Syntheses of strychnos and aspidospermatan-type alkaloids. 8. Selective total syntheses of mossambine and 14-epi-mossambine by a radical cyclization reaction

Article abstract of DOI:10.1021/jo961023s

Mossambine (6) was obtained by a six-step reaction sequence from the indoloazepine ester 7. Radical cyclization of the tetracyclic vinyl iodide 12a provided a racemic pentacyclic ketone 16E, which could be converted to either enantiomer by condensation with (S or R)-N,S-dimethyl-S-phenylsulfoximine and selective pyrolysis of the resulting diastereomeric alcohols 18 and 19 or 20 and 21. Selective reductions of the resolved (or racemic) ketone 16E profided mossambine (6) and its hydroxy epimer 17.

Full text of DOI:10.1021/jo961023s

J . Org. Chem. 1996, 61, 7873-7881
7873
Syn th eses of Str ych n os a n d Asp id osp er m a ta n -Typ e Alk a loid s. 8.
Selective Tota l Syn th eses of Mossa m bin e a n d 14-epi-Mossa m bin e
by a Ra d ica l Cycliza tion Rea ction 1
Martin E. Kuehne,* Tiansheng Wang, and Denis Seraphin
Department of Chemistry, University of Vermont, Burlington, Vermont 05405
Received May 31, 1996X
Mossambine (6) was obtained by a six-step reaction sequence from the indoloazepine ester 7. Radical
cyclization of the tetracyclic vinyl iodide 12a provided a racemic pentacyclic ketone 16E, which
could be converted to either enantiomer by condensation with (S or R)-N,S-dimethyl-S-phenylsul-
foximine and selective pyrolysis of the resulting diastereomeric alcohols 18 and 19 or 20 and 21.
Selective reductions of the resolved (or racemic) ketone 16E provided mossambine (6) and its hydroxy
epimer 17.
Sch em e 1
We have previously described two alternative strate-
gies for the syntheses of strychnos alkaloids (1, R ) alkyl,
R′ ) H), namely the intramolecular Diels-Alder cycliza-
tions of indoloacrylate enamines (2, path A, Scheme 1),
which could also be applied to syntheses of aspidosper-
matan alkaloids (1, R ) H, R′ ) alkyl), and a tandem
cyclization-sigmatropic rearrangement sequence (3, path
B). The key consideration in these reaction sequences
was a direct generation of the vinylogous urethane
function that is ubiquitous to the majority of the penta-
cyclic alkaloids of these classes. Thus, we were able to
synthesize dihydroakuammicine and its C-20 epimer (1,
R ) Et, R′ ) H),2 tubotaiwine (1, R ) H, R′ ) Et),2
echitamidine and its C-20 and C-19 epimers (1, R ) CH-
(OH)CH3, R′ ) H),3 lagunamine (1, R ) H, R′ ) CH(OH)-
CH3),4 and condylocarpine (1, R ) H, R′ ) CHCH3)4 by
path A and echitamidine and akuammicine (1, R )
CHCH3, R′ ) H)5 by path B, and we could also obtain a
total synthesis of strychnine6,7 by subsequent reduction
of the vinylogous urethane function derived from path
B.
Before embarking on these syntheses, we had explored
an alternative formation of the pentacyclic strychnos
alkaloid skeleton, which was based on cyclization of ring
D seco precursors 4. This concept has since provided very
successful syntheses of strychnine by Stork8 and Rawal,9
when applied to corresponding dihydro compounds (di-
hydro 4, X ) Y ) H, amine in place of imine). However,
to satisfy our goal of maintaining the vinylogous urethane
function of the pentacycle 1, it seemed clear that at the
imine oxidation level 4, a tautomerization to a conjugated
enamine 5 had to be avoided (e.g., 4, X ) Y * H). A
carbonyl, or masked carbonyl group at C-14, suggested
itself as a suitable blocking group for maintaining the
imine and acrylate functionalities of a cyclization precur-
sor 4, and mossambine (6),10 a C-14 hydroxylated pen-
tacyclic alkaloid, albeit of uncertain stereochemistry,
seemed an interesting target for testing this synthetic
strategy. While syntheses of strychnos alkaloids have
received much recent attention,11 there have been no
other entries into C-14-oxygenated structures.
Nb-Alkylation of the indoloazepine 7 (Scheme 2),12
which was obtained in three steps from tryptamine (43%
overall yield), with (Z)-1-bromo-2-iodo-2-butene13 pro-
vided a 70% yield of the allylic amine 8a . Pyrolysis of
this azepine in refluxing toluene, in the presence of
2-acetoxyacetaldehyde, led to transient generation of an
enamine acrylate 9a and its cyclization, with stereose-
X Abstract published in Advance ACS Abstracts, October 15, 1996.
(1) Preliminary communication: Kuehne, M. E.; Wang, T.; Seraphin,
D. Synlett 1995, 557.
(2) Kuehne, M. E.; Frasier, D. A.; Spitzer, T. D. J . Org. Chem. 1991,
56, 2696.
(3) Kuehne, M. E.; Brook, C. S.; Frasier, D. A.; Xu, F. J . Org. Chem.
1994, 59, 5977.
(4) Kuehne, M. E.; Brook, C. S.; Frasier, D. A.; Xu, F. J . Org. Chem.
1995, 60, 1864.
(5) Kuehne, M. E.; Xu, F.; Brook, C. S. J . Org. Chem. 1994, 59, 7803.
(6) Parsons, R. L.; Berk, J . D.; Kuehne, M. E. J . Org. Chem. 1993,
58, 7482.
(7) Kuehne, M. E.; Xu, F. J . Org. Chem. 1993, 58, 7490.
(8) Stork, G. Lecture at Ischia School of Organic Chemistry, Ischia
Porto, Italy, Sept 21, 1992.
(10) (a) Stauffacher, D. Helv. Chim. Acta 1961, 44, 2006. (b)
Monseur, X.; Goutarel, R.; LeMen, J .; Wilson, J .; Budzikiewicz, H.;
Djerassi, C. Bull. Soc. Chim. Fr. 1962, 1088.
(11) Bosch, J .; Bonjoch, J .; Amat, M. In The Alkaloids; Cordell, G.
A., Ed.; Academic Press: New York, 1996; Vol. 48, p 75.
(12) Kuehne, M. E.; Bohnert, J . C.; Bornmann, W. G.; Kirkemo, C.
L.; Kuehne, S. E.; Seaton, P. J .; Zebovitz, T. C. J . Org. Chem. 1985,
50, 919.
(13) (a) Ensley, H. E.; Buescher, R. R.; Lee, K. J . Org. Chem. 1982,
47, 404. (b) For methodology see: Corey, E. J .; Kirst, H. A.; Katzenel-
lenbogen, J . A. J . Am. Chem. Soc. 1970, 92, 6314.
(9) Rawal, V. H.; Iwasa, S. J . Org. Chem. 1994, 59, 2685.
S0022-3263(96)01023-7 CCC: $12.00 © 1996 American Chemical Society

7874 J . Org. Chem., Vol. 61, No. 22, 1996
Kuehne et al.
Sch em e 2a
Sch em e 3a
a
Key: (a) NaBH4, CeCl3, MeOH/THF (1:1), 6:17 (5:1), pure
mossambine (6) was then obtained by crystallization from metha-
nol; (b) L-Selectride/THF, 0 °C.
Attempted radical cyclizations of the bromo and chloro
analogues 12b and 12c, prepared in analogy to formation
of the iodo compound 12a , did not yield more than traces
of the pentacyclic products 16E and 16Z.
Reduction of the major ketonic olefin isomer 16E with
sodium borohydride and ceric chloride (Scheme 3) gave
racemic mossambine ((()-6) and its hydroxy epimer (()-
17 in a ratio of 5:1 (96%). Alternatively, the epimer (()-
17 could be formed exclusively (96%) with L-Selectride
(Aldrich).
The relative stereochemistry of the hydroxyl function
in the epimers (()-6 and (()-17 was established by NMR
NOE experiments, which showed interaction of the
hydrogens at C-14 â (δ 4.47) and C-21 R (δ 3.77) in 14-
epi-mossambine ((17), but not in mossambine ((()-6).
NOE coupling of the C-18 methyl group (δ 1.78) with the
C-15 methine hydrogen (δ 3.95 in (()-6 and δ 4.17 in (()-
17), expected for the E-olefins, was also observed as well
as coupling of the olefinic C-19 hydrogen (δ 5.74) with
the C-21 R hydrogen (δ 3.50) in mossambine ((()-6).
Comparison of an NMR spectrum of natural mossambine
with spectra of the synthetic product (()-6 showed a good
match, with the C-14 R hydrogen signal at δ 3.72,
whereas the epimer (()-17 displayed the C-14 â hydrogen
signal at δ 4.47. These NMR data allowed stereochemical
assignment to the natural product.
a
For series a , X ) I: (1) (Z)-1-bromo-2-iodo-2-butene, K2CO3,
Et3N, acetone, rt, 3 h; (2) AcOCH2CHO, toluene, reflux, 2 h; (3)
K2CO3, MeOH/H2O; (4) (PhSeO)2O, benzene, reflux, 30 min; (5)
TFAA-DMSO-Et3N, CH2Cl2, -70 °C; (6) t-BuOCl, Et3N, CH2Cl2
0 °C; (7) (Z)-1-bromo-2-iodo-2-butene/THF; (8) Bu3SNH, AIBN,
benzene, 85 °C.
lective formation of the tetracyclic acetate 10a , in 93%
yield.14 Hydrolysis of the acetate gave the corresponding
alcohol 11a (95%) and oxidation of this vinylogous
urethane with phenylseleninic anhydride15-17 then pro-
vided the imino enone 12a (63%).
This key cyclization precursor could also be obtained,
in better overall yield, by Swern oxidation of the alcohol
11a (87%) and reaction of the resulting ketone 13a with
tert-butyl hypochlorite and triethylamine (100%).
In a third sequence to the imino enone 12a the
tetracyclic amine 1418 was alkylated with (Z)-1-bromo-
2-iodo-2-butene (75%). The resulting vinylogous ure-
thane 15a , on reaction with phenylseleninic anhydride,
then also led to oxygenation at C-14 and formation of the
imino acrylate 12a (35%).
A radical cyclization of the tetracyclic iodide 12a could
now be induced by its reaction with tri-n-butyltin hydride
in refluxing benzene. The pentacyclic vinylogous ure-
thane product was reproducibly obtained in at least 51%
yield as a 1.5-1.8:1 E:Z mixture of olefin isomers 16E
and 16Z. Crystallization provided the pure E isomer
from chromatographically enriched fractions.
In order to obtain a chiral resolution of the synthetic
products, the racemic ketone 16E was treated with [(S
or R)-(N-methylphenylsulfonimidoyl)methyl]lithium at
-78 °C.19 The diastereomeric C-14 alcohol product pairs
(1:1) 18 and 19 or 20 and 21, respectively (Scheme 4),
could be separated by chromatography. When they were
heated at 150 °C under vacuum, the C-14 (S)-S (S)
compound 19 reverted to the ketone (+)-16E with [R]24
D
+779°, while the C-14 (R)-S (S) diastereomer 18 was
recovered unchanged. Analogously, the C-14 (R)-S (R)
alcohol 20 decomposed to the ketone (-)-16E with [R]24
D
-783°, while its diastereomer 21 resisted cleavage. It
was thus possible to selectively generate either pure
natural ([R]25D -) or unnatural ([R]25D +) mossambine (6)
by subsequent reduction of the ketone. This method
allows the selective generation of either enantiomer of
mossambine from the racemic ketone 16E without sepa-
ration of intermediate diastereomers by chromatography
or crystallization.
(14) For methodology see: Kuehne, M. E.; Kuehne, S. E. J . Org.
Chem. 1993, 58, 4147.
(15) Danieli, B.; Lesma, G.; Palmisano, G.; Riva, R. J . Chem. Soc.,
Chem. Commun. 1984, 909.
(16) Kuehne, M. E.; Podhorez, D. E.; Mulamba, T.; Bornmann, W.
G. J . Org. Chem. 1987, 52, 347.
(17) Danieli, B.; Lesma, G.; Palmisano, G.; Passarella, D.; Silvani,
A. Tetrahedron 1994, 50, 6941.
(18) Kuehne, M. E.; Matsko, T. H.; Bohnert, J . C.; Motyka, L.; Oliver-
Smith, D. J . Org. Chem. 1981, 46, 2002.
(19) (a) J ohnson, C. R.; Zeller, J . R. Tetrahedron 1984, 40, 1225.
