries 1-3). A solvent system comprising
tetrahydrofuran, containing 3.2 equiv of 1,2-dimethoxyethane
(DME), however led to a significant improvement, furnishing
the three-component adduct (+)-46 in 53% yield, albeit still
mixed with 31% of (+)-37, the latter not having undergone the
second alkylation (entry 5).
(31) (a) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203. (b) Cink, R.
D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122.
(32) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(33) (a) Fleming, F. F.; Funk, L.; Altundas, R.; Tu, Y. J. Org. Chem.
2001, 66, 6502. (b) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(34) Kropp, P. J.; Daus, K. A.; Tubergen, M. W.; Kepler, K. D.; Wilson,
V. P.; Craig, S. L.; Baillargeon, M. M.; Breton, G. B. J. Am. Chem. Soc.
1993, 115, 3071.
(35) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357.
J. Org. Chem, Vol. 71, No. 7, 2006 2553

Smith and Kim
TABLE 2. Three-Component Linchpin Union with Aziridine
(+)-47
provided ketone (+)-45, which upon treatment with lithium
hexamethyldisilazide (LHMDS) in the presence of TMSCl
furnished the kinetic silyl enol ether. RCM employing the second
generation Grubbs catalyst (38) efficiently led to the requisite
advanced tricyclic dithiane (+)-44 as a beautiful crystalline solid
(mp 101 °C) in 81% yield for the two steps.36 Single-crystal
X-ray analysis established both the structure and relative
stereochemistry of (+)-44.
Stereoselective Installation of the C(6) Axial Methyl
Group. To install the requisite axial methyl group at C(6) in
(+)-44 via an SN2 tactic, equatorial alcohol (+)-50 was prepared
by reduction of (+)-44 with NaBH4; a single isomer resulted
(Scheme 18). The stereogenicity of the newly generated
secondary hydroxyl was secured by NMR analysis. Unfortu-
nately, all attempts to displace the derived tosylate in (+)-51
with a variety of nucleophiles either proceeded in low yield or
furnished elimination products.
SCHEME 18
yield (%)
entry
solvents
(+)-46
(+)-37
1
2
3
4
5
Et2O, HMPA (0.7 equiv)
THF, HMPA (0.4 equiv)
THF, DMPU (1 equiv)
THF
6
12
56
70
no desired product
39
53
24
31
THF, DME (3.2 equiv)
Ring Closing Metathesis Construction of 8b-Azacenaph-
thylene Ring System. Removal of the two silyl groups in (+)-
46 with TBAF next furnished the corresponding diol, which
was subjected to the one-flask sequential cyclization protocol
(Scheme 17); pleasingly, indolizidine (+)-49 was obtained in
70% yield. Acid promoted removal of the acetonide then
SCHEME 17
We next turned to the C(6) exomethylene derivative (+)-52,
prepared from (+)-44 via Wittig olefination, followed by
removal of the dithiane (Scheme 19). Not surprisingly, hydro-
genation again proceeded from the less hindered R face to
furnish predominately the C(6) equatorial methyl congener (-)-
40 (ca. 5:1) under both neutral or acidic conditions.
SCHEME 19
Undaunted, we explored the methyl enol ether derived from
ketone (+)-44, reasoning that it might be possible to modulate
(36) (a) Okada, A.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2001,
42, 8023. (b) Arisawa, M.; Theeraladanon, C.; Nishida, A.; Nakagawa, M.
Tetrahedron Lett. 2001, 42, 8029.
2554 J. Org. Chem., Vol. 71, No. 7, 2006

Strategy for Indolizidine Alkaloid Syntheses
TABLE 3. Hydrolysis of Methyl Enol Ethers with HCl
entry
conditions
temp (°C)
time (h)
53/54a
conversiona (%)
1
2
3
4
4 M HCl/THF (1/1)
6 M HCl/THF (1/1)
6 M HCl/THF (1/1)
6 M HCl/THF (1/1)
23
0
0
12
14
24
45
1.2/1
6/1
4/1
100
70
93
0
-20
1
a Determined by H NMR on the crude reaction mixtures.
