Enantioselective total synthesis of cis-trikentrin B

Article abstract of DOI:10.1021/jo951767q

Natural cis-trikentrin B was synthesized enantioselectively using, as key steps, an intramolecular Diels-Alder reaction of an allenic dienamide followed by aromatization to construct an indole ring and cleavage of bicyclo[2.2.1]heptene to launch a cis-dimethylcyclopentane ring. Diels-Alder adducts 9 and 10 were elaborated to provide allenic dienamide 25, and its intramolecular Diels-Alder reaction proceeded smoothly. Aromatization to an indole ring and stereoselective cleavage of the bicyclo[2.2.1]heptene ring were performed successfully. Introduction of an (E)-butenyl group via addition of propylmagnesium bromide and subsequent anti elimination of water gave natural cis-trikentrin B.

Full text of DOI:10.1021/jo951767q

3406
J . Org. Chem. 1996, 61, 3406-3416
En a n tioselective Tota l Syn th esis of cis-Tr ik en tr in B
Mase Lee, Izumi Ikeda, Tsuyoshi Kawabe, Sayaka Mori, and Ken Kanematsu*
Institute of Synthetic Organic Chemistry, Faculty of Pharmaceutical Sciences, Kyushu University 62,
Maidashi, Higashi-ku, Fukuoka 812-82, J apan
Received September 27, 1995X
Natural cis-trikentrin B was synthesized enantioselectively using, as key steps, an intramolecular
Diels-Alder reaction of an allenic dienamide followed by aromatization to construct an indole ring
and cleavage of bicyclo[2.2.1]heptene to launch a cis-dimethylcyclopentane ring. Diels-Alder
adducts 9 and 10 were elaborated to provide allenic dienamide 25, and its intramolecular Diels-
Alder reaction proceeded smoothly. Aromatization to an indole ring and stereoselective cleavage
of the bicyclo[2.2.1]heptene ring were performed successfully. Introduction of an (E)-butenyl group
via addition of propylmagnesium bromide and subsequent anti elimination of water gave natural
cis-trikentrin B.
In tr od u ction
Trikentrins are a series of polyalkylindole alkaloids
that were isolated from the marine sponge Trikentrion
flabelliforme collected from coastal waters off Darwin,
Australia, by Capon et al. in 1986 (Figure 1).1
The structures and relative configurations of these
compounds were also reported by Capon’s group. This
series of alkaloids exhibits growth inhibitory activity
toward the Gram-positive bacteria Bacillus subtilis.1 This
is a new class of indole alkaloid in that, in addition to
having an alkyl substituent, these compounds contain a
dimethylcyclopentane ring fused to the benzene ring of
the indole skeleton. Because of their unique structure
and lack of structural relationship with major antibiotics,
trikentrins have intrigued many chemists.
cis-Trikentrin B (1) is a minor component in the isolate,
occupying 0.007% of the dry weight, and is obtained only
as a mixture with trans-isotrikentrin B (2).1 Several
syntheses have been reported in this family, not only to
develop synthetic routes, but also to establish the abso-
lute configuration of the cis and trans trikentrins.
The first total synthesis of trikentrin A was culminated
by MacLeod et al. using aryl radical cyclization as the
main strategy.2a Later, Boger et al. reported synthesis
based on a heteroaromatic azadiene Diels-Alder reac-
tion.2b
F igu r e 1. Trikentrins.
The first total synthesis of cis-trikentrin B was re-
ported by our laboratory, using our new strategy to
construct the indole skeleton by an intramolecular Diels-
Alder reaction of allenic dienamide.2c During the course
of our systematic studies, Natsume et al. reported the
first asymmetric synthesis of cis-trikentrin B and as-
signed the absolute configuration as 6R,8S through
comparison of CD spectra of the mixture of synthesized
cis-trikentrin B and trans-trikentrin B with that of an
authentic sample.2d Herein, we report the full details of
an asymmetric synthesis using the strategy that we
developed in the racemic total synthesis of cis-trikentrin
B (eq 1).2c
The strategy is based on the facile formation of a
partially hydrogenated indole skeleton via an intramo-
lecular Diels-Alder reaction, exploiting the high reactiv-
ity of allene as a dienophile. The merit of this strategy
in constructing polyalkylindole skeletons like the triken-
trins lies in the potential to control the site of substitution
through modification of the substitution pattern on the
allenic dienamide. As seen in eq 1, a substituent on the
terminal carbon of the diene portion can be converted to
a substituent on C5 directly.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) (a) Capon, R. J .; MacLeod, J . K.; Scammells, P. J . Tetrahedron
1986, 42, 6545. (b) Herb, R.; Carroll, A. R.; Yoshida, W. Y.; Scheuer,
P. J .; Paul, V. J . Tetrahedron 1990, 46, 3089.
(2) (a) MacLeod, J . K.; Monahan, L. C. Tetrahedron Lett. 1988, 29,
391. (b) Boger, D. L.; Zhang, M. J . Am. Chem. Soc. 1991, 113, 4230.
(c) Yasukouchi, T.; Kanematsu, K. Tetrahedron Lett. 1989, 30, 6559.
(d) Muratake, H.; Mikawa, A.; Seino, T.; Natsume, M. Chem. Pharm.
Bull. 1994, 42, 846.
The second point of this strategy is concerned with
stereoselective cleavage of the bicyclo[2.2.1]heptene sys-
tem derived from the Diels-Alder adduct of cyclopenta-
diene to lead to the cis-disubstituted cyclopentane ring,
followed by a series of transformations that result in cis-
dimethyl groups. Our retrosynthetic analysis is outlined
in Scheme 1.
S0022-3263(95)01767-1 CCC: $12.00 © 1996 American Chemical Society

Enantioselective Total Synthesis of cis-Trikentrin B
J . Org. Chem., Vol. 61, No. 10, 1996 3407
Sch em e 1. Retr osyn th etic An a lysis
The last problem that remained was the introduction
of an (E)-butenyl group at the C6 position of the indole
ring. We employed a Wittig reaction in our previously
reported study which resulted in a Z, E mixture from
which the E isomer was difficult to isolate.
In the present synthesis, we adopted Natsume’s method
of addition-anti elimination used in his synthesis of cis-
trikentrin B.2d
Resu lts a n d Discu ssion
Koizumi’s Diels-Alder adduct was prepared according
to his report3 (Scheme 2). A diastereomeric mixture of
sulfoxides 13 and 14 was isolated by fractional crystal-
lization using hexane-diethyl ether as the solvent.
During the early stages of our investigation, this
operation was performed by the common method of
preferential crystallization of one diastereomer.7 But this
was time-consuming and limited to a small scale opera-
tion. Eventually, by careful regulation of the crystal-
lization conditions, the two diastereomers were crystal-
lized in morphologically different crystals discernible
with the naked eye (cubics of about 1 cm diameter and
needles of 3 mm width and over 2 cm length), and the
isolation was performed by simply picking out the dif-
ferent crystals with tweezers.
The R diastereomer 14 was used in the synthesis, and
the S diastereomer 13 was epimerized to afford an R,S
mixture using a reduction-reoxidation process. Initially,
this process was performed with two sequential reactions
using titanium trichloride followed by m-chloroperbenzoic
acid. Over the series of steps, Z-E isomerization oc-
curred, and the Z:E ratio obtained was similar to that
observed during the original conversion of 11 to 12.
Later, a more convenient method of oxidoreduction, using
both titanium trichloride and hydrogen peroxide in one
pot, was developed, combining the two reactions.8 Ad-
dition of titanium trichloride to an ethanolic solution of
sulfide at room temperature until the violet color of the
reagent no longer disappeared and consecutive addition
of hydrogen peroxide gave good results.
However, the problem of Z-E isomerization persisted.
Oxidation of the sulfide with m-chloroperbenzoic acid
gave sulfoxide in the same Z:E ratio as that of the
reaction with hydrogen peroxide. A pH-controlled oxida-
tion with monoperoxyphthalic acid magnesium salt
(MMPP) in a buffered solution (pH 7.0) gave the same
result. These facts suggested that Z-E isomerization
occurs in the reduction stage with titanium trichloride.
The Diels-Alder reaction, according to Koizumi’s
method, afforded the adduct in excellent yield with good
enantioselectivity.3b The obtained Diels-Alder adduct
was transformed as shown in Scheme 3.
In constructing the cis-dimethylcyclopentane ring enan-
tioselectively, the enantiomeric purity depends exclu-
sively on the facial selectivity and regioselectivity of the
intermolecular Diels-Alder reaction to prepare the bicyclo-
[2.2.1]heptene ring. If we can prepare a stereocontrolled
Diels-Alder adduct as a synthon, after indole ring
formation, the facial selectivity can be converted to
enantioselectivity during the cleavage of the double bond
of the bicyclo[2.2.1]heptene system.
We chose Koizumi’s sulfoxide 93 as the starting mate-
rial. Using proper transformations, it was envisaged that
sulfoxide 9 would be converted to ketosilyl ether 8 easily.
The carbonyl group was destined to be converted to an
exocyclic olefin and part of a diene. Compound 8, which
was employed in our racemic synthesis,2c could lead to
7. Oppolzer’s two-step conversion proved to be a conve-
nient method of generating dienes like 6 in the racemic
synthesis.2c,4 However, later, we developed a new syn-
thon 10 using our original strategy that employs allene-
1,3-dicarboxylate as a dienophile.5 So, the conversion of
10 to 7 was also investigated for applicability. Ho-
mologative allenylation can give the key intermediate,
allenic dienamide.6
After the construction of indole 5, it appeared to be
clear that the cleavage of the bicyclo[2.2.1]heptene ring
would lead to the cis-disubstituted cyclopentane ring of
compound 4. The manipulation of the substituents to the
dimethyl groups of compound 3 would be executed under
mild conditions to prevent epimerization.
The adduct 9 was taken to 15 via a Pummerer
rearrangement and then transformed to dimethylketal-
ized compound 16 for further reaction.
We originally planned to prepare compound 20 to fix
the endo configuration of the menthyl ester moiety so as
to simplify subsequent operations, but the elimination
of trifluoroacetic acid occurred spontaneously under the
reaction conditions. Fortunately, the endo configuration
of the menthyl ester was revived in the ketalization step
to make the operations and spectral analyses of the
(3) (a) Takayama, H.; Iyobe, A.; Koizumi, T. Chem. Commun. 1986,
771. (b) Arai, Y.; Hayashi, Y.; Yamamoto, M.; Takayama, H.; Koizumi
T. Chem. Lett. 1987, 185.
(4) (a) Oppolzer, W.; Bieber, L.; Francotte, E. Tetrahedron Lett. 1979,
11, 981. (b) Kiefer, H. Synthesis 1972, 39.
(5) Aso, M.; Ikeda, I.; Kawabe, T.; Shiro, M.; Kanematsu, K.
Tetrahedron Lett. 1992, 33, 5787.
(6) Crabbe, P.; Fillion H.; Andre, D.; Luche J .-L. Chem. Commun.
1979, 859.
(7) J acques, J .; Collet, A.; Wilen, S. H. Enantiomers, Racemates and
Resolutions; J ohn Wiley & Sons: New York, 1981.
(8) (a) Takayama, H.; Hayashi, K.; Koizumi, T. Tetrahedron Lett.
1986, 27, 5509. (b) Watanabe, Y.; Numata, T.; Oae, S. Synthesis 1981,
204.

3408 J . Org. Chem., Vol. 61, No. 10, 1996
Lee et al.
Sch em e 2a
a
Reagents and conditions: (i) m-CPBA, CH2Cl2, 0 °C; chromatographed; (ii) fractional crystallization; (iii) TiCl3, EtOH, rt; (iv) Et2AlCl
in hexane, cyclopentadiene, CH2Cl2, -78 °C; (v) TiCl3, EtOH, rt; then H2O2, 0 °C.
