Synthesis of C-3′ methyl taxotere (docetaxel)

Article abstract of DOI:10.1021/jo026460n

Protected (3R,4S)-N-Boc-3-hydroxy-4-methyl-4-phenylazetidin-2-one has been synthesized stereoselectively and used to esterify protected 10-desacetylbaccatin III to give, following removal of the protecting groups, novel C-3′ methyl taxotere (docetaxel).

Full text of DOI:10.1021/jo026460n

paper, the synthesis of C-3′ methyl taxotere (4) from
protected 10-desacetylbaccatin III (2) and protected
(3R,4S)-N-Boc-3-hydroxy-4-methyl-4-phenylazetidin-2-
one (3) is described (eq 1).3 The latter has been prepared
in enantiopure form through a novel Staudinger ketene-
ketimine cycloaddition reaction.
Syn th esis of C-3′ Meth yl Ta xoter e
(Doceta xel)
Christophe Lucatelli, Florian Viton, Yves Gimbert,* and
Andrew E. Greene*
LEDSS, Universite´ J oseph Fourier, Chimie Recherche,
BP 53X, 38041 Grenoble Cedex, France
yves.gimbert@ujf-grenoble.fr
Received September 19, 2002
Abstr a ct: Protected (3R,4S)-N-Boc-3-hydroxy-4-methyl-4-
phenylazetidin-2-one has been synthesized stereoselectively
and used to esterify protected 10-desacetylbaccatin III to
give, following removal of the protecting groups, novel C-3′
methyl taxotere (docetaxel).
Taxol (paclitaxel, 1a ), found naturally in different
species of Taxus, and taxotere (docetaxel, 1b), a semi-
synthetic analogue first prepared at ICSN in France, are
remarkable broad-spectrum cancer chemotherapeutic
agents that act by stabilizing microtubules, thus thwart-
ing mitosis.1
â-Lactams have proven highly popular as side-chain
equivalents for the synthesis of taxol and taxotere, as well
as numerous analogues,1 and therefore, extension of this
methodology for the synthesis of C-3′ methyl taxotere was
envisaged. The planned preparation of the appropriate
â-lactam was, however, uncertain since it required a
relatively unusual ketene-ketimine pairing in a [2 + 2]
Staudinger cycloaddition; moreover, it assumed that the
cycloaddition would proceed with a useful level of asym-
metric induction with a readily cleavable imine chiral
auxiliary, which was unprecedented for the creation of a
C-4 quaternary stereogenic center.4,5
The success of these two worldwide-marketed com-
pounds has been accompanied by a major search for
analogues with improved properties (inter alia: simpler
structures, higher water solubility, increased activity,
less tendency to induce multi-drug resistance). We have
previously reported2 the synthesis of C-2′ methyl taxotere
and the favorable effect of this methyl substituent on the
biological activity of the molecule in microtubule stabi-
lization and KB and KB-VI cytotoxicity assays. In this
Our successful route to the desired â-lactam, inspired
in part by the work of Commerc¸on6 and Lawrence,7 began
with commercially available (S)-(-)-1-(4-methoxyphenyl)-
ethylamine,8,9 which was smoothly converted with ac-
etophenone and p-toluenesulfonic acid in refluxing tolu-
(3) In view of the large number of diverse taxol and taxotere
derivatives published to date, it is surprising that this is apparently
the first example of substitution at C-3′.
(4) (a) Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of
â-Lactams; Georg, G. I., Ed.; VCH Publishers: New York, 1993; pp
295-368. (b) Palomo, C.; Aizpurua, J . M.; Garcia, J . M.; Galarza, R.;
Legido, M.; Urchegui, R.; Roma´n, P.; Luque, A.; Server-Carrio´, J .;
Linden, A. J . Org. Chem. 1997, 62, 2070-2079. (c) Palomo, C.;
Aizpurua, J . M.; Gamboa, I.; Oiarbide, M. Eur. J . Org. Chem. 1999,
3223-3235.
(5) For general reviews on asymmetric methods to create quaternary
centers and use of these methods in natural product synthesis, see:
Fuji, K. Chem. Rev. 1993, 93, 2037-2066. Corey, E. J .; Guzman-Perez,
A. Angew. Chem., Int. Ed. 1998, 37, 388-401 and references therein.
(6) Bourzat, J . D.; Commerc¸on, A. Tetrahedron Lett. 1993, 34, 6049-
6052.