SCHEME 20
the direction of protonation during the subsequent hydrolysis
of the enol ether. Toward this end, Wittig olefination of (+)-
44 (Table 3) with methoxymethyl triphenylphosphonium chlo-
ride employing t-BuOK to generate the ylide furnished an E/Z
mixture (ca. 4:3) of methyl enol ethers, which were not
separated. Initial hydrolysis at room temperature with 4 M HCl
for 12 h led to a mixture (ca. 1:1) of aldehydes (entry 1).
However, when the hydrolysis was conducted with 6 M HCl at
0 °C for 14 h, the desired axial aldehyde 53 was obtained as
the major diastereomer (6:1; 1H NMR), at a conversion of 70%
(entry 2). After 24 h, further conversion resulted (93%) with a
moderate reduction in selectivity (4:1), due to equilibration
between the two epimeric aldehydes (entry 3). At low temper-
atures, the hydrolysis process not surprisingly proved to be very
slow (entry 4). These results, while clearly very pleasing,
were striking given that the â face of the enol ether olefin
is sterically more hindered than the R face. To account for
these observations, we invoke an explanation based upon
electrostatic repulsion; that is, axial delivery of a proton, the
first step in the enol ether hydrolysis, would be encumbered
electronically by repulsion between an incoming hydronium ion
and the positive charge of the protonated nitrogen, thus favoring
equatorial delivery.
Final Elaboration of Alkaloid (-)-205B: Application of
the Toyooka End-Game. Without separation of the epimeric
aldehydes (53 and 54), reduction with NaBH4 furnished alcohol
(+)-55 in 74% isolated yield, after careful removal of the equa-
torial congener (+)-56 by flash chromatography (18%; Scheme
20).37 Mesylation of (+)-55, followed by reduction with Super-
Hydride (LiHBEt3) and removal of the dithiane next furnished
ketone (-)-41, which was subjected to the Toyooka endgame
sequence,13 comprising Wittig methylenation and acid-catalyzed
isomerization of the resultant exomethylene alkene to the internal
olefin. The natural enantiomer of alkaloid (-)-205B was
obtained as the major product (6.2:1; NMR). Separation by flash
chromatography furnished (-)-2; the yield for the two-step end
game was 64%. Synthetic (-)-2 possessed spectral data {e.g.,
400 and 500 MHz 1H and 125 MHz 13C NMR; [R]D ) -8.3 (c
0.12, CHCl3); lit.12 -8.5 (c 0.59, CHCl3)} identical in all
(37) The stereochemistry of (+)-55 was later confirmed by comparison
of the NMR data of (-)-41 with those of known (+)-41; see ref 13.
J. Org. Chem, Vol. 71, No. 7, 2006 2555

Smith and Kim
respects to those reported for both the natural12 and synthetic
antipodes {[R]D ) +8.1 (c 1.05, CHCl3)},13 except, of course,
in the latter case for the chiroptical properties.38
(25 µL, 0.323 mmol, 3.0 equiv) was added dropwise. The solution
was warmed to ambient temperature and stirred for 1 h. The
resultant mixture was poured into water (5 mL) and extracted with
Et2O (4 × 10 mL). The combined organic layers were washed with
brine (10 mL), dried over MgSO4, filtered, and concentrated in
vacuo. The crude mesylates were dissolved in MeOH (5 mL), and
K2CO3 (0.060 g, 0.43 mmol, 4.1 equiv) was added. After the
mixture was stirred for 3 h at ambient temperature, Na2HPO4 (0.80
g, 5.63 mmol, 53 equiv) was added. Then, 5% Na-Hg (0.6 g × 4)
was added every 40 min for 2 h, and the mixture was stirred for an
additional 1.5 h. The mixture was filtered through Celite and washed
with EtOAc. Brine (10 mL) was added to the mixture, and the layers
were separated. The aqueous layer was extracted with Et2O (3 ×
15 mL), and the combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. Flash chromatography on silica
gel, using ethyl acetate/hexanes (1:1) as eluant, afforded (-)-17
(0.033 g, 0.101 mmol, 95% over 2 steps) as a colorless oil: Rf
0.35 (hexanes/ethyl acetate 1/1); [R]20D -71.7 (c 0.30, CHCl3); IR
(film) 2954 (s), 2929 (s), 2869 (m), 1465 (m), 1422 (m), 1379 (m),
Conclusion
An efficient, highly stereocontrolled general strategy for the
construction of 3,5-disubstituted indolizidine alkaloids has been
developed, exploiting a three-component linchpin union of TBS
dithiane employing N-Ts aziridines as the second electrophile,
followed in turn by a one-flask sequential cyclization. To
showcase the utility of this synthetic strategy, (-)-indolizidine
223AB was constructed in 10 steps, in 10% overall yield from
aldehyde 7. The synthetic strategy was then extended to the
total synthesis of the natural enantiomer of alkaloid (-)-205B,
a sequence which proceeded with a longest linear sequence of
19 steps and an overall yield of 5.6% from aldehyde (-)-34.
