Totally stereocontrolled nitrone-ketene acetal based synthesis of (2S,3S)-N-benzoyl-and N-boc-phenylisoserine

Article abstract of DOI:10.1021/jo971009v

A novel, nitrone-ketene acetal based approach to enantiopure (2S,3S)-N- benzoyl- and N-boc-phenylisoserine has been realized. The convergent approach, which involves the intermediacy of isoxazolidinones, proceeds in up to 59% overall yield and requires only three operations from the starting nitrones.

Full text of DOI:10.1021/jo971009v

6672
J . Org. Chem. 1997, 62, 6672-6677
Tota lly Ster eocon tr olled Nitr on e-Keten e Aceta l Ba sed Syn th esis
of (2S,3S)-N-Ben zoyl- a n d N-Boc-p h en ylisoser in e†
Sylvie J ost, Yves Gimbert, and Andrew E. Greene*
Universite´ J oseph Fourier de Grenoble, Chimie Recherche (LEDSS), 38041 Grenoble Cedex, France
Fre´de´ric Fotiadu
Universite´ d’Aix-Marseille, ENSSPICAM, 13397 Marseille Cedex 20, France
Received J une 4, 1997X
A novel, nitrone-ketene acetal based approach to enantiopure (2S,3S)-N-benzoyl- and N-boc-
phenylisoserine has been realized. The convergent approach, which involves the intermediacy of
isoxazolidinones, proceeds in up to 59% overall yield and requires only three operations from the
starting nitrones.
The important cancer chemotherapeutic agents pacli-
taxel (Taxol®) and docetaxel (Taxotere®) are currently
best secured by a partial synthesis approach that,
formally, joins baccatin III with (2R,3S)-N-benzoylphen-
ylisoserine and 10-desacetylbaccatin III with (2R,3S)-N-
boc-phenylisoserine, respectively (eq 1).1 This conceptu-
ally simple approach, which was first demonstrated to
be viable in 1988,2 has to date fostered an impressive
number of often highly imaginative routes to the (2R,3S)-
phenylisoserine side chains for use in the esterification
reactions.1
In 1994 we disclosed the surprising result that cycli-
cally protected (2S,3S)-phenylisoserine derivatives could
also be employed in these esterifications for they too
yielded paclitaxel and docetaxel on deprotection.3 Inter-
est today in this anti stereoisomer also stems from the
disclosure by Kingston and co-workers4 that (4S,5R)-2,4-
diphenyloxazoline-5-carboxylic acid, which is prepared
conveniently from (2S,3S)-phenylisoserine derivatives,5
is an effective esterification partner for protected baccatin
III. While syntheses of the 2R,3S (syn) side chains are
far more numerous than those of the 2S,3S (anti), there
are several different routes to the latter. These include
enzymatic resolution,5a,6 enzymatic reduction,7 enantio-
and diastereoselective condensation and Michael
addition,5b,c,8 and chiral pool9 based approaches. In most
of the approaches, however, high enantiomeric and
diastereomeric excesses are largely offset by mediocre
yields and/or the number of steps required.
‡ This paper is dedicated to Prof. Maitland J ones, J r., on the occasion
of his 60th birthday.
* Tel: (33) 4-76-51-46-86. FAX: (33) 4-76-51-43-82; E-mail: Andrew.
Greene@ujf.grenoble-fr. Correspondence concerning the theoretical
calculations should be directed to Dr. F. Fotiadu.
X Abstract published in Advance ACS Abstracts, September 1, 1997.
(1) For reviews on the occurrence, biological properties, and syn-
theses of these compounds and congeners, see: Blechert, S. and
Gue´nard, D. In The Alkaloids, Chemistry and Pharmacology; Brossi,
A., Ed.; Academic Press: San Diego, 1990; Vol. 39, pp 195-238.
Kingston, D. G. I.; Samaranayake, G.; Ivey, C. A. J . Nat. Prod. 1990,
53, 1. Kingston, D. G. I. Pharmacol. Ther. 1991, 52, 1. Swindell, C. S.
Org. Prep. Proc. Int. 1991, 23, 465. Borman, S. Chem. Eng. News 1991,
69 (35), 11; 1992, 70 (41), 30. Potier, P.; Gue´nard, D.; Gue´ritte-
Voegelein, F. Acc. Chem. Res. 1993, 26, 160. Lavelle, F.; Gue´ritte-
Voegelein F.; Gue´nard, D. Bull. Cancer 1993, 80, 326. Kingston, D. G.
I.; Molinero, A. A.; Rimoldi, J . M. Prog. Chem. Org. Nat. Prod. 1993,
61, 1. Suffness, M. In Annual Reports in Medicinal Chemistry; Bristol,
J . A., Ed.; Academic Press: San Diego, 1993; Vol. 28, pp 305-314.
Nicolaou, K. C.; Dai W.-M.; Guy, R. K. Angew. Chem., Int. Ed. Engl.
1994, 33, 15. Georg, G. I.; Ali, S. M.; Zygmunt, J .; J ayasinghe, L. R.
Exp. Opin. Ther. Patents 1994, 4, 109. Chen, S. H.; Farina, V. In The
Chemistry and Pharmacology of Taxol and Its Derivatives; Farina, V.,
Ed; Elsevier: Amsterdam, 1995. J enkins, P. Chem. Br. 1996, 32 (11),
43.
Tomoda, Takeuchi, and Nomura first demonstrated the
feasiblity of the addition of O-silylated ketene acetals to
nitrones to afford racemic â-amino ester derivatives,
although with modest (2-3:1) diastereoselectivity at the
alkyl(or aryl)-substituted R and â centers.10 It was felt
(5) (a) Gou, D.-M.; Liu, Y.-C.; Chen, C.-S. J . Org. Chem. 1993, 58,
1287. (b) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J . J . Chem. Soc.,
Perkin Trans. 1 1994, 2385. (c) Gennari, C.; Vulpetti, A.; Donghi, M.;
Mongelli, N.; Vanotti, E. Angew. Chem., Int. Ed. Engl. 1996, 35, 1723.
(6) Ho¨nig, H.; Seufer-Wasserthal, P.; Weber, H. Tetrahedron 1990,
46, 3841; Tetrahedron Lett. 1990, 31, 3011.
(7) Cabon, O.; Larcheveˆque, M.; Buisson, D.; Azerad, R. Tetrahedron
Lett. 1992, 33, 7337. Patel, R. N.; Banerjee, A.; Howell, J . M.;
McNamee, C. G.; Brozozowski, D.; Mirfakhrae, D.; Nanduri, V.;
Thottathil, J . K.; Szarka, L. J . Tetrahedron: Asymmetry 1993, 4, 2069.
