Highly diastereoselective alkylation, acylation and aldol condensation of cis- and trans-(N-acyloyl)hexahydrobenzoxazolidin-2-ones

Article abstract of DOI:10.1016/S0957-4166(00)00492-4

The potential of hexahydrobenzoxazolidinones 1a-d as chiral auxiliaries was explored. N-Acylation of 1a-d, 2a-d and 3a-d was followed by methylation and benzylation via the corresponding sodium enolates generated by treatment with NaHMDS. Diastereoselectivities of 98 percent or higher were observed. The absolute configuration of the newly created stereogenic center was established by chemical correlation with 2-benzyl-1-propanol. The stereochemical results are congruent with addition to the electrophile from the less hindered face of a (Z)-configured enolate, the sodium cation being coordinated by both carbonyl oxygens of the substrate, cis- and trans-N-Propionyl derivatives 2a-d were treated with Bu2BOTf/Et3N to give dialkylboron enolates 6a-d, which were then reacted with acetaldehyde and benzaldehyde. 1H and 13C NMR analyses showed the formation of a single diastereomeric aldol addition product, whose relative configuration was ascertained as syn from the measurement of the 3J_H(2),(H(3) coupling constants, and whose absolute configuration was determined by X-ray crystallographic analysis. The results are rationalized in terms of a Zimmerman-Traxler transition state, with a (Z)-configured enolate where boron is coordinated to the aldehyde carbonyl rather than the oxazolidinone carbonyl. Substrate 2a was also reacted with acyi chlorides via the sodium enolate (NaHMDS). The effect of reaction conditions on O- versus C-acylation, as well as the influence of solvent.

Full text of DOI:10.1016/S0957-4166(00)00492-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 69–79
Highly diastereoselective alkylation, acylation and aldol
condensation of cis- and
trans-(N-acyloyl)hexahydrobenzoxazolidin-2-ones
Cecilia Anaya de Parrodi,a,* Angel Clara-Sosa,a,b Lydia Pe´rez,a,b Leticia Quintero,b,*
Virginia Maran˜o´n,b,c Rube´n A. Toscano,d Judit A. Avin˜a,c Susana Rojas-Limae and
Eusebio Juaristic,*
aDepto. de Qu´ımica y Biolog´ıa, Universidad de las Ame´ricas-Puebla, Santa Catarina Ma´rtir, 72820 Cholula, Mexico
bCentro de Investigacio´n de la Fac. de Ciencias Qu´ımicas, Universidad Auto´noma de Puebla, 72570 Puebla, Mexico
cDepto. de Qu´ımica, Centro de Investigacio´n y de Estudios Avanzados del Instituto Polite´cnico Nacional, 07000 Mexico,
D.F., Mexico
dInstituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico, Ciudad Universitaria, 04510 Mexico, D.F., Mexico
eCentro de Investigaciones Qu´ımicas, Universidad Auto´noma del Estado de Hidalgo, 42076 Pachuca, Hidalgo, Mexico
Received 25 October 2000; accepted 27 November 2000
Abstract—The potential of hexahydrobenzoxazolidinones 1a–d as chiral auxiliaries was explored. N-Acylation of 1a–d, 2a–d and
3a–d was followed by methylation and benzylation via the corresponding sodium enolates generated by treatment with NaHMDS.