(b) J ohnson, C. R. Aldrichim. Acta 1985, 18, 3.

Synthesis of Mossambine
Sch em e 4
J . Org. Chem., Vol. 61, No. 22, 1996 7875
F igu r e 1.
Sch em e 5a
a
(1) TMSTfI, Et3N, rt; (2) NiCl2/CrCl2, DMSO, rt; (3) Bu3SnH,
AIBN, 85 °C; (4) (COD)2Ni, Et3N, MeCN, rt.
Exp er im en ta l Section
(()-(3a R*,11b R*)-Met h yl 3-[(Z)-(2-Iod o-2-b u t en yl)]-
2,3,3a ,4,5,7-h exa h yd r o-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r -
boxyla te (15a ). A mixture of 10.31 g of 2-butyn-1-ol (0.147
mol), 20 mL of tri-n-butyltin hydride (74.35 mmol) and 0.3 g
of AIBN was heated in an oil bath at 85 °C for 2 h. Distillation
under vacuum then gave 21.45 g of (Z)-2-(tri-n-butylstannyl)-
2-buten-1-ol (80%): bp 130-133 °C/0.2 mm.13a
To 10.0 g of (Z)-2-(tri-n-butylstannyl)-2-buten-1-ol (27.7
mmol) in 200 mL of carbon tetrachloride in an ice bath was
added 8.5 g of iodine (67 mmol) in one portion. After the
mixture was stirred for 10 min, 50 mL of 10% sodium bisulfite
was added. The aqueous layer was extracted with 2 × 100
mL of ether. The combined organic layers were washed with
brine, dried (Na2SO4), and concentrated under vacuum. The
residue was purified on a SiO2 flash column (20% to 50% ether/
hexane) to give 4.13 g of pure (Z)-2-iodobuten-1-ol13a followed
by 0.657 g of a 2:1 Z/E mixture (the ratio was determined by
The selective pyrolyses of iminosulfoxides 19 and 20
can be seen (Figure 1) as the result of a favored
conformation with steric and stereoelectronic optimiza-
tion of the C-C bond cleavage, if one considers the
alternatives for relative orientation of the sulfoxide vs
S-phenyl bonds.
For a possible alternative to the radical cyclization of
the vinyl iodide enone 12a , the ketone 13a was converted
to its trimethylsilyl enol ether derivative 22a (Scheme
5). However, from treatment of this compound with tri-
n-butyltin hydride only the tertiary alcohol E and Z olefin
isomers 23 and 24 were obtained in low yield (10%). The
corresponding vinyl bromide 22b gave a somewhat higher
yield (18%) of these products.
1
integration of the well-resolved vinylic proton in the H NMR
spectrum). Total 4.787 g (87%) of Z-isomer: TLC (ethyl ether/
hexane, 1:1) Rf ) 0.46; 1H NMR (500 MHz, CDCl3) δ 5.97 (qt,
J ) 6.5, 1.5 Hz, 1 H), 4.25 (dt, J ) 6.5, 1 Hz, 2 H), 1.84 (t, J
) 6.7 Hz, 1 H), 1.80 (dt, J ) 6, 1 Hz, 3 H).
To a solution of 1.268 g (6.40 mmol) of (Z)-2-iodo-2-buten-
1-ol in 15 mL of dry ethyl ether was added 0.24 mL (2.5 mmol)
of phosphorus tribromide at 0 °C. The mixture was stirred
for 22 h. Then 30 mL of cold aqueous potassium carbonate
was added. After separation and extraction with 2 × 30 mL
of ether, the combined ether layers were washed with brine
and dried (Na2SO4). Concentration under vacuum then gave
1.241 g of the bromoiodide.13b It was directly used in the
following alkylation.
A mixture of 0.578 g (2.14 mmol) of the tetracyclic amine
1418 and 0.649 g (2.40 mmol) of the above bromoiodide, in 20
mL of THF, was stirred at rt for 24 h and at 50 °C for 5 h.
After addition of 0.5 g of potassium carbonate and 0.5 mL of
water, stirring was continued at rt overnight. Removal of THF
under vacuum gave a residue, which was partitioned between
50 mL of water and 50 mL of dichloromethane. The water
layer was extracted with 2 × 20 mL of dichloromethane, and
the combined dichloromethane solutions were dried (Na2SO4)
and concentrated. Column chromatography on silica gel with
Still better yields of these cyclization products were
obtained from reactions of bromo and chloro ketones 13b
and 13c with bis(1,5-cyclooctadiene)nickel,20,21 where 23
and 24 were obtained 1:1, in 72% yield, and 1:1.4, in 53%
yield, respectively. These are the first examples of
intramolecular reactions of vinyl halides with a ketone,
induced by this nickel reagent. With NiCl2/CrCl2 and the
iodide 13a an 86% yield of the pure Z-isomer 24 was
obtained.
(20) Bonjoch, J .; Sole´, D.; Bosch, J . J . Am. Chem. Soc. 1995, 117,
11017.
(21) Sole´, D.; Cancho, Y.; Llebaria, A.; Moreto, J . M.; Delgado, A. J .
Am. Chem. Soc. 1994, 116, 12133.

7876 J . Org. Chem., Vol. 61, No. 22, 1996
Kuehne et al.
9:1 hexane/ethyl acetate then gave 0.718 g of the Nb-alkylated
product as a white foam (75%): 1H NMR (500 MHz, CDCl3) δ
8.93 (br s, 1 H), 7.20 (d, J ) 7.4 Hz, 1 H), 7.15 (t, J ) 7.7 Hz,
1 H), 6.87 (t, J ) 7.4 Hz, 1 H), 6.81 (d, J ) 7.7 Hz, 1 H), 5.95
(q, J ) 6.3 Hz, 1 H), 3.77 (s, 3 H), 3.71 (br d, J ) 13.8 Hz, 1
H), 3.45 (d, J ) 13.8 Hz, 1 H), 3.22 (d, J ) 4.6 Hz, 1 H), 2.98
(dd, J ) 8.7, 6.6 Hz, 1 H), 2.64-2.56 (m, 2 H), 2.35 (td, J )
13.8, 2.8 Hz, 1 H), 2.02 (td, J ) 11.9, 6.5 Hz, 1 H), 1.90 (br d,
J ) 13.3 Hz, 1 H), 1.81 (d, J ) 6.3 Hz, 3 H), 1.74 (dd, J )
11.8, 4.7 Hz, 1 H), 1.04 (dt, J ) 13.2, 4.2 Hz, 1 H; 13C NMR
(125 MHz, CDCl3) δ 168.31, 164.94, 143.13, 137.27, 130.89,
127.64, 211.94, 120.21, 110.03, 108.97, 95.56, 65.59, 65.30,
55.48, 50.69, 49.80, 42.69, 29.26, 21.55, 18.49; IR (film) νmax
3377, 3053, 2945, 2914, 2853, 2793, 1733, 1677, 1477, 1465,
49.93, 41.75, 23.75, 21.68, 21.32; IR (film) νmax 3374, 2949,
2851, 1729, 1681, 1613, 1482, 1466, 1375, 1279, 1251, 1213,
1200, 1134, 1089, 1029, 799, 746 cm-1; UV (EtOH) λmax 206,
226, 298, 326 nm; MS m/z (rel intens) 509 (4.8, M + 1), 508
(21, M), 449 (10), 448 (43), 422 (19), 322 (11), 321 (49), 295
(9), 294 (84), 289 (8), 286 (28), 285 (25), 267 (8), 264 (14), 259
(12), 253 (7), 252 (63), 243 (11), 235 (9), 228 (29), 227 (21), 226
(77), 225 (52), 224 (66), 217 (28), 214 (20), 207 (17), 206 (14),
196 (18), 195 (27), 194 (28), 193 (34), 182 (20), 181 (35), 180
(40), 169 (24), 168 (67), 167 (77), 166 (10), 165 (11), 155 (15),
154 (68), 128 (18), 127 (34), 124 (19), 115 (20), 114 (24), 96
(78), 84 (26), 82 (18), 72 (78), 70 (18), 69 (22), 55 (21), 54 (75),
53 (100). Anal. Calcd for C22H25N2O4I: C, 51.98; H, 4.96; N,
5.51; I, 24.96. Found: C, 52.11; H, 4.90; N, 5.38; I, 25.30.
(()-(3a R*,4R*,11bR*)-Meth yl 3-((Z)-2-Iod obu t-2-en -1-
yl)-2,3,3a ,4,5,7-h exa h yd r o-4-h yd r oxy-1H-p yr r olo[2,3-d ]-
ca r ba zole-6-ca r boxyla te (11a ). A mixture of 1.39 g of the
acetate 10a (2.73 mmol), 0.400 g of potassium carbonate (2.89
mmol), 40 mL of methanol, and 2.5 mL of water was heated
at reflux for 30 min. The reaction mixture was cooled and
concentrated. To the residue was added 50 mL of water. After
extraction with 3 × 50 mL of dichloromethane, drying (Na2SO4),
and concentration, the residue was purified on a flash SiO2
column, eluting with 4:1 ethyl ether:hexane. Thus, 1.212 g of
pure alcohol 11a was obtained (yield 95%), with mp 173-174
°C, from ethanol: TLC (ethyl ether/hexane, 5:1) Rf ) 0.31
(CAS, blue); 1H NMR (500 MHz, CDCl3) δ 9.02 (br s, 1 H),
7.16-7.13 (m, 2 H), 6.89 (t, J ) 7.4 Hz, 1 H), 6.82 (d, J ) 8.1
Hz, 1 H), 5.95 (q, J ) 6.3 Hz, 1 H), 4.01 (br s, 1 H), 3.78 (d, J
) 13.8 Hz, 1 H), 3.74 (s, 3 H), 3.51 (d, J ) 13.8 Hz, 1 H), 3.09
(s, 1 H), 3.01 (dd, J ) 8.7, 6.5 Hz, 1 H), 2.94 (ddd, J ) 16, 3.2,
2 Hz, 1 H), 2.69 (dd, J ) 16, 2 Hz, 1 H), 2.66-2.61 (m, 1 H),
2.05 (ddd, J ) 12.1, 12.1, 6.5 Hz, 1 H), 1.81 (d, J ) 6.3 Hz, 3
H), 1.71 (dd, J ) 11.9, 4.7 Hz, 1 H), 1.60 (br d, J ) 6.0 Hz, 1
H, OH); 13C NMR (125 MHz, CDCl3) δ 169.03, 164.51, 142.95,
137.19, 131.51, 127.90, 122.05, 120.71, 109.68, 109.39, 87.30,
72.78, 68.32, 66.03, 54.68, 50.93, 50.37, 41.67, 26.31, 21.60;
IR (film) νmax 3452, 3383, 2976, 2941, 2850, 2788, 1675, 1610,
1482, 1469, 1439, 1386, 1348, 1290, 1249, 1214, 1121, 1088,
1061, 1023, 750 cm-1; UV (EtOH) λmax 206, 228, 300, 326 nm;
MS m/z (rel intens) 467 (M+1, 2), 466 (M, 5), 448 (7), 422 (8),
339 (4), 321 (6), 253 (9), 252 (100), 244 (10), 243 (47), 226 (16),
195 (12), 181 (16), 180 (13), 169 (14), 168 (30), 167 (25), 154
(47), 128 (10), 127 (18), 115 (18), 96 (23), 72 (45), 70 (17), 54
(44), 53 (77). Anal. Calcd for C20H23N2O3I: C, 51.51; H, 4.97;
N, 6.01. Found: C, 51.54; H, 4.94; N, 5.93.
(()-(3a R*,11b R*)-Met h yl 3-((Z)-2-Iod ob u t -2-en -1-yl)-
2,3,3a ,4-tetr a h yd r o-4-oxo-1H-p yr r olo[2,3-d ]ca r ba zole-6-
ca r boxyla te (12a ). a. A mixture of 0.415 g of the alcohol
11a (0.89 mmol) and 0.332 g of benzeneseleninic anhydride
(0.92 mmol, 1.04 equiv) in 15 mL of dry benzene was heated
at reflux for 15 min. After cooling and evaporation, the residue
was purified by flash SiO2 column, eluting with 1:1 ethyl ether/
hexane, to afford 0.257 g of the product 12a as a brown foam;
yield 63%.
b. To a solution of 0.913 g of the tetracyclic ketone 13a
(1.966 mmol) and 0.384 mL of triethylamine (2.76 mmol, 1.4
equiv) in 65 mL of dichloromethane, in an ice bath, was added
dropwise 0.282 mL of tert-butyl hypochlorite (2.36 mmol, 1.2
equiv). The reaction mixture was stirred at 0 °C for 10 min
and then brought to room temperature, diluted with 80 mL of
dichloromethane, and washed with brine. After the solution
was dried and evaporated under vacuum, 0.987 g of product
was obtained. TLC (silica gel, ethyl ether/hexane, 3:1) showed
only one spot. The product 12a was used directly in the next
step without further purification.