(8) Corey, E. J .; Choi, S. Tetrahedron Lett. 1991, 32, 2857. Hattori,
K.; Yamamoto, H. Tetrahedron 1994, 50, 2785. See also: Escalante,
J . J uaristi, E. Tetrahedron Lett. 1995, 36, 4397. Warmerdam, E. G. J .
C.; van Rijn, R. D.; Brussee, J .; Kruse, C. G.; van der Gen, A.
Tetrahedron: Asymmetry 1996, 7, 1723.
(2) Denis, J .-N.; Greene, A. E.; Gue´nard, D.; Gue´ritte-Voegelein, F.;
Mangatal, L.; Potier, P. J . Am. Chem. Soc. 1988, 110, 5917-5919.
Denis, J .-N.; Greene, A. E.; Gue´nard, D.; Gue´ritte-Voegelein, F. U.S.
Patent (Centre National de la Recherche Scientifique) 4924011, May
8 1990.
(3) Denis, J .-N.; Kanazawa, A. M.; Greene, A. E. Tetrahedron Lett.
1994, 35, 105.
(9) Dondoni, A.; Perrone, D. Synthesis 1993, 1162.
(10) (a) Tomoda, S.; Takeuchi, Y.; Nomura, Y. Chem. Lett. 1982,
1787. (b) See also: Kita, Y.; Itoh, F.; Tamura, O.; Ke, Y. Y.; Tamura,
Y. Tetrahedron Lett. 1987, 28, 1431. Kita, Y.; Tamura, O.; Itoh, F.;
Kishino, H.; Miki, T.; Kohno, M.; Tamura, Y. J . Chem. Soc., Chem.
Commun. 1988, 761.
(4) Kingston, D. G. I.; Chaudhary, A. G.; Gunatilaka, A. A. L.;
Middleton, M. L. Tetrahedron Lett. 1994, 35, 4483.
S0022-3263(97)01009-8 CCC: $14.00 © 1997 American Chemical Society

Nitrone-Ketene Acetal Based Synthesis of Phenylisoserines
J . Org. Chem., Vol. 62, No. 19, 1997 6673
a chiral nitrone or a chiral O-silylated ketene acetal, or
both in combination, if well chosen, might through this
reaction provide stereoselective access to the N-benzoyl-
and N-boc-phenylisoserine side chains (eq 2).11 In this
paper we detail an effective, alternative approach to the
2S,3S side chains based on such nitrone-O-silylated
ketene acetal couplings. To the best of our knowledge,
these are the first examples of chirality control in this
reaction through the use of removable auxiliary groups.
it not only facilated the purification and identification of
the diastereomers but also served, as will be seen, to
labilize the N-O bond and to simplify the removal and
recovery of the chiral auxiliaries of starting chiral O-
silylated ketene acetals.
A second approach to a diastereo- and enantiomerically
pure isoxazolidinone intermediate involved the use of a
chiral ketene acetal with N-benzyl-C-phenylnitrone. The
initial, and ultimately the best, chiral ketene acetal
examined was that derived from readily available (1R,2S)-
2-phenylcyclohexanol (TPCHR,S):17 the known18 glycolate
was converted into its triethylsilyl derivative, which was
then transformed to the Z ketene acetal (7, Z:E ) 95:5)
in 73% overall yield. In the presence of N-benzyl-C-
phenyl nitrone (6)19 and zinc iodide in acetonitrile-
dichloromethane, this ketene acetal reacted smoothly to
give the expected adduct 8 as a 90:10 mixture of anti and
syn diastereomers in 94% yield (eq 4). The two anti
diastereomers were present in a 97:3 ratio and the two
syn in a 80:20 ratio.14 After removal of the two minor
diastereomers by silica gel chromatography, the mixture
was subjected to acidic conditions to effect deprotection
and cyclization, which afforded the enantiopure isoxazo-
lidinone 9 in 77% yield (72% overall) and intact (1R,2S)-
2-phenylcyclohexanol in 82% yield.
The chiral nitrone (R)-N-(R-methylbenzyl)-C-phenylni-
trone (2) was readily prepared by condensation of (R)-
N-(R-methylbenzyl)hydroxylamine12 with benzaldehyde.
In combination with the achiral E ketene acetal 3,
derived from methyl (triethylsilyloxy)glycolate,13 in ac-
etonitrile-dichloromethane under zinc iodide catalysis10b
thio nitrone provided a 93:7 mixture of anti and syn
diastereomers 4 in better than 98% yield (eq 3). The two
Double induction, however, proved the most remark-
able: while (S)-N-(R-methylbenzyl)-C-phenylnitrone in
combination with the above ketene acetal 7 provided a
mixture of diastereomers (anti:syn, 85:15; 87% yield), the
matched20 antipodal nitrone 2 delivered only the desired
2S,3S diastereomer 10 in essentially quantitative yield.
Exposure of this derivative to acid afforded the expected
isoxazolidinone 5 in pure form in 74% yield (73% overall)
together with the chiral auxiliary in 79% yield (eq 5).
Tomada10a and Kita10b have both proposed a stepwise
mechanism for the nitrone-O-silylated ketene acetal
anti diastereomers, the major products, were present in
an 80:20 ratio and the two syn in a 65:35 ratio.14-16
Conveniently, the mixture of diastereomers on treatment
with acid smoothly underwent deprotection with con-
comitant cyclization to afford an easily separated mixture
of the corresponding isoxazolidinones. The 3S,4S dias-
tereomer 5 was isolated pure in ca. 50% overall yield.
This transformation was of considerable importance for
(16) One other chiral nitrone, the R,R′-dichlorophenyl analogue of
2, was also tested with the above ketene acetal 3. (R)-1-(2,6-Dichlo-
rophenyl)ethylamine, which in several instances has been shown to
be a more effective inductor than R-methylbenzylamine (Polniaszek,
R. P.; Kaufman, C. R. J . Am. Chem. Soc. 1989, 111, 4859. Polniaszek,
R. P.; Dillard, L. W. Tetrahedron Lett. 1990, 31, 797. Polniaszek, R.
P.; Belmont, S. E.; Alvarez, R. J . J . Org. Chem. 1990, 55, 215), was
prepared as previously described (Polniaszek, R. P.; Lichti, C. F. Synth.
Commun. 1992, 22, 171) and then transformed12 to the corresponding
hydroxylamine, which was condensed with benzaldehyde to give the
nitrone. Disappointingly, although the ratio of the anti diastereomers
improved (89:11) while the combined yield remained high (92%), the
anti and syn products were now formed in similar amounts (56:44).
