Stereoselective synthesis of chiral IBR2 analogues

Article abstract of DOI:10.1021/jo802607f

Two stereoselective routes were developed to synthesize optically pure IBR2 analogues 1-16. The first features addition of N-Boc-3-bromoindole 26 to the sulfinamide 25, providing a 1:1 ratio of the separable diasteroisomers 27 and 28 in good yield. In a s

Full text of DOI:10.1021/jo802607f

Stereoselective Synthesis of Chiral IBR2 Analogues
Xiao-Long Qiu,*,† Jiewen Zhu,† Guikai Wu,† Wen-Hwa Lee,*,† and
A. Richard Chamberlin‡,§
Department of Biological Chemistry, School of Medicine, Department of Chemistry, and Department of
Pharmaceutical Sciences, UniVersity of California, IrVine, IrVine, California 92697
qiux@uci.edu; whlee@uci.edu
ReceiVed NoVember 24, 2008
Two stereoselective routes were developed to synthesize optically pure IBR2 analogues 1-16. The first
features addition of N-Boc-3-bromoindole 26 to the sulfinamide 25, providing a 1:1 ratio of the separable
diasteroisomers 27 and 28 in good yield. In a straightforward fashion, the sulfinamides 27 and 28 were
conveniently converted into the key amines 39 and 47 over 8 steps, respectively, from which a series of
3,4-dihydroisoquinolinyl IBR2 analogues 1-14 containing fluorinated and trifluoromethylated benzyl
groups were prepared. Another route highlights the highly enantioselective addition of indole to the sulfonyl
amide 50 with bifunctional aminothioureas 57 and 58 as catalysts. After the reaction conditions were
optimized, the desired sulfonyl amides (R)-55 and (S)-55 were obtained in 99% ee and 98% ee, respectively.
Acylation of (R)-55 and (S)-55 separately and subsequent allylation gave compounds 60 and 63,
respectively, which were further subjected to RCM to furnish compounds 61 and 64 and, after removal
of the Boc groups, the desired IBR2 analogues 15 and 16.
It is well-known that Rad51 plays an essential role in DNA
damage repair and cell proliferation. For example, it has been
demonstrated that inactivation of mouse Rad51 gene would
result in embryonic lethality1 and depletion of Rad51 in DT40
chicken B lymphocytes clearly leads to cell cycle arrest and
subsequent cell death.2 Expression of Rad51 protein and the
rate of Rad51-mediated homologous recombination (HR) are
both elevated in various types of rapidly proliferating cancer
cells, including breast cancer, pancreatic cancer, nonsmall-cell
lung carcinoma, glioblastoma, acute myelogenous leukemia
(AML), and chronic myelogenous leukemia (CML), compared
to normal cells.3-6 It is also well-known that Rad51 overex-
pression may contribute to tumor progression7 and is positively
correlated with the resistance to DNA damage inducing radio-
or chemotherapies,8 whereas its depletion with siRNA or
antisense increases radiosensitivity.9,10 Moreover, Rad51 inter-
(3) Qiao, G.-B.; Wu, Y.-L.; Yang, X.-N.; Zhong, W.-Z.; Xie, D.; Guan, X.-
Y.; Fischer, D.; Kolberg, H.-C.; Kruger, S.; Stuerzbecher, H.-W. Br. J. Cancer
2005, 93, 137.
* To whom correspondence should be addressed.
† Department of Biological Chemistry, School of Medicine.
‡ Department of Chemistry.
(4) Slupianek, A.; Hoser, G.; Majsterek, I.; Bronisz, A.; Malecki, M.; Blasiak,
J.; Fishel, R.; Skorski, T. Mol. Cell. Biol. 2002, 22, 4189.
(5) Han, H.; Bearss, D. J.; Browne, L. W.; Calaluce, R.; Nagle, R. B.; Von
Hoff, D. D. Cancer Res. 2002, 62, 2890.
§ Department of Pharmaceutical Sciences.
(1) Tsuzuki, T.; Fujii, Y.; Sakumi, K.; Tominaga, Y.; Nakao, K.; Sekiguchi,
M.; Matsushiro, A.; Yashimura, Y.; Morita, T. Proc. Natl. Acad. Sci. U.S.A.
1996, 93, 6236.
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A.; Ogawa, H.; Takata, M.; Yamaguchi-Iwai, Y.; Takeda, S. EMBO J. 1998,
17, 598.
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T. Cancer Res. 2002, 62, 219.
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D.; Wennborg, A. Exp. Cell Res. 2001, 268, 61.
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26, 2859.
2018 J. Org. Chem. 2009, 74, 2018–2027
10.1021/jo802607f CCC: $40.75 2009 American Chemical Society
Published on Web 02/03/2009

Synthesis of Chiral IBR2 Analogues
With these considerations in mind, two types of chiral IBR2
analogues, 1-2 and 15-16, were designed, synthesized (Figure
1). Another rationale for designing these compounds was that
IBR compounds, from molecular docking study, may bind with
Rad51 by extending its phenyl sulfonyl moiety into a binding
site for Phe1524 of BRC4 of BRCA2. Nevertheless, the binding
model needs to be refined and consolidated, because it is not
completely clear at the moment how the orientation of iso-
quinoline and indole ring systems may affect the activity. One
of the interesting questions is how the dihedral angle of
indole-C1-N-sulfonyl (and hence the orientation of the indole
moiety) may affect activity. Thus, the 3,4-dihydro 6-membered
ring and the 7-membered ring analogues 1-2, 15-16 may be
beneficial for assessment of this specific question. Chiral
analogues 1-2 featured the transformation of the double bond
of enamine moiety in IBR2 to a single bond. Additionally, in
view of the fact that introduction of fluorine atom(s) into many
biologically active molecules could bring about remarkable and
profound changes in their physical, chemical, and biological
properties, including a profound effect on drug disposition, in
terms of distribution, drug clearance, route(s), extent of drug
metabolism, and metabolic stability,18 a series of monofluori-
nated and trifluoromethylated IBR2 analogues 3-14 were also
synthesized, in addition to 15-16 containing an enlarged
isoquinoline ring.
FIGURE 1. Structure of IBR2 and rationale of the designed chiral IBR2
analogues.
acts with the tumor suppressor BRCA2 via direct binding to its
six conserved BRC repeats.11,12 In the presence of excess BRC
peptide derived from BRCA2, DNA binding and nucleoprotein
filament formation of Rad51 were disrupted in vitro.13 In cancer
cells, an excess of BRC repeats inhibits IR-induced Rad51 foci
formation.14,15 These results suggest that the binding of exog-
enous BRC repeats inhibits the Rad51 functions both in vitro
and in vivo. Consistent with this observation, the crystal
structure of teh Rad51-BRC peptide complex16 shows that the
BRC repeat mimics the Rad51 oligomerization motif. Thus,
small molecules mimicking elements of the BRC repeat structure
show some promise in treating cancer by potentially preventing
the deleterious effects of Rad51 overexpression.
Very recently, our group successfully validated a small
molecular inhibitor of Rad51, designated as IBR2 (Figure 1),
by a reverse yeast two-hybrid screening.17 Rad51 was rapidly
degraded in IBR2-treated cancer cells, and the homologous
recombination repair was impaired, subsequently leading to cell
death. In spite of the efficacy of IBR2 in our original studies,
some problems were apparent. First of all, IBR2 is not stable
and was found to decompose to the extent of approximately
50% (0.1 M in CH2Cl2) after 2 months, producing indole (40%
yield) along with other unidentified compounds. Additionally,
the corresponding biological results will be integrated into a
complete SAR analysis project. Additionally, the bioactivity of
IBR2 was not high and IC50 values were in the range of 10-20
µM for most cancer cell lines. Thus, we sought to develop an
efficient synthetic route by which more stable and highly
bioactive IBR2 analogues might be produced. Since one possible
source of instability in IBR2sas well as a logical candidate for
structure variation in analoguessis the enamide-containing
heterocycle ring of the dihydroisoquiniline ring, we further
envisioned testing a convergent strategy for preparing analogues
that would bring together the requisite structural components,
isoquinoline, indole, and benzylsulfonyl, and allow for the
eventual preparation of a wide variety of IBR2 variants.
Results and Discussion
Stereoselective Synthesis of IBR2 Analogues 1-14. Al-
though there are some reports on the synthesis of racemic
tetrahydroisoquinolines and their derivatives,19 introducing a
chiral center at the 1-position on the isoquinoline scaffold
efficiently has been proven difficult. Takamura et al. have tried
to stereoselectively synthesize 1-substituted isoquinoline (as well
as quinoline) using bifunctional Lewis acid-base catalysts.20
Although working efficiently in quinoline substrates, the
bifunctional catalysts gave only poor diastereoselectivity (∼3%
ee) in isoquinoline substrates (R ) H). Their modeling studies
suggested that there seems to be no significant preference
between the two transition states involving either the s-cis or
s-trans acyl isoquinolium intermediates, at least sterically.
Establishing C1 chirality of tetrahydroisoquinoline via a ring-
closure substrate-induction was accomplished in the Bringmann
group utilizing a chiral center at the 3-position.21 However, our
system does not have a preexisting chiral center on the substrate.
Thus, it would be more reasonable and supposedly effective to
use 1,2-induction, if substrate-induction would be the only
option. Hence we considered to alternatively use a chiral
auxiliary group on the N to facilitate this. The retrosynthetic
analysis of chiral IBR2 analogues 1-14 (Figure 2) was based
(9) Sak, A.; Stueben, G.; Groneberg, M.; Bo¨cker, W.; Stuschke, M. Br. J.
Cancer 2005, 92, 1089.
(10) Ohnishi, T.; Taki, T.; Hiraga, S.; Arita, N.; Morita, T. Biochem. Biophys.
Res. Commun. 1998, 245, 319.
(11) Chen, P.-L.; Chen, C.-F.; Chen, Y.; Xiao, J.; Sharp, Z. D.; Lee, W.-H.
Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 5287.
(12) Chen, C.-F.; Chen, P.-L.; Zhong, Q.; Sharp, Z. D.; Lee, W.-H. J. Biol.
Chem. 1999, 274, 32931.
(13) Davies, A. A.; Masson, J.-Y.; McIlwraith, M. J.; Stasiak, A. Z.; Stasiak,
A.; Venkitaraman, A. R.; West, S. C. Mol. Cell 2001, 7, 273.
(14) Yu, V. P. C. C.; Koehler, M.; Steinlein, C.; Schmid, M.; Hanakahi,
L. A.; Van Gool, A. J.; West, S. C.; Venkitaraman, A. R. Genes DeV. 2000, 14,
1400.