1438, 1302, 1276, 1248, 1241, 1190, 1087, 1058, 782, 745 cm-1
;
UV (EtOH) λmax 210, 226, 298, 328 nm; MS m/z (rel intens)
450 (12), 351 (3), 323 (4), 254 (2), 237 (4), 236 (43), 228 (25),
227 (100), 214 (11), 210 (5), 209 (6), 194 (5), 182 (8), 181 (12),
168 (10), 167 (13), 154 (16), 143 (6), 127 (5), 98 (5); high-
resolution MS, EI ionization, calcd for C20H23N2O2I 450.0804,
found 450.0807.
Meth yl 3-(2-Iodobu t-2-en -1-yl)-1,2,3,4,5,6-h exah ydr oaze-
p in o[4,5-b]in d ole-5-ca r boxyla te (8a ). To 3.50 g (14.3 mmol)
of the indoloazepine 7 in 80 mL of acetone were added 4.60 g
of 1-bromo-2-iodo-2-butene (see above, 17 mmol), 6 g of
potassium carbonate, and 6 mL of triethylamine. After
vigorous stirring at room temperature for 3 h, the reaction
mixture was filtered and the residue washed with acetone. The
filtrate was concentrated and purified by flash silica gel
chromatography, eluting with 1:1 ethyl ether/hexane to give
4.23 g of the alkylated azepine 8a (70%) as a white powder.
An analytical sample, crystallized from methanol, had mp
130-131 °C: TLC (SiO2, 2:1 ethyl ether/hexane) Rf ) 0.40
1
(CAS spray, blue); H NMR (500 MHz, CDCl3) δ 8.32 (br s, 1
H), 7.47 (d, J ) 7.7 Hz, 1 H), 7.26 (d, J ) 7.7 Hz, 1 H), 7.12 (t,
J ) 7.5 Hz, 1 H), 7.08 (t, J ) 7.5 Hz, 1 H), 5.89 (q, J ) 6.4 Hz,
1 H), 4.01 (dd, J ) 7, 2.4 Hz, 1 H), 3.76 (s, 3 H), 3.52-3.45 (m,
2 H), 3.40 (dd, J ) 13.2, 7.1 Hz, 1 H), 3.17 (dd, J ) 13.2, 2.6
Hz, 1 H), 3.02-2.98 (m, 1 H), 2.94-2.91 (m, 2 H), 2.81-2.77
(m, 1 H), 1.82 (d, J ) 6.4 Hz, 3 H); 13C NMR (125 MHz, CDCl3)
δ 172.46, 134.83, 131.96, 128.53, 121.52, 119.22, 117.99,
114.03, 110.67, 109.59, 68.69, 56.00, 54.30, 52.46, 45.77, 24.17,
21.71; IR (film) νmax 3396, 3057, 2948, 2913, 2825, 1730, 1645,
1491, 1462, 1434, 1374, 1341, 1251, 1207, 1163, 1139, 1029,
917, 813, 745, 720 cm-1; UV (EtOH) λmax 208, 228, 284, 294
nm; MS m/z (rel intens) 424 (5), 298 (3), 297 (20), 265 (1), 243
(2), 229 (1), 228 (8), 223 (3), 216 (4), 215 (8), 214 (12), 202 (19),
183 (11), 181 (13), 170 (10), 169 (32), 156 (30), 155 (14), 154
(42), 128 (20), 127 (22), 115 (13), 96 (69), 69 (16), 54 (65), 53
(100). Anal. Calcd for C18H21N2O2I: C, 50.96; H, 4.99; N, 6.60;
I, 29.91. Found: C, 51.02; H, 4.96; N, 6.49; I, 29.74.
(()-(3a R*,4R*,11bR*)-Meth yl 3-((Z)-2-Iod obu t-2-en -1-
yl)-2,3,3a ,4,5,7-h exa h yd r o-4-a cet oxy-1H -p yr r olo[2,3-d ]-
ca r ba zole-6-ca r boxyla te (10a ). The indoloazepine (8a ) (3.78
g, 8.91 mmol) and 6.8 mL of a 1.45 N acetoxyacetaldehyde22
solution in dichloromethane (9.86 mmol, 1.1 equiv) were mixed
with 70 mL of dry toluene. After being connected to a Dean-
Stark trap filled with 4 Å molecule sieves, the mixture was
heated at reflux for 2 h. Cooling, and removal of solvents
under vacuum, gave a residue, which was triturated with ether
to give 2.337 g of product as a white powder. The ether filtrate
was concentrated and the residue was flash chromatographed
on silica gel, eluting with 1:1 ethyl ether/hexane to afford
another 1.881 g of pure product: total product 4.218 g; yield
93%; mp 165-165.5 °C (needles from ethanol); TLC (SiO2,
1
ethyl ether/hexane, 2:1) Rf ) 0.44 (CAS, blue); H NMR (500
MHz, CDCl3) δ 9.00 (br s, 1 H), 7.18 (t, J ) 7.7 Hz, 1 H), 7.15
(d, J ) 7.3 Hz, 1 H), 6.90 (t, J ) 7.4 Hz, 1 H), 6.85 (d, J ) 7.7
Hz, 1 H), 5.95 (q, J ) 6.4 Hz, 1 H), 5.05 (bs, 1 H), 4.03 (d, J )
13.9 Hz, 1 H), 3.78 (s, 3 H), 3.52 (d, J ) 13.9 Hz, 1 H), 3.14 (br
s, 1 H), 3.04-2.98 (m, 2 H), 2.70-2.64 (m, 2 H), 2.08 (td, J )
12.0, 6.6 Hz, 1 H), 1.84 (s, 3 H), 1.81 (d, J ) 6.4 Hz, 3 H), 1.75
(dd, J ) 12.0, 4.8 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ
170.74, 168.89, 163.90, 143.21, 137.04, 131.67, 128.05, 122.21,
120.62, 109.52, 109.35, 89.06, 71.21, 70.06, 65.27, 54.79, 50.98,
c. A mixture of 0.197 g (0.44 mmol) of the tetracycle 15 and
0.252 g (0.70 mmol) of phenylseleninic anhydride in 30 mL of
dry benzene was stirred at 70 °C for 35 min. After cooling,
benzene was removed under vacuum, the residue was dis-
solved in 15 mL of dichloromethane, and the solution washed
twice with saturated aqueous potassium bicarbonate, dried
(Na2SO4), and concentrated. The residue was flash chromato-
graphed (SiO2, ethyl acetate/hexane, 1:3) to give 0.070 g (35%)
of the imino ketone 12a .
For 12a : TLC (ethyl ether/hexane, 3:1) Rf ) 0.38 (CAS, blue
1
(22) Nagasawa, J .; Araki, Y.; Ishido, Y. J . Org. Chem. 1981, 46, 1734.
faded to greenish yellow); H NMR (500 MHz, CDCl3) δ 7.97

Synthesis of Mossambine
J . Org. Chem., Vol. 61, No. 22, 1996 7877
(d, J ) 7.5 Hz, 1 H), 7.82 (d, J ) 7.6 Hz, 1 H), 7.43 (t, J ) 7.6
Hz, 1 H), 7.33 (t, J ) 7.5 Hz, 1 H), 6.84 (s, 1 H), 6.01 (q, J )
6 Hz, 1 H), 4.24 (d, J ) 14 Hz, 1 H), 3.98 (s, 3 H), 3.97 (d, J )
14 Hz, 1 H), 3.49 (s, 1 H), 2.93-2.88 (m, 1 H), 2.46-2.40 (m,
1 H), 2.05-2.00 (m, 1 H), 1.79 (d, J ) 6 Hz, 3 H); 13C NMR
(125 MHz, CDCl3) δ 202.74, 172.86, 164.15, 154.68, 144.42,
138.68, 135.59, 133.02, 128.65, 127.51, 124.09, 122.74, 108.17,
71.03, 64.13, 63.74, 53.19, 47.96, 34.73, 21.65; IR (film) νmax
2949, 2850, 2831, 1737, 1678, 1607, 1467, 1438, 1264, 1208,
1142, 912, 771, 733 cm-1; UV (EtOH) λmax 208, 244, 274, 338
nm; MS m/z (rel intens) 463 (M + 1, 3), 462 (M, 14), 351 (3),
335 (13), 279 (5), 254 (25), 253 (14), 222 (30), 221 (22), 195
(16), 194 (22), 193 (14), 181 (10), 180 (16), 168 (17), 167 (24),
166 (23), 154 (15), 127 (23), 115 (49), 89 (13), 55 (13), 54 (60),
Hz, 1 H), 5.57 (qt, J ) 6.9, 2 Hz, 1 H), 4.21 (br s, 1 H), 3.84 (d,
J ) 2 Hz, 1 H), 3.78 (s, 3 H), 3.74 (dd, J ) 15, 2 Hz, 1 H),
3.44-3.38 (m, 1 H), 3.30-3.25 (m, 1 H), 3.20 (d, J ) 15 Hz, 1
H), 3.08-3.02 (m, 1 H), 2.06-2.02 (m, 1 H), 1.63 (dt, J ) 6.9,
1.8 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 211.08, 167.33,
166.03, 143.67, 138.86, 135.56, 128.53, 123.08, 121.81, 121.00,
109.96, 95.39, 66.99, 63.85, 59.10, 57.67, 51.37, 47.99, 46.51,
12.91; IR (film) νmax 3353, 2951, 2855, 1743, 1727, 1675, 1596,
1476, 1465, 1435, 1384, 1282, 1239, 1198, 1169, 1095, 1061,
1038, 955, 909, 781, 763, 740, 663 cm-1; UV (EtOH) λmax 206,
230, 300, 316, 340 nm; MS m/z (rel intens) 337 (M + 1, 14),
336 (M, 61), 308 (65), 307 (33), 293 (50), 277 (17), 276 (18),
275 (29), 261 (30), 252 (24), 250 (14), 249 (63), 248 (25), 247
(41), 241 (19), 238 (16), 235 (58), 234 (26), 233 (23), 232 (18),
231 (13), 221 (29), 220 (37), 219 (26), 206 (48), 205 (32), 204
(42), 194 (35), 193 (33), 192 (30), 191 (38), 180 (38), 154 (69),
149 (84), 139 (46), 138 (35), 128 (31), 121 (100), 115 (47), 111
(90), 108 (84), 84 (95), 77 (48), 71 (47), 69 (40); high-resolution
MS, EI ionization, calcd for C20H20N2O3 336.1474, found
336.1481.
53 (100); high-resolution MS, EI ionization, calcd for C20H19
N2O3I 462.0440, found 462.0428.
-
(()-(3a R*,11b R*)-Met h yl 3-((Z)-2-Iod ob u t -2-en -1-yl)-
2,3,3a ,4,5,7-h exa h yd r o-4-oxo-1H-p yr r olo[2,3-d ]ca r ba zole-
6-ca r boxyla te (13a ). To a solution of 0.52 mL of DMSO (7.33
mmol, 3.6 equiv) in 50 mL of dichloromethane, at -70 °C, was
added dropwise 0.863 mL of trifluoroacetic anhydride (6.11
mmol, 3 eq). After 20 min, 0.950 g of the tetracyclic alcohol
11a (2.04 mmol) in 20 mL of dichloromethane was added at
-65 to -70 °C. Stirring was continued at the same temper-
ature for 1 h before addition of 2.84 mL of triethylamine (20.1
mmol, 10 equiv). After being stirred for 2 h, the reaction
mixture was gradually warmed to rt. The mixture was diluted
with 100 mL of dichloromethane, washed with saturated
aqueous sodium bicarbonate, and dried (Na2SO4). Removal
of solvents under vacuum gave a residue, which was purified
by flash SiO2 column (2:1 hexane/ethyl ether) to give 0.824 g
of the ketone 13a (87%). Continuing elution with ether/hexane
(4:1) gave 0.099 g of the starting material 11a (10% recovery).
