Stereoselective formation of carbon-carbon bonds via SN2- displacement: Synthesis of substituted cycloalkyl[b]indoles

Article abstract of DOI:10.1021/jo051146p

A general asymmetric synthesis of substituted cycloalkyl[b]indoles has been accomplished. The key features of this approach are (1) the utilization of a Japp-Klingemann condensation/Fischer cyclization to prepare cycloalkyl[b] indolones, (2) the asymmetric borane reduction of these heterocyclic ketones with (S)-OAB to obtain enantiomerically pure alcohols, and (3) the stereoselective S_N2-displacement of these indole alcohol substrates with a carbon nucleophile under Mitsunobu conditions to set the C₁ or C₃ tertiary carbon stereocenter. The use of trimethylphosphine (PMe₃) and bis(2,2,2-trichloroethyl) azodicarboxylate (TCEAD) was found to have an effect on the Mitsunobu dehydrative alkylation.

Full text of DOI:10.1021/jo051146p

Stereoselective Formation of Carbon-Carbon Bonds via
SN2-Displacement: Synthesis of Substituted Cycloalkyl[b]indoles
Michael C. Hillier,* Jean-Franc¸ois Marcoux, Dalian Zhao, Edward J. J. Grabowski,
Arlene E. McKeown, and Richard D. Tillyer
Department of Process Research, Merck and Company, P.O. Box 2000, Rahway, New Jersey 07065
michael_hillier@merck.com
Received June 7, 2005
A general asymmetric synthesis of substituted cycloalkyl[b]indoles has been accomplished. The
key features of this approach are (1) the utilization of a Japp-Klingemann condensation/Fischer
cyclization to prepare cycloalkyl[b]indolones, (2) the asymmetric borane reduction of these
heterocyclic ketones with (S)-OAB to obtain enantiomerically pure alcohols, and (3) the stereose-
lective SN2-displacement of these indole alcohol substrates with a carbon nucleophile under
Mitsunobu conditions to set the C1 or C3 tertiary carbon stereocenter. The use of trimethylphosphine
(PMe3) and bis(2,2,2-trichloroethyl) azodicarboxylate (TCEAD) was found to have an effect on the
Mitsunobu dehydrative alkylation.
Introduction
Structurally, cycloalkyl[b]indoles containing prochiral
substituents on the alkane ring represent a class of
molecules not often found in the literature. Despite this
relative rarity, these compounds are of interest due to
the wide range of biological activity that they exhibit.1
For example, chiral cycloalkyl[b]indoles similar to 1
(Figure 1) that contain an acetic acid appendage at the
C1 or C3 position have been found to be effective antago-
nists of the prostaglandin D2 receptor.2 The interaction
of this receptor with its natural substrate, prostaglandin
D2 (PGD2), results in inflammation of the nasal vascu-
lature and congestion.3 This condition is commonly
referred to as seasonal allergic rhinitis and affects
millions of people annually.4 Consequently, since com-
pounds of the general structure 15 can inhibit the
FIGURE 1. Retrosynthesis of C1- and C3-substituted cy-
cloalkyl[b]indoles.
interaction of the DP-receptor with PGD2, they may
represent a possible treatment for the general allergic
response.
(1) (a) Asselin, A. A.; Humber, L. G.; Komlossy, J. J. Med. Chem.
1976, 19, 792-797. (b) Asselin, A. A.; Humber, L. G.; Dobson, T. A.
U.S. Patent 4,057,599, 1977. (c) Failli, A. A.; Steffan, R. J.; Kreft, A.
F.; Caggiano, T. J.; Caufield, C. E. U.S. Patent 5 830 911, 1998. (d)
Kong, Y. C.; Ng, K. H.; Wat, K. H.; Wong, A.; Saxena, I. F.; Cheng, K.
F.; But, P. P. H.; Chang, H. T. Planta Med. 1985, 50, 304-307. (e)
Cheng, K. F.; Cheung, M, K.; Kong, Y, C. Aust. J. Chem. 1997, 50,
349-353. (f) Dionne, G.; Asselin, A. A.; Humber, L. G. U.S. Patent
4,235,903, 1098.
(5) (a) Guindon, Y.; Yoakim, C.; Gillard, J. W.; Girard, Y. Eur. Patent
0 300 676, 1984. (b) Labelle, M.; Sturino, C.; Roy, B. WO Patent 01/
79169 A2, 2001. (c) Labelle, M.; Sturino, C.; Roy, B.; Berthelette, C.;
Boyd, M.; Lachance, N.; Scheigetz, J. WO Patent 02/008186 A2, 2002.
(d) Berthelette, C.; Lachance, N.; Li, L.; Sturino, C.; Zhaoyin, W. WO
Patent 03/062200 A2, 2003. (e) Li, L.; Beaulieu, C.; Guay, D.; Sturino,
C.; Wang, Z. WO Patent 04/103970 A1, 2004. (f) Lachance, N.; Sturino,
C. WO Patent 04/111047 A2, 2004. (g) Berthelette, C.; Boyd, M. J.;
Lachance, N.; Roy, B.; Sturino, C. F.; Scheigetz, J.; Zamboni, R. J. J.
Labelled Compd. Radiopharm. 2004, 47, 107-113.
(2) Breyer, R. M.; Bagdassarian, C. K.; Myers, S. A.; Breyer, D.
Annu. Rev. Pharmacol. Toxicol. 2001, 41, 661-690.
(3) Anonymous, Expert Opin. Ther. Patents 2002, 12, 597-599.
(4) (a) McMenamin, P. Ann. Allergy 1994, 73, 35-39. (b) Tang, R.
B.; Tsai, L. C.; Hwang, H. M.; Hwang, B.; Wu, K G.; Hung, M. W.
Clin. Exp. Allergy 1990, 20, 33-38.
10.1021/jo051146p CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/20/2005
J. Org. Chem. 2005, 70, 8385-8394
8385

Hillier et al.
TABLE 1. Japp-Klingemann Condensation
SCHEME 1. Fischer Cyclization of 7a
entry aniline
X
Y
ester
n
product yield, %
1
2
3
4
5
6
5a
5b
5b
5c
5d
5e
F
Br
H
H
H
F
6a
6a
6b
6b
6b
6b
1
1
2
2
2
2
7a
7b
7c
7d
7e
7f
>95
>95
92
>95
90
72
H
H
carboxylic acid of ethyl 2-oxocyclopentane carboxylate 6a
(n ) 1) following a literature protocol.10 In our hands the
desired hydrazone 7a was isolated along with the ring-
opened 8 and triazene 9 impurities, which were not easily
removed from the product mixture. According to Linstead
and co-workers11 the open-chain species 8 results from
condensation of 6a with the diazonium salt of 5a followed
by in situ hydrolysis. This side reaction could be avoided
by careful monitoring of the ester saponification until
>98% conversion or by removal of excess 6a by extrac-
tion. The triazene adduct 9 arises from condensation of
the unreacted aniline 5a with the forming diazonium
species.12 This could be partially avoided by rapid addi-
tion of NaNO2 to a cooled slurry of the HCl salt of 5a;
however, the internal reaction temperature needed to be
kept below 10 °C to avoid decomposition via loss of
nitrogen. An alternative solution was to remove the
water-insoluble triazene by filtration of the diazonium
salt solution prior to reaction with the carboxylic acid of
6a. Using these modifications the corresponding keto-
hydrazone 7a was isolated in 95% yield as a free flowing
solid after filtration and drying.13 This same methodology
was utilized for the construction of other aryl-substituted
hydrazones to give products 7b-f in good to excellent
yield (72-95%) as stable crystalline solids (Table 1).14
None of these materials required purification and could
be isolated directly from the aqueous reaction mixture
by simple filtration.
Optimization of the Fischer cyclization was carried out
on 7a under acidic conditions in order to construct the
cycloalkyl[b]indolone core system (Scheme 1). Reaction
of this substrate in the presence of excess Eaton’s reagent
(P2O5, MsOH) at room temperature gave the diamine 11,
which could not be converted to the desired product 10a,
even upon heating. When this reaction was repeated and
7a was added to a heated solution of Eaton’s reagent (60
°C), an intense exotherm (ca. 260 °C) was observed and
very little product recovered (ca. <5%). Alternatively,
when the reaction was repeated in acetonitrile (ACN) at
65 °C using 0.9 M H2SO4 in water (1.5 equiv) as the acid
promoter, some of the ketone 10a (40%) was isolated
F
F
OMe
H
In these laboratories various racemic approaches to
this class of heterocyclic compounds (1) have been
formulated which rely upon chiral resolution5,6 to obtain
optically pure material. Alternatively the enantioselective
synthesis of two related derivatives has also been
achieved.7 Toward the development of a more general
asymmetric route to these molecules, we became inter-
ested in utilizing an SN2-type displacement of a chiral
alcohol 3 with an enolate equivalent to set the carbon
stereocenter of 2. Similar methodology has been demon-
strated in a stepwise fashion for the stereoselective
formation of carbon-carbon bonds in a few cases.8
Recently, a one-pot dehydrative alkylation of a variety
of chiral benzylic alcohols was developed using triethyl
methanetricarboxylate (TEMT) as the nucleophile under
Mitsunobu-type conditions.9 We envisioned that this
methodology would be useful for the synthesis of 2 and
that the triester moiety could be converted to the acid 1
after saponification and decarboxylation. Fischer cycliza-
tion of the corresponding keto-hydrazone would provide
the cycloalkyl[b]indolone (4), which after asymmetric
reduction would give the chiral indole alcohol 3. In this
paper we detail the asymmetric synthesis of the general
structure 1 via this approach.
Results and Discussion
Japp-Klingemann Condensation and Fischer
Cyclization. Construction of the cycloalkyl[b]indolone
core began with the preparation of a keto-hydrazone
precursor using the Japp-Klingemann reaction (Table
1). In initial experiments we examined the condensation
of the diazonium salt of 5a (X ) F, Y ) Br) and the
(6) Shafiee, A.; Upadhyay, V.; Corley, E. G.; Biba, M.; Zhao, D.;
Marcoux, J.-F.; Campos, K. R.; Journet, M.; King, A. O.; Larsen, R.
D.; Grabowski, E. J. J.; Volante, R. P.; Tillyer, R. D. Tetrahedron:
Asymmetry, in press.
(7) (a) Campos, K. R.; Journet, M.; Lee, S.; Grabowski, E. J. J.;
Tillyer, R. D. J. Org. Chem. 2005, 70, 268-274. (b) Evans, D. A.;
Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942-8943.
(8) (a) Ashwell, M. A. WO Patent 94/08983, 1994. (a) Uenishi, J.;
Hamada, M. Chem. Pharm. Bull. 2002, 50, 687-700. (b) Uenishi, J.;
Hamada, M. Synthesis 2002, 625-630. (c) Bolshan, Y.; Chen, C.-y.;
Chilenski, J. R.; Gosselin, F.; Mathre, D. J.; O’Shea, P. D.; Roy, A.;
Tillyer, R. D. Org. Lett. 2004, 6, 111-114. (d) O’Shea, P. D.; Chen,
C.-y.; Chen, W.; Dagneau, P.; Frey, L. F.; Grabowski, E. J. J.;
Marcantonio, K. M.; Reamer, R. A.; Tan, L.; Tillyer, R. D.; Roy, A.;
Wang, X.; Zhao, D. J. Org. Chem. 2005, 70, 3021-3030.