(15) Yuan, S.-S. F.; Lee, S.-Y.; Chen, G.; Song, M.; Tomlinson, G. E.; Lee,
E. Y-H. P. Cancer Res. 1999, 59, 3547.
(16) Pellegrini, L.; Yu, D. S.; Lo, T.; Anand, S.; Lee, M.; Blundell, T. L.;
Venkitaraman, A. R. Nature 2002, 420, 287.
(17) (a) Lee, W.-H.; Chen, P.-L.; Zhu, J. , PCT Int. Appl. WO 2006044933
A2 20060427, 2006. (b) Lee, W.-H.; Chen, P.-L.; Zhou, L.; Zhu, J. , PCT Int.
Appl. WO 2007120726 A2 20071025, 2007.
(18) (a) Biomedical Frontiers of Fluorine Chemistry; ACS Symposium Series
639; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; American Chemical Society:
Washington, DC, 1996. (b) Fluorine-Containing Synthons; ACS Symposium
Series 911; SoloshonokV. A., Ed.; American Chemical Society: Washington,
DC, 2005. (c) Park, B. K.; Kitteringham, N. R. Drug Metab. ReV. 1994, 26,
605. (d) Bo¨hm, H.-S.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Mu¨ller,
K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637. (e) Mueller, K.;
Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(19) (a) Ryan, R. P.; Hamby, R. A.; Wu, Y.-H. J. Org. Chem. 1975, 40,
724. (b) Venkov, A. P.; Statkova-Abeghe, S. M.; Donova, A. K. Cent. Eur.
J. Chem. 2004, 2, 234. (c) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci.
U.S.A. 2006, 13, 8928.
(20) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 122, 6327.
`
(21) Bringmann, G.; GuEnther, C.; Peters, E.-M.; Peters, K. Tetrahedron
2001, 57, 1253.
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Qiu et al.
produced in a 1:1 ratio,23 showing somewhat disappointingly
that the chiral sulfinimine auxiliary had no influence on the facial
selectivity of attack by the lithiated indole nucleophile under
these conditions. Although excellent selectivity was achieved
in a somewhat different system (see below), in this particular
case the diastereoisomers 27 and 28 could be readily separated
by silica gel column chromatography. The Ellman auxiliary thus
serves in this case as a very convenient resolving agent, allowing
the preparation of both enantiomers of IBR2 analogues.
Thus, starting with the optically pure sulfinimide 27, HCl-
mediated removal of the tert-butanesulfinyl group cleanly
provided the amine product 29 in 95% yield (Scheme 2).
Subjecting the amine 29 to hydrogenation provided the amino
alcohol 30 in 95% yield, which was further protected with
TBDMSCl to afford compound 31 in 70% overall yield.
Exposure of the amine 31 to CbzCl/DMAP/CH2Cl2 delivered
compound 32 in 96% yield and subsequent removal of the silyl
group in 32 with TBAF yielded the alcohol 33 in 92% yield.
Additionally, treatment of 30 with CbzCl/DMAP could alter-
natively afford 33 in 52% yield along with the bis-Cbz
compound 34 in 20% yield. Alcohol 33 was further mesylated
to give compound 35 in 88% yield. Once hydrogenation of the
mesylate 35 was carried out with Pd/C as catalyst in EtOH,24
the desired cyclic amine 36 was isolated in 97% yield, which
led directly to the desired sulfonamide 37 in 78% yield via
benzylsulfonylation. Unfortunately, TFA-mediated removal of
the Boc group in 37 only gave the IBR2 analogue 38 in low
yield and furthermore was determined to have racemized by
chiral HPLC analysis. To solve this problem, we slightly
reordered the synthetic route, removing the Boc group prior to
benzylsulfonylation. Thus, exposure of amine 36 to NaOMe/
MeOH/THF for 2 days furnished the indole derivative 39 in
86% yield,25 which was then subjected to benzylsulfonylation
to afford the desired chiral IBR2 analogue 1. Chiral HPLC
analysis confirmed that enantiomeric purity of 1 was very
high (98% ee favorite R), and its absolute configuration was
further confirmed by X-ray diffraction. In addition, a series
of chiral monofluorinated and trifluoromethylated IBR2
analogues, 3-5 and 9-11, were also accessed via sulfony-
lation of the key intermediate 39 with different fluorinated
arylsulfonyl chlorides.
FIGURE 2. Retrosynthetic analysis of target molecules 1-14.
SCHEME 1
on the asymmetric induction provided by Ellman’s N-tert-butyl
sulfinimine as the chiral auxiliary22 for selectively introducing
the single stereogenic center in the targets. Our chiral target
molecules would be delivered via benzylsulfonylation of the
intermediate 17 and subsequent deprotection, and cyclization
of intermediate 18 would pave the way to the amine 17. The
amine 18 in turn might be provided by means of addition of
protected 3-bromoindole 19 to the N-tert-butyl sulfinimine
derivative 20, which could be obtained by condensation between
the aldehyde 21 and the chiral Ellman reagent 22.
The synthesis embarked with the conversion of the com-
mercially available bromide 23 into the aldehyde 24 in two steps,
including benzylation followed by treatment with n-BuLi/THF/
DMF at -78 °C (Scheme 1). Next, condensation of the aldehyde
24 with (R)-Ellman sulfinamide 22 gave the sulfinimine deriva-
tive 25 in 79% yield. Addition proceeded well by treatment of
compound 25 with a solution of 1-Boc-3-lithioindole (prepared
in situ via reaction of 1-Boc-3-bromoindole 26 with n-BuLi) at
-78 °C, and the desired sulfinimides were isolated in 83% yield.
Unfortunately, the two diastereoisomers 27 and 28 were
Utilizing similar reaction procedures, the S configuration IBR2
analogues 2, 6-8, and 12-14 were also prepared starting from
sulfinimide 28 in a straightforward fashion (Scheme 3).
Highly Enantioselective Synthesis of IBR2 Analogues
15 and 16. Although the first route proved to be satisfactory in
many ways, we opted to explore additional avenues that might
be more concise in general and more enantioselective in the
key bond-forming step. Thus, an alternative retrosynthetic
analysis of chiral IBR2 analogues 15 and 16 inspired an
improved route in which the ring closure to form the nitrogen-
containing ring of the isoquinoline moiety be carried out via
ring closure metathesis (RCM) of an intermediate such as 48,26
and that the absolute stereochemistry would be controlled by
an asymmetric Friedel-Crafts (F-C) reaction of an achiral
(23) For some mechanistic explanation about the poor diastereoselectivity,
see the Supporting Information.
(24) Barrett, S.; Jaen, J. C.; Caprathe, B. W.; Thomas, A. J.; Tecle, Ha. Org.
Prep. Proced. Int. 1997, 29, 330.
(25) Cheng, A. C.; Shulgin, A. T., Jr. J. Org. Chem. 1982, 47, 5258.
(26) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 44, 4413. (b) Trnka,
T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(22) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984–995. (b) Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883.
2020 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of Chiral IBR2 Analogues
SCHEME 2
SCHEME 3
which then provided the imine 50 by condensation with
benzylsulfonamide. The “conventional” N-tosyl imine 53 was
also prepared by a similar sequence (Scheme 4, R ) Ts).
With the imines 50 and 53 in hand, asymmetric F-C
reactions with indole (unprotected) were investigated (Table 1).
First, the applicability of different catalysts was investigated
with N-tosyl imine 53 as substrate (entries 1 and 2). Bisoxazoline
Cu(II) complex 56 (generated in situ through reaction of (S)-
sulfonimine (50) with indole with use of thiourea alkaloids or
bisoxazoline Cu(II) complex as catalysts (Figure 3).27,28
Because the original Zhou and Deng reports of the asym-
metric F-C reactions26-28 included only examples of aryl
sulfoamides, we decided to test benzyl sulfonamides in the same
process. Thus, the requisite starting benzyl imine 50 (Scheme
4, R ) Bn) was readily prepared from 2-bromostyrene, 51, by
treatment of the corresponding bromide 51 with n-BuLi at -78
°C followed by anhydrous DMF to give the aldehyde 52 (73%),
(27) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc.
2006, 128, 8156.
(28) Jia, Y.-X.; Xie, J.-H.; Duan, H.-F.; Wang, L.-X.; Zhou, Q.-L. Org. Lett.
2006, 8, 1621.
FIGURE 3. Retrosynthetic analysis of target molecules 15-16.
J. Org. Chem. Vol. 74, No. 5, 2009 2021

Qiu et al.
SCHEME 4
TABLE 1. Asymmetric Friedel-Crafts Reactions of Imines 50 and 53 with Indole
product
yield(%) ee (%)
conc of
imine (M)
indole
(equiv)
cat.
(10 mol %)
entry
imine
solvent
T (°C)
time (day)
1
2
3
4
5
6
7
8
9
53
53
50
50
50
50
50
50
50
0.08
2.00
1.26
2.0
1.0
0.5
2.0
2.0
2.0
5.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
56
57
57
57
57
57
57
57
58
CH2Cl2
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
rt
50
50
rt
rt
rt
0
0
rt
3
2
2
4
7
7
7
12
7
54: 22
54: 80
55: 48
55: 40
55: 23
55: 13
55: 40
55: 55
55: 42
90 (R)
95 (R)
92 (R)
95 (R)
96 (R)
96 (R)
96 (R)
99 (R)
98 (S)
Bn-bisoxazoline and Cu(OTf)2) catalyzed the F-C reaction of
imine 53 with indole in low yield (22%) and in good enanti-
oselectivity (90% ee) (entry 1). To our delight, substitution of
cinchona-derivated thiourea alkaloid 57 for catalyst 56 dramati-
cally improves this asymmetric F-C reaction, and the desired
sulfonamide 54 was obtained in 80% yield and in 95% ee (entry
2). We were also pleased to find that F-C reaction of 50 with
indole catalyzed by alkaloid 57 at 50 °C delivered the desired
sulfonamide 55 in 48% yield and in 92% ee (entry 3). Although
the yield was slightly decreased, the enantioselectivity could
be further improved to 95% ee when reaction was performed
at room temperature for 4 days (entry 4). The same enantiose-
lectivities were observed when the concentration of indole was
reduced, although the yields of 55 were significantly decreased
(entries 4-6). By prolonging the reaction time from 4 days to
7 days, the asymmetric reaction also proceeded well even at 0
°C, and under those conditions 55 was produced in 40% yield
and in 96% ee (entry 4 vs entry 7). After further optimization,
we established that, at 0 °C for 12 days in EtOAc with thiourea
alkaloid 57 as catalyst, the F-C reaction of 50 with indole gave
the amide 55 in 55% yield and in 99% ee (entry 8). Utilizing
the quinine-derived thiourea alkaloid 58 as catalyst, the F-C
reaction progressed very well and the S configuration product
55 was afforded in 42% yield and 98% ee when the reaction
was performed at room temperature for 7 days (entry 9).
