The first highly stereoselective approach to the mitotic kinesin Eg5 inhibitor HR22C16 and its analogues

Article abstract of DOI:10.1016/j.tetasy.2009.12.029

A general method for the synthesis of the mitotic kinesin Eg5 inhibitor HR22C16 1 and its analogues based on protecting group (PG)-modulated highly diastereoselective Pictet-Spengler reaction of l-tryptophan methyl ester hydrochloride with meta-(RO)-benzaldehyde is described. By using the enantiomerically pure (1R,3S)-1,3-disubstituted tetrahydro-β-carboline trans-4c as a common chiral synthon, HR22C16 1 and its analogues 2 and 3 were synthesized in 90.1%, 90.2%, and 86.5% overall yields, respectively.

Full text of DOI:10.1016/j.tetasy.2009.12.029

Tetrahedron: Asymmetry 21 (2010) 226–231
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The first highly stereoselective approach to the mitotic kinesin Eg5
inhibitor HR22C16 and its analogues
*
Sen Xiao, Xiao-Xin Shi
Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, PO Box 363, 130 Mei-Long Road, Shanghai 200237, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method for the synthesis of the mitotic kinesin Eg5 inhibitor HR22C16 1 and its analogues
Received 7 December 2009
Accepted 22 December 2009
Available online 26 February 2010
based on protecting group (PG)-modulated highly diastereoselective Pictet–Spengler reaction of
phan methyl ester hydrochloride with meta-(RO)-benzaldehyde is described. By using the enantiomeri-
cally pure (1R,3S)-1,3-disubstituted tetrahydro-b-carboline trans-4c as common chiral synthon,
L-trypto-
a
HR22C16 1 and its analogues 2 and 3 were synthesized in 90.1%, 90.2%, and 86.5% overall yields,
respectively.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
reaction should be investigated and fully understood. Herein we
report our recent study on this important reaction and a general
Cancer is one of the most fatal diseases, especially in the mod-
ern industrialized countries; hence the development of new drugs
for the treatment of cancer is very important for human health.
Traditional successful anticancer drugs such as vinca alkaloids, tax-
ol, and epothilone perturb mitosis and disrupt proper cell division
by targeting tubulin (the subunit of microtubules), thus leading
ultimately to apoptosis of cancer cells. However, these drugs have
undesired mechanism-based side effects,1 because microtubles
are also involved in many other cellular processes.2–4 The mitotic
kinesin Eg5, also known as kinesin spindle protein (KSP), plays
an important role in the early stage of mitosis, it mediates separa-
tion of centrosome and formation of the bipolar mitotic spindle.5,6
Inhibition of Eg5 provides a new strategy for cancer treatment,
drugs which target Eg5 might have less side effects, since Eg5 is
exclusively involved in the formation and function of the mitotic
spindle.7,8
approach to HR22C16 and its analogues.
H
N
O
10
S
11a
2
9
8
11
5
1
3
N
O
NH
6
N
H
N
4
7
O
O
OH
OH
Monastrol
(IC50 = 10 µM)
HR22C16 1
(IC50 = 0.80 µM)
O
O
Ph
( )4
N
N
NH2
N
N
N
N
H
H
O
O
Since the discovery of the first Eg5 inhibitor (monastrol in
Scheme 1),9 increasing interest has been shown, leading to other
types of Eg5 inhibitors being found.10–23 Recently, HR22C16 1
and it analogues 2 and 3 (Scheme 1) have been proven to be
effective Eg5 inhibitors with smaller IC50 values.10,24,25 All these
OH
OH
HR22C16 analogue 2
(IC50 = 0.65 µM)
HR22C16 analogue 3
(IC50 = 0.09 µM)
compounds contain
a tetracyclic tetrahydro-b-carboline-fused
Scheme 1. Kinesin spindle protein (KSP) inhibitors.
hydantoin scaffold, which bears a meta-hydroxy group on the aro-
matic ring at C-5 and possesses two stereogenic centers at C-5 and
C-11a with (S)- and (R)-configurations, respectively. Obviously, the
2. Results and discussion
Pictet–Spengler reaction of L-tryptophan with meta-hydroxy benz-
aldehyde is the key step for the synthesis of Eg5 inhibitor HR22C16
and its analogues, therefore the stereoselectivity of this particular
At first, the high stereoselectivity of Pictet–Spengler reaction of
-tryptophan methyl ester hydrochloride with meta-hydroxy benz-
aldehyde was obtained via a two-step procedure (Scheme 2), in
which refluxing in isopropanol produced a mixture mix-4a–HCl
(R = H) of almost equal molar hydrochloride salts of cis- and
L
* Corresponding author.
trans-1,3-disubstituted tetrahydro-b-carboline 4a, and then
a
E-mail address: xxshi@ecust.edu.cn (X.-X. Shi).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.029

S. Xiao, X.-X. Shi / Tetrahedron: Asymmetry 21 (2010) 226–231
CHO
COOMe
227
3
3
COOMe
H
COOMe
NH3Cl
a
H
+
1
1
NH
H
NH
H
N
H
NOE
N
H
NOE
N
H
OR
COOMe
3
OH
OAc
cis-4a-HCl (R=H)
cis-4b-HCl (R=Ac)
cis-4a
cis-4b
1
NH2Cl
b
N
H
CIAT
3
trans-4c-HCl (R=Bz)
trans-4d-HCl (R=Allyl)
COOMe
H
3
COOMe
H
1
1
NH
NH
NOE
NOE
OR
N
N
H
H
NOE
NOE
H
mix-4-HCl
H
H
H
Scheme 2. The highly stereoselective Pictet–Spengler reaction of
methyl ester hydrochloride with meta-(RO)-benzaldehyde via
Reagents and conditions: (a) refluxing in isopropanol for 5 h; (b) refluxing in a
mixed solvent of toluene and nitromethane (see also Table 1).