(7) (a) Brown, S.; J ordan, A. M.; Lawrence, N. J .; Pritchard, R. G.;
McGown, A. T. Tetrahedron Lett.1998, 39, 3559-3562. (b) See also:
Bull, S. D.; Davies, S. G.; Kelly, P. M.; Gianotti, M.; Smith, A. D. J .
Chem Soc., Perkin Trans. 1 2001, 3106-3111.
* To whom correspondence should be addressed. Tel: (33)-4-76-51-
46-86. Fax: (33)-4-76-51-44-94.
(1) For reviews on the occurrence, biological properties, and syn-
theses of taxol, taxotere, and congeners, see: (a) Nicolaou, K. C.; Dai
W.-M.; Guy, R. K. Angew. Chem., Int. Ed. Engl. 1994, 33, 15-44. (b)
Georg, G. I.; Ali, S. M.; Zygmunt, J .; J ayasinghe, L. R. Exp. Opin. Ther.
Pat. 1994, 4, 109-120. (c) The Chemistry and Pharmacology of Taxol
and Its Derivatives; Farina, V., Ed.; Elsevier: Amsterdam, 1995. (d)
Taxol: Science and Applications, Suffness, M., Ed.; CRC Press: Boca
Raton, FL, 1995. (e) J enkins, P. Chem. Britain 1996, 32 (11), 43-46.
(f) Kingston, D. G. I. J . Nat. Prod. 2000, 63, 726-734. (g) Kingston,
D. G. I. J . Chem. Soc., Chem. Commun. 2001, 867-880.
(2) Denis, J .-N.; Fkyerat, A.; Gimbert, Y.; Coutterez, C.; Mantellier,
P.; J ost, S.; Greene, A. E. J . Chem Soc., Perkin Trans. 1 1995, 1811-
1815. See also: Ge´nisson, Y.; Massardier, C.; Gautier-Luneau, I.;
Greene, A. E. J . Chem Soc., Perkin Trans. 1 1996, 2869-2872. Kant,
J .; Schwartz, W. S.; Fairchild, C.; Gao, Q.; Huang, S.; Long, B. H.;
Kadow, J . F.; Farina, V.; Vyas, D. Tetrahedron Lett. 1996, 37, 6495-
6498. Ojima, I.; Wang, T.; Delaloge, F. Tetrahedron Lett. 1998, 39,
3663-3666. Barboni, L.; Lambertucci, C.; Ballini, R.; Appendino, G.;
Bombardelli, E. Tetrahedron Lett. 1998, 39, 7177-7180.
(8) Lancaster Synthesis, Bischheim-Strasbourg, France.
(9) Our earlier efforts with 1-phenylethylamine and 1-(2,6-dichlo-
rophenyl)ethylamine were unsuccessful: the â-lactam resulting from
the former could not be cleanly freed of the R-methylbenzyl group and
the acetophenone imine derived from the latter proved a poor ketene
partner in the Staudinger reaction.
10.1021/jo026460n CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/22/2002
9468
J . Org. Chem. 2002, 67, 9468-9470

SCHEME 1
prepared from 8a in 94% yield by treatment with Boc
anhydride in the presence of triethylamine and DMAP.
The esterification of the 7,10-ditroc derivative16 of 10-
desacetylbaccatin III (2) with â-lactam 8b to give ester
9 proved particularly challenging, undoubtedly due to the
additional steric impediment present in 8b, but was
finally achieved in moderate yield with sodium hexa-
methyldisilazide according to the Ojima protocol.17 Triple
deprotection of this ester with zinc-copper couple in
acetic acid16 then afforded C-3′ methyl taxotere (4) in 76%
yield following silica gel purification.
C-3′ methyl taxotere at 10 and 20 µM concentrations
displayed no activity in microtubule stabilization assays
(taxotere at 5 µM ) 100%). This surprising result
indicates that the C-3′ methyl may act to destabilize
certain favorable hydrophobically collapsed conforma-
tions, but caveats have been sounded on this type of
interpretation.1f,g
In summary, a Staudinger reaction has been used in
the preparation of the first example of a C-3′-substituted
taxol or taxotere derivative. While the biological results
with this derivative are disappointing, the present work
does serve to broaden the scope of the Staudinger reaction
by demonstrating it is possible to access valuable4b,5
enantiopure 4,4-disubstituted â-lactams through the use
of imines with cleavable chiral controllers.
ene to the known10 imine derivative 5 (Scheme 1). The
Staudinger reaction4 of this imine with acetoxyacetyl
chloride and triethylamine in dichloromethane produced
in high yield a separable 70:30 mixture11 of the 2S,3R
and the 2R,3S diastereomers, respectively, to the exclu-
sion of the 2 other possible isomers.12,13 That the major
isomer was in fact the 2S,3R (6) was established by X-ray
diffraction analysis of the corresponding alcohol,14,15
obtained by saponification.
