Total synthesis of the tricyclic marine alkaloids (-)-lepadiformine, (+)-cylindricine C, and (-)-fasicularin via a common intermediate formed by formic acid-induced intramolecular conjugate azaspirocyclization

Article abstract of DOI:10.1021/ja040213e

A very short and efficient enantioselective total synthesis of the tricyclic marine alkaloids (-)-lepadiformine (3), (+)-cylindricine C (1c), and (-)-fasicularin (4) has been developed utilizing the formyloxy 1-azaspiro[4.5]decane 5 as a common intermedia

Full text of DOI:10.1021/ja040213e

Published on Web 01/11/2005
Total Synthesis of the Tricyclic Marine Alkaloids
(-)-Lepadiformine, (+)-Cylindricine C, and (-)-Fasicularin via
a Common Intermediate Formed by Formic Acid-Induced
Intramolecular Conjugate Azaspirocyclization
Hideki Abe, Sakae Aoyagi, and Chihiro Kibayashi*
Contribution from the School of Pharmacy, Tokyo UniVersity of Pharmacy and Life Science,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received September 13, 2004; Revised Manuscript Received November 3, 2004; E-mail: kibayasi@ps.toyaku.ac.jp
Abstract: A very short and efficient enantioselective total synthesis of the tricyclic marine alkaloids (-)-
lepadiformine (3), (+)-cylindricine C (1c), and (-)-fasicularin (4) has been developed utilizing the formyloxy
1-azaspiro[4.5]decane 5 as a common intermediate. The key strategic element for the synthesis was the
formic acid-induced intramolecular conjugate azaspirocyclization, which proved to be a highly efficient and
stereoselective way to rapid construction of the 1-azaspirocyclic substructure of these natural products in
a single operation. Thus, the common intermediate 5, synthesized in two steps with 70% overall yield
starting from the known (S)-N-Boc-2-pyrrolidinone 7 via the conjugate spirocyclization using an acyclic
ketoamide 6, was utilized for the concise and stereoselective total synthesis of (-)-lepadiformine (3), which
was accomplished in seven steps with 45% overall yield from 5 (31% yield from 7). The developed strategy
based on the conjugate spirocyclization was also applied to the stereoselective total synthesis of (+)-
cylindricine C (1c), which was achieved in 10 steps from 5 in 18% overall yield (12% yield from 7). Further
application of this approach using 5 led to the synthesis of (-)-fasicularin (4), wherein an extremely efficient
method for the introduction of the thiocyanato group via an aziridinium intermediate at the last step was
developed. Thus, the highly efficient first enantioselective total synthesis of (-)-fasicularin was accomplished
in nine steps with an overall yield of 41% from 5 (28% yield from 7).
Introduction
It was found to be moderately cytotoxic toward various tumor
cell lines in vitro. Moreover, a recent study indicated that
Tunicates (ascidians) have been proven to be a particularly
rich source of a variety of structurally fascinating and bioactive
nitrogen compounds.1 Since the first members were reported
in 1993 by Blackman et al., 11 cylindricines A-K (1a-k) have
been identified from the Tasmanian ascidians ClaVelina cylin-
drica as new marine alkaloids2 with an azatricyclic ring system
unprecedented among natural products, consisting of the per-
hydropyrrolo[2,1-j]quinoline or the perhydropyrido[2,1-j]quino-
line. Shortly after the first isolation of cylindricines A (1a) and
B (1b),2a Biard and co-workers reported the isolation and
structure elucidation of a closely related marine alkaloid, named
lepadiformine, from the marine tunicate ClaVelina lepadiformis
collected in the Mediterranean near Tunisia3a in 1994 and later
from ClaVelina moluccensis found along the Djibouti coast.3b
lepadiformine is very active in the cardiovascular system in vivo
and in vitro and suggested that it has antiarrhythmic properties.3b
On the basis of extensive spectral analysis, this alkaloid was
assigned the unusual zwitterionic structure 2 including a cis-
1-azadecalin BC ring system as seen in cylindricines 1a-k. In
addition to these tricyclic natural products, fasicularin (4) was
discovered in 1997 by Patil and co-workers4 from the Micro-
nesian ascidian Nephteis fasicularis, which has selective activity
against a DNA repair-deficient organism and is cytotoxic to
Vero cells. The structure and relative stereochemistry of 4 were
deduced on the basis of NMR studies, though the absolute
configuration is still unknown.