With these procedures providing ample quantities of enan-
tioenriched chiral precursors, we proceeded to test the proposed
RCM. Thus, protection of the chiral amide (R)-55 with Boc2O
gave compound 59 in 96% yield, which was further subjected
to allylation to afford the diene 60 in almost quantitative yield
(Scheme 5). RCM of compound 60 catalyzed by Grubbs first
generation catalyst smoothly provided the cyclic precursor 61
in good yield.29 Finally, removal of the Boc group with
Verkade’s base delivered the desired IBR2 analogue 15 in 65%
yield.30 The absolute configuration of compound 15 was
confirmed by X-ray diffraction. Using similar reaction condi-
tions, the corresponding S-enantiomer, 16, was also conveniently
prepared starting from the optically pure (S)-55 (Scheme 6).
In summary, we have developed two routes to synthesize
enantiomerically pure IBR2 analogues 1-16. One route features
the addition of N-Boc-3-bromoindole 26 to the sulfinamide 25,
providing good yield of the readily separable diasteroisomers
27 and 28 in a 1:1 ratio, and allowing for the preparation of
useful amounts of either enantiomer in this series of analogues.
The other route highlights the highly enantioselective addition
of unprotected indole to the sulfonyl amide 50, mediated by
bifunctional amino-thioureas 57 and 58 as catalysts. Screening
the biological activity of the IBR2 analogues 1-16, and others
prepared by this methodology, in a series of cancer cell lines is
in progress and will be reported elsewhere.
(29) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.; Nishida, A. J.
Org. Chem. 2006, 71, 4255.
(30) Shieh, W.-C.; Xue, S.; McKenna, J.; Prasad, K.; Repic, O.; Blacklock,
T. Tetrahedron Lett. 2006, 47, 5645.
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Synthesis of Chiral IBR2 Analogues
SCHEME 5
CDCl3) δ 192.4, 141.5, 138.3, 134.2, 133.5, 131.9, 131.7, 128.3,
127.4, 127.4, 126.8, 72.8, 70.6, 32.9; MS (ESI) m/z 241 (M + H+),
263 (M + Na+); ESI-HRMS calcd for C16H17O2 (M + H+)
241.1228, found 241.1231.
(R)-2-Methylpropane-2-sulfinic Acid 1-[2-(2-Benzyloxyethyl)-
phenyl]meth-(E)-ylideneamide (25). To a solution of aldehyde
24 (490 mg, 2.04 mmol) and (R)-tert-butanesulfinamide 22 (280
mg, 2.31 mmol) in THF (20 mL) was added Ti(OEt)4 (20% in
EtOH, 2.3 mL). The resulting mixture was stirred at room
temperature overnight. Then, H2O (30 mL) was added to quench
the reaction and CH2Cl2 (20 mL) was added. After filtration, the
filtrate was extracted with CH2Cl2 (3 × 30 mL). The combined
organic phases were dried over anhydrous Na2SO4. The solvent
was removed and the residue was purified by silica gel chroma-
tography (hexane/EtOAc ) 10:1) to give compound 25 (556 mg,
79%) as a light yellow oil. [R]20D -95.7 (c 0.93 CH2Cl2); 1H NMR
(500 MHz, CD2Cl2) δ 8.86 (s, 1H), 7.95 (dd, J ) 8.3, 1.3 Hz, 1H),
7.45 (ddd, J ) 7.8, 7.3, 1.3 Hz, 1H), 7.37-7.24 (m, 7H), 4.50-4.45
(m, 2H), 3.73-3.65 (m, 2H), 3.28 (t, J ) 6.8 Hz, 2H), 1.23 (s,
9H); 13C NMR (125 MHz, CD2Cl2) δ 162.2, 141.2, 139.1, 133.0,
132.4, 131.9, 130.2, 128.8, 128.0, 127.9, 127.4, 73.4, 71.4, 57.9,
33.9, 22.8; MS (ESI) m/z 344 (M + H+), 366 (M + Na+); ESI-
HRMS calcd for C20H25NO2SNa (M + Na+), 366.1504, found
366.1497.
3-[(R)-[2-(2-Benzyloxyethyl)phenyl]-((R)-2-methylpropane-2-
sulfinylamino)methyl]indole-1 Carboxylic Acid tert-Butyl Ester
(27) and 3-[(S)-[2-(2-Benzyloxyethylphenyl]-((R)-2-methylpropane-
2-sulfinylamino)methyl]indole-1-carboxylic Acid tert-Butyl Ester
(28). Under the protection of N2, a solution of 3-bormo-1-N-tert-
butyloxycarbonylindole 26 (600 mg, 2.00 mmol) in THF (10 mL)
was cooled to -78 °C. n-BuLi (0.7 mL, 2.86 M in hexane, 2.00
mmol) was added dropwise. The resulting mixture was stirred at
-78 °C for 30 min. Then, a solution of compound 25 (535 mg,
1.56 mmol) in THF (6 mL) was added dropwise. After the mixture
was stirred at -78 °C for 20 min, H2O (3 mL) was dropwise added
to quench the reaction. The mixture was warmed to room
temperature and H2O (50 mL) was added. The resulting aqueous
solution was extracted with CH2Cl2 (3 × 50 mL). The combined
organic layers were washed with brine, and then dried over
anhydrous Na2SO4. After filtration and removal of the solvent in
vacuo, the residue was purified by silica gel column chromatography
(hexane/EtOAc ) 5:1 to 4:1) to afford 27 (less polar, 415 mg,
47.5%) as a white foam and 28 (more polar, 430 mg, 49%) as a
white foam. 27: [R]20D -25.9 (c 0.75 CHCl3); 1H NMR (500 MHz,
CDCl3) δ 8.08 (d, J ) 8.0 Hz, 1H), 7.80 (d, J ) 8.5 Hz, 1H), 7.65
(d, J ) 7.0 Hz, 1H), 7.35-7.15 (m, 11H), 6.21 (d, J ) 2.5 Hz,
1H), 4.46-4.40 (m, 2H), 3.79 (s, 1H), 3.70-3.65 (m, 1H),
3.62-3.57 (m, 1H), 3.03-2.93 (m, 2H), 1.62 (s, 9H), 1.21 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 149.9, 138.7, 138.5, 137.1, 135.9,
130.5, 128.7, 128.5, 128.3, 128.0, 127.8, 127.7, 126.8, 125.7, 125.1,
123.4, 122.4, 119.8, 115.6, 84.3, 73.1, 70.8, 56.1, 50.6, 33.1, 28.4,
22.9; MS (ESI) m/z 561 (M + H+); ESI-HRMS calcd for
SCHEME 6
Experiment Section
2-(2-Benzyloxyethyl)benzaldehyde (24). A mixture of TBAI
(30 mg, 0.08 mmol) and NaH (255 mg, 60% in oil, 6.37 mmol) in
THF (15 mL) was cooled to 0 °C. Then, compound 23 (1.07 g,
5.33 mmol) in THF (15 mL) was added dropwise. The resulting
mixture was heated to 45 °C for 20 min. After that, the mixture
was cooled to 0 °C again and BnBr (1.37 g, 7.99 mmol) was added
dropwise. The mixture was stirred overnight at room temperature.
H2O (50 mL) was added to quench the reaction and the mixture
was extracted with CH2Cl2 (3 × 100 mL). The combined organic
phases were dried over anhydrous Na2SO4. After removal of all
the solvent, the residue was purified by silica gel chromatography
(hexane/EtOAc ) 100:1) to afford an oil (1.54 g). This oil (1.54
g) was dissolved in THF (20 mL) and the resulting solution was
cooled to -78 °C. n-BuLi (3.20 mL, 2.46 M in hexane, 7.94 mmol)
was added dropwise. After the mixture was stirred at -78 °C for
30 min, anhydrous DMF (1.36 mL, 17.56 mmol) was added
dropwise. The mixture was stirred for another 30 min before H2O
(5 mL) was added to quench the reaction. After the mixture was
warmed to room temperature, H2O (100 mL) was added and the
mixture was extracted with CH2Cl2 (3 × 100 mL). The combined
organic layers were dried over anhydrous Na2SO4. After removal
of all the solvent, the residue was purified by silica gel chroma-
tography (hexane/EtOAc ) 100:1 to 15:1) to afford 24 as an oil
C33H40N2O4SNa (M + Na+) 583.2606, found 583.2628. 28: [R]20
D
+2.6 (c 1.15 CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H),
7.60 (s, 1H), 7.36 (d, J ) 7.5 Hz, 2H), 7.28-7.06 (m, 10H), 6.18
(d, J ) 3.0 Hz, 1H), 4.52-4.46 (m, 2H), 3.90 (d, J ) 3.0 Hz, 1H),
3.77-3.72 (m, 2H), 3.24-3.14 (m, 2H), 1.66 (s, 9H), 1.23 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 149.7, 139.0, 138.3, 137.4, 135.9,
130.5, 129.1, 128.4, 128.3, 128.2, 127.6, 127.5, 126.8, 125.4, 124.6,
122.6, 121.6, 120.4, 115.3, 83.4, 73.0, 70.8, 56.0, 51.8, 32.2, 28.3,
22.9; MS (ESI) m/z 583 (M + Na+); ESI-HRMS calcd for
C33H40N2O4SNa (M + Na+) 583.2606, found 583.2597.
3-{(R)-Amino[2-(2-benzyloxyethyl)phenyl]methyl}indole-1-car-
boxylic Acid tert-Butyl Ester (29). To a solution of 27 (376 mg,
0.67 mmol) in MeOH (7 mL) was added 4 M HCl solution (in
dioxane, 7 mL). After the mixture was stirred at room temperature
for 30 min, the mixture was carefully poured into an aqueous
NaHCO3 solution (3.00 g of NaHCO3 in H2O (50 mL)). Then, the
resulting aqueous solution was extracted with CH2Cl2 (3 × 60 mL).