L
-tryptophan
a
CIAT process.
O
OBz
trans-4c
trans-4d
Figure 1. NOEs of compounds 4a–4d.
process via crystal-induced asymmetric transformation (CIAT)26–38
in a mixed solvent of toluene and nitromethane afforded cis-4a–HCl
in 93% yield and with 98% de. However, high trans-stereoselectivity
rather than cis-stereoselectivity is required to satisfy the absolute
configurations of the two stereogenic centers of the title com-
pounds HR22C16 and its analogues. Fortunately, after trial and er-
ror, we finally obtained the desired high trans-stereoselectivity. It
was found that a protecting group of the meta-hydroxy group of
the aromatic aldehyde could modulate the stereoselectivity of
the above-mentioned Pictet–Spengler reaction. As can be seen
from Table 1, the stereoselectivities of the reaction dramatically
varied depending on the protecting groups. When R is either H
or Ac, the reaction produced cis-4a–HCl or cis-4b–HCl in high yield
and with high stereoselectivity (Table 1, entries 1 and 2) after the
CIAT process; when R is either Bz or allyl, the reaction produced
trans-4c–HCl or trans-4d–HCl in high yield and with high stereose-
lectivity (Table 1, entries 3 and 4). The high diastereoselectivity of
this CIAT process could be attributed to the large solubility differ-
ence between both hydrochloride salts (cis-4–HCl and trans-4–HCl)
in the reaction solvent.26
With the desired compounds trans-4c and trans-4d in hand, we
attempted to develop a general approach to the three title com-
pounds 1–3. Considering the fact that the Bz-protecting group
can be more easily removed than an allyl group, compound
trans-4c was chosen as the starting material for the following
syntheses.
As depicted in Scheme 3, HR22C16 1, compound 2, and com-
pound 3 can be readily synthesized from the enantiomerically pure
(1R,3S)-1,3-disubstituted tetrahydro-b-carboline trans-4c. Com-
pound trans-4c was treated successively with 0.5 equiv of triphos-
gene and 5.0 equiv of butylamine or benzylamine at 0 °C in the
presence of 5.0 equiv of triethylamine, after acidifying with exces-
sive aqueous 2 M HCl and continuous stirring at room temperature
for 25 h, the one-pot reaction produced tetracyclic compound 5a or
5b in 91% or 92% yield without isolation of intermediates as shown
in the square parenthesis of Scheme 3. When butylamine or ben-
zylamine was replaced by 5-azido-pentyl amine which was pre-
pared from the bistosylate of 1,5-pentandiol according to
a
known method,39 compound 5c was obtained in 93% yield. Com-
pounds 5a and 5b were then transformed into the title compounds
HR22C16 1 and its analogue 2 in almost quantitative yields via
alcoholysis in methanol at reflux in the presence of catalytic
amounts of potassium carbonate. Compound 6 was also obtained
in nearly quantitative yield after removal of the protecting group
of compound 5c via methanolysis under the same conditions.
Reduction of the azido group of compound 6 was finally performed
via Pd/C-catalyzed hydrogenation at room temperature in
methanol to afford compound 3 in 94% yield, while Staudinger
reduction40,41 of the azido group of compound 6 with triphenyl-
phosphine only gave compound 3 in 85% yield.
Table 1
Modulation of protecting groups on the stereoselectivities of Pictet–Spengler
reactions (see also Scheme 2) via CIAT process
Entry
R
Tol/CH3NO2 Time (h)a Product 4 (cis:trans)b Yieldc (%)
1
2
3
4
H
Ac
Bz
1:1
2:1
2:1
12
18
18
20
4a (99:1)
4b (99:1)
4c (1:99)
4d (1:99)
93
95
95
96
Allyl 6:1
a
b
c
Under reflux.
Determined by both 1H NMR (500 MHz) and HPLC.
Isolated yield based on two steps.
The stereochemistry of all four compounds cis-4a, cis-4b, trans-
3. Conclusion
4c, and trans-4d was unequivocally assigned according to correla-
tion spots (NOEs in Figure 1) in the 1H–1H NOESY spectra of these
compounds. In the 1H–1H NOESY spectra of cis-4a, there are corre-
lation spots between H-1 (5.22 ppm) and H-3 (3.93 ppm), which
means that H-1 and H-3 have a cis-relationship; in the 1H–1H
NOESY spectra of cis-4b, there are correlation spots between H-1
(5.26 ppm) and H-3 (3.97 ppm), which also means that H-1 and
H-3 have a cis-relationship; in the 1H–1H NOESY spectra of trans-
4c, H-3 (3.99 ppm) does not correlate with H-1 (5.43 ppm), but it
correlates with two neighboring ortho-protons (7.10–7.24 ppm)
on the aromatic ring at C-1, meaning that H-1 and H-3 have a
trans-relationship; in the 1H–1H NOESY spectra of trans-4d, H-3
(4.00 ppm) does not correlate with H-1 (5.38 ppm), but it corre-
lates with the two neighboring ortho-protons (6.84–6.89 ppm) on
the aromatic ring at C-1, also meaning that H-1 and H-3 have a
trans-relationship.