(10) (a) Lions, F. J. Proc. R. Soc. N. S. Wales 1932, 66, 516-525.
(b) Phillips, R. R. Organic Reactions; John Wiley and Sons: New York,
1959; Vol. 10, pp 143-178.
(11) See: Linstead, R. P.; Wang, A. B.-L. J. Chem. Soc. 1937, 807-
814 and references therein.
(12) (a) Hartman, W. W.; Dickey, J. B. Organic Synthesis; Wiley:
New York 1948; Collect Vol. II, pp 163-265. (b) Sˇtefane, B.; Ko_cevar,
M.; Polanc, S. J. Org. Chem. 1997, 62, 7165-7169.
(13) The hydrazone was isolated as an inseparable mixture of
isomers.
(14) The yield of the methoxy-substituted derivative 7d was lower
due to some decomposition that was observed during the reaction.
(9) Hillier, M. C.; Desrosiers, J.-N.; Marcoux, J.-F.; Grabowski, E.
J. J. Org. Lett. 2004, 6, 573-576.
8386 J. Org. Chem., Vol. 70, No. 21, 2005

Synthesis of Substituted Cycloalkyl[b]indoles
TABLE 2. Fischer Cyclization and Benzylation
TABLE 3. Asymmetric Reduction of
Cycloalkyl[b]indolones
13
X
Y
n
yield, %
ee, %
aa
b
c
d
e
f
H
Br
H
H
H
F
1
1
2
2
2
2
98
90
91
96
96
98
97
93
97
93
90
95
H
Fischer cyclization benzylation
H
substrate, 7
n
X
Y
10, yield %
13, yield %
F
F
a
b
c
d
e
f
1
1
2
2
2
2
F
Br
H
H
H
F
84
95
92
89
90
50
84a
87
85
89
90
90
OMe
H
H
H
a Bn ) p-chlorobenzyl.
F
F
OMe
H
in methylene chloride at -20 °C to give the chiral alcohols
14a-f in 90-98% isolated yield and 90-97% enantio-
meric excess (ee) (Table 3). We were gratified to find that
the optical purity of these products could be upgraded to
>99% ee after a single recrystallization from EtOAc/
hexanes. The use of less than stoichiometric amounts of
the (S)-OAB catalyst gave lower yields of product and
poorer enantioselectivity.20 The workup of this reaction
was of some importance as the use of methanol and acid
to quench resulted in significant decomposition via
methanolysis at the carbinol center.21 This was avoided
using a nonacidic workup with isopropyl alcohol as the
proton source. Other methods for the asymmetric reduc-
tion of the ketone were examined, such as asymmetric
hydrogenation22 and Binal-H,23 but these procedures were
found to be inferior to the OAB method. We were able to
obtain an X-ray crystal structure of 14a, which confirms
the absolute sense of stereochemistry obtained in this
reaction (Figure 2).
Mitsunobu Displacement. With the requisite alco-
hols 14a-f in hand, we set about examining the dehy-
drative alkylation of one of these intermediates under
Mitsunobu conditions (Table 4). In initial trials treatment
of a solution of the 5-bromo-7-fluoro-substituted cyclo-
pent[b]indanol 14a, triphenylphosphine (PPh3, 2 equiv),
and triethyl methanetricarboxylate (TEMT, 2 equiv) in
THF at -78 °C with diethyl azodicarboxylate (DEAD, 2
equiv) provided product 16a in 10% yield and 26% ee
after warming to room temperature.24 The use of a
different activator, N,N,N′,N′-tetramethyldiazene-1,2-
dicarboxamide (TMDD), did not improve upon this result.
a Bn ) p-chlorobenzyl.
along with a significant amount of the dimeric species
12 (30%).15 Formation of this dimer could be avoided by
heating the reaction to 80 °C to give 10a in 70% isolated
yield. When the concentration of acid was doubled (1.8
M H2SO4, 3 equiv), the keto-indole 10a was produced
in 84% yield after heating for 1 h at 80 °C.
These conditions were applied to the cyclization 7b-f
to provide the corresponding cycloalkyl[b]indolones 10b-f
in reasonable to excellent yield (Table 2). Cyclization of
the difluoro keto-hydrazone 7e gave the desired product
10e along with some of the desfluoro compound 10d (ca.
5%).16 This byproduct most likely results from SNAr-
displacement of the ortho aryl fluoride during the sig-
matropic rearrangement step of this reaction.17 Only the
methoxy-substituted substrate 7f underwent Fischer
cyclization in poor yield (50%) due to decomposition
during the reaction. However, in all cases the products
could be isolated by simple filtration and did not require
further purification. Benzylation of the indole nitrogen
(Table 2) was carried out under phase-transfer conditions
using tetrabutylammonium bromide (TBABr) as the
transfer catalyst (2 mol %).18 The benzylated keto indole
products 13a-f were isolated in 84-90% yield after
workup and recrystallization from MeOH.
Asymmetric Reduction of the Cycloalkyl[b]indo-
lones. Asymmetric reduction of the cycloalkyl[b]indolone
substrates 13a-f was accomplished using a stoichiomet-
ric amount of (S)-oxazaborolidine (OAB)19 and BH3‚DMS
(20) In general, we found these substrates to be very unreactive
under catalytic OAB reducing conditions.
(21) For example, 14a could be completely converted to racemic 15
upon standing as a solution in MeOH after 24 h.
(15) For similar conditions, see: (a) Fink, D. M.; Palermo, M. G.;
Bores, G. M.; Huger, F. P.; Kurys, B. E.; Merriman, M. C.; Olsen, G.
E.; Petko, W.; O’Malley, G. J. Bioorg. Med. Chem. Lett. 1996, 6, 625-
630. (b) Xing, C.; Wu, P.; Skibo, E. B. J. Med. Chem. 2000, 43, 457-
466. (c) Skibo, E. B.; Xing, C.; Dorr, R. T. J. Med. Chem. 2001, 44,
3545-3562.
(16) The mono-fluoro derivative 10d could be removed by column
chromatography.
(17) (a) Brook, G. M. J. Chem. Soc., Perkin Trans. 1 1983, 4, 821-
825. (b) Benke, F. D.; Brook, G. M. J. Fluorine Chem. 1984, 26, 77-
86.
(18) Protection of the indole nitrogen under non-phase-transfer
conditions led to poor product yield due to decomposition.
(19) (a) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen,
K.; Carroll, J. D.; Corley, E. G.; Grabowski, E. J. J. J. Org. Chem. 1993,
58, 2880-2888. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed.
Engl. 1998, 37, 1986-2012.
(22) For a general review, see: Blaser, H.-U.; Malan, C.; Pugin, B.;
Spindler, F.; Steiner, H.; Studer, M. Adv. Synth. Catal. 2003, 345, 103-
151.
(23) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am.
Chem. Soc. 1984, 106, 6709-6716.
(24) Two equivalents of each reagent with respect to starting
material was required for complete conversion to product for the
Mitsunobu displacement reaction.
J. Org. Chem, Vol. 70, No. 21, 2005 8387

Hillier et al.
TABLE 5. Scope of the Mitsunobu Displacement
Reactiona
triester 16
alcohol 14
n
X
Y
yield, %
ee, %
b
1
H
H
A: nr
B: 90
C: 61
A: 95
B: 95
C: 80
B: 91
C: 84
B: 90
C: 91
B: 92
C: 80
60
65
50
67
75
71
80
82
95
53
67
c
2
H
H
FIGURE 2. X-ray crystal structure of 14a.
d
e
f
2
2
2
F
H
F
TABLE 4. Mitsunobu Displacement of 14a
F
OMe
H
a Conditions: (A) DEAD, THF, -78 °C to room temperature;
(B) DEAD, toluene, 0 °C to room temperature; (C) TCEAD, toluene,
0 °C to room temperature.
yield, ee,
activator PR3 solvent
T, °C
%
%
toluene and the reaction was carried out at 0 °C, 16a
was formed in 84% yield and 85% ee.
DEAD
TMDD
TMDD
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
PPh3 THF
PPh3 THF
PBu3 THF
PBu3 THF
PBu3 toluene -78 to room temperature
PBu3 MTBE -78 to room temperature
PMe3 THF
PMe3 THF
PMe3 THF
PMe3 THF
-78 to room temperature
-78 to room temperature
-78 to room temperature
-78 to room temperature
10
18
45
95
95
81
88
90
92
95
nr
84
26
nd
67
67
66
71
85
86
74
94
Having developed conditions for the Mitsunobu activa-
tion and SN2-displacement of 14a, the other indole alcohol
substrates 14b-f were examined (Table 5). In one case
we were surprised to find that the dehydrative alkylation
of the unsubstituted cyclopent[b]indole derivative 14b did
not proceed at -78 °C with DEAD and PMe3 in THF even
after warming to room temperature (Conditions A). When
this reaction was repeated in toluene at 0 °C (Conditions
B) the desired product 16b was produced in 90% yield
but with significant erosion of optical purity (60% ee). A
similar result was obtained with the methoxy-substituted
alcohol 14f, which underwent displacement with signifi-
cant loss of enantiomeric purity (53% ee) compared to
starting material. On the other hand, when these condi-
tions were applied to the dehydrative alkylation of 14c-
e, the triester products 16c-e were isolated with mod-
erate to good enantiomeric purity (67-82% ee) and in
excellent yield (90-95%). When these reactions were
repeated using bis(2,2,2-trichloroethyl) azodicarboxylate
(TCEAD) as the activator in toluene at 0 °C (Conditions
C), we were gratified to find a general improvement in
the enantiomeric purity of the triester adducts thus
obtained. For example, reaction of the 5,7-difluoro-
substituted substrate 14e gave 16e in 91% yield and 95%
ee using TCEAD as the activator compared to 90% yield
and 82% ee using DEAD. Similar improvements were
seen with all other substrates (Table 5) under these
conditions.
-78 to room temperature
-50
0
-78a
TCEAD PMe3 THF
-78 to room temperature
TCEAD PMe3 toluene 0 to room temperature
85
a DEAD was added over 2.5 h; Bn ) p-chlorobenzyl.
However, when tributylphosphine (PBu3) was used in-
stead of PPh3, 16a could be recovered in 45% yield and
67% ee. The use of DEAD as the activator resulted in a
much improved 95% yield of product but no difference
in optical purity (67% ee).25 Changing solvent to either
toluene or tert-butyl methyl ether (MTBE) did not change
this outcome. A significant discovery came when a less
sterically hindered phosphine, trimethylphosphine (PMe3),
was used instead of PBu3. In this case 16a could be
isolated in good yield (88%) and an improved enantio-
meric purity of 85% ee. No difference was observed when
the reaction was carried out at -50 °C; however, at 0 °C
significant erosion of product optical purity occurred (74%
ee). On the basis of this result, the reaction was repeated
at -78 °C and DEAD over 2.5 h via syringe pump.26 The
resulting solution was aged overnight at -78 °C, and the
triester 16a was isolated in 95% yield and 94% ee after
workup and purification. Another commercially avail-
able activator, bis(2,2,2-trichloroethyl) azodicarboxylate
(TCEAD), was also examined, but no reaction was
observed in THF as solvent, even after warming to room
temperature. However, when THF was replaced by
From the results presented above it is apparent that
a number of factors affect the extent of stereochemical
inversion during the Mitsunobu dehydrative alkylation.
