Highly diastereoselective enolate addition of O-protected α-hydroxyacetate to (SR)-tert-butanesulfmylimines: Synthesis of taxol side chain

Article abstract of DOI:10.1021/jo052298n

The taxol side chain (s_R,2R,3-5)-N-tert-butanesulfinyl-O-Boc-3- phenylisoserine benzyl ester 4c was synthesized through a lithium enolate addition of O-Boc-α-hydroxyacetate benzyl ester 5c to benzylidene (S _R)-tert-butanesulfinamide 6a in excellent yield and diastereoselectivity. By similar approach, a series of enantiopure 3-substituted isoserine benzyl esters 4 useful for the semi-syntheses of taxol derivatives were also prepared in high to excellent yields and diastereoselectivities. The diastereoselective addition mechanism was discussed on the basis of the experimental observation.

Full text of DOI:10.1021/jo052298n

Highly Diastereoselective Enolate Addition of O-Protected
r-Hydroxyacetate to (SR)-tert-Butanesulfinylimines: Synthesis of
Taxol Side Chain
Yin Wang, Qin-Fei He, Hao-Wei Wang, Xuan Zhou, Zhi-Yan Huang, and Yong Qin*
Department of Chemistry of Medicinal Natural Products and Key Laboratory of Drug Targeting,
West China School of Pharmacy, and National Key Laboratory of Biotherapy, Sichuan UniVersity,
Chengdu 610041, P. R. China
yanshuqin@yahoo.com
ReceiVed NoVember 5, 2005
The taxol side chain (SR,2R,3S)-N-tert-butanesulfinyl-O-Boc-3-phenylisoserine benzyl ester 4c was
synthesized through a lithium enolate addition of O-Boc-R-hydroxyacetate benzyl ester 5c to benzylidene
(SR)-tert-butanesulfinamide 6a in excellent yield and diastereoselectivity. By similar approach, a series
of enantiopure 3-substituted isoserine benzyl esters 4 useful for the semi-syntheses of taxol derivatives
were also prepared in high to excellent yields and diastereoselectivities. The diastereoselective addition
mechanism was discussed on the basis of the experimental observation.
Introduction
breVifolia. For this reason, extensive efforts have been focused
on semi-synthesis3 of taxol by the condensation of commercially
available 14-â-hydroxy-10-deacetylbacctin III 2 with a side
chain such as N-benzoyl-(2R, 3S)-3-phenylisoserine 3 (Figure
1). Therefore, over the last 20 years, the efficient synthesis of
enantiopure side chain 3 has attracted much attention from
academic community as well as industry.4 In this article, we
report a highly diastereoselective enolate addition of O-Boc-
R-hydroxyacetate to benzylidene (SR)-tert-butanesulfinamide to
lead directly to the formation of N,O-protected (SR,2R,3S)-3-
phenylisoserine ester 4c in excellent yield. The efficiency and
applicable scope of tert-butanesulfinylimine enolate addition to
prepare a series of enantiopure 3-substituted isoserines 4 were
well demonstrated.
Taxol 1,1 isolated from Taxus breVifolia, is considered the
most promising anticancer drug. Considering the complexity
of taxol and the fact that the content of taxol in the bark of T.
breVifolia is only about 0.03%, the major barrier for medical
usage of taxol is resource limitation. Mass production by total
synthesis2 and by isolation from the natural resource no doubt
is not economical and has sacrificed the rare species of T.
(1) (a) Horwitz, S. B. J. Nat. Prod. 2004, 67, 136. (b) Miller, M. L.;
Ojima, I. Chem. Rec. 2001, 1, 195. (c) Kingston, D. G. I. Chem. Commun.
2001, 867. (d) Wani, M. C.; Taylor, H. I.; Wall, M. E.; Coggon, P.; McPhail,
A. T. J. Am. Chem. Soc. 1971, 93, 2325.
(2) (a) Kusama, H.; Hara, R.; Kawahara, S.; Nishimori, T.; Kashima,
H.; Nakamura, N.; Morihira, K.; Kuwajima, I. J. Am. Chem. Soc. 2000,
122, 3811. (b) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.;
Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y.; Hasegawa,
M.; Yamada, K.; Saitoh, K. Chem.-Eur. J. 1999, 5, 121. (c) Wender, P.