In conclusion, a dramatic modulation of protecting groups
(R = H, Ac, Bz or allyl) over the stereoselectivities of the Pictet–
Spengler reactions of L-tryptophan methyl ester hydrochloride
with meta-(RO)-PhCHO was observed, the desired high trans dia-
stereoselectivities were obtained by using benzoyl or allyl as a pro-
tecting group. A highly stereoselective approach for the syntheses
of the mitotic kinesin Eg5 inhibitor HR22C16 1 and its analogues 2
and 3 from enantiomerically pure (1R,3S)-1,3-disubstituted tetra-
hydro-b-carboline trans-4c has been developed. It is noteworthy
that the primary amine R’NH2 used in the formation of the hydan-
toin ring is not limited to butylamine, benzylamine, and 5-azido-
pentylamine, so the synthetic approach outlined in Scheme 3 is a
general one, and may be quite useful for the construction of
HR22C16-like tetracyclic scaffold.

228
S. Xiao, X.-X. Shi / Tetrahedron: Asymmetry 21 (2010) 226–231
O
COOMe
NH
COOMe
N
R'
a
b
N
NHR'
N
N
H
N
H
N
H
91% for 5a
92% for 5b
93% for 5c
O
O
OBz
OBz
OBz
trans-4c
5a (R'=Bu)
5b (R'=Bn)
5c (R'=5-azido-pentyl)
O
N
R'
c
N
N
H
O
99% for 1
98% for 2
99% for 6
1 (R'=Bu)
2 (R'=Bn)
6 (R'=5-azido-pentyl)
OH
O
N
O
O
N3
NH2
N
N
d
N
N
H
N
H
94%
O
OH
OH
6
3
Scheme 3. Syntheses of HR22C16 1 and its analogues 2 and 3 from compound trans-4c. Reagents and conditions: (a) 0.5 equiv of triphosgene and 5.0 equiv of triethylamine,
in toluene, 0 °C for 15 min; then 5.0 equiv of R0NH2, 0 °C for 15 min; (b) excess aqueous 2 M HCl, at room temperature for 25 h; (c) catalytic amount of K2CO3, refluxing in
methanol for 2 h; (d) catalytic amounts of Pd/C, 1 atm of H2, in methanol, at room temperature for 10 h.
The title compound HR22C16 1 was synthesized from trans-4c
in 90.1% yield or from -tryptophan methyl ester hydrochloride
in 85.6% overall yield; compound 2 was synthesized from trans-
4c in 90.2% yield or from -tryptophan methyl ester hydrochloride
in 85.7% overall yield; compound 3 was synthesized from trans-4c
continued at reflux for 12 h, the mixture was cooled down to room
temperature. A pale yellow solid was collected in a Buchner funnel
by suction and was rinsed with a small amount of fresh mixed sol-
vent of nitromethane and toluene (1:1). The solid was then parti-
tioned between ethyl acetate (40 mL) and saturated aqueous
solution of sodium bicarbonate (30 mL). The organic layer was sep-
arated and dried over anhydrous MgSO4. Evaporation of the solvent
under vacuum gave a crude product which was purified by flash
chromatography to afford compound 4a (3.37 g, 9.39 mmol) in
93% yield.
L
L
in 86.5% yield or from
82.2% overall yield.
L-tryptophan methyl ester hydrochloride in
4. Experimental
4.1. General methods
4.2.1. (1S,3S)-Methyl 1-(3-hydroxyphenyl)-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b] indole-3-carboxylate 4a
Melting points are uncorrected. 1H and 13C NMR spectra were
acquired on a Bruker AM-500, chemical shifts were given on the
delta scale as parts per million (ppm) with tetramethylsilane
(TMS) as the internal standard. IR spectra were recorded on a Nico-
let Magna IR-550. Mass spectra were recorded on HP5989A. Opti-
cal rotations were measured on a WZZ-1S automatic polarimeter at
room temperature. Column chromatography was performed on sil-
ica gel (Qingdao Ocean Chemical Corp.). All chemicals were analyt-
Mp 267–268 °C. ½a D20
ꢀ
¼ ꢁ45:1 (c 1.5, DMF). 1H NMR (acetone-
d6)
d 2.54 (br s, 1H), 2.89 (ddd, J1 = 14.6 Hz, J2 = 11.1 Hz,
J3 = 2.4 Hz, 1H), 3.12 (ddd, J1 = 14.8 Hz, J2 = 4.1 Hz, J3 = 1.8 Hz, 1H),
3.77 (s, 3H), 3.93 (dd, J1 = 11.1 Hz, J2 = 4.1 Hz, 1H), 5.22 (s, 1H),
6.78 (ddd, J1 = 8.3 Hz, J2 = 2.2 Hz, J3 = 0.7 Hz, 1H), 6.85 (dd,
J1 = 2.1 Hz, J2 = 1.7 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.98–7.06 (m,
2H), 7.17 (dd, J1 = 7.8 Hz, J2 = 7.8 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H),
7.49 (d, J = 7.4 Hz, 1H), 8.19 (s, 1H), 9.18 (s, 1H). 13C NMR
(DMSO-d6) d 172.99, 157.49, 143.52, 136.42, 135.44, 129.32,
126.59, 120.72, 119.40, 118.43, 117.54, 115.33, 114.84, 111.29,
106.88, 57.76, 56.24, 51.77, 25.54. MS m/z (relative intensity) 323
(M++1, 20), 322 (M+, 100), 321 (23), 307 (8), 273 (4), 263 (47),
248 (9), 246 (10), 235 (61), 234 (65), 229 (17), 220 (9), 218 (23),
206 (11), 204 (10), 191 (4), 169 (20), 144 (19), 131 (4), 120 (5),
115 (6), 102 (3), 89 (2). IR (KBr) 3404, 2975, 1751, 1731, 1600,
1455, 1288, 1276, 1242, 1000, 760 cmꢁ1. HRMS (EI) calcd for
C19H18N2O3: 322.1317; found: 322.1314.