1
(1.09 g, 84%). H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 7.76
(dd, J ) 7.6, 1.2 Hz, 1H), 7.43 (td, J ) 7.5, 1.2 Hz, 1H), 7.31 (td,
J ) 7.4, 0.8 Hz, 1H), 7.28-7.20 (m, 6H), 4.44 (s, 2H), 3.66 (t, J
) 6.4 Hz, 2H), 3.30 (t, J ) 6.4 Hz, 2H); 13C NMR (100.5 MHz,
J. Org. Chem. Vol. 74, No. 5, 2009 2023

Qiu et al.
The combined organic layers were washed with brine and then dried
over anhydrous Na2SO4. After filtration and removal of the solvent
in vacuo, the residue was purified by silica gel column chroma-
138.6, 137.2, 136.6, 136.0, 131.2, 129.0, 128.7, 128.3, 127.9, 127.1,
126.9, 124.9, 124.6, 122.9, 122.3, 120.0, 115.5, 84.1, 67.1, 64.1,
49.2, 36.1, 28.3, 26.1, 18.5, -5.3; MS (ESI) m/z 632 (M + NH4+),
1246 (2 M + NH4+), 1251 (2 M + Na+); ESI-HRMS calcd for
C36H46N2O5SiNa (M + Na+) 637.3074, found 637.3060.
tography (CH2Cl2/MeOH ) 30:1) to afford 29 (290 mg, 95%) as
1
a clear oil. [R]20 -66.4 (c 1.10 CHCl3); H NMR (500 MHz,
D
CDCl3) δ 8.11 (br, 1H), 7.52 (d, J ) 1.0 Hz, 1H), 7.32-7.13 (m,
11H), 7.08-7.05 (m, 1H), 5.65 (s, 1H), 4.48 (s, 2H), 3.77-3.68
(m, 2H), 3.22-3.16 (m, 1H), 3.09-3.03 (m, 1H), 1.86 (br, 2H),
1.66 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 150.0, 142.9, 138.3,
136.6, 136.1, 130.2, 129.4, 128.5, 127.8, 127.8, 127.4, 127.2, 127.1,
125.5, 124.5, 123.4, 122.6, 120.0, 115.4, 83.7, 73.2, 71.4, 48.9,
33.0, 28.4; MS (ESI) m/z 457 (M + H+), 913 (2 M + Na+); ESI-
HRMS calcd for C29H33N2O3 (M + H+) 457.2491, found 457.2482.
3-{(R)-Amino[2-(2-hydroxyethyl)phenyl]methyl}indole-1-car-
boxylic Acid tert-Butyl Ester (30). To a stirred solution of 29 (290
mg, 0.64 mmol) in MeOH (10 mL) was added 1 M HCl in dioxane
(1 mL), followed by Pd/C (200 mg, 10% Pd). The mixture was
hydrogenated at room temperature under 1 atm for 1 h. Then, the
mixture was filtrated and the filtrate was neutralized with a NaHCO3
aqueous solution (500 mg NaHCO3 in 100 mL of H2O). The
resulting mixture was extracted with CH2Cl2 (3 × 60 mL). The
combined organic layers were washed with brine, and then dried
over anhydrous Na2SO4. After filtration and removal of the solvent
in vacuo, the residue was purified by silica gel column chroma-
tography (CH2Cl2/MeOH ) 30:1) to deliver compound 30 as a
white foam (220 mg, 95%). [R]20D -59.9 (c 1.10 CHCl3); 1H NMR
(400 MHz, CD2Cl2) δ 8.12 (d, J ) 8.4 Hz, 1H), 7.67 (s, 1H),
7.32-7.22 (m, 3H), 7.10-7.03 (m, 4H), 5.61 (s, 1H), 4.02-3.97
(m, 1H), 3.76 (ddd, J ) 10.0, 9.8, 3.6 Hz, 1H), 3.25 (ddd, J )
14.4, 9.6, 4.4 Hz, 1H), 3.06-2.98 (m, 4H), 1.70 (s, 9H); 13C NMR
(125 MHz, CD2Cl2) δ 150.2, 141.8, 139.8, 136.6, 131.0, 129.4,
128.5, 127.6, 127.1, 125.7, 125.0, 123.6, 122.9, 120.3, 115.8, 84.4,
64.3, 49.4, 36.3, 28.5; MS (ESI) m/z 733 (2 M + H+); ESI-HRMS
calcd for C22H26N2O3Na (M + Na+) 389.1841, found 389.1851.
3-((R)-Amino{2-[2-(tert-butyldimethylsilanyloxy)ethyl]phenyl}-
methyl)indole-1-carboxylic Acid tert-Butyl Ester (31). The white
foam 30 (220 mg, 0.81 mmol) was dissolved in CH2Cl2 (15 mL).
After the solution was cooled to 0 °C, imidazole (78 mg, 1.15
mmol) and DMAP (5 mg, 0.04 mmol) were added. Five minutes
later, a solution of TBDMSCl (150 mg, 1.00 mmol) was added
dropwise. The resulting mixture was stirred at room temperature
for 1.5 h. After that, all the solvent was removed in vacuo. The
residue was purified by silica gel column chromatography (CH2Cl2/
MeOH ) 40:1) to afford 31 (271 mg, 70%) as a light yellow oil.
[R]20D -60.8 (c 1.00 CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.19
(br, 1H), 7.56 (d, J ) 1.0 Hz, 1H), 7.40 (d, J ) 7.0 Hz, 1H),
7.35-7.26 (m, 4H), 7.24-7.16 (m, 2H), 5.72 (s, 1H), 3.97-3.89
(m, 2H), 3.17-3.12 (m, 1H), 3.07-3.02 (m, 1H), 2.02 (br, 2H),
1.73 (s, 9H), 0.91 (s, 9H), 0.05, 0.04 (2s, 6H); 13C NMR (125 MHz,
CDCl3) δ 149.8, 142.4, 136.3, 130.4, 129.1, 127.2, 126.8, 126.8,
125.2, 124.3, 123.3, 122.4, 119.8, 115.2, 83.6, 64.6, 48.6, 35.7,
28.2, 25.9, 18.4, -5.4; MS (ESI) m/z 503 (M + Na+), 961 (2 M +
H+); ESI-HRMS calcd for C28H40N2O3SiNa (M + Na+) 503.2706,
found 503.2704.
3-{(R)-Benzyloxycarbonylamino[2-(2-hydroxyethyl)phenyl]meth-
yl}indole-1-carboxylic Acid tert-Butyl Ester (33). To a solution of
compound 32 (331 mg, 0.53 mmol) in THF (20 mL) was added
TBAF (1 M in THF, 0.59 mL) dropwise at 0 °C. Then, the mixture
was stirred at room temperature for 30 min. After that, all the
solvent was removed and the residue was purified by silica gel
chromatography (hexane/EtOAc ) 2:1) to give compound 33 (249
mg, 92%) as a white foam. [R]20D +18.9 (c 1.10 CH2Cl2); 1H NMR
(500 MHz, CD2Cl2) δ 8.09 (d, J ) 8.0 Hz, 1H), 7.42 (d, J ) 7.5
Hz, 1H), 7.37-7.24 (m, 10H), 7.20-7.14 (m, 2H), 6.47 (d, J )
7.0 Hz, 1H), 5.70 (d, J ) 7.5 Hz, 1H), 5.16-5.08 (m, 2H),
3.88-3.84 (m, 2H), 2.98-2.87 (m, 2H), 2.21 (br, 1H), 1.62 (s,
9H); 13C NMR (125 MHz, CD2Cl2) δ 156.2, 150.1, 139.8, 137.8,
137.2, 136.5, 131.1, 129.2, 129.0, 128.6, 128.5, 128.4, 127.4, 127.3,
125.3, 125.2, 123.2, 121.9, 120.1, 115.9, 84.6, 67.4, 64.2, 49.4,
36.3, 28.4; MS (ESI) m/z 523 (M + Na+), 1023 (2 M + Na+);
ESI-HRMS calcd for C30H32N2O5Na (M + Na+) 523.2209, found
523.2206.
3-{(R)-Benzyloxycarbonylamino[2-(2-benzyloxycarbonyloxyeth-
yl)phenyl]methyl}indole-1-carboxylic Acid tert-Butyl Ester (34). To
a 0 °C solution of 30 (206 mg, 0.56 mmol) in CH2Cl2 (12 mL)
was added DIPEA (111 µL, 0.62 mmol) followed by CbzCl (84
µL, 0.56 mmol) dropwise. The mixture was stirred at room
temperature for 10 min. Then, all the solvent was removed in vacuo
and the residue was purified by silica gel chromatography (hexane/
EtOAc ) 2:1) to give the compound 33 (165 mg, 52%) as an oil
and 34 (80 mg, 20%) as an oil. Compound 34: [R]20D +5.8 (c 1.10
CH2Cl2); 1H NMR (400 MHz, CD2Cl2) δ 8.12 (d, J ) 8.0 Hz, 1H),
7.44-7.26 (m, 16H), 7.20-7.15 (m, 2H), 6.45 (d, J ) 7.6 Hz,
1H), 5.62 (d, J ) 7.8 Hz, 1H), 5.19-5.10 (m, 4H), 4.50-4.44 (m,
1H), 4.36-4.30 (m, 1H), 3.16-3.05 (m, 2H), 1.64 (s, 9H); 13C
NMR (125 MHz, CD2Cl2) δ 155.9, 155.5, 150.1, 139.7, 137.3,
136.5, 136.1, 135.7, 131.1, 129.3, 129.0, 129.0, 128.9, 128.8, 128.6,
128.5, 128.4, 127.8, 127.6, 125.2, 123.2, 121.9, 120.2, 115.8, 84.5,
70.0, 68.4, 67.4, 49.2, 32.2, 28.4; MS (ESI) m/z 635 (M + H+),
652 (M + NH4+), 657 (M + Na+); ESI-HRMS calcd for
C38H38N2O7Na (M + Na+) 657.2577, found 657.2578.