The novel structural features and biological significance of
these tricyclic alkaloids represent a promising new class of
nitrogen heterocycles biosynthesized by ascidians (such as
indolizidines, quinolizidines, and decahydroquinolines) and have
been receiving increasing attention as challenging targets for
total synthesis.5 In 2000, we achieved the first total syntheses
(1) For recent reviews on marine natural products, see: (a) Davidson, B. S.
Chem. ReV. 1993, 93, 1771-1791. (b) Faulkner, D. J. Nat. Prod. Rep. 1994,
11, 355-394. (c) Faulkner, D. J. Nat. Prod. Rep. 1995, 12, 223-269. (d)
Faulkner, D. J. Nat. Prod. Rep. 1996, 13, 75-125. (e) Faulkner, D. J. Nat.
Prod. Rep. 1998, 15, 113-158. (f) Faulkner, D. J. Nat. Prod. Rep. 1999,
16, 155-198.
(2) (a) Blackman, A. J.; Li, C.; Hockless, D. C. R.; Skelton, B. W.; White, A.
H. Tetrahedron 1993, 49, 8645-8656. (b) Li, C.; Blackman, A. J. Aust. J.
Chem. 1994, 47, 1355-1361. (c) Li, C.; Blackman, A. J. Aust. J. Chem.
1995, 48, 955-965.
(3) (a) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren, J.;
Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691-2694. (b) Juge´,
M.; Grimaud, N.; Biard, J. F.; Sauviat, M. P.; Nabil, M.; Verbist, J. F.;
Petit, J.-Y. Toxicon 2001, 39, 1231-1237.
(4) Patil, A. D.; Freyer, A. J.; Reichwein, R.; Cartre, B.; Killmer, L. B.;
Faucette, L.; Johnson, R. K.; Faulkner, D. J. Tetrahedron Lett. 1997, 38,
363-364.
(5) For brief reviews on the synthesis of lepadiformine and related tricyclic
marine alkaloids, see: (a) Weinreb, S. M. Acc. Chem. Res. 2003, 36, 59-
65. (b) Kibayashi, C.; Aoyagi, S.; Abe, H. Bull. Chem. Soc. Jpn. 2003, 76,
2059-2074.
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J. AM. CHEM. SOC. 2005, 127, 1473-1480
1473

A R T I C L E S
Abe et al.
Scheme 1
construction of the 1-azaspirocyclic core. In this article, we wish
to describe in detail the development of this azaspirocyclization
methodology and the general utility of this methodology for a
highly efficient enantioselective total synthesis of the tricyclic
marine alkaloids cylindricine C (1c), lepadiformine (3), and
fasicularin (4).10
Results and Discussion
Formic Acid-Induced Intramolecular Spirocyclization of
Conjugated Diene-Ketoamides. Intramolecular reaction of the
N-acyliminium species with simple alkenes or alkenylsilanes
has been of great importance for the synthesis of nitrogen
heterocycles and has found widespread use in total synthesis
of natural products,11 but relatively few examples exist on the
use of this reaction for the construction of azaspirocycles. Such
N-acyliminium ion-based spirocyclization leading to spirolac-
tams has been initially investigated by Speckamp12 and Evans13
and utilized for the synthesis of perhydrohistrionicotoxin, and
recently this methodology was successfully applied by Weinreb8c
in the total synthesis of lepadiformine.
At the outset of our studies toward the total synthesis of the
tricyclic alkaloids 1c, 3, and 4 as shown retrosynthetically in
Scheme 1, we envisioned a new variant of N-acyliminium ion-
based spirocyclization using an acyclic ketoamide 6 bearing a
conjugated diene, which was anticipated to lead to the formation
of the spirocyclic AC ring system, which is a common
substructure present in this class of alkaloids, and simultaneous
introduction of an oxygen functionality into the olefinic tether.
The resulting spirocyclic formate 5 could serve as a common
intermediate for the synthesis of each of the three target alkaloids
1c, 3, and 4 by way of the subsequent construction of the B
ring.
Figure 1. Tricyclic marine alkaloids isolated from the ascidians.
