Synthesis of hexahydropyrrolo[2,3-b]indole alkaloids based on the aza-Pauson-Khand-type reaction of alkynecarbodiimides

Article abstract of DOI:10.1021/jo071137b

(Chemical Equation Presented) Upon treatment with 30 mol % of Co ₂(CO)₈ and 30 mol % of TMTU in toluene at 70°C, benzene-bridged alkynecarbodiimides efficiently underwent a ring-closing reaction to give the pyrrolo[2,3-b]-indol-2-ones in good yields. These conditions could nearly suppress the formation of the urea derivatives, which were consistently observed when 10 mol % of Co₂(CO)₈ and 60 mol % of TMTU in benzene were used. The synthesis of the eight hexahydropyrrolo[2,3-b]indole alkaloids was accomplished from the resulting pyrrolo[2,3-b]indol-2-ones via the introduction of an angular substituent at the C_3a-position by treatment with NaBH₄/alkyl bromide as the crucial step.

Full text of DOI:10.1021/jo071137b

Synthesis of Hexahydropyrrolo[2,3-b]indole Alkaloids Based on the
Aza-Pauson-Khand-Type Reaction of Alkynecarbodiimides
Daisuke Aburano, Tatsunori Yoshida, Naoki Miyakoshi, and Chisato Mukai*
DiVision of Pharmaceutical Sciences, Graduate School of Natural Science and Technology,
Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan
cmukai@kenroku.kanazawa-u.ac.jp
ReceiVed May 30, 2007
Upon treatment with 30 mol % of Co2(CO)8 and 30 mol % of TMTU in toluene at 70 °C, benzene-
bridged alkynecarbodiimides efficiently underwent a ring-closing reaction to give the pyrrolo[2,3-b]-
indol-2-ones in good yields. These conditions could nearly suppress the formation of the urea derivatives,
which were consistently observed when 10 mol % of Co2(CO)8 and 60 mol % of TMTU in benzene
were used. The synthesis of the eight hexahydropyrrolo[2,3-b]indole alkaloids was accomplished from
the resulting pyrrolo[2,3-b]indol-2-ones via the introduction of an angular substituent at the C3a-position
by treatment with NaBH4/alkyl bromide as the crucial step.
SCHEME 1
Introduction
We have recently been investigating the intramolecular
Pauson-Khand-type reaction (PKTR) of phenylsulfonyl-
allenynes 1 resulting in the development of an efficient method1
for the construction of the 2-phenylsulfonylbicyclo[5.3.0]deca-
1,7-dien-9-one 2 (n ) 1) as well as the 2-phenylsulfonylbicyclo-
[4.3.0]nona-1,6-dien-8-one 2 (n ) 0) skeletons. This procedure
was also shown to be used for the preparation of the larger-
sized 2-phenylsulfonylbicyclo[6.3.0]undeca-1,8-dien-10-ones 2
(n ) 2).2 As an extension of our work in this area, we found in
the previous paper3 that the carbodiimide group of the benzene-
bridged alkynecarbodiimide compounds 3, an isoelectronic
diaza-alternative of the allene functionality, serves as one of
the π bond components in the PKTR under Co2(CO)8-catalyzed
conditions4 to give the corresponding pyrrolo[2,3-b]indol-2-ones
4 in low to moderate yields (Scheme 1). The resulting pyrrolo-
[2,3-b]indol-2-one derivative could successfully be converted
into the calabar bean alkaloid, (()-physostigmine (5), a repre-
sentative hexahydropyrrolo[2,3-b]indole alkaloid. We now
describe in detail the further investigation of the Co2(CO)8-
catalyzed aza-PKTR of alkynecarbodiimides and its application
to the total synthesis of several hexahydropyrrolo[2,3-b]indole
alkaloids.
* To whom correspondence should be addressed. Phone: +81-76-234-4411.
Fax: +81-76-234-4410.
(1) (a) Mukai, C.; Nomura, I.; Yamanishi, K.; Hanaoka, M. Org. Lett.
2002, 4, 1755-1758. (b) Mukai, C.; Nomura, I.; Kitagaki, S. J. Org. Chem.
2003, 68, 1376-1385. (c) Mukai, C.; Inagaki, F.; Yoshida, T.; Kitagaki, S.
Tetrahedron Lett. 2004, 45, 4117-4121. (d) Mukai, C.; Inagaki, F.; Yoshida,
T.; Yoshitani, K.; Hara, Y.; Kitagaki, S. J. Org. Chem. 2005, 70, 7159-
7171. (e) Inagaki, F.; Mukai, C. Org. Lett. 2006, 8, 1217-1220. (f) Inagaki,
F.; Kawamura, T.; Mukai, C. Tetrahedron 2007, 63, 5154-5160.
(2) Mukai, C.; Hirose, T.; Teramoto, S.; Kitagaki, S. Tetrahedron 2005,
61, 10983-10994.
Results and Discussion
Yang and co-workers4 developed a novel intramolecular
Co2(CO)8-catalyzed Pauson-Khand reaction (PKR) of enynes
(3) Mukai, C.; Yoshida, T.; Sorimachi, M.; Odani, A. Org. Lett. 2006,
8, 83-86.
(4) Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z. Org.
Lett. 2005, 7, 593-595.
10.1021/jo071137b CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/10/2007
6878
J. Org. Chem. 2007, 72, 6878-6884

Synthesis of Hexahydropyrrolo[2,3-b]indole Alkaloids
TABLE 1. Co2(CO)8-Catalyzed Aza-PKTR of 6a
TABLE 2. Co2(CO)8-Catalyzed Aza-PKTR of 6
product (%)a
Co2(CO)8
(mol %)
TMTU
(mol %)
Co2(CO)8/
TMTU
7a
(%)
8a
(%)
entry
entry sub. R1
R2
R3
7
8
1
2
3
4
5
6
7
8
10
20
30
40
20
20
30
30
30
30
60
120
180
240
80
60
90
60
30
1/6
1/6
1/6
1/6
1/4
1/3
1/3
1/2
1/1
1/1
54
71
69
66
69
72
84
82
77
84
19
7
6
7
9
6
6
5
a
1b 6a Me p-MeOC6H4 TMS
7a: 84 (54) 8a: -c (19)
7b: 77 (57) 8b: -c (6)
7c: 92 (37d) 8c: -c (6)
7d: 65 (41d) 8d: -c (15)
7e: 65 (66) 8e: -c (10)
2
3
4
5
6
6b
6c
6d
6e
6f
H
H
H
H
H
H
H
p-PhOC6H4 TMS
PMB
Me
TMS
TMS
p-MeOC6H4 Pr
p-MeOC6H4 (CH2)2CHCMe2 7f: 49 (44) 8f: 5 (13)
p-MeOC6H4 (CH2)2OTBS
p-MeOC6H4 CH2OTHP
7
8
6g
6h
7g: 64 (48) 8g: -c (8)
7h: 35 (5)
8h: -c (-c)
9
9
10
11
6i MeO p-MeOC6H4 TMS
6j MeO Me TMS
6k Cl p-MeOC6H4 TMS
7i: 64 (54) 8i: -c (18)
7j: 74 (55d) 8j: -c (10)
7i: 71 (52) 8i: -c (7)
10b
30
a
a A trace amount of 8 was detected by TLC. b Toluene was used under
a Number in parentheses indicates the chemical yield (%) of the product
obtained under the previous conditions (10 mol % of Co2(CO)8 and 60
mol % of TMTU in benzene at 70 °C). b The result obtained in Table 1,
entry 1 is cited from Table 1. c A trace amount of 8 was detected by TLC.