3-{(R)-Benzyloxycarbonylamino[2-(2-methanesulfonyloxyethyl)-
phenyl]methyl}indole-1-carboxylic Acid tert-Butyl Ester (35). Com-
pound 34 (249 mg, 0.5 mmol) was dissolved in CH2Cl2 (20 mL)
and the resulting solution was cooled to 0 °C. After DMAP (5 mg,
0.04 mmol) and DIPEA (104 µL, 0.58 mmol) were added
sequentially, MsCl (60 µL, 0.77 mmol) was added dropwise. The
mixture was stirred at room temperature for 30 min. After that, the
solvent was removed in vacuo and the residue was purified by silica
gel column chromatography (hexane/EtOAc ) 4:1 to 3:1) to afford
35 (255 mg, 88%) as a white foam. [R]20D +28.4 (c 1.05 CHCl3);
1H NMR (400 MHz, CDCl3) δ 8.10 (d, J ) 8.0 Hz, 1H), 7.47-7.21
(m, 12H), 7.12 (s, 1H), 6.41 (d, J ) 8.0 Hz, 1H), 5.52 (d, J ) 8.0
Hz, 1H), 5.15 (dd, J ) 12.4, 12.4 Hz, 2H), 4.54-4.49 (m, 1H),
4.45-4.39 (m, 1H), 3.21-3.11 (m, 2H), 2.80 (s, 3H), 1.65 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 155.7, 149.8, 139.2, 136.5, 136.0,
134.0, 131.1, 128.7, 128.4, 128.3, 128.2, 128.0, 127.0, 125.2, 123.2,
121.4, 119.8, 115.6, 84.5, 69.9, 67.3, 48.6, 37.1, 32.4, 28.3; MS
(ESI) m/z 601 (M + Na+), 1179 (2 M + Na+); ESI-HRMS calcd
for C31H34N2O7SNa (M + Na+) 601.1984, found 601.1981.
(R)-3-(1,2,3,4-Tetrahydroisoquinolin-1-yl)indole-1-carboxylic Acid
tert-Butyl Ester (36). To a solution of 35 (255 mg, 0.44 mmol) in
EtOH (15 mL) was added Pd/C (120 mg, 10% Pd). The mixture
was hydrogenated at room temperature under 1 atm for 1.5 h. Then,
the solvent was removed in vacuo and the residue was purified by
silica gel column chromatography (CH2Cl2/MeOH ) 40:1 to 10:
3-((R)-Benzyloxycarbonylamino{2-[2-(tert-butyldimethylsilanylo-
xy)ethyl]phenyl}methyl)indole-1-carboxylic Acid tert-Butyl Ester
(32). To a 0 °C solution of 31 (271 mg, 0.56 mmol) in CH2Cl2 (15
mL) was added DMAP (5 mg, 0.04 mmol) and DIPEA (150 µL,
0.84 mmol). After the mixture was stirred at 0 °C for 10 min, CbzCl
(115 µL, 0.82 mmol) was added dropwise. The mixture was stirred
at room temperature for 20 min. Then, all the solvent was removed
in vacuo and the residue was purified by silica gel column
chromatography (hexane/EtOAc ) 12:1) to afford 32 (331 mg,
96%) as a white foam. [R]20D +7.6 (c 0.98 CHCl3); 1H NMR (500
MHz, CDCl3) δ 8.15 (d, J ) 6.5 Hz, 1H), 7.43-7.22 (m, 13H),
6.48 (d, J ) 8.5 Hz, 1H), 5.65 (d, J ) 10.0 Hz, 1H), 5.22 (dd, J )
12.5, 12.5 Hz, 2H), 3.99-3.95 (m, 1H), 3.88-3.84 (m, 1H),
3.09-3.04 (m, 1H), 2.98-2.93 (m, 1H), 1.72 (s, 9H), 0.88 (s, 9H),
0.01, -0.01 (2s, 6H); 13C NMR (125 MHz, CDCl3) δ 155.6, 149.9,
1) to afford 36 (149 mg, 97%) as a white foam. [R]20 +17.0 (c
D
1
0.40 CHCl3); H NMR (500 MHz, CDCl3) δ 8.20 (d, J ) 6.5 Hz,
2024 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of Chiral IBR2 Analogues
1H), 7.55 (s, 1H), 7.47 (d, J ) 8.0 Hz, 1H), 7.36 (t, J ) 8.0 Hz,
1H), 7.26-7.21 (m, 3H), 7.14-7.11 (m, 1H), 7.03 (d, J ) 8.0 Hz,
1H), 5.57 (s, 1H), 4.63 (br, 1H), 3.39 (dt, J ) 12.5, 6.0 Hz, 1H),
3.25-3.13 (m, 2H), 3.00 (dt, J ) 15.5, 5.5 Hz, 1H), 1.73 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 149.9, 136.0, 135.9, 134.6, 129.3,
129.2, 127.8, 127.0, 126.2, 126.0, 124.7, 122.8, 122.2, 120.3, 115.5,
84.1, 53.5, 41.8, 28.9, 28.4; MS (ESI) m/z 349 (M + H+), 697 (2
M + H+); ESI-HRMS calcd for C22H25N2O2 (M + H+) 349.1916,
found 349.1912.
1H), 3.24 (ddd, J ) 13.6, 4.4, 4.4 Hz, 1H), 3.01 (ddd, J ) 17.2,
6.0, 4.4 Hz, 1H), 2.77 (dd, J ) 4.0, 2.8 Hz, 1H); 13C NMR (125
MHz, CD2Cl2) δ 136.9, 136.3, 134.1, 131.2, 129.6, 129.6, 128.8,
128.8, 128.7, 127.4, 126.9, 126.6, 125.9, 123.1, 120.8, 120.4, 117.7,
111.9, 59.3, 53.1, 40.0, 29.1; MS (ESI) m/z 403 (M + H+), 420
(M + NH4+), 425 (M + Na+); ESI-HRMS calcd for C24H23N2O2S
(M + H+) 403.1480, found 403.1476.
(R)-2-(2-Fluorophenylmethanesulfonyl)-1-(1H-indol-3-yl)-1,2,3,4-
tetrahydroisoquinoline (3). Compound 3 (45 mg, 75%) was
prepared as a white foam with the same conditions as described
3-((R)-2-Phenylmethanesulfonyl-1,2,3,4-tetrahydroisoquinolin-
1-yl)indole-1-carboxylic Acid tert-Butyl Ester (37). To a 0 °C
solution of compound 36 (8 mg, 0.023 mmol) in CH2Cl2 (2 mL)
was added BnSO2Cl (21 mg, 0.11 mmol). Then, DMAP (5 mg,
0.04 mmol) was added and the resulting mixture was stirred at room
temperature for 30 min. After that, all the solvent was removed
and the residue was purified by silica gel column chromatography
1
for compound 1. [R]20 +110.0 (c 0.60 CH2Cl2); H NMR (400
D
MHz, CD2Cl2) δ 8.31 (s, 1H), 7.70 (d, J ) 8.0 Hz, 1H), 7.39 (dt,
J ) 8.0, 0.8 Hz, 1H), 7.29-7.23 (m, 3H), 7.19 (ddd, J ) 8.2, 0.8,
1.2 Hz, 1H), 7.15-7.07 (m, 3H), 7.05-7.01 (m, 2H), 6.95 (ddd, J
) 9.6, 1.2, 1.2 Hz, 1H), 6.82 (d, J ) 2.4 Hz, 1H), 6.41 (s, 1H),
3.98 (s, 2H), 3.77 (ddt, J ) 6.4, 6.8, 1.6 Hz, 1H), 3.44 (ddd, J )
16.6, 4.8, 2.0 Hz, 1H), 3.14 (ddd, J ) 18.0, 6.8, 5.6 Hz, 1H), 2.86
(ddd, J ) 16.8, 1.2, 0.8 Hz, 1H); 13C NMR (125 MHz, CD2Cl2) δ
162.7, 160.7, 136.9, 136.2, 134.0, 133.0, 133.0, 131.0, 130.9, 129.7,
128.6, 127.5, 126.8, 126.7, 126.1, 124.6, 124.6, 123.0, 120.7, 120.4,
117.5, 117.3, 117.2, 116.0, 115.8, 111.8, 53.3, 52.0 (d, J ) 2.1
Hz), 39.9, 28.8; 19F NMR (376 MHz, CD2Cl2) δ -117.5 (s, 1F);
MS (ESI) m/z 421 (M + H+), 438 (M + NH4+), 443 (M + Na+);
ESI-HRMS calcd for C24H22FN2O2S (M + H+) 421.1386, found
421.1371.
(R)-2-(3-Fluorophenylmethanesulfonyl)-1-(1H-indol-3-yl)-1,2,3,4-
tetrahydroisoquinoline (4). Compound 4 (35 mg, 73%) was
prepared as a white foam with the same conditions as described
for the compound 1. [R]20D +72.7 (c 0.60 CH2Cl2); 1H NMR (400
MHz, CD2Cl2) δ 8.36 (s, 1H), 7.76 (d, J ) 8.0 Hz, 1H), 7.43 (d,
J ) 8.0 Hz, 1H), 7.25-7.19 (m, 3H), 7.16-7.10 (m, 3H), 7.02 (d,
J ) 7.6 Hz, 1H), 6.95 (td, J ) 8.4, 2.0 Hz, 1H), 6.84 (d, J ) 2.4
Hz, 1H), 6.70 (d, J ) 7.6 Hz, 1H), 6.60 (d, J ) 9.6 Hz, 1H), 6.42
(s, 1H), 3.92 (d, J ) 13.6 Hz, 1H), 3.86 (d, J ) 13.6 Hz, 1H), 3.58
(dd, J ) 6.4, 6.4 Hz, 1H), 3.24 (ddd, J ) 13.6, 4.4, 4.4 Hz, 1H),
3.02 (ddd, J ) 17.6, 6.8, 4.8 Hz, 1H), 2.79 (dd, J ) 16.8, 3.2 Hz,
1H); 13C NMR (125 MHz, CD2Cl2) δ 163.9, 161.9, 136.8, 136.2,
134.0, 132.0, 131.9, 130.4, 130.3, 129.6, 128.6, 127.5, 127.0, 127.0,
126.9, 126.7, 125.9, 123.2, 120.8, 120.3, 118.1, 117.9, 117.7, 115.8,
115.6, 111.9, 58.8, 53.1, 40.1, 29.2; 19F NMR (376 MHz, CD2Cl2)
δ -113.8 (s, 1F); MS (ESI) m/z 421 (M + H+), 438 (M + NH4+),
443 (M + Na+); ESI-HRMS calcd for C24H22FN2 O2S (M + H+)
421.1386, found 421.1385.
