Enantioseleetive synthesis of marine indole alkaloid hamacanthin B

Article abstract of DOI:10.1021/jo0108109

An enantioselective total synthesis of hamacanthin B (1) is described. This synthesis is based on the asymmetric synthesis of (S)-2-azido-(indol-3-yl)ethylamine 7, which is coupled with the 3-indolyl-α-oxoacetyl chloride 8 and subsequently used in a successful intramolecular Staudinger-aza Wittig cyclization to form the central dihydropyrazinone ring. The stereochemistry of naturally isolated hamacanthin B is revealed as the (S)-configuration.

Full text of DOI:10.1021/jo0108109

1396
J . Org. Chem. 2002, 67, 1396-1398
En a n tioselective Syn th esis of Ma r in e
In d ole Alk a loid Ha m a ca n th in B
Biao J iang,* Cai-Guang Yang, and J un Wang
The State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, Peoples Republic of China
F igu r e 1.
With the above results in mind, we envisioned that
hamacanthin B had the same (S)-configuration as
hamacanthin A. Thus, vinyl indole 2 was subjected to
AD-mix-â to give (R)-1-(indol-3-yl)-1,2-ethanediol 3 in
89% yield and 98% ee. Selective tosylation of the primary
hydroxyl group in vicinal diol 3 was accomplished in 75%
yield using dibutyltin oxide and tosyl chloride in dichlo-
romethane.5 Displacement of tosylate 4 with NaN3 in
DMF gave the azide 5 in 80% yield. Although many
useful methods have been reported for reduction of an
azido to amino group,6 most of them were with limited
success. For example, LiAlH4 could not only reduce the
azido group but could also induce partial debromination
of the 6-bromo substituent in the indole ring. Triphen-
ylphosphine did not produce the desired product at all.
However, we found that the reduction procedure using
tin(II) chloride dihydrate as reductant worked well for
our desired transformation.7 Treatment of azide 7 with
an excess of tin(II) chloride dihydrate in methanol at 30
°C for 20 h and subsequent protection of the resulting
amino group with (Boc)2O provided 6 in 74% yield in two
steps. Mitsunobu’s procedure8 was employed to convert
the secondary hydroxyl in compound 6 to an azido group
to give 7 in 83% yield (Scheme 1).
With (S)-2-azido-(indol-3-yl)ethylamine 7 in hand, the
central pyrazinone ring was constructed by coupling
amine with 6-bromo-3-indolyl-R-oxoacetyl chloride 8,9
followed by an intramolecular Staudinger-aza-Wittig
cyclization10 which we have successfully employed for the
synthesis of the antipode of hamacantin A.4 As shown in
Scheme 2, key intermediate 7 underwent CF3COOH-
mediated cleavage of the Boc group followed by coupling
with 6-bromo-3-indolylacetyl chloride 8 to readily afford
compound 9 in 93% yield for two steps. Subsequent
formation of the central pyrazinone ring was achieved
by reaction of azide 9 and tributylphosphine in toluene
at ambient temperature for 2 h and then refluxing for
12 h to provide the expected cyclized product 10 in 82%
yield. The tosyl group used in indole protection can be
removed with LiAlH4, alkaline hydrolysis,11 or a milder
and chemoselective method involving the use of an excess
jiangb@pub.sioc.ac.cn
Received August 9, 2001
Abstr a ct: An enantioselective total synthesis of hamacan-
thin B (1) is described. This synthesis is based on the
asymmetric synthesis of (S)-2-azido-(indol-3-yl)ethylamine
7, which is coupled with the 3-indolyl-R-oxoacetyl chloride
8 and subsequently used in a successful intramolecular
Staudinger-aza Wittig cyclization to form the central di-
hydropyrazinone ring. The stereochemistry of naturally
isolated hamacanthin B is revealed as the (S)-configuration.