A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.; Granicher,
C.; Houze, J. B.; Janichen, J.; Lee, D.; Marquess, D. G.; McGrane, P. L.;
Meng, W.; Mucciaro, T. P.; Muhlebach, M.; Natchus, M. G.; Paulsen, H.;
Rawlins, D. B.; Satkofsky, J.; Shuker, A. J.; Sutton, J. C.; Tayler, R. E.;
Tomooka, K. J. Am. Chem. Soc. 1997, 119, 2755. (d) Master, J. J.; Link,
J. T.; Snyder, L. B.; Young, W. B.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 1995, 34, 1723. (e) Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang, F.;
Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.;
Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi,
K. K.; Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc. 1994, 116, 1597. (f)
Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R.
K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.;
Sorensen, E. J. Nature 1994, 367, 630.
(3) (a) Gennari, C.; Vulpetti, A.; Donghi, M.; Mongelli, N.; Vanotti, E.
Angew. Chem., Int. Ed. 1996, 35, 1723. (b) Ojima, I. Acc. Chem. Res. 1995,
28, 383. (c) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.
Tetrahedron 1992, 48, 6985.
(4) (a) Tosaki, S.; Tsuji, R.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 2147. (b) Kudyba, I.; Raczko, J.; Jurczak, J. J. Org. Chem.
2004, 69, 2844. (c) Juhl, K.; Jorgensen, K. A. J. Am. Chem. Soc. 2003,
124, 2420. (d) Aggarwal, V. K.; Vasse, J. L. Org. Lett. 2003, 5, 3987. (e)
Schade, W.; Reissig, H. U. J. Prakt. Chem. 1999, 341, 685. (f) Li, G.;
Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35, 451. (g)
Ojima, I. Acc. Chem. Res. 1995, 28, 383. (h) Wang, Zh.-M.; Kolb, H. C.;
Sharpless, K. B. J. Org. Chem. 1994, 59, 5104. (i) Crispino, G. A.; Jeong,
K. S.; Kolb, H. C.; Wang, Zh.; Xu, D. J. Org. Chem. 1993, 58, 3785. (j)
Hattori, K.; Miyata, M.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 1151.
(k) Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320. (l) Denis, J.
N.; Correa, A.; Greene, A. E. J. Org. Chem. 1990, 55, 1957.
10.1021/jo052298n CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/13/2006
1588
J. Org. Chem. 2006, 71, 1588-1591

Synthesis of Taxol Side Chain
TABLE 1. Diastereoselective Addition of 5 to
(SR)-N-(Benzylidene)-tert-butanesulfinamide 6aa
entry acetate 5
R1
R2
base
yield of 4b
dr
1
2
3
4
5
6
5a
5b
5c
5c
5c
5c
5c
5c
5d
MeOCO Bn LDA
4a (45)
4b (56)
4c (86)
4c (36)
4c (43)
4c (97)
4c (50)
4c (85)
4d (96)
88:12:0:0c
-
d
Cbz
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Bn LDA
Bn LDA
>99:0:0:0e
>99:0:0:0e
>99:0:0:0e
>99:0:0:0e
>99:0:0:0e
>99:0:0:0e
>99:0:0:0e
Bn BuLi
Bn tBuLi
Bn LiHMDS
Bn LiHMDS
Bn LiHMDS
Me LiHMDS
7f
8g
9
a All reactions were conducted at -78 °C in THF using 1 equiv of 6a,
5 equiv of 5, and 5 equiv of base unless specifically indicated. b Isolated
yield. In parentheses, percent value. c The dr value was based on isolated
isomers, and the absolute configuration of minor isomer was not identified.
d Other isomers were isolated as an inseparable and unidentified mixture
contaminated with byproducts. e A dr value of >99% indicated that other
isomers were not observed. f At -45 °C. g At -78 °C, 3 equiv of 5c and
LiHMDS were used.
FIGURE 1. Structure of taxol, bacctin III, and taxol side chains.