(R)-2-(4-Fluorophenylmethanesulfonyl)-1-(1H-indol-3-yl)-1,2,3,4-
tetrahydroisoquinoline (5). Compound 5 (50 mg, 83%) was
prepared as a white foam with the same conditions as described
for the compound 1. [R]20D +80.6 (c 0.42 CH2Cl2); 1H NMR (500
MHz, CD2Cl2) δ 8.33 (s, 1H), 7.73 (d, J ) 6.0 Hz, 1H), 7.42 (d,
J ) 6.4 Hz, 1H), 7.24-7.19 (m, 3H), 7.14-7.10 (m, 2H), 7.09 (d,
J ) 6.0 Hz, 1H), 6.88-6.82 (m, 5H), 6.39 (s, 1H), 3.93 (d, J )
10.8 Hz, 1H), 3.85 (d, J ) 11.2 Hz, 1H), 3.55 (ddt, J ) 10.8, 5.2,
5.2 Hz, 1H), 3.23 (ddd, J ) 13.2, 3.2, 1.2 Hz, 1H), 3.01 (ddd, J )
14.2, 5.6, 4.0 Hz, 1H), 2.78 (ddd, J ) 13.4, 1.2, 0.8 Hz, 1H); 13C
NMR (125 MHz, CD2Cl2) δ 136.9, 136.3, 134.1, 133.0, 132.9,
129.7, 128.7, 127.5, 126.9, 126.7, 125.9, 125.6, 125.6, 123.2, 120.8,
120.4, 115.8, 111.9, 58.5, 53.1, 40.1, 29.2; 19F NMR (376 MHz,
CD2Cl2) δ -114.6 (s, 1F); MS (ESI) m/z 443 (M + Na+); ESI-
HRMS calcd for C24H21FN2O2SNa (M + Na+) 443.1205, found
443.1197.
(hexane/EtOAc ) 10:1 to 5:1) to afford 37 (9 mg, 78%) as a white
1
foam. [R]20 +56.0 (c 1.06 CHCl3); H NMR (500 MHz, CDCl3)
D
δ 8.15 (d, J ) 7.5 Hz, 1H), 7.93 (d, J ) 7.5 Hz, 1H), 7.41 (ddd,
J ) 9.3, 1.5, 1.0 Hz, 1H), 7.35-7.28 (m, 3H), 7.23-7.18 (m, 5H),
7.06 (d, J ) 7.5 Hz, 1H), 7.02 (d, J ) 7.5 Hz, 2H), 6.41 (s, 1H),
4.04 (dd, J ) 13.5, 13.5 Hz, 2H), 3.67 (dd, J ) 6.5, 6.5 Hz, 1H),
3.30 (ddd, J ) 16.5, 4.5, 2.0 Hz, 1H), 3.05 (ddd, J ) 17.5, 7.0, 4.5
Hz, 1H), 2.81 (dd, J ) 3.5, 4.4 Hz, 1H), 1.72 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 149.7, 135.3, 134.4, 133.4, 130.6, 129.2,
129.1, 128.6, 128.4, 128.3, 128.0, 127.3, 126.5, 126.4, 124.9, 123.1,
121.7, 120.5, 115.2, 84.3, 77.4, 59.3, 51.9, 39.5, 28.2; MS (ESI)
m/z 520 (M + NH4+), 525 (M + Na+); ESI-HRMS calcd for
C29H34N3O4S (M + NH4+) 520.2270, found 520.2278.
1-(1H-Indol-3-yl)-2-phenylmethanesulfonyl-1,2,3,4-tetrahydroiso-
quinoline (38). To a 0 °C solution of 37 (148 mg, 0.295 mmol) in
CH2Cl2 (8 mL) was added a solution of TFA (1 mL) in CH2Cl2 (2
mL) dropwise. Then, the resulting mixture was stirred at room
temperature for 3 h. A solution of NaHCO3 (1.3 g, 15.47 mmol) in
H2O (50 mL) was carefully added to quench the reaction. The
mixture was extracted with CH2Cl2 (3 × 25 mL). The combined
organic layers were washed with brine, and then dried over
anhydrous Na2SO4. After filtration and removal of the solvent in
vacuo, the residue was purified by silica gel column chromatography
(hexane/EtOAc ) 4:1 to 3:1) to deliver the racemic compound 38
(66 mg, 56%) as a white foam.
(R)-1-(1H-Indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (39). To a
0 °C solution of 36 (139 mg, 0.40 mmol) in THF (9 mL) was added
a solution of NaOMe (108 mg, 1.997 mmol) in MeOH (9 mL) in
one portion. The resulting mixture was stirred at room temperature
for 2 days. Then, all the solvent was removed in vacuuo and the
residue was purified by silica gel column chromatography (CH2Cl2/
MeOH ) 15:1 to 5:1) to afford 39 (85 mg, 86%) as a white foam.
[R]20D +7.6 (c 1.00 CH2Cl2); 1H NMR (400 MHz, CD2Cl2) δ 8.63
(s, 1H), 7.42 (d, J ) 8.0 Hz, 1H), 7.33 (d, J ) 8.4 Hz, 1H),
7.19-7.12 (m, 3H), 7.03-6.98 (m, 2H), 6.94-6.92 (m, 2H), 5.45
(s, 1H), 3.29-3.23 (m, 1H), 3.12-3.00 (m, 2H), 2.92-2.84 (m,
1H), 2.70 (br, 1H); 13C NMR (125 MHz, CD2Cl2) δ 139.2, 137.2,
135.9, 129.5, 128.1, 126.9, 126.6, 126.0, 124.6, 122.4, 120.2, 119.9,
119.8, 111.8, 54.7, 42.6, 30.3; MS (ESI) m/z 249 (M + H+); ESI-
HRMS calcd for C17H17N2 (M + H+) 249.1392, found 249.1391.
(R)-1-(1H-Indol-3-yl)-2-phenylmethanesulfonyl-1,2,3,4-tetrahy-
droisoquinoline (1). To a 0 °C solution of 39 (66 mg, 0.27 mmol)
in CH2Cl2 (6 mL) was added DMAP (3 mg, 0.025 mmol) and
DIPEA (57 µL, 0.32 mmol). Then, a solution of BnSO2Cl (61 mg,
0.32 mmol) in CH2Cl2 (2 mL) was added dropwise. The resulting
mixture was stirred at room temperature for 15 min. After that, all
the solvent was removed in vacuo and the residue was purified by
silica gel column chromatography (hexane/EtOAc ) 4:1 to 3:1) to
(R)-1-(1H-Indol-3-yl)-2-(2-trifluoromethylphenylmethanesulfonyl)-
1,2,3,4-tetrahydroisoquinoline (9). Compound 9 (30 mg, 85%) was
prepared as a white foam with the same conditions as described
1
for compound 1. [R]20 +115.8 (c 0.43 CH2Cl2); H NMR (400
D
MHz, CD2Cl2) δ 8.30 (s, 1H), 7.76 (d, J ) 8.0 Hz, 1H), 7.65 (d,
J ) 7.6 Hz, 1H), 7.56-7.48 (m, 2H), 7.43 (t, J ) 7.6 Hz, 1H),
7.38 (d, J ) 8.4 Hz, 1H), 7.27-7.24 (m, 2H), 7.21-7.15 (m, 2H),
7.12-7.08 (m, 2H), 6.80 (d, J ) 2.0 Hz, 1H), 6.48 (s, 1H), 4.10
(d, J ) 14.0 Hz, 1H), 4.03 (d, J ) 14.4 Hz, 1H), 3.87 (ddd, J )
13.8, 7.0, 1.2 Hz, 1H), 3.51 (ddd, J ) 13.4, 4.4, 4.8 Hz, 1H), 3.20
afford 1 (94 mg, 88%) as a white foam. [R]20 +90.4 (c 1.04
D
1
CH2Cl2); H NMR (400 MHz, CD2Cl2) δ 8.36 (s, 1H), 7.74 (d, J
) 8.0 Hz, 1H), 7.42 (d, J ) 8.0 Hz, 1H), 7.27-7.11 (m, 8H), 7.03
(d, J ) 8.0 Hz, 1H), 6.92 (d, J ) 7.2 Hz, 2H), 6.85 (d, J ) 2.4 Hz,
1H), 6.42 (s, 1H), 3.95-3.86 (m, 2H), 3.56 (dd, J ) 6.4, 6.4 Hz,
J. Org. Chem. Vol. 74, No. 5, 2009 2025

Qiu et al.
(ddd, J ) 18.4, 7.2, 5.6 Hz, 1H), 2.92 (dd, J ) 4.0, 4.8 Hz, 1H);
13C NMR (125 MHz, CD2Cl2) δ 137.0. 136.0, 133.9, 133.6, 132.4,
129.8, 129.8, 129.0, 128.8, 128.2 (q, J ) 1.9 Hz), 127.7, 127.0 (q,
J ) 4.7 Hz), 126.8, 126.7, 126.0, 126.0, 123.5, 123.0, 120.7, 120.6,
120.4, 120.4, 117.4, 111.8, 55.0, 53.5, 39.7, 28.4; 19F NMR (376
MHz, CD2Cl2) δ -58.7 (s, 3F); MS (ESI) m/z 471 (M + H+), 488
(M + NH4+), 493 (M + Na+); ESI-HRMS calcd for C25H25F3N3O2S
(M + NH4+) 488.1620, found 488.1633.
(R)-1-(1H-Indol-3-yl)-2-(3-trifluoromethylphenylmethanesulfonyl)-
1,2,3,4-tetrahydroisoquinoline (10). Compound 10 (41 mg, 88%)
was prepared as a white foam with the same conditions as described
for compound 1. [R]20D +63.2 (c 0.89 CH2Cl2); 1H NMR (500 MHz,
CD2Cl2) δ 8.38 (s, 1H), 7.82 (d, J ) 8.0 Hz, 1H), 7.51 (d, J ) 7.5
Hz, 1H), 7.44 (dt, J ) 8.0, 1.0 Hz, 1H), 7.32 (t, J ) 7.5 Hz, 1H),
7.26-7.15 (m, 5H), 7.12 (td, J ) 8.0, 1.5 Hz, 1H), 7.03 (s, 1H),
7.02 (d, J ) 8.5 Hz, 1H), 6.83 (d, J ) 2.5 Hz, 1H), 6.47 (s, 1H),
3.98 (d, J ) 13.5 Hz, 1H), 3.93 (d, J ) 13.5 Hz, 1H), 3.50 (ddt, J
) 14.5, 6.0, 1.3 Hz, 1H), 3.20 (ddd, J ) 13.3, 4.0, 4.5 Hz, 1H),
3.02 (ddd, J ) 17.5, 6.0, 5.0 Hz, 1H), 2.78 (dd, J ) 3.0, 3.5 Hz,
1H); 13C NMR (125 MHz, CD2Cl2) δ 136.8, 136.2, 134.7, 133.9,
131.1, 130.9, 130.8, 130.6, 130.1, 129.6, 129.5, 128.7, 127.8 (q, J
) 3.1 Hz), 127.5, 126.9, 126.8, 125.9, 125.6 (q, J ) 3.8 Hz), 123.4,
123.3, 121.0, 120.0, 117.7, 112.0, 58.8, 53.0, 40.2, 29.3; 19F NMR
(376 MHz, CD2Cl2) δ -63.2 (s, 3F); MS (ESI) m/z 471 (M + H+),
488 (M + NH4+), 493 (M + Na+); ESI-HRMS calcd for
C25H25F3N3O2S (M + NH4+) 488.1620, found 488.1621.