of racemic lepadiformine and fasicularin using an intramolecular
acylnitroso Diels-Alder strategy.6 This lepadiformine synthesis
and X-ray crystallographic analysis of the lepadiformine hy-
drochlolide led to the revision of the proposed structure 27 of
lepadiformine to 3, which has the trans-fused 1-azadecalin BC
ring with the B ring in an unusual twist boat form, thereby
having the hexyl group in an equatorial position. In addition, it
was shown that the natural material isolated by Biard is actually
the hydrochloride salt of 3 rather than a zwitterion as originally
postulated. After the relative stereochemistry of lepadiformine
was thus established,8 its absolute configuration was first
assigned as depicted in Figure 1 by the Weinreb group8c via
the total synthesis of the natural enantiomer of lepadiformine
using an intramolecular spirocyclization of a cyclic N-acylimin-
ium ion with an allylsilane as a pivotal step. Shortly after this
report, we independently came to the same conclusion for the
absolute stereochemistry by the enantioselective synthesis of 3
and chiral HPLC analysis of the synthetic material and the
natural product.9 The strategy utilized in this approach to 3 was
based on formic acid-induced intramolecular conjugate spiro-
cyclization, which proved to be a very efficient way to rapid
As a test of the feasibility of this spirocyclization methodol-
ogy, we first subjected various conjugated diene-ketoamides to
formic acid-initiated azacyclization which may occur via an in
(6) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2000, 122, 4583-
4592.
(7) For synthesis of the putative structure 2 of lepadiformine (as a non-
zwitterionic form), see: (a) Werner, K. M.; de los Santos, J. M.; Weinreb,
S. M.; Shang, M. J. Org. Chem. 1999, 64, 686-687. (b) Werner, K. M.;
de los Santos, J. M.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1999, 64,
4865-4873. (c) Abe, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 2000,
41, 1205-1208. (d) See also ref 6. For synthesis of the other three
diastereomers of 2, see: (e) Pearson, W. H.; Barta, N. S.; Kampf, J. W.
Tetrahedron Lett. 1997, 38, 3369-3372. (f) Pearson, W. H.; Ren, Y. J.
Org. Chem. 1999, 64, 688-689.
(10) For a preliminary report of a part of this work on the synthesis of
lepadiformine, see ref 9.
(11) For reviews of the chemistry of N-acyliminium ions, see: (a) Speckamp,
W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367-4416. (b) Hiemstra, H.;
Speckamp, W. N. In The Alkaloids; Brossi, A., Ed.; Academic Press: San
Diego, CA, 1988; Vol. 32, pp 271-339. (c) Hiemstra, H.; Speckamp, W.
N. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, pp 1047-1109. (d) Speckamp, W. N.;
Moolenaar, M. J. Tetrahedron 2000, 56, 3817-3856.
(8) For syntheses of lepadiformine (3), which appeared after establishment (ref
6) of the relative stereochemistry of lepadiformine, see: Racemic 3: (a)
Sun, P.; Sun, C.; Weinreb, S. M. Org. Lett. 2001, 3, 3507-3510. (b)
Greshock, T. J.; Funk, R. L. Org. Lett. 2001, 3, 3511-3514. (-)-3: (c)
Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem. 2002, 67, 4337-4345.
(9) Abe, H.; Aoyagi, S.; Kibayashi, C. Angew. Chem., Int. Ed. 2002, 41, 3017-
3020.
(12) (a) Schoemaker, H. E.; Speckamp, W. N. Tetrahedron Lett. 1978, 1515-
1518. (b) Schoemaker, H. E.; Speckamp, W. N. Tetrahedron Lett. 1978,
4841-4844. (c) Schoemaker, H. E.; Speckamp, W. N. Tetrahedron 1980,
36, 951-958.
(13) Evans, D. A.; Thomas, E. W. Tetrahedron Lett. 1979, 411-414.
9
1474 J. AM. CHEM. SOC. VOL. 127, NO. 5, 2005

Total Synthesis of Tricyclic Marine Alkaloids
A R T I C L E S
Table 1. Conjugated Diene-Iminium Ion Spirocyclization of Ketoamides by Treatment with Formic Acida
a All reactions were performed at a substrate concentration of 0.05 M in the appropriate solvent containing formic acid in a 1:1 ratio. b Isolated yield.
c The reaction was nonstereoselective.
