A concise route to (+)-lactacystin

Article abstract of DOI:10.1021/jo048817o

A facile chromatography-free route to Kang's intermediate for the synthesis of (+)-lactacystin, a potent proteasome inhibitor, has been developed starting with Brown's asymmetric crotylation of tert-butyl 5-formyl-2,2-dimethyl-1,3- dioxan-5-ylcarbamate, e

Full text of DOI:10.1021/jo048817o

A Con cise Rou te to (+)-La cta cystin
SCHEME 1. Retr osyn th etic An a lysis
Hidenori Ooi, Norihisa Ishibashi, Yoshiharu Iwabuchi,
J un Ishihara, and Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki
University, Nagasaki 852-8521, J apan
susmi@net.nagasaki-u.ac.jp
Received J uly 13, 2004
Abstr a ct: A facile chromatography-free route to Kang’s
intermediate for the synthesis of (+)-lactacystin, a potent
proteasome inhibitor, has been developed starting with
Brown’s asymmetric crotylation of tert-butyl 5-formyl-2,2-
dimethyl-1,3-dioxan-5-ylcarbamate, easily available from
2
-amino-2-(hydroxymethyl)propane-1,3-diol (Tris).
Lactacystin (1), a metabolite isolated from Streptomy-
1
ces sp. OM-6519, has attracted considerable interest due
to its highly potent and selective inhibition of the 20S
2
proteasome. Since the 20S proteasome participates in
an extraordinarily wide range of cellular processes (e.g.,
cell cycle progression, antigen presentation to the im-
mune system, and inflammatory responses through
protein processing), lactacystin and clasto-lactacystin (2)
reaction of the corresponding ester with isopropylmag-
nesium bromide involving a concomitant addition-reduc-
tion process (vide infra). We envisaged that lactam 3
could be expeditiously accessed from prochiral aldehyde
(omuralide), an active species inhibiting the proteasome
in cells, are very important tools for the study of protein
3
biochemistry and cell biology. In addition, these biologi-
7
via 6 and 5 by transformations involving asymmetric
cal features make lactacystin a potential drug candidate
crotylation, formation of the lactam ring, and transposi-
tion of the acetonide group creating the C5 quaternary
chiral center (Scheme 1).
4
for the treatment of arthritis, asthma, and stroke. Their
high demand in biological research and the intriguing
chemical structure have spurred much research on the
synthesis of lactacystin and a number of total and formal
syntheses have been achieved5 since Corey et al. re-
2
-Amino-2-(hydroxymethyl)propane-1,3-diol (Tris) (8)
was successively subjected to tert-butoxycarbonylation
and acetalization in one pot to give alcohol 9 in 87% yield.
Swern oxidation of 9 afforded aldehyde 10 in 98% yield,
asymmetric crotylation of which was then examined
,6
7
ported the first synthesis of (+)-lactacystin in 1992. We
describe herein a new concise route to (+)-lactacystin
from 2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris).
10
11
using crotylboronate 12 and crotylborane 13. When
0 was reacted with 12 at 0 °C in toluene, alcohol 11
8
Kang et al. developed a highly stereoselective route
1
9
to Baldwin’s intermediate 4 from lactam 3 through
was obtained almost quantitatively with excellent dias-
tereoselectivity (>98% de) but the enantioselectivity was
very low (16% ee). To attain better enantioselectivity, we
carried out this reaction at -78 °C but 10 did not react
with 12 at all under such conditions. On the other hand,
(1) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi,
R.; Tanaka, H.; Sasaki, Y. J . Antibiot. 1991, 44, 113-116. (b) Omura,
S.; Natsuzaki, K.; Fujimoto, T.; Kosuge, K.; Furuya, T.; Fujita, S.;
Nakagawa, A. J . Antibiot. 1991, 44, 117-118.
(
2) Fenteany, G.; Standaert, R. F.; Reichard, G. A.; Corey, E. J .;
Schreiber, S. L. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3358-3362.
(b) Fenteany, G.; Standaert, R. F.; Lane, W. S.; Choi, S.; Corey, E. J .;
(6) (a) Iwama, S.; Gao, W.-G.; Shinada, T. Ohfune, Y. Synlett 2000,
1631-1633. (b) Care, S. N.; Corey, E. J . Org. Lett. 2001, 3, 1395-
1397. (c) Cook, G. R.; Shanker, P. S. J . Org. Chem. 2001, 66, 6818-
6822. (d) Green, M. P.; Prodger, J . C.; Hayes, C. J . Tetrahedron Lett.
2002, 43, 6609-6611. (e) Page, P. C. B.; Leach, D. C.; Hayman, C. M.;
Hamzah, A. S.; Allin, S. M.; McKee, V. Synlett 2003, 1025-1027. (f)
Page, P. C. B.; Hamzah, A. S.; Leach, D. C.; Allin, S. M.; Andrews, D.
M.; Rassias, G. A. Org. Lett. 2003, 5, 353-355. (g) Brennan, C. J .;
Pattenden, G.; Rescourio, G. Tetrahedron Lett. 2003, 44, 8757-8760.
(h) Donohoe, T. J .; Sintim, H. O.; Sisangia, L.; Harling, J . D. Angew.