Over the past few years, much attention has been paid
to the search for certain bisindole secondary metabolites,
containing either an imidazole- or piperazine-derived
spacer unit, due to their novel structural features and
broad spectrum of powerful biological activities.1,2 Hama-
canthin B (1), one member of the family of naturally
occurring bis(indol-3-yl)dihydropyrazinones, was isolated
from a deep-water marine sponge Hamacantha sp. and
has been reported to show significant antimicrobial activ-
ity against Candida albicans and Cryptococcus neofor-
mans. On the basis of NMR spectroscopy, its structure
was elucidated to be 3,5-bis(6-bromoindol-3-yl)-5,6-dihy-
dro-2(1H)-pyrazinone, but its absolute configuration was
not assigned.3 In this Note, we describe the first enan-
tioselective synthesis of hamacanthin B (1, Figure 1) and
demonstrate that the stereochemistry of natural hamacan-
thin B is (S).
Recently, we developed methodology for the prepara-
tion of an antipode of hamacanthin A, which has the
bisindolyl group linking the 5,6-postion of dihydropyrazi-
none. It is revealed that natural hamacanthin A has the
(S)-configuration. The (R)-chiral center in the antipode
of hamacanthin A was created by using (S)-1-(indol-3-
yl)-1,2-ethanediol as starting material, which was gener-
ated by the osmium tetraoxide-catalyzed asymmetric
dihydroxylation (Sharpless AD reaction) of vinyl indole
2 using AD-mix-R.4
(1) Faulkner, D. J . Nat. Prod. Rep. 2001, 18, 1 and references
therein.
(5) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643.
(6) For a review, see: Scriven, E. F. V.; Turnbull, K. Chem. Rev.
1988, 88, 297.
(7) Boger, D. L.; Patane, M. A.; Zhou, J . J . Am. Chem. Soc. 1994,
116, 8544.
(8) Mitsunobu, O. Synthesis 1981, 1.
(9) Da Settimo, A.; Saettone, M. F.; Nannipieri, E.; Barili, P. Gazz.
Chim. Ital. 1967, 97, 1304.
(10) (a) For an excellent review, see: Molina, P.; Vilaplana, M. J .
Synthesis 1994, 1197. (b) For recent examples of intramolecular aza-
Wittig reaction in organic synthesis, see: (i) Sugimori, T.; Okawa, T.;
Eguchi, S.; Yashima, E.; Okamoto, Y. Chem. Lett. 1997, 869. (ii)
Fresneda, P. M.; Molina, P.; Sanz, M. A. Synlett 2000, 1190. (iii) Kamal,
A.; Laxman, E.; Reddy, P. S. M. M. Tetrahedron Lett. 2000, 41, 8631.
(11) Bowman, R. E.; Evans, D. D.; Islip, P. J . Chem. Ind. 1971, 33.
(2) For related bisindole natural alkaloids, see: (a) Tsujii, S.;
Rinehart, K. L.; Gunasekera, S. P.; Kashman, Y.; Cross, S. S.; Lui, M.
S.; Pomponi, S. A.; Diaz, M. C. J . Org. Chem. 1988, 53, 5446. (b)
Kohmoto, S.; Kashman, Y.; McConnell, O. J .; Rinehart, K. L.; Wright,
A.; Koehn, F. J . Org. Chem. 1988, 53, 3116. (c) Wright, A. E.; Pomponi,
S. A.; Cross, S. S.; McCarthy, P. J . Org. Chem. 1992, 57, 4772. (d)
Capon, R. J .; Rooney, F.; Murray, L. M.; Collins, E.; Sim, A. T. R.;
Rostas, J . A. P.; Butler, M. S.; Carrol, A. R. J . Nat. Prod. 1998, 61,
660. (e) Cutignano, A.; Bifulco, G.; Bruno, I.; Casapullo, A.; Gomez-
Paloma, L.; Riccio, R. Tetrahedron 2000, 56, 3743. (f) Casapullo, A.;
Bifulco, G.; Bruno, I.; Riccio, R. J . Nat. Prod. 2000, 63, 447.
(3) Gunasekera, S. P.; McCarthy, P. J .; Kelly-Borges, M. J . Nat.