(R)-1-(1H-Indol-3-yl)-2-(4-trifluoromethylphenylmethanesulfonyl)-
1,2,3,4-tetrahydroisoquinoline (11). Compound 11 (36 mg, 85%)
was prepared as a white foam with the same conditions as described
for compound 1. [R]20D +71.7 (c 0.48 CH2Cl2); 1H NMR (400 MHz,
CD2Cl2) δ 8.34 (s, 1H), 7.74 (d, J ) 8.0 Hz, 1H), 7.44-7.40 (m,
3H), 7.25-7.19 (m, 3H), 7.15-7.09 (m, 2H), 7.05 (d, J ) 8.0 Hz,
2H), 6.99 (d, J ) 8.0 Hz, 1H), 6.83 (d, J ) 2.8 Hz, 1H), 6.38 (s,
1H), 4.01 (d, J ) 13.6 Hz, 1H), 3.93 (d, J ) 13.6 Hz, 1H), 3.60
(ddt, J ) 13.8, 6.4, 1.4 Hz, 1H), 3.26 (ddd, J ) 13.6, 4.0, 4.4 Hz,
1H), 3.03 (ddd, J ) 17.4, 6.0, 4.4 Hz, 1H), 2.81 (dd, J ) 2.8, 3.6
Hz, 1H); 13C NMR (125 MHz, CD2Cl2) δ 136.9, 136.2, 133.9,
133.8, 131.6, 130.5, 129.6, 128.6, 127.5, 126.8, 126.8, 126.0, 125.7
(q, J ) 3.8 Hz), 123.5, 123.2, 120.8, 120.4, 117.6, 112.0, 58.9,
53.2, 40.1, 29.1; 19F NMR (376 MHz, CD2Cl2) δ -63.3 (s, 3F);
MS (ESI) m/z 471 (M + H+), 488 (M + NH4+), 493 (M + Na+);
ESI-HRMS calcd for C25H22F3N2O2S (M + H+) 471.1354, found
471.1351.
2-Vinylbenzaldehyde (52). To a solution of compound 51 (5.00
g, 25.91 mmol) in THF (80 mL) was added n-BuLi (1.6 M in
hexane, 20 mL, 32.00 mmol) at - 78 °C dropwise. After the
mixture was stirred at -78 °C for 30 min, anhydrous DMF (4.0
mL, 51.66 mmol) was added dropwise. Then, the mixture was
stirred at -78 °C for another 30 min. H2O (5 mL) was added to
quench the reaction. The mixture was warmed to room temperature.
H2O (100 mL) was added and the mixture was extracted with
CH2Cl2 (3 × 50 mL). The organic phases were dried with anhydrous
Na2SO4. After removal of all the solvent, the residue was purified
by silica gel chromatography (hexane/EtOAc ) 40:1) to give
compound 52 (2.50 g, 73%) as an oil. 1H NMR (500 MHz, CD2Cl2)
δ 10.28 (s, 1H), 7.82 (d, J ) 8.0 Hz, 1H), 7.61-7.54 (m, 3H),
7.46-7.43 (m, 1H), 5.73 (dd, J ) 17.3, 1.3 Hz, 1H), 5.51 (dd, J )
11.3, 1.3 Hz, 1H); 13C NMR (125 MHz, CD2Cl2) δ 192.7, 140.8,
134.2, 133.9, 133.4, 131.7, 128.5, 127.8, 119.5; MS (ESI) m/z 133
(M + H+), 155 (M + Na+); ESI-HRMS calcd for C9H8ONa (M +
Na+) 155.0473, found 155.0470.
After removal of all the solvent, the residue was recrystallized from
hexane/EtOAc (2:1) to afford compound 53 (518 mg, 43%) as a
1
white solid. H NMR (500 MHz, CDCl3) δ 9.46 (s, 1H), 8.12 (d,
J ) 8.0 Hz, 1H), 7.95 (d, J ) 8.0 Hz, 2H), 7.63-7.57 (m, 2H),
7.40 (d, J ) 8.0 Hz, 3H), 7.34-7.29 (m, 1H), 5.65 (dd, J ) 34.3,
14.3 Hz, 2H), 2.49 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.6,
144.8, 142.5, 135.4, 134.7, 132.9, 130.0, 129.9, 129.3, 128.2, 128.2,
127.8, 121.1, 21.8; MS (ESI) m/z 286 (M + H+), 437 (M + Na+),
593 (2 M + Na+); ESI-HRMS calcd for C16H16NO2S (M + H+)
286.0896, found 286.0901.
Preparation of Amide (R)-54 with Bisoxazoline Cu(II) Complex
As Catalyst. Cu(OTf)2 (98%, 15.0 mg, 0.04 mmol), and (S)-Bn-
bisoxazoline (22 mg, 0.06 mmol) were dissolved in CH2Cl2 (5 mL)
under N2 atmosphere. The solution was stirred at room temperature
for 2 h, then 4 Å molecular sieves (100 mg) was added and the
mixture was stirred for another 10 min. Subsequently, compound
53 (114 mg, 0.4 mmol) and indole (234 mg, 2.0 mmol) were added,
and the reaction mixture was stirred at room temperature. The
mixture was stirred for 3 days. After that, the solvent was removed
under vacuum and the residue was purified by flash column
chromatography on silica gel eluted with hexane/EtOAc (3:1) to
afford compound (R)-54 (36 mg, 22%, 90% ee) as a white foam.
Preparation of Amide (R)-54 with Cinchona-Derivated Thio-
urea Alkaloid 57 As Catalyst. To a mixture of compound 53 (85
mg, 0.3 mmol) and catalyst 57 (18 mg, 0.03 mmol) in EtOAc (150
µL) was added indole (70 mg, 0.6 mmol) in one portion. Then, the
mixture was heated to 50 °C and reaction was stirred at 50 °C for
48 h. After that, all the solvent was removed and the residue was
purified by silica gel chromatography (hexane/EtOAc ) 3:1) to
give (R)-54 (96 mg, 80%, 95% ee) as a white foam.
N-[(R)-(1H-Indol-3-yl)(2-vinylphenyl)methyl]-4-methylbenzene-
sulfonamide, (R)-54. [R]20D +54.0 (c 1.0 CH2Cl2, 95% ee); 1H NMR
(400 MHz, CD2Cl2) δ 8.16 (s, 1H), 7.57 (d, J ) 8.4 Hz, 2H),
7.40-7.32 (m, 3H), 7.24-7.15 (m, 6H), 7.00 (t, J ) 8.0 Hz, 1H),
6.83 (dd, J ) 17.2, 10.8 HZ, 1H), 6.58 (d, J ) 2.4 Hz, 1H), 6.09
(d, J ) 6.8 Hz, 1H), 5.52 (dd, J ) 17.6, 0.8 Hz, 1H), 5.20 (d, J )
10.8, 1.0 Hz, 1H), 5.13 (d, J ) 6.4 Hz, 1H), 2.39 (s, 3H); 13C
NMR (125 MHz, CD2Cl2) δ 144.0, 137.8, 137.8, 137.1, 136.7,
134.4, 129.9, 128.2, 128.0, 127.7, 127.6, 126.9, 126.0, 124.9, 123.1,
120.4, 119.4, 117.4, 116.3, 111.8, 52.2, 21.7; MS (ESI) m/z 420
(M + NH4+), 425 (M + Na+), 822 (2 M + Na+); ESI-HRMS calcd
for C24H22N2O2SNa (M + Na+) 425.1300, found 425.1293.
N-[(R)-(1H-Indol-3-yl)(2-vinylphenyl)methyl]-C-phenylmethane-
sulfonamide, (R)-55. Compound (R)-55 was prepared, under dif-
ferent temperature and substrate concentration, using a similar
reaction condition as described for (R)-54 with thiourea alkaloid
57 as catalyst. [R]20D +80.2 (c 0.51 CH2Cl2); 1H NMR (400 MHz,
CD2Cl2) δ 8.23 (s, 1H), 7.64 (dd, J ) 7.6, 1.2 Hz, 1H), 7.59-7.53
(m, 1H), 7.52-7.49 (m, 1H), 7.42-7.37 (n, 3H), 7.32-7.18 (m,
4H), 7.12-7.06 (m, 3H), 7.03 (d, J ) 10.8 Hz, 1H), 6.80 (dd, J )
2.6, 1.2 Hz, 1H), 6.34 (d, J ) 7.6 Hz, 1H), 5.63 (dd, J ) 17.0, 1.4
Hz, 1H), 5.32 (dd, J ) 15.6, 1.6 Hz, 1H), 4.96 (d, J ) 7.6 Hz,
1H), 4.05 (d, J ) 14.0 Hz, 1H), 4.00 (d, J ) 13.6 Hz, 1H); 13C
NMR (125 MHz, CD2Cl2) δ 138.6, 137.2, 136.9, 134.4, 131.2,
129.5, 128.9, 128.7, 128.7, 127.9, 127.4, 126.0, 124.5, 123.1, 120.6,
120.0, 118.0, 116.7, 111.9, 60.6, 52.6; MS (ESI) m/z 420 (M +
NH4+), 425 (M + Na+), 822 (2 M + NH4+); ESI-HRMS calcd for
C24H26N3O2S (M + NH4+) 420.1746, found 420.1746.
N-[(S)-(1H-Indol-3-yl)(2-vinylphenyl)methyl]-C-phenylmethane-
sulfonamide (S)-55. Compound (S)-55 was prepared at room
temperature with a similar reaction condition as described for (R)-
4-Methyl-N-[1-(2-vinylphenyl)meth-(E)-ylidene]benzenesulfona-
mide (53). To a solution of compound 52 (556 mg, 4.21 mmol) in
THF (15 mL) was added toluenesulfonyl amide (936 mg, 5.48
mmol). Then, Ti(OEt)4 (20% in EtOH, 5 mL) was added dropwise.