Sch em e 3a
a
Reagents and conditions: (i) TFAA, 2,6-lutidine, CH2Cl2, rt; (ii) methyl orthoformate, MeOH, p-TsOH, reflux; (iii) LiAlH4, ether, rt;
(iv) 5% HCl, THF; (v) TBDMSCl, imidazole, DMAP, CH2Cl2, rt; (vi) Reformatsky reaction.
following steps simple. This fact was confirmed by
NOESY spectra of compounds 17 and 18.
proceeded in refluxing dry tetrahydrofuran.9a However,
the yield was low and unreproducible. A modified
reaction using silver-doped zinc laminate could not be
controlled easily.9b The reaction hardly occurred under
-10 °C and gave decomposed products above 0 °C.
Mukaiyama’s method, which employs metallic zinc gen-
erated in situ, proceeded smoothly at room temperature
to a certain point but no further and resulted in a modest
yield even with a large excess of reagents.9c
Finally, Toda’s Reformatsky reaction in the absence
of solvent was adopted.9d This reaction proceeded at
room temperature in good yield and, moreover, cleanly,
making it possible to recover the unreacted starting
material easily. This reaction occurred stereoselectively
and afforded compound 19 via attack from the convex
face.
Reduction with lithium aluminum hydride and subse-
quent deketalization gave keto alcohol 18 in good yield.
Next, the alcohol was protected with a tert-butyldimeth-
ylsilyl group.
Direct transformation of compound 8 to compound 21
by a Wittig reaction did not occur under various condi-
tions probably because of the bulkiness of both reactants
and the lability of 8 in considerably basic conditions (eq
2).
Next, transformation to launch diene and dienophile
was attempted (Scheme 4).
Dehydration of 19 was accomplished under basic
conditions with thionyl chloride and triethylamine. This
anti elimination step afforded Z,E geometric isomers in
almost equal amounts. After the cyclization and aroma-
tization, these two isomers should give the same product,
so the unseparated mixture was carried on. However,
for the purpose of comparison with the regioconfirmed
(9) (a) For a review, see: Fu¨rstner, A. Synthesis 1989, 571. (b) Csuk,
R.; Fu¨rstner, A.; Weidmann, H. Chem. Commun. 1986, 775. (c) Harada,
T.; Mukaiyama, T. Chem. Lett. 1982, 161. (d) Tanaka, K.; Kishigami,
S.; Toda, F. J . Org. Chem. 1991, 56, 4333.
This difficulty was circumvented by an addition-
dehydration method. A classical Reformatsky reaction

Enantioselective Total Synthesis of cis-Trikentrin B
J . Org. Chem., Vol. 61, No. 10, 1996 3409
Sch em e 4a
Sch em e 5a
a
a
Reagents and conditions: (i) Ag2CO3 on Celite, benzene, reflux;
Reagents and conditions: (i) thionyl chloride, pyridine, 0 °C;
(ii) LiOH, THF-H2O; TMSCHN2, MeOH-benzene; (iii) TBDMSCl,
imidazole, DMAP, CH2Cl2; (iv) DIBALH, CH2Cl2, -78 °C; (v) TrCl,
TEA, DMAP, CH2Cl2; (vi) Bu4NF in THF (vii) PCC, CH2Cl2.
(ii) DIBALH, ether, 0 °C; (iii) TrCl, TEA, DMAP, CH2Cl2, rt; (iv)
Bu4NF in THF solution, rt; (v) PCC, Celite, CH2Cl2, rt; (vi)
propargylamine, MS 4A, ether; pivaloyl chloride, 2,4,6-collidine,
CH2Cl2, rt; (vii) formalin diisopropylamine, CuBr, 1,4-dioxane,
reflux.
Sch em e 6a
synthesis to be described in Scheme 5, isolation on a
spectroscopic scale was performed at each step.
Reduction with diisobutylaluminum hydride afforded
compound 23, which was transformed to trityl ether 21.
Deprotection of silyl ether 21 followed by oxidation with
pyridinium chlorochromate on celite afforded aldehyde
7.10 This oxidation step proceeded at a fast rate for 2 h
and then slowed. This was not prevented by a large
excess of reagent, probably because of the formation of
acetal between the starting material and the product
aldehyde 7, given the acidic nature of pyridinium chlo-
rochromate. However, a buffered reaction using sodium
acetate powder resulted in a slower reaction. Reaction
with neutral pyridinium dichromate proceeded very
slowly as well. Thus, the starting material was recycled
after 2 h of reaction and subsequent isolation from
product.
Reaction of 7 with propargylamine in the presence of
molecular sieves gave the desired propargylimine com-
pound, and according to Oppolzer’s method, this was
immediately treated with pivaloyl chloride using collidine
as a base.4a The resulting propargylamine compound 6
was treated with formaldehyde and diisopropylamine and
a catalytic amount of cuprous bromide according to the
Crabbe protocol of homologative allenylation.6
a
Reagents and conditions: (i) toluene, 160 °C, sealed tube; (ii)
MnO2, CH2Cl2, rt.
hydrolyzed and esterified with Shioiri’s reagent13 without
purification (Scheme 5). The procedures outlined in
Scheme 4 then afforded synthetic intermediate 7 in good
yield.
The spectra of the intermediates shown in Scheme 5
were compared with those of the intermediates shown
in Scheme 4. The less polar compound 22a showed
spectral patterns similar to the corresponding methyl
ester 28, and the structure of the more polar compound
was assigned as regioisomeric structure 22b. The spec-
troscopic data of 23a and successive compounds all
matched.
Intramolecular Diels-Alder reaction of the allenic
dienamide 25 in a sealed tube proceeded smoothly to give
cyclized compound in 88% yield (Scheme 6).
Previous reports from our laboratory on the effects of
substituents stated that a substituent on the same
position of the diene as the (trityloxy)methyl group of
compound 25 retards the intramolecular Diels-Alder
reaction.14a But, the problem of the contribution of the
s-cis conformer can be precluded by adopting the exocyclic
diene fixed in a rigid ring system. The steric hindrance
of the bulky (trityloxy)methyl group can be compensated
for by the effect of a pivaloyl group, bringing the diene
Later, we developed a more convenient synthon for
preparing the key intermediate 7.5 This synthon 10 was
prepared by Diels-Alder reaction of cyclopentadiene with
optically active allene-1,3-dicarboxylate. The absolute
configuration of this compound had been confirmed by
X-ray analysis, and the applicability of this synthon had
been proved by its successful conversion to cyclosarko-
mycin.11
Compound 10 was converted to 26 according to the
cyclosarkomycin synthesis,11 and 26 was oxidized follow-
ing Fetizon’s procedure.12 The lactone thus produced was
(12) (a) Balogh, V.; Fetizon, M.; Golfier, M. J . Org. Chem. 1971, 36,
1339. (b) McKillop, A.; Young, D. W. Synthesis 1979, 401.
(13) (a) Shioiri, T.; Aoyama, T. Yuki Gosei Kagaku Kyokai Shi 1986,
44, 149. (b) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull.
1981, 29, 1475. (c) Mori, S.; Sakai, I.; Aoyama, T.; Shioiri, T. Ibid. 1982,
30, 3380.
(10) For
a review, see: Piancatelli, G.; Scettri, A.; D’awia, M.
Synthesis 1982, 245.
(11) Ikeda, I.; Kanematsu, K. Chem. Commun. 1995, 453.

3410 J . Org. Chem., Vol. 61, No. 10, 1996
Lee et al.
Sch em e 7a
Sch em e 8a
a
Reagents and conditions: (i) NaBH4, MeOH, rt; (ii) MsCl, TEA
a
Reagents and conditions: (i) OsO4, MsNH2, NMO, pyridine,
ether, 0 °C; (iii) Zn, NaI, DME, reflux.
ether-1,4-dioxane-H2O, rt; (ii) NaIO4, THF-H2O, rt; (iii) NaBH4
(0.25 equiv), EtOH, -10 °C; (iv) MsCl, TEA, ether, 0 °C; (v) Zn,
NaI, DME, reflux.
Sch em e 9a
and the allenic dienophile moieties in closer proximity
to facilitate the reaction.14
Aromatization of the obtained cyclic product represents
another important point of our strategy. Using p-
chloranil in refluxing tetrahydrofuran produced irrepro-
ducible results and often resulted in yields below 10%.
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or o-
chloranil did not afford the desired product. In the end,
aromatization with manganese dioxide proceeded at room
temperature, and the recovery of the remaining starting
material was easy.15
The stereoselective cleavage of the bicyclo[2.2.1]-
heptene ring and installation of the cis-dimethyl groups
commenced with dihydroxylation of the olefin using a
catalytic amount of osmium tetraoxide with N-methyl-
morpholine N-oxide as a cooxidant and a stoichiomeric
amount of methanesulfonamide16 (Scheme 7).
The reaction proceeded at the same speed when using
p-toluenesulfonamide; however, methanesulfonamide was
adopted for practical reasons in that the Rf value of the
product 30 was near that of p-toluenesulfonamide.
Further oxidation of the diol with sodium periodate
gave cis-dialdehyde 4 in 96% yield. Direct cleavage using
Lemieux oxidation conditions resulted in a low yield as
in the reported case of simple bicyclo[2.2.1]heptene ring
without the indole system.2d,17 The selective reduction
of aldehyde 4 containing the indolylamide moiety was
effected by reduction with an exactly stoichiometric
amount of sodium borohydride at -10 °C to give 31 in
90% yield.
a
Reagents and conditions: (i) PhSO2Cl, NaH, 18-crown-6, THF,
rt; (iii) CSA, MeOH-THF, rt.
reduction was conducted with an excess of sodium
borohydride at room temperature to give wholly reduced
compound 34 (Scheme 8).
The mesylation step proceeded cleanly under mild
conditions, leaving no monomesylated product. Reduc-
tion of the dimesylate to dimethyl compound 36 was
effected by Fujimoto’s method.18 Reduction of the same
compound with Super hydride afforded many undesirable
compounds probably because of the high basicity of the
reagent along with its nucleophilicity.
Deprotection of the trityl ether with acid resulted in
complete decomposition and loss of the indole skeleton
(eq 3).
However, the subsequent mesylation afforded mainly
monomesylated compounds in the presence of some
desired dimesylate 32. Moreover, the obtained dimesy-
late resisted to subsequent reduction to dimethyl com-
pound 33. Thus, we returned to compound 4, and the
This was thought to be caused by the π excessive
nature of the bare indole system which could induce
electrophilic reaction of the ring system with acid.
Accordingly, introduction of an electron-withdrawing
group on the indole ring became necessary before treat-
ment with acid (Scheme 9).
Introduction of a phenylsulfonyl group onto the nitro-
gen atom of the indole ring without producing the usually
predominant 3-substituted isomer was accomplished with
benzenesulfonyl chloride and sodium hydride using 18-
crown-6 as a counterion to the indolyl anion, although
(14) (a) Hayakawa, K.; Yasukouchi, T.; Kanematsu, K. Tetrahedron
Lett. 1986, 27, 1837. (b) Boeckman, J r., R. K.; Ko, S. S. J . Am. Chem.
Soc. 1982, 104, 1033. (c) J ung, M. E.; Gervay, J . J . Am. Chem. Soc.
1991, 113, 224.
(15) J ansen, A. B. A.; J ohnson,J . M.; Surtees, J . R. J . Chem. Soc.
1964, 5573.
(16) Sharpless, K. B.; Amberg, W.; Bennani, Y.; Crispino, G. A.;
Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;
Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768.
(17) Demuth, M.; Ritterskamp, P.; Weigt, E.; Schaffner, K. J . Am.
