Asymmetric Michael addition using N-cinnamoyl- and N-crotonyl-trans- hexahydrobenzoxazolidin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2005.10.065

Preparation of N-cinnamoyl- and N-crotonyl-oxazolidin-2-ones 2 and 3 or ent-2 and ent-3 from (4S,5S)- and (4R,5R)-trans-hexahydrobenzoxazolidin-2-ones 1 or ent-1 are reported. Stereoselective copper promoted conjugated additions of Grignard reagents to ch

Full text of DOI:10.1016/j.tetlet.2005.10.065

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8649–8652
Asymmetric Michael addition using N-cinnamoyl- and
N-crotonyl-trans-hexahydrobenzoxazolidin-2-ones
a
a
a,
b,
*
*
´
`
Lydia Perez, Sylvain Bernes, Leticia Quintero and Cecilia Anaya de Parrodi
aCentro de Investigacio´n de la Facultad de Ciencias Quı´micas, Universidad Auto´noma de Puebla, 72570 Puebla, Mexico
bDepto. de Quı´mica y Biologı´a, Universidad de las Ame´ricas-Puebla, Santa Catarina Ma´rtir, 72820 Cholula, Mexico
Received 8 September 2005; revised 9 October 2005; accepted 17 October 2005
Abstract—Preparation of N-cinnamoyl- and N-crotonyl-oxazolidin-2-ones 2 and 3 or ent-2 and ent-3 from (4S,5S)- and (4R,5R)-
trans-hexahydrobenzoxazolidin-2-ones 1 or ent-1 are reported. Stereoselective copper promoted conjugated additions of Grignard
reagents to chiral N-enoyl amides 2 and 3 or ent-2 and ent-3 in the presence of Zn(II) salts afforded the 1,4-addition products 4–11
and the corresponding enantiomers.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Michael addition reactions represent one of the most
important carbon–carbon bond forming reactions in
modern synthetic organic chemistry.1 The asymmetric
1,4-addition reactions of organometallics into a,b-unsatu-
rated esters and amides have been demonstrated to
provide products in high chemical and stereochemical
purity, and represent a valuable transformation to
achieve chiral b-substituted carboxylic acids.2
The preparation of N-enoyl-oxazolidinones 2 and 3 or
ent-2 and ent-3 (Table 1) was performed by deprotona-
tion of the chiral auxiliaries 1 and ent-1 with NaH
(2.5 equiv) in THF at 25 ꢁC for 1 h.8 The acylating
agents (1.5 equiv, cinnamoyl- and crotonyl chloride)
were slowly added at 25 ꢁC and the reaction mixture
was stirred for 2h. The crude products were purified
by column chromatography on silica gel affording the
N-enoyl-amides 2 and 3 or ent-2 and ent-3 in 80–81%
yield (Table 1).
Organocopper reagents are among the most versatile
reagents available for conjugate addition reactions.3
Chiral catalysts4 and chiral auxiliaries5 have been used
efficiently for copper promoted asymmetric conjugated
additions of Grignard reagents.
Table 1. N-Acylation of trans-oxazolidin-2-ones 1 and ent-1
O
O
O
O
1. NaH (2.5 equiv)
THF, 25 oC, 1 h
2. RCH=CHCOCl
(1.5 equiv), THF
25 oC, 2 h
O
Recently, we reported a convenient procedure for the
preparation of (4S,5S)- and (4R,5R)-trans-hexahydro-
benzoxazolidin-2-ones 1 and ent-1 from inexpensive
cyclohexene oxide and (S)-a-phenylethylamine.6,7
N
N
H
1 or ent-1
2 or ent-2
3 or ent-3
We now report the preparation of N-cinnamoyl- and N-
crotonyl-amides 2 and 3 or ent-2 and ent-3,8 and the
asymmetric Michael addition reactions in the presence
of Grignard reagents, CuBr–DMS (dimethyl sulfide),
DMS, and Zn(II) salts.
