Total Synthesis of (-)-Cylindricine C

Article abstract of DOI:10.1021/jo990363l

(-)-Cylindricine C has been synthesized from commercially available (S)-(-)-1,2,4-butanetriol in 11 steps with an overall yield of 12%. The key step utilizes a CrCl₂ reduction of an azide to form the corresponding amine with a subsequent double Michael addition to create the tricyclic skeleton of cylindricine from a monocyclic substrate.

Full text of DOI:10.1021/jo990363l

J . Org. Chem. 1999, 64, 5183-5187
5183
Tota l Syn th esis of (-)-Cylin d r icin e C
Gary A. Molander* and Magnus Ro¨nn
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215
Received March 1, 1999
(-)-Cylindricine C has been synthesized from commercially available (S)-(-)-1,2,4-butanetriol in
11 steps with an overall yield of 12%. The key step utilizes a CrCl2 reduction of an azide to form
the corresponding amine with a subsequent double Michael addition to create the tricyclic skeleton
of cylindricine from a monocyclic substrate.
Cylindricines A-J (1a -j) were first isolated by Black-
man et al.1 from the ascidian Calvelina cylindrica off the
coast of Tasmania. These alkaloids represent one class
of a family of compounds with similar structures that
include the clavepictines2 and fasicularin3 (Figure 1).
Lepadiformine4 is also presumably among this class, but
its published structure has been questioned by the groups
of Weinreb5 and Pearson.6 Members of this general
ensemble of compounds exhibit bioactivity against brine
shrimp in a bioassay1a and a DNA-repair-deficient yeast
strain3 and also inhibit growth of murine leukemia and
human solid tumor cell lines.2 Moreover, the tricyclic
system of the cylindricines is comprised of a spirocyclic
amine that makes them an interesting target for total
synthesis.
Several approaches to the cylindricines and related
compounds have been recorded. Pearson and co-workers
utilized their elegant 2-azapentadienyl anion cycloaddi-
tion chemistry in conjunction with an intramolecular
reductive amination to construct the perhydropyrrolo[2,1-
F igu r e 1.
j]quinoline system of these marine alkaloids.6 A conver-
gent, stereoselective approach comprising an intramo-
lecular nitrone/diene dipolar cycloaddition was employed
by Weinreb and co-workers en route to the putative
structure of lepadiformine.5 Finally, a double Michael
addition of NH3 to a conjugated dienone system served
as the key step in the highly efficient synthesis of (()-
cylindricines A, D, and E, as reported by Snider and Liu.7
Herein, we report the first enantioselective total synthe-
sis of (-)-cylindricine C.
Sch em e 1
Retrosynthetic analysis (Scheme 1) reveals a poten-
tially convenient route to cylindricine C via the azide 2a .
Reduction of this azide to the corresponding amine
followed by a double Michael addition would provide
cylindricine C (1c) in a single step. (S)-(-)-1,2,4-Butane-
(1) (a) Blackman, A. J .; Li, C.; Hockless, D. C. R.; Skelton, B. H.
Tetrahedron 1993, 49, 8645. (b) Blackman, A. J .; Li, C. Aust. J . Chem.
1994, 47, 1355. (c) Blackman, A. J .; Li, C. Aust. J . Chem. 1995, 48,
955.
(2) Raub, M. F.; Cardelina, J . H., II; Choudhary, M. I.; Ni, C.-Z.;
Clardy, J .; Alley, M. C. J . Am. Chem. Soc. 1991, 113, 3178.
(3) Patil, A. D.; Freyer, A. J .; Reichwein, R.; Carte, B.; Killmer, L.
B.; Faucette, L.; J ohnson, R. K.; Faulkner, D. J . Tetrahedron Lett. 1997,
38, 363.
(4) Biard, J . F.; Guyot, S.; Roussakis, C.; Verbist, J . F.; Vercauteren,
J .; Weber, J . F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691.
(5) Werner, K. M.; de los Santos, J . M.; Weinreb, S. M.; Shang, M.
J . Org. Chem. 1999, 64, 686.
(6) (a) Pearson, W. H.; Barta, N. S.; Kampf, J . W. Tetrahedron Lett.
1997, 38, 3369. (b) Pearson, W. H.; Ren, Y. J . Org. Chem. 1999, 64,
688.
triol, cyclohexanone, and E-trimethyl-1-octenylstannane
were envisioned as the three major building blocks for
the construction of 2a . Challenges to overcome in this
approach would include the prevention of a hydroxyl
group Michael addition en route from the enol triflate to
the azide 2a , selective reduction of the azide to the amine
in the presence of the dienone, and realization of the
double Michael addition of the resulting amine to the
highly hindered dienone system. Should these obstacles
be conquered, the route designed would be highly con-
(7) Snider, B. B.; Liu, T. J . Org. Chem. 1997, 62, 5630.