Prod. 1994, 57, 1437.
(4) J iang, B. Yang, C.-G.; Wang, J . J . Org. Chem. 2001, 66, 4865.
10.1021/jo0108109 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/24/2002

Notes
J . Org. Chem., Vol. 67, No. 4, 2002 1397
CHCl3); IR (KBr) 3352 cm-1; 1H NMR (CDCl3, 300 MHz) δ 8.15
(d, J ) 1.6 Hz, 1H), 7.76 (d, J ) 8.4 Hz, 2H), 7.55 (s, 1H), 7.46
(d, J ) 8.4 Hz, 1H), 7.33 (dd, J ) 8.5 and 1.7 Hz, 1H), 7.25 (d,
J ) 8.4 Hz, 2H), 5.02 (m, 1H), 3.84 (m, 2H), 2.72 (d, J ) 3.9 Hz,
1H), 2.36 (s, 3H), 2.18 (t, J ) 5.8 Hz, 1H); 13C NMR (CDCl3, 75
MHz) δ 145.4, 135.8, 134.6, 130.0, 127.6, 127.8, 126.8, 126.6,
123.8, 121.8, 121.2, 118.6, 116.6, 68.3, 66.4, 21.5; EIMS m/e
Sch em e 1
(relative intensity) 411/409 (8/8), 155 (62). Anal. Calcd for C17H16
-
BrNO4S: C, 49.76; H, 3.90; N, 3.41. Found: C, 49.38; H, 4.20;
N, 3.28.
(R)-1-(N-Tosyl-6-br om oin d ol-3-yl)-2-[(tosyl)oxy]-1-eth a -
n ol (4). A mixture of diol 3 (1.36 g, 3.3 mmol) and Bu2SnO (0.91
g, 3.65 mmol) in benzene (30 mL) was refluxed for 2 h to remove
water. After cooling to room temperature, the solvent was
removed, and CH2Cl2 (30 mL) and tosyl chloride (0.69 g, 3.65
mmol) were added. Refluxing was continued for 6 h, after which
the mixture was diluted with 30 mL of CH2Cl2 and washed with
saturated NaHCO3 and brine successively. The organic phase
was dried over Na2SO4 overnight, filtered, and concentrated to
give a syrupy residue which was purified by flash chromatog-
raphy (silica, Hex/AcOEt 2:1) to give 4 (1.4 g, 75%) as a white
o
solid. Mp 154 C; [R]20D ) -17 (c 0.525, acetone); IR (KBr) 3518,
Sch em e 2
1598 cm-1; 1H NMR (DMSO-d6, 300 MHz) δ 7.99 (d, J ) 1.3 Hz,
1H), 7.90 (d, J ) 8.4 Hz, 2H), 7.68 (s, 1H), 7.42 (m, 5H), 7.32
(dd, J ) 8.5 and 1.5 Hz, 1H), 7.16 (d, J ) 8.1 Hz, 2H), 5.92 (d,
J ) 4.95 Hz, 1H), 5.01 (m, 1H), 4.16 (d, J ) 4.95 Hz, 2H), 2.35
(s, 3H), 2.33 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ 145.9,
144.7, 135.0, 134.0, 131.6, 130.4, 129.6, 127.4, 127.2, 126.7, 126.1,
124.7, 122.3, 121.9, 121.8, 117.4, 115.5, 72.4, 63.9, 21.1, 21.0;
ESIMS m/e 563.6. Anal. Calcd for C24H22BrNO6S2: C, 51.06; H,
3.90; N, 2.48. Found: C, 51.13; H, 3.90; N, 2.54.
(R)-1-(N-Tosyl-6-br om oin d ol-3-yl)-2-a zid o-1-eth a n ol (5).