d 20 mol % of Co2(CO)8 and 120 mol % of TMTU were used.
the same conditions.
in benzene at 70 °C in the presence of tetramethylthiourea
(TMTU) in an atmosphere of CO, in which the combination of
5 mol % of Co2(CO)8 with 30 mol % of TMTU (Co2(CO)8/
TMTU ) 1/6) was found to be the most effective. In our
previous paper,3 we applied Yang’s conditions4 (10 mol % of
Co2(CO)8/60 mol % of TMTU ) 1/6) to the alkynecarbodi-
imides 6a, for example, to produce the pyrrolo[2,3-b]indol-2-
one 7a5,6 in 54% yield along with the urea derivative 8a in 19%
yield, which must have been formed by hydrolysis of the starting
material 6a. Thus, the first Co2(CO)8-catalyzed aza-PKTR of
the alkynecarbodiimides could be developed, but the formation
of some amounts of the urea derivatives such as 8a seemed to
be the drawback of this transformation. To suppress the
formation of the byproduct as well as improve the chemical
yield of the desired pyrrolo[2,3-b]indol-2-one derivative, our
initial effort was directed toward the evaluation of the loading
amount of Co2(CO)8 and the ratio between Co2(CO)8 and
TMTU. These results are summarized in Table 1. Entry 1 shows
the previous result3 for comparison. A significant improvement
in the chemical yield of 7a as well as suppression of 8a was
attained when the loading amount of catalysts was doubled while
retaining the ratio between Co2(CO)8 and TMTU (1/6) (entry
2). Two other conditions, with increasing loading amounts of
the catalysts with the same ratio between Co2(CO)8 and TMTU
(1/6), provided results similar to that of entry 2 (entries 3 and
4). Entries 5 and 6 with 20 mol % of Co2(CO)8 indicated that
decreasing the ratio of TMTU to Co2(CO)8 from 1/6 to 1/4 or
1/3 did not produce any specific changes compared to entry 2.
The conditions with 30 mol % of Co2(CO)8 and 90 or 60 mol
% of TMTU, however, effected the ring-closing reaction,
resulting in the second improvement regarding the yield of 7a
(entries 7 and 8). In addition, it was found that an equal amount
of Co2(CO)8 and TMTU was effective for the byproduct
suppression. In fact, compound 7a was obtained in a slightly
lower yield (77%) with a trace amount of 8a (entry 9). Finally,
the PKTR of 6a proceeded in toluene under the same conditions
as entry 9 to give 7a in 84% yield together with a trace amount
of 8a. Thus, the improved reaction conditions (30 mol % of
Co2(CO)8 and 30 mol % of TMTU in toluene) provided 7a in
a satisfactory yield accompanied by a very small amount of
the urea derivative 8a.
We next investigated the generality of the optimized condi-
tions (30 mol % of Co2(CO)8 and 30 mol % of TMTU in
toluene) using the same ten substrates 6b-k as examined in a
previous report.3 These results are summarized in Table 2
accompanied by the previous results. As can be seen, the
chemical yields of 7 were vastly improved in most cases. In
particular, compounds 6 having a TMS group at the alkyne
terminus consistently produced the corresponding ring-closed
products 7 in high yields. For compounds 6e-g with a terminal
alkyl tether, the chemical yield of the products 7e-g was
somewhat lower compared to those of the TMS derivatives
7a-d,i-k. The propargyl ether derivative 6h gave the corre-
sponding ring-closed product 7h in 35% yield (entry 8), which
was previously obtained in only 5% yield when the former was
treated with two catalysts in the ratio of 1 to 6. The other point
that needs to be mentioned is that the formation of 8 could be
nearly suppressed except for compound 6f that produced the
urea 8f in 5% yield (entry 6). On the basis of the results in
Table 2, it might be concluded that the Co2(CO)8-catalyzed aza-
PKTR of the N-[2-(1-alkynyl)phenyl]-N′-substitutedcarbodi-
imides 6 smoothly proceeds in the presence of 30 mol % of
Co2(CO)8 and 30 mol % of TMTU in toluene at 70 °C to
produce the pyrrolo[2,3-b]indol-2-one derivatives 7 in acceptable
yields.
The next phase of this investigation was to accomplish the
total synthesis of the hexahydropyrrolo[2,3-b]indole alkaloids
based on the newly developed Co2(CO)8-catalyzed aza-PKTR
of the alkynecarbodiimide derivatives. As shown in Scheme 2,
we have already succeeded in the efficient transformation3 of
(5) Saito reported the stoichiometric aza-PKTR, which involves the
cyclocarbonylation of the alkynecarbodiimide substrates to provide the
corresponding diazabicyclic compounds under the Mo(CO)6-mediated
conditions: Saito, T.; Shiotani, M.; Otani, T.; Hasaba, S. Heterocycles 2003,
60, 1045-1048.
(6) Recently, the Rh(I)-catalyzed PKTR of alkynecarbodiimide deriva-
tives was reported by Saito: Saito, T.; Sugizaki, K.; Otani, T.; Suyama, T.
Org. Lett. 2007, 9, 1239-1241.
the pyrrolo[2,3-b]indol-2-one 7j into esermethole (11),7
a
precursor of physostigmine (5),8 via compounds 9 and 10. The
J. Org. Chem, Vol. 72, No. 18, 2007 6879

Aburano et al.
SCHEME 2
SCHEME 3
crucial operation for the conversion of 7j into 9 could be
interpreted by the initial hydride attack at the C3-position (1,4-
reduction) of 9 resulting in the formation of the indole
intermediate, which subsequently reacted with HCHO at the
C3a-position to produce the indolenine derivative. The formed
imine moiety (N8-C8a) would be susceptible to the hydride
reduction, followed by reductive N-methylation to furnish 9.
The relative stereochemistry of 9, in particular, the relationship
between the C3-TMS group and the angular hydroxymethyl
moiety,9 was determined to be cis by an NOE experiment.
By taking advantage of the procedures described in Scheme
2, we first examined the synthesis of (()-flustramide B (21).10
The 6-bromopyrrolo[2,3-b]indol-2-one derivative 16, a key
intermediate for the natural product target, was prepared via
the aza-PKTR as follows (Scheme 3). 5-Bromo-2-iodoaniline
(12) was converted into the alkynylaniline 13 in 98% yield by
the Sonogashira coupling reaction,11 which was subsequently
treated with triphosgene12 to give the urea 14 in 91% yield.
The alkynecarbodiimide 15, a substrate for the aza-PKTR, was
obtained in 85% yield by the dehydration reaction of 14 with
carbon tetrabromide and triphenylphosphine.13 Upon exposure
to 30 mol % of Co2(CO)8 and 30 mol % of TMTU in toluene,
compound 15 underwent the ring-closing reaction as expected
to give the desired pyrrolo[2,3-b]indol-2-one 16 in 72% yield.