10.1021/jo990363l CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/11/1999

5184 J . Org. Chem., Vol. 64, No. 14, 1999
Molander and Ro¨nn
Sch em e 2
vergent as well as efficient. Thus, the final cascade of
reactions leading to cyclindricine would establish two of
the three rings as well as three stereogenic centers in a
single process.
LDA/Tf2Ph,12 and Tf2O/di-tert-butylpyridine.13 Unfortu-
nately, all of these protocols gave low yields of the desired
product or an unacceptably high amount of the undesired,
less substituted, enol triflate. As a result, a two-step
procedure was employed. Treating the ketone 4 with (i-
Pr)2NMgBr in Et2O followed by entrapment of the enolate
with TMSCl14 smoothly furnished the more substituted
TMS-enol ether 5, containing around 3% of the undesired
enolate.15 The TMS-enol ether was converted to the
corresponding enol triflate 6 by treatment with MeLi
followed by trapping the enolate with Tf2NPh16 in THF/
TMEDA to give 6 in 89% yield from 4, which was also
contaminated with 3% of the undesired isomer. Perform-
ing this reaction using only THF as solvent gave a higher
amount of the undesired isomer (5-15%) as the temper-
ature had to be elevated to room temperature to allow
complete trapping of the enolate. Thus, it proved advan-
tageous to use TMEDA as a cosolvent, thereby allowing
the reaction to be performed at 0 °C. At this temperature,
no further isomerization of the intermediate enolate was
observed. Carbonylative Stille coupling11 of 6 with E-tri-
methyl-1-octenylstannane17 afforded the dienone 7 in
79% yield.
Resu lts a n d Discu ssion
With the strategic analysis in place, attention was
directed toward execution of the synthetic plan (Scheme
2). Selective protection of the commercially available (S)-
(-)-1,2,4-butanetriol as its five-membered ring pentyl-
idene ketal,8 followed by tosylation of the primary alcohol,
provided the known tosylate 39 in 72% overall yield.
Coupling of tosylate 3 and the cyclohexanone moiety was
best accomplished using the anion of cyclohexanone
dimethylhydrazone as the alkylating agent. Hydrolysis
of the hydrazone using standard acidic conditions gave,
in addition to the free carbonyl, a considerable amount
of deprotected diol, which in turn internally protected the
newly formed ketone. To prevent this, a metal-ion-
promoted procedure involving Cu(II)10 was used for the
hydrolysis of the hydrazone to provide a 1:1 diastereo-
meric mixture of the ketone 4 in 77% yield. With this
near neutral procedure, no detectable amount of diol or
internally protected ketone was observed.
Hydrolysis of 7 using acidic conditions, such as MeOH/
cat. TsOH or MeOH/cat. PPTS gave the desired diol 8a
in low yield. The major product from these reactions was
a less polar component, most likely the Michael addition
product resulting from addition of the secondary alcohol
to the enone resulting in the formation of a spirofuran.
As a viable alternative, hydrolysis to the desired diol 8a
was accomplished in 83% yield under metal-ion-promoted
Formation of the more substituted enol triflate 6
from 4 was examined using (i-Pr)2NMgBr/Tf2NPh,11
(8) Protection as an acetonide gives a higher amount of the six-
membered ketal. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed.; Wiley: New York, 1991.
(9) Bo¨rjesson, L.; Cso¨regh, I.; Welch, C. J . J . Org. Chem. 1995, 60,
2989.
(10) Corey, E. J .; Knapp, S. Tetrahedron Lett. 1976, 3667.
(11) Crisp, G. T.; Scott, W. J .; Stille, J . K. J . Am. Chem. Soc. 1984,
106, 7500.
(13) Stang, P. J .; Treptow, W. Synthesis 1980, 283.
(14) Krafft, M. E.; Holton, R. A. Tetrahedron Lett. 1983, 24, 1345.
(15) According to 1H NMR analysis.
(12) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1983, 24, 979.
(16) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1983, 24, 979.

Total Synthesis of (-)-Cyclindricine C
J . Org. Chem., Vol. 64, No. 14, 1999 5185
Sch em e 3
conditions, using catalytic amounts of Pd(II) in MeCN/
H2O.18 Again, the remainder of the reaction mixture was
a less polar component, probably the Michael addition
product. The reaction could be quenched before all the
substrate was consumed, giving about 70% yield of the
diol 8a and 25% recovered substrate 7, the latter of which
could be recycled.