situ generated cyclic N-tosyliminium and N-acyliminium species
in 5- and 6-exo-trig modes14 leading to spirocyclic formate esters
(Table 1). When the Boc carbamate 8, which bears a tosyl group
on the nitrogen, was treated with formic acid in dichloromethane
at room temperature, the intramolecular spirocyclization oc-
curred via N-tosyliminium ion formation leading to the 1-azaspiro-
[4.4]nonane ring system with introduction of the formyloxy
group at the C3′ position as expected, producing 12 in 43%
yield, although the reaction required long reaction time (40 h)
for completion (entry 1). Under the same conditions, the N-tosyl
Boc-carbamate 9 also underwent similar spirocyclization,
thereby providing the 1-azaspiro[4.5]decane 13 in 55% yield
(entry 2). When the Boc carbamate 10 lacking the tosyl
substituent at the nitrogen was used, the spirocyclization in
acetonitrile proceeded smoothly via cyclic N-acyliminium ion
formation and was completed in 2 h at 0 °C to afford the
1-azaspiro[4.5]decane 14 in 54% yield (entry 3). The spirocy-
clization of 10 proceeded more smoothly by employing toluene-
THF (19:1) as the solvent, which was completed in 1 h at 0 °C
to yield 14 in 66% yield (entry 4). This is in marked contrast
to the case with the reported cyclic acyliminium ion-olefin
cyclization that requires long reaction time (e.g., 40 h at 36-
40 °C12c and 32 h at 25 °C13 for lactams with terminal olefins,
and 8 days at 44 °C for a lactam with an inner olefin12b). On
the other hand, when the same conditions used for 10 indicated
in entry 4 were applied to the Boc carbamate 11, no reaction
was observed (entry 5). Even under the forcing conditions
(CH3CN, room temperature, 16 h), treatment of 10 with formic
acid did not lead to spirocyclization to the expected 1-azaspiro-
[5.5]undecane but instead removal of the Boc group to form
the tetrahydropyridine 15 (entry 6).
(14) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-736.
9
J. AM. CHEM. SOC. VOL. 127, NO. 5, 2005 1475

A R T I C L E S
Scheme 2
Abe et al.
the 1-azaspiro[4.5]decane ring formation proceeded with com-
plete stereoselection in the desired sense, although the con-
comitant formate substitution at C3′ occurred with low diaste-
reoselectivity in a ratio of 1.6:1 favoring the 3′â-formate as
determined by HPLC analysis. It is noteworthy that the
ketoamide bearing a conjugated diene system such as 6 smoothly
underwent the conjugate spirocyclization because, contrary to
this result, similar treatment of the ketoamide bearing the
nonconjugated olefin, 18, with formic acid in CH2Cl2 or without
a solvent at room temperature resulted in no spirocyclization,
but only removal of the Boc group took place to form the
cyclized imine 19.
The success of this conjugate spirocyclization using 6 can
be accounted for by a π-complex theory (Scheme 3).19 Thus,
the cyclic N-acyliminium ion 20 generated in situ from 6 forms,
in an equilibrium process, a π-complex 21 with a nitrogen-
stabilized carbocation. Subsequently, formate anion attacks this
π-complex 21 in such a manner that only a six-membered ring
is formed with generation of a stable allyl cation moiety in the
unsaturated alkyl side chain as in 22, which is then attacked by
formate ion leading to the spirocyclic product 5. The stereo-
chemical outcome observed for this cyclization is understandable
in terms of nonbonded interactions in the π-complexes 21A-D
with chairlike six-membered transition structures, where nu-
cleophilic attack of the olefin moiety would occur from the
sterically less hindered â face (opposite to the 5-benzyloxym-
ethyl group) of the cationic pyrrolidine ring (Figure 2). In the
These results suggested that the spirocyclization preferentially
occurred via the intermediacy of five-membered ring N-
tosyliminium and N-acyliminium ions generated from the
ketoamides 8-10 rather than via the six-membered ring
analogue formed from 11. These observations are consistent
with a recent report from Eberlin and co-workers15 on electro-
philic reactivity of a series of the cyclic N-acyliminium ions,
which shows that the LUMO energy of five-membered ring
N-acyliminium ions with exocyclic amide carbonyl groups is
lower than that of six-membered ring analogues, and, indeed,
the five-membered ring iminium ions were found to be more
reactive toward electrophilic addition reactions than the six-
membered ring analogues.
The conjugate spirocyclization protocol leading to spirocyclic
formates in a single operation developed here seems to be
particularly attractive for an efficient and rapid entry into the
azatricyclic marine alkaloids, where the AC ring system is
assembled, and which also allows the oxygenated functionality
to be placed in the appropriate position in the olefinic side chain
for potential future elaboration of the B ring. Thus, our initial
efforts have focused on the preparation of the spirocyclic formate
ester 5 using this methodology as indicated in Scheme 1. The
synthesis commenced with the known (S)-N-Boc-2-pyrrolidi-
none 7,16 which upon treatment with the (5E,7E)-tetradeca-5,7-
dienyl Grignard reagent 16 yielded the N-Boc-amino ketone 617
(Scheme 2). Treatment of a solution of 6 in toluene-THF
(95:5) with formic acid at 0 °C for 2 h initiated a sequence of
conjugate spirocyclization culminating in the formation of the
azaspirocyclic formate ester 5 in 88% yield.18 In this reaction,
Figure 2. Stereoselective formation of the (6S)-formate 5 in the conjugated
diene-N-acyliminium ion spirocyclization.
transition structures 21C and 21D, which lead to the (6R)-isomer
23, the N-Boc group displays unfavorable nonbonded interac-
tions with the axially oriented diene moiety and the 1,3-diaxial
(15) D’Oca, M. G. M.; Moraes, L. A. B.; Pilli, R. A.; Eberlin, M. N. J. Org.