Chem., Int. Ed. 2004, 43, 2293-2296.
Schreiber, S. L. Science 1995, 268, 726-731. (c) Dick, L. R.; Cruik-
shank, A. A.; Grenier, L.; Melandri, F. D.; Nunes, S. L.; Stein, R. L. J .
Biol. Chem. 1996, 271, 7273-7275. (d) Adams, J . A.; Stein, R. Ann.
Rep. Med. Chem. 1996, 31, 279-288. (e) Groll, M.; Ditzel, L.; L o¨ we,
J .; Stock, D.; Bochtler, M.; Bartunik, H. D.; Huber, R. Nature 1997,
3
86, 463-471. (f) Dick, L. R.; Cruikshank, A. A.; Destree, A. T.; Grenier,
L.; McCormack, T. A.; Melandri, F. D.; Nunes, S. L.; Palombella, V.
J .; Parent, L. A.; Plamondon, L.; Stein, R. L. J . Biol. Chem. 1997, 272,
1
2
82.
(3) DeMartino, G. N.; Slaughter, C. A. J . Biol. Chem. 1999, 274,
2123-22126.
(7) Corey, E. J .; Reichard, G. A. J . Am. Chem. Soc. 1992, 114,
10677-10678.
(4) (a) Conner, E. M.; Brand, S.; Davis, J . M.; Laroux, F. S.;
Palombella, V. J .; Fuseler, J . W.; Kang, D. Y.; Wolf, R. E.; Grisham,
M. B. J . Pharm. Exp. Therap. 1997, 282, 1615-1622. (b) Soucy, F.;
Grenier, L.; Behnke, M. L.; Destree, A. T.; McCormack, T. A.; Adams,
J .; Plamondon, L. J . Am. Chem. Soc. 1999, 121, 9967-9976 and
references therein.
(8) Kang, S. H.; J un, H.-S. Chem. Commun. 1998, 1929-1930.
(9) Uno, H.; Baldwin, J . E.; Russell, A. T. J . Am. Chem. Soc. 1994,
116, 2139-2140.
(10) (a) Roush, W. R.; Halterman, R. L. J . Am. Chem. Soc. 1986,
108, 3422-3434. (b) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz,
A. D.; Halterman, R. L. J . Am. Chem. Soc. 1990, 112, 6339-6348.
(11) (a) Brown, H. C.; Bhat, K. S. J . Am. Chem. Soc. 1986, 108, 293-
294. (b) Brown, H. C.; Bhat, K. S. J . Am. Chem. Soc. 1986, 108, 5919-
5923.
(5) For reviews on synthetic efforts towards lactacystin, see: (a)
Corey, E. J .; Li, W.-D. Z. Chem. Pharm. Bull. 1999, 47, 1-10. (b) Masse,
C. E.; Morgan, A. J .; Adams, J .; Panek, J . S. Eur. J . Org. Chem. 2000,
2
1
513-2528.
0.1021/jo048817o CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/29/2004
J . Org. Chem. 2004, 69, 7765-7768
7765

SCHEME 2a
SCHEME 3a
a
Reagents and conditions: (a) PDC, DMF, then CH2N2-Et2O,
THF; (b) i-PrMgBr, Et2O, CH2Cl2; (c) p-TsOH‚H2O, MeOH, 60 °C;
(d) Et3SiCl, pyridine, then Ac2O, DMAP; (e) 47% HF, 0 °C; (f)
H2CrO4, acetone, 0 °C; (g) 0.2 M NaOH; (h) bis(2-oxo-3-oxazolidi-
nyl)phosphinic chloride (BOPCl), Et3N, CH2Cl2; (i) N-acetyl-L-
cysteine, Et3N, CH2Cl2.
a
synthesis of 3 from Tris did not require any chromato-
Reagents and conditions: (a) Boc2O, DMF then (MeO)2CMe2,
p-TsOH‚H2O; (b) (COCl)2, DMSO, CH2Cl2, -78 °C, then Et3N; (c)
3, THF-Et2O, -78 °C, then 3 M NaOH, 30% H2O2, reflux; (d) O3,
NaHCO3, CH2Cl2-MeOH, -78 °C, then Me2S; (e) PDC, CH2Cl2;
f) p-TsOH‚H2O, acetone.
graphic purification.