Selective oxidative cleavage of the exocyclic nitrogen-
benzylic carbon bond could be cleanly effected by using
cerium ammonium nitrate (CAN) in aqueous acetonitrile
to provide in 87% yield the enantiopure â-lactam 7a . This
material was next treated with potassium hydroxide in
aqueous THF to obtain the corresponding alcohol 7b (87%
yield), which was converted into the ethoxyethyl (EE)
derivative 8a with ethyl vinyl ether and a catalytic
amount of methanesulfonic acid in THF (80% yield). The
â-lactam 8b for the upcoming esterification was easily
Exp er im en ta l Section
The reaction mixture was generally poured into water, and
the separated aqueous phase was then thoroughly extracted 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 pentane, dichloromethane, pyridine,
and triethylamine were distilled from calcium hydride.
N-[(1S)-1-(4-Meth oxyp h en yl)eth yl]-N-[(1E)-1-p h en yleth -
ylid en e]a m in e (5).10 A solution of 4.00 g (26.5 mmol) of (S)-
(-)-1-(4-methoxyphenyl)ethylamine, 3.20 g (26.6 mmol) of ace-
tophenone, and 0.015 g (0.08 mmol) of p-toluenesulfonic acid in
50 mL of toluene was stirred at reflux with removal of water
for 72 h. The cooled reaction mixture was treated with 4 mL of
an aqueous solution of saturated Na2CO3 and then extracted
with ether, which was washed with brine, dried over Na2SO4,
and filtered. Removal of the solvents and the small excess of
acetophenone under reduced pressure left 6.60 g of essentially
pure imine 5. The analytical sample was prepared by evaporative
distillation (ca. 130 °C, 0.1 Torr) of a small amount of this
(10) Gauthrie, R. D.; Hedrick, J . L. J . Am. Chem. Soc. 1973, 95,
2971-2977.
(11) For comparison, the imine from benzaldehyde and 1-phenyl-
ethylamine with acetoxyacetyl chloride has been reported to give
diastereomeric ratios of 60:40 and 75:25 (60 and 74% yields).6,7a
(12) For a recent discussion of the stereochemical outcome of the
Staudinger reaction, see: Arrieta, A.; Lecea, B.; Cossio, F. P. J . Org.
Chem. 1998, 63, 5869-5876. See also ref 4a,c.
material: mp 43-45 °C; [R]26 +39.4 (c 1.0, CHCl3); IR 1632
D
cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.41 (d, J ) 6.5 Hz, 3 H),
2.14 (s, 3 H), 3.66 (s, 3 H), 4.67 (q, J ) 6.5 Hz, 1 H), 6.74-7.70
(m, 9 H); 13C NMR (75.5 MHz, CDCl3) δ 15.9, 25.5, 55.7, 59.6,
114.2, 127.2, 128.0, 128.5, 129.7, 138.9, 142.0, 158.6, 163.6.
(2S,3R)-1-[(1S)-1(4-Meth oxyph en yl)eth yl]-2-m eth yl-4-oxo-
2-p h en yla zetid in -3-yl Aceta te (6). To a stirred solution of 4.80
g (19.0 mmol) of the above imine 5 and 6.80 mL (4.94 g, 48.8
mmol) of triethylamine in 60 mL of dichloromethane at 0 °C
was added dropwise 2.80 g (20.5 mmol) of acetoxyacetyl chloride,
and stirring was continued for 3 h at 0 °C and 12 h at 20 °C.
Water was then added, and the crude reaction product was
isolated with dichloromethane in the usual way and purified by
(13) In THF, the ratio was higher, but the yield was considerably
lower (83:17, 43%). Solvent effects on the ratio of diastereomers in the
Staudinger reaction have previous been noted. See, for example, ref
7a.