SCHEME 1. Diastereoselective Addition of 5 to
tert-Butanesulfinylimine 6a
SCHEME 2 a
Results and Discussion
In recent years, Davis, Ellman, and co-workers have dem-
onstrated well the diastereoselective sulfinylimine enolate
addition reaction as one of the important reactions of C-C bond
formation for preparing chiral â-amino acid ester and R,â-
diamino acid ester.5,6 In continuing our study on chiral tert-
butanesulfinamide chemistry,7 we envisioned that enantiopure
3-phenylisoserine ester 4 with a (2R,3S) configuration may be
directly assembled by the diastereoselective addition of an
enolate of O-protected R-hydroxyacetate 5 to enantiopure tert-
butanesulfinylimine 6a, although theoretically four isomers will
be formed in the addition reaction (Scheme 1).
a Reagents and conditions: (a) 6 N HCl in MeOH, 1 h, 96%. (b) PhCOCl/
NaHCO3, aq. THF, 85%.
was isolated in 86% yield when acetate 5c (R1 ) Boc, R2 )
Bn) was used. After screening a couple of bases (Table 1, entries
3-6), the best result was achieved using 5 equiv of LiHMDS
as a base and 5 equiv of 5c at -78 °C in THF. Under the best
condition, we were able to isolate 4c (R1 ) Boc, R2 ) Bn) in
97% yield as sole adduct (Table 1, entry 6). Attempts to raise
the reaction temperature and reduce the quantity of lithium
enolate of 5c unfortunately resulted in lower yields, although
the diastereoselectivities were kept the same (Table 1, entries 7
and 8). Methyl acetate 5d gave a similar result compared with
benzyl acetate 5c (Table 1, entry 9).
Initial experiments showed that the addition reaction of imine
6a with a series of lithium enolates of benzyl acetates 5 (R1 )
t
t
Et3Si, BuMe2Si, Bn, p-MeOC6H4, BuCO, and Bz, R2 ) Bn),
generated by the reaction of 5 with LDA at -78 °C in THF,
respectively, gave unexceptionally a complicated mixture in low
yield. When the hydroxyl-protecting group of benzyl acetate 5
was changed to a carbonate group (5a, R1 ) MeOCO, R2 )
Bn), we were pleased to find that the major syn-adduct 4a with
a (2R,3S) configuration was isolated in 45% yield and moderate
diastereoselectivity (Table 1, entry 1).8 With the size increase
of R1 from methoxy carbonyl group to tert-butoxy carbonyl
group, the yield and diastereoselectivity were greatly improved
(Table 1, entries 1-3). Only one adduct, 4c, was observed and
The absolute stereochemistry of major adduct 4 was verified
by converting 4d into the known methyl ester of (2R,3S)-3-
benzoyl-3-phenylisoserine (-)-8 with the same rotation and
identical 1H NMR spectrum compared with that of the literature
data (Scheme 2). (-)-8, mp: 183-184 °C, [R]25D -48.8 (c 1.25,
MeOH) {lit.1d [R]23 -49.6 (MeOH), lit.9 [R]23 -48.0
D
D
(MeOH)}. The absolute configuration of the major adduct was
further unambiguously confirmed by the X-ray crystallographic
analysis of 4c as SR,2R,3S.10
It was interesting to find the applicable scope and efficiency
of current imine enolate addition strategy for the preparation
of enantiopure isoserine 4 with different substituents at position-
3, since taxol analogues with a variety of substituents instead
of phenyl group at position-3 of the side chain have shown equal
or even better anticancer profile, and some of them are being
studied in different stages of clinical trials.11
(5) For reviews on chiral sulfinylimine chemistry, see: (a) Zhou, P.;
Chen, B. C.; Davis, F. A. Tetrahedron 2004, 60, 8003. (b) Ellman, J. A.;
Owens, T. D. Pure Appl. Chem. 2003, 75, 39. (c) Ellman, J. A.; Owens, T.
D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (d) Davis, F. A.; Zhou, P.;
Chen, B. C. Chem. Soc. ReV. 1998, 27, 13.