For the ketone 13a , mp 134-135 °C (ether/hexane): TLC
A pure Z-isomer sample was obtained by flash chromato-
graphic purification (SiO2, 30:70:0.5, hexane/ethyl acetate/
triethylamine): TLC (ethyl acetate/hexane/triethylamine, 90:
1
10:0.5) Rf ) 0.48 (CAS, blue); H NMR (500 MHz, CDCl3) δ
8.87 (br s, 1 H), 7.16-7.12 (m, 2 H), 6.89 (t, J ) 7.5 Hz, 1 H),
6.78 (d, J ) 7.7 Hz, 1 H), 5.70 (q, J ) 6.9 Hz, 1 H), 4.04 (br s,
1 H), 3.95 (d, J ) 2.3 Hz, 1 H), 3.80 (s, 3 H), 3.65 (d, J ) 15.6
Hz, 1 H), 3.43 (br d, J ) 15.6 Hz, 1 H), 3.32-3.27 (m, 1 H),
3.20-3.15 (m, 1 H), 2.78-2.73 (m, 1 H), 2.08-2.03 (m, 1 H),
1.67 (d, J ) 6.9 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 212.21,
167.66, 164.77, 144.11, 138.45, 133.91, 128.49, 123.06, 121.62,
121.01, 110.03, 98.32, 66.48, 64.34, 54.97, 51.41, 49.94, 48.37,
46.59, 13.17; IR (film) νmax 3357, 2949, 2921, 2854, 1744, 1675,
1604, 1465, 1437, 1381, 1314, 1242, 1200, 1101, 1062, 744
cm-1; UV (EtOH) λmax 206, 234, 298, 334 nm; MS m/z (rel
intens) 337 (18), 336 (53), 334 (8), 309 (20), 308 (98), 307 (25),
294 (15), 293 (100), 278 (10), 277 (18), 276 (19), 275 (35), 262
(11), 261 (44), 252 (15), 250 (17), 249 (84), 248 (26), 247 (39),
241 (25), 235 (73), 234 (26), 233 (29), 221 (25), 220 (30), 219
(22), 206 (40), 205 (23), 204 (30), 194 (31), 193 (33), 192 (30),
191 (27), 181 (22), 180 (28), 169 (26), 168 (34), 167 (52), 166
(45), 154 (43), 149 (49), 138 (36), 127 (22), 123 (23), 121 (55),
116 (20), 115 (22), 111 (49), 110 (20), 109 (21), 108 (39), 103
(21), 97 (22), 91 (46), 86 (28), 85 (20), 84 (56), 83 (21), 71 (33),
69 (22), 57 (29), 56 (26), 54 (31).
1
(ethyl ether/hexane, 1:1) Rf ) 0.43 (CAS, greenish blue); H
NMR (500 MHz, CDCl3) δ 9.14 (br s, 1 H), 7.44 (d, J ) 7.4 Hz,
1 H), 7.16 (t, J ) 7.7 Hz, 1 H), 6.91 (t, J ) 7.5 Hz, 1 H), 6.80
(d, J ) 7.7 Hz, 1 H), 5.95 (q, J ) 6.4 Hz, 1 H), 3.77 (d, J ) 14
Hz, 1 H), 3.74 (s, 3 H), 3.72 (dd, J ) 14, 1 Hz, 1 H), 3.51 (d, J
) 17.1 Hz, 1 H), 3.32 (dd, J ) 17.1, 1.7 Hz, 1 H), 3.20 (d, J )
1 Hz, 1 H), 3.06-2.98 (m, 2 H), 2.55 (dt, J ) 12.6, 8.6 Hz, 1
H), 2.04 (ddd, J ) 12.6, 12.6, 2.9 Hz, 1 H), 1.79 (d, J ) 6.4 Hz,
3 H); 13C NMR (125 MHz, CDCl3) δ 206.00, 167.65, 162.34,
143.41, 135.68, 132.49, 128.36, 123.03, 121.36, 109.28, 108.01,
87.80, 67.92, 63.69, 57.57, 51.06, 50.28, 40.14, 35.85, 21.61;
IR (film) νmax 3373, 3056, 3019, 2980, 2949, 2913, 2851, 2809,
2252, 1714, 1690, 1683, 1635, 1617, 1597, 1480, 1469, 1436,
1385, 1244, 1137, 1045, 910, 733 cm-1. UV (EtOH) λmax 206,
226, 300, 330 nm; MS m/z (rel intens) 465 (M + 1, 7), 464 (M,
17), 437 (14), 436 (90), 377 (9), 376 (13), 352 (3), 351 (28), 349
(10), 309 (23), 256 (10), 255 (72), 249 (13), 228 (25), 227 (50),
224 (6), 223 (20), 221 (7), 214 (49), 209 (7), 197 (6), 196 (28),
195 (50), 194 (50), 182 (16), 181 (46), 180 (15), 170 (14), 169
(38), 168 (91), 167 (100), 166 (19), 160 (13), 155 (12), 154 (75),
143 (15), 142 (12), 141 (18), 140 (45), 128 (19), 127 (35), 115
(43), 96 (18), 89 (14), 86 (12), 84 (26), 82 (12), 77 (24), 63 (11);
high-resolution MS, EI ionization, calcd for C20H21N2O3I
464.0597, found 464.0587.
(()-Mossa m bin e (6) a n d Its En a n tiom er s. To a stirred
solution of 15 mg of the E-ketone 16E (0.045 mmol) and 22
mg of CeCl3 in 3 mL of methanol and 3 mL of THF, cooled in
an ice bath, was added 40 mg of sodium borohydride, by
portions, over 30 min. The reaction was brought to room
temperature, and 30 mL of saturated aqueous sodium bicar-
bonate solution was added. Extraction with 4 × 15 mL of
chloroform, followed by drying (Na2SO4) and evaporation, gave
the crude product, which was purified by flash SiO2 column
(70:30:0.5 ethyl acetate/methanol/triethylamine) to afford 14.5
mg of product as a mixture of 1:5 R/â-hydroxy epimers, as
determined by 1H NMR (96%). Crystallization of the mixture
from methanol then gave 9.3 mg (62%) of pure mossambine
as white crystals: mp 219-220 °C; TLC (ethyl acetate/
methanol, 1:1) Rf ) 0.24 (CAS, blue); 1H NMR (500 MHz,
CDCl3) δ 8.83 (br s, 1 H), 7.19 (d, J ) 7.4 Hz, 1 H), 7.14 (t, J
) 7.7 Hz, 1 H), 6.91 (t, J ) 7.4 Hz, 1 H), 6.81 (d, J ) 7.7 Hz,
1 H), 5.74 (q, J ) 6.7 Hz, 1 H), 3.95 (d, J ) 3.1 Hz, 1 H), 3.84
(t, J ) 2.4 Hz, 1 H), 3.77 (s, 3 H), 3.72 (t, J ) 3.1 Hz, 1 H),
3.50 (d, J ) 13.2 Hz, 1 H), 3.15 (d, J ) 13.2 Hz, 1 H), 2.98 (dd,
J ) 14.7, 7.1 Hz, 1 H), 2.93-2.86 (m, 2 H), 1.86 (dd, J ) 11.9,
5.9 Hz, 1 H), 1.78 (dd, J ) 6.7 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 169.54, 167.88, 144.49, 135.47, 132.21, 127.88, 123.90,
121.26, 120.01, 109.78, 97.91, 70.49, 65.25, 58.67, 54.69, 53.97,
51.20, 44.69, 36.32, 12.66; IR (film) νmax 3350, 2948, 2915, 2902,
2864, 1660, 1604, 1478, 1467, 1433, 1310, 1254, 1232, 1209,
1199, 1122, 1102, 1063, 1035, 840, 747, 665 cm-1; UV (EtOH)
λmax 206, 230, 300, 330 nm; MS m/z (rel intens) 339 (M + 1,
5), 338 (M, 29), 309 (4), 293 (3), 279 (5), 277 (4), 266 (4), 263
(3), 261 (4), 252 (11), 249 (3), 247 (3), 238 (5), 235 (5), 234 (8),
222 (4), 221 (6), 220 (13), 216 (6), 208 (7), 207 (7), 206 (19),
204 (7), 194 (8), 193 (9), 192 (8), 191 (12), 181 (7), 180 (15),
(()-(19,20E an d -Z)-14-Oxoaku am m icin e (16E an d 16Z).
A solution of 0.987 g of the imino ketone 12a , obtained from
the above hypochlorite procedure, and 10 mg of AIBN, in 131
mL of dry benzene, was degassed with argon for 10 min and
then immersed into an oil bath at 85 °C. A solution of 1.85
mL of tri-n-butyltin hydride (6.88 mmol, 3.5 eq) and 240 mg
of AIBN in 12 mL of benzene was added to the above solution
by a syringe pump over 12 h. After cooling, the solvent was
removed under reduced pressure and the residue was purified
by flash SiO2 column, eluting with 75:25:0.5 ethyl acetate/
hexane/triethylamine. Collection of the appropriate fractions
gave two fractions: the first fraction, 0.145 g, E-isomer/Z-
isomer 1:2.5 (determined by 1H NMR) and the second fraction,
0.193 g, E-isomer/Z-isomer 5.5:1. Total 0.338 g (51% over last
two steps). Crystallization of the second fraction from metha-
nol gave 58 mg of pure E-isomer, which had mp 215-216 °C:
TLC (ethyl acetate/hexane/triethylamine, 9:1:0.5) Rf ) 0.40
(CAS, blue); 1H NMR (500 MHz, CDCl3) δ 9.09 (br s, 1 H),
7.17-7.14 (m, 2 H), 6.90 (t, J ) 7.5 Hz, 1 H), 6.79 (d, J ) 7.8

7878 J . Org. Chem., Vol. 61, No. 22, 1996
Kuehne et al.
178 (6), 169 (6), 168 (6), 167 (11), 166 (6), 165 (9), 154 (17),
149 (6), 144 (8), 139 (9), 137 (12), 130 (6), 128 (7), 127 (9), 122
(20), 121 (100), 108 (7), 106 (7), 95 (9), 91 (8), 86 (14), 84 (15),
80 (11), 77 (11); high-resolution MS, EI ionization calcd for
C20H22N2O3 338.1630, found 338.1627; FAB (+H) calcd 339.17,
found 339.17; (+Li) calcd 345.18, found 345.18.
The same procedure was repeated, starting with 26.3 mg
of the racemic ketone 16E and the R-sulfonimine. Thus, 7.9
mg (30%, 60% of theoretical) of the (-)-ketone was obtained,
[R]24 ) -783°. The spectroscopic data of the chiral ketone
D
were identical to those of the racemic sample.
Deter m in a tion of th e Ee Va lu e by Ch ir a l Sh ift Re-
a gen t. An enantiomeric excess >99.5% for the resolved ketone
16E was determined by 1H-NMR shift studies using a gradual
addition of a 0.1 M solution of Eu(hfc)3, [tris[3-(heptafluoro-
propylhydroxymethylene)-d-camphorato]europium(III)] in chlo-
roform-d to the pentacyclic racemate or to the chiral ketone
16E. The allylic methyl proton signal at δ 1.63 was split to
give signals at δ 2.05 and 1.97 for the (-)- and the (+)-ketone,
and the indole proton signal at δ 9.09 was split to give signals
at δ 9.84 and δ 9.71 for the (-)- and the (+)-ketone.
Sep a r a tion a n d Ch a r a cter iza tion of th e Tw o Dia ster -
eom er ic Su lfoxim in e a n d Keton e Ad d u cts. Following the
above procedure, starting from 30 mg of the ketone 16E and
10 equiv of (R)-(-)-N,S-dimethyl-S-phenylsulfoximine and 8
equiv of n-butyllithium, a mixture of the adducts, contami-
nated with the starting sulfoximine, was obtained after
workup. Washing of the mixture with ether-hexane (4×) then
gave a white solid, which was the pure, less polar diastereomer
(by TLC). The washings were concentrated and purified by
flash chromatography (SiO2, 0.5:10:90 triethylamine/hexane/
ethyl acetate) to afford the pure polar diastereomer.
The same sodium borohydride reduction procedure was
repeated with 7 mg of the (+)-ketone 16E, resulting in 4 mg
of (+)-mossambine: mp 236-237 °C (MeOH); [R]24 ) +480°
D
(c ) 0.015, CHCl3); high-resolution MS, FAB ionization, calcd
for C20H23N2O3 339.17, found 339.17.
Repetition of the same reduction procedure with 4 mg of
the (-)-ketone 16E gave 2.1 mg of (-)-mossambine after
crystallization from methanol: mp 238-239 °C; [R]22.4
)
D
-482° (c ) 0.021, CHCl3); high-resolution MS, FAB ionization,
calcd for C20H23N2O3 339.17, found 339.17; EI ionization, calcd
for C20H22N2O3 338.1630, found 338.1629.