Treatment of 16 with NaCNBH3 under acidic conditions in the
presence of 3-methyl-2-butenal provided the N8-prenylpyrrolo-
[2,3-b]indol-2-one 18 in 25% yield and the corresponding N8-H
derivative 17 in 50% yield, the latter of which could be easily
converted into the former in 68% yield by the standard
N-prenylation. In sharp contrast to the reaction of 7j with HCHO
(Scheme 2),3 the reductive alkylation step with 3-methyl-2-
butenal was markedly retarded presumably due to the bulkiness
of 3-methyl-2-butenal compared to HCHO and/or deactivation
by the C6-bromo functionality on the benzene ring. Removal
of a hydroxyl group at an allylic position was essential to
complete the transformation of 18 into 21. The hydroxyl group
of compound 19, derived from 18, was activated by acylation
to give the acetoxy derivative 20, which was subsequently
exposed to lithium di-tert-butylbiphenylide (LiDBB)14 at -78
°C to give (()-debromoflustramide B (22)10b,15 in 40% yield
instead of (()-flustramide B (21). A small amount of 23 was
(7) Esermethole (11) has already been converted into (()-physostigmine
(5): Yu, Q.-S.; Brossi, A. Heterocycles 1988, 27, 745-750.
(8) For the recent total synthesis of physostigmine, see: (a) Node, M.;
Hao, X.; Nishide, K. Chem. Pharm. Bull. 1996, 44, 715-719. (b) Matsuura,
T.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500-6503.
(c) Kawahara, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 675-
678. (d) Tanaka, K.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001,
42, 1049-1052. (e) Mekhael, M. K. G.; Heimgarther, H. HelV. Chim. Acta
2003, 86, 2805-2813. (f) Haung, A.; Kodanko, J. J.; Overman, L. E. J.
Am. Chem. Soc. 2004, 126, 14043-14053. (g) Santros, P. E.; Srinivasan,
N.; Almeida, P. S.; Lob, A. M.; Prabhakar, S. Tetrahedron 2005, 61, 9147-
9156. (h) Rigby, J. H.; Sidique, S. Org. Lett. 2007, 9, 1219-1221.
(9) Compound 9 was converted into the acetoxy derivative 9′ in 74%
yield by a conventional procedure. An NOE experiment of 9′ revealed a
14.7% enhancement between the C3-TMS group and the methylene protons
of the acetoxymethyl functionality indicating that compounds 9 and 9′ should
have the relative stereochemistry depicted in Scheme 2. The opposite
stereochemical relationship between the TMS group and the hydroxymethyl
moiety (trans-relationship) might be reasonable on the basis of the proposed
mechanism. Presumably isomerization of the bulky TMS group from the
concave face to the convex face would occur during the reaction.
(10) For the recent total synthesis of flustramide B and flustramine B,
see: (a) Hino, T.; Tanaka, T.; Matsuki, K.; Nakagawa, M. Chem. Pharm.
Bull. 1983, 31, 1806-1808. (b) M.-Rois, M. S.; S-Castillo, O. R.; T.-Serrato,
J. J.; J.-Nathan, P. J. Org. Chem. 2001, 6, 1186-1192. (c) Austin, J. F.;
Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5482-5487. (d) Kawasaki, T.; Shinada, M.;
Kamimura, D.; Ohzono, M.; Ogawa, A. Chem. Commun. 2006, 420-422.
(11) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467-4470.
1
detected and then characterized by H NMR. The isolation of
23 suggested that the debromination of 20 would be faster than
(14) Krief, A.; Laval, A.-M.; Shastri, M. Acros Org. Acta 1995, 1,
32-33.
(15) For the recent total synthesis of debromoflustramide B and debro-
moflustramine B, see: (a) Jensen, J.; Anthoni, U.; Christphersen, C.; Nielson,
P. Acta Chem. Scand. 1995, 49, 68-71. (b) Cardoso, A. S.; Srinivasan, N.;
Lobo, A. M.; Prabhankar, S. Tetrahedron Lett. 2001, 42, 6663-6666. (c)
M.-Rios, M. S.; R.-Becerril, E.; J.-Nathan, P. Tetrahedron: Asymmetry 2005,
16, 2493-2499. (d) Miyamoto, H.; Okawa, Y.; Nakazawa, A.; Kobayashi,
S. Tetrahedron Lett. 2007, 48, 1805-1808, and ref 10b.
(12) (a) Majer, P.; Randad, R. S. J. Org. Chem. 1994, 59, 1937-1938.
(b) Weiberth, F. J. Tetrahedron Lett. 1999, 40, 2895-2898.
(13) Nishikawa, T.; Ohyabu, N.; Yamamoto, N.; Isobe, M. Tetrahedron
1999, 55, 4325-4340.
6880 J. Org. Chem., Vol. 72, No. 18, 2007

Synthesis of Hexahydropyrrolo[2,3-b]indole Alkaloids
TABLE 3. Alkylation at the C3-Position of 7d under Reductive
Conditions
SCHEME 4
entry
R-X
product
R
yield (%)
1
2
3
4
5
6
BnBr
24a
24b
24c
24d
24e
24f
Bn-
54
51
45
64
25
H2CCHCH2Br
HCCCH2Br
(Me)2CCHCH2Br
H2CCHCO2Me
Bul
H2CCHCH2-
HCCCH2-
(Me)2CCHCH2-
MeO2CCH2CH2-
Bu-
SCHEME 5
the deacetoxylation under the stated conditions. In addition, we
examined some typical radical conditions16 to remove the
hydroxyl group from the 1-hydroxyl-3-methyl-2-butenyl moiety.
However, it turned out that the dehydroxylation was accomp-
anied by migration of the double bond resulting in the formation
of both the 3-methyl-1-butenyl as well as 3-methyl-2-butenyl
functionalities.
To overcome the difficulty encountered in the dehydroxyla-
tion step (undesired debromination and/or double bond migra-
tion), an alternative procedure, which would enable the intro-
duction of the angular alkyl appendage at the C3a-position of
the pyrrolo[2,3-b]indol-2-one skeleton without the dehydroxy-
lation step, had to be mandatory. Thus, alkyl halides were
employed as alkylating agents instead of the aldehyde coun-
terparts in the above transformation. Furthermore, we envisaged
that NaBH4 would be better than NaCNBH3 because NaCNBH3
requires an acidic condition that must partially retard the N8-
alkylation during the final step.17 Upon exposure to NaBH4 in
acetonitrile at 0 °C in the presence of benzyl bromide, the pyr-
rolo[2,3-b]indol-2-one 7d underwent a successive 1,4-reduction,
benzylation at the C3a-position, and reduction of the formed
imine moiety to provide 24a in 54% yield (Table 3, entry 1).