(14) Crystal data for C19NO3H21: orthorhombic, P212121, a ) 8.787-
(2) Å, b ) 10.580(1) Å, c ) 21.090(3) Å, V ) 1960.8(5) Å3, Z ) 4, dcalcd
) 1.197 mg/m3, F(000) ) 752, θ range 2.10-72°, 2229 measured
reflections, 2229 independent reflections, R(1) [I > 1.5σ(I)] ) 0.044,
wR2 [all data] ) 0.0468, GoF (all data) ) 1.887.
(15) The minor isomer was assigned the alternative “cis” configu-
ration (2R, 3S) from X-ray diffraction analysis. Crystal data for C21
-
NO4H23
:
monoclinic, P21, a ) 7.2889(7) Å, b ) 7.5705(6) Å, c )
(16) Se´nilh, V.; Gue´ritte, F.; Gue´nard, D.; Colin, M.; Potier, P. C.
R. Seances Acad. Sci., Ser. 2 1981, 293, 501-503 (troc ) 2,2,2-
trichloroethoxycarbonyl).
(17) Ojima, I.; Sun, C. M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kuduk,
S. Tetrahedron Lett. 1993, 34, 4149-4152.
15.566(2) Å, â ) 96.4(4)°, V ) 853.6(5) Å3, Z ) 2, dcalcd ) 1.211 mg/m3,
F(000) ) 332, θ range 2.63-30°, 10 043 measured reflections, 4544
[R(int) ) 0.09] independent reflections, R(1) [I > 3σ(I)] ) 0.0496, wR2
[all data] ) 0.0664, GoF (all data) ) 1.903.
J . Org. Chem, Vol. 67, No. 26, 2002 9469

medium-pressure chromatography on silica gel with 5-10%
ethyl acetate in pentane to afford 1.90 g (28%) of the minor
diastereomer, followed by 4.30 g (64%) of the major diastereomer
6: [R]25D -15.2 (c 1.0, CHCl3); IR 3012, 1752, 1730 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.48 (s, 3 H), 1.54 (d, J ) 7.2 Hz, 3 H), 1.76
(s, 3 H), 3.70 (s, 3 H), 4.40 (q, J ) 7.2 Hz, 1 H), 5.23 (s, 1 H),
6.72-7.24 (m, 9 H); 13C NMR (75.5 MHz, CDCl3) δ 20.3, 21.3,
22.6, 54.1, 55.8, 68.3, 83.4, 114.4, 128.3, 128.4, 128.5, 129.3,
134.0, 137.7, 159.6, 164.6, 170.0. Anal. Calcd for C21H23NO4: C,
71.37; H, 6.56; N, 3.96. Found: C, 71.45; H, 6.57; N, 4.03.
(3R,4S)-3-Hyd r oxy-4-m et h yl-4-p h en yl-1-[(1S)-1-p h en yl-
eth yl]a zetid in -2-on e (6′) (6, OH Rep la ces CH3CO2). A solu-
tion of 1.48 g (4.19 mmol) of acetate 6 in 245 mL of THF was
treated with 25 mL (25 mmol) of 1 M aqueous potassium
hydroxide and then stirred for 12 h at 20 °C. The crude product
was isolated with ethyl acetate in the usual manner and purified
by dry silca gel chromatography with 50% ethyl acetate in
hexane to afford 1.15 g (88%) of the corresponding alcohol 6′ as
a white solid: mp 193-195; [R]25D +141.2 (c 1.0, CHCl3); IR 3282,
1730 cm-1; 1H NMR (300 MHz, (CD3)2SO) δ 1.48 (d, J ) 7.0 Hz,
3 H), 3.29 (s, 3 H), 3.73 (s, 3 H), 4.41 (q, J ) 7.0 Hz, 1 H), 4.52
(d, J ) 6.8 Hz, 1 H), 5.81 (d, J ) 6.8 Hz, 1 H), 6.86-7.38 (m, 9
H); 13C NMR (75.5 MHz, (CD3)2SO) δ 22.4, 23.3, 53.2, 55.9, 69.2,
84.3, 114.4, 127.5, 128.2, 128.3, 129.2, 135.9, 140.8, 159.0, 169.0.
Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found:
C, 73.56; H, 6.76; N, 4.55.