To a solution of compound 4 (1.2 g, 2.13 mmol) in anhydrous
DMF (20 mL) was added NaN3 (0.52 g, 8 mmol). The mixture
was stirred for 12 h at 80 °C and then allowed to cool to room
temperature. Then water (50 mL) was added to quench the
reaction. The aqueous layer was extracted with ethyl acetate (3
× 50 mL). The combined organic layers were washed with water
and brine successively, dried over anhydrous sodium sulfate,
filtered, and concentrated. The residue was purified by flash
chromatography (silica, Hex/AcOEt 3:1) to give 5 (0.74 g, 80%)
as a white solid. Mp 164 °C; [R]20 ) -65 (c 0.580, acetone); IR
D
Mg in methanol;12 however, we found that all the known
procedures proved less successful for the removal of the
tosyl group in compound 10. Finally, treatment of 10 with
L-Selectride in refluxing THF for 3 h gave 1 in 75% yield.
The specific rotation of 1 was +183 (c 0.1, CH3OH). Com-
parison with naturally isolated hamacanthin B, which
has a positive specific rotation of +176 (c 0.1, CH3OH),
revealed that natural hamacanthin B has the (S)-con-
figuration. The 1H and 13C NMR chemical shifts and
coupling constants of synthetic hamacanthin B cor-
responded to those reported for hamacanthin B isolated
from Nature.
(KBr) 3360, 2113 cm-1 1H NMR (DMSO-d6, 300 MHz) δ 8.05
;
(d, J ) 1.3 Hz, 1H), 7.89 (d, J ) 8.4 Hz, 2H), 7.77 (s, 1H), 7.72
(d, J ) 8.5 Hz, 1H), 7.46-7.41 (m, 3H), 5.95 (br d, J ) 4.3 Hz,
1H), 5.03 (m, 1H), 3.59-3.46 (m, 2H), 2.33 (s, 3H); 13C NMR
(DMSO-d6, 100 MHz) δ 145.8, 135.2, 133.9, 130.4, 127.8, 126.7,
126.3, 124.3, 123.8, 122.8, 117.5, 115.6, 65.6, 55.5, 21.0; EIMS
m/e (relative intensity) 436/434 (1). Anal. Calcd for C17H15
-
BrN4O3S: C, 46.89; H, 3.45; N, 12.87. Found: C, 46.61; H, 3.48;
N, 12.80.
(R)-2-N-(ter t-Bu tyloxycar bon yl)-1-(N-tosyl-6-br om oin dol-
3-yl)-1-eth a n ol (6). To a suspension of compound 5 (690 mg,
1.58 mmol) in MeOH (30 mL) under argon was added tin(II)
chloride dihydrate (1.08 g, 4.8 mmol). The reaction mixture was
stirred for 20 h at 30 °C and diluted with water (10 mL) and 6
N NaOH (10 mL). The resulting mixture was stirred for 30 min
and then extracted with ethyl acetate (3 × 50 mL). The combined
organic layer was dried over anhydrous sodium sulfate, filtered,
and concentrated to give the amine as a foam, which was used
in the next step without purification. To a mixture of the crude
amine and Et3N (0.5 mL, 3 mmol) in dichloromethane (20 mL)
was added di-tert-butyl dicarbonate (415 mg, 1.9 mmol) in an
ice-cooled bath. The reaction was stirred at room temperature
for 3 h and diluted with dichloromethane (10 mL), then washed
with water and brine, dried (Na2SO4), and concentrated in vacuo.
The crude product was purified by flash chromatography (silica,
Hex/AcOEt 2:1) to provide compound 6 (600 mg, 74% yield in
Exp er im en ta l Section
Gen er a l. Anhydrous reactions were performed in oven-dried
glassware under a positive pressure of nitrogen. Melting points
were determined in an apparatus and uncorrected. Optical
rotations were recorded at the Na-D line in a 1 dm cell at 20 °C.
Infrared (IR) spectra were determined on thin film. 1H NMR
spectra were recorded at 300 or 600 MHz and were referenced
to tetramethylsilane (TMS) at 0.00 ppm. 13C NMR spectra were
recorded at 75 or 100 MHz. Flash chromatography was per-
formed using silica gel H (10-40 µm).