(6) (a) Davis, F. A.; Deng, J. Org. Lett. 2004, 6, 2789. (b) Davis, F. A.;
Prasad, K. R.; Nolt, M. B.; Wu, Y. Org. Lett. 2003, 5, 925. (c) Evans, J.
W.; Ellman, J. A. J. Org. Chem. 2003, 68, 9948. (d) Tang, T. P.; Ellman,
J. A. J. Org. Chem. 2002, 67, 7819.
(7) (a) Huang, Zh. Y.; Zhang, M.; Wang, Y.; Qin, Y. Synlett 2005, 1334.
(b) Ke, B.; Qin, Y.; He, Q. F.; Huang, Zh. Y.; Wang, F. P. Tetrahedron
Lett. 2005, 46, 1751. (c) Qin, Y.; Wang, C.; Huang, Zh. Y.; Xiao, X.; Jiang,
Y. Zh. J. Org. Chem. 2004, 69, 8533.
(9) Denis, J. N.; Greene, A. E.; Serra, A. A.; Luche, M. J. J. Org. Chem.
1986, 51, 46.
(10) A colorless crystal of 4c (C25H31N1O6S1, mp 148-149 °C) suitable
for X-ray analysis was obtained by crystallization from acetone/petroleum
1:3. The crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre, CCDC 276473, and are also available in
Supporting Information (the ORTEP/X-ray figure of 4c is shown in
Supporting Information).
(8) The syn-adducts with a typical double doublet ascribed to H-3 were
1
readily differentiated from the anti-adducts with a typical triplet in the H
NMR spectrum.
J. Org. Chem, Vol. 71, No. 4, 2006 1589

Wang et al.
SCHEME 3 a
TABLE 2. Diastereoselective Addition of 5c to
(SR)-tert-Butanesulfinylimines 6
a Reagents and conditions: (a) 10% Pd(OH)2, 1 atm H2 in MeOH, 12 h,
94% yield. (b) 1.5 equiv of 2-chloro-1-methylpyridinium iodide and Et3N
in MeCN at 60 °C, 45% yield.
entry
6
R
4
yielda
drc
1
2
3
4
5
6
7
8
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
4-ClC6H4
3,4-(MeO)2C6H3
4-MeOC6H4
2-BrC6H4
4-NO2C6H4
2-pyridinyl
3-pyridinyl
4-pyridinyl
2-furyl
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
96
89
96b
89
98
94
84
83
84b
97
89
95
96
>99:0:0:0
>99:0:0:0
91:9:0:0c
93:5:2:0c
>99:0:0:0
97:3:0:0c
>99:0:0:0
>99:0:0:0
91:9:-d
>99:0:0:0
>99:0:0:0
98:2:0:0c
>99:0:0:0
9
10
11
12
13
2-thienyl
C6H4(CH2)2
iPr
cyclopropyl
a Isolated yield. b Inseparable mixture of two isomers in 11:1 ratio. c The
ratio was based on 1H NMR integration of crude product; a dr value of
>99% indicated that other isomers were not observed, and the absolute
configuration of minor isomer was not identified. d Other isomers were
isolated as an inseparable and unidentified mixture contaminated with
byproducts.
FIGURE 2. Plausible mechanism for the lithium enolate imine
addition.
To provide a rationale for the observed excellent diastereo-
selectivity using lithium enolate of O-Boc-R-hydroxyacetate 11
as a nucleophile, a tentative mechanism was suggested (Figure
2), which adopted the six/four-membered bicyclic transition state
proposed by Davis, Ellman, and co-workers in their asymmetric
addition reaction of lithium enolate to sulfinylimine.6a,d Both
trans-enolate 11 and imine 6 were linked together through
lithium chelation to form six/four-membered bicyclic transition
states TS-1 and TS-2. TS-1 should be the favored low-energy
transition state, since the cis relationship between a-orientation
R and e-orientation R1 in TS-1 has less steric hindrance and
allows the easier access of C-2 to C-3, compared with the trans
relationship between both e-orientation R and R1 in TS-2. With
the size increase of R1 from methoxy carbonyl group to tert-
butoxy carbonyl group, the addition reaction should be more
likely to occur through TS-1 to afford syn-4 as the dominating
adduct. The suggested mechanism explained well our experi-
mental observation (Table 1, entries 1-3).