The expected N8-benzyl derivative of 24a was not detected in
the reaction mixture. When the reaction mixture was allowed
to stand at room temperature for a prolonged time, the gradual
conversion of 24a into the corresponding N8-benzyl derivative
could be monitored by TLC. Both allyl bromide and propargyl
bromide gave the corresponding pyrrolo[2,3-b]indol-2-ones 24b
and 24c in moderate yields (entries 2,3), and compound 24d
was obtained in a higher yield (64%) when prenyl bromide was
used (entry 4). Although a variety of activated alkyl halides
could be used for this transformation, a simple alkyl halide was
found to be inefficient. In fact, no formation of 24f could be
detected in the reaction with butyl iodide (entry 6). Interestingly,
methyl acrylate acted as a Michael acceptor in this reaction to
produce 24e in a lower yield (entry 5).
24 (and 25 and 26) was determined on the basis of NOE
experiments. The NOE experiment of 24a, for instance, revealed
an 8.9% enhancement between the C3-H and benzyl protons,
strongly suggesting that the TMS group of 24a should be located
on the concave face of the diazabicyclo[3.3.0] ring as depicted
in Table 3. This is in sharp contrast to the stereochemistry of
the TMS group of 9, obtained from 7j under the reductive
conditions with NaCNBH3, being on the convex face.
The final phase of this program involved the transforma-
tion of 24d and its 6-bromo congener into the target natural
products (Schemes 5 and 6). Compound 24d was converted into
(()-debromoflustramide E (27)15d,18 in 83% yield by TBAF
treatment. On the other hand, 24d was consecutively treated
with TBAF at room temperature and then with TBAI in
refluxing acetonitrile (one pot) to produce (()-debromoflustra-
mide B (22)15 in 52% overall yield from 7d. Since both 27 and
22 have already been converted into (()-debromoflustramine
E (28)18 and (()-debromoflustramine B (29),15c,19 respectively,
the present syntheses also amount to the total synthesis of these
alkaloids in a racemic form.
The two additional examples similar to the preparation of 24
from 7d are shown in Scheme 4. The experiments with 7j and
16 indicated that the electronic property of the substituent on
the benzene ring did not affect the reactivity of the starting
pyrrolo[2,3-b]indol-2-ones. The stereochemistry of compounds
Similarly, compound 30 could be prepared from 16 in 65%
yield by prenylation under reductive conditions, which was
(18) For the recent total synthesis of debromoflustramide E and debro-
moflustramine E, see: (a) Mitchell, M. O.; Dorroh, P. Tetrahedron Lett.
1991, 32, 7641-7642. (b) M.-Rios, M. S.; S.-Castillo, O. R.; J.-Nathan, P.
Tetrahedron 2002, 58, 1479-1484 and ref 15d.
(19) Debromoflustramine B was also synthesized by alternative proce-
dures, which did not involve debromoflustramide B, see: (a) Somei, M.;
Yamada, F.; Izumi, T.; Nakajou, M. Heterocycles 1997, 45, 2327-2330.
(b) Tang, G. H.; Zhu, X.; Ganesan, A. Org. Lett. 2003, 5, 1801-1803.
L.-Alvarrado, P.; Caballero, E.; Avendano, C.; Menendez, J. C. Org. Lett.
2006, 8, 4303-4306.
(16) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1975, 1, 1574-1585. (b) Yamamoto, Y.; Hori, A.; Hutchinson, C. R. J.
Am. Chem. Soc. 1985, 107, 2474-2484. (c) Marukawa, K.; Mori, K. Eur.
J. Org. Chem. 2002, 3974-3978 and references cited therein.
(17) Neither compound 24a nor its N8-benzyl derivative could be detected
when compound 7d was treated with benzyl bromide in AcOH/MeCN at 0
°C in the presence of NaCNBH3.
J. Org. Chem, Vol. 72, No. 18, 2007 6881

Aburano et al.
SCHEME 6
2-ones in good yields. These conditions could nearly suppress
the formation of the urea derivatives, which were consistently
observed under the previous conditions. The resulting pyrrolo-
[2,3-b]indol-2-ones were successfully transformed into seven
hexahydropyrrolo[2,3-b]indole alkaloids, (()-flustramide B,
(()-flustramines B and E, (()-debromoflustramides B and E,
and (()-debromoflustramines B and E via the crucial prenylation
at the C3a-position by treatment with NaBH4/prenyl bromide.
An alternative synthesis of (()-physostigmine was accomplished
as well. Thus, we developed a simple and general procedure
for the preparation of pyrrolo[2,3-b]indol-2-ones based on the
Co2(CO)8-catalyzed aza-PKTR of alkynecarbodiimides, and their
conversion to the corresponding hexahydropyrrolo[2,3-b]indole
alkaloids.
Experimental Section
General Procedure for the Ring-Closing Reaction of Carbo-
diimides with Co2(CO)8 and TMTU under an Atmosphere of
CO. To a solution of carbodiimide 6 (0.15 mmol) in toluene (1.5
mL) were added 30 mol % of Co2(CO)8 and 30 mol % of TMTU.
The reaction mixture was heated at 70 °C (oil bath temperature)
under a CO atmosphere until the complete disappearance of the
starting material (monitored by TLC). The reactiom mixture was
concentrated and chromatographed with hexane-AcOEt to afford
pyrrolo[2,3-b]indol-2-one 7.21 Chemical yields of 7 are summarized
in Table 2.
SCHEME 7
5-Bromo-2-[2-(trimethysilyl)ethynyl]aniline (13). To a solution
of 5-bromo-2-iodoaniline22 (2.58 g, 8.59 mmol), PdCl2(PPh3)2 (60.2
mg, 0.0860 mmol), and CuI (33.0 mg, 0.174 mmol) in THF (50
mL) were added trimethylsilylacethylene (1.34 mL, 9.57 mmol)
i
and Pr2NH (9.0 mL) at room temperature. The reaction mixture
was stirred for 2 h, quenched by addition of saturated aqueous
NH4Cl, and extracted with AcOEt. The extract was washed with
water and brine, dried, and concentrated to dryness. The residue
was chromatographed with hexane-AcOEt (15:1) to afford 13 (2.26
g, 98%) as a pale yellow oil: IR 3497, 3394, 2147 cm-1; 1H NMR
δ 7.12 (d, 1H, J ) 8.3 Hz), 6.84 (d, 1H, J ) 2.0 Hz), 6.77 (dd, 1H,
J ) 8.3, 2.0 Hz), 4.27 (s, 2H), 0.25 (s, 9H); 13C NMR δ 149.2,
133.3, 123.7, 120.7, 116.7, 106.7, 100.9, 100.7, 0.0; MS m/z 267
(M+, 88.8); HRMS calcd for C11H14BrNSi 267.0079, found
267.0072.
subsequently desilylated to afford 31 in 85% yield (Scheme 6).
The three-step conversion of 16 into (()-flustramide B (21)10
was also achieved in a satisfactory overall yield. Thus, the
formal total syntheses of (()-flustramine E (32)18 from 31 and
(()-flustraime B (33)10b from flustramide B (21) were also
accomplished.