(R)-1-(N-Tosyl-6-br om oin d ol-3-yl)-1,2-eth a n ed iol (3). Vi-
nyl indole 24 (3.0 g, 8.0 mmol) was subjected to AD-mix-â (12 g)
in tert-butyl alcohol/water (100 mL, 1:1) to give (R)-1-(indol-3-
yl)-1,2-ethanediol 3 in 89% yield and 98% ee.4 The enantiomeric
excess was determined by HPLC using a Chiral OD column with
two steps) as a white solid. [R]20 ) -43 (c 0.475, CHCl3); IR
D
(KBr) 3421, 1691 cm-1; 1H NMR (CDCl3, 300 MHz) δ 8.16 (d, J
) 1.7 Hz, 1H), 7.76 (d, J ) 8.4 Hz, 2H), 7.53 (d, J ) 1.0 Hz, 1H),
7.48 (d, J ) 8.5 Hz, 1H), 7.34 (dd, J ) 8.5 and 1.7 Hz, 1H), 7.25
(d, J ) 8.4 Hz, 2H), 5.03 (m, 1H), 4.94 (br, 1H), 3.6 (m, 1H),
3.33 (m, 2H), 2.36 (s, 3H), 1.45 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 157.1, 145.4, 136.0, 134.9, 130.1, 127.5, 126.8, 126.6,
123.6, 123.2, 121.4, 118.6, 116.7, 80.2, 68.0, 47.0, 28.3, 21.6;
an eluent of 2-propanol/hexane (2/8). [R]20 ) -44.7 (c 0.945,
D
(12) Muratake, H.; Natsume, M. Heterocycles 1989, 29, 783.

1398 J . Org. Chem., Vol. 67, No. 4, 2002
Notes
ESIMS m/e 533.2 (M + Na). Anal. Calcd for C22H25BrN2O5S: C,
51.87; H, 4.91; N, 5.50. Found: C, 51.75; H, 5.11; N, 5.28.
(S)-N-(ter t-Bu tyloxyca r bon yl)-2-(N-tosyl-6-br om oin d ol-
3-yl)-1-a zid oeth yla m in e (7). To a solution of compound 6 (0.54
g, 1.06 mmol) in anhydrous THF (20 mL) were added triph-
enylphosphine (1.05 g, 4 mmol), diethyl azodicarboxylate (40%
in toluene, 1.84 mL, 4 mmol), and diphenylphosphoryl azide
(0.86 mL, 4 mmol) at -20 °C. The mixture was stirred for 6 h
at this temperature and then allowed to warm to room temper-
ature and stirred overnight. The solvent was evaporated under
reduced pressure, and the residue was directly subjected to flash
chromatography (silica, Hex/AcOEt 4:1) to give intermediate 7
(0.47 g, 83%) as a syrup. [R]20D ) +68 (c 0.415, CHCl3); IR (KBr)
tributylphosphine (202 µL, 0.80 mmol). The mixture was stirred
at room temperature for 2 h and then warmed to reflux for 20
h under an argon atmosphere. After the removal of toluene, the
residue was subjected to flash chromatography (silica, Hex/
AcOEt 1:1 and 1:2) to give compound 10 (270 mg, 82%) as a
yellow solid. Mp 166 °C; [R]20D ) +116 (c 0.20, CH3OH); IR (KBr)
1
3397, 1682 cm-1; H NMR (DMSO-d6, 300 MHz) δ 11.69 (br s,
1H), 8.61 (br s, 1H), 8.43 (s, 1H), 8.19 (d, J ) 8.5 Hz, 1H), 8.08
(d, J ) 1.6 Hz, 1H), 7.89 (d, J ) 8.4 Hz, 2H), 7.79 (d, J ) 8.5 Hz,
1H), 7.75 (d, J ) 0.8 Hz, 1H), 7.65 (d, J ) 1.7 Hz, 1H), 7.47 (dd,
J ) 10.2 and 1.7 Hz, 1H), 7.43 (d, J ) 8.2 Hz, 2H), 7.19 (dd, J
) 10.2 and 1.8 Hz, 1H), 5.26 (dd, J ) 10.0 and 4.9 Hz, 1H), 3.63
(dd, J ) 12.9 and 5.0 Hz, 1H), 3.52 (dd, J ) 12.9 and 10.2 Hz,
1H), 2.34 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ 157.6, 157.2,
145.8, 137.2, 135.4, 133.8, 133.3, 130.4, 128.5, 126.7, 126.4, 124.9,
124.3, 123.8, 123.5, 122.8, 117.8, 115.8, 114.9, 114.5, 110.9, 53.2,
42.4, 21.0. Anal. Calcd for C27H20Br2N4O3S: C, 50.63; H, 3.13;
N, 8.75. Found: C, 50.89; H, 3.31; N, 8.55.