1
According to the procedure developed by Kang et al.,8
lactam 3 was successfully converted to Baldwin’s inter-
(
9
mediate 4 in 69% overall yield although the initial J ones
oxidation was performed via PDC oxidation to attain good
reproducibility. Thus, PDC oxidation of 3 followed by
esterification of the resulting carboxylic acid with diazo-
methane gave ester 17 in 71% yield. Upon treatment of
crotylborane 13 reacted smoothly with 10 at -78 °C in
THF-Et O, and after oxidative workup of the reaction
mixture with alkaline hydrogen peroxide, removal of
isopinocampheol by vacuum distillation followed by re-
2
1
7 with isopropylmagnesium bromide at room tempera-
crystallization of the residue from Et O-hexane gave 11
2
ture in Et O, alcohol 19 was obtained stereoselectively
2
with 99% ee in 68% yield. This crotylation reaction was
found to proceed with the enantioselectivity of 90% ee
by HPLC analysis using a chiral column of the corre-
sponding benzoate prepared from a sample purified by
column chromatography of the crude product. Ozonolysis
of 11 gave 14 which was then selectively oxidized with
PDC12 to give lactam 15 in 60% yield. TPAP, Dess-
Martin,14 and Swern oxidations were not effective for this
chemoselective transformation. Treatment of 15 with
through a concomitant addition-reduction process as
depicted in 18. Acidic methanolysis of 19 gave triol 4
quantitatively, the specific rotation and spectral data of
which were identical with those reported by Baldwin et
9
9
al. Following Baldwin’s method, triol 4 thus prepared
was transformed into carboxylic acid 23 in good overall
13
1
5
yield. Finally, according to the established procedure,
(
-)-omuralide (2) and (+)-lactacystin (1) were success-
fully synthesized from 23 (Scheme 3).
2
p-TsOH‚H O in acetone at room temperature led to cleav-
In conclusion, we have developed a practical method
for the synthesis of Kang’s intermediate 3 starting from
age of the tert-butoxycarbonyl group and concomitant
migration of the acetonide group to produce a 5:1 equi-
librium mixture of 3 and 16, quantitatively (Scheme 2).
Pure lactam 3 was obtained by fractional crystallization
of the mixture and the residue was again treated with
2
-amino-2-(hydroxymethyl)propane-1,3-diol (Tris), which
does not require any column chromatography for purifi-
cation. Using this method, a total synthesis of (+)-
lactacystin has been achieved in 16 steps and 13% overall
yield from Tris.
2
p-TsOH‚H O in acetone to convert it to the above-men-
tioned equilibrium mixture. As a result of this sequence,
lactam 3 was obtained in 80% yield from 15. The spectral
data of 3 were identical with those reported by Kang et
Exp er im en ta l Section
8
al. It should be stressed that the above-mentioned
Where appropriate, reactions were performed in flame-dried
glassware under argon. All extracts were dried over MgSO
4
andconcentrated by rotary evaporation below 30 °C at ca. 25
Torr.
(
12) When PCC was used in place of PDC, the R,â-unsaturated
lactam, a dehydration product of 15, was also obtained in 19% yield
along with 15 (46%).
(
13) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 1625-1627.
14) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc., 1991, 113, 7277-
287.
(15) (a) Nagamitsu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.;
Sprengeler, P. A.; Smith, A. B., III. J . Am. Chem. Soc. 1996, 118, 3584-
3590. (b) Corey, E. J .; Li, W.; Reichard, G. A. J . Am. Chem. Soc. 1998,
120, 2330-2336.
(
7
7
766 J . Org. Chem., Vol. 69, No. 22, 2004

ter t-Bu tyl 5-(Hyd r oxym eth yl)-2,2-d im eth yl-1,3-d ioxa n -
-ylca r ba m a te (9). To a suspension of Tris 8 (5.0 g, 41.3 mmol)
(3R,4S)-1-ter t-Bu toxyca r bon yl-4-h yd r oxy-3,8,8-tr im eth -
yl-2-oxo-1-a za -7,9-d ioxa sp ir o[4.5]d eca n e (15). O was intro-
duced into a mixture of 11 (10.2 g, 32.3 mmol) and NaHCO (10.0
g) in CH Cl -MeOH (1:1) (400 mL) at -78 °C for 1 h. Dimethyl
5
3
in DMF (37.5 mL) was added Boc
2
O (10.0 g, 45.3 mmol), and
3
the mixture was stirred at room temperature for 1 h. 2,2-
Dimethoxypropane (6.0 mL, 49.5 mmol) and p-toluenesulfonic
acid monohydrate (400 mg, 2.07 mmol) were added to the
mixture, and stirring was continued overnight. The reaction
2
2
sulfide (4.75 mL, 64.8 mmol) was added, and the mixture was
allowed to warm to room temperature. The reaction mixture was
diluted with CH
to give 14 (11.4 g) as a crystalline solid. To a solution of crude
14 in CH Cl (70 mL) were added PDC (24.4 g, 64.8 mmol) and
Celite (10.0 g), and stirring was continued at room temperature
for 60 h. The reaction mixture was diluted with Et O, filtered
through a Celite pad, and concentrated. Purification of the
residue by recrystalization from Et O-hexane afforded 15 (6.1
g, 60%) as colorless needles: mp 145-147 °C; [R]
CHCl ); FTIR (film) 3465, 1776, 1714, 1295, 1155 cm ; H NMR
(500 MHz, CDCl ) δ 1.25 (d, J ) 7.5 Hz, 3H), 1.41 (s, 3H), 1.54
2 2
Cl , washed with brine, dried,, and concentrated
mixture was diluted with Et
and brine, dried, and concentrated. Recrystallization of the
residue from Et O-hexane afforded 9 (9.42 g, 87%) as colorless
2 3
O, washed with saturated NaHCO
2
2
2
crystals: mp 100-102 °C; FTIR (film) 3309, 1689, 1509, 1371,
2
1
1
3
253, 1166, 1051 cm-1; H NMR (500 MHz, CDCl
3
) δ 1.44 (s,
H), 1.46 (s, 12H), 3.73 (d, J ) 6.5 Hz, 2H), 3.81 (d, J ) 12.5
Hz, 2H), 3.85 (d, J ) 12.5 Hz, 2H), 4.25 (br s, 1H), 5.33 (br s,
H); C NMR (125 MHz, CDCl
4.7, 80.4, 98.7, 156.4; HRMS (EI) calcd for C12
61.1576, found 261.1595. Anal. Calcd for C12
2
2
5
D
+3.9 (c 0.96,
1
1
3
-1
1
6
2
3
) δ 20.2, 26.9, 28.3, 53.3, 64.4,
3
+
H
23NO
5
(M )
: C, 55.16;
3
H
23NO
5
(s, 9H), 1.60 (s, 3H), 2.40 (br s, 1H), 2.71 (dt, J ) 7.0, 13.5 Hz,
1H), 3.41 (dd, J ) 11.5, 2.5 Hz, 1H), 4.04 (dd, J ) 11.5, 2.5 Hz,
H, 8.87; N, 5.36. Found: C, 54.96; H, 8.53; N, 5.62.