(()-14-epi-Mossa m bin e (17). To an ice-cooled solution of
the E-ketone 16E (12 mg, 0.036 mmol) in 2 mL of THF was
added, dropwise, 0.50 mL of a 1 M L-Selectride (Aldrich) in
THF solution (14 equiv). Stirring was continued for 20 min,
when TLC showed absence of starting material. Then 0.3 mL
of water was added, and the resulting mixture was concen-
trated under reduced pressure and partitioned between 30 mL
of saturated aqueous sodium bicarbonate solution and 20 mL
of chloroform. After separation of the two layers, the aqueous
layer was extracted with 3 × 15 mL of chloroform. The
combined organic layers were dried (Na2SO4) and concen-
trated. The residue was purified by flash SiO2 column, eluting
with 75:25:0.1 ethyl acetate/methanol/triethylamine to provide
11.6 mg of the product 17 (96%): mp 200-202 °C (MeOH);
For the less polar diastereomer: TLC (0.5% triethylamine
1
in ethyl acetate) Rf ) 0.25 (CAS, blue); H NMR (500 MHz,
CDCl3) δ 8.94 (br s, 1 H), 7.86 (d, J ) 7.7 Hz, 2 H), 7.64-7.49
(m, 3 H), 7.16-7.08 (m, 2 H), 6.90 (t, J ) 7.5 Hz, 1 H), 6.82 (d,
J ) 7.7 Hz, 1 H), 5.53 (br q, J ) 6.5 Hz, 1 H), 4.57 (br s, 1 H),
3.78 (s, 3 H), 3.67 (br s, 1 H), 3.66 (br s, 2 H), 3.23 (br d, J )
13.9 Hz, 1 H), 3.15 (br d, J ) 13.9 Hz, 1 H), 2.94-2.75 (m, 3
H), 2.57 (s, 3 H), 1.93 (dd, J ) 6.5, 2 Hz, 3 H), 1.80 (dd, J )
12.8, 5.7 Hz, 1 H); 13C-NMR (125 MHz, CDCl3) δ 170.99,
168.59, 143.63, 139.14, 137.33, 133.17, 129.49, 129.02, 127.17,
122.31, 121.25, 119.11, 109.96, 94.46, 72.33, 70.66, 60.69,
56.73, 53.97, 52.38, 51.02, 42.83, 40.84, 28.87, 13.34 (one
carbon was not observed); IR (film) νmax 3357, 2947, 2918, 2875,
2808, 1683, 1675, 1671, 1653, 1602, 1475, 1463, 1436, 1386,
1239, 1203, 1149, 1101, 1081, 912, 816, 734 cm-1; UV (EtOH)
1
TLC (ethyl acetate/methanol, 1:1) Rf ) 0.33 (CAS, blue); H
NMR (500 MHz, CDCl3) δ 9.06 (br s, 1 H), 7.20 (d, J ) 7.5 Hz,
1 H), 7.13 (t, J ) 7.7 Hz, 1 H), 6.89 (t, J ) 7.5 Hz, 1 H), 6.83
(d, J ) 7.7 Hz, 1 H), 5.41 (q, J ) 7 Hz, 1 H), 4.47 (dd, J ) 4,
3 Hz, 1 H), 4.15 (br s, 1 H), 3.95 (t, J ) 2.2 Hz, 1 H), 3.79 (s,
3 H), 3.77 (d, J ) 15.0 Hz, 1 H), 3.29-3.23 (m, 1 H), 2.98 (dd,
J ) 13, 6.6 Hz, 1 H), 2.95 (d, J ) 15 Hz, 1 H), 2.60-2.54 (m,
1 H), 1.81 (dd, J ) 13, 5.6 Hz, 1 H), 1.67 (d, J ) 7 Hz, 3 H);
13C NMR (125 MHz, CDCl3) δ 168.68, 168.36, 143.05, 137.18,
137.05, 127.72, 121.64, 121.32, 120.51, 109.73, 92.43, 68.04,
67.03, 56.58, 55.88, 55.66, 51.09, 45.19, 37.51, 12.90; IR (film)
νmax 3428, 3366, 3357, 2949, 2921, 2869, 1670, 1605, 1479,
1469, 1438, 1384, 1308, 1279, 1241, 1206, 1166, 1105, 1059,
1037, 914, 748 cm-1; UV (EtOH) λmax 206, 230, 300, 330 nm;
MS m/z (rel intens) 339 (M + 1, 3), 338 (M, 11), 309 (2), 307
(2), 293 (1), 279 (3), 277 (2), 266 (3), 263 (2), 252 (6), 249 (1),
247 (2), 238 (3), 235 (3), 234 (5), 220 (6), 216 (3), 208 (4), 207
(3), 206 (10), 204 (3), 194 (4), 193 (4), 192 (5), 191 (6), 180 (7),
178 (3), 167 (7), 165 (4), 154 (8), 139 (5), 137 (10), 130 (3), 123
(3), 122 (20), 121 (100), 115 (5), 109 (4), 108 (5), 106 (4), 103
(4), 97 (4), 95 (4), 91 (4), 86 (10), 84 (13), 82 (5), 77 (5), 71 (6),
69 (7).
λmax 196, 206, 220, 298, 328 nm; MS m/z (rel intens) 508 (0.57),
507 (7), 506 (21), 477 (1), 460 (2), 459 (1), 381 (2), 380 (3), 352
(52), 351 (57), 349 (2), 336 (5), 335 (7), 334 (30), 322 (16), 321
(9), 308 (11), 307 (9), 291 (21), 280 (18), 276 (8), 275 (9), 266
(14), 265 (27), 263 (14), 253 (24), 252 (100), 249 (10), 248 (19),
247 (16), 238 (17), 235 (11), 234 (16), 233 (11), 222 (13), 221
(18), 220 (35), 219 (12), 206 (18), 194 (24), 193 (25), 192 (21),
180 (17), 168 (15), 167 (21), 154 (17), 144 (16), 125 (18), 109
(15), 98 (88), 97 (31), 86 (15), 84 (20), 77 (23), 57 (23), 55 (21);
high-resolution MS, FAB ionization, calcd for C28H31N3O4S +
H 506.2113, found 506.2122.
For the more polar diastereomer: TLC (0.5% triethylamine
1
Resolu tion of (()-14-Oxoa k u a m m icin e (16E). To 0.240
g (1.42 mmol) of (S)-(+)-N,S-dimethyl-S-phenylsulfoximine19
in 3 mL of THF at 0 °C was added, dropwise, 0.50 mL of 2.5
N n-butyllithium (1.2 mmol). The resulting solution was
stirred at rt for 15 min and then cooled to -75 °C. At -75 °C
was added 31 mg of the racemic ketone 16E in 5 mL of THF.
After 30 min saturated aqueous ammonium chloride solution
was added. The mixture was brought to rt, and most of the
solvent was evaporated to give a residue, which was mixed
with aqueous ammonium hydroxide and ammonium chloride
solution and extracted with 4 × 15 mL of chloroform. The
combined chloroform layers were dried over sodium sulfate and
evaporated on a rotary evaporator. The crude diastereomeric
mixture was carefully separated by flash chromatography (9:
1:0.5 ethyl acetate/hexane/triethyl amine). Attempted pyroly-
sis of the less polar isomer at 190 °C, under vacuum for 12 h,
showed only 3% of the ketone in the reaction mixture; all the
rest was still the unreacted adduct. If the pyrolysis temper-
ature rose above 200 °C, the mixture went to a black tar.
Pyrolysis of the more polar isomer at 150 °C for 12 h gave,
after flash chromatographic purification (8:2:0.5 ethyl acetate/
hexane/triethylamine), 10 mg (32% yield, 64% of theoretical)
in ethyl acetate) Rf ) 0.14 (CAS, blue); H NMR (500 MHz,
CDCl3) δ 8.90 (br s, 1 H), 7.89 (d, J ) 7.5 Hz, 2 H), 7.64-7.55
(m, 3 H), 7.27 (d, J ) 7.5 Hz, 1 H), 7.12 (t, J ) 7.7 Hz, 1 H),
6.93 (t, J ) 7.5 Hz, 1 H), 6.83 (d, J ) 7.7 Hz, 1 H), 5.44 (br q,
J ) 6.3 Hz, 1 H), 4.67 (br s, 1 H), 3.86 (br s, 1 H), 3.84 (d, J )
13.8 Hz, 1 H), 3.71 (s, 3 H), 3.29 (br d, J ) 13.9 Hz, 1 H), 3.18
(d, J ) 13.8 Hz, 1 H), 3,16-3.10 (m, 2 H), 3.00-2.89 (m, 2 H),
2.53 (s, 3 H), 1.86 (dd, J ) 12.8, 6.4 Hz, 1 H), 1.64 (dd, J )
6.3, 2 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 172.07, 168.39,
143.78, 138.67, 138.06, 133.45, 133.24, 129.57, 129.28, 126.97,
121.27, 121.10, 119.31, 109.84, 92.93, 72.27, 68.16, 60.04,
57.36, 54.42, 52.55, 50.90, 42.98, 42.42, 28.76, 12.54; IR (film)
νmax 3355, 3054, 2948, 2926, 2875, 2808, 1675, 1601, 1475,
1463, 1382, 1359, 1305, 1278, 1239, 1162, 1130, 1100, 1081,
1058, 1012, 845, 810, 786, 746, 689 cm-1; UV (EtOH) λmax 194,
210, 224, 296, 328 nm; MS m/z (rel intens) 507 (3), 506 (22),
381 (4), 380 (1), 353 (1), 352 (18), 351 (35), 350 (12), 336 (1),
335 (2), 334 (1), 333 (5), 323 (3), 322 (8), 321 (3), 319 (5), 318
(1), 309 (3), 308 (7), 307 (9), 305 (1), 293 (5), 292 (9), 291 (13),
290 (4), 289 (3), 279 (8), 280 (16), 275 (8), 266 (11), 265 (25),
253 (17), 252 (87), 248 (14), 247 (13), 238 (15), 234 (13), 221
(15), 220 (27), 206 (23), 205 (11), 194 (18), 193 (20), 192 (19),
180 (14), 167 (17), 144 (12), 125 (18), 109 (11), 98 (100), 97
(21), 86 (13), 84 (21), 77 (24), 56 (27), 55 (19), 54 (18); high-
of the (+)-ketone: [R]26.6 ) +778° (c ) 0.095, CDCl3). The
D
spectroscopic data matched those of the racemic sample.

Synthesis of Mossambine
J . Org. Chem., Vol. 61, No. 22, 1996 7879
resolution MS, FAB ionization, calcd for C28H31N3O4S + H
506.2113, found 506.2110.
(11), 53 (47), 51 (17). Anal. Calcd for C22H25N2O4Br: C, 57.28;
H, 5.46; N, 6.07; Br, 17.32. Found: C, 57.32; H, 5.47; N, 5.96;
Br, 17.34.
Met h yl 3-(2-Br om ob u t -2-en -1-yl)-1,2,3,4,5,6-h exa h y-
d r oa zep in o[4,5-b]in d ole-5-ca r boxyla te (8b). To 1.50 g of
(Z)-2-bromo-2-buten-1-ol23 (9.93 mmol) in 20 mL of dry ethyl
ether at 0 °C, was added, dropwise, 0.38 mL (4 mmol) of
phosphorus tribromide. The resulting solution was stirred at
room temperature for 18 h and then diluted with 50 mL of
ether. The ether was washed with saturated aqueous sodium
bicarbonate and brine and dried. Evaporation of the solvent
gave crude (Z)-1,2-dibromo-2-butene, which was used directly
in the next step.