Chem. Soc. 1986, 108, 4149.
(18) Fujimoto, Y.; Tatsuno, T. Tetrahedron Lett. 1976, 3325.

Enantioselective Total Synthesis of cis-Trikentrin B
J . Org. Chem., Vol. 61, No. 10, 1996 3411
in modest yield.19 At first, this introduction was at-
tempted with sodium hydride in refluxing dimethoxy-
ethane solution and little compound 39 was obtained,
while 38 was not obtained at all. Compound 38 obtained
under the milder conditions described above proved to
be unstable under the refluxing conditions used to
synthesize it without crown ether.
Sch em e 10a
Subsequent removal of the trityl group with acid
proceeded smoothly at room temperature to give 39 in
good yield, which is the same key intermediate Natsume
et al. used in their synthesis of cis-trikentrin B. Spectral
data agreed with those reported by Natsume.2d
Though the phenylsulfonyl group proved to be stable
to Grignard reaction conditions and dehydration condi-
tions with acid in Natsume’s synthesis, it was difficult
to introduce effectively because of the low activity of both
the indole nitrogen as a nucleophile and benzenesulfonyl
chloride as an electrophile. Given the low yield, we
attempted to introduce a different electron-withdrawing
protective group. This protective group should be intro-
duced efficiently and should survive under Grignard
conditions and the acidic conditions used in dehydration
step.
First, we attempted to use a pivaloyl group, anticipat-
ing that this bulky group would prevent the indolyl amide
from being deprotected by propylmagnesium bromide.
However, it proved difficult to introduce this bulky group
effectively.
We investigated the acetyl group which could be
introduced in good yield and determined proper condi-
tions for the Grignard reaction that avoided deprotection
of the indolyl acetamide (Scheme 10).
The reaction of compound 36 with acetyl chloride and
sodium hydride using 18-crown-6 afforded product 40 in
92% yield. Interestingly, the reaction using 15-crown-5
instead of 18-crown-6 did not proceed under the same
conditions. However, 18-crown-6 and potassium tert-
butoxide afforded 40 in a similar yield under the same
conditions.15
a
Reagents and conditions: (i) acetyl chloride, NaH, 18-crown-
6, THF rt; (ii) CSA, MeOH-THF, rt; (iii) MnO2, CH2Cl2, rt; (iv)
propylmagnesium bromide THF, -10 °C; (v) p-TsOH, benzene, 50
°C; (vi) NaBH4, MeOH, rt.
Subsequent deprotection of trityl ether and the oxida-
tion of the thus obtained alcohol 41 was effected at room
temperature. The addition of propylmagnesium bromide
to aldehyde 42 conducted at -10 °C afforded compound
43 successfully without nucleophilic attack on the indolyl
acetamide. Dehydration with p-toluenesulfonic acid
completed the introduction of the 1 (E)-butenyl group.2d
Natsume et al. utilized refluxing ethanolic potassium
hydroxide to remove the phenylsulfonyl group.2d Re-
moval of the acetyl group from the nitrogen atom was
effected by reduction with sodium borohydride at room
temperature to give cis-trikentrin B, which is unstable
F igu r e 2. CD spectrum of cis-trikentrin B.
chromatography on Kieselgel 60 (230-400 mesh). All solvents
were purified and dried prior to use. All reactions sensitive
to moisture or air were performed under Ar. All extracted
solutions were dried over anhydrous Na2SO4 prior to evapora-
tion.
1
and darkened on standing as in Capon’s report.1 IR, H
NMR, 13C NMR, mass, and CD spectral data of 1 all
Syn th esis of Men th yl Bicyclo[2.2.1]h ep ta -1,4-d ien e-1-
ca r boxyla te (15). A solution of 9 (436 mg, 1.09 mmol) in dry
CH2Cl2 (10 mL) was treated with TFAA (0.31 mL) and 2,6-
lutidine (0.258 mL, 2.19 mmol) under Ar. The reaction
mixture was stirred at rt for 30 min. The resulting mixture
was extracted with ether, and the combined organic layer was
washed with 10% aqueous HCl solution, followed by saturated
NaHCO3 solution and then brine. The solvent was removed
in vacuo. Purification of the residue by column chromatog-
raphy [hexane-ethyl acetate (10:1)] afforded 15 (416 mg,
quantitative) as a colorless oil: HR FABMS calcd for C23H29O2-
NS 383.1919, found 383.1917; FABMS m/ z (rel intensity) 384
(M + H+, base), 383 (M+, 47), 246 (73), 228 (58), 200 (34); IR
agreed with those of Natsume (Figure 2).2d
Exp er im en ta l Section
Melting points were uncorrected. 1H and 13C NMR spectra
were determined at 270 and 67.8 MHz, respectively. Mass
spectra and high-resolution mass spectra (HRMS) were de-
termined on J EOL D-300 or J EOL DX-300. Specific rotations
were measured on a J ASCO DIP-360 digital polarimeter. CD
spectra were taken on a J ASCO 720W polarimeter. Analytical
thin-layer chromatographies (TLC) were performed on pre-
coated Kieselgel 60 F254
. Nonflash chromatography separa-
tions were performed on Kieselgel 60 (70-230 mesh) and flash
1
νmax (CHCl3) cm-1 1690; H NMR (CDCl3) δ 8.61 (1 H, ddd, J
) 1.0, 4.9, 2.3 Hz), 7.67 (1 H, dt, J ) 1.7, 7.6 Hz), 7.43 (1 H,
ddd, J ) 1.0, 7.6, 2.3 Hz), 7.23 (1 H, ddd, J ) 1.0, 4.9, 7.4 Hz),
(19) Guida, W. C.; Mathre, D. J . J . Org. Chem. 1980, 45, 3172.

3412 J . Org. Chem., Vol. 61, No. 10, 1996
Lee et al.
6.87 (1 H, dd, J ) 3.0, 4.6 Hz), 6.74 (1 H, dd, J ) 3.0, 4.6 Hz),
4.74 (1 H, dt, J ) 4.3, 10.9 Hz), 4.02 (1 H, brs), 3.56 (1 H, brs),
2.22-0.76 (18 H, m); 13C NMR (CDCl3) δ 164.27, 156.46,
150.14, 143.08, 140.65, 137.56, 136.70, 126.96, 122.02, 74.24,
74.12, 69.89, 57.33, 51.37, 47.14, 41.33, 41.25, 34.34, 31.39,
C14H25O2Si (M + H+) 253.1624, found 253.1616; FABMS m/ z
(rel intensity) 253 (M + H+, base), 211 (37), 195 (93), 137 (50),
93 (34), 66 (11); 1H NMR (CDCl3) δ 6.53 (1 H, dd, J ) 3.0, 5.6
Hz), 6.04 (1 H, dd, J ) 3.0, 6.3 Hz), 3.86 (1 H, m), 3.21 (1 H,
brs), 3.19-3.04 (2 H, m), 2.40-2.33 (1 H, m), 2.18 (1 H, brd, J
) 9.2 Hz),1.91 (1 H, brd J ) 9.2 Hz), 0.87 (9 H, s), 0.08(6 H,
26.44, 23.80, 21.99, 20.85, 20.74, 16.71; [R]28 -241.1 (c 0.53,
D
CHCl3).
s); [R]25 -303 (c 0.53, CHCl3).
D
Syn th esis of Men th yl (1S)-2,2-Dim eth oxybicyclo[2.2.1]-
h ep t-4-en e-1-ca r boxyla te (16). A solution of 15 (482 mg,
1.26 mmol) in dry methanol (26 mL) was treated with
p-toluenesulfonic acid monohydrate (260 mg, 1.36 mmol) and
trimethyl orthoformate (4.27 mL, 39.03 mmol). The reaction
mixture was refluxed for 5 h. Then the solvent was removed
in vacuo, and the resulting mixture was neutralized with
saturated NaHCO3 solution and extracted with ether. The
combined organic layer was washed with brine, and the solvent
was removed in vacuo. Purification of the residue by column
chromatography [hexane-ethyl acetate (10:1)] afforded 16 (268
mg, 63%) as a colorless oil: HR FABMS calcd for C20H32O4
336.2300, found 336.2301; FABMS m/ z (rel intensity) 336 (M+,
56), 305 (44), 270 (19), 181 (48), 167 (base); IR νmax (neat) cm-1
Syn th esis of (1R,2S)-Eth yl 2-[(ter t-Bu tyld im eth ylsi-
loxy)m et h yl]-1-h yd r oxyb icyclo[2.2.1]h ep t -4-en e-1-a ce-
ta te (19). 8 (5 g, 19.81 mmol), zinc powder (17.5 g, 0.27 mol),
and NH4Cl powder (7.2 g, 0.13 mol) was mixed in a mortar
and transferred to a steel dipper. Ethyl bromoacetate (12 mL,
0.05 mol) was added to the resulting mixture. After spontane-
ous exothermic reaction ceased, the resulting mixture was
allowed to stand at rt for 2 h. The resulting hard cake was
crushed, and saturated NH4
Cl solution was added and ho-
mogenized in a mortar. The resulting mixture was filtered
off and washed with ethyl acetate. The mother liquor was
extracted with ethyl acetate. The combined organic layer was
washed with brine, and the solvent was removed in vacuo.
Purification of the residue by column chromatography [hex-
ane-ethyl acetate (10:1)] afforded 19 (5.14 g, 85%) as a
colorless oil: HR FABMS calcd for C18
1
1735; H NMR (CDCl3) δ 6.60 (1 H, dd, J ) 2.6, 5.6 Hz), 6.04
(1 H, dd, J ) 3.0, 5.6 Hz), 4.65 (1 H, dt, J ) 4.3, 10.9 Hz), 3.41
(1 H, s), 3.15 (1 H, s), 3.03 (1 H, d, J ) 3.3 Hz), 2.98 (1 H, brs),
2.94 (1 H, brs), 2.00-0.75 (18 H, m); 13C NMR (CDCl3) δ
170.79, 139.02, 130.00, 113.11, 74.17, 54.86, 50.71, 50.32,
50.16, 47.27, 46.99, 44.05, 40.81, 34.38, 31.34, 26.31, 23.64,
22.03, 20.79, 16.56.
H33O4Si (M + H+)
341.2148, found 341.2158; FABMS m/ z (rel intensity) 341 (M
+ H+, base), 323 (53), 283 (23), 257 (28), 217 (36), 73 (38); IR
1
νmax (neat) cm-1 3520, 1740; H NMR (CDCl3) δ 6.29-6.26 (1
H, dd, J ) 3.0, 5.3 Hz), 6.22-6.18 (1 H, dd, J ) 3.0, 5.6 Hz),
4.22-4.15 (1 H, m), 3.59 (1 H, dd, J ) 6.3, 10.2 Hz), 3.42 (1 H,
dd, J ) 7.9, 10.2 Hz), 3.35 (1 H, s), 2.95 (1 H, brs), 2.86 (1 H,
brs),2.73 (2 H, q, J ) 14.8 Hz), 2.06-2.00 (1 H, m), 1.56(1 H,
s) 1.53 (1H, dd, J ) 2.0, 9.2 Hz), 1.40 (H, d, J ) 9.2 Hz), 1.29
(3 H, t, J ) 7.3 Hz), 0.89 (9 H, s), 0.04 (6 H, d, J ) 2.31 Hz);
13C NMR (CDCl3) δ 235.07, 172.34, 135.81, 134.97, 79.66,
63.77, 60.54, 52.84, 52.37, 47.20, 46.74, 45.20, 25.88, 18.15,
14.17.