As shown in Table 2, the additions of 5c to both aromatic
and alkyl imines 6 were completed within 6 h to afford the
desired syn-4 as the major adduct in high to excellent yields
and diastereoselectivities under our best conditions. The ratio
was determined by careful 1H NMR analyses of the crude
product and each purified minor component. For most of the
addition reactions, the reactions were very clean and only one
adduct was detected by TLC analysis after quenching the
reactions. The reactions with electron-rich imines such as 6c,
6d, 6j, and 6k proceeded rapidly and were completed within 1
h (Table 2, entries 2, 3, 9, and 10), whereas the electron-poor
imines 6f-6i exhibited a lower reactivity and required a longer
reaction time (4-6 h) (Table 2, entries 5-8). For the addition
reaction generating minor isomers (Table 2, entries 4, 6, and
12), the major adduct syn-4 was easily separated from its minor
isomers by chromatography purification. The exception was the
reaction with imines 6d and 6j, where the major adducts 4g
and 4m were isolated, respectively, as an inseparable mixture
contaminated with one minor isomer (Table 2, entries 3 and
9).
Conclusion
We have described that the enantiopure 3-substituted isoserine
4 with a (SR,2R,3S) absolute stereochemistry can be readily
prepared in high to excellent yields by the diastereoselective
enolate addition of O-Boc-R-hydroxyacetate 5 with (SR)-tert-
butanesulfinylimine 6. To the best of our knowledge, the current
method provides the most straightforward access to enantiopure
3-substituted isoserine 4, which is useful for the semi-syntheses
of taxol and its derivatives.
The N,O-protected isoseric acid and â-lactam were commonly
used for the semi-synthsis of taxol.2b,4l,12 With adduct 4c in
hands, our attention was then focused on preparing the isoseric
acid 9 and â-lactam 10 by selective manipulating of the
protecting groups in 4c. Acid 9 and â-lactam 10 were readily
synthesized by the following two steps. Thus, hydrogenolysis
of 4c under 1 atm of hydrogen pressure for 12 h in the presence
of 5% Pd(OH)2 (Pearlman’s catalyst) afforded 9 in 94% yield.
When 9 was treated with 1.5 equiv of 2-chloro-1-methyl-
pyridinium iodide and Et3N in MeCN at 60 °C for 6 h, the
â-lactam 10 was obtained in 45% yield as well as some
unidentified byproducts (Scheme 3).
Experimental Section
General Procedure for the Addition of O-Protected r-Hy-
droxyacetate 5 with (SR)-tert-Butanesulfinylimine 6. Under N2,
to a solution of O-protected R-hydroxyacetate 5 (10.0 mmol) in 25
mL of dry THF was added a solution of base (10.0 mmol) at -78
°C. After being stirred for 1 h at -78 °C, the mixture was added
to (SR)-tert-butanesulfinylimine 6 (2.0 mmol in 5 mL of dry THF
and was stirred at -78 °C for 1-6 h until imine 6 was completely
consumed and checked by TLC analysis. The reaction mixture was
(11) Cragg, G. M.; Newman, D. J. J. Nat. Prod. 2004, 67, 232.
(12) Denis, J. N.; Greene, A. E.; Guenard, D.; Gueritte-Voegelein, F.;
Mangatal, L.; Potier, P. J. Am. Chem. Soc. 1988, 110, 5917.
1590 J. Org. Chem., Vol. 71, No. 4, 2006

Synthesis of Taxol Side Chain
quenched at -78 °C with saturated NH4Cl solution and extracted
with ethyl acetate (3 × 20 mL). The combined organic phases were
dried with anhydrous MgSO4. The solvent was removed under
vacuum, and the residue was purified by chromatography to give
adduct 4 and other isomers. The results were shown in Tables 1
and 2.
chloride (1.0 mmol) were added successively at 0 °C. After being
stirred for 2 h at 0 °C, the reaction mixture was extracted with
CH2Cl2 (3 × 10 mL). The combined organic phases were dried,
and the solvent was removed under vacuum to give a residue, which
was purified by chromatography to give 8 (0.123 g, 82% overall
yield two steps).
