Asymmetric synthesis of γ-keto-δ-lactam derivatives: Application to the synthesis of a conformationally constrained surrogate of ala-ser dipeptide

Full text of DOI:10.1021/jo0159688

J . Org. Chem. 2001, 66, 7915-7918
7915
piperidine alkaloids. We have also used this core struc-
ture for the efficient preparation of the corresponding
3-amino-2-piperidone derivative. The latter as unnatural
amino acid belongs to a class of compounds that exhibit
important biological activities10 and are being elaborated
with increasing frequency as small ring constrained
nonpeptide scaffolds, in the design and synthesis of
peptidomimetics.11 In this context, we also report the
efficient enantioselective preparation of a novel confor-
mationally constrained surrogate of Ala-Ser dipeptide,
in which the conformational restriction is caused by a
bond between the â-carbon of alanine and γ-carbon of
serine. Such constrained pseudopeptides are very inter-
esting targets because of their potential for probing
various recognition events in protein chemistry and
biology.12
Previously reported syntheses of R,â-unsaturated γ-keto-
δ-lactam structural motif include the kinetic resolution
of a 2-furfurylamine,13 its transformation to the corre-
sponding dihydropyridone and further oxidation to δ-lac-
tam. Recently, we developed a new synthetic methodology
for the enantioselective transformation of D-glucal to
chiral 2-furylsulfonamide 1 and its subsequent oxidative
cyclization to (2S)-hydroxymethyl-dihydropyridone 2.14
Continuing our investigations on the applications of this
methodology, we describe herein the efficient synthesis
of diversely substituted δ-lactam derivatives in a limited
number of steps and avoiding the kinetic resolution step.
As chiral key intermediate in our syntheses we used
the of R,â-unsaturated-γ-keto-δ-lactam 3, which was
obtained in almost quantitative yield by J ones oxidation
of 6-hydroxy-1,6-dihydro-2H-pyridin-3-one 2, or directly
from N-furfurylsulfonamide 1 upon prolonged exposure
to a large excess of m-CPBA (Scheme 1). Hydrogenation
of 3 with Zn powder and acetic acid furnished the
corresponding saturated 3,5-dione 4, which may be
elaborated in the enantioselective synthesis of (-)-
prosopinine, according to a recently reported synthetic
route.15
Asym m etr ic Syn th esis of γ-Keto-δ-la cta m
Der iva tives: Ap p lica tion to th e Syn th esis
of a Con for m a tion a lly Con str a in ed
Su r r oga te of Ala -Ser Dip ep tid e
Sofia D. Koulocheri,† Prokopios Magiatis,‡ and
Serkos A. Haroutounian*,†
Chemistry Laboratory, Agricultural University of Athens,
Iera odos 75, Athens 11855, Greece, and Department of
Pharmacy, University of Athens, Panepistimiopolis
Zografou, Athens 15771, Greece
sehar@aua.gr
Received J uly 27, 2001
Optically active δ-lactams (2-piperidones) are common
structural subunits and building blocks of a wide variety
of naturally occurring piperidine and indolizidine alka-
loids,1 which possess valuable biological and pharmaco-
logical properties.2 Thus, many saturated and unsatur-
ated 2-piperidones have been used as chiral key inter-
mediates in the preparation of numerous natural and
synthetic compounds3 with significant anticancer,4 anti-
HIV,5 anti-inflamatory,6 and glycosidase inhibition7 ac-
tivities. Consequently, the development of synthetic
methods for the efficient preparation of various optically
active δ-lactams is the subject of particular interest and
research activity.8 As a part of our ongoing studies on
the synthesis of chiral piperidine derivatives,9 we envi-
sioned the framework of R,â-unsaturated-γ-keto-δ-lactam
3 as a flexible intermediate for the convenient enantio-
selective preparation of various δ-lactam building blocks
amenable for the synthesis of various biologically active
* To whom correspondence should be addressed. Fax: +30-1-
5294265. Phone: +30-1-5294247.
† Agricultural University of Athens.
‡ University of Athens.
(1) For comprehensive recent reviews see the following. (a) Piperi-
dine alkaloids: Laschat, S.; Dickner, T. Synthesis 2000, 178. (b)
Indolizidine alkaloids: Nehmr, A. E. Tetrahedron 2000, 56, 8579.