R
Product Yield (%)a [a]D
b
Entry Oxazolidinone
R
1
2
3
4
1
Ph
CH3
Ph
2
81
81
80
80
+11.0
+7.4
1
3
ent-1
ent-1
ent-2
ꢀ10.9
CH3 ent-3
ꢀ7.0
a Yields were measured after purification by column chromatography
on silica gel [hexanes–EtOAc (6:1)].
b Optical rotations were measured in c 1.0, CHCl3.
*
Corresponding authors. Tel.: +52 222 229 2670; fax: +52 222 229
2419; e-mail: cecilia.anaya@udlap.mx
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.065

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L. Pe´rez et al. / Tetrahedron Letters 46 (2005) 8649–8652
Table 2. 1,4-Addition to (4S,5S,20E)-N-(cinnamoyl)- and N-(crotonyl)-oxazolidin-2-ones 2 and 3
O
N
O
1. CuBrS(CH3)2 (1.5 equiv), THF, –40 oC, 2 h
O
O
O
2. ZnX2 (0.3 equiv), R'MgBr (3 equiv), THF
–40 oC to 25 oC, 20 min
N
O
R = Ph; 2
R = Me; 3
R = Ph; 4 - 7
R = Me; 8 - 11
R'
R
R
Entry
Substrate
R0
ZnX2
Major producta
Yield (%)b
dr (R:S)c
d
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
3
3
3
3
3
Me
Me
Me
Me
Me
Et
n-Pr
n-Bu
Ph
Ph
Et
n-Pr
n-Bu
(4S,5S,30R)-4
(4S,5S,30R)-4e
(4S,5S,30R)-4
(4S,5S,30R)-4
(4S,5S,30R)-4
(4S,5S,30R)-5
(4S,5S,30R)-6
(4S,5S,30R)-7
(4S,5S,30S)-8
(4S,5S,30S)-8e
(4S,5S,30S)-9
(4S,5S,30S)-10
(4S,5S,30S)-11
40
75
7287:13
7279:19
70
81
80
76
44
75
79
76
78
78:22
91:9
ZnI2
ZnBr2
ZnCl2
Zn(CF3SO3)2
ZnI2
ZnI2
ZnI2
d
85:14
90:10
86:14
84:16
41:59
25:75
12:88
16:84
19:81
9
10
11
12
13
ZnI2
ZnI2
ZnI2
ZnI2
a Configuration of major products were assigned by chemical correlation with the corresponding carboxylic acids, by optical rotation and HPLC
analysis with a Chiralcel OD column, see Ref. 9.
b Yields were measured after purification by column chromatography on silica gel [hexanes–EtOAc (5:1)].
c Diastereoisomeric ratios were measured from 1H NMR spectra of crude products.
d Conjugated additions were performed in the absence of zinc salt.
e Assignments of absolute configuration were obtained by X-ray diffraction crystallography from suitable single crystals.
First, N-cinnamoyl-amide 2 (1 equiv) was added to
CuBr–DMS complex (1.5 equiv), followed by the addi-
tion of MeMgBr (3 equiv) in THF at ꢀ40 ꢁC, affording
(4S,5S,30R)-4 as the major diastereoisomer (Table 2,
entry 1). The 1,4-addition reaction gave low yield
(40%) and moderate diastereoisomeric ratio (78:22).
Then, improved yields (up to 75%) and diastereoiso-
meric ratios (up to 91:9) were obtained in the presence
of zinc salts (0.3 equiv): -chloride, -bromide, -iodide,
and -triflate (Table 2, entries 2–5). The best diastereoiso-
meric ratio was observed by adding ZnI2 (Table 2, entry
2). So, we proceeded to perform the conjugated addition
of other copper-promoted Grignard reagents to N-cin-
namoyl-oxazolidinone 2 employing Et-, n-Pr-, and n-Bu-
MgBr in the presence of ZnI2. The diastereoisomeric
ratios were measured on clearly resolved 1H NMR
signals of the crude reactions (Table 2, entries 7–9).