ically pure. The L-tryptophan methyl ester hydrochloride was
prepared according to a known procedure.42
4.2. Typical two-step procedure for the Pictet–Spengler reac-
tion of
L-tryptophan methyl ester hydrochloride with meta-
(RO)-benzaldehyde
To
a
solution of meta-hydroxy benzaldehyde (1.36 g,
-tryp-
11.14 mmol) in isopropanol (25 mL) was added powdered
D
tophan methyl ester hydrochloride (2.57 g, 10.09 mmol). The mix-
ture was heated to reflux while being stirred, and then stirring was
continued for around 5 h under refluxing. The reaction solution
was then concentrated to dryness under vacuum to give a crude
solid product.
The above-mentioned crude solid product was then suspended
in a mixed solvent of nitromethane (12 mL) and toluene (12 mL),
and the suspension was heated to reflux, and then stirring was
4.2.2. (1S,3S)-Methyl 1-(3-acetoxyphenyl)-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b] indole-3-carboxylate 4b
Mp 220–221 °C. ½a D20
ꢀ
¼ ꢁ7:2 (c 3.3, CHCl3). 1H NMR (cDCl3) d
2.26 (s, 3H), 3.00 (ddd, J1 = 15.0 Hz, J2 = 11.1 Hz, J3 = 2.4 Hz, 1H),
3.22 (ddd, J1 = 15.1 Hz, J2 = 4.2 Hz, J3 = 1.8 Hz, 1H), 3.81 (s, 3H),
3.97 (dd, J1 = 11.0 Hz, J2 = 4.2 Hz, 1H), 5.26 (s, 1H), 7.07–7.16 (m,

S. Xiao, X.-X. Shi / Tetrahedron: Asymmetry 21 (2010) 226–231
229
4H), 7.22 (d, J = 7.4 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.39 (dd,
J1 = 7.8 Hz, J2 = 7.8 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.55 (br s, NH
on the indole ring, 1H). 13C NMR (CDCl3) d 173.60, 170.12,
151.40, 143.09, 136.78, 134.59, 130.30, 127.40, 126.60, 122.40,
122.38, 122.25, 119.98, 118.61, 111.62, 109.20, 58.63, 57.26,
52.74, 26.14, 21.48. MS m/z (relative intensity) 365 (M++1, 21),
364 (M+, 100), 363 (23), 349 (7), 321 (8), 305 (55), 290 (6), 277
(32), 261 (25), 235 (64), 229 (27), 218 (28), 206 (14), 204 (15),
191 (5), 169 (29), 144 (28), 130 (4), 115 (6), 102 (2), 77 (2), 43
(6). IR (KBr) 3390, 2975, 1745, 1739, 1600, 1452, 1370, 1268,
1211, 744 cmꢁ1. HRMS (EI) calcd for C21H20N2O4: 364.1423; found:
364.1424.
separatory funnel, the organic phase was separated and washed
twice with brine (2 ꢂ 10 mL). The organic solution was dried over
anhydrous sodium sulfate and was then concentrated in vacuo to
give a crude product which was purified by flash chromatography
to afford compound 5a (1.16 g, 2.35 mmol) in 91% yield.
4.3.1. (5R,11aS)-2-Butyl-5-(3-benzoyloxyphenyl)-6H-1,2,3,5,11,
11a-hexahydro- imidazo[1,5-b]-b-carboline-1,3-dione 5a
Mp 130–131 °C. ½a D20
ꢀ
¼ ꢁ199:0 (c 0.9, CHCl3). 1H NMR (CDCl3) d
0.93 (t, J = 7.4 Hz, 3H), 1.30–1.36 (m, 2H), 1.58–1.64 (m, 2H), 2.89
(ddd, J1 = 15.2 Hz, J2 = 11.0 Hz, J3 = 1.6 Hz, 1H), 3.47–3.54 (m, 3H),
4.30 (dd, J1 = 11.0 Hz, J2 = 5.5 Hz, 1H), 6.31 (s, 1H), 7.12–7.30 (m,
6H), 7.39 (dd, J1 = 7.9 Hz, J2 = 7.9 Hz, 1H), 7.47 (dd, J1 = 7.9 Hz,
J2 = 7.7 Hz, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H),
8.11 (d, J = 8.2 Hz, 2H), 8.15 (br s, NH on the indole ring, 1H). 13C
NMR (CDCl3) d 173.44, 165.77, 155.59, 151.89, 141.66, 137.34,
134.38, 130.78, 130.76, 130.68, 129.59, 129.16, 126.62, 126.39,
123.40, 122.90, 122.15, 120.61, 118.99, 112.01, 108.53, 53.69,
52.15, 39.25, 30.80, 24.00, 20.60, 14.22. MS m/z (relative intensity)
494 (M++1, 27), 493 (M+, 100), 492 (7), 442 (1), 388 (66), 372 (15),
360 (3), 339 (4), 296 (13), 294 (3), 261 (9), 234 (8), 233 (6), 217 (5),
206 (4), 204 (5), 169 (6), 105 (33), 77(7). IR (KBr) 3388, 2959, 2873,
1767, 1738, 1707, 1600, 1453, 1425, 1270, 1245, 1082, 1064, 745,
711 cmꢁ1. HRMS (EI) calcd for C30H27N3O4: 493.2002; found:
493.1995.