(2) For a recent review, see: Asano, N.; Nash, R. J .; Molyneux, R.
J .; Fleet, G. W. J . Tetrahedron: Asymmetry 2000, 11, 1645.
(3) Pilli, R. A.; Russowsky, D. Trends Org. Chem. 1997, 6, 101.
(4) (a) Tsuruoka, T.; Nakabayashi, S.; Fukuyasu, H.; Ishii, Y.;
Yamamoto, H.; Inouye, S.; Kondo, S. E Patent 328111 A2, 1989. (b)
Fleet, G. W. J .; Ramsden, N. G.; Witty, D. R. Tetrahedron 1990, 45,
319.
(5) (a) Ratner, L.; Heyden, N. V.; Dedera, D. Virology 1991, 181,
180. (b) Wilker, D. A.; Holan, G. J . Med. Chem. 1989, 32, 2084. (c)
Fleet, G. W. J .; Karpas, A.; Dwek, R. A.; Fellows, L. E.; Tyms, A. S.;
Petursson, S.; Namgoong, S. K.; Ramsden, N. G.; Smith, P. W.; Son,
J . C.; Wilson, F.; Witty, D. R.; J acob, G. S.; Rademacher, T. W. FEBS
Lett. 1988, 237, 128.
Modified Luche reduction of ketolactam 3 furnished the
allylic alcohol 5 as a single diastereomer (Scheme 2). The
diastereoselectivity of this reduction step is attributed
to the apparent hydride attack on the less hindered face
of the molecule (Figure 1). Subsequent catalytic hydro-
genation and benzylation provided compound 7, a key
intermediate of the chiral synthesis of (+)-spectaline.16
The configuration of compound 6 was elucidated by 2D
COSY and NOESY studies. Thus, the strong NOE
(6) Tsuruoka, T.; Yuda, Y.; Nakabayashi, A.; Katano, K.; Sezaki,
M.; Kondo, S. J . Patent 63216867 A2, 1988.
(7) Fleet, G. W. J .; Ramsden, N. G.; Dwek, R. A.; Rademacher, T.
W.; Fellows, L. E.; Nash, R. J .; Green, D. S. C.; Winchester, B. J . Chem.
Soc., Chem. Commun. 1988, 483.
(8) For representative recent examples on 2-piperidinone syntheses,
see: (a) J ohnson, T. A.; Curtis, M. D.; Beak, P. J . Am. Chem. Soc. 2001,
123, 1004. (b) Williams, S. J .; Hoos, R.; Winters, S. G. J . Am. Chem.
Soc. 2000, 122, 2223. (c) Nishimura, Y.; Adachi, H.; Satoh, T.; Shitara,
E.; Nakamura, H.; Kojima, F.; Takeuchi, T. J . Org. Chem. 2000, 65,
4871. (d) Paulvannan, K.; Chen, T. J . Org. Chem. 2000, 65, 6160. (e)
Amat, M.; Bosch, J .; Hidalgo, J .; Canto´, M.; Pe´rez, M.; Llor, N.; Molins,
E.; Miravitlles, C.; Orozco, M.; Luque, J . J . Org. Chem. 2000, 65, 3074.
(f) Kang, J .; Lee, C. W.; Lim, G. J .; Cho, B. T. Tetrahedron: Asymmetry
1999, 10, 657. (g) Maldaner, A. O.; Pilli, R. A. Tetrahedron 1999, 55,
13321.
(10) Estiarte, A. E.; Diez, A.; Rubiralta, M.; J ackson, R. F. W.
Tetrahedron 2001, 57, 157, and refs therein.
(11) (a) Piro´, J .; Rubiralta, M.; Giralt, E.; Diez, A. Tetrahedron Lett.
2001, 42, 871. (b) Polyak, F.; Lubell, W. D. J . Org. Chem. 2001, 66,
1171. (c) Weber, K.; Ohnmacht, U.; Gmeiner, P. J . Org. Chem. 2000,
65, 7406. (d) Ru¨bsam, F.; Mazitscheck, R.; Giannis, A. Tetrahedron
2000, 56, 8481.
(12) For recent examples of syntheses of enantiopure constrained
pseudopeptides, see: Feng, Z.; Lubell, W. D. J . Org. Chem. 2001, 66,
1181 and refs 1 and 2 therein.