First and foremost, PMe3 is required to ensure good yield
and enantiomeric purity of the displacement product.
This has been observed previously9 and may be due to
an increase in the SN2-reaction pathway leading to
inversion versus nonselective SN1-type alkylation. Clearly,
the nature of the activator is also important since bis-
(2,2,2-trichloroethyl) azodicarboxylate (TCEAD) results
(25) Diisopropylazodicarboxylate (DIAD) could be used instead of
DEAD with little affect on the reaction outcome.
(26) The addition of DEAD is exothermic and can result in a 20 °C
temperature change during uncontrolled reagent addition.
8388 J. Org. Chem., Vol. 70, No. 21, 2005

Synthesis of Substituted Cycloalkyl[b]indoles
and a diminished 59% ee.27 The same procedure was
utilized for the saponification and decarboxylation of 16f,
which gave 17f in 74% overall yield and with no loss in
enantiomeric purity (67% ee). In contrast, when AcOH
was used during the decarboxylation step of this sub-
strate, the product 17f was found to have undergone
significant racemization (50% ee).
TABLE 6. Saponification and Decarboxylation of
16a-fa
In summary, an asymmetric seven-step synthesis of
C1- and C3-substituted cycloalkyl[b]indoles 17a-f has
been developed. The key features of this approach are
(1) efficient preparation of the cycloalkyl[b]indolones
10a-f via Japp-Klingemann condensation and Fischer
cyclization, (2) asymmetric reduction of these intermedi-
ates to provide the chiral alcohol substrates 14a-f in
excellent enantiomeric purity, and (3) stereoselective SN2-
displacement of these derivatives under Mitsunobu-type
conditions with triethyl methanetricarboxylate (TEMT)
as the carbon nucleophile to set the tertiary carbon
stereocenter. The key to the effectiveness of the dehy-
drative alkylation is the use of PMe3, which ensures both
good yield and reasonable enantiomeric purity of product.
Substrates containing electron-withdrawing substituents
(14a,d,e) on the aromatic portion of the indole core
underwent dehydrative alkylation to give product with
less racemization compared to 14b,c,f. The erosion of
enantiomeric purity could be overcome somewhat through
the use of bis(2,2,2-trichloroethyl) azodicarboxylate
(TCEAD), which generally provided product in higher
enantiomeric purity compared to DEAD. We are cur-
rently examining the source of this improvement and the
use of this reagent in other systems.
triester, 16
acid, 17
yield, %
n
X
Y
ee, %
conditions
ee, %
ab
b
c
d
e
f
1
1
2
2
2
2
F
Br
H
H
H
F
94
66
75
80
95
67
A
B
A
A
A
B
86
65
90
79
92
74
94
59
75
80
95
67
H
H
F
F
OMe
H
a Conditions: (A) AcOH, reflux, (B) neutralize then toluene,
reflux. b Bn ) p-chlorobenzyl.
in higher enantiomeric purity of product compared to the
use of DEAD in most cases (e.g., 14b-f). Substrate
structure and electronics also have some influence on the
course of this reaction. For example, the unsubstituted
six-membered hydroxyl cycloalkyl[b]indole 14c undergoes
dehydrative alkylation under optimized conditions with
some loss in enantiomeric purity (75% ee). Compare this
result to the significant amount of racemization obtained
during alkylation of the five-membered ring derivative
14b (65% ee). Substrates containing electron-withdraw-
ing groups on the aromatic portion of the indole core, such
as 14a,d,e, react with moderate to little racemization
under optimized conditions. The opposite result is ob-
served with the relatively electron-rich alcohol 14f, which
undergoes the Mitsunobu displacement to give product
with significant erosion in optical purity (67% ee).
Finally, the effect of reaction solvent depends on the
substrate, but toluene generally ensures good yield and
greater reactivity when TCEAD is used as the activator.
Saponification and Decarboxylation. The final
steps in this synthetic strategy involved conversion of the
triester moiety of 16a-f to the corresponding acetic acid
functionality via a saponification and decarboxylation
sequence (Table 6). For example, the basic hydrolysis of
16a (94% ee) was achieved by refluxing the substrate in
methanol in the presence of excess NaOH to give the tris-
carboxylate. This intermediate was not isolated but was
carried on crude to give the acid 17a in 86% overall yield
and 94% ee after refluxing in AcOH (Conditions A). We
were encouraged to see that the enantiomeric purity of
product had not changed compared to that of starting
material. This same method was used for the saponifica-
tion and decarboxylation of 16c-e to give 17c-e in good
yield (79-92%) with no loss of enantiomeric purity.
Unfortunately, the unsubstituted five-membered ring
derivative 16b was found to be acid sensitive and
decomposed under the acidic decarboxylation conditions.
This substrate required careful neutralization of the
sodium salt intermediate followed by decarboxylation in
refluxing toluene (Conditions B) to give 17b in 65% yield
Experimental Section
General Japp-Klingemann Procedure. Sodium Car-
boxylate Preparation. A three-neck flask was charged with
ethyl 2-oxocyclopentanecarboxylate 6a or ethyl 2-oxocyclohex-
anecarboxylate 6b (1 mol), water (2 L), and 5 N NaOH (1.1
mol), and the resulting solution was stirred for 48 h at room
temperature. This mixture was extracted with MTBE (2 × 400
mL) to remove any residual unreacted starting material, and
the aqueous phase containing the sodium carboxylate was
returned to the original three-neck flask. This solution was
cooled to 0 °C, treated dropwise with concentrated HCl (1.1
mol) over 15 min, and aged at this temperature for 45 min.
Diazonium Salt Preparation. To a mixture of the aniline 5
(1 mol) in water (0.6 L) at room temperature was added
concentrated HCl (3 mol), and the resulting thick white slurry
was cooled to 0 °C. A solution of NaNO2 (1 mol) in water (0.7
L) was added slowly over 25 min, at such a rate as not to
exceed an internal temperature of 10 °C, and the reaction was
aged for 30 min before filtration to remove any insoluble
precipitate.
Japp-Klingemann Reaction. To the pre-prepared sodium
carboxylate solution at 0 °C was added to the filtered diazo-
nium solution dropwise over 40 min at a temperature range
of 0-4 °C. The resulting thick yellow slurry was stirred to room
temperature, filtered, and dried under a stream of nitrogen
to give product 7.
(1E/Z)-Cyclopentane-1,2-dione (2-Bromo-4-fluorophen-
yl)hydrazone (7a). 7a was isolated in 95% yield as a mixture
of hydrazone isomers (4:1) from the aniline 5a and 2-oxocy-
clopentanecarboxylate 6a according to the general Japp-
Klingemann procedure as a yellow solid: mp 182-187 °C; 1H
NMR (CDCl3) δ 12.9 (s, 0.2 H, minor), 8.53 (s, 0.8 H, major),
(27) This substrate (17f) is extremely sensitive and rapidly decom-
poses in the presence of acid.
J. Org. Chem, Vol. 70, No. 21, 2005 8389

Hillier et al.
7.57-7.51 (comp, 1.2 H), 7.44 (dd, J ) 5.6, 9.1 Hz, 0.8 H,
major), 7.26-7.16 (comp, 1 H), 2.71 (t, J ) 7.4 Hz, 1.6 H,
major), 2.68 (t, J ) 7.4 Hz, 0.4 H, minor), 2.47 (t, J ) 7.6 Hz,
0.4 H, minor), 2.36 (t, J ) 7.8 Hz, 1.6 H, major), 2.03-1.96
(comp, 2 H); 13C NMR (DMSO-d6) δ 204.0 (major), 203.0
(minor), 157.4 (d, JCF ) 242.4 Hz, minor), 157.1 (d, JCF ) 242.1
Hz, major), 145.9 (minor), 140.5 (major), 138.4 (d, JCF ) 2.5
Hz, minor), 137.8 (d, JCF ) 2.6 Hz, major), 119.7 (d, JCF ) 25.9
) 3.3, 22.4 Hz, major), 112.0 (dd, JCF ) 3.4, 22.1 Hz, minor),
104.6 (dd, JCF ) 22.3, 27.1 Hz, major), 104.5 (dd, JCF ) 22.3,
27.1 Hz, minor), 40.7 (minor), 40.0 (major), 32.2 (major), 26.7
(minor), 23.1 (major), 22.4 (minor), 22.0 (major), 21.9 (minor);
IR (CDCl3) ν 3084, 2943, 2869, 1639, 1721, 1439, 1287, 1190,
1137, 959, 846, 703 cm-1. Anal. Calcd for C12H12F2N2O
[238.09]: C, 60.50; H, 5.08; N, 11.76. Found: C, 60.41; H, 4.90;
N, 11.67.
(1E/Z)-Cyclohexane-1,2-dione (4-Methoxyphenyl)hy-
drazone (7f). 7f was prepared in 72% yield from the aniline
5e and 2-oxocyclopentanecarboxylate 6b according to the
general Japp-Klingemann procedure. Spectral data matched
that for the known compound.28
Hz, minor), 119.6 (d, JCF ) 25.8 Hz, major), 117.9 (d, JCF
8.1, minor), 116.3 (d, JCF ) 22.4 Hz, major), 116.2 (d, JCF
)
)
22.2 Hz, minor), 114.9 (d, JCF ) 8.2 Hz, major), 109.5 (d, JCF
) 10.1 Hz, minor), 107.2 (d, JCF ) 9.8 Hz, major), 38.5 (major),
37.9 (minor), 29.1 (major), 25.6 (minor), 19.3 (major), 17.3
(minor); IR (CDCl3) ν 3332, 1713, 1560, 1516, 1458, 1184, 1047,
852 cm-1; MS (ESI) calcd for C11H10BrFN2O + H: M + H
(theory), 285.0033; M + H (found), 285.0039.
General Fischer Cyclization Procedure. To a three-neck
round-bottom flask equipped with a mechanical stirrer, a
condenser, and nitrogen inlet was charged the hydrazone 7
(10 mmol) and MeCN (25 mL). A solution of 1.8 M H2SO4 in
water (17 mL, 30 mmol) was added in one portion, and the
resulting mixture was heated under reflux (80 °C) for 5-6 h.
After the reaction was judged complete by HPLC analysis,
water (50 mL) was added and the resultant slurry stirred at
room temperature for 1-2 h before filtration. The collected
product 10 was washed with MeCN:water (1:3, 50 mL) and
water (3 × 50 mL) and dried to give product.
(1E/Z)-Cyclopentane-1,2-dione Phenylhydrazone (7b).
7b was prepared in 95% yield as a mixture of hydrazone
isomers (24:1) from the aniline 5b and 2-oxocyclopentanecar-
boxylate 6a according to the general Japp-Klingemann
procedure as a yellow solid: mp 235-237 °C; 1H NMR (DMSO-
d6) δ 12.65 (s, 0.04 H, minor), 9.89 (s, 0.96 H, major), 7.27-
7.29 (comp, 4 H), 6.90-6.83 (m, 1 H), 2.62 (t, J ) 7.5 Hz, 2 H),
2.41 (t, J ) 7.8 Hz, 0.08 H, minor), 2.29 (t, J ) 7.9 Hz, 1.92 H,
major), 1.97 (t, J ) 7.7 Hz, 1 H), 1.93 (t, J ) 7.7 Hz, 1 H); 13
C
5-Bromo-7-fluoro-1,4-dihydrocyclopenta[b]indol-3(2H)-
one (10a). 10a was isolated in 84% yield from 7a according
to the general Fischer cyclization procedure as a solid: mp
204-206 °C; 1H NMR (DMSO-d6) δ 11.9 (s, 1 H), 7.48 (d, J )
9.0, 2 H), 2.95-2.93 (m, 2 H), 2.86-2.84 (m, 2 H); 13C NMR
NMR (DMSO-d6) δ 202.8, 144.6, 142.2, 129.5, 121.6, 114.3,
37.9, 26.3, 17.4; IR (CDCl3) ν 3256, 1699, 1558, 1525, 1456,
1419, 1228, 1173 cm-1; MS (ESI) calcd for C11H12N2O: M + H
(theory), 189.1022; M + H (found), 189.1020.