Diastereoselectivities of 98% or higher were observed. The absolute configuration of the newly created stereogenic center was
established by chemical correlation with 2-benzyl-1-propanol. The stereochemical results are congruent with addition to the
electrophile from the less hindered face of a (Z)-configured enolate, the sodium cation being coordinated by both carbonyl
oxygens of the substrate. cis- and trans-N-Propionyl derivatives 2a–d were treated with Bu2BOTf/Et3N to give dialkylboron
1
enolates 6a–d, which were then reacted with acetaldehyde and benzaldehyde. H and 13C NMR analyses showed the formation
of a single diastereomeric aldol addition product, whose relative configuration was ascertained as syn from the measurement of
3
the JH(2%)/H(3%) coupling constants, and whose absolute configuration was determined by X-ray crystallographic analysis. The
results are rationalized in terms of a Zimmerman–Traxler transition state, with a (Z)-configured enolate where boron is
coordinated to the aldehyde carbonyl rather than the oxazolidinone carbonyl. Substrate 2a was also reacted with acyl chlorides
via the sodium enolate (NaHMDS). The effect of reaction conditions on O- versus C-acylation, as well as the influence of solvent
and additives on diastereoselectivity, are discussed. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
One of the most practical methods for the enantioselec-
tive synthesis of chiral molecules involves the
diastereoselective alkylation of enolates, whose CꢀC
faces were rendered diastereotopic owing to the pres-
ence of chiral auxiliaries in the substrate.1 The use of
enantiomerically pure oxazolidin-2-one derivatives A
and B as chiral auxiliaries in such asymmetric processes
was first reported by Evans et al.2 and the enormous
utility of these and related oxazolidinones has been
amply demonstrated.3
In 1997 we reported4 a convenient procedure for the
preparation of both pairs of enantiomeric hexahy-
drobenzoxazolidin-2-ones 1a–d from inexpensive cyclo-
hexene oxide and (S)-a-phenylethylamine.5 We now
report the use of 1a–d as effective chiral auxiliaries for
the stereoselective alkylation, acylation, and aldol con-
densation of propionic and hydrocinnamic acids.
* Corresponding authors. E-mail: anaya@mail.udlap.mx; lquinter@
siu.cen.buap.mx; juaristi@relaq.mx
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00492-4

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C. Anaya de Parrodi et al. / Tetrahedron: Asymmetry 12 (2001) 69–79
2. Results and discussion
2 and 3 with NaHMDS, at −78°C in THF, and alkyla-
tion performed at −78°C“rt, using 3–5 equivalents of
electrophile. Assessment of diastereomeric product
ratios (dr) was achieved by high resolution (400 MHz)
1H NMR spectroscopic analysis of the crude products.
As summarized in Tables 1 and 2, a single alkylated
product was obtained with ds]98%.
cis- and trans-Hexahydrobenzoxazolidinones 1a–d were
N-acylated following the established protocol,6 by
treatment with n-butyllithium at 0°C, followed by addi-
tion (−78°C) of propionyl chloride to generate the
N-propionyl derivatives 2a–d (83–99% yield)4 and of
hydrocinnamoyl chloride to give 3a–d (98–99% yield)
(Scheme 1).
The absolute configuration of the newly created stereo-
genic center at C(2%) in products cis- and trans-4 was
established by means of chemical correlation with 2-
benzyl-1-propanol. Thus, reduction of (4S,5S,2%R)-4
with LiAlH4 afforded (R)-2-benzyl-1-propanol, (R)-5
{[h]2D5=+10.9 (c=2.0, C6H6); lit.3j [h]D=+11.1 (c=1.25,
C6H6)}, in 90% yield. Similarly, (4R,5R,2%S)-4,
(4R,5S,2%R)-4 and (4S,5R,2%S)-4 were correlated with
(S)-5, (R)-5 and (S)-5, respectively.
2.1. Part A. Diastereoselective alkylation of 2a–d and
3a–d
The alkylation of 2a–d with benzyl bromide, and the
alkylation of 3a–d with iodomethane proceeded with
very high diastereoselectivity, showing the potential of
oxazolidinones 1 in asymmetric synthesis (Scheme 2).
Enolates 2-Na and 3-Na were prepared by treatment of
Scheme 1. Conditions: i, n-BuLi/THF, 0°C, 30 min. ii, CH3CH2COCl or PhCH2CH2COCl, −78°C, 1 h.
Scheme 2. Conditions: i, NaHMDS (2 equiv.)/THF, −78°C, 30 min. ii, PhCH2Br (3–5 equiv.)/THF, −78°C“rt, 6+24 h. iii, CH3I
(3–5 equiv.) THF, −78°C“rt, 6+24 h.