ter t-Bu tyl 5-For m yl-2,2-d im eth yl-1,3-d ioxa n -5-ylca r ba m -
a te (10). To a solution of oxalyl chloride (6.7 mL, 76.7 mmol) in
1
4
1
H), 4.57 (d, J ) 11.5 Hz, 1H), 4.64 (d, 1H, J ) 5.5 Hz, 1H),
.79 (d, J ) 11.5 Hz, 1H); 13C NMR (125 MHz, CDCl
9.2, 28.1, 28.6, 40.0, 59.9, 61.3, 62.2, 83.7, 98.8, 150.5, 175.1;
) δ 8.2,
3
CH
C. After the mixture was stirred for 30 min at -78 °C, a solution
of 9 (10.0 g, 38.4 mmol) in CH Cl (25 mL) was added, and
2 2
Cl (200 mL) was added DMSO (8.2 mL, 0.12 mol) at -78
+
HRMS (EI) calcd for C14
00.1447. Anal. Calcd for C15
Found: C, 56.96; H, 7.83; N, 4.42.
H
22NO
6
[(M - Me) ] 300.1446, found
6
°
3
H
25NO
: C, 57.13; H, 7.99; N, 4.44.
2
2
stirring was continued at -78 °C for 30 min. The reaction
mixture was treated with triethylamine (32.1 mL, 0.23 mol),
allowed to warm to room temperature, and stirred for 30 min.
The reaction mixture was diluted with 1 M HCl (20 mL), washed
(4a S ,7R ,7a S )-Te t r a h yd r o-4a -(h yd r oxym e t h yl)-2,2,7-
tr im eth yl[1,3]d ioxin o[5,4-b]p yr r ol-6(4H)-on e (3). To a solu-
tion of 15 (500 mg, 1.59 mmol) in acetone (20 mL) was added
p-toluenesulfonic acid monohydrate (15.0 mg, 0.79 mmol), and
the mixture was stirred at room temperature for 25 h. The
with saturated NaHCO
Recrystallization of the residue from Et
g, 98%) as colorless crystals: mp 116-119 °C; FTIR (film) 3328,
697, 1513, 1375, 1253, 1166 cm-1; 1H NMR (500 MHz, CDCl
δ 1.47 (s, 15H), 3.96 (br d, J ) 12.0 Hz, 2H), 4.07 (d, J ) 12.0
3
and brine, dried, and concentrated.
2
O-hexane gave 10 (9.78
reaction mixture was diluted with CHCl
NaHCO , dried, and concentrated to give a 5:1 mixture of 3 and
16 (354 mg). Compound 3 (197 mg) was obtained by fractional
crystallization from CH Cl -Et O, and the mother liquor was
3
, washed with saturated
1
3
)
3
1
3
Hz, 2H), 5.55 (br s, 1H), 9.64 (s, 1H); C NMR (125 MHz, CDCl
3
)
2
2
2
δ 19.7, 27.3, 28.2, 59.9, 62.7, 81.0, 98.8, 151.9, 155.4, 199.3;
treated again with p-toluenesulfonic acid monohydrate in ac-
etone as described above. This equilibration-separation se-
quence was repeated three times to afford additional 3 (77 mg).
Compound 3 (274 mg, 80% total yield) was obtained as colorless
+
HRMS (EI) calcd for C11
44.1203. Anal. Calcd for C12
Found: C, 55.48; H, 7.92; N, 5.47.
H
18NO
5
[(M - Me) ] 244.1185, found
2
H
21NO
5
: C, 55.58; H, 8.16; N, 5.40.