(13) For a review on the preparation of asymmetric R-furfurylamines
and their synthetic applications, see: Zhou, W.-S.; Lu, Z.-H.; Xu, Y.-
M.; Liao, L.-X.; Wang, Z.-M. Tetrahedron 1999, 55, 11959.
(14) Koulocheri, S. D.; Haroutounian, S. A. Synthesis 1999, 1889.
(15) Toyooka, N.; Yoshida, Y.; Yotsui, Y.; Momose, T. J . Org. Chem.
1999, 64, 4914.
(9) Koulocheri, S. D.; Haroutounian, S. A. Tetrahedron Lett. 1999,
40, 6869.
(16) Momose, T.; Toyooka, N.; J in, M. J . Chem. Soc., Perkin Trans.
1 1997, 2005.
10.1021/jo0159688 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/17/2001

7916 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
Sch em e 1a
F igu r e 2. NOE correlations in 6.
Sch em e 3a
a
Reagents and conditions: (a) m-CPBA, CH2Cl2, 2 h; (b) large
excess of m-CPBA, CH2Cl2, 6 h; (c) J ones reagent, Me2CO; (d) Zn,
AcOH, CH2Cl2.
Sch em e 2a
On the other hand, compound 6 by a Mitsunobu
reaction provided the diastereomeric lactam 8 which is
the key intermediate for the chiral synthesis of (-)-
prosophylline.15
Treatment of unsaturated dione 3 with an excess of
hydrazoic acid (prepared in situ) in a 1:1 mixture of
AcOH/AcONa provided in high yield the corresponding
aminoenyl derivative 9 through a 1,4-reductive addition
mechanism, previously reported for of R,â-unsaturated
dicarbonyl systems and naphthoquinones (Scheme 3).17
Catalytic hydrogenation of compound 9 proved trouble-
some, since this system is inert under usual conditions,
while under more vigorous conditions (high pressure,
PtO2 catalyst, etc.) produced a variety of byproducts. The
hydrogenation was carried out efficiently only by an
ultrasound promoted reaction, using Zn powder in acetic
acid and provided the corresponding aminodione which
is unstable to the workup. Thus, the product was reacted
in situ with benzyl chloroformate to give the very stable
compound 10 as the 6S, 3R diastereomer ([R]22D ) -13.3
(c 0.3, EtOAc) in 80% overall yield. Reduction with
NaBH4 produced diastereoselectively the corresponding
hydroxylated derivative 11 which by a series of consecu-
tive protection, oxidation and deprotections furnished
smoothly the desired target Ala-Ser surrogate 12. This
dipeptide, except of an amide bond, contains a confor-
mational restriction through a bond between the â-carbon
of alanine and γ-carbon of serine.
a
Reagents and conditions: (a) CeCl3‚7H2O, NaBH4, MeOH; (b)
H2, Pd/C, EtOAc; (c) NaH, BnBr, Bu4NI, THF; (d) DEAD-TPP,
PhCO2H, THF.
The stereochemistry of key intermediate 5-hydroxy-3-
carbobenzoxyamino-2-pyridone 11 was unambiguously
assigned considering the strong 1,3-diaxial NOE interac-
F igu r e 1. Spatial view of the hydride attack on compound 3.
correlation between H-5ax and H-3ax and the small
coupling constant between the â H-6 and H-5 are indica-
tive of a 4C1 chairlike conformation and the equatorial
disposition of the hydroxy group (Figure 2).
(17) (a) Koulocheri, S. D.; Haroutounian, S. A.; Apostolopoulos, C.
D.; Chada, R. K.; Couladouros, E. A. Eur. J . Org. Chem. 1999, 1449.
(b) Couladouros, E. A.; Apostolopoulos, C. D. Synlett 1996, 341.

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7917
(6S)-6-(ter t-Bu tyld ip h en ylsila n yloxym eth yl)-1-(tolu en e-
4-su lfon yl)p ip er id in e-2,5-d ion e 4. To a stirred solution of
compound 3 (0.5 g, 0.95 mmol) and AcOH (5 mL) in CH2Cl2 (7
mL) was added well-powdered zinc dust (0.32 g) portionwise.