(0.44 mmol) of acetal 8a , 0.400 mL (290 mg, 2.87 mmol) of
triethylamine, 450 mg (2.06 mmmol) of di-tert-butyl dicarbonate,
and a catalytic amount of DMAP in 4.0 mL of ethyl acetate was
stirred for 36 h. The reaction mixture was then processed with
ethyl acetate in the usual way and the crude product was
purified by dry silica gel (pretreated with 2.5% triethylamine
v/v) chromatography with 30% ethyl acetate in pentane to give
145 mg (94%) of acetal 8b as a yellow oil: [R]25 +71.3 (c 1.0,
D
CHCl3); IR 1812, 1730 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.93-
1.09 (m, 6 H), 1.32 (s, 9 H), 1.92 (s, 3 H), 3.16-3.65 (m, 3 H),
4.47-4.75 (m, 1 H), 7.30 (s, 5 H). Anal. Calcd for C19H27NO5:
C, 65.31; H, 7.79; N, 4.01. Found: C, 65.53; H, 7.86; N, 4.13.
2′-O-Eth oxyeth yl-3′-m eth yl-7,10-d itr oc Ta xoter e (9). To
a solution of 51 mg (0.057 mmol) of 7,10-ditroc-10-deacetylbac-
catin III in 0.105 mL of THF at -50 °C was added dropwise a
solution of 1 M NaHMDS in THF (0.063 mL, 0.063 mmol). The
reaction mixture was stirred for 0.5 h while the temperature
was allowed to reach -35 °C at which time a solution of 30 mg
(0.086 mmol) of â-lactam 8b was added. The reaction mixture
was allowed to warm to 0 °C over 0.5 h and was then processed
with ethyl acetate in the usual way. The crude product was
purified by dry silica gel (pretreated with 2.5% triethylamine
v/v) chromatography with 20% ethyl acetate in pentane to give
30 mg (42%) of ester 9 as a white solid: 1H NMR (300 MHz,
CDCl3) δ 1.07-1.29 (m, 8 H), 1.52 (m, 3 H), 1.75 (m, 3 H), 1.84
(m, 5 H), 1.91 (s, 2 H), 2.24 (s, 1.5 H), 2.31 (s, 1.5 H), 2.51 (m, 1
H), 3.22-3.53 (m, 1 H), 3.74 (m, 1 H), 4.06 (m,1 H), 4.22 (m, 2
H), 4.50 (m, 1 H), 4.69 (s, 2 H), 4.84 (m, 2 H), 5.41-5.65 (m, 2
H), 5.91 (br s, 1 H), 6.12 (d, J ) 4.7 Hz, 1 H), 7.11-8.09 (m, 10
H); mass spectrum (ES+), m/z 1266 (M + Na)+.
(2S,3R)-2-Meth yl-4-oxo-2-ph en ylazetidin -3-yl Acetate (7a).
A solution of 580 mg (1.64 mmol) of acetate 6 in 35 mL of 3:2
water-acetonitrile at 0 °C was treated with 2.70 g (4.92 mmol)