(17) Whitesell, J . K.; Lawrence, R. M. Chim. 1986, 40, 318. The other
chiral auxiliaries examined were 8-phenylmenthol, phenylethanol, and
3,3-dimethyl-2-butanol.
(11) For examples of the application of chiral nitrones and chiral
dipolarophiles in asymmetric synthesis, see: Murahashi, S.-I.; Imada,
Y.; Kohno, M; Kawakami, T. Synlett 1993, 395. For an alternative
approach, see: Seerden, J .-P. G.; Scholte op Reimer, A. W. A.; Scheeren,
H. W. Tetrahedron Lett. 1994, 35, 4419. Seerden, J .-P. G.; Kuypers,
M. M. M.; Scheeren, H. W. Tetrahedron: Asymmetry 1995, 6, 1441.
(12) Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron 1985, 41, 3455.
(13) Ketene acetal 3 was prepared by a modification of the procedure
described by Hattori and Yamamoto: Hattori, K.; Yamamoto, H. J .
Org. Chem. 1993, 58, 5301. The E:Z ratio was 74:26. The tert-
butyldimethylsilyl and benzyl protecting groups were found to be less
effective in this work.
(14) These ratios were determined by proton NMR analysis. The
anti-syn stereochemical assignments were established by NMR after
cyclization of the purified or partially purified components to the
corresponding isoxazolidinones; the absolute stereochemistry was
assigned after conversion of the isoxazolidinones to the known isoserine
derivatives.
(18) Georg. G. I.; Cheruvallath, Z. S.; Himes, R. H.; Mejillano, M.
R.; Burke, C. T. J . Med. Chem. 1992, 35, 4230.
(19) Murahasi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe,
S. J . Org. Chem. 1990, 55, 1736. Murahashi, S.-I.; Shiota, T.; Imada,
Y. Org. Synth. 1991, 70, 265.
(15) The corresponding Z ketene acetal produced a 63:37 anti to syn
ratio in 63% yield.
(20) See: Masamune, S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.

6674 J . Org. Chem., Vol. 62, No. 19, 1997
J ost et al.
F igu r e 1. Proposed transition states for the formation of
(2S,3S)-phenylisoserines 4 (left) and 8 and 10 (right).
In summary, a novel, nitrone-ketene acetal based
approach to enantiopure (2S,3S)-N-benzoyl- and N-boc-
phenylisoserine has been realized. The convergent ap-
proach, which proceeds in up to 59% overall yield and
requires only three operations from the starting nitrones,
may also prove useful for the enantioselective synthesis
of other â-amino acid derivatives.
reaction involving an initial transfer of the silyl group
to the nitrone followed by combination of the resultant
N-(silyloxy)imminium ion and ester enolate through an
open transition state. While such a mechanism cannot
be completely ruled out, a well-organized, closed transi-
tion state would seem more likely, particularly in the
presence of zinc iodide. The zinc should facilitate adja-
cency of the reactants, which would be expected to lead
to the formation of a pentacoordinated silicon. Theoreti-
cal calculations support the involvement of a pentacoor-
dinated silicon and indicate that the carbon-carbon bond
formation will occur through a pseudochair or a pseudo-
twist transition state.21 Adduct 4 would then arise
through reaction of the E ketene acetal 3 with the nitrone
primarily through the former, whereas adducts 8 and 10
would be formed from the Z ketene acetal 7 and the
nitrones through the latter, in which unfavorable non-
bonded steric interactions between the triethylsilyloxy
group and the nitrone phenyl are avoided (Figure 1).
Exp er im en ta l Section
Isolation of the crude product was generally accomplished
by pouring the reaction mixture into water and then thor-
oughly extracting the separated aqueous phase with the
specified solvent. After being washed with 10% aqueous HCl
and/or NaHCO3 (if required), water, and saturated aqueous
NaCl, the combined organic phases were dried over anhydrous
Na2SO4 or MgSO4 and then filtered and concentrated under
reduced pressure on a Bu¨chi Rotovapor to yield the crude
reaction product. Tetrahydrofuran and ether were distilled
from sodium-benzophenone, and methanol was distilled from
magnesium. Pentane, dichloromethane, acetonitrile, N,N-
dimethylformamide, HMPA, and triethylamine were distilled
from calcium hydride.22
Both isoxazolidinones 5 and 9 efficiently provided the
desired phenylisoserine derivatives on one-pot double
hydrogenolysis-benzoylation/tert-butoxycarbonylation (eq
6). The isoxazolidinones in methanol containing acetic
acid or a catalytic amount of perchloric acid in the
presence of Pearlman’s catalyst were smoothly converted
at room temperature under hydrogen at 1 atm to (2S,3S)-
phenylisoserine, which was treated in situ with benzoyl
chloride and sodium bicarbonate or boc anhydride and
triethylamine to yield the anti side chains 1a and 1b.
The corresponding methyl esters, obtained in 70-81%
overall yield, were identical in all respects with indepen-
dently prepared samples.
(R)-(-)-N-(r-Meth ylben zyl)-C-p h en yln itr on e (2). To a
solution of 11.36 g (50.0 mmol) of (R)-(+)-N-(R-methylbenzyl)-
hydroxylammonium oxalate12 in 250 mL of dry THF under
argon was added 16.8 g (200 mmol) of sodium bicarbonate,
5.08 mL (5.30 g, 50.0 mmol) of benzaldehyde, and an excess
of anhydrous magnesium sulfate. The reaction mixture was
stirred at 20 °C overnight and then filtered through a pad of
anhydrous sodium sulfate. The filtrate was concentrated
under reduced pressure to leave an oil, which was purified by
silica gel chromatography with 20% ethyl acetate in hexane
to give 11.04 g (98%) of nitrone 2: [R]20 -48.2 (c 1.0, CHCl3);
D
mp 52 °C; 1H NMR (200 MHz) δ 1.87 (d, J ) 6.9 Hz, 3 H),
5.16 (q, J ) 6.9 Hz, 1 H), 7.20-7.40 (m, 3 H), 7.40-7.60 (m, 6
H), 8.15-8.30 (m, 2 H); 13C NMR (50.3 MHz) δ 18.8 (CH3),
74.6 (CH), 126.9 (2 CH), 128.1 (2 CH), 128.3 (3 CH), 128.4 (2
CH), 129.9 (CH), 130.4 (C), 132.6 (CH), 138.3 (C); mass
spectrum (CI) m/z 226 (MH+, 100%), 210, 122, 105.
Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22.
Found: C, 79.76; H, 6.73; N, 5.93.
(E)-1-((ter t-Bu t yld im et h ylsilyl)oxy)-1-m et h oxy-2-(t r i-
eth ylsilyloxy)eth ylen e (3). A mixture of 7.7 mL (9.0 g, 100
mmol) of methyl glycolate, 17.0 g (250 mmol) of imidazole, and
20.3 mL (18.2 g, 120 mmol) of triethylsilyl chloride in 100 mL
of dry DMF was stirred at 20 °C overnight. Pentane and
saturated aqueous sodium bicarbonate were added to the
mixture, and the product was then isolated in the usual
manner to give 21.0 g of methyl (triethylsilyloxy)acetate: 1H
NMR (200 MHz) δ 0.65 (qd, J ) 8.0, 1.5 Hz, 6 H), 0.98 (t, J )
8.0 Hz, 9 H), 3.75 (s, 3 H), 4.25 (s, 2 H); 13C NMR (75.5 MHz)
δ 4.1 (3 CH2), 6.2 (3 CH3), 51.3 (CH3), 61.1 (CH2), 171.8 (C);
IR 1766, 1149, cm-1; mass spectrum (CI) m/z 222 (69%), 205
(MH+, 62%), 175 (100%), 132, 117.
(21) In this preliminary study the AM1 semiempirical molecular
orbital method was employed (Dewar, M. J . S.; Zoebisch, E. G.; Healy,
E. F.; Stewart, J . J . P. J . Am. Chem. Soc. 1985, 107, 3902). All
calculations were performed with the AMPAC 4.5 code (Semichem,
Shawnes, KS 66216). The RHF, closed-shell, ground state was used
in all cases. Force calculations were performed on the local minima
and the transition states to verify that they had no and one and only
one negative force constant, respectively. In addition, some ab initio
calculations have been carried out with the 3-21G* basis set using the
Gaussian 92 program on stationary points found at the semiemprical
level (Frisch, M. J .; Trucks, G. W.; Head-Gordon, M.; Gill, W. P. M.;
Wong, M. W.; Foresman, J . B.; J ohnson, B. G.; Schlegel, H. B.; Robb,
M. A.; Reploge, E. S.; Gomperts, R.; Andres, J . L.; Raghavachari, K.;
Binkley, J . S.; Gonzalez, C.; Martin, R. L.; Fox, D. J .; Defrees, D. J .;
Baker, J .; Stewart, J . J . P.; Pople, J . A. Gaussian 92; Gausssian Inc.:
Pittsburgh, PA, 1992). Details can be found in the Supporting Informa-
tion.
Anal. Calcd for C9H20O3Si: C, 52.90; H, 9.86. Found: C,
52.78; H, 9.84.
To a stirred solution of 1.98 mL (1.66 g, 11.7 mmol) of
tetramethylpiperidine in 48 mL of THF at 0 °C under argon
(22) For the analytical instruments used in this work, see: B. M.
de Azevedo, M.; Greene, A. E. J . Org. Chem. 1995, 60, 4940.

Nitrone-Ketene Acetal Based Synthesis of Phenylisoserines
J . Org. Chem., Vol. 62, No. 19, 1997 6675
was added dropwise 4.30 mL (10.8 mmol) of a 2.5 M solution
of n-butyllithium in hexanes. The resulting solution was
stirred for 15 min at 0 °C and then cooled to -100 °C and
treated dropwise first with a solution of 1.93 g (12.8 mmol) of
tert-butyldimethylsilyl chloride in 4.0 mL of THF and then
with a solution of 2.04 g (10.0 mmol) of the above ester in 8.0
mL of THF. The reaction mixture was stirred at -100 °C for
an additional 10 min, whereupon it was allowed to warm
slowly to 20 °C. After being stirred for 1 h at this temperature,
the reaction mixture was diluted with 400 mL of hexane and
filtered through a pad of Celite. The filtrate was concentrated
under reduced pressure, and the residue was dissolved in
hexane, which was washed with saturated aqueous sodium
bicarbonate and water and dried over anhyd magnesium
sulfate. The crude product was then isolated in the normal
manner and purified by evaporative distillation (40 °C/0.005
mbar) to give 1.83 g (58%) of ketene acetal 3 (E:Z, 74:26) as a
colorless oil: 1H NMR (200 MHz, E-isomer) δ 0.13 (s, 6 H),
0.63 (q, J ) 7.8 Hz, 6 H), 0.91 (s, 9 H), 0.96 (t, I ) 7.8 Hz, 9
H), 3.61 (s, 3 H), 5.41 (s, 1 H); 13C NMR (50.3 MHz, E-isomer)
δ -5.0 (2 CH3), 4.3 (3 CH2), 6.5 (3 CH3), 18.0 (C), 25.6 (3 CH3),
56.0 (CH3), 108.7 (CH), 148.9 (C); IR 3061,1701, 1229, 1178
cm-1; mass spectrum (CI) m/ z 394, 319 (MH+, 100%), 305, 275,
132.
Anal. Calcd for C26H46O3Si2: Mr, 462.2985. Found: Mr
(mass spectrum), 462.2965.
Nitr on e-Keten e Aceta l Con d en sa tion s. Gen er a l P r o-
ced u r e. The pure ketene acetal was added over 1 h to a
stirred solution at 20 °C under argon of the nitrone in 1:1
acetonitrile-dichloromethane containing zinc iodide (0.5-1
equiv, dried under vacuum for 10 min at 300 °C). After being
stirred for an additional 1 h at 20 °C, the reaction mixture
was processed with ether in the normal manner and the crude
product was purified by silica gel chromatography with ether
in hexane to give the adduct.