1276 (w), 1166 (m, br), 1089 (w) cm-1 1H NMR (500 MHz,
;
Experimental Section
CDCl3) δ 3.26 (app t, J ) 8.3 Hz, 1H), 2.96-2.87 (m, 4H), 2.76
(ABXY, JAB ) 14.4, JAY ) 7.3, JAX ) 4.4, JBY ) 6.5, JBX ) 4.4,
∆νAB ) 21.1 Hz, 2H), 2.47 (app dt, J ) 13.1 and 2.4 Hz, 1H),
2.40 (app dt, J ) 13.4 and 2.4 Hz, 1H), 2.02-1.97 (m, 2H), 1.91-
1.85 (m, 2H), 1.67-1.62 (m, 1H), 1.55-1.37 (m, 6H), 1.37-1.22
(m, 5H), 1.12-1.08 (m, 2H), 0.94 (app t, J ) 7.0 Hz, 3H), 0.90
(app t, J ) 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 58.1,
53.8, 51.4, 49.3, 43.4, 42.7, 35.2, 29.4, 29.1, 26.7, 26.3, 26.1, 25.7,
25.5, 22.9, 18.7, 14.4, 14.2; high-resolution mass spectrum (ESI)
m/z 328.2145 [(M + H)+; calcd for C18H34NS2: 328.2133].
(-)-Indolizidine 223AB (1). A suspension of Raney Ni in water
(Raney Ni 2800 from Aldrich, 1 mL) was added to a solution of
dithiane (-)-17 (0.021 g, 0.064 mmol) in EtOH (4 mL). The
mixture was stirred under H2 (1 atm) vigorously for 12 h at ambient
temperature. The mixture was filtered through Celite and washed
with EtOH (20 mL). The filtrate was evaporated and diluted with
Et2O (20 mL), and 5 M KOH (5 mL) was added. The layers were
separated, and the aqueous layer was extracted with Et2O (3 × 10
mL). The combined organic layers were dried over Na2SO4, filtered,
and concentrated in vacuo. After basifying silica gel with NH4OH/
ether/pentane (1/12/87), flash chromatography on the basified silica
gel, using ethyl acetate as eluant, provided (-)-1 (0.0098 g, 0.044
mmol, 69% yield) as a pale yellow oil: Rf 0.55 (CH2Cl2/methanol
5/1); [R]20 -43 (c 0.47, n-hexane), [R]20 -85 (c 0.42, MeOH);
Procedure for Three-Component Linchpin Union: (-)-N-
((1R)-1-{2-[(2R,5S)-2,5-bis-(tert-Butyl-dimethyl-silyloxy)-nonyl]-
[1,3]dithian-2-ylmethyl}-butyl)-4-methyl-benzenesulfonamide (3).
A solution of dithiane 5 (0.351 g, 1.50 mmol, 1.20 equiv) in Et2O
(3 mL) was cooled to -78 °C and treated with a 1.5 M solution of
t-BuLi (1.04 mL, 1.56 mmol, 1.25 equiv) dropwise via syringe.