(SR,2R,3S)-N-tert-Butanesulfinyl-O-methoxycarbonyl-3-phen-
ylisoserine Benzyl Ester 4a: Purified by chromatography (acetone/
petroleum 1:4, Rf 0.4) as viscous oil, 1H NMR (400 MHz, CDCl3)
δ 7.28-7.41 (m, 10H), 5.27 (d, J ) 2.8 Hz, 1 H), 5.21 (d, J )
12.4 Hz, 1H), 5.14 (d, J ) 12.4 Hz, 1H), 5.03 (dd, J ) 10.0, 2.8
Hz, 1H), 4.13 (d, J ) 9.6 Hz, 1H), 3.76 (s, 3H), 1.14 (s, 9H) ppm;
13C NMR (100 MHz, CDCl3) δ 167.1, 154.6, 137.7, 134.67, 134.60,
128.58, 128.52, 128.4, 128.3, 128.2, 127.0, 78.6, 67.6, 60.2, 56.6,
55.2, 22.3 ppm; HRMS-ESI calcd for C22H27N1Na1O4S1 (M + Na)+
456.1457, found 456.1451.
(2R,3S)-3-Phenylisoserine Methyl Ester 7. The analytic sample
was purified by chromatography (acetone/petroleum 1:4, Rf 0.2)
as a white solid, mp 103-105 °C, [R]25 +10.6° (c 1.0, MeOH);
D
IR (KBr) 3367, 3308, 3070, 2855, 2707, 1730, 1449, 1434, 1365,
1280, 1198, 1160, 1082, 922 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.41-7.26 (m, 5H), 4.30 (m, 2H), 3.80 (s, 3H), 2.00 (s, br, 2H)-
ppm; 13C NMR (100 MHz, CDCl3) δ 173.6, 141.9, 128.4, 127.5,
126.6, 75.0, 57.8, 52.3 ppm.
(2R,3S)-N-Benzoyl-3-phenylisoserine Methyl Ester 8: Purified
by chromatography (acetone/petroleum 1:4, Rf 0.5) as a white solid,
mp 183-184 °C, [R]25D -48.8 (c 1.3, MeOH) {lit.1d [R]23D -49.6
Isomer of 4a: Purified by chromatography (acetone/petroleum
1:4, Rf 0.35) as viscous oil, 1H NMR (400 MHz, CDCl3) δ 7.19-
7.39 (m, 10H), 5.39 (d, J ) 5.2 Hz, 1H), 5.10 (d, J ) 12.4 Hz,
1H), 5.03 (d, J ) 12.4 Hz, 1H), 4.91 (t, J ) 5.2 Hz, 1H), 4.22 (d,
J ) 4.8 Hz, 1H), 3.79 (s, 3H), 1.16 (s, 9H) ppm; 1HRMS-ESI calcd
for C22H27N1Na1O4S1 (M + Na)+ 456.1457, found 456.1454.
(SR,2R,3S)-N-tert-Butanesulfinyl-O-Cbz-3-phenylisoserine
Benzyl Ester 4b: Purified by chromatography (acetone/petroleum
1:7, Rf 0.2) as viscous oil, IR (KBr) 3300, 2959, 1750, 1498, 1455,
1
(MeOH), lit.9 [R]23 -48.0 (MeOH)}. H NMR was identical to
D
literature report.1d,9 IR (KBr) 3391, 3367, 1735, 1639, 1580, 1521,
1489, 1449, 1292, 1261, 1208, 1111 cm-1; H NMR (400 MHz,
1
CDCl3) δ 7.77 (m, 2H), 7.27-7.56 (m, 8H), 6.98 (d, J ) 8.8 Hz,
1H), 5.74 (dd, J ) 9.2, 0.8 Hz, 1H), 4.64 (dd, J ) 4.0, 2.4 Hz,
1H), 3.85 (s, 3H), 3.27 (d, J ) 3.6 Hz, 1H) ppm.