(A) (R)-(-)-N-(r-Meth ylben zyl)-C-ph en yln itr on e (2) with
(E)-1-((ter t-Bu tyld im eth ylsilyl)oxy)-1-m eth oxy-2-(tr ieth -
ylsilyloxy)eth ylen e (3) To Give 4. From 293 mg (1.30
mmol) of nitrone 2 and 831 mg (2.61 mmol) of ketene acetal 3
in 2.6 mL of solvent was obtained 696 mg (98%) of a mixture
(4) of the four diastereomers (93% anti (80:20), 7% syn (65:
35)),14
which could be partially separated by repeated chroma-
tography: 1H NMR (300 MHz) major anti (2S,3S) δ 0.20-0.40
(m, 6 H), 0.26 (s, 3 H), 0.51 (s, 3 H), 0.62 (t, J ) 7.9 Hz, 9 H),
0.96 (s, 9 H), 1.26 (d, J ) 6.6 Hz, 3 H), 3.71 (s, 3 H), 3.80 (q,
J ) 6.6 Hz, 1 H), 4.14 (d, J ) 10.4 Hz, 1 H), 4.68 (d, J ) 10.4
Hz, 1 H), 7.10-7.50 (m, 10 H); minor anti (2R,3R, selected
resonances) δ 1.02 (d, J ) 6.9 Hz, 3 H), 3.57 (s, 3 H), 4.23 (q,
J ) 6.9 Hz, 1 H), 4.55 (d, J ) 9.7 Hz, 1 H); major syn δ 0.18
(s, 3 H), 0.26 (s, 3 H), 0.59 (q, J ) 7.6 Hz, 6 H), 0.90-1.00 (m,
18 H), 1.35 (d, J ) 6.6 Hz, 3 H), 3.23 (s, 3 H), 3.94 (q, J ) 6.6
Hz, 1 H), 4.00 (d, J ) 7.8 Hz, 1 H), 4.72 (d, J ) 7.8 Hz, 1 H),
7.10-7.50 (m, 10 H); minor syn δ -0.07 (m, 3 H), 0.13 (s, 3
H), 0.59 (q, J ) 7.6 Hz, 6 H), 0.90-0.95 (m, 18 H), 1.01 (d, J
) 6.9 Hz, 3 H), 3.38 (s, 3 H), 4.2 (deformed d, 1 H), 4.44 (q, J
) 6.9 Hz, 1 H), 4.58 (d, J ) 6.1 Hz, 1 H), 7.10-7.50 (m, 10 H);
IR 3088, 3063, 3029, 1743, 1605, 1118 cm-1; mass spectrum
(CI) m/ z 544 (MH+), 340 (100%), 236, 105.
Anal. Calcd for C15H34O3Si2: C, 56.55; H, 10.76. Found:
C, 56.53; H, 10.89.
(Z)-1-((t er t -B u t y ld im e t h y ls ily l)o x y )-1-(((1R ,2S )-2-
p h en ylcycloh exyl)oxy)-2-(tr ieth ylsilyloxy)eth ylen e (7). A
mixture of 3.89 g (16.6 mmol) of (1R,2S)-2-phenylcyclohexyl
glycolate,18 2.80 g (41.1 mmol) of imidazole, and 3.35 mL (3.01
g, 20.0 mmol) of triethylsilyl chloride in 41 mL of dry DMF
was stirred at 20 °C overnight. Pentane and saturated
aqueous sodium bicarbonate were added to the mixture, and
the product was then isolated in the usual manner to give 5.80
Anal. Calcd for C30H49O4NSi2: C, 66.25; H, 9.08; N, 2.58.
Found: C, 66.54; H, 9.24; N, 2.54.
g
(100%) of (1R,2S)-2-phenylcyclohexyl (triethylsilyloxy)-
acetate: [R]23D -16.7 (c 2.2, CHCl3); 1H NMR (200 MHz) δ 0.47
(qd, J ) 8.0, 1.0 Hz, 6 H), 0.86 (t, J ) 8.0 Hz, 9 H), 1.20-1.75
(m, 4 H), 1.75-2.00 (m, 3 H), 2.05-2.30 (m, 1 H) ; 2.64 (td, J
) 11.0, 3.7 Hz, 1 H), 3.89 (ABq, J AB ) 16.7 Hz, δA-δB ) 36.1
Hz, 2 H), 5.06 (deformed td, J ) 10.5, 4.5 Hz, 1 H), 7.10-7.30
(m, 5 H); 13C NMR (75.5 MHz) δ 4.1 (3 CH2), 6.4 (3 CH3), 24.7
(CH2), 25.7 (CH2), 32.2 (CH2), 33.9 (CH2), 49.7 (CH), 61.0 (CH2),
76.0 (CH), 126.3 (CH), 127.3 (2 CH), 128.2 (2 CH), 142.8 (C),
170.8 (C); IR 3085, 3063, 3030, 1755, 1603, 1149 cm-1; mass
spectrum (CI) m/ z 366, 349 (MH+, 100%), 319, 208, 191, 178,
159, 132, 117, 108.
(B) N-Ben zyl-C-p h en yln itr on e (6) w ith (Z)-1-((ter t-
Bu t yld im et h ylsilyl)oxy)-1-(((1R,2S)-2-p h en ylcycloh ex-
yl)oxy)-2-(tr ieth ylsilyloxy)eth ylen e (7) To Give 8. From
662 mg (3.14 mmol) of nitrone 6 and 2.90 g (6.27 mmol) of
ketene acetal 7 in 6.3 mL of solvent was obtained 1.99 g (94%)
of a mixture (8) of the four diastereomers (90% anti (97:3),
10% syn (80:20)),14 which could be partially separated by
repeated chromatography: 1H NMR (200 MHz) major anti
(2S,3S) δ 0.55 to -0.25 (m, 3 H), -0.15 to 0.10 (m, 3 H), 0.46
(qd, J ) 7.9, 2.7 Hz, 6 H), 0.80-0.96 (m, 18 H), 1.10-2.05 (m,
8 H), 2.66 (deformed td, J ) 11.2, 3.4 Hz, 1 H), 3.50-3.80 (m,
A of an AB, 1 H), 3.93 (d, B of an AB, J ) 13.3 Hz, 1 H), 4.46
(d, J ) 4.1 Hz, 1 H), 4.90-5.10 (m, 1 H), 4.99 (deformed td, J
) 10.5, 3.7 Hz, 1 H), 7.05-7.40 (m, 13 H), 7.55-7.75 (m, 2 H);
Anal. Calcd for C20H32O3Si: C, 68.92; H, 9.25. Found: C,
68.33; H, 9.23.