(()-(3a R*,4R*,11bR*)-Meth yl 3-((Z)-2-Br om obu t-2-en -
1-yl)-2,3,3a ,4,5,7-h exa h yd r o-4-h yd r oxy-1H-p yr r olo[2,3-d ]-
ca r ba zole-6-ca r boxyla te (11b). To 1.886 g of the acetate
10b (4.09 mmol) in 35 mL of methanol and 2 mL of water was
added 0.565 g of potassium carbonate (1 equiv). After being
heated at reflux for 45 min, the reaction mixture was concen-
trated and the residue was dissolved in 120 mL of dichlo-
romethane and washed with 40 mL of brine. After drying and
concentration, the crude product was flash chromatographed
on silica gel (1:3 hexane/ethyl ether) to provide 1.448 g of the
alcohol 11b (85%): mp 159-160 °C (ethanol); TLC (SiO2, ethyl
To the above crude dibromide, in 50 mL of acetone, was
added 1.60 g of indoloazepine 7 (6.55 mmol), 2.72 g of
potassium carbonate (3 equiv), and 2.74 mL of triethylamine
(3 equiv). After being stirred vigorously at rt for 3 h, the
reaction mixture was filtered and the residual solid was
washed with acetone. The filtrate was concentrated under
vacuum and purified by flash silica gel column (1/2 hexane:
ethyl ether) to give 1.962 g of the alkylated azepine 8b (79%):
mp 122-124 °C (MeOH); TLC (SiO2, 3:1 ethyl ether/hexane)
1
ether/hexane, 3:1) Rf ) 0.12 (CAS, blue); H NMR (500 MHz,
CDCl3) δ 9.04 (br s, 1 H), 7.18-7.15 (m, 2 H), 6.90 (t, J ) 7.5
Hz, 1 H), 6.84 (d, J ) 7.9 Hz, 1 H), 6.07 (q, J ) 6.5 Hz, 1 H),
3.98 (br s, 1 H), 3.79 (d, J ) 14.1 Hz, 1 H), 3.77 (s, 3 H), 3.61
(d, J ) 14.1 Hz, 1 H), 3.11 (s, 1 H), 3.07 (dd, J ) 8.8, 6.5 Hz,
1 H), 2.94 (ddd, J ) 15.7, 2.4, 2.0 Hz, 1 H), 2.75 (ddd, J ) 13,
8.8, 4.8 Hz, 1 H), 2.65 (dd, J ) 15.7, 2.0 Hz, 1 H), 2.07 (td, J
) 12.1, 6.5, 1 H), 1.80 (d, J ) 6.4, 3H), 1.73 (dd, J ) 12.0, 4.7
Hz, 1 H), 1.38 (d, J ) 7.3 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 169.13, 164.63, 143.00, 137.26, 128.02, 126.60, 125.87,
122.25, 120.87, 109.45, 87.29, 72.96, 68.69, 63.06, 54.74, 51.03,
50.75, 41.64, 26.30, 16.64; IR (film) νmax 3452, 3385, 2966, 2915,
2852, 2801, 1673, 1608, 1465, 1437, 1283, 1248, 1199, 1122,
745 cm-1; UV (ethanol) λmax 206, 228, 300, 324 nm; MS m/z
(rel intens) 420 (9), 418 (7), 402 (8), 400 (7), 391 (3), 389 (4),
376 (10), 374 (9), 339 (7), 321 (9), 305 (3), 303 (3), 244 (12),
243 (41), 228 (6), 227 (4), 226 (10), 225 (10), 217 (9), 214 (7),
207 (7), 206 (94), 204 (100), 202 (10), 196 (5), 195 (6), 184 (6),
183 (6), 182 (7), 181 (6), 180 (8), 169 (10), 168 (19), 167 (25),
154 (32), 135 (15), 133 (15), 115 (10), 96 (15), 72 (34), 70 (13),
53 (57). Anal. Calcd for C20H23N2O3Br: C, 57.58; H, 5.07; N,
6.71; Br, 19.15. Found: C, 57.51; H, 5.12; N, 6.62; Br, 19.33.
(()-(3a R*,11bR*)-Meth yl 3-((Z)-2-Br om obu t-2-en -1-yl)-
2,3,3a ,4,5,7-h exa h yd r o-4-oxo-1H-p yr r olo[2,3-d ]ca r ba zole-
6-ca r boxyla te (13b). To 0.383 mL of DMSO in 50 mL of
dichloromethane at -75 °C was added dropwise 0.572 mL of
trifluoroacetic anhydride. After 20 min, 1.134 g of the alcohol
11b in 10 mL of dichloromethane was added, dropwise.
Stirring was continued at -70 °C for 1 h before adding 4.7
mL of N,N-diisopropylethylamine (10 eq). The reaction mix-
ture was stirred at -70 °C for 1 h, and the dry ice-acetone
bath was removed. When the mixture had gradually warmed
to rt, it was diluted with 50 mL of dichloromethane, washed
with saturated sodium bicarbonate, and dried. Concentration
1
Rf ) 0.41 (CAS, greyish blue); H NMR (500 MHz, CDCl3) δ
8.36 (br s, 1 H), 7.48 (d, J ) 7.8 Hz, 1 H), 7.30 (d, J ) 7.8 Hz,
1 H), 7.14 (t, J ) 7.5 Hz, 1 H), 7.09 (t, J ) 7.5 Hz, 1 H), 6.02
(q, J ) 6.5 Hz, 1 H), 4.07 (dd, J ) 7.3, 2.6 Hz, 1 H), 3.77 (s, 3
H), 3.57 (br s, 2 H), 4.44 (dd, J ) 13.3, 7.4 Hz, 1 H), 3.24 (dd,
J ) 13.3, 2.6 Hz, 1 H), 3.07-3.02 (m, 1 H), 2.96-2.87 (m, 3
H), 1.81 (d, J ) 6.5 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
172.44, 134.88, 131.98, 128.57, 126.58, 125.94, 121.61, 119.31,
118.03, 114.05, 110.69, 65.74, 56.92, 54.61, 52.38, 45.67, 24.11,
16.64; IR (film) νmax 3377, 3353, 2945, 2913, 2852, 2792, 1733,
1677, 1610, 1477, 1465, 1438, 1302, 1276, 1249, 1241, 1212,
1190, 1087, 1057, 1041, 782, 745 cm-1; UV (EtOH) λmax 208,
228, 284, 292 nm; MS m/z (relative intensity) 378 (16), 376
(14), 320 (6), 318 (6), 298 (4), 297 (24), 243 (3), 239 (6), 238
(8), 237 (5), 228 (3), 223 (3), 216 (6), 215 (18), 214 (20), 210
(6), 203 (6), 202 (55), 184 (7), 183 (21), 182 (6), 178 (7), 177
(6), 176 (14), 174 (8), 170 (10), 169 (17), 168 (13), 162 (10), 160
(6), 158 (6), 157 (21), 156 (100), 155 (6), 154 (33), 144 (29), 143
(18), 140 (6), 131 (7), 130 (15), 129 (17), 128 (19), 127 (12), 115
(12), 99 (16), 97 (8), 96 (92), 86 (31), 84 (83), 82 (17), 77 (10),
55 (11), 53 (47), 51 (17). Anal. Calcd for C18H21N2O2Br: C,
57.30; H, 5.61; N, 7.43; Br, 21.18. Found: C, 57.37; H, 5.57;
N, 7.30; Br, 21.13.
(()-(3a R*,4R*,11bR*)-Meth yl 3-((Z)-2-Br om obu t-2-en -
1-yl)-2,3,3a ,4,5,7-h exa h yd r o-4-a cetoxy-1H-p yr r olo[2,3-d ]-
ca r ba zole-6-ca r boxyla te (10b). A mixture of 1.908 g of the
azepine 8b (5.06 mmol) and 4 mL of a 1.45 N solution of
acetyloxyacetaldehyde in dichloromethane (1.15 eq) in 40 mL
of toluene was heated under a Dean-Stark trap at reflux
overnight. Cooling to rt and removal of solvents gave a
residue, which was purified by flash SiO2 column (1/1 ethyl
ether:hexane), to afford 1.968 g of the acetate 10b (84%): mp
157-157.5 °C (needles from ethanol); TLC (SiO2, 2:1 ethyl
ether/hexane) Rf ) 0.43 (CAS, blue); 1H NMR (500 MHz,
CDCl3) δ 9.00 (br s, 1 H), 7.18 (t, J ) 7.7 Hz, 1 H), 7.15 (d, J
) 7.4 Hz, 1 H), 6.90 (t, J ) 7.4 Hz, 1 H), 6.85 (d, J ) 7.7 Hz,
1 H), 6.06 (q, J ) 6.5 Hz, 1 H), 5.00 (br s, 1 H), 4.00 (d, J )
14.4 Hz, 1 H), 3.78 (s, 3 H), 3.64 (d, J ) 14.4 Hz, 1 H), 3.15 (br
s, 1 H), 3.07 (dd, J ) 8.9, 6.5 Hz, 1 H), 2.99-2.92 (m, 1 H),
2.83-2.78 (m, 1 H), 2.62 (dd, J ) 15.8, 2.3 Hz, 1 H), 2.11-
2.05 (m, 1 H), 1.84 (s, 3 H), 1.79 (d, J ) 6.5 Hz, 3 H), 1.75 (dd,
J ) 12, 4.8 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 170.73,
168.92, 163.90, 143.28, 137.06, 128.07, 126.40, 126.01, 122.30,
120.66, 109.35, 89.05, 71.40, 70.05, 62.07, 54.77, 50.99, 50.12,
41.65, 23.68, 21.33, 16.66; IR (film) νmax 3372, 2946, 2855, 2803,
1729, 1681, 1611, 1478, 1468, 1437, 1374, 1282, 1249, 1202,
1130, 1090, 1034, 913, 800, 746 cm-1; UV (ethanol) λmax 208,
226, 298, 326 nm; MS m/z (rel intens) 378 (16), 376 (14), 320
(6), 318 (6), 298 (4), 297 (24), 239 (6), 238 (8), 237 (5), 216 (6),
215 (18), 214 (20), 210 (6), 203 (6), 202 (55), 184 (7), 183 (21),
176 (14), 170 (10), 169 (17), 168 (13), 162 (10), 157 (21), 156
(100), 154 (33), 144 (29), 143 (18), 130 (15), 129 (17), 128 (19),
127 (12), 116 (12), 99 (16), 86 (31), 84 (83), 82 (17), 77 (10), 55
and flash SiO2
column chromatography (1/1 ethyl ether:
hexane) gave 0.963 g of the ketone 13b (86%). Continued
elution with 3:1 ether/hexane gave 0.123 g of recovered
starting alcohol 11b (11%).
For the ketone 13b: mp 115 °C (needles from ethanol); TLC
(SiO2, ethyl ether/hexane, 2:1) Rf ) 0.43 (CAS, greenish blue);
1H NMR (500 MHz, CDCl3) δ 9.11 (br s, 1 H), 7.41 (d, J ) 7.4
Hz, 1 H), 7.18 (t, J ) 7.7 Hz, 1 H), 6.93 (t, J ) 7.4 Hz, 1 H),
6.82 (d, J ) 7.7 Hz, 1 H), 6.06 (q, J ) 6.5 Hz, 1 H), 3.83 (d, J
) 14 Hz, 1 H), 3.76 (s, 3 H), 3.76 (d, J ) 14 Hz, 1 H), 3.50 (d,
J ) 17.4 Hz, 1 H), 3.31 (dd, J ) 17.4, 1.6 Hz, 1 H), 3.26 (s, 1
H), 3.18-3.13 (m, 1 H), 3.07-3.03 (m, 1 H), 2.58-2.52 (m, 1
H), 2.08-2.04 (m, 1 H), 1.78 (d, J ) 6.5 Hz, 3 H); 13C NMR
(125 MHz, CDCl3) δ 206.57, 167.90, 162.52, 143.55, 135.82,
128.50, 126.89, 125.60, 123.08, 121.57, 109.38, 87.97, 67.72,
60.46, 57.63, 51.19, 50.36, 40.14, 35.79, 16.66; IR (film) νmax
3367, 2947, 1717, 1683, 1610, 1467, 1437, 1243, 1208, 1136,
749 cm-1; UV (ethanol) λmax 206, 230, 298, 330 nm; MS m/z
(rel intens) 418 (16), 416 (15), 391 (99), 390 (64), 388 (58), 331
(7), 330 (10), 329 (10), 328 (11), 310 (5), 309 (28), 305 (27), 303
(32), 301 (10), 256 (9), 255 (64), 249 (11), 228 (17), 227 (28),
226 (13), 214 (40), 196 (19), 195 (53), 194 (18), 182 (11), 181
(14), 180 (16), 169 (27), 168 (67), 167 (79), 166 (20), 154 (30),
140 (20), 115 (28), 96 (13), 86 (18), 84 (37), 53 (100), 51 (20).
Anal. Calcd for C20H21N2O3Br: C, 57.56; H, 5.07; N, 6.71; Br,
19.15. Found: C, 57.51; H, 5.12; N, 6.62; Br, 19.33.
Met h yl 3-(2-Ch lor ob u t -2-en -1-yl)-1,2,3,4,5,6-h exa h y-
d r oa zep in o[4,5-b]in d ole-5-ca r boxyla te (8c). Chlorine gas
was bubbled into 8.928 g (89.2 mmol) of methyl crotonate in
(23) Fevig, J . M.; Marquis, R. W., J r.; Overman, L. E. J . Am. Chem.
Soc. 1991, 113, 5085.

7880 J . Org. Chem., Vol. 61, No. 22, 1996
Kuehne et al.