The resulting solution was warmed to -45 °C over 1 h and then
cooled to -78 °C. A solution of epoxide (+)-4 (0.340 g, 1.25 mmol)
in Et2O (2 mL) was added dropwise to the reaction mixture at -78
°C via cannula. The resultant solution was warmed to -25 °C over
1 h, stirred for an additional 4 h at -25 °C, and cooled to -78 °C.
A solution of aziridine (-)-6 (0.390 g, 1.63 mmol, 1.30 equiv) in
Et2O (2 mL) and HMPA (0.15 mL, 0.82 mmol, 0.65 equiv) was
added dropwise to the reaction mixture at -78 °C via cannula.
After 10 min, the reaction vessel was transferred to a 0 °C bath
and stirred for 7 h at 0 °C. The resultant mixture was poured into
saturated aqueous NH4Cl (5 mL) and extracted with Et2O (3 × 10
mL). The combined organic layers were washed with brine (5 mL),
dried over MgSO4, filtered, and concentrated in vacuo. Flash
chromatography on silica gel, using diethyl ether/hexanes (1:20)
and then ethyl acetate/hexanes (1:12) as eluant, provided (-)-3
(0.521 g, 0.700 mmol, 56% yield) as a colorless oil and dithiane
(-)-15 (0.150 g, 0.300 mmol, 24% yield). For (-)-3: Rf 0.50
(hexanes/ethyl acetate 5/1); [R]20D -6.4 (c 0.75, CHCl3); IR (film)
3228 (m, br), 2955 (s), 2930 (s), 2857 (m), 1463 (m), 1330 (m),
D
D
IR (film) 2956 (s), 2926 (s), 2856 (m), 2789 (m), 1462 (m), 1454
1
(m), 1379 (m), 1180 (w), 1130 (w) cm-1; H NMR (500 MHz,
1254 (m), 1160 (s), 1051 (m, br), 836 (s), 774 (m), 663 (m) cm-1
;
CDCl3) δ 3.30 (app br t, J ) 9.1 Hz, 1H), 2.40-2.36 (m, 2H),
1.90-1.84 (m, 2H), 1.78-1.71 (m, 3H), 1.67-1.65 (m, 1H), 1.49-
1.40 (m, 4H), 1.38-1.17(m, 6H), 1.16-1.01 (m, 4H), 0.92 (app t,
J ) 7.2 Hz, 3H), 0.90 (app t, J ) 7.2 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 59.0, 58.5, 56.5, 35.9, 32.4, 31.0, 30.1, 29.1, 26.4,
25.0, 24.7, 23.0, 19.0, 14.5, 14.2; high-resolution mass spectrum
(CI) m/z 223.2300 [(M)+; calcd for C15H29N: 223.2300].