of cerium ammonium nitrate and then stirred for 4 h at this
temperature. The crude product was isolated with ethyl acetate
in the usual way and purified by dry silica gel chromatography
with 40% ethyl acetate in pentane to give 314 mg (87%) of lactam
3′-Meth yl Ta xoter e (4). A mixture of 30 mg (0.024 mmol) of
ester 9 and 240 mg (ca. 3.7 mmol) of Zn/Cu couple in 3.0 mL of
1:1 methanol-acetic acid was stirred for 1.5 h at 65 °C. The
reaction mixture was then processed with ethyl acetate in the
normal manner and the crude product was purified by prepara-
tive silica gel TLC with 5% methanol in dichloromethane to give
15 mg (76%) of 3′-methyl taxotere (4) as a white amorphous
7a as a yellow oil: [R]25 -14.5 (c 1.0, CHCl3); IR 3265, 1787,
D
1755 cm-1; H NMR (300 MHz, CDCl3) δ 1.69 (s, 3 H), 1.90 (s,
1
3 H), 5.52 (s, 1 H), 7.34 (s, 5 H), 7.62 (s, 1 H); 13C NMR (75.5
MHz, CDCl3) δ 20.3, 25.7, 64.2, 83.4, 126.8, 128.3, 128.6, 139.1,
165.3, 167.0. Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N,
6.39. Found: C, 65.67; H, 6.07; N, 6.27.
solid: [R]25 -30.4 (c 1.0, CHCl3); IR 3436, 1713 cm-1; 1H NMR
D
(300 MHz, CDCl3) δ 1.10 (s, 3 H), 1.22 (s, 3 H), 1.25 (s, 3 H),
1.42 (s, 9 H), 1.67-2.04 (m, 12 H), 2.28 (s, 3 H), 2.56 (m, 1 H),
3.83 (d, J ) 6.6 Hz, 1 H), 4.14-4.30 (m, 3 H), 4.62 (br s, 1 H),
4.92 (d, J ) 8.8 Hz, 2 H), 5.16 (s, 1 H), 5.52 (m, 1 H), 5.64 (d, J
) 6.9 Hz, 1 H), 5.97 (m, 1 H), 7.38 (m, 5 H), 7.51 (t, J ) 7.2 Hz,
2 H), 7.64 (t, J ) 7.2 Hz, 1 H), 8.07 (d, J ) 7.4 Hz, 2 H); 13C
NMR (75.5 MHz, CDCl3) δ 8.9, 13.2, 14.2, 19.8, 21.2, 25.5, 27.3,
28.6, 34.8, 35.9, 41.9, 45.3, 56.5, 60.9, 64.8, 70.4, 70.9, 73.4, 73.9,
76.7, 76.9, 77.9, 78.2, 79.7, 79.7, 83.1, 124.8, 126.6, 128.2, 129.1,
132.7, 134.5, 137.7, 141.0, 165.9, 169.3, 170.4, 210.4; mass
spectrum (ES+), m/z 822 (M+H)+; HRMS (ES+) m/z calcd for
C44H55NO14Na (M + Na)+ 844.3520, found 844.3521.
(3R,4S)-3-Hydr oxy-4-m eth yl-4-ph en ylazetidin -2-on e (7b).
A solution of 395 mg (1.80 mmol) of acetate 7a in 20 mL of THF
was treated with 3.5 mL (3.5 mmol) of 1 M aqueous potassium
hydroxide and then stirred for 12 h at 20 °C. The crude product
was isolated with ethyl acetate in the usual way to afford 277
mg (87%) of alcohol 7b as a white solid: mp 182 °C; [R]25D +15.3
(c 1.0, CHCl3); IR 3278, 1744 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.80 (s, 3 H), 4.69 (s, 1 H), 6.78 (s, 1 H), 7.34-7.42 (m, 5 H);
13C NMR (75.5 MHz, CDCl3) δ 26.5, 66.3, 84.6, 126.9, 128.4,
129.1, 164.2. Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N,
7.90. Found: C, 67.31; H, 6.26; N, 7.90.
(3R,4S)-3-(1-Eth oxyeth oxy)-4-m eth yl-4-p h en yla zetid in -
2-on e (8a ). To a solution of 100 mg (0.56 mmol) of alcohol 7b in
8.0 mL of THF at 0 °C was added 0.125 mL (94 mg, 1.31 mmol)
of ethyl vinyl ether and a catalytic amount of methanesulfonic
acid. The reaction mixture was stirred for 6 h, whereupon the
crude product was isolated with ethyl acetate in the normal way
and purified by dry silica gel (pretreated with 2.5% triethyl-
amine, v/v) chromatography with 30% ethyl acetate in pentane
Ack n ow led gm en t. We thank Dr. C. Philouze for the
X-ray structure determination, Drs. A. Commerc¸on and
C. Combeau for the bioassays, and Dr. C. Fontaine for
help with NMR interpretations. Financial support from
Universite´ J oseph Fourier and the CNRS (UMR 5616)
and a fellowship award from the MESR to C.L. are
gratefully acknowledged.
to afford 112 mg (80%) of acetal 8a as a yellow oil: [R]25 +56.7
D
(c 1.0, CHCl3); IR 3273, 1763 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.08 (m, 6 H), 1.77 (s, 3 H), 3.35 (m, 2 H), 4.69 (m, 2 H), 7.31
(s, 5 H). Anal. Calcd for C14H19NO3: C, 67.45; H, 7.68; N, 5.62.
Found: C, 67.02; H, 7.70; N, 5.43.
Su p p or tin g In for m a tion Ava ila ble: X-ray data for com-
pounds 6′ and 6 (2R, 3S). This material is available free of
charge via the Internet at http://pubs.acs.org.
ter t-Bu tyl (2S,3R)-3-(1-Eth oxyeth oxy)-2-m eth yl-4-oxo-2-
p h en yla zetid in e-1-ca r boxyla te (8b). To a solution of 110 mg
J O026460N
9470 J . Org. Chem., Vol. 67, No. 26, 2002