4.2.3. (1R,3S)-Methyl 1-(3-benzoyloxyphenyl)-2,3,4,9-tetra
hydro-1H-pyrido[3,4-b] indole-3-carboxylate 4c
Mp 185–186 °C. ½a D20
ꢀ
¼ ꢁ33:5 (c 0.9, CHCl3). 1H NMR (CDCl3) d
2.37 (br s, 1H), 3.14 (ddd, J1 = 15.4 Hz, J2 = 6.8 Hz, J3 = 1.2 Hz, 1H),
3.28 (dd, J1 = 15.5 Hz, J2 = 5.4 Hz, 1H), 3.72 (s, 3H), 3.99 (dd,
J1 = 6.3 Hz, J2 = 5.9 Hz, 1H), 5.43 (s, 1H), 7.10–7.24 (m, 6H), 7.39
(dd, J1 = 7.9 Hz, J2 = 7.9 Hz, 1H), 7.48 (dd, J1 = 7.9 Hz, J2 = 7.7 Hz,
2H), 7.54 (d, J = 7.6 Hz, 1H), 7.62 (dd, J1= 7.5 Hz, J2 = 7.5 Hz, 1H),
7.77 (br s, NH on the indole ring, 1H), 8.15 (d, J = 7.8 Hz, 2H). 13C
NMR (CDCl3) d 174.64, 165.92, 151.76, 144.65, 136.92, 134.31,
133.31, 130.79, 130.23, 129.87, 129.19, 127.41, 126.51, 122.54,
122.34, 122.04, 120.01, 118.77, 111.87, 108.99, 55.06, 52.73,
52.72, 25.51. MS m/z (relative intensity) 427 (M++1, 23), 426 (M+,
100), 425 (15), 411 (10), 367 (32), 352(9), 350 (10), 340 (6), 321
(12), 304 (4), 261 (7), 234 (19), 229 (15), 217 (12), 206 (9), 204
(7), 169 (18), 144 (13), 130 (4), 105 (78), 77 (17). IR (KBr) 3395,
2980, 1735, 1605, 1454, 1271, 1225, 1065, 750, 705 cmꢁ1. HRMS
(EI) calcd for C26H22N2O4: 426.1580; found: 426.1581.
4.3.2. (5R,11aS)-2-Benzyl-5-(3-benzoyloxyphenyl)-6H-
1,2,3,5,11,11a-hexahydro- imidazo[1,5-b]-b-carboline-1,3-dione
5b
Mp 125–126 °C. ½a D20
ꢀ
¼ ꢁ146:8 (c 1.7, CHCl3). 1H NMR (CDCl3) d
2.83 (ddd, J1 = 15.2 Hz, J2 = 11.1 Hz, J3 = 1.6 Hz, 1H), 3.49 (dd,
J1 = 15.3 Hz, J2 = 5.5 Hz, 1H), 4.35 (dd, J1 = 11.0 Hz, J2 = 5.5 Hz, 1H),
4.64 (d, J = 14.6 Hz, 1H), 4.74 (d, J = 14.6 Hz, 1H), 6.32 (s, 1H),
7.16 (td, J1 = 7.7 Hz, J2 = 0.8 Hz, 2H), 7.21 (td, J1 = 7.1 Hz,
J2 = 0.9 Hz, 2H), 7.23–7.34 (m, 5H), 7.37–7.43 (m, 3H), 7.49 (dd,
J1 = 7.9 Hz, J2 = 7.7 Hz, 2H), 7.53 (d, J = 7.8 Hz, 1H), 7.63 (t,
J = 7.5 Hz, 1H), 7.97 (br s, NH on the indole ring, 1H), 8.13 (d,
J = 7.8 Hz, 2H). 13C NMR (CDCl3) d 173.04, 165.75, 155.22, 151.92,
141.54, 137.27, 136.63, 134.38, 130.78, 130.71, 130.44, 129.62,
129.36, 129.26, 129.23, 129.17, 128.59, 127.88, 126.56, 126.44,
123.42, 122.96, 122.20, 120.59, 118.99, 53.81, 52.18, 43.00, 23.80.
MS m/z (relative intensity) 528 (M++1, 31), 527 (M+, 100), 449
(3), 436 (16), 422 (52), 406 (12), 405 (7), 365 (5), 339 (3), 330
(10), 261 (7), 234 (7), 217 (4), 204 (4), 169 (3), 105 (31), 91 (10),
77 (7). IR (KBr) 3409, 2950, 1768, 1740, 1711, 1450, 1270, 1244,
1078, 749, 706 cmꢁ1. HRMS (EI) calcd for C33H25N3O4: 527.1845;
found: 527.1849.