Synthesis of â-Lactam 10. Adduct 4c (1.255 g, 2.6 mmol) in
20 mL of MeOH was subjected to hydrogenolysis under 1 atm
hydrogen pressure in the presence of 10% of Pd(OH)2 for 12 h.
After we removed the Pd(OH)2 by filtration, we evaporated the
mixture to dryness. The residue was purified by chromatography
(CH2Cl2/MeOH/AcOH 10:1:0.1, Rf 0.3) to afford acid 9 (0.931 g,
93% yield). Under N2, a mixture of acid 7 (0.820 g, 2.1 mmol),
Et3N (0.323 g, 3.2 mmol), and 2-chloro-1-methylpyridinium iodide
(0.800 g, 3.2 mmol) in 15 mL of dry MeCN was refluxed for 6 h.
The solvent was removed by evaporation, and the residue was
subjected to chromatography (acetone/petroleum 1:8, Rf 0.2) to give
â-lactam 10 (0.347 g, 45% yield).
1
1385, 1270, 1242, 1073, 1040 cm-1; H NMR (400 MHz, CDCl3
) δ 7.24-7.40 (m, 15H), 5.32 (d, J ) 2.8 Hz, 1H), 5.18 (d, J )
12.4 Hz, 1H), 5.15 (d, J ) 12.4 Hz, 1H), 5.12 (d, J ) 12.4 Hz,
1H), 5.09 (d, J ) 12.4 Hz, 1H), 5.03 (dd, J ) 9.6, 2.8 Hz, 1H),
4.12 (d, J ) 9.6 Hz, 1H), 1.12 (s, 9H) ppm; 13C NMR (100 MHz,
CDCl3) δ 167.2, 154.1, 137.7, 134.7, 128.6, 128.58, 128.53, 128.4,
128.21, 128.13, 127.1, 78.7, 70.3, 67.6, 60.3, 56.7, 22.6, 22.5 ppm;
HRMS-ESI calcd for C28H31N1Na1O6S1 (M + Na)+ 532.1770, found
532.1764.
(SR,2R,3S)-N-tert-Butanesulfinyl-O-Boc-3-phenylisoserine
Benzyl Ester 4c: Purified by chromatography (acetone/petroleum
1:8, Rf 0.2) as a white solid, recrystallized from acetone and
petroleum; X-ray (see CIF file); mp 148-149 °C; [R]25D +1.0° (c
1.0, EtOH); IR (KBr) 3296, 2975, 1746, 1497, 1458, 1426, 1395,
(SR,2R,3S)-N-tert-Butanesulfinyl-O-Boc-3-phenylisoserine Acid
9: mp 144-146 °C; [R]25D +23.0° (c 1.2, CHCl3); IR (KBr) 3357,
2980, 1741, 1610, 1452, 1372, 1351, 1309, 1279, 1249, 1229, 1166,
1
1132, 1098, 1006 cm-1; H NMR (400 MHz, DMSO-d6) δ 7.40
1366, 1291, 1243, 1208, 1160, 1113, 1046, 1009, 956, 862 cm-1
;
(d, J ) 7.6 Hz, 2H), 7.27 (t, J ) 7.6 Hz, 2H), 7.22 (m,1H), 6.32
(br, 1H), 4.85 (s, 1H), 4.70 (dd, J ) 9.2, 4.0 Hz, 1H), 1.34 (s, 9H),
1.09 (s, 9H)ppm; 13C NMR (100 MHz, DMSO-d6) δ 170.0, 152.8,
140.9, 128.2, 127.9, 127.1, 80.9, 78.8, 67.2, 58.8, 56.2, 27.7, 25.3,
22.6 ppm; Anal. Calcd for C18H27N1O6S1: C, 56.08; H, 7.06; N,
3.63. Found: C, 55.71; H, 7.06; N, 3.85; HRMS-ESI calcd for
C18H27N1Na1O6S1 (M + Na)+ 408.1457, found 408.1451.