(+)-N-[(1R)-2-{2-[(2S,5S,6S)-2-(tert-Butyl-dimethyl-silanyloxy)-
5-(tert-butyl-diphenyl-silanyloxy)-6-methyl-oct-7-enyl]-[1,3]dithian-
2-yl}-1-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-4-methyl-benzene-
sulfonamide (46): Rf 0.40 (hexanes/ethyl acetate 3/1); [R]20D +7.50
(c 1.00, CHCl3); IR (film) 3207 (m, br), 3070 (w), 2956 (s), 2932
(s), 2892 (s), 2857 (s), 1640 (w), 1599 (w), 1471 (m), 1427 (m),
1323 (m), 1255 (m), 1153 (s), 1107 (s), 1090 (s), 1043 (s), 919
(m), 837 (m), 756 (m), 704 (s) cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.72-7.69 (m, 6H), 7.42-7.35 (m, 6H), 7.20 (d, J ) 8.1 Hz,
2H), 6.34 (d, J ) 3.5 Hz, 1H), 5.95 (ddd, J ) 17.3, 10.7 and 7.0
Hz, 1H), 5.00-4.97 (m, 2H), 4.07 (dd, J ) 9.3 and 3.3 Hz, 1H),
3.97-3.89 (m, 2H), 3.75-3.68 (m, 2H), 3.66-3.61 (m, 2H), 2.86
(ddd, J ) 14.4, 8.4 and 2.7 Hz, 1H), 2.73 (ddd, J ) 14.1, 8.5 and
2.6 Hz, 1H), 2.62 (ddd, J ) 14.3, 7.7 and 2.9 Hz, 1H), 2.51-2.47
(m, 1H), 2.46 (dd, J ) 15.6 and 10.8 Hz, 1H), 2.38 (s, 3H), 2.27-
2.30 (m, 2H), 2.25 (dd, J ) 15.0 and 9.8 Hz, 1H), 2.0-1.87 (m,
1H NMR (500 MHz, CDCl3) δ 7.77 (d, J ) 8.3 Hz, 2H), 7.26 (d,
J ) 8.0 Hz, 2H), 6.36 (d, J ) 3.7 Hz, 1H), 4.11-4.08 (m, 1H),
3.75-3.72 (m, 1H), 3.57-3.55 (m, 1H), 2.79-2.63 (m, 4H), 2.40
(s, 3H), 2.26 (dd, J ) 15.3 and 9.8 Hz, 1H), 2.06 (br d, J ) 15.1
Hz, 1H), 1.95-1.90 (m, 3H), 1.81 (d, J ) 14.8 Hz, 1H), 1.63-
1.60 (m, 1H), 1.53-1.48 (m, 2H), 1.45-1.37 (m, 4H), 1.36-1.20
(m, 7H), 0.95 (s, 9H), 0.91(app t, J ) 6.2 Hz, 3H), 0.89 (s, 9H),
0.82 (app t, J ) 7.3 Hz, 3H), 0.16 (s, 3H), 0.15 (s, 3H), 0.05 (s,
3H), 0.05 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 142.6, 139.0,
129.3, 127.3, 72.4, 71.4, 51.5, 50.6, 41.6, 40.9, 39.2, 37.3, 35.2,
32.5, 27.3, 26.3, 26.0, 25.9, 25.6, 25.2, 22.9, 21.5, 18.2, 18.1, 18.0,
14.1, 14.0, -3.0, -4.3, -4.4; high-resolution mass spectrum (ESI)
m/z 768.3975 [(M + Na)+; calcd for C37H71NO4NaSi2S3: 768.3982].
Procedure for One-Flask Sequential Cyclization: (-)-
(3′R,5′R,8′aS)-3′-Butylhexahydro-5′-propyl-spiro[1,3-dithiane-
2,7′(1′H)-indolizine] (17). Diol (-)-18 (0.055 g, 0.106 mmol) was
dissolved in THF (5 mL), and triethylamine (0.090 mL, 0.64 mmol,
6.0 equiv) was added. The mixture was cooled to 0 °C, and MsCl
(38) We thank Dr. John W. Daly, National Institutes of Health, for kindly
providing the 400 MHz 1H NMR and the proton/carbon HMBC spectra
for the natural antipode of alkaloid 205B.
2556 J. Org. Chem., Vol. 71, No. 7, 2006

Strategy for Indolizidine Alkaloid Syntheses
2H), 1.86 (d, J ) 15.3 Hz, 1H), 1.62-1.50 (m, 2H), 1.44-1.38
(m, 1H), 1.27-1.21 (m, 1H), 1.11 (s, 3H), 1.05 (s, 9H), 0.98 (d, J
) 6.8 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.01 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 141.8, 141.6, 140.7, 136.1, 136.0, 134.8,
134.2, 129.52, 129.49, 128.6, 127.49, 127.46, 126.9, 114.1, 110.3,
77.6, 72.3, 64.5, 64.2, 54.5, 52.0, 41.9, 40.1, 37.1, 34.6, 29.5, 27.1,
26.3, 25.8, 25.4, 21.5, 19.7, 19.5, 18.2, 14.2, -2.9, -4.8; high-
resolution mass spectrum (ESI) m/z 934.4049 [(M +Na)+; calcd
for C48H73NO6NaSi2S3: 934.4036].