4.2.4. (1R,3S)-Methyl 1-(3-allyloxyphenyl)-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b] indole-3-carboxylate 4d
Mp 166–167 °C. ½a D20
ꢀ
¼ ꢁ34:5 (c 1.2, CHCl3). 1H NMR (CDCl3) d
3.13 (ddd, J1 = 15.3 Hz, J2 = 6.6 Hz, J3 = 1.2 Hz, 1H), 3.26 (dd,
J1 = 15.2 Hz, J2 = 5.2 Hz, 1H), 3.72 (s, 3H), 4.00 (dd, J1 = 6.1 Hz,
J2 = 5.9 Hz, 1H), 4.48 (d, J = 5.3 Hz, 2H), 5.25 (dd, J1 = 10.5 Hz, J2
=1.2 Hz, 1H), 5.36 (dd, J1 = 15.4 Hz, J2 = 1.4 Hz, 1H), 5.38 (s, 1H),
5.97–6.04 (m, 1H), 6.84–6.89 (m, 3H), 7.10–7.18 (m, 2H), 7.21–
7.25 (m, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.61(br s, NH on the indole
ring, 1H). 13C NMR (CDCl3) d 174.69, 159.51, 144.20, 136.82,
133.69, 133.63, 130.29, 127.53, 122.49, 121.46, 120.01, 118.78,
118.40, 115.49, 114.69, 111.58, 108.89, 69.36, 55.46, 53.03, 52.70,
25.30. MS m/z (relative intensity) 363 (M++1, 22), 362 (M+, 100),
361 (14), 347 (10), 345 (8), 321 (33), 303 (28), 286 (12), 276 (5),
261 (16), 247 (7), 234 (56), 229 (19), 218 (6), 206 (21), 204 (17),
191 (5), 169 (26), 160 (4), 144 (17), 130 (4), 115 (4), 89 (2). IR
(KBr) 3391, 2980, 1736, 1599, 1488, 1454, 1323, 1268, 1176,
1005, 743 cmꢁ1. HRMS (EI) calcd for C22H22N2O3: 362.1630; found:
362.1631.
4.3.3. (5R,11aS)-2-(5-Azido-pentyl)-5-(3-benzoyloxyphenyl)-
6H-1,2,3,5,11,11a- hexahydro-imidazo[1,5-b]-b-carboline-1,3-
dione 5c
Mp 87–88 °C. ½a 2D0
ꢀ
¼ ꢁ168:4 (c 0.9, CHCl3). 1H NMR (CDCl3) d
4.3. Typical procedure for the preparation of compounds 5a, 5b,
and 5c
1.35–1.42 (m, 2H), 1.58–1.70 (m, 4H), 2.89 (ddd, J1 = 15.2 Hz,
J2 = 11.1 Hz, J3 = 1.4 Hz, 1H), 3.24 (t, J = 6.9 Hz, 2H), 3.47–3.59 (m,
3H), 4.32 (dd, J1 = 11.0 Hz, J2 = 5.5 Hz, 1H), 6.30 (s, 1H), 7.15–7.25
(m, 4H), 7.27–7.31 (m, 2H), 7.40 (dd, J1 = 7.9 Hz, J2 = 7.9 Hz, 1H),
7.48 (dd, J1 = 7.8 Hz, J2 = 7.8 Hz, 2H), 7.56 (d, J = 7.7 Hz, 1H), 7.62
(dd, J1 = 7.4 Hz, J2 = 7.5 Hz, 1H), 8.11 (d, J = 7.3 Hz, 2H), 8.16 (br s,
NH on the indole ring, 1H). 13C NMR (CDCl3) d 173.39, 165.75,
155.43, 151.87, 141.60, 137.30, 134.38, 130.71, 130.67, 130.58,
129.52, 129.15, 126.58, 126.33, 123.39, 122.90, 122.15, 120.60,
118.98, 111.97, 108.46, 53.69, 52.15, 51.70, 39.09, 28.88, 28.24,
24.43, 23.93. MS m/z (relative intensity) 549 (M++1, 6), 548 (M+,
16), 520 (59), 490 (10), 476 (8), 462 (14), 444 (6), 436 (7), 416
(9), 391 (6), 365 (39), 332 (6), 294 (22), 261 (36), 234 (21), 204
(18), 169 (14), 115 (4), 105 (100), 84 (9), 77 (29), 70 (9). IR (KBr)
A solution of compound trans-4c (1.10 g, 2.58 mmol) and trieth-
ylamine (1.31 g, 12.95 mmol) in toluene (20 mL) was cooled to
around 0 °C with an ice-bath. A freshly prepared solution of tri-
phosgene (382 mg, 1.28 mmol) in dichloromethane (2 mL) was
added dropwise over 1 min, and the reaction mixture was then
stirred at 0 °C for around 15 min. Butylamine (0.94 g, 12.85 mmol)
was added, and the mixture was then stirred at 0 °C for around
15 min. After a dilute aqueous HCl solution (2 M, 15 mL) was
added, the ice-bath was removed, and the two-phase reaction mix-
ture was allowed to warm to room temperature and was stirred at
25 °C for around 25 h. After the mixture was transferred into a

230
S. Xiao, X.-X. Shi / Tetrahedron: Asymmetry 21 (2010) 226–231
3321, 3059, 2936, 2858, 2095, 1766, 1731, 1704, 1589, 1452, 1424,
1269, 1243, 1139, 1061, 746, 709, 433 cmꢁ1. HRMS (EI) calcd for
C31H28N6O4: 548.2172; found: 548.2180.
idue was then partitioned between ethyl acetate (30 mL) and
water (20 mL). The organic phase was separated and dried over
anhydrous sodium sulfate. Evaporation of the solvent gave a pale
yellow solid, which was washed several times with a mixed sol-
vent of ethyl acetate and hexane (1:1) to furnish compound 6
4.4. Preparation of HR22C16 1 and its analogue 2
(1.04 g, 2.34 mmol) in 99% yield, mp 127–128 °C. ½a D20
¼ ꢁ204:8
ꢀ
To a solution of compound 5a (1.10 g, 2.23 mmol) in methanol
(10 mL) was added powdered potassium carbonate (28 mg,
0.20 mmol). The solution was then heated at reflux, and stirring
was continued at reflux for 2 h. When the reaction was complete
(TLC), the solvent was removed under a reduced pressure. The res-
idue was then partitioned between ethyl acetate (25 mL) and
water (20 mL). The organic phase was separated and dried over
anhydrous sodium sulfate. Evaporation of the solvent gave crude
product which was purified by flash chromatography to furnish
compound 1 (0.86 g, 2.21 mmol) in 99% yield. For compound 2,
the same procedure as described above was followed.