(DMSO-d6) δ 194.2, 156.7 (d, JCF ) 238.3 Hz), 145.9 (d, JCF
5.6 Hz), 141.7, 139.5, 124.1 (d, JCF ) 10.5 Hz), 118.1 (d, JCF
)
)
(1E/Z)-Cyclohexane-1,2-dione Phenylhydrazone (7c).
7c was prepared in 92% yield from the aniline 5b and
2-oxocyclohexanecarboxylate 6b according to the general
Japp-Klingemann procedure. Spectral data matched that for
the known compound.28
29.2 Hz), 106.2 (d, JCF ) 12.0 Hz), 105.9 (d, JCF ) 22.8 Hz),
41.0, 20.0; IR (CDCl3) ν 3212, 2953, 1361, 1700, 1682, 1270,
1151, 1089 cm-1. Anal. Calcd for C11H7BrFNO [266.97]: C,
49.28; H, 2.63; N, 5.22. Found: C, 49.22; H, 2.30; N, 5.11.
1,4-Dihydrocyclopenta[b]indol-3(2H)-one (10b). 10b
was prepared in 95% yield as a solid from 7b via the general
Fischer cyclization procedure. Spectral data matched that for
the known compound.29
(1E/Z)-Cyclohexane-1,2-dione (4-Fluorophenyl)hydra-
zone (7d). 7d was prepared in 95% yield as a mixture of
hydrazone isomers (10:1) from the aniline 5c and 2-oxocyclo-
hexanecarboxylate 6b according to the general Japp-Klinge-
1
mann procedure as a yellow solid: mp 235-237 °C; H NMR
2,3,4,9-Tetrahydro-1H-carbazol-1-one (10c). 10c was
prepared in 92% yield as a solid from 7c via the general
Fischer cyclization procedure. Spectral data matched that for
the known compound.28
(DMSO-d6) δ 13.47 (s, 0.1 H, minor), 9.86 (s, 0.9 H, major),
7.31-7.27 (comp, 2 H), 7.14-7.08 (comp, 2 H), 2.60-2.54 (m,
0.2 H, minor), 2.55 (t, J ) 6.2 Hz, 1.8 H, major), 2.47-2.42
(m, 0.2 H, minor), 2.40 (t, J ) 6.2 Hz, 1.8 H, major), 1.90-
1.70 (comp, 4 H); 13C NMR (DMSO-d6) δ 197.5 (minor), 194.6
(major), 157.7 (d, JCF ) 236.9 Hz), 141.4 (d, JCF ) 1.6 Hz),
139.1, 116.4 (minor), 116.2 (minor), 116.1, 116, 115.9, 115.8
(minor), 115.7 (major), 115.6 (minor), 40.7 (minor), 40.0
(major), 32.1 (minor), 26.8 (major), 23.5 (minor), 22.3 (major),
22.0 (minor), 21.8 (major); IR (CDCl3) ν 3248, 2937, 1660, 1529,
1513, 1411, 1327, 1206, 1153, 828, 750 cm-1. Anal. Calcd for
C12H13FN2O [220.10]: C, 65.44; H, 5.95; N, 12.72. Found: C,
64.83; H, 5.92; N, 12.45.
6-Fluoro-2,3,4,9-tetrahydro-1H-carbazol-1-one (10d).
10d was synthesized in 89% from 7d according to the general
1
Fischer cyclization procedure as a solid: mp 154-158 °C; H
NMR (DMSO-d6) δ 11.7 (s, 1 H), 7.42 (dd, J ) 2.5, 9.6 Hz, 1
H), 7.39 (dd, J ) 4.5, 9.0 Hz, 1 H), 7.15 (ddd, 2.5, 9.0, 9.6 Hz,
1 H), 2.89 (app t, J ) 6.1 Hz, 1 H), 2.55 (dd, J ) 6.1, 6.9 Hz,
1 H), 2.13 (ddd, J ) 6.1, 6.1, 12.4 Hz, 1 H); 13C NMR (DMSO-
d6) δ 190.9, 158.3 (d, JCF ) 233.9 Hz), 135.0, 133.0, 128.1 (d,
JCF ) 5.6 Hz), 125.6 (d, JCF ) 10.1 Hz), 115.3 (d, JCF ) 26.9
Hz), 114.5 (d, JCF ) 9.6 Hz), 105.6 (d, JCF ) 22.8 Hz), 38.5,
(1E/Z)-Cyclohexane-1,2-dione (2,4-Difluorophenyl)hy-
drazone (7e). 7e was prepared in 90% yield as a mixture of
hydrazone isomers (4:1) from the aniline 5d and 2-oxocyclo-
hexanecarboxylate 6b according to the general Japp-Klinge-
mann procedure as a yellow solid: mp 47-50 °C; 1H NMR
(DMSO-d6) δ 8.52 (s, 0.8 H, major), 9.15 (s, 0.2 H, minor), 7.50
(app dt, J ) 5.9, 9.2 Hz, 0.8 H, major), 7.44 (app t, J ) 5.9, 9.2
Hz, 0.2 H, minor), 7.24 (ddd, J ) 2.8, 8.8, 11.7 Hz, 0.8 H,
major), 7.20 (ddd, J ) 2.8, 8.8, 11.7 Hz, 0.2 H, minor), 7.02-
6.97 (comp, 1 H), 2.60-2.55 (comp, 2 H), 2.48-2.39 (comp, 2
H), 1.85-1.65 (comp, 4 H); 13C NMR (DMSO-d6) δ 198.7
(major), 195.0 (minor), 157.3 (dd, JCF ) 11.4, 240.9 Hz, major),
157.2 (dd, JCF ) 10.9, 240.3 Hz, minor), 150.9 (dd, JCF ) 12.2,
139.8 Hz, minor), 149.7 (dd, JCF ) 12.5, 244.0 Hz, major), 142.4
(minor), 135.5 (major), 129.9 (dd, JCF ) 3.2, 9.6 Hz, minor),
128.6 (dd, JCF ) 3.2, 9.1 Hz, major), 118.2 (dd, JCF ) 3.5, 9.2
Hz, minor), 115.4 (dd, JCF ) 3.1, 9.0 Hz, major), 112.4 (dd, JCF
24.9, 21.1; IR (CDCl3) ν 3264, 1645, 1540, 1481, 1140, 810 cm-1
.
Anal. Calcd for C12H10FNO [203.07]: C, 70.93; H, 4.96; N, 6.89.
Found: C, 70.64; H, 4.95; N, 6.90.
6,8-Difluoro-2,3,4,9-tetrahydro-1H-carbazol-1-one (10e).
10e was synthesized in 90% yield from 7e according to the
general Fischer cyclization procedure as a solid: mp 224-229
1
°C; H NMR (CDCl3) δ 9.27 (brs, 1 H), 7.10 (dd, J ) 2.1, 8.5
Hz, 1 H), 6.91 (ddd, J ) 2.1, 9.3, 11.1 Hz, 1 H), 2.96 (app t, J
) 6.0 Hz, 1 H), 2.69 (dd, J ) 6.0, 7.0 Hz, 1 H), 2.29 (ddd, J )
6.0, 7.0, 12.6 Hz, 1 H); 13C NMR (CDCl3) δ 191.0, 156.2 (dd,
JCF ) 9.5, 236.2 Hz), 149.4 (dd, JCF ) 14.3, 249.9 Hz), 133.7,
128.7 (dd, JCF ) 2.6, 6.1 Hz), 127.9 (dd, JCF ) 6.9, 11.3 Hz),
123.5 (d, JCF ) 13.6 Hz), 101.9 (dd, JCF ) 4.3, 22.8 Hz), 101.5
(dd, JCF ) 20.6, 30.9), 38.6, 24.7, 21.2; IR (CDCl3) ν 3231, 1669,
1632, 1558, 1506, 1135, 823 cm-1. Anal. Calcd for C12H9F2NO
[221.07]: C, 65.16; H, 4.10; N, 6.33. Found: C, 64.81; H, 4.00,
N, 6.24.
(28) Joseph, D.; Martarello, L.; Kirsch, G. J. Chem. Res. (M) 1995,
2001-2114.
(29) Sangeetha, V.; Prasad, K. J. R. Heterocycl. Commun. 2002, 8,
65-70.
8390 J. Org. Chem., Vol. 70, No. 21, 2005

Synthesis of Substituted Cycloalkyl[b]indoles
6-Methoxy-2,3,4,9-tetrahydro-1H-carbazol-1-one (10f).
10f was synthesized in 50% yield as a solid from 7f via the
general Fischer cyclization procedure. Spectral data matched
that for the known compound.28
30.4 Hz), 101.3 (dd, JCF ) 4.7, 22.8 Hz), 49.8, 40.1, 24.3, 21.8;
IR (CDCl3) ν 3064, 2946, 2361, 1262, 1044, 1074, 902, 776 cm-1
Anal. Calcd for C19H15F2NO [311.11]: C, 73.30; H, 4.86; N,
4.50. Found: C, 73.02; H, 4.74; N, 4.50.
.
General Benzylation Procedure. To a solution of the
ketone 10 (10 mmol) in THF:MTBE (1:1, 16 mL) was added
benzyl chloride (10.1 mmol), tetrabutylammonium bromide
(0.2 mmol), and 3.3 N NaOH (50 mmol), and the reaction was
heated to 50 °C for 22 h. The reaction was cooled to room
temperature and diluted with EtOAc (20 mL) and brine (20
mL), and the layers were separated. The organic layer was
concentrated in vacuo, and the crude product 13 was recrystal-
lized from MeOH.
9-Benzyl-6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-1-
one (13f). 13f was isolated in 90% yield from 10f according
to the general benzylation procedure as a solid: mp 120-124
°C; 1H NMR (CDCl3) δ 7.26-7.21 (comp, 4 H), 7.14-7.12
(comp, 2 H), 7.07-7.04 (comp, 2 H), 5.82 (s, 2 H), 3.03 (app t,
J ) 6.0 Hz, 2 H), 2.67 (app t, J ) 6.0 Hz, 2 H), 2.25 (ddd, J )
6.2, 6.2, 12.6 Hz, 2 H); 13C NMR (CDCl3) δ 191.8, 154.4, 138.4,
134.9, 130.3, 128.9, 128.4, 127.0, 126.6, 125.1, 118.5, 111.9,
101.1, 55.7, 47.9, 39.9, 24.6, 21.9; IR (CDCl3) ν 2940, 2834,
1655, 1492, 1453, 1289, 1219 cm-1. Anal. Calcd for C20H19NO2
[305.37]: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.51; H, 6.07;
N, 4.48.