After 2 h of stirring, the mixture was filtered from Celite and
the filtrate was washed with NaHCO3. The aqueous layer was
backwashed with EtOAc. The combined organic extracts were
washed with brine, dried over MgSO4, and chromatographed
using hexane/EtOAc (4:1) yielding the desired product which was
crystallized from hexane (0.49 g, 97%): mp 135-135 °C; [R]22
D
) +3.1 (c 0.45, EtOAc); IR(neat) ν 1715 (CdO), 1636 cm-1 (NCd
O); 1H NMR (400 MHz, CDCl3) δ 0.98 (s, 9H, C-CH3), 1.45 (m,
1H, H-4), 2.40 (s, 3H, ArCH3), 2.53-2.80 (m, 3H, H-4, H-3), 3.93
(dd, J ) 10.6, 3.1 Hz, 1H, CH2a), 4.29 (dd, J ) 10.6, 3.1 Hz, 1H,
CH2b), 4.89 (s, 1H, H-6), 7.25 (m, 2H, ArH), 7.39-7.49 (m, 10H,
ArH), 7.89 (d, J ) 8.2 Hz, 2H, ArH). Anal. Calcd for C29H33NO5-
SSi: C, 65.02; H, 6.21; N, 2.61. Found: C, 65.22; H, 6.13; N,
2.71.
(6S,5S)-6-(ter t-Bu t yld ip h en ylsila n yloxym et h yl)-5-h y-
d r oxy-1-(t olu e n e -4-su lfon yl)-5,6-d ih yd r o-1H -p yr id in -2-
on e 5. To a stirred solution of compound 3 (0.73 g, 1.34 mmol)
and CeCl3‚7H2O (0.25 g, 0.67 mmol) in methanol (15 mL) at -50
°C was added portionwise NaBH4 (0.18 g, 4.67 mmol). After 40
min of stirring at that temperature, the reaction was quenched
with saturated aqueous NH4Cl (15 mL) and extracted repeti-
tively with EtOAc. The combined organic extracts were washed
with brine, dried over MgSO4, and chromatographed (EtOAc/
hexane 1:4) to afford 0.57 g of compound 5 (80%) as white solid:
mp 155-157 °C; [R]22D ) - 1.75 (c 0.65 EtOAc); IR (neat) ν 3440
(OH), 1676 cm-1 (NCdO); 1H NMR (400 MHz, CDCl3) δ 1.02 (s,
9H, CCH3), 2.34 (s, 3H, ArCH3), 3.87 (dd, J ) 10.6, 4.1 Hz, 1H,
CH2a), 4.07 (dd, J ) 10.6, 8.9 Hz, 1H, CH2b), 4.15 (d, J ) 7.5 Hz,
1H, OH), 5.04 (m, 1H, H-5), 5.06 (m, 1H, H-6), 5.68 (dd, J )
10.2, 2.4 Hz, 1H, H-4), 6.69 (dt, J ) 10.2, 1.7 Hz, 1H, H-3), 7.11
(d, J ) 7.5 Hz, 2H, ArH), 7.40 (m, 2H, ArH), 7.46 (m, 4H, ArH),
7.57 (dd, J ) 7.5, 1.3 Hz, 2H, ArH), 7.67 (d, J ) 8.5 Hz, 4H,
ArH). Anal. Calcd for C29H33NO5SSi: C, 65.02; H, 6.21; N, 2.61.
Found: C, 65.29; H, 6.17; N, 2.44.
F igu r e 3. NOE correlations in 11.
tion between the H-3 and H-5, which is indicative of the
diequatorial orientation of the corresponding substituents
(Figure 3). Moreover, the observed NOEs between H-3,
H-5, and H-4eq, the small enhancement between H-4ax
and OH in conjunction with coupling constants of H-5,
reveal the assigned configuration.
In summary, we have demonstrated the usefulness of
of R,â-unsaturated-γ-keto-δ-lactam 3 as chiral key inter-
mediate for the enantio- and diastereocontrolled access
to various δ-lactams, eliminating the need for kinetic
resolution of 2-furyltosylamines or dihydropyridones.