1-[5-Bromo-2-[2-(trimethylsilyl)ethynyl]phenyl]-3-methyl-
urea (14). To a solution of 13 (862 mg, 3.21 mmol) and Et3N (4.9
mL, 35 mmol) in CH2Cl2 (30 mL) was added triphosgene (1.00 g,
3.37 mmol) at 0 °C. After the solution was stirred for 30 min at
room temperature, MeNH2‚HCl (1.10 g, 16.3 mmol) was added to
the reaction mixture, which was then stirred for 1 h, quenched by
addition of water, and extracted with CH2Cl2. The extract was
washed with water and brine, dried, and concentrated to dryness.
The residue was chromatographed with hexane-AcOEt (3:1) to
afford 14 (950 mg, 91%) as colorless needles: mp 175-176 °C
Furthermore, we examined an alternative synthesis of eser-
methole (11) using the newly developed procedure with NaBH4,
although we had recognized that the reaction of 7d with butyl
iodide did not produce the desired product at all (see Table 3,
entry 6). Treatment of 7j with NaBH4 in the presence of methyl
iodide, however, gave the desired product 34 in a rather low
yield (33%) (Scheme 7). Compound 34 has the same stereo-
chemistry20 as compounds 24, 25, and 26, and opposite that of
compound 9 regarding the C3-stereogenic center. Reductive
methylation of 34 gave 35 in a quantitative yield, which was
subsequently exposed to TBAF and LiAlH4 to provide eser-
methole (11) in 85% overall yield. Thus, we could succeed in
the alternative synthesis of 11, but it is obvious that the previous
method3 is much superior to the present one as far as the
synthesis of 11 is concerned.
1
(hexane-AcOEt); IR 3456, 3393, 2149, 1697 cm-1; H NMR δ
8.45 (d, 1H, J ) 2.0 Hz), 7.22 (d, 1H, J ) 8.2 Hz), 7.08-7.05 (m,
2H), 4.80 (s, 1H), 2.91 (d, 3H, J ) 4.9 Hz), 0.28 (s, 9H); 13C NMR
δ 154.9, 141.4, 132.7, 124.9, 124.1, 121.2, 109.8, 102.8, 99.9, 27.3,
-0.1; MS m/z 324 (M+, 41.1); HRMS calcd for C13H17BrN2OSi
324.0294, found 324.0303.
N-[5-Bromo-2-[2-(trimethylsilyl)ethynyl]phenyl]-N′-methyl-
carbodiimide (15). To a solution of 14 (1.23 g, 3.78 mmol) and
Et3N (2.2 mL, 15 mmol) in CH2Cl2 (25 mL) were added CBr4 (2.51
g, 7.56 mmol) and PPh3 (1.98 g, 7.56 mmol) at room temperature.
The reaction mixture was stirred for 30 min and concentrated to
In summary, we have described the efficient Co2(CO)8-
catalyzed PKTR of the benzene-bridged alkynecarbodiimides
under improved conditions (30 mol % of both Co2(CO)8 and
TMTU in toluene at 70 °C) producing the pyrrolo[2,3-b]indol-
(21) The full characterization data for compounds 6, 7, and 8 have already
been reported in the Supporting Information of ref 3.
(22) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Yamanaka, H. Chem. Pharm.
Bull. 1987, 35, 1823-1828.
(20) An 18.3% enhancement between the C3-H and the angular methyl
group was observed in its NOE experiment.
6882 J. Org. Chem., Vol. 72, No. 18, 2007

Synthesis of Hexahydropyrrolo[2,3-b]indole Alkaloids
1
dryness. The residue was chromatographed with hexane-AcOEt
less oil; IR 3601, 1682, 1595 cm-1; H NMR δ 6.88 (d, 1H, J )
(20:1) to afford 15 (980 mg, 85%) as a colorless oil: IR 2154 cm-1
;
7.8 Hz), 6.82 (dd, 1H, J ) 7.8, 1.6 Hz), 6.62 (d, 1H, J ) 1.6 Hz),
5.22 (t, 1H, J ) 6.7 Hz), 5.06 (d, 1H, J ) 9.4 Hz), 4.97 (s, 1H),
4.35 (d, 1H, J ) 9.4 Hz), 3.95 (dd, 1H, J ) 15.6, 6.6 Hz), 3.88
(dd, 1H, J ) 15.6, 6.8 Hz), 2.86-2.83 (m, 4H), 2.53 (d, 1H, J )
17.3 Hz), 1.74-1.73 (m, 9H), 1.54 (s, 3H); 13C NMR δ 172.6,
151.6, 139.8, 136.0, 131.0, 125.6, 122.8, 122.0, 120.3, 112.0, 85.3,
70.8, 54.2, 47.0, 38.3, 27.8, 26.0, 25.7, 18.6, 18.1; MS m/z 418
(M+, 95.5); HRMS calcd for C21H27BrN2O2 418.1256, found
418.1252.
(3R*,8aS*)-3a-(1-Acetoxy-3-methyl-2-butenyl)-6-bromo-8-(3-
methyl-2-butenyl)-1-methyl-3,3a,8,8a-tetrahydropyrrolo[2,3-b]-
indol-2-one (20). To a solution of 19 (20.0 mg, 0.0477 mmol),
pyridine (0.07 mL, 0.2 mmol), and DMAP (0.6 mg, 5 × 10-3mmol)
in CH2Cl2 (1.0 mL) was added Ac2O (7.3 mg, 0.072 mmol) at room
temperature. The reaction mixture was stirred for 20 min, quenched
by addition of water, and extracted with CH2Cl2. The extract was
washed with 5% aqueous HCl and brine, dried, and concentrated
to dryness. The residue was chromatographed with hexane-AcOEt
(1:1) to afford 20 (16.6 mg, 75%) as a mixture of two diastereo-
isomers (10:1) due to the stereogenic center of the allyl alcohol
moiety: the major isomer of 20: colorless oil; IR 1732, 1686, 1597
cm-1; 1H NMR δ 6.88 (d, 1H, J ) 7.8 Hz), 6.83 (dd, 1H, J ) 7.8,
1.6 Hz), 6.63 (d, 1H, J ) 1.6 Hz), 5.54 (d, 1H, J ) 10.0 Hz), 5.21
(tt, 1H, J ) 6.8, 1.4 Hz), 4.94 (dt, 1H, J ) 10.0, 1.4 Hz), 4.79 (s,
1H), 3.96 (dd, 1H, J ) 15.7, 6.5 Hz), 3.87 (dd, 1H, J ) 15.7, 6.8
Hz), 2.86 (s, 3H), 2.80 (d, 1H, J ) 17.1 Hz), 2.58 (d, 1H, J ) 17.1
Hz), 1.97 (s, 3H), 1.75-1.73 (m, 9H), 1.59 (d, 3H, J ) 1.2 Hz);
13C NMR δ 172.0, 169.6, 151.4, 141.8, 136.3, 130.4, 125.8, 123.0,
121.7, 119.9, 118.2, 112.2, 85.2, 72.7, 53.1, 47.0, 38.6, 27.7, 26.0,
25.7, 21.0, 18.7, 18.1; MS m/z 460 (M+, 100); HRMS calcd for
C23H29BrN2O3 460.1362, found 460.1363.