(c 0.2, CHCl3). 1H NMR (DMSO-d6) d 1.23–1.31 (m, 2H), 1.49–
1.59 (m, 4H), 2.80 (dd, J1 = 14.0 Hz, J2 = 11.2 Hz, 1H), 3.28 (t,
J = 6.9 Hz, 2H), 3.34–3.43 (m, 3H), 4.48 (dd, J1 = 10.8 Hz,
J2 = 5.7 Hz, 1H), 6.12 (s, 1H), 6.71 (d, J = 7.0 Hz, 1H), 6.72 (s,
1H), 6.77 (d, J = 7.7 Hz, 1H), 7.01 (dd, J1 = 7.5 Hz, J2 = 7.3 Hz,
1H), 7.09 (dd, J1 = 7.2 Hz, J2 = 7.4 Hz, 1H), 7.15 (dd, J1 = 8.0 Hz,
J2 = 8.3 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H),
9.46 (br s, 1H), 10.93 (br s, 1H). 13C NMR (DMSO-d6) d 172.64,
157.66, 154.28, 141.40, 136.71, 131.22, 129.79, 125.81, 121.70,
118.86, 118.46, 118.20, 115.12, 114.78, 111.43, 106.03, 52.77,
51.40, 50.46, 37.82, 27.78, 27.13, 23.33, 22.78. MS m/z (relative
intensity) 445 (M++1, 8), 444 (M+, 31), 416 (41), 386 (13), 372
(11), 358 (22), 345 (5), 332 (12), 304 (4), 294 (22), 287 (11),
274 (3), 261 (100), 246 (5), 234 (41), 218 (15), 206 (12), 195
(3), 169 (13), 115 (4), 105 (4), 84 (5), 70 (7). IR (KBr) 3328,
2936, 2861, 2096, 1766, 1702, 1589, 1459, 1356, 1327, 1239,
4.4.1. (5R,11aS)-2-Butyl-5-(3-hydroxyphenyl)-6H-1,2,3,5,11,
11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione 1
Off-white solid, mp 107–108 °C (lit.24 107 °C). ½a D20
¼ ꢁ162:2 (c
ꢀ
0.2, CHCl3). 1H NMR (DMSO-d6) d 0.86 (t, J = 7.3 Hz, 3H), 1.20–1.28
(m, 2H), 1.45–1.52 (m, 2H), 2.78 (dd, J1 = 13.9 Hz, J2 = 11.2 Hz, 1H),
3.32–3.42 (m, 3H), 4.48 (dd, J1 = 10.8 Hz, J2 = 5.7 Hz, 1H), 6.12 (s,
1H), 6.70 (d, J = 7.7 Hz, 1H), 6.71 (s, 1H), 6.76 (d, J = 7.7 Hz, 1H),
7.01 (dd, J1 = 7.3 Hz, J2 = 7.2 Hz, 1H), 7.08 (dd, J1 = 7.2 Hz,
J2 = 7.6 Hz, 1H), 7.15 (dd, J1 = 7.9 Hz, J2 = 8.6 Hz, 1H), 7.29 (d,
J = 8.0 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 9.46 (s, 1H), 10.93 (s, 1H).
13C NMR (DMSO-d6) d 172.63, 157.68, 154.31, 141.43, 136.73,
131.24, 129.79, 125.83, 121.69, 118.85, 118.48, 118.20, 115.13,
114.81, 111.43, 106.04, 52.75, 51.40, 37.73, 29.72, 22.82, 19.44,
13.50. MS m/z (relative intensity) 390 (M++1, 24), 389 (M+, 100),
388 (16), 372 (4), 360 (2), 332 (2), 296 (35), 261 (18), 234 (41),
220 (7), 218 (14), 206 (6), 196 (3), 169 (9), 115 (2), 105 (2), 91
(1). IR (KBr) 3340, 2954, 2929, 2870, 1757, 1701, 1591, 1458,
1141, 749 cmꢁ1
found: 444.1913.
. HRMS (EI) calcd for C24H24N6O3: 444.1910;
4.6. (5R,11aS)-2-(5-Amino-pentyl)-5-(3-hydroxyphenyl)-6H-1,2,
3,5,11,11a-hexa- hydro-imidazo[1,5-b]-b-carboline-1,3-dione 3
A solution of compound 6 (1.55 g, 3.49 mmol) in methanol
(20 mL) was placed into a three-necked round-bottomed flask,
which was equipped with a stirrer bar, a gas inlet, and an outlet.