Furthermore, the same intermediate was used for the
convenient synthesis of chiral 3-amino-2-pyridone deriva-
tives and a novel conformationally constrained Ala-Ser
dipeptide surrogate. Studies on the use of these chiral
building blocks for the preparation of natural and syn-
thetic alkaloids, as well as other peptidomimetics are
currently underway.
(6S,5S)-6-(ter t-Bu t yld ip h en ylsila n yloxym et h yl)-5-h y-
d r oxy-1-(tolu en e-4-su lfon yl)p ip er id in -2-on e 6. A solution of
compound 5 (0.5 g, 0.93 mmol) in MeOH (10 mL) was hydroge-
nated over 10% Pd/C (0.05 g) under 1 bar pressure for 40 min.
The mixture was filtered over Celite and partitioned between
EtOAc and water. The aqueous layer was backwashed with
EtOAc. The combined organic extracts were washed with brine,
dried over MgSO4, and concentrated The yellowish slurry was
chromatographed (EtOAc/hexane 1:4) to give compound 6 (0.53
g, 90%) as a white solid that was crystallized from diethyl ether/
hexane to afford white crystals: mp 168-170 °C; [R]22D ) + 1.13
(c 6.2, EtOAc); IR (neat) ν 3407 (OH), 1686 cm-1 (NCdO); 1H
NMR (400 MHz, CDCl3) δ 1.04 (s, 9H, CCH3), 1.99 (m, 1H, C-4eq),
2.12 (m, 1H, C-4ax), 2.37 (s, 3H, ArCH3), 2.44 (m, 1H, 8.5 Hz,
1H, H-3eq), 2.55 (ddd, J ) 18.1, 7.9, 3.1 Hz, 1H, H-3ax), 3.25 (d,
J ) 6.8 Hz, 1H, OH), 3.91 (dd, J ) 10.9, 7.9 Hz, 1H, CH2a), 4.14
(dd, J ) 10.9, 3.4 Hz, 1H, CH2b), 4.18 (m, 1H, H-5), 4.68 (dt, J
) 7.9, 3.4 Hz, 1H, H-6), 7.16 (d, J ) 8.5 Hz, 2H, ArH), 7.32-
7.51 (m, 6H, ArH), 7.62 (dd, J ) 6.5, 1.0 Hz, 2H, ArH), 7.68 (dd,
J ) 7.9, 1.7 Hz, 2H, ArH), 7.73 (d, J ) 8.3 Hz, 2H, ArH). Anal.
Calcd for C29H35NO5SSi: C, 64.77; H, 6.56; N, 2.60. Found: C,
64.86; H, 6.41; N, 2.75.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under
argon unless otherwise noted. Solvents were dried by distillation
prior to use. Tetrahydrofuran was distilled from sodium-ben-
zophenone and methylene chloride over CaH2 immediately prior
to use. (S)-(1-Furan-2-yl-2-tert-butyldiphenylsilyloxy)-N-(toluene-
4-sulfonyl)ethylamine 1 ([R]22 ) -18.7° (c ) 1.35, MeOH); mp
D
) 107-108 °C) and (2S,6S)-2-(tert-butyldiphenylsilyloxymeth-
yl)-6-hydroxy-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridine-3-
one 2 ([R]22 ) +27.9° (c ) 0.98, MeOH), mp ) 97-98 °C) were
D
prepared according to the literature procedure.14 IR spectra were
recorded on a Nicolet Magna 750 series II spectrometer. 1H NMR
spectra were recorded in CDCl3 on Bruker AC-200 or DRX-400
spectrometers (200 and 400 MHz, respectively) using TMS as
internal standard. Melting points were determined on a Bu¨chi
melting point apparatus and are uncorrected. Optical rotations
were measured with a Perkin-Elmer 241 polarimeter at ambient
temperature. TLC was conducted on Merck glass plates coated
with silica gel 60 F254. Flash column chromatography was
performed using Merck silica gel 60 (230-400 mesh ASTM).