The primary alcohol in 8a was selectively protected
using TBSCl/NEt3/DMAP to give the monoprotected diol
8b in 98% yield. A subsequent Mitsunobu reaction using
19
(PhO)2PON3 gave the azide 2b in 76% yield. However,
as the Mitsunobu reaction did not perform consistently
well and purification of the product proved to be difficult,
we examined other routes to 2b. Fortunately, it was
discovered that a more expedient entry to the azide 2b
could be achieved by treatment of the diol 8a with TBSCl/
NEt3/DMAP immediately followed by addition of MsCl/
NEt3 to form the mesylate 8c in essentially quantitative
yield from the diol. Aqueous workup, without further
purification, followed by heating the crude mesylate in
DMF with NaN3 gave the azide 2b in 86% yield (over
three transformations).
Selective reduction of azide 2b initially proved to be
problematic. Employing a transition metal catalyst20 in
combination with H2(g) gave low yields or no yield of the
desired product because of competitive hydrogenation of
the disubstituted double bond; use of SnCl2 or SnCl2/
AlCl321 gave a complex mixture of products. Propane-1,3-
dithiol22 was examined as a reductant, but this reagent
added to the enone in a Michael fashion. Promising
results were achieved in the reduction of the azide, using
trialkyl or triaryl phosphines as well as trialkyl phos-
phites, followed by the hydrolysis of the resulting imi-
nophosphorane.23 The best results along these lines were
achieved using Me3P followed by hydrolysis of the cor-
responding intermediate iminophosphorane with boiling
wet THF. In this case, the TBS-protected cylindricine C
was isolated in 5-25% yield, but the reaction was
capricious, and an alternative reduction of the azide was
sought.
The groups of Kirk24 and Goto25 have reported the
reduction of azides to the corresponding amines, using a
fresh solution of CrCl2. Thus, treating the azide 2b with
an aqueous acidic solution of CrCl2 gave, with concomi-
tant gas evolution, a complex mixture of amines after
basic workup. Instead of isolating the various products,
the crude mixture was dissolved in THF and treated with
TBAF to deprotect the primary alcohol, giving (-)-
cylindricine C 1c in 45% yield26 directly from the azide
2b (Scheme 2).27 The absolute configuration of the
natural product is unknown, and additionally, the optical
rotation has not been determined. Furthermore, appar-
ently no sample remains of the isolated cylindricine C.28
Thus, rac-cylindricine C was prepared by the same route
as described above using rac-1,2,4-butanetriol as sub-
strate. Both enantiopure and racemic cylindricine C were
converted to the corresponding Mosher ester and ana-
1
lyzed by H NMR. These studies revealed the synthetic
(-)-cylindricine C to be of >98% ee.
The formation of three new stereocenters from one is
a highlight of this synthesis and demands further discus-
sion. The stereoinduction at the quaternary center most
likely arises from steric hindrance in the transition state
leading to product. The amine can approach the tetra-
substituted enone from two different directions (Scheme
3). If the amine attacks to give the desired isomer (path
a), the bulky OTBS-group will project away from the
unsaturated side chain. Severe steric interactions are
encountered between the OTBS-group and the enone side
chain if approach is ventured from the opposite face (path
b). The stereochemistry in the second Michael attack is
undoubtedly created by reversibility in the attack (Michael/
retro-Michael), allowing the C6-chain to occupy an equa-
torial orientation. Finally, the stereochemistry R to the
ketone is established by equilibration with base to afford
the stable cis-fusion of the cyclohexanone moiety, with
the proton in an axial orientation.
To our knowledge, no examples of a double Michael
reaction forming a tricyclic skeleton that includes a
spirocyclic center have been described previously in the
literature. The mono-Michael attack of amines, forming
spirocyclic amines, is well described,29 although it seems
advantageous to trap the Michael product as an acetal
using ethylidene glycol to allow complete formation of the
adduct.30 Thus, in Corey’s synthesis of perhydrohistri-
(17) Groh, B L.; Kreager, A. F.; Schneider, J . B. Synth. Commun.
1991, 21, 2065.
(18) Lipshutz, B. H.; Pollart, D.; Monforte, J .; Kotsuki, H. Tetrahe-
dron Lett. 1985, 26, 705.
(19) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahe-
dron Lett. 1973, 1977.
(20) Lindlar’s catalyst, Pd-C, Pd-CaCO3, PtO2, and Raney-Ni were
used for the reduction. Larock, R. C. Comprehensive Organic Trans-
formations; VCH Publishers: New York, 1989.
(21) Maiti, S. N.; Sing, M. P.; Micetich, R. G. Tetrahedron Lett. 1986,
27, 1423.
(27) Spectral data (1H NMR, 13C NMR, LRMS, HRMS) are in
accordance with those presented in the literature, ref 1.
(28) Blackman, A. J ., personal communication.
(29) See for example: (a) Shishido, K.; Sukegawa, Y.; Fukumoto,
K.; Kamitani, T. Heterocycles 1986, 24, 641. (b) Knouzi, N.; Vaultier,
M.; Toupet, L.; Carrie, R. Tetrahedron Lett. 1987, 28, 1757. (c) Bunce,
R. A.; Peeples, C.; J ones, P. B. J . Org. Chem. 1992, 57, 1727.
(30) (a) Bryson, T. A.; Wilson, C. A. Synth. Commun. 1976, 6, 521.