To a stirred solution of 2.20 mL (1.68 g, 10.4 mmol) of
hexamethyldisilazane in 34 mL of THF at 0 °C under argon
was added dropwise 4.50 mL (9.45 mmol) of a 2.1 M solution
of n-butyllithium in hexanes. The resulting solution was
stirred for 15 min at 0 °C and then cooled to -78 °C, and 8.60
mL of HMPA was slowly added. After 5 min, the solution was
cooled to -100 °C and treated first with a solution of 3.00 g
(8.62 mmol) of the above ester in 3.4 mL of THF over 5 min
and then with a solution of 1.69 g (11.2 mmol) of tert-
butyldimethylsilyl chloride in 1.7 mL of THF. The reaction
mixture was stirred at -100 °C for an additional 10 min,
whereupon it was allowed to warm slowly to 20 °C. After being
stirred for 1 h at this temperature, the reaction mixture was
diluted with 260 mL of cold hexane and 86 mL of saturated
aqueous sodium bicarbonate was added. The crude product
was isolated in the usual way and purified by evaporative
distillation (150-160 °C/0.03 mbar) to give 2.92 g (73%) of
ketene acetal 7 (E:Z, 5:95) as a colorless oil: 1H NMR (300
MHz) δ -0.06 (s, 3 H), 0.01 (s, 3 H), 0.55 (q, J ) 7.9 Hz, 6 H),
0.86 (s, 9 H), 0.91 (t, J ) 7.9 Hz, 9 H), 1.20-1.95 (m, 7 H),
2.25-2.35 (m, 1 H), 2.55 (td, J ) 11.2, 3.8 Hz, 1 H), 3.83
(deformed td, J ) 10.0, 4.2 Hz, 1 H), 5.11 (s, 1 H), 7.10-7.35
(m, 5 H); 13C NMR (75.5 MHz) δ -4.4 (2 CH3), 4.7 (3 CH2), 6.6
(3 CH3), 18.2 (C), 24.8 (CH2), 25.7 (3 CH3) ; 25.9 (CH2), 32.4
(CH2), 34.0 (CH2), 50.5 (CH), 81.1 (CH), 109.9 (CH), 126,1 (CH),
128.0 (2 CH), 128.1 (2 CH), 144.2 (C), 145.9 (C); IR 3083, 3063,
major syn (selected resonance) δ 4.37 (d, J ) 6.2 Hz, 1 H); 13
C
NMR (75.5 MHz) major anti (2S,3S) δ -5.5 (CH3), -4.9 (CH3),
4.7 (3 CH2), 6.8 (3 CH3), 18.3 (C), 24.6 (CH2), 25.8 (CH2), 26.2
(3 CH3), 32.1 (CH2), 34.0 (CH2), 49.9 (CH), 59.3 (CH2), 71.7
(CH), 71.9 (CH), 76.5 (CH), 126.4 (CH), 126.9 (CH), 127.3 (CH),
127.5 (2 CH), 127.6 (2 CH), 127.7 (2 CH), 128.3 (2 CH), 130.4
(2 CH), 130.6 (2 CH), 135.7 (C), 139.2 (C), 143.0 (C), 172.5 (C);
major syn (selected resonances) δ -4.3 (CH3), 26.9 (CH2), 30.9
(CH2), 49.4 (CH), 61.0 (CH2), 73.6 (CH), 78.0 (CH), 127.1 (CH),
131.6 (CH), 135.1 (C), 138.3 (C), 143.3 (C), 171.4 (C); IR 3087,
3063, 3030, 1748, 1604, 1140 cm-1; mass spectrum (EI) m/ z
674 (M+), 658, 644, 616, 588, 326, 159, 91 (100%).
Anal. Calcd for C40H59O4NSi2: C, 71.27; H, 8.82; N, 2.08.
Found: C, 71.33; H, 9.07; N, 2.01.
(C) (R)-(-)-N-(r-Meth ylben zyl)-C-ph en yln itr on e (2) with
(Z)-1-((ter t-Bu tyld im eth ylsilyl)oxy)-1-(((1R,2S)-2-p h en yl-
cycloh exyl)oxy)-2-(tr ieth ylsilyloxy)eth ylen e (7) To Give
10. From 110 mg (0.49 mmol) of nitrone 2 and 450 mg (0.97
mmol) of ketene acetal 7 in 1.0 mL of solvent was obtained
329 mg (98%) of the 2S,3S anti diastereomer 10 as a viscous
1
oil: [R]20 2.0 (c 1.6, CHCl3); H NMR (200 MHz) δ 0.04 (q, J
D
) 7.9 Hz, 6 H), 0.25 (s, 3 H), 0.38 (s, 3 H), 0.55 (t, J ) 7.9 Hz,
9 H), 0.96 (s, 9 H), 1.29 (d, J ) 6.7 Hz, 3 H), 1.40-1.70 (m, 4
H), 1.75-2.05 (m, 3 H), 2.35-2.50 (m, 1 H), 2.77 (deformed
td, J ) 11.0, 3.4 Hz, 1 H), 3.97 (q, J ) 6.7 Hz, 1 H), 4.18 (d, J
) 7.9 Hz, 1 H), 4.51 (d, J ) 7.9 Hz, 1 H), 4.96 (deformed td, J
3030, 1704, 1604, 1202, 1159 cm-1
.

6676 J . Org. Chem., Vol. 62, No. 19, 1997
J ost et al.
) 10.2, 4.5 Hz, 1H), 7.05-7.45 (m, 15 H); 13C NMR (75.5 MHz)
δ -3.8 (CH3), -2.6 (CH3), 4.4 (3 CH2), 6.5 (3 CH3), 18.8 (C),
21.0 (CH3), 24.8 (CH2), 25.9 (CH2), 26.6 (3 CH3), 32.3 (CH2),
34.6 (CH2), 49.7 (CH), 64.9 (CH), 71.5 (CH), 71.9 (CH), 77.4
(CH), 126.5 (CH), 126.7 (2 CH), 126.9 (CH), 127.6 (2 CH), 127.8
(2 CH), 128.2 (2 CH), 128.4 (2 CH), 128.7 (CH), 131.8 (2 CH),
135.3 (C), 143.3 (C), 143.7 (C), 172.5 (C); IR 3087, 3062, 3030,
1744, 1605, 1246, 1123 cm-1; mass spectrum (EI) m/z 688 (M+),
672, 658, 630, 602, 340, 236, 159, 105 (100%), 91, 75, 41.
Anal. Calcd for C41H61O4NSi2: C, 71.57; H, 8.94 ; N, 2.04.
Found: C, 71.90; H, 8.96; N, 2.15.
Dep r otection -Cycliza tion of Con d en sa tion P r od u cts
to Isoxa zolid in on es. Gen er a l P r oced u r e. A stirred solu-
tion of the condensation product in acetic acid under argon
was heated at 50 °C until no starting material remained (TLC).