80 mL of dichloromethane for 40 min. The solution was
purged with argon for 5 min before 25 mL of triethylamine in
200 mL of pentane was added dropwise. After being heated
at reflux for 2 h and cooled to rt, the mixture was filtered,
and the filtrate was dissolved in 300 mL of ether, washed with
brine, and dried over sodium sulfate. Evaporation of solvents
gave a residue, which was distilled to afford the 4.12 g (34%)
of methyl (Z)-2-chlorocrotonate: bp 50-53 °C/12 mmHg.24 1H
NMR showed only one isomer.
To the chloro ester (3.58 g, 26.6 mmol) in 30 mL of dry THF
was added 60 mL of 1 M DIBAL, dropwise, at -78 °C, over
1.5 h. The reaction mixture was brought to rt and stirred
overnight. The reaction was quenched with 5 mL of methanol,
and then 50 mL of 15% HCl was added. The layers were
separated, and the aqueous phase was extracted with 2 × 50
mL of ether. The combined organic phases were washed with
brine and dried (Na2SO4). After the solvents were removed
under vacuum, the residue was distilled to give the 2.41 g of
the pure alcohol (85%): bp 64-65 °C/12 mm; 1H NMR (500
MHz, CDCl3) δ 5.84 (q, J ) 6.3 Hz, 1 H), 4.14 (s, 2 H), 2.37 (br
s, 1 H), 1.75 (d, J ) 6.3 Hz, 3 H); 13C NMR (125 MHz, CDCl3)
δ 134.06, 121.93, 66.73, 13.52; IR (film) νmax 3326, 2922, 2863,
1667, 1447, 1381, 1299, 1223, 1149, 1087, 1047, 1013, 922, 813,
698, 646, 586 cm-1; MS m/z (rel intens) 108 (14), 106 (42), 105
(5), 93 (6), 91 (25), 90 (5), 89 (11), 88 (9), 78 (5), 72 (5), 71
(100), 69 (14), 63 (5), 54 (10), 52 (33), 50 (7), 42 (37), 41 (67),
39 (33), 37 (10), 31 (18), 29 (15), 27 (23). Anal. Calcd for C4H7-
OCl: C, 45.09; H, 6.62; Cl, 33.27. Found: C, 45.30; H, 6.84;
Cl, 33.04.
was concentrated and purified by flash SiO2 column (ether/
hexane, 1:1), giving an additional 1.027 g of product: total
1.639 g (81%); mp 146-147 °C (needles from ethanol); TLC
(ether/hexane, 2:1) Rf ) 0.48 (CAS, blue); 1H NMR (500 MHz,
CDCl3) δ 9.03 (br s, 1 H), 7.17 (t, J ) 7.7 Hz, 1 H), 7.15 (d, J
) 7.4 Hz, 1 H), 6.89 (t, J ) 7.3 Hz, 1 H), 6.84 (d, J ) 7.7 Hz,
1 H), 5.86 (q, J ) 6.5 Hz, 1 H), 4.98 (s, 1 H), 3.90 (d, J ) 14.3
Hz, 1 H), 3.77 (s, 3 H), 3.59 (d, J ) 14.3 Hz, 1 H), 3.16 (s, 1 H),
3.09-3.06 (m, 1 H), 2.97 (dd, J ) 16, 2 Hz, 1 H), 2.88-2.83
(m, 1 H), 2.61 (dd, J ) 16, 2 Hz, 1 H), 2.10-2.04 (m, 1 H),
1.83 (s, 3 H), 1.78 (d, J ) 6.5 Hz, 3 H), 1.74 (dd, J ) 12, 4.8
Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 170.60, 168.75, 163.77,
143.16, 136.95, 132.61, 127.98, 123.02, 122.22, 120.59, 109.27,
88.93, 71.39, 69.89, 60.04, 54.68, 50.88, 50.12, 41.51, 23.58,
21.22, 13.79; IR (film) νmax 3373, 2945, 2857, 2808, 1729, 1681,
1611, 1479, 1467, 1372, 1353, 1305, 1279, 1247, 1211, 1201,
1132, 1090, 1059, 1035, 969, 800, 747, 695 cm-1; UV (EtOH)
λmax 206, 226, 298, 328 nm; MS m/z (rel intens) 420 (M + 2,
2), 419 (M + 1, (13), 418 (M, 20), 417 (38), 416 (38), 385 (5),
381 (8), 359 (10), 358 (31), 357 (34), 356 (78), 332 (9), 331 (6),
330 (30), 322 (8), 321 (43), 286 (22), 285 (19), 259 (9), 228 (12),
227 (12), 226 (34), 225 (20), 217 (8), 214 (11), 209 (9), 204 (32),
203 (12), 202 (100), 196 (9), 195 (12), 194 (11), 193 (3), 182
(10), 180 (13), 169 (12), 168 (30), 167 (24), 162 (18), 160 (59),
154 (19), 132 (19), 89 (13). Anal. Calcd for C22H25N2O4Cl: C,
63.38; H, 6.04; N, 8.72; Cl, 8.50. Found: C, 63.58; H, 6.13; N,
8.62; Cl, 8.42.
(()-(3a R*,4R*,11bR*)-Meth yl 3-((Z)-2-Ch lor obu t-2-en -
1-yl)-2,3,3a ,4,5,7-h exa h yd r o-4-h yd r oxy-1H-p yr r olo[2,3-d ]-
ca r ba zole-6-ca r boxyla te (11c). A mixture of the acetate 10c
(1.518 g, 3.64 mmol) and 0.53 g of potassium carbonate (3.83
mmol, 1.05 equiv) in 40 mL of methanol and 3 mL of water
was heated to reflux for 40 min. After concentration, the
residue was dissolved in 100 mL of dichloromethane and
washed with 50 mL of brine. Drying (Na2SO4) and evaporation
gave the crude product, which was purified by flash SiO2
column (ether/hexane, 3:1) to give 1.315 g of the alcohol 11c
as a white solid: mp 137-138 °C (from methanol); TLC (ether/
hexane, 3:1) Rf ) 0.19 (CAS, blue); 1H NMR (500 MHz, CDCl3)
δ 9.04 (s, 1 H), 7.19-7.16 (m, 2 H), 6.90 (t, J ) 7.5 Hz, 1 H),
6.84 (d, J ) 7.7 Hz, 1 H), 5.86 (q, J ) 6.4 Hz, 1 H), 3.95 (br s,
1 H), 3.78 (s, 3 H), 3.70 (br d, J ) 14.4 Hz, 1 H), 3.54 (d, J )
14.4 Hz, 1 H), 3.13 (s, 1 H), 3.09-3.06 (m, 1 H), 2.96-2.92 (m,
1 H), 2.82-2.77 (m, 1 H), 2.63 (d, J ) 15.2 Hz, 1 H), 2.11-
2.04 (m, 1 H), 1.80 (d, J ) 6.4 Hz, 3 H), 1.73 (dd, J ) 11.8, 4.9
Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 168.65, 164.09, 142.78,
136.96, 132.57, 127.54, 122.36, 121.73, 120.30, 109.12, 87.20,
72.50, 68.22, 60.66, 54.37, 50.50, 50.33, 41.34, 25.89, 13.48;
IR (film) νmax 3431, 3384, 2945, 2917, 2850, 2804, 1674, 1634,
1610, 1479, 1466, 1438, 1383, 1348, 1305, 1283, 1250, 1211,
1200, 1125, 1088, 1062, 1046, 1020, 923, 874, 808, 772, 745,
695 cm-1; UV (EtOH) λmax 206, 230, 300, 326 nm; MS m/z (rel
intens) 377 (3), 376 (8), 375 (12), 374 (16), 358 (6), 357 (5),
356 (17), 345 (6), 339 (6), 332 (7), 330 (18), 321 (6), 244 (10),
243 (27), 228 (5), 226 (8), 225 (4), 14 (4), 195 94), 182 (5), 169
(5), 168 (12), 167 (10), 162 (30), 161 (9), 160 (100), 158 (7), 155
(6), 154 (17), 128 (5), 127 (5), 115 (5), 89 (14). Anal. Calcd for
C20H23N2O3Cl: C, 64.08; H, 6.18; N, 7.47; Cl, 9.46. Found: C,
64.36; H, 6.28; N, 7.45; Cl, 9.34.
To an ice-cooled solution of 1.00 g of (Z)-2-chlorobuten-1-ol
(9.39 mmol) in 20 mL of dry ether was added, dropwise,
phosphorus tribromide (0.357 mL, 3.76 mmol). After being
stirred at rt for 18 h, the reaction mixture was diluted with
50 mL of ether and washed with aqueous sodium bicarbonate
solution and brine. Drying (Na2SO4) and concentration of the
ether layer gave the crude chlorobromide, which was used
directly for the following alkylation.
A mixture of 1.91 g of indoloazepine 7 (7.8 mmol), the above
bromide, 3.3 g of potassium carbonate, and 3.3 mL of triethyl-
amine in 50 mL of acetone was stirred vigorously at rt for 3 h.
Filtration and concentration gave the crude product 8c, which
was purified by flash SiO2 column (ethyl ether/hexane, 1:1) to
afford 1.71 g of the alkylated azepine as a white powder
(66%): mp 106-107 °C (from ethanol); TLC (ether/hexane, 2:1)
1
Rf ) 0.41 (CAS, blue); H NMR (500 MHz, CDCl3) δ 8.3 (s, 1
H), 7.46 (d, J ) 7.5 Hz, 1 H), 7.22 (d, J ) 7.7 Hz, 1 H), 7.11 (t,
J ) 7.5 Hz, 1 H), 7.07 (t, J ) 7.7 Hz, 1 H), 5.78 (q, J ) 6.6 Hz,
1 H), 3.94 (dd, J ) 6.7, 2 Hz, 1 H), 3.73 (s, 3 H), 3.43 (s, 2 H),
3.43 (dd, J ) 13.4, 6.7 Hz, 1 H), 13.3, 2 Hz, 1 H), 3.11 (dd, J
) 13.3, 2.4 Hz, 1 H), 3.05-3.01 (m, 1 H), 2.95-2.78 (m, 3 H),
1.79 (d, J ) 6.6 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 172.40,
134.73, 132.65, 132.01, 128.43, 122.94, 121.45, 119.16, 117.94,
113.85, 110.66, 64.38, 56.97, 54.83, 52.29, 45.63, 24.14, 13.82;
IR (film) νmax 3392, 3354, 2948, 2916, 2828, 1730, 1663, 1459,
1434, 1340, 1287, 1240, 1207, 1163, 1027, 963, 917, 818, 743,
723 cm-1; UV (EtOH) λmax 206, 228, 284 nm; MS m/z (rel
intens) 335 (8), 334 (31), 333 (29), 332 (88), 301 (3), 297 (12),
296 (8), 273 (2), 259 (9), 243 (5), 237 (4), 216 (13), 215 (46),
214 (31), 203 (13), 202 (86), 201 (11), 184 (11), 183 (35), 182
(8), 170 (13), 169 (23), 168 (5), 157 (14), 156 (100), 155 (25),
154 (43), 144 (11), 143 (11), 142 (7), 133 (7), 132 (15), 131 (26),
130 (33), 129 (21), 128 (21), 127 (13), 118 (18), 116 (22), 115
(12), 96 (41), 89 (14). Anal. Calcd for C18H21N2O2Cl: C, 64.96;
H, 6.36; N, 8.42; Cl, 10.68. Found: C, 65.24; H, 6.44; N, 8.28;
Cl, 10.51.