C. Anaya de Parrodi et al. / Tetrahedron: Asymmetry 12 (2001) 69–79
71
Table 1. Diastereoselectivity of alkylation of trans-N-acylated hexahydrobenzoxazolidin-2-onesa
Entry
Substrate (2 or 3)
R2X
Productb
4
Yield (%)
[h]D
4
Dsc (%)
1
2
3
4
(4S,5S)-2a
(4R,5R)-2b
(4S,5S)-3a
(4R,5R)-3b
BnBrd
BnBrd
CH3I
CH3I
(4R,5S,2%R)
(4R,5R,2%S)
(4S,5S,2%S)
(4R,5R,2%R)
41
40
80
78
−52.3
+53.9
+68.8
−68.3
\98
\98
\98
\98
a For conditions, see Scheme 2.
b Configuration at C(2%) established by chemical correlation. See text.
c Single diastereomeric product detected by 1H NMR spectroscopy.
d Bn=benzyl.
Table 2. Diastereoselectivity of alkylation of cis-N-acylated hexahydrobenzoxazolidin-2-onesa
Entry
Substrate (2 or 3)
R2X
Productb
4
Yield (%)
[h]D
4
Dsc (%)
1
2
3
4
(4S,5R)-2c
(4R,5S)-2d
(4S,5R)-3c
(4R,5S)-3d
BnBrd
BnBrd
CH3I
CH3I
(4S,5R,2%R)
(4R,5S,2%S)
(4S,5R,2%S)
(4R,5S,2%R)
31
34
78
75
+21.1
−20.0
+76.5
−78.2
\98
\98
\98
\98
a For conditions, see Scheme 2.
b Configuration at C(2%) established by chemical correlation. See text.
c Single diastereomeric product detected by 1H NMR spectroscopy.
d Bn=benzyl.
Scheme 3. Conditions: i, NaHMDS (2 equiv.)/THF, −78°C, 30 min. ii, R2X=PhCH2Br or CH3I (3–5 equiv.)/THF, −78°C,
rt“6+24 h. iii, LiAlH4/THF, 25°C, 3 h.

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C. Anaya de Parrodi et al. / Tetrahedron: Asymmetry 12 (2001) 69–79
The results collected in Tables 1 and 2 are consistent
with the intermediacy of (Z)-configured enolates7 where
the sodium cation is chelated by both carbonyl oxy-
gens, and the electrophile is incorporated from the less
sterically hindered face of the enolate (Scheme 3).
synthesis of b-hydroxy carbonyl segments.3g,8
cis- and trans-Oxazolidin-2-ones 2a–d were treated with
n-Bu2BOTf and triethylamine to afford boron enolates
6a–d, which were then reacted with acetaldehyde and
1
benzaldehyde. H and 13C NMR analysis of the crude
Analysis of the data collected in Tables 1 and 2 also
demonstrates that it is the configuration at C(4) in the
substrate oxazolidinone that dictates the relative reac-
tivity of the diastereotopic faces in the derived eno-
late—the chirality center at C(5) playing an
inconspicuous role as stereodirecting moiety. Thus,
both the cis and trans isomers of the auxiliary with, say,
(R)-configuration at C(4) are complementary in their
stereoinducing capacity to either the cis or trans isomer
of the (S)-configured hexahydrobenzoxazolidinones.
products showed the presence of a single diastereoiso-
meric aldol addition product 7; the results from these
experiments are summarized in Table 3.
The syn relative configuration for all aldol products 7
1
was established from the observed H NMR coupling
constants for the vicinal protons at the newly created
stereogenic centers.2a,d,9 Indeed, as can be seen in Table
3
4, JH(2%)/H(3%) for all products 7 fall in the range of
2.9–4.4 Hz, which is consistent with expected values for
syn configuration. (By contrast, anti diastereomers
3
2.2. Part B. Diastereoselective aldol addition reaction
of 2a–d with aldehydes
exhibit coupling constants JH(2%)/H(3%)=7–9 Hz.2a,d,9
)
The aldol reaction is one of the most useful reactions of
enolates, being a powerful tool for the stereoselective
The assignment of the absolute configuration in aldol
products 7 was possible by means of X-ray diffraction
Table 3. Diastereoselectivity of the aldol reaction of boron enolates 6a–d with acetaldehyde and benzaldehydea
Starting oxazolidinone
RCHO
Yield (%)
Dsb (%)
Relativec configuration
Absoluted configuration
[h]D 7
2a, trans-(4S,5S)
2a, trans-(4S,5S)
2b, trans-(4R,5R)
2b, trans-(4R,5R)
2c, cis-(4S,5R)
2c, cis-(4S,5R)
2d, cis-(4R,5S)
2d, cis-(4R,5S)
CH3CHO 65
PhCHO 60
CH3CHO 60
PhCHO 70
CH3CHO 60
PhCHO 70
CH3CHO 60
PhCHO 70
]98
]98
]98
]98
]98
]98
]98
]98
syn
syn
syn
syn
syn
syn
syn
syn
(4S,5S,2%S,3%R)
(4S,5S,2%S,3%S)
(4R,5R,2%R,3%S)
(4R,5R,2%R,3%R)
(4S,5R,2%S,3%R)
(4S,5R,2%S,3%S)
(4R,5S,2%R,3%S)
(4R,5S,2%R,3%R)
+51.0
+20.1
−50.8
−20.1
+78.0
+70.1
−77.3
−71.2
a Conditions: i, Bu2BOTf (1.2 equiv.)/Et3N, CH2Cl2, −78°C“rt, 30 min. ii, RCHO (2.0 equiv.), −78°C, 5.5 h, then H2O2, 1.5 h.