After being allowed to cool to 20 °C, the reaction mixture was
treated with a solution of HF in water and then stirred until
no further evolution was observed (TLC), whereupon it was
partially concentrated under reduced pressure. The crude
product was isolated with ether in the usual manner and
purified by silica gel chromatography with ethyl acetate in
hexane to give the isoxazolidinone as a white solid.
of 55.5 mg (0.20 mmol) of isoxazolidinone 5 and 19.4 mg of
Pd(OH)2 on carbon (Pearlman’s catalyst) in 3.2 mL of methanol
containing a few drops of perchloric acid was vigorously stirred
under hydrogen until no starting material remained (TLC) and
then placed under an argon atmosphere and neutralized with
10% aqueous sodium bicarbonate. The resulting mixture was
cooled to 0 °C and treated with an additional 4.7 mL of 10%
aqueous sodium bicarbonate followed by 68 µL (82 mg, 0.59
mmol) of benzoyl chloride. After completion of the reaction
(TLC), the mixture was acidified to pH 1 with 6 N HCl and
thoroughly extracted with dichloromethane, which was then
dried over magnesium sulfate, filtered, and concentrated under
reduced pressure. The residue, dissolved in a minimum
amount of acetone, yielded 57 mg of acid on addition of hexane.
Treatment of the acid with CH2N2 in ether at 0 °C provided
the corresponding methyl ester, which was purified by silica
gel chromatography with ethyl acetate in hexane to give 42.6
mg (73%) of 1a as a white solid.
(B) F r om Isoxa zolid in on e 9. A mixture of 30.0 mg (0.11
mmol) of isoxazolidinone 9 and 11.0 mg of Pd(OH)2 on carbon
(Pearlman’s catalyst) in 1.8 mL of methanol containing a few
drops of perchloric acid was vigorously stirred under hydrogen
until no starting material remained (TLC) and then placed
under an argon atmosphere and neutralized with 10% aqueous
sodium bicarbonate. The resulting mixture was cooled to 0
°C and treated with an additional 2.7 mL of 10% aqueous
sodium bicarbonate followed by 39 µL (47 mg, 0.34 mmol) of
benzoyl chloride. After completion of the reaction (TLC), the
mixture was processed as above to give 27.4 mg of acid, which
provided 23.3 mg (70%) of methyl ester 1a , identical to that
(A) (3S,4S)-4-Hyd r oxy-3-p h en yl-N-(1-p h en yleth yl)isox-
a zolid in on e (5) fr om 4. From 800 mg (1.47 mmol) of the
mixture (4) of the four diastereomers, 30 mL of acetic acid,
and 15 mL of 0.1 M HF, 188 mg (45%) of isoxazolidinone 5
and 37.4 mg (6%) of the corresponding O-tert-butyldimethyl-
silyl derivative were obtained, together with small amounts
of the diastereomeric products. Minor trans diastereomer: 1H
NMR (200 MHz) δ 1.51 (d, J ) 7.8 Hz, 3 H), 2.95 (br s, 1 H),
4.13 (q, J ) 6.8 Hz, 1 H), 4.23 (d, J ) 10.3 Hz, 1H), 4.60 (d, J
) 10.3 Hz, 1 H), 7.10-7.20 (m, 4 H), 7.20-7.35 (m, 6 H); 13C
NMR (50.3 MHz) δ 15.8 (CH3), 65.0 (CH), 74.1 (CH), 76.2 (CH),
127.6 (2 CH), 127.9 (CH), 128.1 (2 CH), 128.2 (2 CH), 128.6
(CH), 128.8 (2 CH), 135.8 (C), 139.5 (C), 173.3 (C); IR 3425,
3088, 3064, 3034, 1782, 1135 cm-1; mass spectrum (CI) m/ z
284 (MH+,100%), 210 , 120, 105. Major cis diastereomer: 1H
NMR (200 MHz) δ 1.59 (d, J ) 6.9 Hz, 3 H), 2.10-2.55 (br s,
1H), 3.99 (q, J ) 6.9 Hz, 1 H), 4.20-4.50 (m, 2 H), 7.05-7.40
(m, 10 H). Minor cis diastereomer: 1H NMR (200 MHz) δ 1.47
(d, J ) 6.5 Hz, 3 H), 2.00 (br s, 1 H), 4.26 (q, J ) 6,5 Hz, 1 H),
4.71 (deformed ABq, J AB ) 7.7 Hz, δA-δB ) 23.8 Hz, 2 H),
obtained in A: mp 158-159 °C (lit.23 mp 158-159 °C); [R]21
D
-23.7 (c 1.1, CHCl3) [lit.5a [R]20 -23 (c 1, CHCl3)]; H NMR
1
D
(200 MHz) δ 3.05 (d, J ) 6.5 Hz, 1 H); 3,71 (s, 3 H), 4.70 (dd,
J ) 6.5, 3.8 Hz, 1 H), 5.61 (dd, J ) 8.6, 3.8 Hz, 1 H), 7.14
(deformed d, J ) 8.6 Hz, 1 H), 7.25-7.36 (m, 5 H), 7.37-7.56
(m, 3 H), 7.76-7.84 (m, 2 H); 13C NMR (75.5 MHz) δ 52.5
(CH3), 55.6 (CH), 73.0 (CH), 127.0 (2 CH), 127.4 (2 CH), 128.2
(CH), 128.5 (4 CH), 131.6 (CH), 134.1 (C), 136.6 (C), 166.7 (C),
172.1 (C); IR (KBr) 3446, 3323, 3089, 3064, 3032, 3004, 1745,
1643, 1604, 1257 cm-1; mass spectrum (CI) m/ z 300 (MH+,
100%).
Anal. Calcd for C17H17O4N: C, 68.22; H, 5.72; N, 4.68.
Found: C, 68.30; H, 5.60; N, 4.64.
7.10-7.60 (m, 10 H). Isoxazolidinone 5: mp 37-40 °C; [R]20
D
1
148 (c 1.3, CHCl3); H NMR (200 MHz) δ 1.56 (d, J ) 7.1 Hz,
(+)-Meth yl (2S,3S)-3-(N-(ter t-Bu toxyca r bon yl)a m in o)-
2-h yd r oxy-3-p h en ylp r op a n oa te (1b). (A) F r om Isoxa zo-
lid in on e 5. A mixture of 58 mg (0.20 mmol) of isoxazolidinone
5 and 17.6 mg of Pd(OH)2 on carbon (Pearlman’s catalyst) in
3 mL of methanol-acetic acid (98:2) was vigorously stirred
under hydrogen until no starting material remained (TLC) and
then placed under an argon atmosphere and neutralized with
triethylamine. The resulting mixture was treated with an
additional 171 µL (124 mg, 1.23 mmol) of triethylamine
followed by 223 mg (1.02 mmol) of di-tert-butyl dicarbonate.