(()-(3a R*,11bR*)-Meth yl 3-((Z)-2-Ch lor obu t-2-en -1yl)-
2,3,3a ,4,5,7-h exa h yd r o-4-oxo-1H-p yr r olo[2,3-d ]ca r ba zole-
6-ca r boxyla te (13c). To 0.435 mL of DMSO (6.13 mmol) in
50 mL of dichloromethane at -70 °C was added dropwise 0.693
mL of trifluoroacetic anhydride (4.91 mmol). After 15 min, a
precooled solution of the alcohol 11c (1.15 g, 3.07 mmol) in 15
mL of dichloromethane was added. Stirring was continued
at the same temperature for 45 min, and then 4.4 mL (25.3
mmol) of N,N-diisopropylethylamine was added. After 1 h,
the reaction mixture was gradually warmed to rt, diluted with
100 mL of dichloromethane, washed with brine, and dried
(Na2SO4). After concentration and flash silica gel column
chromatography (ether/hexane, 1:2) 0.923 g of the ketone 13c
was obtained as a white powder (81%). Continuing elution of
the column by ether/hexane (6:1) gave 0.151 g of the starting
alcohol (13%). For the ketone 13c: TLC (ether/hexane, 1:1)
(()-(3a R*,4R*,11bR*)-Meth yl 3-((Z)-2-Ch lor obu t-2-en -
1-yl)-2,3,3a ,4,5,7-h exa h yd r o-4-a cetoxy-1H-p yr r olo[2,3-d ]-
ca r ba zole-6-ca r boxyla te (10c). The alkylated azepine 8c
(1.616 g, 4.86 mmol) and 3.7 mL of 1.45 N acetoxyacetalde-
hyde22 in dichloromethane (5.365 mmol, 1.1 equiv) were mixed
in 50 mL of dry toluene. With a Dean-Stark trap, the mixture
was heated at reflux for 3 h. Removal of solvents with a rotary
evaporator gave a residue, which was triturated with ether to
afford 0.612 g of product, as a white solid. The mother liquor
1
Rf ) 0.48 (CAS, greenish blue); H NMR (500 MHz, CDCl3) δ
(24) Kamigata, N.; Satoh, T.; Yoshida, M. Bull. Chem. Soc. J pn.
1988, 61, 449.
9.12 (br s, 1 H), 7.35 (d, J ) 7.5 Hz, 1 H), 7.18 (t, J ) 7.7 Hz,

Synthesis of Mossambine
J . Org. Chem., Vol. 61, No. 22, 1996 7881
1 H), 6.92 (t, J ) 7.5 Hz, 1 H), 6.81 (d, J ) 7.7 Hz, 1 H), 5.85
(q, J ) 6.6 Hz, 1 H), 3.75 (s, 3 H), 3.73 (d, J ) 14.3 Hz, 1 H),
3.68 (d, J ) 14.3 Hz, 1 H), 3.51 (d, J ) 17.3 Hz, 1 H), 3.29 (dd,
J ) 17.3, 1.6 Hz, 1 H), 3.26 (s, 1 H), 3.20-3.15 (m, 1 H), 3.08-
3.05 (m, 1 H), 2.57-2.51 (m, 1 H), 2.06-2.02 (m, 1 H), 1.78 (d,
J ) 6.6 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 206.51, 167.85,
162.48, 143.55, 135.79, 132.03, 128.47, 123.82, 122.90, 121.54,
109.37, 87.96, 67.54, 58.57, 57.64, 51.16, 50.43, 40.12, 35.49,
13.84; IR (film) νmax 3373, 2948, 2916, 2856, 2817, 1710, 1682,
1611, 1479, 1467, 1438, 1384, 1318, 1280, 1244, 1210, 1190,
1137, 1101, 1044, 748 cm-1; UV (EtOH) λmax 206, 228, 298,
330 nm; MS m/z (rel intens) 375 (3), 374 (9), 373 (11), 372 (30),
347 (5), 346 (29), 345 (24), 344 (100), 343 (11), 315 (4), 310 (4),
309 (22), 286 (6), 285 (13), 284 (15), 261 (8), 260 (8), 259 (34),
257 (14), 256 (13), 255 (47), 249 (5), 228 (15), 227 (20), 226 (7),
223 (6), 214 (21), 196 (14), 195 (31), 194 (10), 182 (6), 181 (7),
180 (7), 170 (5), 169 (17), 168 (43), 167 (46), 166 (11), 154 (16),
143 (6), 141 (7), 140 (10), 128 (6), 127 (6), 115 (12), 89 (16);
high-resolution MS, FAB ionization, calcd for C20H21N2O3ClLi
379.14, found 379.14.
(()-15-n or -(E a n d Z)-19,20-Did eh yd r o-14-h yd r oxy-
p seu d ovin ca d iffor m in e (23 a n d 24). a. To a suspension
of 0.128 g (1.04 mmol) of chromium(II) chloride and 0.003 g of
nickel(II) chloride in 3 mL of DMSO was added a solution of
0.040 g (0.086 mmol) of the iodo ketone 13a in 1 mL of DMSO,
at rt. After 2 h, the reaction was quenched with water (20
mL) and the mixture extracted with 3 × 10 mL of chloroform.
The combined extracts were washed with water, dried (Na2SO4),
and concentrated. The residue was purified by flash chroma-
tography (SiO2, 0.5:20:80 triethylamine/methanol/ethyl ac-
etate) to generate 0.025 g of the pure Z-isomer 24 (86%): TLC
(triethylamine/methanol/ethyl acetate 0.5:10:90) Rf ) 0.36
(CAS, blue); 1H NMR (500 MHz, CDCl3) δ 9.14 (br s, 1 H),
7.36 (d, J ) 7.4 Hz, 1 H), 7.17 (td, J ) 7.7, 1.2 Hz, 1 H), 6.92
(td, J ) 7.4, 0.9 Hz, 1 H), 6.85 (d, J ) 7.7 Hz, 1 H), 5.61 (qt,
J ) 7.2, 2 Hz, 1 H), 3.96 (br d, J ) 14.4 Hz, 1 H), 3.79 (s, 3 H),
3.56 (d, J ) 2 Hz, 1 H), 3.47 (dt, J ) 14.4, 2 Hz, 1 H), 3.44-
3.39 (m, 1 H), 3.36 (dd, J ) 16, 2 Hz, 1 H), 2.81-2.76 (m, 1
H), 2.29-2.23 (m, 1 H), 2.27 (d, J ) 16 Hz, 1 H), 1.97 (dd, J )
7.3, 5.2 Hz, 1 H), 1.95 (dt, J ) 7.2, 1.8 Hz, 3 H), 1.81 (br s, 1
H); 13C NMR (125 MHz, CDCl3) δ 168.94, 164.20, 143.35,
142.75, 137.42, 128.10, 122.64, 121.46, 120.30, 109.29, 88.66,
82.92, 78.77, 60.54, 56.56, 55.04, 51.13, 40.03, 33.92, 13.25;
IR (film) νmax 3369, 2947, 2920, 2854, 1676, 1609, 1480, 1467,
1437, 1387, 1288, 1249, 1201, 1125, 1043, 745 cm-1; UV
(EtOH) λmax 208, 226, 296, 328 nm; MS m/z (relative intensity)
340 (M + 2, 1), 339 (M + 1, 11), 338 (5, M), 307 (1), 228 (1),
216 (1), 215 (2), 169 (1), 168 (3), 167 (3), 166 (1), 154 (3), 153
(2), 140 (1), 128 (1), 127 (1), 125 (7), 124 (100), 115 (1), 96 (1),
94 (1), 82 (1), 81 (1), 79 (1), 77 (1), 67 (1), 55 (1), 52 (1); high-
resolution MS, EI ionization, calcd for C20H20N2O3 338.1630,
found 338.1627.
methanol in ethyl acetate) to afford 29 mg (72%) of the cyclized
products 23 and 24 as a 1:1 E/Z mixture (by NMR).
d. To 0.257 g of the bromo ketone 13b (0.616 mmol) and
0.258 mL of triethylamine (3 equiv) in 10 mL of dichlo-
romethane, stirred in an ice bath, was added, dropwise,
trimethylsilyl triflate (0.298 mL, 2.5 equiv). The reaction
mixture was stirred at rt overnight. TLC then showed only a
trace of the starting material. After removal of solvents under
vacuum, the residue was dissolved in 1% triethylamine/ether.
Filtration and concentration gave 0.275 g (91%) of the enol
ether 22b, which was directly used in the next step.
The silyl enol ether 22b (0.275 g) was mixed with 0.226 mL
of tri-n-butyltin hydride and 20 mg of AIBN in 40 mL of dry
benzene. After being degassed with argon for 10 min, the
mixture was immersed in an oil bath at 80-85 °C and stirred
for 3 h. Further equal amounts of tin hydride and AIBN were
added, and the reaction mixture was kept at 85 °C overnight.
After cooling and concentration, the residue was dissolved in
10 mL of methanol and 8 mL of 20% hydrochloric acid, and
stirred for 1 h. The methanol was evaporated, and concen-
trated ammonium hydroxide was added to make the mixture
strongly basic. Extraction with 3 × 40 mL of dichloromethane,
drying, concentration, followed by flash SiO2 column chroma-
tography (ethyl acetate/methanol/triethylamine 90:10:1) af-
forded 0.034 g of the pentacyclic alcohols 23 and 24 as a 1:2
E/Z mixture (18% over two steps). Careful flash chromato-
graphic purification (SiO2, 5-10% methanol in dichloromethane)
of the mixture afforded the pure analytical E-isomer 23: TLC
(SiO2, triethylamine/methanol/ethyl acetate 0.5:10:90) Rf
)
1
0.41 (CAS, blue); H NMR (500 MHz, CDCl3) δ 9.13 (br s, 1
H), 7.36 (d, J ) 7.4 Hz, 1 H), 7.17 (td, J ) 7.7, 1 Hz, 1 H), 6.92
(td, J ) 7.4, 0.8 Hz, 1 H), 6.85 (d, J ) 7.7 Hz, 1 H), 5.77 (qt,
J ) 6.9, 2.3 Hz, 1 H), 4.12 (br d, J ) 14.6 Hz, 1 H), 3.78 (s, 3
H), 3.54 (d, J ) 1.7 Hz, 1 H), 3.51-3.46 (m, 1 H), 3.45 (br d,
J ) 14.6 Hz, 1 H), 2.94 (dd, J ) 16, 2 Hz, 1 H), 2.86-2.82 (m,
1 H), 2.30-2.24 (m, 1 H), 2.25 (d, J ) 16 Hz, 1 H), 1.96-1.91
(m, 1 H), 1.70 (d, J ) 6.9 Hz, 3 H); 13C NMR (125 MHz,
methanol-d4) δ 170.01, 163.12, 145.37, 144.49, 137.36, 129.67,
123.07, 122.15, 119.56, 110.83, 90.75, 80.37, 78.90, 57.77,
56.24, 54.95, 51.52, 40.17, 36.39, 14.57; IR (film) νmax 3371,
3054, 2949, 2923, 2855, 1676, 1610, 1467, 1438, 1386, 1288,
1247, 1203, 1126, 911, 731 cm-1; UV (ethanol) λmax 208, 224,
298, 328 nm; MS m/z (rel intens) 340 (2, M + 2), 339 (10, M +
1), 338 (7, M), 307 (1), 228 (1), 216 (1), 215 (2), 214 (2), 196
(1), 195 (1), 194 (1), 183 (1), 182 (1), 170 (1), 169 (2), 168 (5),
167 (5), 154 (5), 153 (2), 149 (3), 140 (2), 128 (2), 127 (3), 125
(13), 124 (100), 115 (2), 96 (2), 56 (2), 55 (2), 54 (3).
e. The same procedure was repeated, starting with 0.232 g
of the iodo ketone 13a and 0.017 g (10%) of the cyclized
products 23 and 24, was isolated as a 1:1 E/Z mixture.
Ack n ow led gm en t. This work was supported by the
Cancer Institute of the National Institutes of Health
with Grant No. RO1 CA 12010. We are indebted to
Robert Bennett of our group for low-resolution mass
spectra and to Dr. Fred Strobel of the Emory University
Mass Spectrometry Facility for high-resolution mass
spectra. Professor Louisette Le Men-Olivier kindly
provided an NMR spectrum of natural mossambine.
b. To 120 mg (0.44 mmol) of di(cycloocta-1,5-diene)nickel
in 2 mL of dry acetonitrile was added 2 mL of an acetonitrile
solution of 54 mg of the chloro ketone 13c (0.145 mmol) and
0.061 mL of triethylamine. The mixture was stirred overnight
at rt. Evaporation of solvent with a rotary evaporator gave a
residue, which was purified by flash chromatography on silica
gel. Elution with 1:1 ether/hexane gave 28 mg of unreacted
ketone. Continuing elution with 30% methanol in ethyl
acetate afforded the cyclized products 23 and 24 as a mixture
of 1:1.4 E/Z geometric isomers (53%, based on consumed
starting material).
c. To 100 mg (0.36 mmol) of di(cycloocta-1,5-diene)nickel
in 3 mL of acetonitrile was added a solution of 50 mg (0.12
mmol) of bromo ketone 13b and 0.05 mL (0.4 mmol) of
triethylamine in 2 mL of acetonitrile. The reaction mixture
was stirred at rt for 3 h. Evaporation gave a residue, which
was purified by flash chromatography on silica gel (25%
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and 13C
NMR spectra for compounds 6, 8a -c, 10a -c, 11a -c, 12a ,
13a -c, 15, 16Z, 16E, 17, 20, 21, 23, and 24 (57 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 O961023S