2
5
8
20
needles: mp 148-150 °C; [R]
31.4 (c 1.10, CHCl )]; FTIR (neat) 3222, 2937, 1673, 1375, 1224,
060 cm ; H NMR (500 MHz, CDCl ) δ 1.10 (d, J ) 7.5 Hz,
D
+29.4 (c 1.04, CHCl
3
) [lit. [R]
D
ter t-Bu tyl (1′S,2′S)-5-(1′-Hyd r oxy-2′-m eth ylbu t-3′-en yl)-
,2-d im eth yl-1,3-d ioxa n -5-ylca r ba m a te (11). To a solution of
+
1
3
2
-
1
1
potassium tert-butoxide (33.4 g, 0.297 mol) in THF (150 mL) was
added trans-2-butene (46.9 mL, 0.595 mol) at -78 °C, and then
n-butyllithium (1.56 M in hexane, 191 mL, 0.297 mol) was added
over 2 h. The reaction mixture was allowed to warm to -50 °C,
and stirring was continued for 10 min. The mixture was then
recooled to -78 °C, and a solution of (-)-B-methoxydiisopi-
3
3
3
)
H), 1.34 (s, 3H), 1.39 (s, 3H), 2.79 (dt, J ) 13.5, 7.5 Hz, 1H),
.58 (d, J ) 12.0 Hz, 1H), 3.62 (d, J ) 11.5 Hz, 2H), 3.69 (dd, J
1
3
12.0, 1.5 Hz, 2H), 4.15 (d, J ) 6.0 Hz, 1H), 7.11 (s, 1H);
C
NMR (125 MHz, CDCl
3
) δ 7.9, 22.0, 25.4, 40.4, 62.0, 62.7, 65.0,
+
7
0.9, 99.6, 180.5; HRMS (EI) calcd for C10
found 215.1155. Anal. Calcd for C10
N, 6.51. Found: C, 55.66; H, 7.73; N, 6.55.
H
17NO
4
(M ) 215.1158,
H
17NO
4
: C, 55.80; H, 7.96;
nocamphenylborane (78.3 g, 0.247 mol) in Et
added over 1 h. After the mixture was stirred for 30 min at -78
C, BF ‚Et O (62.8 mL, 0.496 mol) was added over 30 min, and
2
O (247 mL) was
°
3
2
Met h yl (4a S,7R,7a S)-Hexa h yd r o-2,2,7-t r im et h yl-6-oxo-
[1,3]d ioxin o[5,4-b]p yr r ole-4a -ca r boxyla te (17). To a solution
of 3 (1.38 g, 6.41 mmol) in DMF (25 mL) were added Celite (3.50
g) and PDC (7.20 g, 19.2 mmol), and the mixture was stirred at
room temperature for 52 h. The reaction mixture was diluted
then a solution of 10 (25.7 g, 99.1 mmol) in THF (300 mL) was
added over 40 min. After being stirred at -78 °C for 14 h, the
mixture was allowed to warm to 0 °C and treated with 3 M
NaOH (465 mL) and 30% H
refluxed for 16 h, extracted with Et
2
O
2
(190 mL). The mixture was
O, dried, and concentrated.
2 2
with CH Cl , filtered through a Celite pad, and concentrated.
2
After removal of the resulting isopinocampheol by vacuum
The residue was dissolved in THF (50 mL), and an ethereal
solution of diazomethane was added to this mixture at 0 °C until
the carboxylic acid disappeared on TLC. The reaction mixture
distillation (1 mmHg, 60-70 °C), the residue was recrystallized
from Et
crystals: mp 127-128 °C; [R]
film) 3305, 3077, 1673, 1558, 1448, 1369, 1309, 1259, 1180, 1116
2
O-hexane to give 11 (21.2 g, 68%, 99% ee) as colorless
24
2 3
was concentrated and chromatographed (SiO , 40 g, CHCl /
D
-17.0 (c 1.27, CHCl
3
); FTIR
(
MeOH ) 20/1) to afford 17 (1.11 g, 71%) as a yellow crystalline
-
1
1
solid which was recrystallized from AcOEt-hexane to give
cm ; H NMR (500 MHz, CDCl
3
) δ 1.12 (d, J ) 7.0 Hz, 3H),
colorless crystals: mp 155-158 °C; [R]25
1
.42 (s, 6H), 1.44 (s, 9H), 2.28 (br t, J ) 7.0 Hz, 1H), 3.52 (br d,
D
3
+9.1 (c 1.08, CHCl );
-
1 1
J ) 6.5 Hz, 1H), 3.72 (dd, J ) 12.0, 2.5 Hz, 1H), 3.84 (d, J )
FTIR (film) 3251, 1720, 1440, 1382, 1249, 1022 cm ; H NMR
(500 MHz, CDCl
1
2
(
2.0 Hz, 1H), 3.94 (d, J ) 12.0 Hz, 1H), 4.10 (dd, 1H, J ) 12.0,
.5 Hz, 1H), 4.98-5.04 (m, 2H), 5.10 (br d, J ) 8.5 Hz, 1H), 5.20
3
) δ 1.15 (d, J ) 7.5 Hz, 3H), 1.38 (d, J ) 0.5
Hz, 3H), 1.49 (d, J ) 0.5 Hz, 3H), 2.63 (m, 1H), 3.76 (d, J ) 12.5
Hz, 1H), 3.78 (s, 3H), 4.27 (d, J ) 12.5 Hz, 1H), 4.62 (dd, J )
1
3
br s, 1H), 5.97 (dddd, J ) 17.3, 10.5, 9.0, 8.5 Hz, 1H); C NMR
5.0, 1.5 Hz, 1H), 6.26 (br s, 1H); 13C NMR (125 MHz, CDCl
) δ
(125 MHz, CDCl
3
) δ 19.1, 20.3, 28.1, 28.4, 40.3, 55.8, 63.4, 65.2,
3
7
NO
NO
7.1, 80.4, 98.3, 114.5, 139.5, 157.2; HRMS (EI) calcd for C16
H
H
29
-
-
7.4, 20.5, 26.8, 40.3, 53.1, 61.8, 63.2, 71.4, 98.9, 171.5, 178.5;