b Single diastereomeric product detected by 1H and 13C NMR.
3
c From JH(2%)/H(3%); see text.
d By chemical correlation and/or X-ray structure determination.
Figure 1. Structure and solid-state conformation of (4R,5R,2%R,3%R)-N-(3-hydroxy-2-methyl-3-phenylpropionyl)hexahydrobenz-
oxazolidin-2-one.

C. Anaya de Parrodi et al. / Tetrahedron: Asymmetry 12 (2001) 69–79
73
Figure 2. Structure and solid-state conformation of (4S,5R,2%S,3%R)-N-(3-hydroxy-2-methylbutanoyl)hexahydrobenzoxazolidin-2-
one.
Table 4. 1H NMR coupling constants between H(2%) and
H(3%) in aldol products 7
The absolute configuration of the enantiomeric products,
(4S,5S,2%S,3S)-7 and (4R,5S,2%R,3%S)-7, was assigned on
the basis of the observed physical properties (similar
melting point, opposite sign of optical rotation) and
1
spectroscopic properties (identical H and 13C NMR).
Since the syn relative configuration for all aldol products
7 had been determined (see Table 3), and because
electrophilic addition takes place on the less hindered
face of the enolate (see Table 3), the absolute configura-
tion of the remaining aldol products in Table 3 could then
be assigned with some confidence.
Aldol product l H(2%) (ppm) l H(3%) (ppm) 3JH(2%)/H(3%)
7
(Hz)
The observed stereoselectivity in the formation of aldol
products 7 (Table 3) can be rationalized in terms of a
six-membered cyclic, Zimmerman–Traxler-type transi-
tion state. Scheme 4 includes a reasonable model for an
illustrative example, the addition of (Z)-configured7
boron enolate (4S,5S)-2a-BBu2 to acetaldehyde, afford-
ing (4S,5S,2%S,3%R)-7. It can be appreciated that the more
reactive (less sterically hindered) Re face of the enolate
adds to the Si face of the aldehyde, so that the methyl
group adopts a pseudoequatorial position (Scheme 4).
(4S,5S,2%S,3%R) 3.59
(4S,5S,2%S,3%S) 4.03
(4R,5R,2%R,3%S) 3.67
(4R,5R,2%R,3%R) 4.03
4.06
5.20
4.15
5.20
2.9
2.9
2.9
2.9
(4S,5R,2%S,3%R) 3.64
(4S,5R,2%S,3%S) 4.01
(4R,5S,2%R,3%S) 3.62
(4R,5S,2%R,3%R) 4.02
4.36
5.02
4.34
5.01
3.0
4.4
3.0
4.4
structure determination of (4R,5R,2%R,3%R)-7 and
(4S,5R,2%S,3%R)-7, which correspond to the addition
products between trans-(4R,5R)-2b and benzaldehyde,
and between cis-(4S,5R)-2c and acetaldehyde (Figs. 1
and 2).10
2.3. Part C. Diastereoselective C-acylation reaction of
trans-(4S,5S)-2a-Na
Although the acylation reaction of enolates containing
chiral oxazolidinone auxiliaries has been less exploited
Scheme 4.