General Asymmetric Reduction Procedure. To a solu-
tion of the ketone 13 (10 mmol) in CH2Cl2 (10 mL) at -20 °C
was added (S)-oxazaborolidine (OAB) (1 M, 10 mL, 10 mmol),
the solution was aged for 20 min, and 10 M BH3‚DMS was
added (1 mL, 10 mmol) dropwise over 10 min. The reaction
was stirred for 3.5 h at -20 °C, quenched by addition of iPrOH
(0.6 mL), and warmed to room temperature. Solvent was
removed in vacuo via rotary evaporation, and the crude
product was concentrated from iPrOH (25 mL) three times and
passed through a plug of silica gel eluting with EtOAc/hexanes
(1:2). The filtrate was concentrated in vacuo, and the semipure
solid product 14 was recrystallized from EtOAc/hexanes.
5-Bromo-4-(4-chlorobenzyl)-7-fluoro-1,4-dihydrocyclo-
penta[b]indol-3(2H)-one (13a). 13a was prepared in 84%
yield from 10a according to the general benzylation procedure
except that p-chlorobenzyl chloride was used instead of benzyl
1
chloride: mp 152-156 °C; H NMR (CDCl3) δ 7.34 (ddd, J )
2.3, 2.3, 9.0 Hz, 2 H), 7.22 (ddd, J ) 2.4, 2.4, 8.5 Hz, 2 H),
6.97 (d, J ) 8.5 Hz, 2 H), 5.98 (s, 2 H), 3.06-2.99 (m, 4 H); 13
C
NMR (CDCl3) δ 194.4, 157.0 (d, JCF ) 242.6 Hz), 144.6 (d, JCF
) 5.6 Hz), 141.3, 137.3, 133.1, 128.7, 127.7, 126.0 (d, JCF
)
9.8 Hz), 120.8 (d, JCF ) 28.9 Hz), 105.9 (d, JCF ) 22.3 Hz),
104.8 (d, JCF ) 11.3 Hz), 47.5, 41.4, 19.3; IR (CDCl3) ν 3060,
2933, 1675, 1492, 1208, 1144 cm-1. Anal. Calcd for C18H12-
BrClFNO [392.65]: C, 55.06; H, 3.08; N, 3.57. Found: C, 54.85;
H, 2.75; N, 3.50.
4-Benzyl-1,4-dihydrocyclopenta[b]indole-3(2H)-one
(13b). 13b was prepared in 87% yield from 10b according to
the general benzylation procedure as an orange solid: mp
(3R)-5-Bromo-4-(4-chlorobenzyl)-7-fluoro-1,2,3,4-tet-
rahydrocyclopenta[b]indol-3-ol (14a). 14a was prepared
in 98% assay yield and 97.4% ee [SFC conditions: Chiralcel
OD-H, 20% MeOH in CO2, 1.5 mL/min for 30 min, tR ) 8.4
min (R), 16.3 min (S)] from 13a according to the general
asymmetric reduction procedure. This material was recrystal-
lized from EtOAc/hexanes to give 14a in 93% recovery as a
1
107-110 °C; H NMR (CDCl3) δ 7.72 (ddd, J ) 1.0, 1.0, 8.0
Hz, 1 H), 7.49-7.36 (m, 2 H), 7.34-7.22 (m, 5 H), 7.19 (dddd,
J ) 4.0, 4.0, 8.0, 8.0 Hz, 1 H), 5.54 (s, 2 H), 3.09-3.07 (m, 2
H), 3.03-3.01 (m, 2 H); 13C NMR (CDCl3) δ 194.5, 145.5, 144.3,
138.6, 137.5, 128.7, 127.6, 127.3, 126.9, 123.5, 121.8, 120.4,
111.8, 47.3, 41.5, 19.6; IR (CDCl3) ν 3062, 2924, 1673, 1475,
1256, 1055, 744 cm-1. Anal. Calcd for C18H15NO [261.12]: C,
82.73; H, 5.79; N, 5.36. Found: C, 82.65; H, 5.79; N, 5.36.
white solid in >99% ee according to SFC analysis: mp 123-
1
125 °C; [R]23 +24.1 (c ) 0.017, CH2Cl2); H NMR (CDCl3) δ
D
7.24 (ddd, J ) 2.5, 2.5, 9.1 Hz, 2 H), 7.13 (ddd, J ) 2.7, 2.7,
8.7 Hz, 2 H), 6.89 (ddd, J ) 2.3, 2.3, 8.6 Hz, 2 H), 5.97 and
5.63 (ABq, J ) 17.0 Hz, 1 H), 5.18 (brs, 1 H), 3.03-2.89 (m, 2
H), 2.76-2.68 (m, 1 H), 2.35-2.27 (m, 1 H), 1.68 (brs, 1 H);
13C NMR (CDCl3) δ 156.8 (d, JCF ) 240 Hz) 149.0, 137.8, 134.5,
132.9 128.7, 127.0, 126.5 (d, JCF ) 9.8 Hz), 121.3 (d, JCF ) 4.9
Hz), 115.5 (d, JCF ) 28.6 Hz), 104.4 (d, JCF ) 22.5 Hz), 103.4
(d, JCF ) 11.8 Hz) 69.9, 48.2, 45.5, 39.9, 22.1; IR (CDCl3) ν
3325, 2937, 2868, 1487, 1405, 1205, 1130 cm-1. Anal. Calcd
for C18H14BrClFNO [394.99]: C, 54.78; H, 3.58; N, 3.55.
Found: C, 54.66; H, 3.27; N, 3.43.
9-Benzyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (13c).
13c was prepared in 85% yield from 10c according to the
general benzylation procedure as a solid: mp 117-120 °C; 1H
NMR (CDCl3) δ 7.69 (ddd, J ) 1.0, 1.0, 8.0 Hz, 1 H), 7.37-
7.34 (m, 2 H), 7.29-7.13 (m, 6 H), 5.85 (s, 2 H), 3.07 (app t, J
) 6.1 Hz, 2 H), 2.67 (dd, J ) 6.1, 7.4 Hz, 2 H), 2.26 (m, 2 H);
13C NMR (CDCl3) δ 191.9, 139.4, 138.4, 129.9, 129.8, 128.5,
127.1, 126.9, 126.7, 125.1, 121.3, 120.3, 110.9, 47.9, 40.0, 24.7,
21.8; IR (CDCl3) ν 3060, 3030, 2940, 1656, 1612, 1461, 1181,
930, 744 cm-1. Anal. Calcd for C19H17NO [275.13]: C, 82.88;
H, 6.22; N, 5.09. Found: C, 82.59; H, 6.11; N, 5.13.
9-Benzyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-1-
one (13d). 13d was isolated in 89% yield from 10d according
to the general benzylation procedure as a solid: mp 97-100
°C; 1H NMR (CDCl3) δ 7.33-7.20 (comp, 5 H), 7.13-7.09
(comp, 3 H), 5.83 (s, 2 H), 3.01 (app t, J ) 6.2 Hz, 2 H), 2.68
(app t, J ) 5.8 Hz, 2 H), 2.25 (ddd, J ) 6.2 Hz, 6.2 Hz, 12.6
Hz, 2 H); 13C NMR (CDCl3) δ 192.0, 157.8 (dd, JCF ) 237.8
Hz), 138.0, 135.9, 131.0, 129.2 (d, JCF ) 5.8 Hz), 128.5, 127.2,
126.6, 125.1 (d, JCF ) 9.5 Hz), 115.8 (d, JCF ) 26.9 Hz), 112.0
(d, JCF ) 9.2 Hz), 105.5 (d, JCF ) 23.1 Hz), 48.0, 39.9, 24.5,
21.8; IR (CDCl3) ν 2941, 1658 1489, 1457, 1161 cm-1. Anal.
Calcd for C19H16FNO [293.12]: C, 77.80; H, 5.50; N, 4.77.
Found: C, 77.62; H, 5.33; N, 4.77.
(3R)-4-Benzyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-
ol (14b). 14b was prepared in 90% yield and 93% ee [SFC
conditions: Chirapak AD column, 4% MeOH in CO2 for 4 min
then ramp to 40% MeOH at 2% per min, 1.5 mL/min, tR
)
15.2 min (S), 16.6 min (R)] from 13b according to the general
reduction procedure. This material was recrystallized from
EtOAc/hexanes to give 14b in 78% recovery and >99% ee
according to SFC analysis as a solid: mp 170-172 °C; [R]23
D
1
+41.8 (0.008, CH2Cl2); H NMR (DMSO-d6) δ 7.40 (ddd, J )
1.0, 1.0, 7.4 Hz, 1 H), 7.32-7.19 (comp, 6 H), 7.00 (dddd, J )
1.2, 7.1, 7.1, 22.5 Hz, 1 H), 5.43 and 5.31 (ABq, J ) 16 Hz, 2
H), 5.24-5.20 (m, 1 H), 2.89 (dddd, J ) 1.4, 4.2, 8.3, 14.1 Hz,
1 H), 2.85-2.77 (m, 1 H), 2.63 (ddd, J ) 4.6, 8.3, 13.0 Hz, 1
H), 2.24 (ddd, J ) 3.8, 7.8, 12.3 Hz, 1 H); 13C NMR (DMSO-
d6) δ 147.2, 141.3, 138.8, 128.8, 127.5, 127.4, 124.0, 121.2,
119.4, 119.3, 118.8, 111.0, 68.3, 47.4, 22.5; IR (CDCl3) ν 3358,
2910, 1451, 1212, 1154, 1036, 736 cm-1. Anal. Calcd for C18H17-
NO [263.13]: C, 82.10; H, 6.51; N, 5.32. Found: C, 81.83; H,
6.40; N, 5.35.
(3R)-9-Benzyl-2,3,4,9-tetrahydro-1H-carbazol-1-ol (14c).
14c was prepared in 91% yield and 97% ee [SFC conditions:
Chiralcel OD-H column, 30% MeOH in CO2 for 10 min, 1.5
mL/min, tR ) 6.8 (S), 8.5 (R)] from 13c according to the general
reduction procedure. This material was recrystallized from
9-Benzyl-6,8-difluoro-2,3,4,9-tetrahydro-1H-carbazol-
1-one (13e). 13e was isolated in 90% yield from 10e according
to the general benzylation procedure as a solid: mp 83-85
1
°C; H NMR (CDCl3) δ 7.31-7.08 (comp, 6 H), 6.87 (ddd, J )
2.2, 9.2, 11.9 Hz, 1 H), 5.97 (s, 2 H), 2.97 (app t, J ) 6.1 Hz,
2 H), 2.67 (dd, J ) 6.1, 6.9 Hz, 2 H), 2.24 (ddd, J ) 6.1, 6.1,
6.9 Hz, 2 H); 13C NMR (CDCl3) δ 192.0, 156.6 (dd, JCF ) 9.7,
240.1 Hz), 149.9 (dd, JCF ) 13.5, 250.7 Hz), 138.8, 131.8, 129.9
(dd, JCF ) 2.0, 3.7 Hz), 128.4, 127.6 (dd, JCF ) 6.5, 10.6 Hz),
127.1, 126.6, 124.3 (d, JCF ) 8.9 Hz), 102.6 (dd, JCF ) 22.9,
J. Org. Chem, Vol. 70, No. 21, 2005 8391

Hillier et al.