over K2CO3. The solvent was removed in vacuo. Quick flash
chromatography on silica gel, using acetone/hexanes (1:1) as eluant,
afforded a mixture (ca. 4:3) of methyl enol ethers containing some
phosphine impurity. The mixture was then dissolved (without further
purification) in THF (4 mL) and cooled to 0 °C, and precooled (0
°C) 6 M HCl (4 mL) was added. After the reaction mixture was
stirred for 24 h at 0 °C, saturated NaHCO3 aqueous solution (40
mL) was added slowly at 0 °C. The resulting solution was extracted
with ether (3 × 50 mL). The combined organic layers were dried
over Na2SO4 and concentrated in vacuo to afford the crude
aldehyde. To a solution of the crude aldehyde in MeOH (5 mL) at
0 °C was added NaBH4 (0.019 g, 0.50 mmol, 4.8 equiv). After 40
min, saturated NH4Cl aqueous solution (1 mL) was added, and
solvents were removed in vacuo. The residue was partitioned
between ethyl acetate (50 mL) and water (5 mL), and the organic
layer was separated. The aqueous layer was then extracted with
ethyl acetate (2 × 5 mL), and the combined organic layers were
dried over Na2SO4 and concentrated in vacuo. Purification by
preparative-TLC (hexanes/acetone, 1/1, 500 µm plate) afforded (+)-
55 (24.0 mg, 0.0765 mmol, 74% yield for 3 steps) as a colorless
oil and (+)-56 (5.7 mg, 0.018 mmol, 18% yield for 3 steps) as a
colorless oil. For (+)-55: Rf 0.20 (hexanes/acetone 1/1); [R]20D +4.8
(c 0.50, CHCl3); IR (film) 3378 (m, br), 2925 (s), 1456 (m), 1375
(+)-(3′R,5′R,8′aR)-Hexahydro-5′-(2-methyl-1,3-dioxolan-2-yl)-
3′-[(1S)-1-methyl-2-propenyl]-spiro[1,3-dithiane-2,7′(1′H)-in-
dolizine] (49): Rf 0.60 (hexanes/ethyl acetate 4/1); mp 122 °C;
[R]20 +53.0 (c 1.00, CHCl3); IR (film) 3074 (w), 2949 (s), 1636
D
(m), 1422 (m), 1379 (m), 1137 (m), 1049 (s) cm-1; 1H NMR (500
MHz, CDCl3) δ 5.83-5.76 (m, 1H), 4.95 (ddd, J ) 6.8, 1.9 and
1.6 Hz, 1H), 4.92 (d, J ) 1.6 Hz, 1H), 4.10-3.96 (m, 1H), 3.95-
3.87 (m, 3H), 3.47-3.41 (m, 2H), 3.35 (dd, J ) 11.2 and 3.1 Hz,
1H), 3.09-3.05 (m, 1H), 3.01 (ddd, J ) 14.3, 9.2 and 3.2 Hz, 1H),
2.86-2.79 (m, 2H), 2.71 (ddd, J ) 14.4, 7.1 and 3.3 Hz, 1H), 2.58
(app dt, J ) 13.6 and 2.9 Hz, 1H), 2.20 (app dt, J ) 12.9 and 2.9
Hz, 1H), 2.03-1.96 (m, 2H), 1.76-1.70 (m, 2H), 1.61-1.55 (m,
2H), 1.37-1.26 (m, 2H), 1.32 (s, 3H), 0.99 (d, J ) 6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 144.1, 112.2, 111.9, 64.5, 64.2,
60.8, 57.2, 54.6, 49.6, 43.0, 37.5, 36.7, 29.9, 26.2, 26.0, 25.4, 22.8,
19.9, 14.2; high-resolution mass spectrum (ESI) m/z 370.1861 [(M
+ H)+; calcd for C19H32NO2S2: 370.1874].