The crude products were purified by column chromato-
graphy on silica gel affording the conjugated addition
compounds 5–7 in good yields after column chromato-
graphy (76–81%).
Et-, n-Pr-, and n-BuMgBr in the presence of ZnI2. The
1,4-addition reactions afforded 9–11 in good yields after
column chromatography purification (Table 2, entries
11–13, 76–79% yield, and up to 12:88 dr).
Finally, we performed the conjugated addition reactions
to the enantiomers (4R,5R,20E)-N-cinnamoyl- and N-
crotonyl-oxazolidin-2-ones ent-2 and ent-3 using the
protocol already described. The Michael reactions affor-
ded ent-4–ent-11 (Table 3, entries 1–8, 74–81% yield, and
up to 10:90 dr).
Chemical correlation by basic hydrolysis of N-cinna-
moyl- and N-crotonyl-1,4-addition products 4–11 and
ent-4–ent-11 afforded the corresponding 3-phenyl- and
3-methyl-carboxylic acids, which were previously
reported in the literature, and the oxazolidinones 1
and ent-1 were recovered (81–90% yield).9
The products 4 and 8 (Table 2, entries 2and 10) were
recrystallized from hexanes–isopropanol (10:1). The
absolute configuration at the new stereogenic center in
both compounds were assigned by X-ray diffraction
analysis from suitable single crystals.10,11
The same methodology for the conjugated addition of
copper-promoted Grignard reagent was performed with
N-crotonyl amide 3 in the presence of PhMgBr. By the
same token, without ZnI2 afforded (4S,5S,30S)-8 as the
major diastereoisomer in low yield and poor diastereo-
isomeric ratio (Table 2, entry 9, 44% yield, dr 41:59).
Addition of ZnI2 to the reaction mixture increased both
yield and diastereoisomeric ratio (Table 2, entry 10, 75%
yield, 25:75). So, we proceeded to perform the conju-
gated addition to N-crotonyl-hexahydrobenzoxazol-
idin-2-one 3 of organocopper reagents formed with
As is well known, bulkier groups at position 4 of oxa-
zolidin-2-ones induced higher stereoselectivities on the
b-position of the double bond, that is: phenyl > tert-
butyl > isopropyl ꢁ benzyl.3 We compared the diastereo-
selectivities obtained with our oxazolidinones 2 and 3
in the absence of ZnI2 with other chiral auxiliaries,
and we observed that the results were only slightly better
than those reported with N-enoyl-4-benzyl-2-oxazolidi-

L. Pe´rez et al. / Tetrahedron Letters 46 (2005) 8649–8652
8651
Table 3. 1,4-Addition to (4R,5R,20E)-N-(cinnamoyl)- and N-(crotonyl)-oxazolidin-2-ones ent-2 and ent-3
O
O
N
1. CuBrS(CH3)2 (1.5 equiv), THF, –40 oC, 2 h
O
O
O
O
2. ZnI2 (0.3 equiv), R'MgBr (3 equiv), THF
N
–40 oC to 25 oC, 20 min
R= Ph; ent-2
R= Me; ent-3
R= Ph; ent-4 - ent-7
R= Me; ent-8 - ent-11
R'
R
R
Entry
Substrate
R0
Major producta
Yield (%)b
dr (R:S)c
1
2
3
4
5
6
7
8
ent-2
ent-2
ent-2
ent-2
ent-3
ent-3
ent-3
ent-3
Me
Et
n-Pr
n-Bu
Ph
Et
n-Pr
n-Bu
(4R,5R,30S)-ent-4
(4R,5R,30S)-ent-5
(4R,5R,30S)-ent-6
(4R,5R,30S)-ent-7
(4R,5R,30R)-ent-8
(4R,5R,30R)-ent-9
(4R,5R,30R)-ent-10
(4R,5R,30R)-ent-11
75
81
79
77
74
78
78
75
10:90
12:88
15:85
18:82
74:26
85:15
80:20
77:23
a Configuration of major products were assigned by chemical correlation with the corresponding carboxylic acids, by optical rotation and HPLC
analysis with a Chiralcel OD column, see Ref. 9.