Chem. 2001, 66, 3854-3864.
(16) (a) Katoh, T.; Nagata, Y.; Kobayashi, Y.; Arai, K.; Minami, J.; Terashima,
S. Tetrahedron Lett. 1993, 34, 5743-5746. (b) Katoh, T.; Nagata, Y.;
Kobayashi, Y.; Arai, K.; Minami, J.; Terashima, S. Tetrahedron 1994, 50,
6221-6238.
(18) When the reaction was carried out in formic acid without solvent at room
temperature for 1 h, the spirocyclization was accompanied by cleavage of
the N-Boc protecting group.
(17) For the organometallic ring-opening reaction of N-alkoxycarbonyl lactams,
see: Giovannini, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem. 1989,
54, 228-234.
(19) Dewar, M. J. S.; Reynolds, C. H. J. Am. Chem. Soc. 1984, 106, 1744-
1750.
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Total Synthesis of Tricyclic Marine Alkaloids
A R T I C L E S
Scheme 3
Scheme 4 a
use of PtO2 catalyst and ethyl acetate as solvent without
diethylamine for the same reaction remarkably improved the
yield of 26 to 86%. After removal of the Boc protecting group
with trifluoroacetic acid, the resultant amino alcohol 27 was
subjected to cyclodehydration23 using CBr4 and PPh3 with
complete inversion of the configuration at C3′ to form the
tricyclic amine 28 in 82% yield. Hydrogenolytic removal of
the benzyl protecting group was done using Pd(OH)2 on carbon
in methanol furnished (-)-lepadiformine (3) whose spectral
properties were identical in all respects with those of an authentic
sample of racemic lepadiformine (()-3 previously prepared by
us.6 The optical rotation of synthetic alkaloid 3 was measured:
[R]28D -15.0 (c 0.37, MeOH) for the free base (oil) and [R]26
D
+2.6 (c 0.54, CHCl3) for the hydrochloride salt (colorless gum).
Although comparison of the optical rotation of our synthetic
sample with that of the natural product was impossible since
the rotation of the natural product (actually the hydrochloride
salt6) had been reported3a to be zero, synthetic 3 proved to be
identical with natural lepadiformine, kindly provided by Profes-
sor Biard, on the basis of their chromatographic behavior on
HPLC chiral phase.9
The enantioselective total synthesis of (-)-lepadiformine (3)
has thus been accomplished by employing a conjugate azaspi-
rocyclization methodology in seven steps with an overall yield
of 45% from the common intermediate 5 (31% yield from the
pyrrolidinone 7), making this the most efficient and the shortest
synthesis of 3 reported to date.6,8
The Total Synthesis of (+)-Cylindricine C. Having devel-
oped the extremely efficient approach to lepadiformine (3)
utilizing the spirocyclic alcohol 24a stereoselectively derived
from the enone 25, we next attempted to exploit this intermediate
24a for the synthesis of the related marine alkaloid cylindricine
C (1c).24,25
Cylindricine C (1c), possessing the perhydropyrrolo[2,1-j]-
quinoline framework, is intimately related to lepadiformine (3),
differing structurally only in the cis/trans stereorelationship of
the BC ring system and the functionality at C7. While the
synthesis of both enantiomers of cylindricine C has been
achieved,24 the absolute configuration of natural cylindricine C
remains unassigned since the optical rotation of the natural
product has not been determined and no sample remains of the
isolated cylindricine C. Biogenetically, it can be envisaged that
both tunicate alkaloids 1c and 3 presumably arise from an amino
acid-derived azaspirocyclic compound, corresponding to the AC
a Reagents and conditions: (a) K2CO3, MeOH-H2O, room temperature,
98%; (b) MnO2, CH2Cl2, room temperature, 91%; (c) method A: (R)-
oxazaborolidine, BH3‚THF, 0 °C, 77% (60% de); method B: (S)-BINAL-
H, THF, -78 °C, 92% (97% de); (d) H2, PtO2, AcOEt, 86%; (e) CF3CO2H,
CH2Cl2, room temperature, 91%; (f) Ph3P, CBr4, Et3N, CH2Cl2, room
temperature, 82%; (g) H2, Pd(OH)2-C, MeOH, 87%.
hydrogens of the newly formed cyclohexane ring, respectively.