1H NMR δ 7.27 (d, 1H, J ) 8.3 Hz), 7.18 (d, 1H, J ) 1.9 Hz),
7.14 (dd, 1H, J ) 8.3, 1.9 Hz), 3.17 (s, 3H), 0.27 (s, 9H); 13C
NMR δ 143.0, 134.8, 132.4, 127.1, 126.9, 122.9, 117.5, 101.7,
101.0, 32.3, -0.02; MS m/z 306 (M+, 29.9); HRMS calcd for
C13H15BrN2Si 306.0188, found 306.0181.
6-Bromo-1-methyl-3-(trimethylsilyl)pyrrolo[2,3-b]indol-2-
one (16). According to the standard ring-closing procedure, 15 (305
mg, 0.993 mmol) was treated with Co2(CO)8 (102 mg, 0.298 mmol)
and TMTU (39.3 mg, 0.298 mmol) under a CO atmosphere to afford
16 (238 mg, 72%) as purple needles: mp 130-131 °C (hexane);
1
IR 1740, 1649, 1591 cm-1; H NMR δ 7.23 (d, 1H, J ) 1.7 Hz),
7.20 (d, 1H, J ) 7.8 Hz), 7.04 (dd, 1H, J ) 7.8, 1.7 Hz), 3.10 (s,
3H), 0.37 (s, 9H); 13C NMR δ 177.2, 173.1, 163.7, 153.6, 134.6,
127.5, 127.1, 126.6, 124.1, 123.5, 25.5, -1.0; MS m/z 334 (M+,
44.3). Anal. Calcd for C14H15BrN2OSi: C, 50.15; H, 4.51; N, 8.36.
Found: C, 50.00; H, 4.50; N, 8.29.
(3R*,3aS*,8aS*)-6-Bromo-3a-(1-hydroxy-3-methyl-2-butenyl)-
1-methyl-3-(trimethylsilyl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]in-
dol-2-one (17) and (3R*,3aS*,8aS*)-6-Bromo-3a-(1-hydroxy-
3-methyl-2-butenyl)-1-methyl-8-(3-methyl-2-butenyl)-3-(tri-
methylsilyl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-2-one (18).
To a solution of 16 (33.5 mg, 0.100 mmol), 3-methyl-2-butenal
(0.168 mL, 2.00 mmol), and AcOH (0.10 mL, 1.5 mmol) in MeCN
(0.5 mL) was added NaCNBH3 (62.8 mg, 1.00 mmol) at 0 °C. The
reaction mixture was stirred for 10 min, quenched by addition of
saturated aqueous NaHCO3, and extracted with AcOEt. The extract
was washed with water and brine, dried, and concentrated to
dryness. The residue was chromatographed with hexane-AcOEt
(2:1 to 1:3) to afford 17 (20.6 mg, 50%) and 18 (11.0 mg, 25%).
Both 17 and 18 were obtained as a mixture of two diastereoisomers
(10:1) due to the stereogenic center of allyl alcohol moiety. The
major isomer of 17: colorless needles; mp 238-239 °C (hexane-
(3aR*,8aS*)-3a,8-Bis(3-methyl-2-butenyl)-1-methyl-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indol-2-one (22) (Debromoflustramide
B). A solution of lithium di-tert-butylbiphenylide (LiDBB) in THF
was prepared as follows: Lithium (10.0 mg, 1.42 mmol) was added
to a solution of p,p′-di-tert-butylbiphenyl (310 mg, 1.19 mmol) in
THF (7 mL) at room temperature. The mixture was vigorously
stirred at room temperature until dark green radical anion was
developed, at which time the reaction mixture was cooled in an
ice bath. After being stirred at 0 °C for 3 h, a solution of LiDBB
in THF, thus prepared, was added to a solution of 20 (7.5 mg, 0.016
mmol) in THF (2 mL) at -78 °C until the reaction mixture turned
deep green. The reaction mixture was stirred for 10 min, quenched
by addition of water, and extracted with AcOEt. The extract was
washed with water and brine, dried, and concentrated to dryness.
The residue was chromatographed with hexane-AcOEt (2:1) to
1
AcOEt); IR 3605, 3404, 1664 cm-1; H NMR δ 7.13 (d, 1H, J )
7.8 Hz), 6.88 (d, 1H, J ) 7.8 Hz), 6.74 (s, 1H), 5.24 (d, 1H, J )
4.2 Hz), 5.07 (d, 1H, J ) 9.3 Hz), 4.54-4.51 (m, 2H), 2.91 (s,
3H), 2.28 (s, 1H), 1.74 (d, 6H, J ) 10.0 Hz), -0.06 (s, 9H); 13C
NMR δ 175.6, 152.3, 140.3, 127.7, 127.5, 122.7, 121.6, 121.5,
112.9, 81.3, 72.5, 57.6, 41.9, 28.1, 26.2, 18.7, -0.7; MS m/z 422
(M+, 12.1); HRMS calcd for C19H27BrN2O2Si 422.1025, found
422.1025. The major isomer of 18: colorless oil; IR 3609, 3404,
1
1663, 1595 cm-1; H NMR δ 7.06 (d, 1H, J ) 7.8 Hz), 6.79 (dd,
1H, J ) 7.8, 1.6 Hz), 6.51 (d, 1H, J ) 1.6 Hz), 5.08 (t, 1H, J )
6.1 Hz), 5.03 (d, 1H, J ) 9.3 Hz), 4.95 (s, 1H), 4.47 (d, 1H, J )
9.3 Hz), 3.85 (d, 2H, J ) 6.1 Hz), 2.98 (s, 3H), 2.27 (s, 1H), 1.74-
1.71 (m, 12H), -0.10 (s, 9H); 13C NMR δ 176.9, 153.6, 139.7,
135.7, 127.4, 127.2, 123.0, 121.8, 119.9, 119.5, 110.4, 86.8, 72.4,
56.9, 46.3, 42.0, 29.7, 26.1, 25.7, 18.7, 18.1, -0.7; MS m/z 490
(M+, 75.6); HRMS calcd for C24H35BrN2O2Si 490.1651, found
490.1653.
afford 22 (2.1 mg, 40%) as a colorless oil: IR 1678, 1605 cm-1
;
1H NMR (DMSO-d6) δ 7.07-7.03 (m, 2H), 6.66 (t, 1H, J ) 7.3
Hz), 6.51 (d, 1H, J ) 7.8 Hz), 5.18 (t, 1H, J ) 6.6 Hz), 4.96 (t,
1H, J ) 7.3 Hz), 4.78 (s, 1H), 4.02 (dd, 1H, J ) 15.7, 6.6 Hz),
3.88 (dd, 1H, J ) 15.7, 6.6 Hz), 2.73 (s, 3H), 2.56 (d, 1H, J )
16.9 Hz), 2.46 (d, 1H, J ) 16.9 Hz), 2.36 (dd, 1H, J ) 14.4, 8.1
Hz), 2.29 (dd, 1H, J ) 14.4, 6.3 Hz), 1.69 (d, 6H, J ) 11.5 Hz),
1.63 (s, 3H), 1.50 (s, 3H); 13C NMR (DMSO-d6) δ 171.1, 149.0,
135.3, 134.5, 134.4, 128.4, 123.3, 121.1, 119.1, 118.4, 108.6, 86.3,
49.4, 46.0, 41.4, 36.9, 27.3, 25.7, 25.5, 17.88, 17.86; MS m/z
324 (M+, 47.6); HRMS calcd for C21H28N2O 324.2202, found
324.2205.