(6S)-6-(ter t-Bu tyld ip h en ylsila n yloxym eth yl)-1-(tolu en e-
4-su lfon yl)-1,6-d ih yd r op yr id in e-2,5-d ion e 3. To an ice-cold
solution of compound 2 (0.8 g, 1.5 mmol) in acetone (10 mL) was
added dropwise J ones reagent (0.5 mL). After being stirred for
20 min, the solid inorganic byproducts were eliminated by
decantation and the liquid layer was concentrated to a residue
that was partitioned in EtOAc and water. The organic layer was
separated, washed with brine, dried over MgSO4, and evapo-
rated. The residue was crystallized from cold diethyl ether to
(5S,6S)-5-Ben zyl-6-(ter t-bu tyldiph en ylsilan yloxym eth yl)-
1-(tolu en e-4-su lfon yl)p ip er id in -2-on e 7. To an ice-cold stirred
solution of compound 6 (0.24 g, 0.44 mmol) in THF (1 mL) was
added portionwise sodium hydride (12.6 mg, 0.53 mmol). The
reaction mixture was allowed to warm to 15 °C and stirred for
an additional 20 min. Then a catalytic amount of Bu4NI (8 mg,
0.022 mmol) and benzyl bromide (74 µL, 0.66 mmol) were added.
After 2 h of stirring at that temperature, the reaction was
quenched with saturated aqueous NH4Cl and extracted with
EtOAc. The combined organic extracts were washed with brine,
dried over MgSO4, and chromatographed (EtOAc/hexane 1:4) to
give 0.22 g of compound 7 as white crystals (80%): mp 152-
afford 0.76 g of compound 3 (95%): mp 200-201 °C dec; [R]22
D
) +13.2 (c 1.6, EtOAc); IR (neat) ν 1725 (CdO), 1690 cm-1 (NCd
1
O); H NMR (400 MHz, CDCl3) δ 0.89 (s, 9H, C-CH3), 2.44 (s,
3H, CH3), 4.15 (m, 2H, CH2), 5.01 (m, 1H, H-6), 6.68 (d, J )
10.2 Hz, 1H, H-3), 6.73 (d, J ) 10.2 Hz, 1H, H-4), 7.25 (d, J )
8.6 Hz, 2H, ArH), 7.41 (m, 10H, ArH), 7.91 (d, J ) 8.6 Hz, 2H,
ArH). Anal. Calcd for C29H31NO5SSi: C, 65.26; H, 5.85; N, 2.62.
Found: C, 65.39; H,6.01; N, 2.71.
153 °C; [R]22 ) +14.5 (c 1.2, MeOH); IR (neat) ν 1686 cm-1
D
(NCdO); 1H NMR (200 MHz, CDCl3) δ 0.98 (s, 9H, CCH3), 2.15-
2.25 (m, 2H, H-4), 2.32 (m, 1H, H-3), 2.40 (s, 3H, ArCH3), 2.45
(m, 1H, H-3), 3.91 (dd, J ) 10.9, 9.9 Hz, 1H, CH2a), 3.92 (m, 1H,
H-5), 4.14 (dd, J ) 10.9, 3.4 Hz, 1H, CH2b), 4.52 (d, J ) Hz, 1H,

7918 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
CH2Ar), 4.71 (d, J ) Hz, 1H, CH2Ar), 4.90 (m, 1H, H-6) 7.21 (d,
J ) 8.3 Hz, 2H, ArH). 7.25-7.51 (m, 10H, ArH), 7.59 (m, 3H,
ArH), 7.69 (d, J ) 8.3 Hz, 2H, ArH), 7.92 (d, J ) 8.3 Hz, 2H,
ArH). Anal. Calcd for C36H41NO5SSi: C, 68.87; H, 6.58; N, 2.23.
Found: C, 69.01; H, 6.44; N, 2.11.