(b) Harris, M.; Grierson, D.-S.; Husson, H.-P. Tetrahedron Lett. 1981,
22, 1511.
(22) Bayley, H.; Standring, D. N.; Knowles, J . R. Tetrahedron Lett.
1978, 3633.
(23) For a review of the Staudinger reaction see: Gololobov, Y. G.;
Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron 1981, 37, 437.
(24) Kirk, D. N.; Wilson, M. A. J . Chem. Soc. C 1971, 414.
(25) Kondo, T.; Nakai, H.; Goto, T. Tetrahedron 1973, 29, 1801.
(26) Average of five attempts using 20-40 mg of substrate giving
37-55% (-)-cylindricine C.

5186 J . Org. Chem., Vol. 64, No. 14, 1999
Molander and Ro¨nn
4-[2-(Tr im eth ylsila n yloxy)cycloh ex-1-en yl]-(1,2S)-bu -
ta n ed iol, O-3-P en tylid in e Aceta l (5). To a solution of
diisopropylamine (3.1 g, 30 mmol) in Et2O (80 mL) was added
MeMgBr (10.2 mL of a 3.0 M solution in Et2O, 30 mmol). After
the mixture was stirred for 12 h at room temperature, a white
thick slurry had been formed to which ketone 4 (6.2 g, 24
mmol) in Et2O (20 mL) was added dropwise. After 15 min,
TMSCl (8.0 g, 73 mmol), NEt3 (8.0 g, 79 mmol), and HMPA
(2.1 g, 12 mmol) were added consecutively. After the mixture
was stirred for 20 h, Et2O was added, and the organic solution
was washed with an ice-cooled saturated solution of NaHCO3,
dried over MgSO4, and evaporated. The crude material was
dissolved in 9:1 hexanes/EtOAc and filtered through a short
silica plug to remove polar impurities. The silica plug was
washed with an additional portion of 9:1 hexanes/EtOAc, the
organic layers were combined, and the solvent was evaporated
to give 5 in essentially quantitative yield. The silyl enol ether
5 was used in the subsequent step without any further
onicotoxin the formation of a spirocyclic amine proved
to be difficult, and mixtures of the Michael adduct and
the starting amino enone were isolated.31 On the other
hand, in a similar study Magnus et al. isolated the
Michael product with no detectable traces of the amine
enone moiety.32 In their synthesis of racemic cylindri-
cines, Snider and co-workers performed a double Michael
addition, although this procedure did not include the
formation of a spirocyclic amine.7
Con clu sion s
An efficient, enantioselective synthesis of (-)-cylindri-
cine C has been developed with an overall yield of 17%
over nine steps, starting from tosylate 3. The key step is
the reduction of an azide to the corresponding amine with
a subsequent double Michael addition. In this step, two
rings and three new stereocenters are created with good
selectivity.
1
purification. Rf ) 0.56 (9:1 hexanes/EtOAc). H NMR: δ 4.03
(m, 2H), 3.46 (app t, J ) 7.2 Hz, 1H), 2.07 (m, 1H), 1.99 (m,
2H), 1.93 (m, 3H), 1.73 (m, 1H), 1.60 (m, 6H), 1.52 (m, 3H),
0.88 (t, J ) 7.5 Hz, 3H), 0.87 (t, J ) 7.5 Hz, 3H), 0.14 (s, 9H).
13C NMR: δ 143.5, 114.7, 112.3, 76.4, 70.2, 31.6, 30.3, 29.9,
29.8, 27.7, 26.3, 23.6, 23.0, 8.3, 8.0, 0.8. IR (CDCl3): 1254, 1190,
1165, 1078 cm-1. HRMS calcd for C18H34O3Si 326.2277, found
326.2260. LRMS (EI): m/z 326 (52), 297 (64), 223 (70), 183
(92), 133 (65), 73 (100).
Exp er im en ta l Section
Gen er a l. NMR spectra were recorded in CDCl3 at 500 MHz
for 1H and 100 MHz for 13C using chloroform (7.24 ppm for
1H, 77.00 ppm for 13C) as an internal reference unless
otherwise stated. Optical rotations were measured using the
D-line of Na at 25 °C. Analytical thin-layer chromatography
(TLC) was performed on Merck silica gel plates using UV light,
p-anisaldehyde, or ceric ammonium nitrate solutions for
visualization. Flash chromatography was performed using
Scientific Adsorbent Inc. silica gel (40 µm). All reactions were
performed under a dry atmosphere of argon using oven- and/
or flame-dried glassware, except for those reactions utilizing
water as solvent, which were run under air. THF and Et2O
were distilled from Na-benzophenone ketyl radical immedi-
ately before use. CH2Cl2, TMEDA, NEt3, and i-Pr2NH were
distilled from CaH2. E-Trimethyl-1-octenylstannane,17 (S)-4-
tosyloxy-1,2-O-3-pentylidene-1,2-butanediol (3),9 and the CrCl2-
solution33 were prepared according to the literature. Alkyl-
lithium reagents were titrated before use using diphenylacetic
acid. Other reagents were purchased from Aldrich and were
used without further purification.