Syn th esis of (1R)-2,2-Dim eth oxybicyclo[2.2.1]h ep t-4-
en e-1-eth a n ol (17). A solution of 16 (1.71 g, 5.08 mmol) in
dry ether (20 mL) was treated with LAH (217 mg, 5.72 mmol)
at 0 °C. The reaction mixture was warmed to rt and stirred
for 30 min at rt. The resulting solution was quenched with
saturated NH4Cl solution and extracted with ether. The
combined organic layer was washed with brine, and the solvent
was removed in vacuo. Purification of the residue by column
chromatography [hexane-ethyl acetate (1:1)] afforded 17 (920
mg, 98%) as a colorless oil: HR FABMS calcd for C10H16O3
184.1099, found 184.1101; FABMS m/ z (rel intensity) 184 (M+,
18), 167 (base), 153 (74), 101 (63), 93 (33), 79 (22), 55 (13); IR
Syn t h esis of (1S,4R)-E t h yl [3-[(ter t-Bu t yld im et h yl-
siloxy)m et h yl]b icyclo[2.2.1]h ep t -5-en -2-ylid en e]-1-a ce-
ta te (22). Thionyl chloride (7.5 mL, 102.82 mmol) was added
dropwise to a solution of 19 (5 g, 14.68 mmol) in dry pyridine
(300 mL) at 0 °C, and the reaction mixture was stirred at 0
°C for 15 min. The resulting mixture was neutralized with
10% sulfuric acid solution and extracted with ether. The
combined organic layer was washed with saturated NaHCO3
solution followed by brine. The solvent was removed in vacuo.
Purification of the residue by column chromatography [hex-
ane-ethyl acetate (10:1)] afforded 22 (3.44 g, 73%) as a
colorless oil: HR FABMS calcd for C18H31O3Si (M + H+)
323.2042, found 323.2038; FABMS m/ z (rel intensity) 323 (M
1
νmax (neat) cm-1 3410; H NMR (CDCl3) δ 6.26 (1 H, dd, J )
3.0, 5.6 Hz), 6.08 (1 H, dd, J ) 3.0, 5.6 Hz), 3.52 (1 H, ddd, J
) 2.3, 5.9, 13.5 Hz), 3.34 (1 H, m), 3.30 (3 H, s), 3.22 (3 H, s),
2.93 (1H, brs), 2.72 (1 H, brs), 2.36 (2 H, m), 2.26 (1 H, dd, J
) 4.0, 8.62 Hz), 1.75 (1 H, d, J ) 9.2 Hz), 1.62 (1 H, dt, J )
2.0, 6.6 Hz); [R]25 -32.3 (c 1.0, CHCl3).
D
Syn th esis of (2R)-2-(Hyd r oxym eth yl)n or bor n -4-en -1-
on e (18). A solution of 17 (6.35 g, 34.47 mmol) in THF (360
mL) was treated with 5% HCl solution (24 mL), and the
reaction mixture was stirred at rt for 20 min. The solvent of
the resulting mixture was removed in vacuo, and the residue
was neutralized with NaHCO3 powder. CH2Cl2 (100 mL) was
added, the resulting solution was dried over anhydrous Na2-
SO4, and the solvent was removed in vacuo. Purification of
the residue by column chromatography [hexane-ethyl acetate
(2:1)] afforded 18 (4.51 g, 95%) as a colorless oil: HR FABMS
calcd for C8H11O2 (M + H+) 139.0759, found 139.0758; FABMS
m/ z (rel intensity) 139 (M + H+, base), 138 (M+, 9), 107 (10),
66 (28), 55 (5); IR νmax (neat) cm-1 3410, 1735; 1H NMR (CDCl3)
δ 6.56 (1 H, dd, J ) 2.6, 5.6 Hz), 6.08 (1 H, dd, J ) 3.6, 4.6
Hz), 3.62 (1 H, dd, J ) 10.9, 6.9 Hz), 3.49 (1 H, dd, J ) 10.9,
6.9 Hz), 3.15 (1 H, t, J ) 1.3 Hz), 3.11 (1 H, dd, J ) 1.6, 3.3
Hz), 2.62(1H, brs), 2.39 (1 H, dt, J ) 3.3, 7.1 Hz), 2.23 (1 H, d,
J ) 9.2 Hz), 2.00(1 H, d, J ) 9.2 Hz); 13C NMR (CDCl3) δ
+ H
+, 54), 277 (58), 265 (base), 73 (51); IR νmax (neat) cm-1
1715. 22a : 1H NMR (CDCl3) δ 6.33 (1 H, dd, J ) 3.0, 5.6 Hz),
6.01 (1 H, dd, J ) 3.0, 5.3 Hz), 5.85 (1 H, d, J ) 2.0 Hz), 4.24
(1 H, dd, J ) 4.6, 9.6 Hz), 4.14 (2 H, dd, J ) 6.9, 14.2 Hz),
3.26 (2 H, dd, J ) 1.7, 3.0 Hz), 3.20 (1 H, brs), 2.78 (1 H, t, J
) 9.9 Hz), 1.74 (1 H, d, J ) 8.6 Hz), 1.44 (1 H, d, J ) 8.6 Hz),
1.26 (3 H, t, J ) 7.1 Hz), 0.91 (9 H, s), 0.06 (6 H, s); 13
C NMR
(CDCl3) δ 235.36, 166.45, 164.04, 137.98, 131.77, 112.38, 64.17,
59.74, 54.55, 49.80, 49.20, 44.16, 25.94, 18.22, 14.30. 22b: 1H
NMR (CDCl3) δ 6.19 (1 H, dd, J ) 3.0, 5.6 Hz), 6.07-6.15 (1
H, m), 5.63 (1 H, d, J ) 1.7 Hz), 4.52 (1 H, brs), 4.16 (2 H, q,
J ) 7.3 Hz), 3.56 (1 H, dd, J ) 5.6, 9.9 Hz), 3.12 (2 H, t, J )
9.6 Hz), 3.06 (1 H, brs), 2.82-2.78 (1 H, m), 1.76 (1 H, brd, J
) 8.9 Hz), 1.47 (1 H, brd, J ) 8.9 Hz), 1.28 (3 H, t, J ) 7.3
Hz), 0.91 (9 H, s), 0.05 (6 H, s);
13C NMR (CDCl3) δ 235.08,
166.55, 165.47, 136.21, 133.29, 111.40, 66.86, 59.59, 49.80,
49.49, 48.99, 42.87, 42.41, 25.88, 18.25, 14.33, 14.20.
214.94, 140.80, 129.87, 64.86, 56.33, 50.09, 49.59, 41.94; [R]28
-720 (c 1.0, CHCl3).
D
Syn t h esis of (1S,4R)-[3-[(ter t-Bu t yld im et h ylsiloxy)-
m eth yl]bicyclo[2.2.1]h ep t-5-en -2-ylid en e]-1-eth a n ol (23).
A solution of DIBALH (100 mL, 0.93 M in hexane solution)
was added dropwise to a solution of 22 (10.96 g, 33.98 mmol)
in dry ether (900 mL) at 0 °C under Ar. The reaction mixture
was stirred at 0 °C for 2 h. The resulting mixture was
quenched with 5% HCl and extracted with ether. The com-
bined organic layer was washed with saturated NaHCO3
solution, followed by brine. The solvent was removed in vacuo.
Purification of the residue by column chromatography [hex-
ane-ethyl acetate (1:1)] afforded 23 (8.51 g, 89%) as a colorless
Syn th esis of (2R)-2-[(ter t-Bu tyldim eth ylsiloxy)m eth yl]-
n or bor n -4-en -1-on e (8). A solution of 18 (4.51 g, 32.64 mmol)
in dry CH2Cl2 (100 mL) was treated with tert-dimethylsilyl
chloride (8.8 g, 58.4 mmol), imidazole (58.75 mmol), and a
catalytic amount of DMAP. The reaction mixture was stirred
at rt for 2 h. The resulting mixture was extracted with CH2-
Cl2, the combined organic layer was washed with brine, and
the solvent was removed in vacuo. Purification of the residue
by column chromatography [hexane-ethyl acetate (1:1)] af-
forded 8 (7.28 g, 96%) as a colorless oil: HR FABMS calcd for

Enantioselective Total Synthesis of cis-Trikentrin B
J . Org. Chem., Vol. 61, No. 10, 1996 3413
oil: HR FABMS calcd for C20H32O4 336.2300, found 336.2301;
FABMS m/ z (rel intensity) 253 (M + H+, base), 211 (37), 195
(93), 137 (50), 93 (34), 66 (11); IR νmax (neat) cm-1 3325. 23a :
1H NMR (CDCl3) δ 6.11 (2 H, brs), 5.63 (1 H, dt, J ) 2.0, 6.9
Hz), 4.09 (2 H, d, J ) 7.3 Hz), 3.56 (1 H, dd, J ) 6.3, 10.0 Hz),
3.19 (1 H, dd, J ) 8.6, 9.9 Hz),3.14 (1 H, brs), 3.05 (1 H, brs),
2.92-2.83 (1 H, m), 1.93 (1 H, brs), 1.62 (1 H, dt, J ) 1.7, 8.3
Hz), 1.41 (1 H, dt, J ) 1.7, 8.3 Hz), 0.91 (9 H, s), 0.06 (6 H, s).
23b: 1H NMR (CDCl3) δ 6.13-6.01(1 H, m), 5.28 (1 H, t, J )
5.9 Hz), 4.33-4.11 (2 H, m), 3.65-3.54 (1 H, m), 3.48 (1 H,
brd, J ) 7.6 Hz), 3.06 (1 H, brt), 2.72 (1 H, brm), 1.68 (1 H,
m), 1.43 (2 H, m), 0.91 (9 H, s), 0.04 (6 H, s).
Syn th esis of (1R,4S)-3-[2-(Tr ip h en ylm eth oxy)eth yli-
d en e]-3-[(ter t-bu tyld im eth ylsiloxy)m eth yl]bicyclo[2.2.1]-
h ep t-5-en e (21). A solution of 23 (3.8 g, 13.55 mmol) in dry
CH2Cl2 (290 mL) was treated with TrCl (16 g, 57 mmol),
triethylamine (19 mL, 260 mmol), and DMAP (870 mg, 7.12
mmol). The reaction mixture was stirred at rt for 10 h. The
resulting mixture was poured into ice-water and extracted
with CH2Cl2. The combined organic layer was washed with
NH4Cl solution, followed by water and then brine. The solvent
was removed in vacuo. Purification of the residue by column
chromatography [hexane-ethyl acetate (20:1)] afforded 21
(6.46 g, 91%) as a colorless oil: HR FABMS calcd for C35H43O2-
Si (M + H+) 523.3032, found 523.3028; FABMS m/ z (rel
intensity) 523 (M + H+, 1), 243 (base); IR νmax (neat) cm-1 no
characteristic peak; 1H NMR (CDCl3) δ 7.46-7.42 (6 H, m),
7.32-7.19 (9 H, m), 6.10 (2 H, t, J ) 1.7 Hz), 5.63 (1 H, t, J )
5.3 Hz), 3.19 (1 H, dd, J ) 8.6, 9.9 Hz),3.14 (1 H, brs), 3.05 (1
H, brs), 2.92-2.83 (1 H, m), 3.62-3.44 (2 H, m), 3.37 (1 H, dd,
J ) 5.0, 10.2 Hz), 3.14-3.13 (1 H, m), 3.05 (1 H, brs), 2.78 (1
H, dd, J ) 9.9, 10.9 Hz), 2.66-2.55 (1 H, m), 1.60 (1 H, brd, J
) 8.2 Hz), 1.37 (1 H, brd, J ) 8.2 Hz), 0.83 (9 H, s), -0.11 (6
H, d, J ) 5.3 Hz).