The latter steric interaction between the N-Boc group and the
1,3-diaxial hydrogens is also present in the transition structure
21B, which leads to the (6S)-isomer 5. Neither of these
interactions is present in the transition structure 21A, and
therefore, of the four possible chairlike transition structures
21A-D, 21A is the least disfavored and leads to the observed
(6S)-product 5.
The Total Synthesis of (-)-Lepadiformine. The formate
ester 5 (1.6:1 epimeric mixture) thus obtained underwent basic
hydrolysis followed by MnO2 oxidation to form the R,â-
conjugated ketone 25 (Scheme 4). Since reduction of 25 to the
corresponding alcohol with BH3‚THF (THF, 0 °C) was almost
nonstereoselective (24a/24b ) 1.15:1 based on HPLC analysis),
Corey’s (R)-oxazaborolidine-catalyzed asymmetric borane re-
duction20 was performed to obtain enantioselectively the desired
3′R-alcohol 24a (as a major isomer), but with somewhat
disappointing diastereoselectivity (24a/24b ) 80:20 in 77% total
yield). However, when (S)-BINAL-H21 was used, 24a was
obtained with much improved diastereoselectivity and in a
higher yield (98.5:1.5 in 92% total yield). Catalytic hydrogena-
tion of 24a over 10% palladium on carbon in methanol was
carried out in the presence of diethylamine (1 equiv) to prevent
benzyl ether hydrogenolysis,22 affording 26 in 64% yield. The
(22) For inhibition of hydrogenolysis of benzyl ether groups with Pd-C in the
presence of ammonia and amines, see: Sajiki, H. Tetrahedron Lett. 1995,
36, 3465-3468.
(23) Shishido, Y.; Kibayashi, C. J. Org. Chem. 1992, 57, 2876-2883.
(24) For synthesis of (-)-cylindricine C, see: (a) Molander, G. A.; Ro¨nn, M.
J. Org. Chem. 1999, 64, 5183-5187. For syntheses of (+)-cylindricine C,
see: (b) Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 4599-4602. (c)
Arai, T.; Abe, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 2004, 45,
5921-5924.
(20) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am.
Chem. Soc. 1987, 109, 7925-7926.
(21) Noyori, R.; Tanino, I.; Tanimoto, Y. J. Am. Chem. Soc. 1979, 101, 3129-
3131.
(25) For syntheses of other cylindricine alkaloids, see: (a) (()-cyclindricine
A, D, and E: Snider, B. B.; Liu, T. J. Org. Chem. 1997, 62, 5630-5633.
(b) (()-Cylindricine A and B: Liu, J. F.; Heathcock, C. H. J. Org. Chem.
1999, 64, 8263-8266. (c) (+)-Cylidricine D and E: ref 24b.
9
J. AM. CHEM. SOC. VOL. 127, NO. 5, 2005 1477

A R T I C L E S
Scheme 5 a
Abe et al.
a chair-chair conformation, indicated that 36 is more stable
by 5.5 kcal/mol than 35 in their optimized structures. These
calculations suggested that 35 would easily epimerize to provide
the more thermodynamically stable 36 having the stereochem-
istry required for the structure of cylindricine C. Thus, upon
exposing 35 to aqueous K2CO3 in methanol at room temperature
for 2 h, complete epimerization at C7a occurred to form 36 as
a single isomer in 86% yield. Finally, the benzyl group of 36
was removed by hydrogenolysis using Pd(OH)2 in MeOH to
give (+)-cylindricine C (1c). The synthetic material of 1c has
an optical rotation of [R]21 +63.1 (c 0.44, CH2Cl2) (ref 24b
D
[R]25 +61 (c 0.4, CH2Cl2); for (-)-cylindricine C24a [R]25
D
D
-64 (c 0.2, CH2Cl2)) and displayed spectroscopic data (1H and
13C NMR) identical to those reported2b for the natural product.
The Total Synthesis of (-)-Fasicularin. Encouraged by the
results described above, we next explored the possibility of
extending the conjugate spirocyclization methodology to the
enantioselective synthesis of fasicularin (4). As described above,
the total synthesis of (()-fasicularin was first reported by us in
2000. After this report, the second synthesis of (()-4 using a
2-amidoacrolein Diels-Alder cycloaddition was published by
Funk and Maeng,27 and more recently the formal construction
of 4 starting from (S)-5-hydroxy-2-piperidone has been reported
by the Dake group.28 However, these syntheses suffered from
very poor overall yields (0.9 and 2.4%), mainly due to difficulty
in incorporation of the thiocyanato group in the final step, which
was performed by a Mitsunobu procedure (HSCN, Ph3P,
DEAD)6 or an SN2 displacement of the mesylate by Bu4NSCN27
resulting in very low yield (20%) of fasicularin in each case.