1
(w), 1275 (w), 1144 (w), 1040 (w), 754 (m) cm-1; H NMR (500
MHz, CDCl3) δ 3.85 (ABX, JAB ) 10.1, JAX ) 4.8, JBX ) 3.5,
∆νAB ) 76.3 Hz, 2H), 3.73 (d, J ) 12.7 Hz, 1H), 3.65-3.58 (m,
1H), 2.95-2.86 (m, 2H), 2.82-2.73 (m, 2H), 2.54-2.49 (m, 1H),
2.10 (app t, J ) 13.1 Hz, 1H), 2.04-1.92 (m, 4H), 1.86 (d, J )
13.6 Hz, 1H), 1.76 (d, J ) 14.3 Hz, 1H), 1.75-1.70 (m, 1H), 1.70
(dd, J ) 13.9 and 11.9 Hz, 1H), 1.64 (ddd, J ) 13.8, 3.5 and 2.0
Hz, 1H), 1.59 (br s, 1H), 1.36-1.23 (m, 3H), 0.86 (d, J ) 6.5 Hz,
3H); 13C NMR (125 MHz, C6D6) δ 67.7, 58.0, 54.9, 51.7, 50.5,
39.9, 37.3, 34.0, 33.9, 33.3, 28.1, 27.1, 25.9, 25.4, 25.4, 18.9; high-
resolution mass spectrum (ESI) m/z 314.1614 [(M + H)+; calcd
for C16H28NOS2: 314.1612].
Procedure for Ring Closing Metathesis Construction of 8b-
Azacenaphthylene Ring System: (+)-(2′aR,5′aR,8′S,8′aR)-Oc-
tahydro-8′-methyl-spiro[1,3-dithiane-2,4′-[4H]pyrrolo[2,1,5-de]-
quinolizin]-6′(2′H)-one (44). To a solution of LiHMDS (1.0 M in
THF, 0.29 mL, 1.5 equiv) in THF (3 mL) at -78 °C was added
trimethysilyl chloride (0.074 mL, 0.583 mmol, 3.0 equiv) and a
solution of ketone (+)-45 (63 mg, 0.194 mmol) in THF (2 mL).
After 2 h at -78 °C, the reaction was quenched by addition of
saturated NaHCO3 aqueous solution (2 mL), and the mixture was
allowed to warm to ambient temperature. The mixture was poured
into water (5 mL) in a separatory funnel and extracted with ether
(3 × 10 mL). The combined organic layers were washed with brine
(10 mL), dried over Na2SO4, and concentrated in vacuo to afford
the crude enol ether. To a solution of the crude enol ether in benzene
(150 mL) was added Grubbs second generation catalyst (38) (16
mg, 0.019 mmol, 0.10 equiv). The reaction mixture was stirred at
65 °C overnight, then cooled to ambient temperature and concen-
trated in vacuo. Flash chromatography on silica gel using hexanes/
ethyl acetate (10/1 f 5/1 f 2/1) as eluant afforded (+)-44 (0.047
g, 0.158 mmol, 81% yield for 2 steps) as a white solid: Rf 0.25
Alkaloid 205B (-)-2: Rf 0.20 (ethyl acetate); [R]20 -8.3 (c
D
0.12, CHCl3); IR (film) 2959 (m), 2924 (m), 2841 (m), 1655 (w),
1458 (m), 1376 (m), 1170 (m) cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.18 (br s, 1H), 3.79 (br s, 1H), 2.98 (dd, J ) 11.4 and 4.6 Hz,
1H), 2.17-2.10 (m, 3H), 1.93-1.88 (m, 1H), 1.71-1.79 (m, 1H),
1.62 (s, 3H), 1.49-1.26 (m, 6H), 1.18 (d, J ) 7.2 Hz, 3H), 0.84
(d, J ) 6.4 Hz, 3H); 1H NMR (500 MHz, C6D6) δ 5.19 (br s, 1H),
3.87 (br s, 1H), 2.95 (dd, J ) 11.5 and 4.6 Hz, 1H), 2.15 (dd, J )
9.8 and 5.2 Hz, 1H), 2.06 (app t, J ) 14.3 Hz, 1H), 2.02-1.95 (m,
1H), 1.84-1.79 (m, 1H), 1.59 (s, 3H), 1.60-1.53 (m, 1H), 1.39-
1.21(m, 6H), 1.29 (d, J ) 7.1 Hz, 3H), 0.81 (d, J ) 6.6 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 129.5, 125.6, 60.5, 58.1, 56.5, 35.5,
32.6, 32.4, 29.2, 28.4, 28.4, 23.5, 20.2, 18.8;13C NMR (125 MHz,
C6D6) δ 129.9, 126.9, 61.0, 59.0, 57.0, 36.4, 33.4, 33.2, 30.2, 29.2,
28.7, 24.2, 20.8, 19.4; high-resolution mass spectrum m/z 205.1830
[(M)+; calcd for C14H23N: 205.1831].