b Yields were measured after purification by column chromatography on silica gel [hexanes–EtOAc (5:1)].
c Diastereoisomeric ratios were measured from 1H NMR spectra of crude products.
nones.3b,f However, in the presence of ZnI2, we observed
a substantial improvement on diastereoselectivities,
56, 8033–8061; (c) Feringa, B. L. Acc. Chem. Res. 2000,
33, 346–353; (d) Ramon, D.; Yus, M. Angew. Chem., Int.
Ed. 2005, 44, 1602–1634.
which were similar to those reported with N-enoyl-4-iso-
3. (a) Taylor, R. J. K.; Casy, G. In Organocopper Reagents–
propyl-2-oxazolidinones.3e We surmise that it is due to
A Practical Approach; Taylor, T. J. K., Ed.; Oxford
the chelation of Zn(II) with the carbonyl groups, so
the precomplexed Zn(II)/oxazolidinones seemed to react
in a syn-s-cis conformation.
´
University Press: Oxford, 1994; (b) Nicolas, E.; Russel, K.
C.; Hruby, V. J. J. Org. Chem. 1993, 58, 766–770; (c)
Bergdahl, M.; Iliefski, T.; Nilsson, M.; Olsson, T. Tetra-
hedron Lett. 1995, 36, 3227–3230; (d) Nakamura, E.; Mori,
S. Angew. Chem., Int. Ed. 2000, 39, 3750–3771; (e) Pollock,
P.; Dambacher, J.; Annes, R.; Bergdahl, M. Tetrahedron
Lett. 2002, 43, 3693–3697; (f) Dambacher, J.; Anness, R.;
Pollock, P.; Bergdahl, M. Tetrahedron 2004, 60, 2097–
2110; (g) Maezaki, N.; Sawamoto, H.; Suzuki, T.; Yoshi-
gami, R.; Tanaka, T. J. Org. Chem. 2004, 69, 8387–8398.
The study of stereoselective conjugated addition reac-
tions is an ongoing project in our laboratory. Prelimi-
nary results showed that Michael addition reactions to
trans-N-cinnamoyl- and N-crotonyloxazolidin-2-ones 2
and 3 or ent-2 and ent-3 in the presence of ZnI2
(0.3 equiv) proceed with good yields (75–81%) and good
diastereoisomeric ratios (up to 91:9). The configuration
of the new stereogenic center is based on the chiral auxi-
liaries 1 or ent-1 employed.
´
4. (a) Des Mazery, R.; Pullez, M.; Lopez, F.; Harutyunyan,
S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc.
2005, 127, 9966–9967; (b) Arink, A. M.; Braam, T. W.;
Keeris, R.; Jastrzebski, J. T. B. H.; Benhaim, C.; Rosset,
S.; Alexakis, A.; van Knoten, G. Org. Lett. 2004, 6, 1959–
1962.
5. (a) Qian, X.; Russel, K. C.; Boteju, L. W.; Hruby, V. J.
Tetrahedron 1995, 51, 1033–1054; (b) Wipf, P.; Takahashi,
H. Chem. Commun. 1996, 2675–2676; (c) Andersson, P.
G.; Schink, H. E.; Osterlund, K. J. Org. Chem. 1998, 63,
8067–8070; (d) Williams, D. R.; Kissel, W. S.; Li, J. J.
Tetrahedron Lett. 1998, 39, 8593–8596; (e) Schneider, C.;
Reese, O. Synthesis 2000, 1689–1694; (f) Dambacher, J.;
Bergdahl, M. Org. Lett. 2003, 5, 3539–3541.