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C. Anaya de Parrodi et al. / Tetrahedron: Asymmetry 12 (2001) 69–79
Table 5. C- versus O-acylation in the reaction of 2a-Na with acetyl chloride under various reaction conditions
Entry
CH3COCl:THF
Time of addition (min)
Temp. (°C)
C- versus O-acylation
1
2
3
3:97
3:97
100:0
10
1
0
−78
−78
−40
18:82
54:41
89:11
Figure 3. Structure and solid-state conformation of (4S,5S)-N-[1-acetoxy-(1Z)-propenyl]hexahydrobenzoxazolidin-2-one.
than the analogous asymmetric alkylation and aldol
additions, it has been shown to be an efficient means
for the enantioselective formation of chiral 1,3-dicar-
bonyl derivatives.3i,11,12 In the present study, trans-
(4S,5S)-N-(propionyl)hexahydrobenzoxalidin-2-one 2a
was metallated with NaHMDS,13 and the resulting
enolates were then treated with various acyl chlorides
(vide infra).
The (Z)-configuration in O-acylated derivative 8 was
established by means of X-ray crystallography (Fig. 3)
and is in line with expectation of relative steric hin-
drance due to allylic A1,3 strain.7
With suitable conditions for the C-acylation of enolate
2a-Na, we proceeded to explore solvent and additive
effects on the diastereoselectivity of the reaction. To
1
this end, crude reaction products were analyzed by H
A critical issue, not always addressed in other publica-
tions in this field, is the question of O- versus C-acyla-
tion of the enolate. In our hands, when the enolate
from oxazolidinone 2a and 1.0 M NaHMDS, in THF
solution, was treated with dilute CH3COCl (slow addi-
tion), most of the reaction proceeded to afford the
O-acylated product (entry 1, Table 5). The ratio of C-
versus O-acylation improved when the dilute solution
of acetyl chloride in THF was added rapidly to the
enolate solution (entry 2, Table 5) and synthetically
useful C-regioselectivity was achieved when neat acetyl
chloride was rapidly added to the enolate (entry 3,
Table 5).
NMR spectroscopy. Most useful was the chemical shift
for H(2%)—the major diastereomeric product consis-
tently appearing at lower field (l=4.6–4.8 ppm) relative
to the minor isomer (l=4.2–4.3 ppm) (Table 6).14
In THF solvent addition of MgCl2 or MgBr2 to the
reaction had a detrimental effect both on regioselectiv-
ity and diastereoselectivity (entries 2 and 3, Table 6) of
the reaction. Similarly, addition of 4-N,N-dimethyl-
aminopyridine (DMAP) reduced the regioselectivity
from an 82:18 ratio in favor of C-acylation, to a 45:55
ratio, with a slight predominance of O-acylation (entry
4 in Table 6).

C. Anaya de Parrodi et al. / Tetrahedron: Asymmetry 12 (2001) 69–79
75
Table 6. Solvent and additive effects on the diastereoselectivity in the C-acylation of 2a-Na with acetaldehyde (neat)
Entry
Solvent
Additive
C- versus O-acylation
(2%R):(2%S) ratio
1
2
3
4
5
6
THF
THF
THF
THF
CH2Cl2
CH2Cl2
–
82:18
46:54
4:96
45:55
99:1
89:11
58:42
60:40
99:1
99:1
97:3
MgCl2
MgBr2
DMAPa
–
DMAPa
97:3
a DMAP=4-dimethylaminopyridine.
Figure 4. Structure and solid-state conformation of (4S,5S,2%R)-N-(2-acetyl-1-propionyl)hexahydrobenzoxazolidin-2-one.
By contrast, the acylation reaction in CH2Cl2 solvent
was both highly regio- and diastereoselective, affording
(4S,5S,2%R)-9 as the only product (entry 5 in Table 6).
In the presence of DMAP, both the regio- and
diastereoselectivity dropped slightly, from 99 to 97%
(entry 6, Table 6).
Table 7. Diastereoselectivity in the C-acylation of 2a-Na with various acyl chlorides in CH2Cl2 solvent
Entry
RCOCl
C:O Acylation ratio
(2%R):(2%S) ratio
Total yield (%)
1
2
3
4
5
CH3COCl
EtCOCl
(CH3)2CHCOCl
PhCOCl
99:1
94:6
93:7
70:30
97:3
99:1
99:1
43:57
48:52
44:56
87
90
85
93
91
PhCH2COCl

76
C. Anaya de Parrodi et al. / Tetrahedron: Asymmetry 12 (2001) 69–79
The assignment of the absolute configuration in the main
product was achieved by X-ray diffraction analysis (Fig.