Then the reaction mixture was filtered over Celite, the pH was
adjusted to 8 by addition of Et3N, and CbzCl (0.17 mL, 1.2 mmol)
was added. The reaction mixture was stirred for 30 min,
quenched with saturated aqueous NH4Cl, and extracted with
EtOAc. The organic extract was washed with brine, dried over
MgSO4, and chromatographed (EtOAc/hexane 1:4) to give 0.52
(2S,3R)-Ben zoic Acid 2-(ter t-Bu tyld ip h en ylsila n yloxym -
eth yl)-6-oxo-1-(tolu en e-4-su lfon yl)-1,2,3,6-tetr a h yd r op yr i-
d in -3-yl Ester 8. To a solution of compound 6 (0.29 g, 0.53
mmol), triphenylphosphine (0.17 g, 0.64 mmol), and benzoic acid
(80 mg, 0.64 mmol) in dry THF (3 mL) was added dropwise
diethyl azodicarboxylate (DEAD) (0.1 mL, 0.64 mmol). After the
mixture was stirred for 2 h, the solvent was evaporated, and
the residue was diluted with CH2Cl2 and washed with saturated
aqueous NaHCO3 and brine. The organic layer was separated,
dried over MgSO4, and chromatographed (EtOAc/hexane 9:1)
yielding 0.28 g of 8 which was crystallized from hexane (81%):
g of compound 10 as white crystals (80%): mp 178-179 °C; [R]22
D
) -13.3 (c 0.3 EtOAc); IR (neat) ν 3440 (OH), 3310 (NH), 1720
1
(CdO), 1640 cm-1 (NCdO); H NMR (400 MHz, CDCl3) δ 0.97
(s, 9H, CCH3), 2.44 (s, 3H, ArCH3), 2.64 (dd, J ) 16.2, 14.1 Hz,
1H, H-4ax), 3.30 (dd, J ) 16.2, 5.3 Hz, 1H, H-4eq), 4.00 (dd, J )
11.0, 2.6 Hz, 1H, CH2a), 4.33 (dd, J ) 11.0, 1.8 Hz, 1H, CH2b),
4.91 (br s, 1H, H-6), 5.06 (s, 2H, CH2), 5.08 (m, 1H, H-3), 5.51
(d, J ) 4 Hz, 1H, NH), 7.28-7.54 (m, 17H, ArH), 7.85 (d, J )
8.3 Hz, 2H, ArH). Anal. Calcd for C37H40N2O7SSi: C, 64.89; H,
5.89; N, 4.09. Found: C, 65.01; H, 5.75; N, 3.99.
mp 142-144 °C; [R]22 ) -4.5 (c 0.95, EtOAc); IR (neat) ν 1730
D
(3R,5S,6S)-[6-(ter t-Bu t yld ip h en ylsila n yloxym et h yl)-5-
h yd r oxy-2-oxo-1-(t olu en e-4-su lfon yl)p ip er id in -3-yl]ca r -
ba m ic Acid Ben zyl Ester 11. To an ice-cold stirred solution
of compound 10 (0.1 g, 0.146 mmol) in methanol (3 mL) was
added portionwise NaBH4 (11 mg, 0.292 mmol), while the pH of
the reaction was adjusted and maintained to 5-6 by addition
of acetic acid. After 40 min of stirring at that temperature, the
reaction was quenched with water and extracted with EtOAc.
The combined organic extracts were washed with brine, dried
over MgSO4, and chromatographed (EtOAc/hexane 1:4) to afford
(OCdO), 1650 cm-1 (NCdO); 1H NMR (200 MHz, CDCl3) δ 0.98
(s, 9H, CCH3), 1.42 (m, 1H, H-4), 1.65 (m, 1H, H-4), 1.9 (m, 2H,
H-3), 2.35 (s, 3H, ArCH3), 3.95 (dd, J ) 10.2, 5.1 Hz, 1H, CH2a),
4.02 (dd, J ) 10.2, 5.1 Hz, 1H, H-6), 4.09 (tr, J ) 10.2 Hz, 1H,
CH2b), 5.40 (s, 1H, H-5), 6.92 (d, J ) 7.9 Hz, 2H, ArH), 7.32 (m,
3H, ArH), 7.4 (m, 4H, ArH), 7.52 (m, 3H, ArH), 7.59 (m, 3H,
ArH), 7.72 (m, J ) 7.9 Hz, 2H, ArH), 7.92 (d, J ) 7.9 Hz, 2H,
ArH). Anal. Calcd for C36H39NO6SSi: C, 67.37; H, 6.12; N, 2.18.
Found: C, 67.51; H, 6.01; N, 2.25.