1H NMR (400 MHz, CDCl3) δ 7.22-7.41 (m, 10H), 5.27 (d, J )
0.8 Hz, 1H), 5.17 (s, 2H), 5.01 (d, J ) 9.6 Hz, 1H), 4.14 (d, J )
9.6 Hz, 1H), 1.39 (s, 9H), 1.15 (s, 9 H) ppm; 13C NMR (100 MHz,
CDCl3) δ 167.5, 152.1, 137.8, 134.6, 128.5, 128.4, 128.0, 127.1,
83.3, 77.6, 67.4, 60.4, 56.6, 27.4, 22.3 ppm; Anal. Calcd for
C25H33N1O6S1: C, 63.13; H, 6.99; N, 2.95. Found: C, 63.08; H,
6.98; N, 3.08; HRMS-ESI calcd for C25H33N1Na1O6S1 (M + Na)+
498.1926, found 498.1921.
(SR,3R,4S)-N-tert-Butanesulfinyl-3-(tert-butoxycarbonate)-4-
phenyl-â-lactam 10: White solid, mp 125-127 °C; [R]25D +56.2°
(c 1.2, CHCl3); IR (KBr) 2979, 1792, 1745, 1458, 1369, 1278, 1252,
1130, 1101, 1047, 1014 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.33-
7.45 (m, 5H), 5.74 (d, J ) 6.0 Hz, 1H), 5.36 (d, J ) 6.0 Hz, 1H),
1.16 (s, 9H), 1.03 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ
167.8, 150.6, 133.0, 129.7, 129.1, 128.4, 83.6, 57.7, 57.3, 27.1,
22.3 ppm; Anal. Calcd for C18H25NO5S: C, 58.83; H, 6.86; N, 3.81.
Found; C, 58.77; H, 6.94; N, 3.86; HRMS-ESI calcd for C18H25N1-
Na1O5S1 (M + K)+ 406.1091, found 406.1098.
(SR,2R,3S)-N-tert-Butanesulfinyl-O-Boc-3-phenylisoserine Meth-
yl Ester 4d: Purified by chromatography (acetone/petroleum 1:8,
Rf 0.2) as a white solid, mp 85-87 °C; [R]25D +8.6° (c 1.2, CHCl3);
IR (KBr) 3345, 2957, 1745, 1499, 1461, 1393, 1370, 1352, 1310,
1
1280, 1162, 1136, 1080, 1018, 951 cm-1; H NMR (400 MHz,
CDCl3) δ 7.28-7.43 (m, 5H), 5.25 (d, J ) 2.8 Hz, 1H), 5.01 (dd,
J ) 10.0, 2.8 Hz, 1H), 4.16 (d, J ) 10.0 Hz, 1H), 3.78 (s, 3H),
1.41 (s, 9H), 1.19 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ
168.1, 152.2, 138.0, 128.6, 128.1, 127.1, 83.4, 60.3, 56.7, 52.4,
27.5, 22.6, 22.4 ppm; Anal. Calcd for C19H29N1O6S1: C, 57.14; H,
7.32; N, 3.51. Found: C, 57.10; H, 7.30; N, 3.64; HRMS-ESI calcd
for C19H29N1Na1O6S1 (M + Na)+ 422.1613, found 422.1608.
Correlation of the Absolute Configurations by Chemical
Transformation. Adduct 4d (0.202 g, 0.5 mmol) was dissolved
in 10 mL of 6 M HCl in MeOH overnight. The mixture was poured
into an ice-cooled saturated NaHCO3 solution and was extracted
with CH2Cl2 (3 × 10 mL). The organic phases were combined and
dried with anhydrous Na2SO4. The solvent was removed under
vacuum to afford 0.098 g of crude 7 (96% yield), which was pure
enough for the next step. The crude 7 was dissolved in 15 mL of
THF. To the THF solution, saturated NaHCO3 (5 mL) and benzoyl
Acknowledgment. This work was supported by the National
Natural Science Foundation of China (No. 20372048 and No.
20572072), Ministry of Education (NCET, RFDP and EYTP),
Sichuan Province Government (No. 04ZQ026-011 and 05JY029-
025-1), and Sichuan University (2005CF01).
Supporting Information Available: 1H NMR and 13C NMR
spectra of compounds 4, 7-10, and X-ray crystallographic data
for 4c as a CIF file. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO052298N
J. Org. Chem, Vol. 71, No. 4, 2006 1591