EtOAc/hexanes to give 14c in 65% recovery and >99% ee
2 mL, 2 mmol), and triethyl methanetricarboxylate (2 mmol)
in THF (5 mL) at -78 °C was added DEAD (2 mmol) via
syringe pump over 2.5 h. The resulting yellow solution was
stirred at -78 °C for 12-18 h, quenched by addition of 3.3 N
NaOH (4 mmol), and warmed to room temperature. The
reaction was diluted with MTBE (5 mL) and stirred at room
temperature for 4 h, and the biphasic mixture was separated.
The organic layer was dried (MgSO4), filtered, and concen-
trated, and the crude residue was purified via flash chroma-
tography eluting with EtOAc/hexanes (1:9).
Mitsunobu Displacement Procedure (Conditions C).
To a solution of the alcohol 14 (1 mmol), PMe3 (1 M in toluene,
2 mL, 2 mmol), and triethyl methanetricarboxylate (2 mmol)
in toluene (5 mL) at 0 °C was added bis(2,2,2-trichloroethyl)
azodicarboxylate (TCEAD, 2 mmol) as a solution in toluene (1
mL), and the resulting yellow solution was stirred for 1 h. The
reaction was quenched by addition of 3.3 N NaOH (4 mmol),
warmed to room temperature, diluted with MTBE (5 mL), and
stirred at room temperature for 4 h. The resulting biphasic
mixture was separated, the organics were dried (MgSO4),
filtered, and concentrated, and the crude residue was purified
via flash chromatography eluting with EtOAc/hexanes (1:9).
according to SFC analysis as a solid: mp 145-147 °C; [R]23
D
1
+74.9 (0.01, CH2Cl2); H NMR (CDCl3) δ 7.59 (d, J ) 7.7 Hz,
1 H), 7.31-7.23 (comp, 1 H), 7.20 (ddd, J ) 1.1, 6.9, 6.9 Hz,
1 H), 7.13 (ddd, J ) 1.1, 7.9, 7.9 Hz, 1 H), 7.05 (d, J ) 6.9 Hz,
2 H), 5.54 and 5.41 (ABq, J ) 16.8 Hz, 2 H), 4.86-4.85 (m,
1 H), 2.94-2.89 (m, 1 H), 2.73-2.65 (m, 1 H), 2.11-1.92 (m,
4 H), 1.64 (d, J ) 7.5 Hz, 1 H); 13C NMR (CDCl3) δ 138.3,
137.1, 135.4, 128.6, 127.1, 126.5, 126.1, 122.3, 119.1, 118.9,
112.5, 109.6, 61.9, 46.5, 33.1, 21.1, 18.4; IR (CDCl3) ν 3343,
2929, 1454, 1206, 1151, 737 cm-1. Anal. Calcd for C19H19NO
[277.15]: C, 82.28; H, 6.90; N, 5.05. Found: C, 82.06; H, 6.73;
N, 4.99.
(1R)-9-Benzyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-
1-ol (14d). 14d was prepared in 96% yield and 93% ee [SFC
conditions: Chiralpak AD-H column, 4% MeOH in CO2 for 4
min then ramp to 40% MeOH at 2% per min, 1.5 mL/min, tR
) 15.7 min (S), 16.9 min (R)] from 13d according to the general
reduction procedure. This material was recrystallized from
EtOAc/hexanes to give 14d in 86% recovery and 99% ee
according to SFC analysis as a solid: mp 139-142 °C; [R]23
D
1
+66 (0.024, CH2Cl2); H NMR (CDCl3) δ 7.31-7.23 (comp, 3
H), 7.21 (dd, J ) 2.6, 9.5 Hz, 1 H), 7.12 (dd, J ) 4.3, 8.9 Hz,
1 H), 7.04-7.01 (comp, 2 H), 6.91 (ddd, J ) 2.6, 9.1, 9.1 Hz, 1
H), 5.52 and 5.38 (ABq, J ) 16.9 Hz, 2 H), 4.84 (brs, 1 H),
2.83 (ddd, J ) 4.4, 4.4, 16.1 Hz, 1 H), 2.67-2.60 (m, 1 H), 2.10-
1.92 (comp, 4 H), 1.65 (brs, 1 H); 13C NMR (CDCl3) δ 157.7 (d,
JCF )234.6 Hz), 138.0, 137.1, 133.7, 128.7, 127.3, 126.6 (d, JCF
) 9.5 Hz), 126.0, 112.4 (d, JCF ) 4.6 Hz), 110.5 (d, JCF ) 25.9
Hz), 110.2 (d, JCF ) 9.6 Hz), 103.8 (d, JCF ) 22.9 Hz), 61.9,
46.7, 33.1, 21.1, 18.4; IR (CDCl3) ν 3310, 2932, 1792, 1653,
1558, 1482, 1456 cm-1. Anal. Calcd for C19H18FNO [295.14]:
C, 77.27; H, 6.43; N, 4.74. Found: C, 76.98; H, 6.19; N, 4.61.
Triethyl [(3R)-5-Bromo-4-(4-chlorobenzyl)-7-fluoro-
1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]methanetri-
carboxylate (16a). 16a was prepared from 14a in 95% yield
in 94% ee [SFC analysis: Chiralcel OD-H, 20% MeOH in CO2,
1.5 mL/min for 15 min, tR ) 3.4 min (R), 4.2 min (S)] according
to the Mitsunobu displacement procedure (Conditions A):
[R]23 +51.3 (c ) 0.021, CH2Cl2); 1H NMR (CDCl3) δ 7.18-
D
1.14 (comp, 2 H), 7.05 (ddd, J ) 2.4, 2.4, 2.4, 1 H), 7.03 (ddd,
J ) 2.4, 2.4, 2.4 Hz, 1 H), 6.69 (d, J ) 8.3 Hz, 2 H), 6.00 and
5.58 (ABq, J ) 17.2 Hz, 1 H), 4.28 (d, J ) 8.9 Hz, 1 H), 4.17-
4.03 (comp, 6 H), 2.91 (dddd, J ) 8.9, 8.9, 8.9, 13.8 Hz, 1 H),
2.78 (dddd, J ) 1.4, 7.6, 8.9, 8.9 Hz, 1 H), 2.65 (ddd, J ) 1.4,
8.9, 8.9, 10.5 Hz), 2.56 (dd, J ) 7.6, 13.8 Hz, 1 H), 1.14 (t, J )
7.2 Hz, 9 H); 13C NMR (CDCl3) δ 166.0, 157.0 (d, JCF ) 239.7
Hz), 147.8, 138.4, 135.7, 132.4, 128.4, 127.4 (d, JCF ) 10.0 Hz),
126.9, 124.9 (d, JCF ) 4.4 Hz), 115.3 (d, JCF ) 28.5 Hz),104.0
(d, JCF ) 11.6 Hz), 103.6 (d, JCF ) 22.5 Hz), 69.5, 62.2, 48.4,
42.9, 35.0, 22.7, 13.6; IR (CDCl3) ν 2980, 2361, 1741, 1200,
1128, 1062 cm-1. MS (ESI) calcd for C28H28NO6ClFBr: M + H
(theory), 608.0851; M + H (found), 608.0847.
(1R)-9-Benzyl-6,8-difluoro-2,3,4,9-tetrahydro-1H-car-
bazol-1-ol (14e). 14e was prepared in 96% yield and 90% ee
[SFC conditions: Chiralcel OD-H column, 4% MeOH in CO2
for 4 min then ramp to 40% MeOH at 2% per min, 1.5 mL/
min, tR ) 13.0 min (S), 13.7 min (R)] from 13e according to
the general reduction procedure. This material was recrystal-
lized from EtOAc/hexanes to give 14e in 74% recovery and 99%
ee according to SFC analysis as a solid: mp 130-132 °C; [R]23
D
1
+73 (0.009, CH2Cl2); H NMR (CDCl3) δ 7.31-7.19 (comp, 3
H), 7.02-6.98 (comp, 3 H), 6.70 (ddd, J ) 2.3, 9.6, 12.3 Hz, 1
H), 5.60 (d, 2 H), 4.80 (brs, 1 H), 2.78 (ddd, J ) 3.0, 3.0, 6.6
Hz, 1 H), 2.63-2.56 (m, 1 H), 2.07-1.89 (comp, 4 H); 13C NMR
Triethyl [(3R)-4-Benzyl-1,2,3,4-tetrahydrocyclopenta-
[b]indol-3-yl]methanetricarboxylate (16b). 16b was pre-
pared from 14b in 61% yield and 65% ee [SFC conditions:
Chiralpak AS-H column, 4% MeOH in CO2 for 4 min then
ramp to 40% MeOH at 2% per min, 1.5 mL/min, tR ) 17.0 min
(S), 18.0 min (R)] according to the Mitsunobu displacement
procedure (Conditions C): 1H NMR (CDCl3) δ 7.45-7.42 (m,
1 H), 7.27-7.18 (comp, 3 H), 7.08-7.01 (comp, 5 H), 5.45 and
5.37 (ABq, J ) 16.9 Hz, 2 H), 4.41 (ddd, J ) 1.8, 1.8, 8.9 Hz,
1 H), 4.09-3.97 (comp, 6 H), 3.02-2.93 (m, 1 H), 2.85 (dddd,
J ) 1.9, 7.6, 7.6, 14.5 Hz, 1 H), 2.72 (ddd, J ) 1.7, 9.3, 14.2
Hz, 1 H), 2.62 (dddd, J ) 1.9, 1.9, 7.6, 13.6 Hz, 1 H); 1.09 (t,
J ) 7.2 Hz, 9 H); 13C NMR (CDCl3) δ 166.3, 142.8, 142.6, 138.7,
128.3, 126.6, 126.1, 124.0, 123.3, 121.3, 119.2, 118.8, 111.0,
69.8, 62.0, 48.2, 42.9, 35.2, 22.8, 13.6; IR (CDCl3) ν 2981, 1744,
1456, 1223, 1065, 740 cm-1. Anal. Calcd for C28H31NO6
[477.22]: C, 70.42; H, 6.54; N, 2.93. Found: C, 70.64; H, 6.62;
N, 2.86.
(CDCl3) δ 156.5 (dd, JCF ) 10.3, 237.0 Hz), 149.2 (dd, JCF
13.8, 246.8 Hz), 139.0, 138.4, 129.5 (dd, JCF ) 6.7, 10.7 Hz),
128.7, 127.3, 125.8, 121.7 (d, JCF ) 8.8 Hz), 113.7 (dd, JCF
)
)
3.3, 4.9 Hz), 61.6, 48.5, 33.1, 21.2, 18.2; IR (CDCl3) ν 4321,
2934, 1574, 1492, 1456, 1425, 1314, 1207, 1137 cm-1. Anal.
Calcd for C19H17F2NO [313.13]: C, 72.83; H, 5.47; N, 4.47.
Found: C, 72.94; H, 5.32; N, 4.55.