(6S)-3-Am in o-6-(ter t-bu tyld ip h en ylsila n yloxym eth yl)-1-
(t olu en e-4-su lfon yl)-1,6-d ih yd r op yr id in e-2,5-d ion e 9. A
stirred solution of compoumd 3 (0.25 g 0.49 mmol) in methanol
(5 mL) was buffered by the addition of a 1:1 mixture AcOH/
AcONa. Then sodium azide (0.22 g, 3.43 mmol) was added
portionwise and the reaction was run for 12 h. The mixture was
partitioned in EtOAc and water. The organic extract was washed
with water, brine, dried over MgSO4 and chromatographed
(EtOAc/hexane 1:2) to afford 0.19 g of compound 9 as white solid
which was crystallized from diethyl ether/hexane (72%): mp
205-206 °C dec; [R]22D ) -4.1 (c 0.54, EtOAc); IR (neat) ν 3465,
3310 (NH2), 1700 (CdO), 1630 cm-1 (NCdO); 1H NMR (400
MHz, CDCl3) δ 0.82 (s, 9H, C-CH3), 2.38 (s, 3H, ArCH3, 4.07
(d, J ) 10 Hz, 1H, CH2b), 4.11 (d, J ) 10 Hz, 1H, CH2a), 4.85 (s,
1H, H-6), 5.29 (s br, 2H, NH), 5.76 (s, 1H, H-4), 7.19-7.40 (m,
10H, ArH), 7.48 (d, J ) 8 Hz, 2H, ArH), 7.87 (d, J ) 8 Hz, 2H,
ArH). Anal. Calcd for C29H32N2O5SSi: C, 63.48; H, 5.88; N, 5.11.
Found: C, 63.52; H, 5.99; N, 4.85.
80 mg of the compound 11 (80%): [R]22 ) +1.1 (c 0.2, EtOAc);
D
IR (neat) ν 3360 (OH), 1715 (OCdO), 1645 cm-1 (NCdO); 1H
NMR (400 MHz, CDCl3) δ 0.99 (s, 9H, CCH3), 2.16 (q, J ) 10.5
Hz, 1H, H-4ax), 2.34 (s, 3H, ArCH3), 2.60 (ddd, J ) 10.5, 5.5, 4.0
Hz, 1H, H-4eq), 3.36 (m, 1H, CH2a), 3.51 (m, 2H, H-6, CH2b), 4.54
(dd, J ) 10.5, 7.0 Hz, 1H, H-3), 4.88 (dd, J ) 10.5, 5.5 Hz, 1H,
H-5), 4.93 (s, 1H, OH), 5.06 (s, 2H, CH2), 5.36 (d, J ) 7.0 Hz,
1H, NH), 7.10 (d, J ) 8 Hz, 2H, ArH), 7.34-7.51 (m, 15H, ArH),
7.56 (d, J ) 8 Hz, 2H, ArH). Anal. Calcd for C37H42N2O7SSi: C,
64.70; H, 6.16; N, 4.08. Found: C, 64.86; H, 6.31; N, 4.03.
(2R,3S,5R)-5-Ben zyloxyca r bon yla m in o-3-h yd r oxy-6-ox-
op ip er id in e-2-ca r b oxylic a cid m et h yl est er 12: mp 121-
123 °C; [R]22D ) -1.8 (c 0.2, EtOAc); IR (neat) ν 3350 (OH), 1735,
1
1715 (OCdO), 1640 cm-1 (NCdO); H NMR (400 MHz, CDCl3)
δ 2.20 (q, J ) 10.1 Hz, 1H, H-4ax), 2.40 (ddd, J ) 10.1, 5, 3.8 Hz,
1H, H-4eq), 3.55 (s, 3H, CH3), 4.51 (dd, J ) 10.1, 7 Hz, 1H, H-5),
4.74 (m, 2H, H-2, 3), 4.90 (s, 1H, OH), 5.15 (s, 2H, CH2), 5.30 (d,
(3R,6S)-[6-(ter t-Bu tyld ip h en ylsila n yloxym eth yl)-2,5-d i-
oxo-1-(tolu en e-4-su lfon yl)piper idin -3-yl]car bam ic Acid Ben -
zyl Ester 10. A solution of compound 9 (0.52 g, 0.95 mmol),
AcOH (5 mL), and well-powdered zinc dust (0.32 g) in CH2Cl2
(7 mL) was sonicated in an ultrasound bath at 35 °C for 30 min.
J
) 7 Hz, 1H, NH), 7.25 (m, 5H, ArH). Anal. Calcd for
C15H18N2O6: C, 55.90; H, 5.63; N, 8.69. Found: C, 56.11; H, 5.43;
N, 8.75.
J O0159688