Conversion of 17 into 18. Prenyl bromide (46.9 mg, 0.315
mmol) was added to a suspension of 17 (40.0 mg, 0.0945 mmol)
and K2CO3 (72.5 mg, 0.525 mmol) in acetone (3.0 mL) at room
temperature. The reaction mixture was refluxed for 6 h, quenched
by addition of water. Acetone was evaporated off, and the residue
was extracted with AcOEt. The extract was washed with water and
brine, dried, and concentrated to dryness. The residue was chro-
matographed with hexane-AcOEt (2:1) to afford 18 (31.6 mg,
68%).
(3aR*,8aS*)-6-Bromo-3a-(1-hydroxy-3-methyl-2-butenyl)-1-
methyl-8-(3-methyl-2-butenyl)-3,3a,8,8a-tetrahydropyrrolo[2,3-
b]indol-2-one (19). To a solution of 18 (29.1 mg, 0.0592 mmol)
in THF (1.0 mL) was added TBAF (1.0 M solution in THF,
0.09 mL, 0.09 mmol) at room temperature. The reaction mixture
was stirred for 10 min, concentrated to dryness, and chromato-
graphed with hexane-AcOEt (1:2) to afford 19 (20.0 mg, 81%)
as a mixture of two diastereoisomer (10:1) due to the stereogenic
center of the allyl alcohol moiety: the major isomer of 19: color-
Reaction of Pyrrolo[2,3-b]indol-2-ones with Alkyl Halides in
the Presence of NaBH4. NaBH4 (0.200 mmol) was added to a
solution of pyrrolo[2,3-b]indol-2-ones, 7d, 7j, and 16 (0.100 mmol)
and alkyl halide (0.500 mmol) in MeCN (1.0 mL) at 0 °C. The
reaction mixture was stirred at 0 °C until complete disappearance
of the starting material (monitored by TLC). The reaction mixture
was quenched by addition of saturated aqueous NaHCO3, and
extracted with AcOEt, then the extract was washed with water and
brine, dried, and concentrated to dryness. The residue was chro-
matographed with hexane-AcOEt to afford the C3a-alkylated
J. Org. Chem, Vol. 72, No. 18, 2007 6883

Aburano et al.
products 24, 25, and 26, respectively. Chemical yields are sum-
marized in Table 3 and Scheme 4.
4.94 (d, 1H, J ) 7.7 Hz), 4.53 (d, 1H, J ) 3.8 Hz), 2.88 (s, 3H),
2.47 (d, 2H, J ) 8.1 Hz), 2.12 (s, 1H), 1.67 (s, 3H), 1.59 (s, 3H),
-0.06 (s, 9H); 13C NMR δ 175.9, 151.3, 135.8, 130.3, 127.1, 122.0,
121.4, 118.4, 112.7, 83.9, 53.1, 45.5, 39.3, 28.1, 26.0, 18.2, -0.7;
MS m/z 406 (M+, 18.8). Anal. Calcd for C19H27BrN2OSi: C, 56.01;
H, 6.68; N, 6.88. Found: C, 55.75; H, 6.65; N, 6.84.
(3R*,3aR*,8aR*)-3a-Benzyl-1-methyl-3-(trimethylsilyl)-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-2-one (24a): colorless
plates: mp 215-216 °C (hexane-AcOEt); IR 3398, 1663, 1609
1
cm-1; H NMR δ 7.34-7.27 (m, 4H), 7.15 (t, 1H, J ) 7.4 Hz),
7.08-7.07 (m, 2H), 6.88 (t, 1H, J ) 7.3 Hz), 6.60 (t, 1H, J ) 7.8
Hz), 5.16 (s, 1H), 4.31 (s, 1H), 3.32 (d, 1H, J ) 13.9 Hz), 3.05 (d,
1H, J ) 13.9 Hz), 2.81 (s, 3H), 2.37 (s, 1H), 0.06 (s, 9H); 13C
NMR δ 175.5, 149.7, 136.5, 131.0, 130.2, 128.8, 128.2, 126.8,
126.3, 118.9, 110.3, 82.4, 54.9, 46.4, 45.7, 27.7, -0.5; MS m/z
350 (M+, 52.5). Anal. Calcd for C21H26N2OSi: C, 71.96; H, 7.48;
N, 7.99. Found: C, 71.75; H, 7.52; N, 7.97.
(3aR*,8aR*)-6-Bromo-3,3a-bis(3-methyl-2-butenyl)-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indol-2-one (21) (Flustramide B). NaBH4
(7.3 mg, 0.20 mmol) was added to a solution of 16 (33.5 mg, 0.100
mmol) and prenyl bromide (149 mg, 1.00 mmol) in MeCN (1.0
mL) at 0 °C. After the solution was stirred for 30 min, TBAF (1.0
M solution in THF, 0.60 mL, 0.60 mmol) was added to the reaction
mixture and stirring was continued for 10 min at room temperature.
TBAI (11.1 mg, 0.0300 mmol) was then added to the reaction
mixture and the mixture was refluxed for 4 h. The reaction mixture
was quenched by addition of water and extracted with AcOEt, and
the extract was washed with water and brine, dried, and concentrated
to dryness. The residue was chromatographed with hexane-AcOEt
(1:1) to afford 21 (30.6 mg, 75%) as a colorless oil: IR 1682, 1597
(3R*,3aR*,8aR*)-1-Methyl-3-(trimethylsilyl)-3a-(2-propenyl)-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-2-one (24b): colorless
1
oil: IR 3400, 2399, 1663 cm-1; H NMR δ 7.12-7.07 (m, 2H),
6.75 (t, 1H, J ) 7.4 Hz), 6.59 (d, 1H, J ) 7.8 Hz), 5.64-5.58 (m,
1H), 5.13-5.06 (m, 3H), 4.44 (s, 1H), 2.89 (s, 3H), 2.62 (dd, 1H,
J ) 14.0, 6.3 Hz), 2.53 (dd, 1H, J )14.0, 8.1 Hz), 2.14 (s, 1H),
-0.08 (s, 9H); 13C NMR δ 175.9, 149.9, 133.0, 130.8, 128.7, 126.0,
119.2, 118.8, 109.9, 83.6, 53.0, 45.6, 45.5, 28.0, -0.7; MS m/z
300 (M+, 62.9); HRMS calcd for C17H24N2OSi 300.1658, found
300.1646.