Thus, there is a great need to develop a new thiocyanation
method that can overcome this problem.
a Reagents and conditions: (a) mCPBA, Na2HPO4, CH2Cl2, 0 °C, 68%
for 30; (b) LiAlH4, Et2O, room temperature, 84%; (c) MsCl (1 equiv), Et3N,
DMAP, CH2Cl2, room temperature, 73%; (d) CF3CO2H, CH2Cl2, room
temperature, then NaHCO3 aq, room temperature, 30 min, 84%; (e) Swern
ox; (f) K2CO3 aq, MeOH, room temperature, 2 h, 86% over two steps; (g)
H2, Pd(OH)2-C, MeOH, 73%.
In the studies on the structure determination of cylindricines
A (1a) and B (1b), these alkaloids are found to form a 3:2
equilibrium mixture, presumably via interconversion through
an aziridinium ion intermediate.2a On the basis of this observa-
tion, we envisioned for the synthesis of fasicularin (4) using an
aziridinium ion intermediate which may undergo nucleophilic
attack of thiocyanate ion with a ring-opening process to form
the thiocyanato-bearing A ring of fasicularin. With this strategy
in mind, we investigated the following approach to 4 starting
from the spirocyclic enone 25. Thus, 25 was subjected to
reduction with (R)-BINAL-H to give the (3′R)-alcohol 24b with
a 9:1 diastereoselectivity (Scheme 6). Hydrogenation of olefin,
followed by deprotection of the amino group, afforded amino
alcohol 38, which was subjected to cyclocondensation (Ph3P,
CBr4, Et3N)23 to yield the tricyclic amine 39. After hydro-
genolytic removal of the benzyl group, upon exposing the
resulting tricyclic amino alcohol 40 to NH4SCN under the
Mitsunobu conditions, a 1:1 mixture of (-)-fasicularin (4) and
41 was obtained in 94% combined yield. When a solution of
the latter product 41 in acetonitrile was allowed to stand at room
temperature for 72 h, (-)-fasicularin was further obtained in
91% yield. Formation of fasicularin was thus attained in
remarkably high combined yield of 90% from the tricyclic amino
alcohol 40. Fasicularin so obtained, having spectral properties
in agreement with those previously reported,4,6 proved to be
enantiomerically pure by chiral HPLC analysis using a Daicel
Chiralpak AD column in comparison with (()-4 previously
ring of these alkaloids, by closure of the B ring (bond formed
C7-C7a). Consequently, we assumed that the correct absolute
stereochemistry for natural cylindricine C is defined by 1c,
which is epimeric with the natural lepadiformine (3) at C7a.
Oxidation of the olefin in the unsaturated alcohol 24a with
mCPBA stereoselectively afforded the syn-hydroxy epoxide 30
(68% yield), presumably via a chelate transition state 29,26 along
with the anti-hydroxy epoxide 31 (14% yield) (Scheme 5).
Reductive ring opening of the epoxide 30 with LiAlH4
proceeded regioselectively to give the 1,3-diol 32 in 84% yield
along with a small amount of the 1,2-diol (ca. 4% yield). The
observed regioselective formation of 32 may be due to hydride
attack at the less sterically hindered C2′ position and/or
neighboring-group participation by the 3′-secondary hydroxyl
substituent. Mesylation of 32 took place at the less hindered
3′-hydroxyl group exclusively to give the mesylate 33. Removal
of the Boc group in 33 with trifluoroacetic acid followed by
treatment with aqueous NaHCO3 resulted in smooth ring closure
(room temperature, 30 min), affording the tricyclic amino
alcohol 34, which was oxidized under Swern conditions to form
the tricyclic ketone 35. To define the conformation of 35
including the trans-1-azadecalin BC ring system, molecular
mechanics (MM2) calculations using CAChe mechanics pro-
gram (version 4.0) were carried out, showing that the piperidone
ring (B ring) of 35 is in the boat conformation at lowest energy
(Figure 3). On the other hand, MM2 calculations on its C7a
epimer 36, which possesses the cis-fused BC ring system with
(27) Maeng, J.-H.; Funk, R. L. Org. Lett. 2002, 4, 331-333.