4-[2-(Tr iflu or om e t h ylsu lfon yloxy)cycloh e x-1-e n yl]-
(1,2S)-bu ta n ed iol, O-3-P en tylid in e Aceta l (6). The crude
silyl enol ether 5 was dissolved in THF (50 mL) and cooled to
0 °C, and MeLi (19 mL of a 1.4 M solution in Et2O, 27 mmol)
was added dropwise. After the mixture was stirred for 30 min
at 0 °C, Tf2NPh (10.5 g, 29 mmol) in THF (20 mL) was added
followed by TMEDA (20 mL). After 30 min at 0 °C, the THF
and Et2O were evaporated under reduced pressure and 7:3
hexanes/EtOAc was added to the residual solution. The organic
layer was washed with H2O, 0.1 M HCl, and H2O, dried over
MgSO4, and evaporated. The crude product was purified by
flash chromatography using 95:5 hexanes/EtOAc as solvent
to give 6 (8.0 g, 86% over two steps) as a clear oil. This material
contained 3% of the less substituted, undesired vinyl triflate,
according to 1H NMR analysis. Rf ) 0.29 (9:1 hexanes/EtOAc).
1H NMR: δ 4.03 (m, 2H), 3.48 (m, 1H), 2.29 (m, 2H), 2.20 (m,
2H), 2.14 (m, 2H), 1.73 (m, 3H), 1.60 (m, 7H), 0.88 (t, J ) 7.5
Hz, 3H), 0.87 (t, J ) 7.5 Hz, 3H). 13C NMR: δ 143.3, 129.7,
118.3 (q, J ) 318 Hz), 112.7, 75.7, 69.8, 31.1, 29.9, 29.6, 28.4,
27.5, 27.0, 23.1, 21.7, 8.2, 7.9. IR (CDCl3): 1409, 1216, 1142
cm-1. HRMS calcd for C16H26F3SO5: 387.1453 (m + H)+, found
387.1471. LRMS (EI): m/z 357 (87), 133 (86), 91 (72), 57 (100),
41 (56).
(2R/S)-{[(3S,4)-O-3-P en tylid en e-3,4-d ih yd r oxybu ta n ]-
1-yl}cycloh exa n on e (4). A solution of LDA was prepared by
adding n-BuLi (6.3 mL of a 1.5 M solution in hexanes, 9.4
mmol) to diisopropylamine (0.99 g, 9.8 mmol) in THF (15 mL)
at 0 °C. After 30 min, cyclohexanone dimethylhydrazone (1.37
g, 9.8 mmol) was added, and the anion was allowed to form
during 1 h at 0 °C. A solution of 3 (2.7 g, 8.2 mmol) in THF (5
mL) was added dropwise to the resulting solution, and after 3
h, the mixture was poured into a solution of Cu(OAc)2 (2.0 g,
11 mmol) in H2O (100 mL) and THF (50 mL). The resulting
bluish suspension was vigorously stirred for 1 h at which time
a brown suspension had formed. The organic solvents were
evaporated under reduced pressure, and the aqueous layer was
extracted with EtOAc. The combined organic layers were
washed with H2O and brine, dried over MgSO4, and evapo-
rated. The crude product was purified by flash chromatography
using 9:1 hexanes/EtOAc as solvent to give 4 (1.6 g, 77%) as a
1-{[1-(3S,4)-Dih yd r oxybu tyl]cycloh ex-1-en yl}n on -2-en -
1-on e, O-3-P en tylid in e Aceta l (7). To LiCl (1.2 g, 28 mmol)
and Pd(PPh3)4 (0.66 g, 0.6 mmol) were added 6 (4.4 g, 11 mmol)
and E-trimethyl-1-octenylstannane (3.8 g, 14 mmol) in THF
(60 mL). A flow of CO (g) was bubbled through the solution
during 30 min. A balloon containing CO (g) was connected to
the vessel, and the temperature was elevated to 55 °C. After
48 h, the solvent was evaporated and replaced by 7:3 hexanes/
EtOAc. The organic layer was washed with H2O and brine,