After that, the resulting mixture was stirred overnight at room
temperature. H2O (30 mL) was added to quench the reaction and
the mixture was filtered. The filtrate was extracted with CH2Cl2 (3
× 30 mL). The organic phases were dried over anhydrous Na2SO4.
54 with thiourea alkaloid 58 as catalyst. [R]20 -63.0 (c 0.75
D
1
CH2Cl2); H NMR (400 MHz, CD2Cl2) δ 8.22 (s, 1H), 7.62 (d, J
) 6.8 Hz, 1H), 7.56-7.54 (m, 1H), 7.49-7.47 (m, 1H), 7.39-7.35
(n, 3H), 7.29-7.17 (m, 4H), 7.09-7.01 (m, 4H), 6.76 (d, J ) 1.6
Hz, 1H), 6.33 (d, J ) 6.4 Hz, 1H), 5.62 (dd, J ) 13.8, 1.0 Hz,
1H), 5.32 (dd, J ) 10.4, 1.2 Hz, 1H), 5.04 (d, J ) 6.0 Hz, 1H),
4.01 (d, J ) 10.4 Hz, 1H), 3.97 (d, J ) 11.2 Hz, 1H); 13C NMR
(125 MHz, CD2Cl2) δ 138.7, 137.4, 137.1, 134.6, 131.3, 129.7,
2026 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of Chiral IBR2 Analogues
129.1, 129.0, 128.8, 128.8, 128.1, 127.4, 126.1, 124.6, 123.2, 120.7,
120.0, 118.1, 116.9, 112.0, 60.8, 52.6; MS (ESI) m/z 425 (M +
Na+), 827 (2 M + Na+); ESI-HRMS calcd for C24H22N2O2SNa
(M + Na+) 425.1300, found 425.1295.
7.0 Hz, 1H), 7.42-7.23 (m, 9H), 7.15-7.13 (m, 2H), 6.90 (s, 1H),
6.57 (s, 1H), 6.46 (d, J ) 12.5 Hz, 1H), 5.57 (ddd, J ) 12.3, 4.5,
2.0 Hz, 1H), 4.37 (dd, J ) 20.5, 5.0 Hz, 1H), 3.92 (d, J ) 13.5
Hz, 1H), 3.68 (d, J ) 13.5 Hz, 1H), 3.62 (dt, J ) 20.5, 2.5 Hz,
1H), 1.63 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 149.9, 138.4,
135.6, 134.9, 133.1, 130.9, 130.3, 130.1, 129.6, 128.8, 128.7, 128.6,
128.6, 128.5, 128.2, 127.0, 125.2, 123.6, 120.0, 116.7, 115.4, 84.4,
59.5, 59.1, 46.6, 28.3; MS (ESI) m/z 532 (M + NH4+), 537 (M +
Na+); ESI-HRMS calcd for C30H30N2O4SNa (M + Na+) 537.1824,
found 537.1813.
3-[(R)-Phenylmethanesulfonylamino(2-vinylphenyl)methyl]indole-
1-carboxylic Acid tert-Butyl Ester (59). To a 0 °C solution of (R)-
55 (77 mg, 0.19 mmol) and DMAP (3 mg, 0.02 mmol) in THF (2
mL) was added a solution of Boc2O (42 mg, 0.19 mmol) in THF
(2 mL) dropwise. Then, the resulting mixture was stirred at room
temperature for 1 h. After that, all the solvent was removed in vacuo
and the residue was purified by silica gel column (hexane/EtOAC
(R)-1-(1H-Indol-3-yl)-2-phenylmethanesulfonyl-2,3-dihydro-1H-
benzo[c]azepine (15). To a stirred solution of 61 (40 mg, 0.077
mmol) in MeOH was added a solution of Verkade’s base (8 mg)
in MeOH (20 µL). Then, the resulting solution was stirred at room
temperature for 2 days. After that, the solvent was removed in vacuo
and the residue was purified by silica gel chromatography (hexane/
EtOAc ) 3:1) to furnish compound 15 (21 mg, 65%) as a white
) 7:1) to give compound 59 (93 mg, 96%) as a white foam. [R]20
D
1
+12.2 (c 1.03 CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.09 (d, J
) 8.0 Hz, 1H), 7.59-7.55 (m, 2H), 7.42-7.36 (m, 3H), 7.34-7.32
(m, 1H), 7.31-7.30 (m, 1H), 7.29-7.26 (m, 1H), 7.24-7.18 (m,
3H), 7.12 (dd, J ) 10.8, 11.2 Hz, 1H), 7.02-7.00 (m, 2H), 6.31
(dd, J ) 1.2, 1.2 Hz, 1H), 5.66 (dd, J ) 1.2, 1.2 Hz, 1H), 5.39 (dd,
J ) 1.6, 1.6 Hz, 1H), 4.99 (d, J ) 8.0 Hz, 1H), 4.07 (d, J ) 14.0
Hz, 1H), 3.95 (d, J ) 14.0 Hz, 1H), 1.65 (s, 9H); 13C NMR (125
MHz, CD2Cl2) δ 149.7, 137.1, 136.7, 133.8, 130.7, 128.7, 128.6,
128.6, 128.5, 128.4, 127.8, 127.3, 124.9, 124.9, 123.0, 121.0, 120.1,
118.5, 115.3, 84.2, 60.3, 51.8, 28.2; MS (ESI) m/z 520 (M + NH4+),
525 (M + Na+), 1022 (2 M + NH4+); ESI-HRMS calcd for
C29H30N2O4SNa (M + Na+) 525.1824, found 525.1827.
foam. In addition, starting material (5 mg) was recovered. [R]20
D
1
+90.3 (c 0.4 CH2Cl2); H NMR (500 MHz, CD2Cl2) δ 8.19 (s,
1H), 7.84 (d, J ) 7.5 Hz, 1H), 7.40-7.36 (m, 4H), 7.32-7.22 (m,
5H), 7.19-7.14 (m, 3H), 6.62 (s, 1H), 6.50 (s, 1H), 6.48 (d, J )
15.0 Hz, 1H), 5.58 (ddd, J ) 10.0, 4.8, 2.0 Hz, 1H), 4.31 (dd, J )
21.0, 5.0 Hz, 1H), 3.95 (d, J ) 13.5 Hz, 1H), 3.65 (d, J ) 13.5
Hz, 1H), 3.54 (dt, J ) 20.5, 2.5 Hz, 1H); 13C NMR (125 MHz,
CD2Cl2) δ 140.0, 137.1, 135.3, 133.4, 131.2, 130.8, 130.5, 129.9,
129.7, 129.3, 128.9, 128.7, 128.7, 128.3, 126.1, 123.2, 120.9, 119.6,
112.5, 111.8, 59.9, 59.6, 46.5; MS (ESI) m/z 437 (M + Na+); ESI-
HRMS calcd for C25H22N2O2SNa (M + Na+) 437.1300, found
437.1297.
3-[(R)-(Allylphenylmethanesulfonylamino)(2-vinylphenyl)meth-
yl]indole-1-carboxylic Acid tert-Butyl Ester (60). To a mixture of
59 (92.7 mg, 0.18 mmol) and Cs2CO3 (72 mg, 0.22 mmol) in DMF
(1 mL) was added allylic bromide (0.05 mL, 0.57 mmol) dropwise.
Then, the mixture was stirred at room temperature until all the
starting material was consumed. The mixture was directly subjected
to purification by silica gel chromatography (hexane/EtOAc ) 10:1
to 7:1) to afford compound 60 (98 mg, 98%) as a white foam. [R]20
Acknowledgement. This work is supported by a Leukemia
& Lymphoma Society grant to W.-H.L., a postdoctoral-
multidisciplinary fellowship to X.-L.Q. from the USA Depart-
ment of Defense Congressionally Directed Medical Research
Programs (W81XWH-06-1-0418), a postdoctoral fellowship to
J.Z. from the California Breast Cancer Research Program, and
a postdoctoral fellowship to G.W. (PDF0600907) from the Susan
Komen Breast Foundation.
D
-7.2 (c 1.36 CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J )
8.4 Hz, 1H), 7.57 (d, J ) 8.0 Hz, 1H), 7.41 (d, J ) 1.2 Hz, 1H),
7.38-7.25 (m, 11H), 7.20-7.11 (m, 2H), 6.83 (s, 1H), 5.68 (dd, J
) 17.4, 1.4 Hz, 1H), 5.40-5.31 (m, 2H), 4.88 (ddd, J ) 22.0,
17.2, 1.2 Hz, 1H), 4.11-3.94 (m, 4H), 1.68 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 149.9, 137.8, 135.6, 134.9, 134.3, 131.1, 129.3,
129.0, 128.8, 128.8, 128.7, 128.1, 127.2, 126.4, 125.1, 123.2, 120.3,
119.8, 118.0, 115.4, 84.4, 60.7, 55.4, 49.2, 28.4; MS (ESI) m/z
560 (M + NH4+), 565 (M + Na+); ESI-HRMS calcd for
C32H34N2O4SNa (M + Na+) 565.2137, found 565.2119.
Supporting Information Available: Copies of 1H NMR, 13
C
NMR, and 19F NMR spectra of compounds 1-16, 24, 25,
27-37, 39-47, 52, 53-55, and 59-64, experimental proce-
dures for compounds 2, 6-8, 12-14, 16, 57, 58, and 62-64,
chiral HPLC analysis of compounds 1-16 and 54-55, crystal-
lographic data (CIF) and ORTEP drawing for compounds 1 and
15, and a mechanism explanation about poor diastereoselectivity.
This material is available free of charge via the Internet at
http://pubs.acs.org.
3-((R)-2-Phenylmethanesulfonyl-2,3-dihydro-1H-benzo[c]azepin-
1-yl)indole-1-carboxylic Acid tert-Butyl Ester (61). To a solution
of 60 (98 mg, 0.18 mmol) in CH2Cl2 (3 mL) was added Grubbs’
first catalyst (7.5 mg, 0.009 mmol). Then, the mixture was heated
to reflux for 4 h. After the mixture was cooled to room temperature
and all the solvent was removed in vacuo, the residue was purified
by silica gel chromatography (hexane/EtOAc ) 15:1) to provide
compound 61 (65 mg, 70%) as a white foam. In addition, starting
1
material (14 mg) was recovered. [R]20 +36.2 (c 0.8 CH2Cl2); H
D
NMR (500 MHz, CDCl3) δ 8.02 (d, J ) 7.5 Hz, 1H), 7.94 (d, J )
JO802607F
J. Org. Chem. Vol. 74, No. 5, 2009 2027