HRMS (EI) calcd for C10H14NO5 [(M - Me) ] 228.0871, found
228.0891. Anal. Calcd for C11 : C, 54.31; H, 7.04; N, 5.76.
Found: C, 54.62; H, 6.97; N, 5.82.
+
+
5
(M ) 315.2046, found 315.2049. Anal. Calcd for C16
29
: C, 60.93; H, 9.27; N, 4.44. Found: C, 61.18; H, 9.04; N,
H17NO
5
5
4
.57. The benzoate, obtained from bonzoylation of a sample
purified by SiO column chromatography (hexane/AcOEt ) 20/
) without recrystallization, showed an enantiomeric purity of
0% ee [HPLC: DAICEL CHIRALCEL OD-H, hexane/2-pro-
2
(4a R,7R,7a S,1′S)-Tet r a h yd r o-4a -(1′-h yd r oxy-2′-m et h yl-
p r op yl)-2,2,7-t r im e t h yl[1,3]d ioxin o[5,4-b]p yr r ol-6(4H )-
1
9
on e (19). To a solution of 17 (300 mg, 1.23 mmol) in Et
mL) was added isopropylmagnesium bromide (0.44 M in Et
2
O (50
O,
panol ) 40/1, flow: 0.5 mL/min, detect: UV 254 nm, retention
time: 12.4 min (enantiomer: 13.8 min)].
2
14 mL, 6.17 mmol) at -20 °C, and the mixture was stirred at
J . Org. Chem, Vol. 69, No. 22, 2004 7767

the same temperature for 30 min. After being stirred at room
temperature for 20 h, the reaction was quenched with saturated
3 h. The reaction was quenched with i-PrOH (5 mL) at 0 °C,
and the reaction mixture was diluted with brine, extracted with
AcOEt-THF (2:3), dried, and concentrated. The residue was
diluted with i-PrOH and filtered through a Celite pad, and the
filtrate was concentrated. The residue was diluted with water
and lyophilized to give 22 (105 mg, 100%) as a pale yellow
powder, which was used for the next reaction without purifica-
NH
with brine, dried, and concentrated. Purification of the residue
by chromatography (SiO 10 g, hexane/AcOEt ) 2/1 to 1/3) gave
7 (80 mg, 27%) and 19 (225 mg, 71%, 97% based on consumed
4
Cl. The reaction mixture was extracted with AcOEt, washed
2
1
1
0
2
3
7) each as colorless crystals: mp 191-193 °C; [R]
.83, CHCl ); FTIR (film) 3249, 2935, 1706, 1376, 1143, 1024
) δ 0.96 (d, J ) 7.0 Hz, 3H),
D
-15.2 (c
3
tion: mp 125-127 °C dec (lit. mp 127 °C dec); H and C NMR
9
1
13
-
1
1
cm ; H NMR (500 MHz, CDCl
3
data were identical with those reported.9
1
1
2
.05 (d, J ) 7.0 Hz, 3H), 1.12 (d, J ) 7.5 Hz, 3H), 1.32 (s, 3H),
.39 (s, 3H), 1.96-2.02 (m, 1H), 2.28 (d, J ) 7.5 Hz, 1H), 2.83-
.89 (m, 1H), 3.52 (d, J ) 12.0 Hz, 1H), 3.65 (dd, J ) 7.5, 3.5
(
3R,4S,5R,1′S)-4-Hydr oxy-5-(1′-h ydr oxy-2′-m eth ylpr opyl)-
3
-m eth ylp yr r olid in -2-on e-5-ca r boxylic Acid (23). A mixture
of 22 (125 mg, 0.396 mmol) in 0.2 M NaOH (6.0 mL) was stirred
at room temperature for 10 h. The reaction mixture was acidified
to pH 1-2 with 1 M HCl at 0 °C and lyophilized. The residue
was dissolved in THF, and the resulting precipitate was removed
Hz, 1H), 3.83 (d, J ) 12.0 Hz, 1H), 4.30 (dd, J ) 6.5, 1.5 Hz,
1
2
1
3
H), 6.05 (s, 1H); C NMR (125 MHz, CDCl
3
) δ 8.2, 16.7, 22.2,
2.6, 24.9, 29.3, 39.4, 63.2, 65.0, 72.7, 77.5, 100.0, 180.1; HRMS
+
(EI) calcd for C12
4
H20NO [(M - Me) ] 242.1392, found 242.1405.