dried over MgSO4, and evaporated. The crude product was
purified by flash chromatography using 95:5 hexanes/EtOAc
as eluent to give 7 (3.4 g, 79%) as a pale yellow oil. Rf ) 0.27
1
clear oil. Rf ) 0.18 (9:1 hexanes/EtOAc). H NMR: δ 4.02 (m,
2H), 3.44 (m, 1H), 2.36 (m, 1H), 2.27 (m, 2H), 2.10 (m, 1H),
2.09 (m, 1H), 1.15-1.90 (m, 12H), 0.86 (m, 6H). 13C NMR: δ
212.98, 212.94, 112.5, 76.5, 76.2, 70.1, 70.0, 50.7, 50.4, 42.1,
42.0, 34.2, 33.8, 31.4, 30.8, 29.9, 29.74, 29.67, 28.1, 28.0, 26.0,
1
(9:1 hexanes/EtOAc). H NMR: δ 6.75 (dt, J ) 7.0, 15.6 Hz,
1H), 6.10 (dt, J ) 1.6, 15.6 Hz, 1H), 3.97 (m, 2H), 3.39 (m,
1H), 2.19 (app ddd, J ) 1.6, 7.0, 7.8 Hz, 2H), 2.11 (m, 2H),
2.04 (m, 3H), 1.96 (m, 1H), 1.71 (m, 1H), 1.61 (m, 3H), 1.56
(m, 4H), 1.42 (m, 2H), 1.26 (m, 8H), 0.85 (t, J ) 6.9 Hz, 3H),
0.84 (t, J ) 7.6 Hz, 3H), 0.83 (t, J ) 7.6 Hz, 3H). 13C NMR: δ
200.5, 150.3, 137.6, 133.6, 130.2, 112.5, 76.0, 69.9, 32.5, 32.3,
31.5, 31.1, 29.9, 29.6, 28.9, 28.7, 28.0, 27.3, 22.5, 22.4, 22.2,
14.0, 8.2, 7.9. IR (CDCl3): 1640, 1464 cm-1. HRMS calcd for
C22H35O3: 347.2586 (m - C2H5)+, found 347.2581. LRMS
(EI): m/z 347 (100), 273 (82), 57 (54). [R]D25 12.4 (c ) 1.0, CH2-
Cl2).
25.4, 25.0, 24.9, 8.2, 7.9. IR (CDCl3): 1706, 1077, 921 cm-1
.
LRMS (EI): m/z 225 (55), 151 (91), 57 (100), 29 (44). Anal.
Calcd for C15H26O3: C, 70.83; H 10.30. Found: C, 70.90; H,
10.30.
(31) Corey, E. J .; Balanson, R. D. Heterocycles 1976, 5, 445.
(32) Venit, J . J .; Magnus, P. Tetrahedron Lett. 1980, 21, 4815.
(33) Rosenkrantz, G.; Mancera, O.; Gatica, J .; Djerassi, C. J . Am.
Chem. Soc. 1950, 72, 4077.

Total Synthesis of (-)-Cyclindricine C
J . Org. Chem., Vol. 64, No. 14, 1999 5187
1-{2-[(3S,4)-Dih yd r oxybu tyl]cycloh ex-1-en yl}n on -2-en -
1-on e (8a ). To acetal 7 (600 mg, 1.6 mmol) in MeCN/H2O (9:
1) (10 mL) was added PdCl2(MeCN)2 (21 mg, 0.08 mmol). After
the resulting light yellow solution was stirred at room tem-
perature for 20 h, 1:1 hexanes/EtOAc was added, and the
mixture was filtered through silica to remove Pd-salts. The
silica was washed with 1:1 hexanes/EtOAc, and the combined
organic portions were evaporated under reduced pressure. The
crude product was purified by flash chromatography using 1:1
hexanes/EtOAc as eluent to give 8a (410 mg, 83%) as a pale
yellow oil. Rf ) 0.20 (1:1 hexanes/EtOAc). 1H NMR: δ 6.85
(dt, J ) 7.0 Hz, 15.6 Hz, 1H), 6.17 (dt, J ) 1.6, 15.6 Hz, 1H),
4.25 (br, 1H), 3.61 (m, 1H), 3.51 (dd, J ) 3.2, 10.9 Hz, 1H),
3.41 (dd, J ) 7.7, 10.9 Hz, 1H), 2.50 (br, 1H), 2.34 (ddd, J )
6.6, 9.7, 13.4 Hz, 1H), 2.21 (m, 4H), 2.09 (m, 2H), 1.97 (m, 2H),
1.68 (m, 2H), 1.39-1.62 (m, 5H), 1.27 (m, 6H), 0.86 (t, J ) 7.1
Hz, 3H). 13C NMR: δ 200.3, 151.2, 139.8, 134.3, 129.1, 70.0,
66.7, 32.6, 31.5, 30.4, 30.3, 28.85, 28.77, 28.0, 27.4, 22.5, 22.3,
22.2, 14.0. IR (CDCl3): 3406, 1664, 1638 cm-1. HRMS calcd
for C19H32O3: 308.2351, found 308.2337. LRMS (EI): m/z 308
and the aqueous layer was extracted with 9:1 hexanes/EtOAc.