(hexanes/ ethyl acetate 1/1); mp 101 °C; [R]20 +93.5 (c 1.00,
D
CHCl3); IR (film) 2951 (s), 1714 (s), 1424 (m), 1241 (m), 1144
1
(m) cm-1; H NMR (500 MHz, CDCl3) δ 3.98 (dd, J ) 12.2 and
3.0 Hz, 1H), 3.57-3.52 (m, 1H), 3.04 (ddd, J ) 13.9, 10.6 and 2.7
Hz, 1H), 2.91-2.83 (m, 2H), 2.74 (ddd, J ) 14.2, 6.1 and 3.0 Hz,
1H), 2.66 (ddd, J ) 14.4, 5.8 and 3.1 Hz, 1H), 2.47 (dd, J ) 17.0
and 4.5 Hz, 1H), 2.25 (app dt, J ) 13.5 and 2.6 Hz, 1H), 2.10-
2.00 (m, 4H), 1.98-1.84 (m, 3H), 1.83-1.73 (m, 1H), 1.64 (app t,
J ) 12.7 Hz, 1H), 1.47-1.40 (m, 2H), 0.95 (d, J ) 6.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 210.1, 63.1, 59.1, 54.6, 49.9, 45.8,
39.5, 35.9, 33.4, 29.2, 28.5, 26.2, 26.1, 25.9, 18.8; high-resolution
mass spectrum (CI) m/z 297.1221 [(M)+; calcd for C15H23NOS2:
297.1221].
Acknowledgment. Financial support was provided by the
National Institutes of Health (Institute of General Medical
Sciences) through Grant GM-29028. The author also thank Dr.
Charles W. Myers, Curator Emeritus, American Museum of
Natural History, New York, NY., for the photograph of the
strawberry poison frog, Dendrobate pumillo, endemic to the Isla
Bastimentos, Bocas, Panama employed as part of the cover
artwork.
Procedure for Stereoselective Installation of the C(6) Axial
Methyl Group: (+)-(2′aR,5′aR,6′R,8′S,8′aR)-Decahydro-8′-
methyl-spiro[1,3-dithiane-2,4′-[4H]pyrrolo[2,1,5-de]quinolizine]-
6′-methanol (55). To a mixture of methoxymethyl triphenylphos-
phonium chloride (0.356 g, 1.04 mmol, 10 equiv) and potassium
tert-butoxide (0.111 g, 0.989 mmol, 9.5 equiv) was added THF (7
mL) at ambient temperature. After 2 min, a solution of (+)-44 (31
mg, 0.104 mmol) in THF (3 mL) was added dropwise via cannula.
After 20 min, water (1 mL) was added, and the mixture was diluted
with EtOAc (70 mL), washed with brine (2 × 5 mL), and dried
Supporting Information Available: Experimental procedures
and spectroscopic and analytical data for all other new com-
1
pounds. Copies of H and 13C NMR spectra for all new com-
pounds. Crystallographic information files (CIF) of (-)-42 and (+)-
44. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO052314G
J. Org. Chem, Vol. 71, No. 7, 2006 2557