Acknowledgments
This work was supported by CONACYT, Consejo Nac-
´
ional de Ciencia y Tecnologıa (Project No. V39500-Q
and Student Grant No. 134558).
6. (a) Anaya de Parrodi, C.; Juaristi, E.; Quintero, L.; Clara-
Sosa, A. Tetrahedron: Asymmetry 1997, 8, 1075–1082; (b)
References and notes
´
Anaya de Parrodi, C.; Clara-Sosa, A.; Perez, L.; Quintero,
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L.; Maranon, V.; Toscano, R. A.; Avina, J. A.; Rojas-
˜ ˜
Lima, S.; Juaristi, E. Tetrahedron: Asymmetry 2001, 12,
69–79.
1. (a) Oare, D. A.; Heathcock, C. H. Top. Stereochem. 1991,
20, 87–170; (b) Trost, B. M.; Fleming, I.. In Compre-
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1991; Vol. 4, pp 1–236; (c) Perlmutter, P. Conjugate
Addition Reactions in Organic Synthesis; Pergamon Press:
Oxford, UK, 1992; (d) Perlmutter, P. In Advances in
Asymmetric Synthesis; Stephenson, G. R., Ed.; Chapman
& Hall: London, UK, 1996; pp 222–230; (e) Krause, N.;
Hoffmann-Roeder, A. Synthesis 2001, 171–196.
7. For recent reviews on the use of (R)- and (S)-a-phenyl-
ethylamine in the preparation of enantiopure compounds,
´
see: (a) Juaristi, E.; Escalante, J.; Leon-Romo, J. L.;
Reyes, A. Tetrahedron: Asymmetry 1998, 9, 715–740; (b)
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Juaristi, E.; Leon-Romo, J. L.; Reyes, A.; Escalante, J.
Tetrahedron: Asymmetry 1999, 10, 2441–2495.
2. (a) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92,
771–806; (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000,
8. (a) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J.
Am. Chem. Soc. 1981, 103, 3099–3111; (b) Gage, J. R.;

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Evans, D. A. Org. Synth. 1990, 68, 83; (c) Ager, D. J.;
Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835–876.
assigned assuming that the configuration of the chiral
starting material was unchanged during the synthesis.
CCDC deposition number: 278745. Structure factors and
raw files are available on request to authors.
9. (a) Meyers, A. I.; Smith, R. K.; Whitten, C. E. J. Org.
Chem. 1979, 44, 2250–2256; (b) Overberger, C. G.; Cho, I.
J. Org. Chem. 1968, 33, 3321–3322; (c) Tomioka, K.;
Suenaga, T.; Koga, K. Tetrahedron Lett. 1986, 27, 369–
372; (d) Meyers, A.; Kamata, K. J. Org. Chem. 1974, 39,
1603–1604.