The combined organic layers was washed with brine, dried
(MgSO4), and evaporated. The crude product was purified by
flash chromatography using 95:5 hexanes/EtOAc as eluent to
give 2b (187 mg, 86%) as a pale yellow oil. Rf ) 0.32 (95:5
1
hexanes/EtOAc). H NMR (C6D6): 6.85 (dt, J ) 7.0, 15.7 Hz,
1H), 6.23 (dt, J ) 1.5, 15.7 Hz, 1H), 3.53 (dd, J ) 3.7, 10.5 Hz,
1H), 3.43 (dd, J ) 6.6, 10.5 Hz, 1H), 3.17 (m, 1H), 2.17 (m,
4H), 1.94 (dd, J ) 1.5, 7.0 Hz, 1H), 1.91 (dd, J ) 1.5, 7.0 Hz,
1H), 1.85 (m, 2H), 1.52 (m, 2H), 1.41 (app pent, J ) 2.9 Hz,
4H), 1.22 (m, 4H), 1.14 (m, 4H), 0.97 (s, 9H), 0.87 (t, J ) 7.1
Hz, 3H), 0.056 (s, 3H), 0.046 (s, 3H). 13C NMR (C6D6): δ 197.8,
148.7, 137.8, 134.8, 130.5, 66.6, 63.6, 32.6, 31.93, 31.88, 29.3,
29.19, 29.16, 28.4, 27.5, 26.0, 22.9, 22.8, 22.6, 18.4, 14.2, -5.4.
IR (CDCl3): 1640, 1254 cm-1. HRMS calcd for C25H42N3O2Si
(m-CH3): 432.3046, found 432.3041. LRMS (EI): m/z 362 (100),
274 (97), 73 (88). [R]D25 13.3 (c ) 0.4, CH2Cl2).
(-)-Cylin d r icin e C. To azide 2b (20 mg, 45 µmol) in THF
(1 mL) was added a fresh solution of CrCl2 (0.5 mL of a 1.4 M
solution, 0.70 mmol). The solution was stirred for 1 h at room
temperature, then K2CO3 (s) (ca. 1 g) was added along with
EtOAc (5 mL). The solution was dried by addition of MgSO4
(s) and stirred until the solids formed a homogeneous mixture
(ca. 30-60 min). The organic layer was filtered through a short
silica plug, and the solids were washed with EtOAc and EtOAc
with 5% NEt3, which also was filtered through the silica plug.
The combined organic layers were evaporated under reduced
pressure, and the residue was dissolved in THF. This solution
was cooled with an icewater bath, and Bu4NF (54 µL of a 1 M
solution in THF, 54 µmol) was added dropwise. After 30 min,
the solution was allowed to warm to room temperature and
was stirred for 10 h. The THF was evaporated, and the crude
mixture was purified by flash chromatography using 9:1
hexanes/EtOAc and 5% NEt3 as eluent to give (-)-cylindricine
C (6.2 mg, 45%)26 as a pale yellow oil with spectral data in
accordance with those reported in the literature.1,35 1H NMR:
δ 3.51 (m, 2H), 3.41 (m, 1H), 3.26 (m, 1H), 2.85 (br, 1H), 2.28
(t, J ) 12.6 Hz, 2H), 2.21 (dd, J ) 2.8, 13.3 Hz, 2H), 2.10 (dd,
J ) 7.8, 12.2 Hz, 1H), 1.81 (dd, J ) 8.5, 13.3 Hz, 1H), 1.70-
25
(16), 247 (92), 149 (100), 41 (54). [R]D 38.2 (c ) 1.0, CH2Cl2).
1-{2-[(3S)-Met h a n esu lfon yloxy-4-ter t-b u t yld im et h yl-
silyloxybu tyl]cycloh ex-1-en yl}n on -2-en -1-on e. To diol 8a
(150 mg, 0.49 mmol) in CH2Cl2 (5 mL) was added NEt3 (74
mg, 0.73 mmol) followed by TBSCl (88 mg, 0.58 mmol) and
DMAP (12 mg, 98 µmol). After the mixture was stirred for 6 h
at room temperature, 8a was completely transformed to the
monoprotected alcohol 8b34 according to TLC. NEt3 (74 mg,
0.73 mmol) was added followed by MsCl (67 mg, 0.58 mmol),
and the mixture was stirred for an additional 3 h. The solvent
was removed under reduced pressure, and the crude mixture
was dissolved in 7:3 hexanes/EtOAc. The crude mixture was
filtered through a short silica plug, and the solvent was
evaporated to give the mesylate 8c in essentially quantitative
yield, which was used in the subsequent step without further
1
purification. H NMR: δ 6.77 (dt, J ) 6.9, 15.7 Hz, 1H), 6.11
(dt, J ) 1.6, 15.7 Hz, 1H), 4.56 (app pent, J ) 5.5 Hz, 1H),
3.67 (m, 2H), 3.01 (s, 3H), 2.21 (app ddd, J ) 1.6, 6.9, 14.9 Hz,
2H), 2.12 (m, 2H), 2.10-2.02 (m, 4H), 1.75 (m, 2H), 1.62 (m,
4H), 1.44 (m, 2H), 1.34-1.22 (m, 6H), 0.87 (br s, 12H), 0.05 (s,
3H), 0.04 (s, 3H). 13C NMR: δ 200.1, 150.6, 137.3, 134.1, 130.0,
84.1, 64.5, 38.4, 32.5, 31.5, 30.4, 30.1, 28.9, 28.7, 28.0, 27.3,
25.8, 22.5, 22.4, 22.1, 18.3, 14.0, -5.47, -5.49.