by filtration. The filtrate was concentrated and diluted with CH
Cl
mg, 100%) was obtained as a pale yellow powder, which was
2
-
(
3R,4S,5R,1′S)-4-H yd r oxy-5-(h yd r oxym et h yl)-5-(1′-h y-
2
-hexane (1:1) to dissolve impurities. After filtration, 23 (92
d r oxy-2′-m eth ylp r op yl)-3-m eth ylp yr r olid in -2-on e (4). To a
solution of 19 (200 mg, 0.78 mmol) in MeOH (5 mL) was added
p-toluenesulfonic acid monohydrate (15 mg, 0.08 mmol), and the
mixture was stirred at 60 °C for 24 h. The reaction was quenched
used for the next reaction without purification: mp 242-244
°C dec; [R]28
+16.1 (c 1.0, CH
OH) [lit. mp 241-243 °C; [R]
9
21
D
3
13
D
1
with aqueous NaHCO
fication of the residue by chromatography (SiO
3
(4 mg/0.2 mL) and concentrated. Puri-
2 g, CHCl
+18.5 (c 1.0, MeOH)]; H and C NMR data were identical with
those reported.9
2
3
/
MeOH ) 4/1) gave 4 (182 mg, 100%) as colorless needles
cla sto-La cta cystin â-La cton e (2). To a solution of 23 (40
mg, 0.17 mmol) in CH Cl (5 mL) were added triethylamine (88.6
2 2
mL, 0.636 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chlo-
ride (80.9 mg, 0.318 mmol) at 0 °C. After being stirred at room
temperature for 3 h, the reaction mixture was diluted with
2
3
(recrystallized from AcOEt): mp 158-161 °C; [R]
D
-10.9 (c
9
22
0
.86, MeOH) [lit. mp 162-163 °C; [R]
[(M - CH
86.1127. H and C NMR data were identical with those
D
-9.7 (c 1.0, MeOH)];
+
HRMS (EI) calcd for C
9
H
16NO
3
2
OH) ] 186.1130, found
1
13
1
9
reported.
AcOEt, washed with H
of the residue by chromatography (SiO
2
O, dried, and concentrated. Purification
, 2 g, AcOEt) afforded 2
(
3R,4S,5R,1′S)-4-Acetoxy-5-(1′-a cetoxy-2′-m eth ylp r op yl)-
2
3
-m eth yl-5-(tr ieth ylsiloxy)m eth ylp yr r olod in -2-on e (20). To
22
(
-
35.5 mg, 96%) as a colorless powder: mp 183-186 °C dec; [R]
D
a solution of 4 (100 mg, 0.46 mmol) in pyridine (2 mL) was added
chlorotriethylsilane (118 µL, 0.70 mmol), and the mixture was
stirred at room temperature for 3 h. 4-(Dimethylamino)pyridine
15b
23
87.0 (c 0.23, MeCN), [lit. mp 185 °C dec; [R]
D
-93.9 (c 0.53,
-1
1
MeCN)]; FTIR (film) 3365, 1828, 1702, 1542 cm ; H NMR (500
MHz, pyridine-d
Hz, 3H), 1.47 (d, J ) 7.5 Hz, 3H), 2.12 (m, 1H), 3.04 (dq, J )
.2, 7.5 Hz, 1H), 4.35 (d, J ) 3.5 Hz, 1H), 5.00 (br s, 1H), 5.67
d, J ) 6.0 Hz, 1H), 7.78 (br s, 1H), 10.4 (s, 1H); 13C NMR (125
MHz, pyridine-d ) δ 8.80, 16.5, 20.4, 29.9, 38.9, 70.6, 77.0, 80.5,
72.4, 177.3; MS (FAB, NBA) m/z 214 (M + H). These data were
5
) δ 1.01 (d, J ) 6.5 Hz, 3H), 1.13 (d, J ) 7.0
(1 piece) and acetic anhydride (434 µL, 4.60 mmol) were added
to the mixture, and stirring was continued at room temperature
for 27 h. The reaction was quenched with MeOH (0.5 mL) with
cooling in an ice bath. The reaction mixture was diluted with
6
(
5
Et
and concentrated. Purification of the residue by chromatography
SiO 5 g, hexane/AcOEt ) 2/1) gave 20 (165 mg, 86%) as a
colorless solid: mp 61-62 °C; [R]
2
O, washed with 0.5% aqueous NaOH, water, and brine, dried,
1
1
5
identical with those reported.