(1R)-9-Benzyl-6-methoxy-2,3,4,9-tetrahydro-1H-carba-
zol-1-ol (14f). 14f was prepared in 98% yield and 95% ee [SFC
conditions: Chiralpak AS-H column, 4% MeOH in CO2 for 4
min then ramp to 40% MeOH at 2% per min, 1.5 mL/min, tR
) 17.0 min (S), 18.0 min (R)] from 13f according to the general
reduction procedure. This material was recrystallized from
EtOAc/hexanes to give 14f in 78% recovery and >99% ee
according to SFC analysis as a solid: mp 203-206 °C; [R]23
D
+82.9 (0.014, CH2Cl2); 1H NMR (CDCl3) δ 7.30-7.21 (comp, 3
H), 7.12 (d, J ) 8.9 Hz, 1 H), 7.04-7.02 (comp, 3 H), 6.85 (dd,
J ) 2.5, 8.9 Hz, 1 H), 5.49 and 5.36 (ABq, J ) 16.9 Hz, 2 H),
4.83 (brs, 1 H), 3.78 (s, 3 H), 2.86 (ddd, J ) 4.0, 4.0, 7.9 Hz, 1
H), 2.69-2.61 (m, 1 H), 2.10-1.90 (comp, 4 H), 1.69 (d, J )
6.9 Hz, 1 H); 13C NMR (CDCl3) δ 154.9, 138.5, 136.2, 132.5,
128.7, 127.2, 126.8, 126.1, 112.4, 112.1, 110.5, 101.0, 62.0, 55.9,
46.7, 33.2, 21.3, 18.6; IR (CDCl3) ν 3420, 1652, 1558, 1484,
1455 cm-1. Anal. Calcd for C20H21NO2 [307.16]: C, 78.15; H,
6.89; N, 4.56. Found: C, 77.98; H, 6.80; N, 4.48.
Triethyl [(1R)-9-Benzyl-2,3,4,9-tetrahydro-1H-carba-
zol-1-yl]methanetricarboxylate (16c). 16c was prepared
from 14c in 80% yield and 75% ee [SFC analysis: Chiralcel
OD-H column, 4% MeOH in CO2 for 4 min then ramp to 40%
MeOH at 2% per min, 1.5 mL/min, tR ) 9.2 min (S), 10.3 min
(R)] according to the Mitsunobu displacement procedure
(Conditions C): 1H NMR (CDCl3) δ 7.47 (d, J ) 7.4 Hz, 1 H),
7.23-7.14 (comp, 4 H), 7.09 (ddd, J ) 1.3, 6.9, 6.9 Hz, 1 H),
7.04 (ddd, J ) 1.3, 7.8, 7.8 Hz, 1 H), 6.87 (d, J ) 6.9 Hz, 2 H),
5.79 and 5.28 (ABq, J ) 17.2 Hz, 1 H), 4.29 (brs, 1 H), 4.07-
3.92 (comp, 6 H), 2.85 (ddd, J ) 1.4, 9.0, 16.4 Hz, 1 H), 2.76
(ddd, J ) 7.7, 10.0, 17.3 Hz, 1 H), 2.43-2.32 (m, 1 H), 2.14
Mitsunobu Displacement Procedure (Conditions A).
To a solution of the alcohol 14 (1 mmol), PMe3 (1 M in THF,
8392 J. Org. Chem., Vol. 70, No. 21, 2005

Synthesis of Substituted Cycloalkyl[b]indoles
(app dq, J ) 3.4, 14.2 Hz, 1 H), 1.89-1.80 (comp, 2 H), 1.09 (t,
J ) 7.2 Hz, 9 H); 13C NMR (CDCl3) δ 166.0, 139.2, 137.5, 134.1,
128.3, 127.2, 126.6, 125.8. 121.8, 118.7, 118.2, 113.1, 109.7,
69.3, 61.8, 46.3, 34.9, 28.5, 20.0, 17.1, 13.5; IR (CDCl3) ν 2981,
1745, 1652, 1558, 1456, 1243, 1070 cm-1. MS (ESI) calcd for
C29H33NO6: M + H (theory), 492.2386; M + H (found),
492.2385.
the trisacid intermediate according to HPLC analysis, the
reaction was cooled to room temperature and solvent was
concentrated in vacuo.
Acidic Decarboxylation Procedure (Conditions A).
The crude product from the saponification reaction (1 mmol)
was dissolved in AcOH (2 mL) and heated to reflux for 24 h.
Solvent was removed in vacuo, and the residual product was
purified by silica gel chromatography eluting with EtOAc:
hexanes (1:3) to give the acid 17.
Nonacidic Decarboxylation Procedure (Conditions B).
The crude saponification product (1 mmol) was taken up in
H2O (4 mL), neutralized by addition of 3 N HCl (5-10 mmol),
and extracted with EtOAc (2 × 2 mL). The combined organics
were dried (MgSO4), solvent was removed in vacuo, and the
crude residue was diluted in toluene (2 mL). This solution was
heated to reflux for 2-4 h and cooled to room temperature,
and solvent was removed via rotary evaporation. The crude
acid product 17 was purified via column chromatography
eluting with EtOAc:hexanes (1:3).
Triethyl [(1R)-9-Benzyl-6-fluoro-2,3,4,9-tetrahydro-1H-
carbazol-1-yl]methanetricarboxylate (16d). 16d was pre-
pared from 14d in 84% yield and 80% ee [SFC analysis:
Chiralpak IA-H column, 4% MeOH in CO2 for 4 min then ramp
to 40% MeOH at 2% per min, 1.5 mL/min, tR ) 7.7 min (S),
8.0 min (R)] according to the Mitsunobu displacement proce-
dure (Conditions C): 1H NMR (CDCl3) δ 7.27-7.16 (comp, 3
H), 7.11 (d, J ) 2.5, 9.3 Hz, 1 H), 7.04 (dd, J ) 4.2, 8.9 Hz, 1
H), 6.86 (d, J ) 6.7 Hz, 2 H), 6.81 (dd, J ) 2.5, 9.3 Hz, 1 H),
5.83 and 5.24 (ABq, J ) 17.2 Hz, 2 H), 4.30 (m, 1 H), 4.08-
3.94 (comp, 6 H), 2.80 (app dd, J ) 7.4, 15.7 Hz, 1 H), 2.72
(ddd, J ) 7.6, 9.7, 17.4 Hz, 1 H), 2.44-2.32 (m, 1 H), 2.16 (app
dq, J ) 3.1, 14.1 Hz, 1 H), 1.88 (ddd, J ) 3.7, 3.9, 8.1 Hz, 1 H),
1.83 (ddd, J ) 3.7, 3.7, 7.7 Hz, 1 H), 1.10 (t, J ) 7.2 Hz, 9 H);
13C NMR (CDCl3) δ 166.0, 157.5 (d, JCF ) 234.0 Hz), 138.9,
136.0, 134.0, 128.4, 127.5 (d, JCF ) 9.5 Hz), 126.7, 125.8, 113.1
(d, JCF ) 4.6 Hz), 110.4 (d, JCF ) 9.6 Hz), 109.9 (d, JCF ) 26.1
Hz), 103.1 (d, JCF ) 22.8 Hz), 69.2, 61.9, 46.6, 34.9, 28.3, 19.9,
17.1, 13.6; IR (CDCl3) ν 2982, 1785, 1746, 1652, 1458, 1244,
1071 cm-1. MS (ESI) calcd for C29H32FNO6: M + H (theory),
509.2292; M + H (found), 510.2287.
Triethyl [(1R)-9-Benzyl-6,8-difluoro-2,3,4,9-tetrahydro-
1H-carbazol-1-yl]methanetricarboxylate (16e). 16e was
prepared from 14e in 91% yield and 95% ee [SFC analysis:
Chiralpak IA-H column, 4% MeOH in CO2 for 4 min then ramp
to 40% MeOH at 2% per min, 1.5 mL/min, tR ) 5.8 min (S),
6.2 min (R)] according to the Mitsunobu displacement proce-
dure (Conditions C): 1H NMR (CDCl3) δ 7.23-7.14 (comp, 3
H), 6.89 (dd, J ) 2.3, 8.7 Hz, 1 H), 6.79 (d, J ) 7.0 Hz, 2 H),
6.60 (ddd, J ) 2.2, 9.4, 12.1 Hz, 1 H), 5.87 and 5.45 (ABq, J )
17.1 Hz, 2 H), 4.29 (m, 1 H), 4.11-3.97 (comp, 6 H), 2.75 (ddd,
J ) 1.3, 7.7, 16.6 Hz, 1 H), 2.67 (ddd, J ) 7.6, 10.3, 17.5 Hz,
1 H), 2.35-2.24 (m, 1 H), 2.21-2.17 (m, 1 H), 1.87-1.78 (comp,
2 H), 1.13 (t, J ) 7.0 Hz, 9 H); 13C NMR (CDCl3) δ 165.9, 156.5
(dd, JCF )10.3, 236.8 Hz), 149.0 (dd, JCF ) 13.8, 247.4 Hz),
130.3 (dd, JCF ) 6.8, 10.6 Hz), 128.4, 126.7, 125.4, 121.9 (d,
JCF ) 8.1 Hz), 114.9 (d, JCF ) 3.6 Hz), 99.0 (dd, JCF ) 3.9,
22.6 Hz), 97.8 (dd, JCF ) 23.1, 29.9 Hz), 69.0, 61.9, 48.2, 34.6,
28.1, 20.0, 16.9, 13.5; IR (CDCl3) ν 2982, 1786, 1746, 1636,
1585, 1494, 1246, 1072 cm-1. MS (ESI) calcd for C29H31F2-
NO6: M + H (theory), 528.2198; M + H (found), 528.2196.
Triethyl [(1R)-9-Benzyl-6-methoxy-2,3,4,9-tetrahydro-
1H-carbazol-1-yl]methanetricarboxylate (16f). 16f was
prepared from 14f in 80% yield and 67% ee [SFC analysis:
Chiralpak IA-H column, 4% MeOH in CO2 for 4 min then ramp
to 40% MeOH at 2% per min, 1.5 mL/min, tR ) 10.6 min (S),
11.0 min (R)] according to the Mitsunobu displacement
procedure (Conditions C): 1H NMR (CDCl3) δ 7.23-7.14 (comp,
3 H), 7.03 (d, J ) 8.9 Hz, 1 H), 6.92 (d, J ) 2.4 Hz, 1 H), 6.86
(d, J ) 7.1 Hz, 2 H), 6.75 (dd, J ) 2.4, 8.8 Hz, 1 H), 5.77 and
5.23 (ABq, J ) 17.2 Hz, 2 H), 4.28 (m, 1 H), 4.07-3.93 (comp,
6 H), 3.84 (s, 3 H), 2.81 (app dd, J ) 7.5, 16.1 Hz, 1 H), 2.72
(ddd, J ) 7.6, 9.9, 17.4 Hz, 1 H), 2.43-2.32 (m, 1 H), 2.14 (app
dq, J ) 3.1, 14.1 Hz, 1 H), 1.85 (comp, 2 H), 1.10 (t, J ) 7.2
Hz, 9 H); 13C NMR (CDCl3) δ 166.2, 153.7, 139.5, 135.0, 133.0,
128.5, 127.6, 126.7, 126.0, 112.9, 111.8, 110.7, 100.4, 69.5, 61.9,
55.8, 46.6, 35.2, 28.6, 20.2, 17.3, 13.7; IR (CDCl3) ν 2982, 1785,
1746, 1500, 1485, 1456, 1243, 1154, 1070 cm-1. MS (ESI) calcd
for C30H35NO7: M + Na (theory), 544.2306; M + Na (found),
544.2303.