25
1.17 (m, 19H), 0.85 (t, J ) 7.1 Hz, 3H). [R]D -64 (c ) 0.2,
CH2Cl2).
(-)-Cylin d r icin e C, Mosh er Ester . To rac- or enantiopure
cylindricine C (2.0 mg, 6.5 µmol) in CH2Cl2 (0.5 mL) at 0 °C
was added NEt3 (1.3 mg, 13 µmol) followed by (R)-(-)-R-
methoxy-R-(trifluoromethyl)phenylacetyl chloride (2.0 mg, 7.8
µmol). After the mixture was stirred for the mixture for 10 h
at 0 °C, the solvent was evaporated and the crude mixture
was purified by flash chromatography using 9:1 hexanes/
EtOAc as eluent to give the Mosher ester of cylindricine C (2.5
mg, 3.5 µmol). The 1H NMR for the enantiopure ester revealed
two dd’s at 3.85 and 4.36 ppm whereas the racemic ester had
these signals and in addition two dd’s at 3.87 and 4.31 ppm,
respectively.36
1-{2-[(3S)-Hyd r oxy-4-ter t-bu tyld im eth ylsilyloxybu tyl]-
cycloh ex-1-en yl}n on -2-en -1-on e (8b). 1H NMR: δ 6.79 (dt,
J ) 6.9, 15.7 Hz, 1H), 6.13 (dt, J ) 1.6, 15.7 Hz, 1H), 3.52 (m,
2H), 3.42 (m, 1H), 2.99 (br, 1H), 2.22 (dd, J ) 1.6, 6.9 Hz, 1H),
2.19 (dd, J ) 1.6, 6.9 Hz, 1H), 2.18-2.00 (m, 6H), 1.68-1.51
(m, 5H), 1.44 (m, 3H), 1.27 (m, 6H), 0.87 (m, 12H), 0.035 (s,
6H). 13C NMR: δ 200.5, 150.5, 138.7, 133.6, 129.9, 70.9, 67.0,
32.5, 31.5, 31.1, 30.7, 28.8, 28.6, 28.0, 27.3, 25.8, 22.5, 22.4,
22.3, 18.2, 14.0, -5.4. IR (CDCl3): 1640, 1257, 920 cm-1. Anal.
Calcd for C25H46O3Si: C, 71.03; H,10.97. Found: C, 71.37; H,
11.09. LRMS (EI): m/z 422 (18), 365 (60), 247 (65), 161 (74),
25
139 (87), 75 (100). [R]D 15.4 (c ) 0.5, CH2Cl2).
Ack n ow led gm en t. The authors thank the National
Institutes of Health (GM38066) for their generous
support of this research. M.R. acknowledges the Stif-
telsen Bengt Lundqvists minne (Sweden) for a postdoc-
toral fellowship.
1-{2-[(3R)-Azid o-4-ter t-bu tyld im eth ylsilyloxybu tyl]cy-
cloh ex-1-en yl}n on -2-en -1-on e (2b). The crude mesylate 8c
was dissolved in DMSO (2 mL), and NaN3 (160 mg, 25 mmol)
was added. After the mixture was stirred at 60 °C for 20 h,
the solution was cooled to room temperature, and 9:1 hexanes/
EtOAc was added. The organic layer was washed with H2O,
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
1
spectra for 1c, 2b, and 5-8. H NMR for pertinent regions of
(34) Alcohol 8b was initially isolated and fully characterized.
(35) The 13C NMR was consistently ca. 0.6 ppm lower than the value
reported in the literature. This is also in accordance with the values
reported by Snider et al., ref 7.
the spectra for the Mosher ester of enantiopure (-)-cylindricine
C and (()-cylindricine C. This material is available free of
charge via the Internet at http://pubs.acs.org.
(36) Copies of the relevant 1H NMR spectra have been submitted
in the Supporting Information.
J O990363L