La cta cystin (1). To a solution of 2 (30 mg, 0.14 mmol) in
CH Cl (4 mL) were added triethylamine (59 µL, 0.42 mmol) and
(
2
2
3
) [lit.9
3
D
-26.7 (c 0.92, CHCl
-26.9 (c 1.0, CHCl )]; FTIR (film) 3201,
2
3
mp 61-62 °C; [R]
745, 1706, 1373, 1232, 1108, 1020 cm ; H NMR (500 MHz,
CDCl ) δ 0.61 (q, J ) 8.0 Hz, 6H), 0.91 (d, J ) 7.0 Hz, 3H), 0.96
t, J ) 8.0 Hz, 9H), 0.99 (d, J ) 7.0 Hz, 3H), 1.07 (d, J ) 7.5 Hz,
D
3
1
2
2
-
1
1
N-acetyl-L-cysteine (19.6 mg, 0.12 mmol), and the mixture was
stirred at room temperature for 14 h. The reaction mixture was
concentrated and purified by chromatography (SiO 2 g, CHCl /
3
(
3
2
3
H), 2.06 (m, 1H), 2.08 (s, 3H), 2.09 (s, 3H), 2.84 (quint, J ) 7.5
MeOH/AcOH ) 10/2/1) to afford 1 (41.5 mg, 79%) as a colorless
Hz, 1H), 3.63 (d, J ) 10.0, 1H), 3.67 (d, J ) 10.0, 1H), 5.09 (d,
powder: mp 233-235 °C dec; [R]22 +72.8 (c 0.40, MeOH) [lit.15a
D
1
3
J ) 4.5 Hz, 1H), 5.54 (d, J ) 7.5 Hz, 1H), 5.83 (s, 1H); C NMR
125 MHz, CDCl
23
mp 236-238 °C dec, [R]
D
+73 (c 0.5, MeOH)]; FTIR (neat) 3334,
1
(
6
C
3
) δ 4.2, 6.7, 9.9, 18.0, 20.4, 20.7, 21.9, 28.9, 39.6,
3.1, 65.8, 72.6, 77.1, 169.4, 170.1, 176.9; HRMS (EI) calcd for
-1
2
1
7
1
1
5
971, 1685, 1619, 1417 cm ; H NMR (500 MHz, pyridine-d ) δ
.20 (d, J ) 7.0 Hz, 3H), 1.27 (d, J ) 7.0 Hz, 3H), 1.58 (d, J )
.5 Hz, 3H), 2.05 (s, 3H), 2.26 (m, 1H), 3.49 (quint, J ) 7.5 Hz,
H), 3.85 (dd, J ) 13.5, 7.0 Hz, 1H), 4.07 (dd, J ) 13.5, 5.0 Hz,
H), 4.61 (d, J ) 7.0 Hz, 1H), 5.35 (d, J ) 7.0 Hz, 1H), 5.42 (br
+
18
H
32NO
6
Si [(M - Et) ] 386.1998, found 386.1995. Anal. Calcd.
for C20
H
37NO
6
Si: C, 57.80; H, 8.97; N, 3.37. Found: C, 58.02;
1
13
H, 9.15; N, 3.42. H and C NMR data were identical with those
reported.
9
dt, J ) 5.0, 7.0 Hz, H), 8.74 (br d, J ) 8.5 Hz, 1H), 9.84 (s, 1H);
(
3R,4S,5R,1′S)-4-Acetoxy-5-(1′-a cetoxy-2′-m eth ylp r op yl)-
-h yd r oxym eth yl-3-m eth ylp yr r olod in -2-on e (21). To a solu-
tion of 20 (180 mg, 0.43 mmol) in MeCN (5.0 mL) was added
7% HF (200 µL) at 0 °C, and the mixture was stirred at room
temperature for 7 h. The reaction mixture was basified with
saturated NaHCO at 0 °C, extracted with CHCl , dried, and
concentrated. Purification of the residue by chromatography
SiO 2 g, CHCl to CHCl
9%) as colorless crystals (recrystallized from Et
13
C NMR (125 MHz, pyridine-d
5
) δ 10.2, 19.9, 21.5, 23.0, 31.5,
5
3
(
2.1, 41.9, 53.0, 76.1, 80.0, 81.4, 170.2, 173.7, 181.3, 203.0; MS
FAB, NBA) m/z 377 (M + H). These data were identical with
4
15
those reported.
3
3
Ack n ow led gm en t. This research was supported by
a Grant-in-Aid for Scientific Research on Priority Areas
A) “Exploitation of Multi-Element Cyclic Molecules”
from the Ministry of Education, Culture, Sports, Science
and Technology, J apan.
(
9
1
-
CH
NO
2
3
3
/MeOH ) 10/1) afforded 21 (129 mg,
O): mp 125-
2
(
2
4
9
24
27 °C; [R]
52.3 (c 0.77, CHCl
D
-50.3 (c 1.0, CHCl
)]; HRMS (EI) calcd for C13
OH) ] 270.1341, found 270.1317. Anal. Calcd for C14
: C, 55.80; H, 7.69; N, 4.65, Found: C, 55.46; H, 7.61; N,
3
) [lit. mp 122-123 °C; [R]
D
3
H20NO
5
[(M -
H -
23
+
2
6
.62. H and C NMR data were identical with those reported.9
1
13
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of compounds 1-4, 9-11, 15, 17, and 19-23.
This material is available free of charge via the Internet at
http://pubs.acs.org.
4
(
3R,4S,5R,1′S)-4-Acetoxy-5-(1′-a cetoxy-2′-m eth ylp r op yl)-
3
-m eth ylp yr r olid in -2-on e-5-ca r boxylic Acid (22). To a solu-
tion of 21 (100 mg, 0.33 mmol) in acetone (10 mL) was added
J ones reagent (2.67 M, 3.7 mL, 9.9 mmol) at 0 °C, and the
mixture was stirred at 0 °C for 3 h and at room temperature for
J O048817O
7
768 J . Org. Chem., Vol. 69, No. 22, 2004