Syn th esis of (1R,4S)-3-[2-(Tr ip h en ylm eth oxy)eth yli-
d en e]bicyclo[2.2.1]h ep t-5-en ]-1-eth a n ol (24). 21 (6.46 g,
12.36 mmol) was treated with a solution of tetrabutylammo-
nium fluoride (28 mL, 1.1 M solution in THF). The reaction
mixture was stirred at rt for 5 h. Brine was added, and the
resulting mixture was extracted with ethyl acetate. The
solvent was removed in vacuo. Purification of the residue by
column chromatography [hexane-ethyl acetate (5:1)] afforded
24 (4.85 g, 96%) as a colorless oil: HR FABMS calcd for
C29H28O2Na (M + Na+) 431.1897, found 431.1986; FABMS m/ z
(rel intensity) 431 (M + Na+, 4), 243 (base), 165 (59), 154 (26);
IR νmax (neat) cm-1 3400. 21a : 1H NMR (CDCl3) δ 7.47-7.42
(6 H, m), 7.32-7.19 (9 H, m), 6.14 (2 H, t, J ) 1.7 Hz), 5.67 (1
H, dt, J ) 2.0, 6.9 Hz), 3.63 (1 H, dd, J ) 7.3, 10.9 Hz), 3.49
(1 H, dd, J ) 6.6, 10.9 Hz), 3.36-3.30 (1 H, m), 3.19-3.17 (1
H, m), 3.10-3.00 (3 H, m), 2.70-2.58 (1 H, m), 1.62 (1 H, brd,
J ) 8.3 Hz), 1.38 (1 H, brd, J ) 8.3 Hz). 21b: 1H NMR (CDCl3)
δ 7.48-7.43 (6 H, m), 7.33-7.19 (9 H, m), 6.08 (1 H, dd, J )
3.0, 5.6 Hz), 5.95 (1 H, dd, J ) 3.0, 5.6 Hz), 5.88 (0.5 H, dd, J
) 3.0, 5.6 Hz), 5.78 (0.5 H, dd, J ) 3.0, 5.6 Hz), 3.68-3.60 (2
H, m), 3.21-3.13 (2 H, m),3.04 (1 H, brs), 2.76-2.72 (1 H, m),
1.60 (1 H, brd, J ) 8.2 Hz), 1.40 (1 H, brd, J ) 8.3 Hz).
Syn th esis of (1R,4S)-3-[2-(Tr ip h en ylm eth oxy)eth yli-
d en e]-3-[(ter t-bu tyld im eth ylsiloxy)m eth yl]bicyclo[2.2.1]-
h ep t-5-en e]-1-ca r ba ld eh yd e (7). A solution of 23 (4.85 g,
11.87 mmol) in CH2Cl2 (75 mL) was treated with PCC (3.5 g,
160 mmol) and celite (1.87 g). The reaction mixture was
stirred at rt for 3 h. The resulting solution was diluted with
ether, passed through a Florisil column, and washed with
ether. The eluent was collected, and the solvent was removed
in vacuo. Purification of the residue by column chromatog-
raphy [hexane-ethyl acetate (5:1)] afforded 7 (3.3 g, 68%) as
a colorless oil: HR FABMS calcd for C20H32O4 336.2300, found
336.2301; FABMS m/ z (rel intensity); IR νmax (neat) cm-1 1710.
7a : 1H NMR (CDCl3) δ 9.01 (1 H, d, J ) 4.3 Hz), 7.48-7.43 (6
H, m), 7.33-7.23 (9 H, m), 6.22 (1 H, dd, J ) 3.0, 5.6 Hz), 6.02
(1 H, dd, J ) 3.3, 5.3 Hz), 5.42 (1 H, t, J ) 5.9 Hz), 3.72-
3.67(2 H, m), 3.38 (1 H, brs), 3.23 (1 H, brs), 1.65 (1 H, t, J )
1.7 Hz), 1.62 (1 H, t, J ) 1.7 Hz), 1.44 (1 H, brd, J ) 8.6 Hz).
7b: 1H NMR (CDCl3) δ 9.82 (1 H, d, J ) 8.2 Hz), 7.45-7.41 (6
H, m), 7.33-7.22 (9 H, m), 5.96 (1 H, dd, J ) 2.6, 5.6 Hz),
5.90-5.87 (1 H, m), 5.72 (1 H, brd, J ) 7.6 Hz), 4.12 (1 H, brs,
J ) 3.0, 5.6 Hz), 3.29 (1 H, brs), 3.20 (1 H, dd, J ) 5.0, 9.2
Hz), 3.00-2.96 (1 H, m), 2.58 (1 H, t, J ) 9.2 Hz), 1.87 (1 H,
brd, J ) 8.9 Hz), 1.56 (1 H, brd, J ) 8.9 Hz), 1.26 (1 H, d, J )
3.0 Hz), 0.88 (1 H, t, J ) 6.9 Hz).
Meth yl (1S,4R)-3-(Hyd r oxym eth yl)bicyclo[2.2.1]h ep t-
5-en e-2-ylid en ea ceta te (27). A solution of 2611 (110 mg, 0.68
mmol) in dry benzene (100 mL) was treated with Fetizon
reagent (4.15 g, ca. 4.15 mmol), and the resulting mixture was
refluxed under Ar for 1 h. After being cooled to rt, the reaction
mixture was filtered, the solvent was removed in vacuo, and
the resulting residue was used for the subsequent reaction
without further purification. A suspension of the crude lactone
and LiOH‚H2O (60 mg, 1.4 mmol) in THF and water (2:1, 15
mL) was stirred at rt for 90 min. Water was added, and the
aqueous layer was washed with hexane. The resulting water
layer was acidified to pH 5 with 10% HCl and extracted with
ether. The solvent was removed in vacuo. The thus obtained
residue was used in the subsequent reaction without further
purification. (Trimethylsilyl)diazomethane in ether was added
to a stirred solution of the residue in methanol (2 mL) and
benzene (7 mL). The reaction mixture was stirred at rt until
the starting material disappeared on TLC, and the solvent of
the resulting mixture was removed in vacuo. Purification of
the residue by column chromatography [hexane-ethyl acetate
(1:1)] afforded 27 (72.5 mg, 54% from 26) as a yellow oil: HR
FABMS calcd for C11H15O3 (M + H+) 195.1022, found 195.1016;
EIMS m/ z (rel intensity) 194 (M+, 38), 117 (base); IR νmax
1
(CHCl3) cm-1 3450, 1700; H NMR (CDCl3) δ 6.37 (1H, dd, J
) 5.5, 2.3 Hz), 6.06 (1H, dd, J ) 5.5, 3.1 Hz), 5.94 (1H, s),
3.83-3.74 (1H, m), 3.70 (3H, s), 3.39 (1H, brs), 3.33 (1H, d, J
) 1.7 Hz), 3.19 (3H, brs), 1.73 (1H, brd, J ) 8.9 Hz), 1.47 (1H,
brd, J ) 8.9 Hz); [R]24 -306.2 (c 1.2, CHCl3).
D
Meth yl (1S,4R)-3-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-
bicyclo[2.2.1]h ep ten e-2-ylid en ea ceta te (28). In a manner
similar to the synthesis of 8, 28 (2.34 g, 94%) was obtained as
a colorless oil from the alcohol 27 (1.55 g, 8.04 mmol): HR
FABMS calcd for C17H29O3Si (M + H+) 309.1887, found
309.1886; EIMS m/ z (rel intensity) 308 (M+, 3.8); IR νmax
1
(CHCl3) cm-1 1710; H NMR (CDCl3) δ 6.33 (1H, dd, J ) 5.6,
3.0 Hz), 6.01 (1H, dd, J ) 5.6, 3.3 Hz), 5.86 (1H, d, J ) 2.3
Hz), 4.25 (1H, dd, J ) 9.4, 5.0 Hz), 3.69 (3H, s), 3.29-3.20
(3H, m), 2.78 (1H, t, J ) 10.2 Hz), 1.73 (1H, brd, J ) 8.6 Hz),
1.44 (1H, brd, J ) 8.6 Hz), 0.91 (9H, s), 0.06 (6H, d, J ) 7.9
Hz); [R]25 -161.9 (c 1.4, CHCl3).
D
(1S,4R)-3-[(ter t-Bu t yld im et h ylsiloxy)m et h yl]b icyclo-
[2.2.1]h ep t-5-en e-2-ylid en eeth a n ol (23a ). A solution of 28
(114 mg, 0.683 mmol) in dry CH2Cl2 (10 mL) was cooled to
-78 °C, and a 0.93 M solution of DIBALH in hexane (1.5 mL,
1.4 mmol) was added dropwise. The mixture was stirred at
-78 °C for 2.5 h, warmed to 0 °C, and quenched with saturated
aqueous NH4Cl solution. The resulting slurry was acidified
to pH 5 with 10% HCl and extracted with CH2Cl2. The solvent
was removed in vacuo. Purification of the residue by column
chromatography [hexane-ethyl acetate (4:1)] afforded 23a
(164 mg, quantitative) as a pale yellow oil: [R]24 -178.6 (c
D
1.4, CHCl3).
(1R,4S)-2-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-3-[2-(tr i-
ph en ylm eth oxy]eth yliden e]bicyclo[2.2.1]h ept-5-en e (21a).
In a manner similar to the synthesis of 21, 21a (2.40 g, 87%)
was obtained as a colorless oil from 23a (1.46 g, 5.24 mmol).
(1R,4S)-3-[2-(Tr ip h en ylm et h oxy)et h ylid en e]b icyclo-
[2.2.1]h ep t-5-en e-2-m eth a n ol (24a ). In a manner similar
to the synthesis of 24, 24a (0.193 g, 97%) was obtained as a
colorless oil from 21a (0.256 g, 0.49 mmol): [R]24 -137.8 (c
D
1.2, CHCl3).
(1R,4S)-3-[2-(Tr ip h en ylm et h oxy)et h ylid en e]b icyclo-
[2.2.1]h ep t-5-en e-2-ca r boxa ld eh yd e (7a ). In a manner
similar to the synthesis of 7, 7a (1.16 g, 77%) was obtained as
a colorless oil from 24a (1.93 g, 3.66 mmol): [R]25 -86.9 (c
D
1.0, CHCl3).
Syn th esis of 2,2-Dim eth yl-N-p r op yn yl-N-[(1R,8S)-[3-
[(2-t r ip h en ylm et h oxy)et h ylid en e]b icyclo[2.2.1]h ep t -5-
en -2-ylid en e]m eth yl]p r op ion a m id e (6). Propargylamine
(0.9 mL, 13.12 mmol) was added dropwise to a solution of 7
(3.04 g, 7.48 mmol) and molecular sieves 4A (12.2 g) in dry
ether (45 mL) at 0 °C. The reaction mixture was warmed to

3414 J . Org. Chem., Vol. 61, No. 10, 1996
Lee et al.
rt and stirred at rt for 5 h. The resulting solution was filtered,
and the solvent was removed in vacuo. The residue was
dissolved in dry CH2Cl2 (60 mL) and cooled to 0 °C. 2,4,6-
Collidine (4.1 mL, 31.03 mmol) and then trimethylacetyl
chloride (1.9 mL, 15.43 mmol) were added dropwise to the
resulting solution. The reaction mixture was warmed to rt
and stirred at rt for 10 h. The resulting solution was extracted
with CH2Cl2, and the combined organic layer was washed with
10% aqueous HCl solution, followed by saturated NaHCO3
solution and then brine. The solvent was removed in vacuo.