(28) Fenster, M. D. B.; Dake, G. R. Org. Lett. 2003, 5, 4313-4316.
(26) Sharpless, K. B.; Verhoeven, T. R. Aldrichimica Acta 1979, 12, 63-74.
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Total Synthesis of Tricyclic Marine Alkaloids
A R T I C L E S
Figure 3. Energy-minimized structures of 35 and 36 (CAChe 4.0 MM2 calculation).
Scheme 6 a
optical rotation of fasicularin have not yet been determined (no
literature data are available) and no original natural sample
remains,29 since the optical rotation value for 4 was first obtained
by the present synthesis, determination of the absolute config-
uration of fasicularin will become possible by reisolation of the
natural product and optical rotation measurement.
Conclusion
The very short and efficient enantioselective total synthesis
of the tricyclic marine alkaloids (-)-lepadiformine (3), (+)-
cylindricine C (1c), and (-)-fasicularin (4) has thus been
developed utilizing the formyloxy 1-azaspiro[4.5]decane 5 as
a common intermediate. The key common strategic element for
the synthesis was the formic acid-induced intramolecular
conjugate azaspirocyclization, which proved to be an efficient
and stereoselective way to rapid construction of the 1-azaspi-
rocyclic core of these natural products. Thus, the common
intermediate 5 incorporating a 3′-oxygenated functionality,
which is important for further ring construction, was synthesized
in two steps with 70% overall yield starting from the known
(S)-N-Boc-2-pyrrolidinone 7 via the conjugate spirocyclization
using an acyclic ketoamide 6. Using 5, we achieved the concise
and stereoselective total synthesis of (-)-lepadiformine (3) in
seven steps with 45% overall yield (31% yield from 7). The
developed strategy based on the conjugate spirocyclization was
also applied to the stereoselective total synthesis of (+)-
cylindricine C (1c), which was achieved in 10 steps from 5 in
18% overall yield (12% yield from 7). Further application of
this approach using 5 led to the synthesis of (-)-fasicularin (4),
wherein an extremely efficient method for the introduction of
the thiocyanato group via an aziridinium intermediate at the
last step was developed. Thus, the highly efficient first enan-
tioselective total synthesis of (-)-fasicularin was accomplished
in nine steps with an overall yield of 41% from 5 (28% yield
from 7). These studies demonstrated that the strategy developed
in this project, conjugate azaspirocyclization and use of the
oxygenated spirocyclic compound 5 as a common intermediate,
a Reagents and conditions: (a) (R)-BINAL-H, THF, -78 °C, 84%, (80%
de); (b) H2, PtO2, AcOEt, room temperature, 81%; (c) CF3CO2H, CH2Cl2,
room temperature, 99%; (d) Ph3P, CBr4, Et3N, CH2Cl2, room temperature,
88%; (e) H2, Pd(OH)2-C, MeOH, 95%; (f) method A: HSCN, Ph3P,
DEAD, toluene, room temperature, 24 h, 20%; method B: NH4SCN, Ph3P,
DEAD, CH2Cl2, room temperature, 15 min, 94%; (g) CH3CN, room
temperature, 72 h, 91%.
obtained by us,6 and was found to have [R]21 -4.4 (c 0.47,
D
MeOH). The present fasicularin formation can be rationalized
by considering the initial formation of the aziridinium ion 42
that undergoes nucleophilic attack of thiocyanate ion with
subsequent expansion reaction of the aziridine.
The first enantioselective total synthesis of (-)-fasicularin
was thus accomplished in nine steps with an overall yield of
41% from the common intermediate 5 (28% yield from the
pyrrolidinone 7). Although the absolute configuration and the
(29) Freyer, A. J. Personal communication.
9
J. AM. CHEM. SOC. VOL. 127, NO. 5, 2005 1479

A R T I C L E S
Abe et al.
represents a highly efficient method for the total synthesis of
the tricyclic marine alkaloids and should be of general utility
in the synthesis of these natural products.
Private School of Japan and also a Grant-in-Aid for Science
Research from the Ministry of Education, Sports and Culture
of Japan (No. 15790018) to which we are grateful.
Acknowledgment. We are grateful to Professor J. F. Biard
(Universite´ de Nantes) for a sample of natural lepadiformine.
This work was supported in part by a grant for private
universities provided by the Ministry of Education, Sports and
Culture and The Promotion and Mutual Aid Corporation for
Supporting Information Available: Experimental procedures
and compound characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA040213E
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1480 J. AM. CHEM. SOC. VOL. 127, NO. 5, 2005