1
3423, 2106, 1709 cm-1; H NMR (CDCl3, 300 MHz) δ 8.17 (d, J
) 1.6 Hz, 1H), 7.77 (dd, J ) 6.7 and 1.7 Hz, 2H), 7.56 (d, J )
0.8 Hz, 1H), 7.52 (d, J ) 8.4 Hz, 1H), 7.38 (dd, J ) 8.5 and 1.6
Hz, 1H), 7.27 (d, J ) 8.4 Hz, 2H), 4.89 (br, 2H), 3.58 (m, 1H),
3.32 (m, 1H), 2.37 (s, 3H), 1.45 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 155.8, 145.6, 136.0, 134.6, 130.2, 127.3, 126.9, 124.5,
121.3, 119.1, 118.5, 116.9, 80.1, 58.5, 44.8, 28.3, 28.3, 21.6;
ESIMS m/z: 556.2 (M + Na). Anal. Calcd for C22H24BrN5O4S:
C, 49.44; H, 4.49; N, 13.11. Found: C, 49.68; H, 4.66; N, 12.96.
(S)-N-[2-Azid o-2-(N-tosyl-6-br om o-in d ol-3-yl)eth yl]-2-(6-
br om o-1H-in d ol-3-yl)-2-oxoa ceta m id e (9). To a stirred solu-
tion of compound 7 (440 mg, 0.82 mmol) in CH2Cl2 (20 mL) was
added trifluoroacetic acid (3.1 mL, 40 mmol) in an ice-water
bath under argon. The reaction solution was stirred at room
temperature overnight and quenched by the addition of water
(20 mL). The water phase was neutralized with aqueous 1 N
NaOH and extracted with CH2Cl2 (2 × 20 mL). The combined
organic layer was washed with saturated NaHCO3 and brine
successively, then dried over Na2SO4, and concentrated in vacuo
to give the crude amine as a yellow oil. To a solution of the yellow
oil and triethylamine (0.42 mL, 3 mmol) in dry DMF (15 mL)
cooled in an ice bath was added dropwise a solution of 6-bromo-
3-indolyl-R-oxoacetyl chloride 84 (432 mg, 1.5 mmol) in dry DMF
(5 mL). After 4 h, water (30 mL) was added and the resulting
mixture was extracted with ethyl acetate (3 × 20 mL). The
organic phase was washed with water and brine successively,
dried (Na2SO4), and then concentrated in vacuo. Flash chroma-
tography (silica, Hex/AcOEt 3:1) gave compound 9 (490 mg, 93%)
Ha m a ca n th in B (1). To a solution of compound 10 (32 mg,
0.05 mmol) in 4 mL of THF was added L-Selectride (1M in THF,
0.5 mL, 0.5 mmol) under an argon atmosphere. After the
resulting solution was refluxed for 4 h, the reaction was
quenched with methanol (2 drops) and diluted by the addition
of water (5 mL). The mixture was extracted with ethyl acetate
(3 × 10 mL). The organic layer was washed with water and brine
successively, dried (Na2SO4), and concentrated in vacuo. Puri-
fication by flash chromatography (silica, CH2Cl2/MeOH 50:1)