Purification of the residue by column chromatography [hex-
ane-ethyl acetate (10:1)] afforded 6 (2.20 g, 56%) as a colorless
oil: HR FABMS calcd for C37H38O2N (M + H+) 528.2902, found
528.2897; FABMS m/ z (rel intensity) 528 (M + H+, 58), 284
(69), 243 (base), 165 (45); IR νmax (neat) cm-1 2250, 1630. 6a :
1H NMR (CDCl3) δ 7.54-7.42 (6 H, m), 7.35-7.19 (9 H, m),
6.38 (1 H, dd, J ) 3.0, 5.1 Hz), 6.22-6.18 (1 H, m), 5.99 (1 H,
t, J ) 5.3 Hz), 4.12 (1 H, dd, J ) 2.3, 16.7 Hz), 4.00 (1 H, dd,
J ) 2.3, 16.7 Hz), 3.80 (2 H, d, J ) 5.3 Hz), 3.60(1 H, brs),
2.07 (1 H, t, J ) 2.3 Hz), 1.79-1.75(1 H, m), 1.02 (9 H, s). 6b:
1H NMR (CDCl3) δ 7.54-7.42 (6 H, m), 7.35-7.19 (9 H, m),
6.61 (1 H, s), 6.22-6.18 (1 H, m), 5.85 (1 H, t, J ) 6.6 Hz),
4.20 (1 H, d, J ) 2.6 Hz), 4.17 (1 H, d, J ) 2.6 Hz), 3.83-3.78
(2 H, m), 3.66 (1 H, brs), 3.40 (1 H, brs), 2.23 (1 H, t, J ) 2.6
Hz), 1.62-1.58(1 H, m), 1.49-1.46(1 H, m), 1.23 (9 H, s).
Syn th esis of Allen ic Dien a m id e 25. A solution of 6 (2.20
g, 4.17 mmol) in 1,4-dioxane (100 mL) was treated with
formalin (34% solution, 1.63 mL, 19 mmol), diisopropylamine
(2 mL, 14.27 mmol), and CuBr (533 mg, 3.72 mmol). The
reaction mixture was refluxed for 5 h. The resulting mixture
was cooled to rt, diluted with ethyl acetate, and filtered. The
solvent was removed in vacuo. Purification of the residue by
column chromatography [hexane-ethyl acetate (10:1)] afforded
25 (1.25 g, 56%) as a colorless oil: HR FABMS calcd for
C38H40O2N (M + H+) 542.3059, found 542.3067; FABMS m/ z
(rel intensity); IR νmax (neat) cm-1 1950, 1600; 1H NMR (CDCl3)
δ 7.46-7.41 (6 H, m), 7.32-7.22 (9 H, m), 6.37 (1 H, dd, J )
3.0, 5.3 Hz), 6.17 (1 H, dd, J ) 3.0, 5.3 Hz), 5.99 (1 H, s), 5.95
(1 H, d, J ) 5.3 Hz), 5.07 (1 H, t, J ) 6.6 Hz), 4.55 (1 H, t, J
) 3.0 Hz), 4.52 (1 H, t, J ) 3.0 Hz), 4.18 (0.5 H, t, J ) 3.0 Hz),
4.12 (0.5 H, t, J ) 3.0 Hz), 3.79 (1 H, dd, J ) 4.3, 5.6 Hz), 3.51
(1 H, brs), 3.31 (1 H, brs), 1.77 (0.5 H, brs), 1.74 (0.5 H, brs),
1.62 (1 H, brs), 1.58 (1 H, d, J ) 8.6 Hz), 1.01 (9 H, s).
δ 7.61-7.44 (8 H, m), 7.35-7.21 (9 H, m), 7.03 (1 H, dd, J )
3.0, 5.3 Hz), 6.81 (1 H, dd, J ) 3.0, 5.3 Hz), 6.57 (1 H, d, J )
4.0 Hz), 4.59 (1 H, brs), 4.21 (2 H, s), 3.84 (1 H, brs), 2.18 (1
H, dt, J ) 1.7, 7.0 Hz), 2.12 (2 H, brd, J ) 7.0 Hz), 1.53 (9 H,
s); 13C NMR (CDCl3) δ 176.84, 150.04, 144.37, 143.80, 138.97,
131.58, 128.84, 127.80, 126.96, 128.25, 125.62, 116.12, 108.52,
87.01, 68.35, 64.26, 51.79, 48.59, 41.19, 31.58, 29.14, 22.64,
14.08; [R]28 +45 (c 1.0, CHCl3).
D
Syn t h esis of (6S,9R)-1-(2,2-Dim et h yl-1-oxop r op yl)-
6,7,8,9-tetr a h yd r o-5-[(tr ip h en ylm eth oxy)m eth yl]-7,8-d i-
h yd r oxy-6,9-m eth a n o-1H-ben z[g]in d ole (30). A solution
of 5 (273 mg, 0.51 mmol) in 1,4-dioxane, water, and ether (5:
1:1, 22 mL) was treated with osmium tetraoxide (2 g/L, 5 mL),
pyridine (0.25 mL), NMO (250 mg, 2.13 mmol), and methane-
sulfonamide (105 mg, 1.10 mmol). The reaction mixture was
stirred at rt for 5 h. A solution of saturated sodium bisulfite
was added to the reaction mixture, and the resulting solution
was stirred at rt for 30 min. The resulting solution was
extracted with ethyl acetate, and the combined organic layer
was washed with 2 N aqueous KOH solution and then brine.
The solvent was removed in vacuo. Purification of the residue
by column chromatography [hexane-ethyl acetate (2:1)] af-
forded 30 (260 mg, 90%) as a colorless oil: HR FABMS calcd
for C38H37O4N 571.2722, found 571.2726; FABMS m/ z (rel
intensity) 571 (M+, 11), 554 (13), 511 (22), 328 (4), 243 (base);
1
IR νmax (neat) cm-1 3475, 1690; H NMR (CDCl3) δ 7.59 (1 H,
d, J ) 3.6 Hz), 7.55-7.60 (6 H, m), 7.47 (1 H, s), 7.39-7.21 (9
H, m), 6.61 (1 H, d, J ) 4.0 Hz), 4.24 (2 H, brs), 4.24-4.18 (1
H, m), 3.82-3.72 (1 H, m), 3.32 (1 H, brs), 3.21 (1 H, m), 3.12
(1 H, d, J ) 1.1 Hz), 2.14 (1 H, d, J ) 9.9 Hz), 1.88 (1 H, brs),
1.74 (1H, d, J ) 9.9 Hz), 1.52 (9 H, s); 13C NMR (CDCl3) δ
177.17, 144.19, 142.30, 131.38, 131.17, 129.37, 128.75, 128.84,
127.02, 125.59, 117.93, 108.45, 87.20, 71.13, 71.03, 67.08,
64.01, 60.35, 51.34, 48.55, 41.52, 41.25, 28.94, 14.17; [R]28D +1.8
(c 0.6, CHCl3).
Syn th esis of (6R,8S)-1-(2,2-Dim eth yl-1-oxop r op yl)-5-
[(tr ip h en ylm eth oxy)m eth yl]-6,8-d ifor m yl-1,6,7,8-tetr a h y-
d r ocyclop en t[g]in d ole (4). A solution of 30 (210 mg, 0.37
mmol) in THF and water (24:7, 31 mL) was treated with
sodium periodate (1.3 g/L,6.08 mmol). The reaction mixture
was stirred at rt for 1 h. Brine was added, and the resulting
solution was extracted with ethyl acetate. The solvent was
removed in vacuo. Purification of the residue by column
chromatography [hexane-ethyl acetate (3:1)] afforded 4 (200
mg, 96%) as a colorless oil: HR FABMS calcd for C38H35O4N
569.2566, found 569.2574; FABMS m/ z (rel intensity) 569 (M+,
Syn t h esis of (6S,9R)-1-(2,2-Dim et h yl-1-oxop r op yl)-
2,4,5,6,9,9b -h exa h yd r o-5-[(t r ip h en ylm et h oxy)m et h yl]-
6,9-m eth a n o-1H-ben z[g]in d ole (29). A solution of 25 (1.24
g, 2.29 mmol) in toluene (30 mL) was heated at 160 °C in a
sealed tube for 7 h. The solvent was removed in vacuo.
Purification of the residue by column chromatography [hex-
ane-ethyl acetate (4:1)] afforded 33 (1.1 g, 88%) as a colorless
oil: HR FABMS calcd for C38H40O2N (M + H+) 542.3059, found
542.3060; FABMS m/ z (rel intensity) 542 (M + H+, 14), 541
(M+, 11), 299 (23), 298 (72), 243 (base), 241 (9), 165 (38); IR
1
1), 556 (4), 540 (8), 243 (base); IR νmax (neat) cm-1 1730; H
NMR (CDCl3) δ 9.68 (1H, d, J ) 0.7 Hz), 9.38 (1H, d, J ) 2.0
Hz), 7.73 (1H, s), 7.68 (1H, d, J ) 4.0 Hz), 7.53-7.48 (6 H, m),
7.35-7.22 (9 H, m), 6.71 (1 H, d, J ) 4.0 Hz), 4.81 (1 H, dd, J
) 2.0, 10.2 Hz), 4.21 (2 H, dd, J ) 5.3, 11.2 Hz), 3.91 (1 H, dt,
J ) 1.7, 9.2 Hz), 2.74 (1 H, dt, J ) 2.0, 13.5 Hz), 2.61-2.49 (1
H, m), 1.49 (9 H, s); 13C NMR (CDCl3) δ 200.54, 199.54, 177.81,
143.86, 136.08, 133.51, 131.26, 131.07, 128.79, 128.69, 127.94,
127.16, 126.67, 126.18, 121.07, 107.83, 87.53, 64.32, 57.68,
55.60, 41.52, 31.58, 28.82, 27.32, 22.64, 14.08.
1
νmax (neat) cm-1 1620. 29a : H NMR (CDCl3) δ 7.48-7.42 (6
H, m), 7.36-7.20 (9 H, m), 6.61-6.57 (2 H, m), 5.56 (1 H, brs),
5.15 (1 H, brs), 4.45 (1 H, dd, J ) 1.7, 13.5 Hz), 4.18 (1 H, dd,
J ) 4.0, 13.5 Hz), 3.74 (1 H, brs), 3.33 (1 H, dd, J ) 4.0, 8.9
Hz), 3.18 (1 H, dd, J ) 4.0, 8.9 Hz), 3.01 (1 H, brs), 2.28-2.23
(1 H, m), 1.30 (9 H, s). 29b: 1H NMR (CDCl3) δ 7.46-7.42 (6
H, m), 7.34-7.24 (9 H, m), 6.45 (1 H, dd, J ) 3.0, 5.0 Hz), 6.25
(1 H, dd, J ) 3.0, 5.0 Hz), 5.46 (1 H, brs), 4.88 (1 H, brs), 4.36
(1 H, dd, J ) 3.0, 13.5 Hz), 4.02 (1 H, dd, J ) 4.6, 13.2 Hz),
3.68 (1 H, brs), 3.00 (1 H, brs), 2.91 (1 H, dd, J ) 3.0, 8.6 Hz),
2.89-2.79 (1 H, m), 2.70-2.58 (1 H, m), 2.50-2.40 (1 H, m),
1.79 (2 H, brd, J ) 5.9 Hz), 1.62 (2 H, brs), 1.25 (9 H, s).