After being stirred overnight, the mixture was diluted with
methanol and filtered to remove the catalyst, and the filtrate
was partitioned between ether and water. The aqueous phase
was separated, acidified at 0 °C to pH 2-4 with 2 N HCl, and
thoroughly extracted with dichloromethane, which was then
dried over sodium sulfate, filtered, and concentrated under
reduced pressure to yield the acid as a white solid. Treatment
of the acid with CH2N2 in ether at 0 °C provided the corre-
sponding methyl ester, which was purified by silica gel
chromatography with ethyl acetate in hexane to afford 49.0
mg (81%) of methyl ester 1b as a white solid.
3 H), 2.64 (deformed d, J ) 3.2 Hz, 1 H), 3.86 (d, J ) 10.9 Hz,
1 H), 3.95 (q, J ) 7,1 Hz, 1 H), 4.56 (deformed dd, J ) 10.9,
3.2 Hz, 1 H), 7.15-7.27 (m, 2 H), 7.28-7.36 (m, 3 H), 7.38-
7.45 (m, 5 H); 13C NMR (50.3 MHz) δ 20.0 (CH3), 63.4 (CH),
73.1 (CH), 75.8 (CH), 127.7 (2 CH), 128.3 (4 CH), 129.1 (4 CH),
172.8 (C); IR 3342, 3089, 3064, 3032, 1782, 1131 cm-1; mass
spectrum (EI) m/ z 283 (M+), 226, 120, 105 (100%), 91, 77, 65,
51, 39.
Anal. Calcd for C17H17O3N: Mr, 283.1208. Found: Mr
(mass spectrum), 283.1216.
(B) (3S,4S)-4-Hyd r oxy-3-p h en yl-N-(1-p h en yleth yl)isox-
a zolid in on e (5) fr om 10. From 168 mg (0.24 mmol) of adduct
10, 4.8 mL of acetic acid, and 2.44 mL of 0.1 M HF, 51.2 mg
(74%) of isoxazolidinone 5, identical with that above, was
produced.
(C) (3S,4S)-N-Ben zyl-4-h yd r oxy-3-p h en ylisoxa zolid i-
n on e (9) fr om 8. From 400 mg (0.59 mmol) of adduct 8 (92%
2S,3S), 12 mL of acetic acid, and 0.100 mL of 48% HF was
obtained 130 mg (72% overall) of isoxazolidinone 9: mp 96-
97 °C; [R]20 166 (c 1.0, CHCl3); 1H NMR (400 MHz) δ 2.84 (d,
D
(B) F r om Isoxa zolid in on e 9. A mixture of 55.1 mg (0.20
mmol) of isoxazolidinone 9 and 20.5 mg of Pd(OH)2 on carbon
(Pearlman’s catalyst) in 3.2 mL of methanol containing a few
drops of perchloric acid was vigorously stirred under hydrogen
until no starting material remained (TLC) and then placed
under an argon atmosphere and neutralized with triethyl-
amine. The resulting mixture was treated with an additional
171 µL (124 mg, 1.23 mmol) of triethylamine followed by 223
mg (1.02 mmol) of di-tert-butyl dicarbonate. After completion
J ) 3.9 Hz, 1 H), 3.92 (d, J ) 14.8 Hz, 1 H), 4.15 (d, J ) 10.8
Hz, 1 H), 4.24 (d, J ) 14.8 Hz, 1 H), 4.65 (dd, J ) 10.8, 3.9 Hz,
1 H), 7.28-7.38 (m, 5 H), 7.40-7.48 (m, 3 H), 7.50-7.55 (m, 2
H); 13C NMR (75.5 MHz) δ 60.9 (CH2), 75.6 (CH), 76.3 (CH),
127.7 (2 CH), 128.0 (CH), 128.5 (2 CH), 129.3 (4 CH), 129.4
(CH), 134.5 (C), 134.7 (C), 172.8 (C); IR 3418, 3107, 3088, 3063,
3032, 1779, 1603, 1136 cm-1; mass spectrum (CI) m/z 287, 270
(MH+, 100%), 226, 196, 124, 106, 76.
Anal. Calcd for C16H15O3N: C, 71.36; H, 5.61 ; N, 5.20.
Found: C, 71.38; H, 5.71; N, 5.00.
(-)-Meth yl (2S,3S)-3-Ben za m id o-2-h yd r oxy-3-p h en yl-
p r op a n oa te (1a ). (A) F r om Isoxa zolid in on e 5. A mixture
(23) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J . Org. Chem. 1992,
57, 6387.

Nitrone-Ketene Acetal Based Synthesis of Phenylisoserines
J . Org. Chem., Vol. 62, No. 19, 1997 6677
of the reaction (TLC), the mixture was processed as above to
give the acid, which provided 42.1 mg (70%) of methyl ester
1b, identical to that obtained in A: mp 136-137 °C; [R]21D 30.1
(c 0.5, CHCl3); 1H NMR (200 Hz) δ 1.41 (br s, 9 H), 2.85
(deformed d, J ) 6.9 Hz, 1 H), 3.68 (s, 3 H), 4.58 (deformed
dd, J ) 6.2, 3.4 Hz, 1 H), 5.08 (deformed dd, J ) 8.7, 2.6 Hz,
1 H), 5.57 (deformed d, J ) 7.9 Hz, 1 H), 7.15-7.40 (m, 5 H);
13C NMR (100.6 MHz) δ 28.3 (3 CH3), 52.6 (CH3), 56.7 (CH),
73.3 (CH), 79.9 (C), 127.2 (2 CH), 128.1 (CH), 128.5 (2 CH),
136.7 (C), 155.0 (C), 172.3 (C); IR (KBr) 3387, 3362, 3038, 3024,
3008, 1722, 1693, 1234, 1172 cm-1; mass spectrum (CI) m/ z
313, 296 (MH+, 100%), 257, 240.
support from the CNRS (UMR 5616, URA 1410) and
Rhoˆne-Poulenc Rorer and a fellowship award from
Rhoˆne-Poulenc Rorer to S.J . are gratefully acknowl-
edged. Calculations were performed on an IBM RISC
SP2 supercomputer at the “Complexe de Calcul de
Saint-J e´roˆme” with the support of the “Re´gion Provence-
Alpes-Coˆte d’Azur”, whom we thank.
Su p p or tin g In for m a tion Ava ila ble: Details on the theo-
retical calcuations (6 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
Anal. Calcd for C15H21O5N: C, 61.00; H, 7.17; N, 4.74.
Found: C, 60.86; H, 7.10; N, 4.64.
Ack n ow led gm en t. We thank Prof. J . Lhomme and
Dr. E. Fouque for their interest in our work. Financial
J O971009V