gave hamacanthin B (1) (18 mg, 75%) as a yellow solid. [R]20
)
D
+183 (c 0.10, CH3OH) {lit.3 [R]20 ) +176 (c 0.10, CH3OH)}; IR
D
(KBr) 1674 cm-1 1H NMR (DMSO-d6, 600 MHz) δ 11.62 (br,
;
1H), 11.13 (s, 1H), 8.48 (br, 1H), 8.41 (s, 1H), 8.30 (d, J ) 9 Hz,
1H), 7.66 (d, J ) 9 Hz, 1H), 7.63 (d, J ) 1.7 Hz, 1H), 7.59 (d, J
) 1.7 Hz, 1H), 7.28 (d, J ) 1.8 Hz, 1H), 7.18 (dd, J ) 8.4 and
1.6 Hz, 1H), 7.14 (dd, J ) 8.4 and 1.6 Hz, 1H), 3.62 (dd, J )
12.8 and 5.0 Hz, 1H), 3.46 (dd, J ) 12.8 and 9.0 Hz, 1H); 1H
NMR (CDCl3/15% CD3OD, 600 MHz) δ 8.52 (br, 1H), 8.29 (d, J
) 8.4 Hz, 1H), 7.60 (m, 3H), 7.29 (d, J ) 8.4 Hz, 1H), 7.27 (s,
1H), 7.22 (dd, J ) 8.4 and 1.8 Hz, 1H), 5.43 (dd, J ) 9.0 and 5.4
Hz, 1H), 3.84 (dd, J ) 13.2 and 4.8 Hz, 1H), 3.70 (dd, J ) 13.2
and 9.0 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 157.3, 157.1,
137.4, 137.1, 132.9, 125.1, 124.1, 123.8, 123.4, 121.4, 120.9, 114.9,
114.8, 114.3, 114.2, 114.0, 111.1, 53.7, 43.3; EIMS m/e (relative
intensity) 486/482 (32/32); HREIMS calcd for C20H1479Br2N4O:
483.9545; found 483.9544. Anal. Calcd for C20H14Br2N4O: C,
49.41; H, 2.90; N, 11.52; Found: C, 49.44; H, 2.98; N, 11.50.
as a light yellow solid. Mp 160 °C; [R]20 ) +37 (c 0.48, CHCl3);
D
IR (KBr) 3377, 2105, 1636 cm-1; H NMR (CDCl3, 300 MHz) δ
1
8.98 (d, J ) 3.2 Hz, 1H), 8.78 (br s, 1H), 8.28 (d, J ) 8.5 Hz,
1H), 8.17 (d, J ) 1.7 Hz, 1H), 7.75 (d, J ) 8.4 Hz, 2H), 7.64 (s,
1H), 7.61 (d, J ) 1.7 Hz, 1H), 7.54 (d, J ) 8.5 Hz, 1H), 7.46 (dd,
J ) 8.5 and 1.6 Hz, 1H), 7.39 (dd, J ) 8.5 and 1.6 Hz, 1H), 4.96
(dd, J ) 8.1 and 5.0 Hz, 1H), 3.88 (m, 1H), 3.63 (m, 1H), 2.32 (s,
3H); 13C NMR (DMSO-d6, 100 MHz) δ 181.5, 163.4, 145.8, 139.4,
137.2, 135.1, 133.6, 130.3, 127.8, 126.7, 125.9, 125.5, 125.2, 122.9,
122.1, 118.2, 118.1, 116.0, 115.8, 115.4, 112.0, 56.1, 41.7, 20.9;
EIMS m/e 640 (M - N3). Anal. Calcd for C27H20Br2N6O4S: C,
47.37; H, 2.92; N, 12.28. Found: C, 47.34; H, 3.20; N, 11.91.
(S)-3-(6-Br om oin d ol-3-yl)-5-(N-tosyl-6-br om oin d ol-3-yl)-
5,6-d ih yd r o-2(1H)-p yr a zin on e (10). To a solution of compound
9 (330 mg, 0.48 mmol) in dry toluene (25 mL) was added
Ack n ow led gm en t. We are grateful for financiall
support from Shanghai Municipal Committee of Science
and Technology.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O0108109