Syn th esis of (6S,9R)-1-(2,2-Dim eth yl-1-oxop r op yl)-,6,9-
d ih yd r o-5-[(tr ip h en ylm eth oxy)m eth yl]-6,9-m eth a n o-1H-
ben z[g]in d ole (5). A solution of 29 (1.05 g, 1.94 mmol) in
dry CH2Cl2 (35 mL) was treated with active MnO2 (5.3 g, 61
mmol). The reaction mixture was stirred at rt for 10 h. The
resulting mixture was filtered, and the solvent was removed
in vacuo. Purification of the residue by column chromatog-
raphy [hexane-ethyl acetate (10:1)] afforded 5 (877 mg, 85%)
as a colorless oil: HR FABMS calcd for C38H35O2N 537.2668,
found 537.2677; FABMS m/ z (rel intensity) 537 (M+, base),
278 (39), 243 (98); IR νmax (neat) cm-1 1400; 1H NMR (CDCl3)
Syn th esis of (6R,8S)-5-[(Tr ip h en ylm eth oxy)m eth yl]-
6,8-bis(h yd r oxym eth yl)-1,6,7,8-tetr a h yd r ocyclop en t[g]-
in d ole (34). A solution of 4 (200 mg, 0.35 mmol) in methanol
(12 mL) was treated with sodium borohydride (100 mg, 2.64
mmol). The reaction mixture was stirred at rt for 2 h. The
solvent was removed in vacuo. Water was added to the residue
and extracted with ether. The combined organic layer was
washed with brine; and the solvent was removed in vacuo.
Purification of the residue by column chromatography [hex-
ane-ethyl acetate (1:2)] afforded 34 (152 mg, 88%) as a
colorless oil: HR FABMS calcd for C33H31O3N 489.2304, found
489.2299; FABMS m/ z (rel intensity) 489 (M+, 26), 307 (22),
289 (11), 243 (base), 230 (16); IR νmax (neat) cm-1 3350; 1H
NMR (CDCl3) δ 9.54 (1H, brs), 7.62 (1H, s), 7.57-7.52 (6 H,
m), 7.49-7.21 (9 H, m), 7.15-7.13 (1 H, m), 6.56 (1 H, dd, J )
2.0, 3.3 Hz), 4.30 (1 H, d, J ) 10.2 Hz), 4.14 (1 H, d, J ) 3.6
Hz), 4.10 (1 H, t, J ) 7.3 Hz), 3.96-3.92 (1 H, m), 3.77 (1 H,
t, J ) 9.9 Hz), 3.49-3.51 (1 H, m), 3.43 (2 H, d, J ) 4.3 Hz),
3.31-3.23 (1 H, dt, J ) 4.6, 13.2 Hz), 2.45-2.33 (1 H, m), 2.03
(2 H, s), 1.66 (1 H, dt, J ) 5.6, 13.2 Hz), 1.25 (2 H, t, J ) 7.3

Enantioselective Total Synthesis of cis-Trikentrin B
J . Org. Chem., Vol. 61, No. 10, 1996 3415
Hz); 13C NMR (CDCl3) δ 143.99, 143.66, 135.80, 135.63, 133.57,
129.31, 129.25, 129.20, 128.80, 127.24, 127.05, 128.68, 128.08,
127.91, 127.67, 127.61, 127.53, 127.32, 127.25, 127.14, 126.08,
124.48, 124.25, 123.87, 121.22, 121.04, 102.50, 102.25, 87.49,
87.45, 69.45, 68.19, 68.14, 67.14, 65.90, 65.43, 65.30, 65.16,
64.71, 60.38, 46.60, 45.42, 43.42, 32.53, 32.48, 21.00, 14.19,
11.00.
d ole (39) (Meth od 1). A solution of 38 (8.8 mg, 0.015 mmol)
in methanol and THF (1:1, 1 mL) was treated with 10-
camphorsulfonic acid (5 mg, 0.01 mmol). The reaction mixture
was stirred for 5 h at rt. Saturated NaHCO3 solution was
added, and the resulting solution was extracted with CH2Cl2.
The combined organic layer was washed with brine, and the
solvent was removed in vacuo. Purification of the residue by
flash column chromatography [hexane-ethyl acetate (2:1)]
afforded 39 (4 mg, 77%) as a colorless oil: HR FABMS calcd
for C20H21O3NS 355.1242, found 355.1240; FABMS m/ z (rel
intensity) 356 (M + H+, base), 281 (M+, 32); IR νmax (CHCl3)
cm-1 3620; 1H NMR (CDCl3) δ 7.61 (1 H, d, J ) 4.0 Hz), 7.57-
7.65 (2 H, m), 7.31-7.50 (4 H, m), 6.68 (1 H, d, J ) 3.6 Hz),
4.83 (1 H, d, J ) 12.5 Hz), 4.72 (1 H, d, J ) 12.5 Hz), 4.12 (1
H, dq, J ) 7.0, 8.6 Hz), 3.38 (1 H, dd, J ) 7.3, 8.6 Hz), 2.51 (1
H, ddd, J ) 8.9, 8.9, 12.5 Hz), 1.61 (1 H, s), 1.56 (1 H, d, J )
12.5 Hz), 1.36 (3 H, d, J ) 6.9 Hz), 1.34 (3 H, d, J ) 7.3 Hz);
13C NMR (CDCl3) δ 135.33, 133.48, 133.36, 132.51, 129.66,
129.08, 126.40, 119.25, 110.95, 77.22, 76.80, 62.77, 41.22,
Syn th esis of (6R,8S)-5-[(Tr ip h en ylm eth oxy)m eth yl]-
6,8-b is[(m esyloxy)m et h yl]-1,6,7,8-t et r a h yd r ocyclop en t -
[g]in d ole (35). Methanesulfonyl chloride (0.15 mL, 1.94
mmol) was added dropwise to a solution of 34 (142 mg, 0.29
mmol) in dry ether (50 mL) and triethylamine (3 mL, 21.52
mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 4
h. Water was added and extracted with CH2Cl2. The solvent
was removed in vacuo. Purification of the residue by column
chromatography [hexane-ethyl acetate (1:1)] afforded 35 (155
mg, 83%) as a colorless oil: HR FABMS calcd for C35H35O7-
NS2 645.1855, found 645.1845; FABMS m/ z (rel intensity) 645
(M+, 19), 386 (11), 243 (base), 154 (85), 136 (66); IR νmax (neat)
cm-1 3475; 1H NMR (CDCl3) δ 8.83 (1H, brs), 7.64 (1H, s),
7.56-7.51 (6 H, m), 7.37-7.21 (10 H, m), 6.61 (1 H, dd, J )
2.0, 3.0 Hz), 4.60 (1 H, dd, J ) 6.0, 9.9 Hz), 4.46 (1 H, t, J )
9.6 Hz), 4.37 (1 H, dd, J ) 3.3, 9.9 Hz), 4.27 (1 H, d, J ) 10.6
Hz), 4.09 (1 H, d, J ) 10.6 Hz), 3.97 (1 H, dd, J ) 7.0, 9.7 Hz),
3.92-3.82 (1 H, m), 3.62-3.52 (1 H, m), 2.98 (3 H, s), 2.70-
2.55 (1 H, m), 2.56 (3 H, s), 1.98 (1 H, dm, J ) 14.5 Hz); 13C
NMR (CDCl3) δ 143.90, 134.67, 132.90, 128.80, 128.73, 128.54,
127.17, 127.99, 126.21, 126.97, 125.18, 122.13, 102.96, 87.46,
74.94, 73.30, 65.00, 45.16, 43.12, 37.38, 36.77, 31.51, 31.12;
38.74, 37.50, 23.62, 23.56; [R]28 +616.3 (c 0.3, CHCl3).
D
Meth od 2. A solution of 36 (10 mg, 0.02 mmol) in dry DME
(0.4 mL) was treated with NaH (60%, 5 mg, 0.125 mmol). The
reaction mixture was stirred at rt for 30 min under Ar.
Benzenesulfonyl chloride (0.004 mL, 0.03 mmol) was added
dropwise, and the resulting mixture was stirred at 80 °C for
2 h. The resulting solution was extracted with ether. The
combined organic layer was washed with brine, and the solvent
was removed in vacuo. Purification of the residue by flash
column chromatography [hexane-ethyl acetate (2:1)] afforded
39 (1 mg, 13%) as a colorless oil.
[R]24 +2.1 (c 0.4, CHCl3).
D
Syn th esis of (6R,8S)-1-Acetyl-5-[(tr ip h en ylm eth oxy)-
m et h yl]-6,8-d im et h yl-1,6,7,8-t et r a h yd r ocyclop en t [g]in -
d ole (40). A solution of 36 (10 mg, 0.02 mmol) in dry THF
was treated with NaH (60%, 5 mg, 0.125 mmol) and 18-crown-6
(9.3 mg, 0.035 mmol). The resulting mixture was cooled to 0
°C, acetyl chloride (0.003 mL, 0.04 mmol) was added dropwise,
and the reaction mixture was stirred overnight at rt. Brine
was added, and the resulting solution was extracted with CH2-
Cl2. The solvent was removed in vacuo. Purification of the
residue by flash column chromatography [hexane-ethyl ac-
etate (8:1)] afforded 40 (10 mg, 92%) as a colorless oil: HR
FABMS calcd for C35H33O2N 499.2511, found 499.2520; FABMS
m/ z (rel intensity) 499 (M+, 5), 243 (base); IR νmax (CHCl3)
Syn th esis of (6R,8S)-5-[(Tr ip h en ylm eth oxy)m eth yl]-
6,8-d im eth yl-1,6,7,8-tetr a h yd r ocyclop en t[g]in d ole (36). A
solution of 35 (145 mg, 0.22 mmol) in dry DME (16 mL) was
treated with NaI (903 mg, 6.02 mmol) and zinc (4 g, 61.2
mmol). The reaction mixture was refluxed for 5 h under Ar.
The resulting mixture was filtered and extracted with CH2-
Cl2. The combined organic layer was washed with brine, and
the solvent was removed in vacuo. Purification of the residue
by column chromatography [hexane-ethyl acetate (8:1)] af-
forded 36 (71.2 mg, 69%) as a white powder: 155 °C dec; HR
FABMS calcd for C33H31ON 457.2405, found 457.2410; FABMS
m/ z (rel intensity) 457 (M+, 27), 243 (base), 214 (16); IR νmax
(neat) cm-1 3500; 1H NMR (CDCl3) δ 8.00 (1H, brs), 7.73 (1H,
s), 7.58-7.49 (6 H, m), 7.36-7.16 (10 H, m), 6.62 (1 H, dd, J
) 2.0, 3.3 Hz), 4.23 (2 H, s), 3.48-3.38 (1 H, m), 3.29-3.17 (1
H, m), 2.62 (1 H, dt, J ) 8.9, 12.9 Hz), 1.44 (3 H, d, J ) 6.9
Hz), 1.45-1.35 (1 H, m), 1.03 (3 H, d, J ) 7.3 Hz); 13C NMR
(CDCl3) δ 144.45, 140.90, 132.12, 129.56, 128.88, 127.73,
127.33, 127.18, 126.87, 123.55, 118.96, 103.23, 86.94, 64.37,
1
cm-1 3620; H NMR (CDCl3) δ 7.74 (1 H, s), 7.59-7.52 (6 H,
m), 7.36-7.21 (10 H, m), 6.71 (1 H, d, J ) 3.6 Hz), 4.25 (1 H,
s), 4.23-4.10 (1 H, m), 3.17-3.11 (1 H, m), 2.64 (3 H, s), 1.83-
1.86 (1 H, m), 1.73-1.64 (1 H, m), 1.44-1.23 (1 H, m), 1.17 (3
H, d, J ) 7.3 Hz), 1.00 (3 H, d, J ) 7.3 Hz); 13C NMR (CDCl3)
δ 167.21, 144.24, 135.46, 131.35, 131.10, 128.78, 127.81,
126.99, 125.75, 118.68, 109.64, 87.07, 63.54, 40.93, 40.08,
60.36, 42.62, 38.82, 36.93, 23.38, 22.23; [R]27 +6.2 (c 0.4,
D
37.83, 24.56, 23.40, 14.08; [R]28 +121 (c 2.7, CHCl3).
CHCl3).