[(3R)-5-Bromo-4-(4-chlorobenzyl)-7-fluoro-1,2,3,4-tet-
rahydrocyclopenta[b]indol-3-yl]acetic Acid (17a). 17a
was isolated from the triester 16a using the general saponi-
fication and acidic decarboxylation (Conditions A) procedures
in 86% yield and 94% ee [SFC analysis: Chiralcel OD-H
column, 20% MeOH in CO2, 1.5 mL/min for 15 min, tR ) 7.3
min (S), 10.4 min (R)] as a yellow solid: mp 188-191 °C; [R]23
D
+51.3 (c ) 0.0207, MeOH); 1H NMR (CDCl3) δ 7.27-2.32
(comp, 2 H), 7.10-7.06 (comp, 2 H), 6.81 (d, J ) 8.2 Hz, 2 H),
5.72 and 5.64 (ABq, J ) 17.5 Hz, 2 H), 3.54 (brs, 1 H), 2.95-
2.75 (comp, 3 H), 2.56 (dd, J ) 3.7, 16.0 Hz, 1 H), 2.39 (dd, J
) 10.2, 16.0 Hz, 1 H), 2.29-2.25 (m, 1 H); 13C NMR (CDCl3) δ
177.4, 158.1, 156.9 (d, JCF ) 241.5), 150.2, 137.5, 134.1, 133.0,
128.9, 127.0 (d, JCF ) 10.1 Hz), 126.7, 119.9 (d, JCF ) 4.4 Hz),
114.6 (d, JCF ) 30.2 Hz), 103.6 (20.1 Hz), 103.2 (d, JCF ) 10
Hz), 48.5, 38.7, 35.6, 35.0, 22.8; IR (CDCl3) 2936, 2361, 1700,
1472, 1406, 1199, 1131 cm-1. Anal. Calcd for C20H16BrClFNO2
[435.00]: C, 55.01; H, 3.69; N, 3.21. Found: C, 55.20; H, 3.66;
N, 3.24.
[(3R)-4-Benzyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-
yl]acetic Acid (17b). 17b was isolated from the triester 16b
using the general saponification and neutral decarboxylation
(Conditions B) procedures in 65% yield and 59% ee [SFC
analysis: Chiralcel OD-H column, 4% MeOH in CO2 for 4 min
then ramp to 40% MeOH at 2% per min, tR ) 15.7 min (S),
1
16.5 min (R)] as an oil: [R]23 +7.1 (0.016, CH2Cl2); H NMR
D
(MeOD-d3) δ 7.43-7.38 (m, 1 H), 7.24-7.12 (comp, 4 H), 7.03-
6.97 (comp, 4 H), 5.33 and 5.24 (ABq, 16.8 Hz, 2 H), 3.51 (m,
1 H), 2.91-1.82 (m, 1 H), 2.80-7.07 (comp, 2 H), 2.57 (dd, J )
4.0, 15.5 Hz, 1 H), 2.28 (dd, J ) 10.0, 15.5 Hz, 1 H), 2.27-1.18
(m, 1 H); 13C NMR (MeOD-d3) δ 174,5, 146.4, 141.7, 138.3,
128.2, 126.8, 126.7, 125.8, 124.2, 120.2, 118.7, 118.3, 118.2,
109.6, 47.1, 38.7, 35.6, 35.0, 22.3; IR (MeOH) ν 3024, 2934,
2855, 1704, 1452, 1345, 1206, 1153, 737 cm-1. MS (ESI) calcd
for C20H19NO2: M + H (theory), 306.1489; M + H (found),
306.1483.
[(1R)-9-Benzyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]ace-
tic Acid (17c). 17c was isolated from the triester 16c using
the general saponification and acidic decarboxylation (Condi-
tions A) procedures in 90% yield and 75% ee [SFC analysis:
Chiralcel OD-H column, 4% MeOH in CO2 for 4 min then ramp
to 40% MeOH at 2% per min, 1.5 mL/min for 15 min, tR
)
12.5 min (R), 13.4 min (S)] as an oil: [R]23 -19.7 (c ) 0.015,
D
MeOH); 1H NMR (MeOD-d3) δ 7.44-7.40 (m, 1 H), 7.23-7.13
(comp, 4 H), 7.04 (app dt, J ) 1.3, 7.0 Hz, 1 H), 6.99 (app dt,
J ) 1.1, 7.1 Hz, 1 H), 6.91-6.89 (comp, 2 H), 5.36 and 5.27
(ABq, J ) 17.2 Hz, 2 H), 3.37 (m, 1 H), 2.84-2.80 (m, 1 H),
2.67-2.59 (m, 1 H), 2.51-2.40 (m, 1 H), 1.95-1.82 (comp, 4
H); 13C NMR (MeOD-d3) δ 174.3, 138.4, 137.2, 136.6, 128.1,
127.2, 126.7, 125.5, 120.8, 118.5, 117.4, 109.9, 109.0, 45.5, 28.3,
27.5, 20.4, 17.8; IR (MeOH) ν 3029, 2931, 1705, 1465, 1301,
739 cm-1. MS (ESI) calcd for C21H21NO2: M + H (theory),
320.1645; M + H (found), 320.1643.
General Saponification Procedure. The triester 16 (1
mmol) was taken up in MeOH (3 mL) and treated with 3.3 N
NaOH (5-10 mmol), and the reaction was heated to reflux
for 24 h. When all of the starting material had converted to
J. Org. Chem, Vol. 70, No. 21, 2005 8393

Hillier et al.
[(1R)-9-Benzyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-
1-yl]acetic Acid (17d). 17d was isolated from the triester 16d
using the general saponification and acidic decarboxylation
(Conditions A) procedures in 79% yield and 80% ee [SFC
analysis: Chiralcel OD-H column, 4% MeOH in CO2 for 4 min
then ramp to 40% MeOH at 2% per min, 1.5 mL/min for 15
min, tR ) 14.4 min (S), 14.8 min (R)] as an oil: [R]23D -25.6 (c
) 22.7, 29.8 Hz), 48.1, 38.3, 28.1, 27.6, 20.8, 17.7; IR (CDCl3)
ν 3031, 2936, 1707, 1641, 1587, 1491, 1454, 1316, 1135, 909,
732 cm-1. MS (ESI) calcd for C21H19F2NO2: M + H (theory),
356.1457; M + H (found), 356.1451.
[(1R)-9-Benzyl-6-methoxy-2,3,4,9-tetrahydro-1H-carba-
zol-1-yl]acetic Acid (17f). 17f was isolated from the triester
16f using the general saponification and neutral decarboxy-
lation (Conditions B) procedures in 74% yield and 67% ee [SFC
analysis: Chiralcel OD-H column, 4% MeOH in CO2 for 4 min
1
) 0.008, CH2Cl2); H NMR (CDCl3) δ 7.32-7.22 (comp, 3 H),
7.16 (dd, J ) 2.5, 9.4 Hz, 1 H), 7.03 (dd, J ) 4.3, 8.9 Hz, 1 H),
6.99-6.94 (comp, 2 H), 6.85 (app dt, J ) 2.5, 11.6 Hz, 1 H),
5.33 and 5.27 (ABq, J ) 17.2 Hz, 2 H), 3.45-3.42 (m, 1 H),
2.82 (dd, J ) 4.6, 15.3 Hz, 1 H), 2.96-2.60 (m, 1 H), 2.56 (dd,
J ) 10.2, 16.0 Hz, 1 H), 2.50 (dd, J ) 3.5, 16.0 Hz, 1 H), 1.99-
then ramp to 40% MeOH at 2% per min, tR ) 15.9 min (S),
1
16.4 min (R)] as an oil: [R]23 -20 (0.004, CH2Cl2); H NMR
D
(CDCl3) δ 7.29-7.21 (comp, 3 H), 7.03 (d, J ) 8.8 Hz, 1 H),
6.99 (d, J ) 2.5 Hz, 1 H), 6.99-6.97 (comp, 2 H), 6.79 (dd, J )
2.5, 8.5 Hz, 1 H), 7.32 and 5.26 (ABq, J ) 17.1 Hz, 2 H), 3.87
(s, 3 H), 3.44-3.42 (m, 1 H), 2.84 (dd, J ) 4.5, 15.3 Hz, 1 H),
2.71-2.64 (m, 1 H), 2.56 (dd, J ) 9.9, 16.0 Hz, 1 H), 2.49 (dd,
J ) 3.9, 16.0 Hz, 1 H), 1.99-1.80 (comp, 4 H); 13C NMR (CDCl3)
δ 177.8, 153.9, 137.9, 137.1, 132.2, 128.7, 127.4, 127.2, 125.8,
111.2, 110.3, 100.5, 55.9, 46.3, 38.5, 28.3, 27.8, 20.9, 18.1, 14.1;
IR (CDCl3) ν 2933, 1701, 1653, 1559, 1482, 1456, 1159, 732
cm-1. MS (ESI) calcd for C22H23NO3: M + H (theory), 350.1751;
M + H (found), 350.1750.
1.80 (comp, 4 H); 13C NMR (CDCl3) δ 177.5, 158.8 (d, JCF
)
234.5 Hz), 138.2, 137.5, 133.5, 128.8, 127.5, 127.4, 125.8, 110.7
(d, JCF ) 4.3 Hz), 110.0 (d, JCF ) 9.6 Hz), 109.4 (d, JCF ) 25.9
Hz), 103.2 (d, JCF ) 23.2 Hz), 46.4, 38.3, 28.3, 27.7, 20.8, 18.0;
IR (CDCl3) ν 2932, 1706, 1624, 1480, 1452, 1293, 1141, 792
cm-1. MS (ESI) calcd for C21H20FNO2: M + H (theory),
338.1551; M + H (found), 338.1544.
[(1R)-9-Benzyl-6,8-difluoro-2,3,4,9-tetrahydro-1H-car-
bazol-1-yl]acetic Acid (17e). 17e was isolated from the
triester 16e using the general saponification and acidic de-
carboxylation (Conditions A) procedures in 92% yield and 95%
ee [SFC analysis: Chiralcel OD-H column, 4% MeOH in CO2
for 4 min then ramp to 40% MeOH at 2% per min, 1.5 mL/
Acknowledgment. We thank Mirlinda Biba for the
development of chiral assays and Dr. Kevin Campos for
useful discussions.
min for 15 min, tR ) 13.3 min (S), 13.7 min (R)] as an oil: [R]23
D
-45.7 (0.024, CH2Cl2); 1H NMR (MeOD-d3) δ 7.31-7.21 (comp,
3 H), 6.98-6.91 (comp, 3 H), 5.49 and 5.40 (ABq, J ) 17.0 Hz,
2 H), 3.45-3.25 (m, 1 H), 2.78 (dd, J ) 4.4, 15.0 Hz, 1 H),
2.67-2.50 (comp, 3 H), 2.00-1.79 (comp, 4 H); 13C NMR
(CDCl3) δ 177.9, 156.6 (dd, JCF ) 10.1, 237.0 Hz), 148.9 (dd,
JCF ) 14.1, 246.7 Hz), 139.5, 138.5, 130.2 (dd, JCF ) 6.7, 10.9
Hz), 128.7, 127.3, 125.5, 121.3 (d, JCF ) 8.8 Hz), 112.0 (dd,
JCF ) 1.6, 5.6 Hz), 99.1 (dd, JCF ) 3.9, 22.9 Hz), 97.4 (dd, JCF
Supporting Information Available: Copies of the 1H
NMR spectra for of all compounds described in the Experi-
mental Section including 11, 12, and 15 and X-ray crystal-
lographic data for 14a. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO051146P
8394 J. Org. Chem., Vol. 70, No. 21, 2005