1
cm-1; H NMR δ 6.85-6.84 (m, 2H), 6.60 (s, 1H), 5.19 (t, 1H, J
) 6.7 Hz), 4.96 (dd, 1H, J ) 8.1, 6.6 Hz), 4.73 (s, 1H), 3.96 (dd,
1H, J ) 15.9, 6.1 Hz), 3.89 (dd, 1H, J ) 15.9, 7.1 Hz), 2.87 (s,
3H), 2.64 (s, 2H), 2.37 (dd, 1H, J ) 14.6, 8.1 Hz), 2.31 (dd, 1H,
J ) 14.6, 6.6 Hz), 1.76-1.70 (m, 9H), 1.56 (s, 3H); 13C NMR δ
172.8, 150.5, 136.00, 135.96, 134.3, 124.3, 122.2, 121.5, 120.1,
118.2, 111.6, 87.4, 49.5, 46.5, 41.7, 37.4, 27.9, 25.9, 25.7, 18.08,
18.07; MS m/z 402 (M+, 13.5); HRMS calcd for C21H27BrN2O
402.1307, found 402.1311.
(3aR*,8aR*)-6-Bromo-1-methyl-3a-(3-methyl-2-butenyl)-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-2-one (31). To a solution
of 30 (37.6 mg, 0.0923 mmol) in THF (1.0 mL) was added TBAF
(1.0 M solution in THF, 0.11 mL, 0.11 mmol) at room temperature.
The reaction mixture was stirred for 10 min, quenched by addition
of water, and extracted with AcOEt. The extract was washed with
water and brine, dried, and concentrated to dryness. The residue
was chromatographed with hexane-AcOEt (1:2) to afford 31 (26.4
mg, 85%) as colorless needles: mp 170-171 °C (Et2O); IR 3433,
1684, 1601 cm-1; 1H NMR (DMSO-d6) δ 7.02-7.01 (m, 2H), 6.74
(dd, 1H, J ) 7.9, 1.6 Hz), 6.65 (d, 1H, J ) 1.5 Hz), 5.06 (t, 1H,
J ) 7.1 Hz), 4.92 (d, 1H, J ) 1.5 Hz), 2.66 (s, 3H), 2.56 (d, 1H,
J ) 16.8 Hz), 2.45 (d, 1H, J ) 16.8 Hz), 2.36-2.27 (m, 2H), 1.64
(s, 3H), 1.48 (s, 3H); 13C NMR (DMSO-d6) δ 171.3, 150.4, 134.4,
133.7, 125.2, 120.9, 120.1, 118.9, 111.3, 81.2, 49.6, 41.1, 35.8,
26.2, 25.7, 17.8; MS m/z 334 (M+, 51.0). Anal. Calcd for
C16H19BrN2O: C, 57.32; H, 5.71; N, 8.36. Found: C, 57.15, H,
5.79, N, 8.27.
(3R*,3aR*,8aR*)-1-Methyl-3-(trimethylsilyl)-3a-(2-propynyl)-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-2-one (24c): colorless oil;
IR 3398, 3308, 1664, 1609 cm-1; 1H NMR δ 7.27-7.25 (m, 1H),
7.11 (td, 1H, J ) 7.6, 1.2 Hz), 6.76 (td, 1H, J ) 7.5, 0.9 Hz), 6.61
(d, 1H, J ) 7.8 Hz), 5.14 (d, 1H, J ) 2.9 Hz), 4.50 (s, 1H), 2.92
(s, 3H), 2.70 (dd, 1H, J ) 16.8, 2.7 Hz), 2.63 (dd, 1H, J ) 16.8,
2.7 Hz), 2.38 (s, 1H), 2.01 (t, 1H, J ) 2.7 Hz), -0.04 (s, 9H); 13
C
NMR δ 175.6, 149.5, 130.2, 129.1, 125.9, 118.9, 110.0, 84.3, 80.0,
71.2, 52.5, 44.2, 31.1, 27.9, -0.8; MS m/z 298 (M+, 98.2); HRMS
calcd for C17H22N2OSi 298.1502, found 298.1499.
(3R*,3aR*,8aR*)-1-Methyl-3a-(3-methyl-2-butenyl)-3-(tri-
methylsilyl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-2-one (24d):
colorless plates: mp 92-93 °C (hexane); IR 3398, 1661, 1609
1
cm-1; H NMR δ 7.12-7.06 (m, 2H), 6.76-6.73 (m, 1H), 6.58
(d, 1H, J ) 7.8 Hz), 5.00-4.98 (m, 2H), 4.42 (s, 1H), 2.90 (s,
3H), 2.55-2.47 (m, 2H), 2.14 (s, 1H), 1.66 (s, 3H), 1.60 (s, 3H),
-0.08 (s, 9H); 13C NMR δ 176.1, 149.9, 135.4, 131.2, 128.5, 125.9,
118.71, 118.68, 109.8, 83.8, 53.6, 45.6, 39.4, 28.0, 25.9, 18.2, -0.7;
MS m/z 328 (M+, 65.5). Anal. Calcd for C19H28N2OSi: C, 69.46;
H, 8.59; N, 8.53. Found: C, 69.17; H, 8.65; N, 8.54.
(3R*,3aR*,8aR*)-3a-(2-Methoxycarbonylethyl)-1-methyl-3-
(trimethylsilyl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-2-one
(24e): colorless oil: IR 3400, 1732, 1664 cm-1; 1H NMR δ 7.10-
7.07 (m, 2H), 6.76 (t, 1H, J ) 7.4 Hz), 6.59 (d, 1H, J ) 8.1 Hz),
5.05 (s, 1H), 4.44 (s, 1H), 3.63 (s, 3H), 2.90 (s, 3H), 2.31-2.24
(m, 2H), 2.19-2.11 (m, 2H), 2.08 (s, 1H), -0.08 (s, 9H); 13C NMR
δ 175.6, 173.4, 149.8, 129.6, 129.0, 126.0, 119.0, 109.9, 83.4, 53.1,
51.8, 46.0, 35.7, 29.3, 27.9, -0.7; MS m/z 346 (M+, 100); HRMS
calcd for C18H26N2O3Si 346.1713, found 346.1715.
Acknowledgment. This work was supported in part by a
Grant-in Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan, for
which we are thankful.
Supporting Information Available: 1H NMR spectra for
(3R*,3aR*,8aR*)-6-Bromo-1-methyl-3a-(3-methyl-2-butenyl)-
3-(trimethylsilyl)-3,3a,8,8-tetrahydropyrrolo[2,3-b]indol-2-one
(30). According to the C3a-alkylation procedure, 30 (56.4 mg, 69%)
was obtained from 16 (67.0 mg, 0.200 mmol), prenyl bromide (149
mg, 1.00 mmol), and NaBH4 (15.2 mg, 0.400 mmol) as colorless
plates: mp 160-161 °C (hexane-AcOEt); IR 3462, 3321, 1663,
1
compounds 9′, 16, 24a,d, 25, 30, 31, and 34, H and 13C NMR
spectra for compounds 11, 13-15, 17-22, 24b,c,e, 26, 27, and
35, characterization data for compounds 25 and 26, and preparation
and characterization data for compounds 9′, 11, 21, 30, 31, 34,
and 35. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
1601 cm-1; H NMR δ 6.94 (d, 1H, J ) 8.0 Hz), 6.86 (dd, 1H, J
) 8.0, 1.6 Hz), 6.71 (d, 1H, J ) 1.6 Hz), 4.99 (d, 1H, J ) 3.8 Hz),
JO071137B
6884 J. Org. Chem., Vol. 72, No. 18, 2007