D
Syn th esis of (6R,8S)-1-(P h en ylsu lfon yl)-5-[(tr ip h en yl-
m et h oxy)m et h yl]-6,8-d im et h yl-1,6,7,8-t et r a h yd r ocyclo-
p en t[g]in d ole (38). A solution of 36 (10 mg, 0.02 mmol) in
dry THF was treated with NaH (60%, 5 mg, 0.125 mmol) and
18-crown-6 (9.3 mg, 0.035 mmol). The resulting mixture was
cooled to 0 °C, benzenesulfonyl chloride (0.004 mL, 0.03 mmol)
was added dropwise, and the reaction mixture was stirred
overnight at rt. Saturated NaHCO3 solution was added, and
the resulting solution was extracted with CH2Cl2. The com-
bined organic layer was washed with brine, and the solvent
was removed in vacuo. Purification of the residue by flash
column chromatography [hexane-ethyl acetate (8:1)] afforded
38 (8.8 mg, 68%) as a colorless oil: HR FABMS calcd for
C39H35O3NS 597.2337, found 597.2344; FABMS m/ z (rel
intensity) 597 (M+, 3), 457 (11), 243 (base); IR νmax (CHCl3)
cm-1 3620; 1H NMR (CDCl3) δ 7.73 (1H, d, J ) 4.6 Hz), 7.66-
7.44 (8 H, m), 7.40-7.13 (14 H, m), 6.76 (1 H, d, J ) 3.6 Hz),
4.16-4.03 (2 H, m), 3.01-2.95 (1 H, m), 2.45-2.34 (1 H, m),
1.50-1.35 (1 H, m), 1.31 (3 H, d, J ) 6.9 Hz), 1.00 (3 H, d, J
) 6.3 Hz); 13C NMR (CDCl3) δ 144.09, 134.81, 133.29, 131.73,
129.55, 129.33, 129.04, 128.70, 127.81, 127.17, 127.02, 126.42,
123.52, 118.95, 111.14, 103.21, 86.88, 63.27, 41.24, 38.61,
Syn th esis of (6R,8S)-1-Acetyl-5-(h yd r oxym eth yl)-6,8-
d im eth yl-1,6,7,8-tetr a h yd r ocyclop en t[g]in d ole (41).
A
solution of 40 (14 mg, 0.03 mmol) in methanol and THF (1:1,
1 mL) was treated with 10-camphorsulfonic acid (10 mg, 0.02
mmol). The reaction mixture was stirred for 5 h at rt.
Saturated NaHCO3
solution was added, and the resulting
solution was extracted with CH2Cl2. The combined organic
layer was washed with brine, and the solvent was removed in
vacuo. Purification of the residue by flash column chroma-
tography [hexane-ethyl acetate (2:1)] afforded 41 (6 mg, 83%)
as a colorless oil: HR FABMS calcd for C16
H19O2N 257.1416,
found 257.1418; FABMS m/ z (rel intensity) 258 (M + H+,
base), 257 (65); IR νmax (CHCl3) cm-1 3620; 1H NMR (CDCl3) δ
7.50 (1 H, s), 7.35 (1 H, d, J ) 4.0 Hz), 6.63 (1 H, d, J ) 3.6
Hz), 4.87 (1 H, dd, J ) 5.0, 13.5 Hz), 1.34 (1 H, dd, J ) 5.3,
13.5 Hz), 4.24-4.19 (1 H, m), 3.51-3.44 (1 H, m), 2.65 (3 H,
s), 2.73-2.62 (1 H, m), 1.61 (1 H, s), 1.53 (1 H, dt, J ) 1.3,
12.9 Hz), 1.34 (3 H, d, J ) 7.3 Hz), 1.21 (3 H, d, J ) 7.3 Hz);
[R]28
+124.2 (c 1.4, CHCl3).
D
Syn th esis of (6R,8S)-1-Acetyl-6,8-d im eth yl-1,6,7,8-tet-
r a h yd r ocyclop en t[g]in d ole-5-ca r boxa ld eh yd e (42). A so-
lution of 41 (38 mg, 0.15 mmol) in CH2Cl2 (8 mL) was treated
with active MnO2 (640 mg, 7.4 mmol). The reaction mixture
was stirred at rt for 10 h. The resulting mixture was filtered,
and the solvent was removed in vacuo. Purification of the
37.38, 23.51, 23.35; [R]24 +98.8 (c 1.4, CHCl3).
D
Syn th esis of (6R,8S)-1-(P h en ylsu lfon yl)-5-(h yd r oxy-
m et h yl)-6,8-d im et h yl-1,6,7,8-t et r a h yd r ocyclop en t [g]in -

3416 J . Org. Chem., Vol. 61, No. 10, 1996
Lee et al.
residue by flash column chromatography [hexane-ethyl ac-
etate (4:1)] afforded 42 (32 mg, 85%) as a colorless oil: HR
FABMS calcd for C16H17O2N 255.1259, found 255.1259; FABMS
m/ z (rel intensity) 256 (M + H+, base), 255 (M+, 90); IR νmax
vacuo. Purification of the residue by flash column chroma-
tography [hexane-ethyl acetate (2:1)] afforded 44 (8.8 mg,
93%) as a white powder: mp 83 °C; HR FABMS calcd for
C19H23ON 281.1780, found 281.1777; FABMS m/ z (rel inten-
sity) 282 (M + H+, 66), 281 (M+, base), 266 (16), 238 (14); IR
νmax (CHCl3) cm-1 3620; 1H NMR (CDCl3) δ 7.52 (1 H, s), 7.31
(1 H, d, J ) 3.6 Hz), 6.60 (1 H, d, J ) 4.0 Hz), 6.56 (1 H, d, J
) 1.3 Hz), 6.24 (1 H, dt, J ) 6.6, 15.8 Hz), 4.26-4.15 (1 H, m),
3.55-3.33 (1 H, m), 2.63 (3 H, s), 2.72-2.60 (1 H, m), 2.33-
2.21 (2 H, m), 1.31 (3 H, d, J ) 7.3 Hz), 1.19 (3 H, d, J ) 7.3
Hz), 1.11 (3 H, t, J ) 7.3 Hz); 13C NMR (CDCl3) δ 167.05,
144.50, 135.27, 132.51, 131.33, 131.16, 130.94, 126.83, 126.20,
1
(CHCl3) cm-1 1715, 1670; H NMR (CDCl3) δ 10.23 (1 H, s),
7.95 (1 H, s), 7.45 (1 H, d, J ) 3.6 Hz), 6.75 (1 H, d, J ) 4.0
Hz), 4.26-4.15 (1 H, m), 4.05-3.94 (1 H, m), 2.70 (3 H, s),
2.79-2.67 (1 H, m), 1.61 (1 H, dd, J ) 1.0, 11.9 Hz), 1.35 (3 H,
d, J ) 7.0 Hz), 1.19 (3 H, d, J ) 7.3 Hz); 13C NMR (CDCl3) δ
191.70, 167.33, 149.01, 136.75, 135.05, 131.04, 128.76, 127.09,
123.95, 109.78, 40.48, 39.49, 37.67, 25.54, 24.58, 24.14; [R]24
+212.8 (c 3.0, CHCl3).
D
Syn th esis of (6R,8S)-6,8-Dim eth yl-1-a cetyl-r-p r op yl-
1,6,7,8-tetr a h yd r ocyclop en t[g]in d ole-5-m eth a n ol (43). A
solution of PrMgBr (2 mol/L solution in THF, 0.24 mL) was
added dropwise to a solution of 42 (57 mg, 0.22 mmol) in dry
THF (8 mL) at -10 °C. The reaction mixture was stirred at
-10 °C for 30 min. The resulting solution was quenched with
a few drops of saturated NH4Cl solution. Brine was added,
and the resulting solution was extracted with CH2Cl2. The
solvent was removed in vacuo. Purification of the residue by
flash column chromatography [hexane-ethyl acetate (2:1)]
afforded 43 (43 mg, 64%) as a colorless oil: HR FABMS calcd
for C19H25O2N 299.1885, found 299.1888; FABMS m/ z (rel
intensity) 299 (M+, 84), 282 (base), 256 (51); IR νmax (CHCl3)
115.76, 109.55, 40.24, 40.20, 26.26, 24.53, 24.50, 13.80; [R]28
D
+334.7 (c 0.8, CHCl3).
Syn th esis of cis-Tr ik en tr in B (1). A solution of 44 (8.8
mg, 0.03 mmol) in dry methanol (1 mL) was treated with
sodium borohydride (6 mg, 0.16 mmol). The reaction mixture
was stirred for 2 h at rt. Brine was added, and the resulting
solution was extracted with CH2Cl2. The solvent was removed
in vacuo. Purification of the residue by flash column chroma-
tography [hexane-ethyl acetate (10:1)] afforded 1 (7 mg, 93%)
as a colorless oil which darkened on standing: HR FABMS
calcd for C17H21N 239.1674, found 239.1672; FABMS m/ z (rel
intensity) 240 (M + H+, 90), 239 (M+, 65), 224 (base); IR νmax
(CHCl3) cm-1 3620; 1H NMR (CDCl3) δ 7.92 (1 H, brs), 7.60 (1
H, s), 7.13 (1 H, dd, J ) 2.31, 3.3 Hz), 6.59 (1 H, dm, J ) 16.2
Hz), 6.52 (1 H, dd, J ) 2.0, 3.3 Hz), 6.17 (1 H, dt, J ) 6.6, 15.5
Hz), 3.49-3.46 (2 H, m), 2.70 (1 H, ddd, J ) 9.1, 9.1, 13.2 Hz),
2.28-2.23 (2 H, m), 1.54 (1 H, ddd, J ) 2.5, 2.5, 13.2 Hz), 1.44
(3 H, d, J ) 7.0 Hz), 1.34 (3 H, d, J ) 7.3 Hz), 1.11 (3 H, t, J
1
cm-1 3620; H NMR (CDCl3) δ 7.58 (1 H, s), 7.35 (1 H, d, J )
3.6 Hz), 6.63 (1 H, d, J ) 3.6 Hz), 5.04-5.00 (1 H, m), 4.25-
4.19 (1 H, m), 3.46-3.41 (1 H, m), 2.65 (3 H, s), 2.69-2.61 (1
H, m), 1.83-1.73 (1 H, m), 1.71-1.63 (1 H, m), 1.61 (1 H, s),
1.55 (1 H, dt, J ) 1.0, 11.9 Hz), 1.38 (3 H, d, J ) 7.0 Hz),
1.34-1.24 (1 H, m), 1.19 (3 H, d, J ) 7.3 Hz), 0.91 (3 H, t, J )
7.4 Hz), 1.03-0.96 (1 H, m); 13C NMR (CDCl3) δ 167.21, 144.03,
137.47, 135.28, 131.55, 126.12, 125.98, 116.40, 109.58, 70.51,
41.66, 40.68, 40.02, 37.83, 24.78, 24.49, 24.24, 19.20, 13.98;
) 7.3 Hz); [R]28 +100.2 (c 0.5, CHCl3).
D
Ack n ow led gm en t. We thank Dr. M. Natsume and
Dr. H. Muratake for charts of their synthetic intermedi-
ates and cis-trikentrin B.
[R]28 +273.2 (c 0.9, CHCl3).
D
Syn th esis of (6R,8S)-5-[(E)-1-Bu ten yl]-6,8-d im eth yl-1-
a cetyl-1,6,7,8-tetr a h yd r ocyclop en t[g]in d ole (44). A solu-
tion of 43 (10 mg, 0.033 mmol) in dry benzene (2 mL) was
treated with p-toluenesulfonic acid monohydrate (0.5 mg, 0.003
mmol). The reaction mixture was stirred for 2 h at 50 °C.
Saturated NaHCO3 solution was added, and the resulting
solution was extracted with CH2Cl2. The combined organic
layer was washed with brine, and the solvent was removed in
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra (54 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O951767Q