11. (4S,5S,30S)-3-(30-Phenylbutanoyl)-hexahydrobenzoxazoli-
din-2-one 8: The product was recrystallized from hexane:
isopropanol (10:1) affording the major diastereoisomer as
colorless crystals; mp 74–78 ꢁC, [a]D ꢀ12.3 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3/TMS) d: 7.17–7.24 (m, 5H),
3.78 (td, 1H, J = 11, J = 4), 3.60 (td, 1H, J = 11, J = 4),
3.36 (dd, 1H, J = 16, J = 6), 3.34 (m, 1H), 3.00 (dd, 1H,
J = 16, J = 6), 2.67 (m, 1H), 2.16 (m, 1H), 1.78 (m, 1H),
1.57 (qd, 2H, J = 12 ,J = 4), 1.30 (d, 3H, J = 8), 1.28 (m,
2H), 0.89 (qd, 1H, J = 12 , J = 4), 13C NMR (100 MHz,
CDCl3/TMS) d: 174.2, 154.7, 145.7, 128.4, 127.1, 126.4,
81.3, 63.0, 44.4, 36.8, 28.5, 28.4, 23.7, 23.5, 22.4; IR
(cmꢀ1): 2866, 2360, 1782, 1689, 1311, 1033, 759; MS (m/z):
287 (M+), 272, 183, 142, 118, 105; HRMS-FAB+
m/z found 288.1600 [(M+H)+ calcd 288.1599 for
C17H21NO3]. X-ray structure: Colorless needle, 0.60 ·
0.14 · 0.14 mm3, C17H21NO3. Monoclinic, P21, a =
10. (4S,5S,30R)-3-(30-Phenylbutanoyl)-hexahydrobenzoxa-
zolidin-2-one 4: The product was recrystallized from
hexane: isopropanol (10:1) affording the major diastereo-
isomer as colorless crystals; mp 72–74 ꢁC, [a]D +13.2( c
1.0, CHCl3); 1H NMR (400 MHz, CDCl3/TMS) d: 7.0–
7.28 (m, 5H); 3.61 (td, 1H, J = 11, J = 4), 3.44 (td, 1H,
J = 11, J = 4), 3.37 (dd, 1H, J = 16, J = 6), 3.34 (m, 1H),
3.00 (dd, 1H, J = 16, J = 6), 2.70 (m, 1H), 2.65 (m, 1H),
1.81 (m, 2H), 1.57 (qd, 1H, J = 12 , J = 4), 1.34 (d, 3H,
J = 8), 1.28 (m, 1H), 1.11 (qd, 2H, J = 12 , J = 4); 13C
NMR (100 MHz, CDCl3/TMS) d: 172.4, 155.2, 144.8,
128.4, 128.3, 127.2, 81.34, 63.0, 44.4, 36.9, 28.5, 28.4, 23.6,
23.5, 22.0; IR (cmꢀ1): 2866, 2360, 1782, 1689, 1311,
1033, 759. MS (m/z): 287 (M+), 272, 183, 142, 118, 105;
HRMS-FAB+ m/z found 288.1604 [(M+H)+ calcd
288.1600 for C17H21NO3]. X-ray structure: Colorless
plate, 0.60 · 0.24 · 0.16 mm3, C17H21NO3. Monoclinic,
˚
11.1885(14), b = 5.4166(6), c = 13.1885(15) A, b =
108.267(9)ꢁ, Z = 2 , qcalc = 1.257 g cmꢀ3. A set of 3033
reflections was collected using Mo-Ka radiation (k =
˚
0.71073 A), corresponding to 2hmax = 52.5ꢁ, and 1706
˚
P21, a = 10.5810(15), b = 5.4279(14), c = 13.743(2) A, b =
independent reflections (Rint = 0.029) were used for the
refinement of 191 parameters, without neither restraints
nor constraints (SHELXTL 5.10 package). H atoms were
placed in idealized positions and refined using a riding
model. Final R indices: R1 = 0.035 for 1379 reflections
with I > 2r(I) and wR2 = 0.092for all data. The absolute
configuration for the chiral centers was assigned assuming
that the configuration of the chiral starting material was
unchanged during the synthesis. CCDC deposition num-
ber: 278746. Structure factors and raw files are available
on request to authors.
95.936(11)ꢁ, Z = 2 , qcalc = 1.216 g cmꢀ3. A set of 3749
reflections was collected using Mo-Ka radiation
˚
(k = 0.71073 A), corresponding to 2hmax = 52.6ꢁ, and
1997 independent reflections (Rint = 0.050) were used for
the refinement of 191 parameters, without neither
restraints nor constraints (SHELXTL 5.10 package). H atoms
were placed in idealized positions and refined using a
riding model. Final R indices: R1 = 0.052for 1442
reflections with I > 2r(I) and wR2 = 0.151 for all data.
The absolute configuration for the chiral centers was