The catalyst Pd/C (10%, 160 mg) was added, and the flask was
then purged several times with hydrogen gas. The reaction mix-
ture was stirred under an atmosphere of hydrogen gas at room
temperature for 10 h. After the reaction was complete, the mix-
ture was allowed to pass through a thin layer of Celite to remove
the catalyst. Evaporation of solvent under vacuum gave a pale
yellow solid which was washed several times with a mixed sol-
vent of ethyl acetate and hexane (1:1) to afford compound 3
(1.37 g, 3.27 mmol) in 94% yield as an off-white solid, mp 112–
1426, 1328, 1240, 1140, 749 cmꢁ1
C23H23N3O3: 389.1739; found: 389.1734.
. HRMS (EI) calcd for
4.4.2. (5R,11aS)-2-Benzyl-5-(3-hydroxyphenyl)-6H-1,2,3,5,11,
11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione 2
Off-white solid, mp 150–151 °C (lit.24 148 °C). ½a D20
¼ ꢁ162:6 (c
ꢀ
113 °C.
½
a 2D0
ꢀ
¼ ꢁ151:5 (c 0.4, CHCl3). 1H NMR (DMSO-d6)
d
0.9, CHCl3). 1H NMR (DMSO-d6) d 2.82 (dd, J1 = 14.1 Hz, J2 = 11.3 Hz,
1H), 3.40 (dd, J1 = 15.1 Hz, J2 = 5.7 Hz, 1H), 4.55–4.63 (m, 3H), 6.14
(s, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 6.77 (d, J = 7.7 Hz, 1H),
7.01 (dd, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H), 7.09 (dd, J1 = 7.5 Hz,
J2 = 7.5 Hz, 1H), 7.15 (dd, J1 = 7.7 Hz, J2 = 7.7 Hz, 1H), 7.22–7.34
(m, 6H), 7.54 (d, J = 7.8 Hz, 1H), 9.46 (s, 1H), 10.94 (s, 1H). 13C
NMR (DMSO-d6) d 172.52, 157.69, 154.11, 141.35, 136.73, 136.62,
131.18, 129.84, 128.61, 127.48, 127.42, 125.82, 121.74, 118.89,
118.52, 118.24, 115.20, 114.86, 111.45, 105.99, 52.98, 51.55,
41.46, 22.82. MS m/z (relative intensity) 424 (M++1, 24), 423 (M+,
100), 422 (10), 406 (2), 345 (2), 332 (28), 330(20), 289 (2), 261
(29), 235 (20), 234 (25), 220 (4), 218 (9), 206 (4), 169 (4), 115
(2), 91 (7). IR (KBr) 3411, 2980, 1765, 1703, 1602, 1453, 1240,
1142, 749, 702 cmꢁ1. HRMS (EI) calcd for C26H21N3O3: 423.1583;
found: 423.1579.
1.20–1.26 (m, 2H), 1.27–1.36 (m, 2H), 1.46–1.54 (m, 2H), 2.48
(t, J = 6.9 Hz, 2H), 2.79 (dd, J1 = 13.9 Hz, J2 = 11.3 Hz, 1H), 3.32–
3.43 (m, 4H), 4.49 (dd, J1 = 10.8 Hz, J2 = 5.7 Hz, 1H), 6.12 (s, 1H),
6.71 (d, J = 7.4 Hz, 1H), 6.72 (s, 1H), 6.76 (d, J = 7.7 Hz, 1H), 7.01
(dd, J1 = 7.4 Hz, J2 = 7.4 Hz, 1H), 7.09 (dd, J1 = 7.2 Hz, J2 = 7.7 Hz,
1H), 7.15 (dd, J1 = 7.7 Hz, J2 = 7.9 Hz, 1H), 7.29 (d, J = 8.0 Hz,
1H), 7.53 (d, J = 7.8 Hz, 1H), 10.94 (br s, 1H). 13C NMR (DMSO-
d6) d 172.64, 157.88, 154.30, 141.38, 136.72, 131.27, 129.75,
125.82, 121.68, 118.85, 118.28, 118.19, 115.19, 114.81, 111.44,
106.00, 52.80, 51.42, 40.85, 38.01, 31.62, 27.45, 23.49, 22.79.
MS m/z (relative intensity) 419 (M++1, 26), 418 (M+, 100), 400
(4), 389 (5), 372 (4), 358 (5), 345 (5), 332 (4), 308 (6), 289 (3),
273 (7), 261 (45), 246 (4), 234 (34), 218 (11), 206 (9), 191(4),
169 (10), 140 (4), 115 (4), 44 (4). IR (KBr) 3338, 2936, 2857,
1764, 1700, 1591, 1456, 1425, 1371, 1238, 1045, 745,
712 cmꢁ1. HRMS (EI) calcd for C24H26N4O3: 418.2005; found:
418.1997.
4.5. (5R,11aS)-2-(5-Azido-pentyl)-5-(3-hydroxyphenyl)-6H-
1,2,3,5,11,11a-hexa-hydro-imidazo[1,5-b]-b-carboline-1,3-
dione 6
Acknowledgments
To a solution of compound 5c (1.30 g, 2.37 mmol) in methanol
(15 mL) was added powdered potassium carbonate (30 mg,
0.22 mmol). The solution was then heated at reflux, and stirring
was continued at reflux for 2 h. When the reaction was complete
(TLC), the solvent was removed under reduced pressure. The res-
We thank the National Natural Science Foundation of China
(No. 20972048) and Shanghai Educational Development Founda-
tion (The Dawn Program: No. 03SG27) for the financial support
of this work.

S. Xiao, X.-X. Shi / Tetrahedron: Asymmetry 21 (2010) 226–231
231
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20. Nakazawa, J.; Yajima, J.; Usui, T.; Ueki, M.; Takatsuki, A.; Imoto, M.; Toyoshima,
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