4). The (R)-configuration at C(2%) is in accord with a
reaction pathway involving addition on the less hindered
face of the enolate; that is, the Si face (cf. Scheme 3 and
Table 6).
112, 97, 81, 74, 57 (base peak), 29. C16H19NO3 (273) calc.
70.33% C, 6.96% H; found 70.40% C, 7.03% H.
4.1.2. (4R,5R)-3b. 0.25 g (98% yield) as white crystals,
1
mp 134–135°C, [h]D25=+78.1 (c=1, CHCl3). H NMR,
13C NMR, IR and mass spectrum similar to those
described for (4S,5S)-3a.
Finally, several other acyl chlorides were used as elec-
trophiles in the acylation reaction of 2a-Na. In contrast
with the observations of Koell and Luetzen,3i we find
that increasing the steric bulk of the acyl group leads to
lower diastereoselectivities (Table 7).
4.1.3. (4S,5R)-3c. 0.26 g (99% yield) as white crystals, mp
60–61°C, [h]2D5=+60.5 (c=1, CHCl3). 1H NMR (400
MHz, CDCl3/TMS) l 1.23 (m, 2H), 1.40 (m, 1H), 1.62
(m, 3H), 2.15 (m, 1H), 2.30 (m, 1H), 2.95 (m, 2H), 3.20
(m, 2H), 4.31 (m, 1H), 4.48 (m, 1H), 7.10–7.30 (m, 5H).
13C NMR (100 MHz, CDCl3/TMS) l 19.0, 20.8, 26.2,
27.1, 30.3, 37.1, 53.7, 74.4, 126.1, 128.4, 128.5, 140.5,
153.7, 172.2. IR (cm−1): 1803.2, 1693.5. Mass (m/z): 197
(molecular ion), 169, 152, 142, 112, 97, 81, 74, 57 (base
peak), 29. C16H19NO3 (273) calc. 70.33% C, 6.96% H;
found 70.25% C, 6.80% H.
3. Conclusions
The high diastereoselectivities observed in the alkylation
reactions of oxazolidinones 2a–d and 3a–d as well as the
high diastereoselectivity found in aldol condensation
reactions of dialkylboron enolates 6a–d demonstrate the
potential of hexahydrobenzoxazolidinones 1a–d as chiral
auxiliaries. Appropriate selection of reaction conditions
(addition order, solvent and presence/absence of addi-
tives) also results in the highly diastereoselective acyla-
tion of 2a (Part C).
4.1.4. (4R,5S)-3d. 0.26 g (99% yield) as white crystals,
mp 58–59°C, [h]2D5=−59.7 (c=1, CHCl3). 1H NMR, 13
C
NMR, IR and mass spectra similar to those described
for (4S,5R)-3c.
4.2. cis- and trans-N-(2%-Benzyl-propionyl)hexahydro-
benzoxazolidin-2-ones (4). General procedure
4. Experimental15
A dry two-necked flask fitted with a magnetic stirrer,
dropping funnel and a low-temperature thermometer
was charged with a mixture of 2 or 3 (0.25 mmol) in THF
(5 mL) under argon. The solution was cooled to −78°C
in an acetone/dry ice bath before the dropwise addition
of a precooled solution of NaHMDS (1 M, hexane, 0.50
mmol). After 45 min at −78°C a precooled solution of
benzyl bromide or methyl iodide (0.75–1.25 mmol) in
THF (5 mL) was added dropwise. The reaction mixture
was stirred during 45 min, and then allowed to warm up
to rt for 4–24 h before quenching with a saturated
solution of NH4Cl (5 mL). Water (25 mL) was added
and the organic material was extracted with CH2Cl2
(3×25 mL), dried with anhydrous Na2SO4, filtered and
evaporated. The crude product was purified by flash
chromatography (petroleum ether/ethyl acetate, 4:1) to
yield 4.
4.1. 3H-Hexahydrobenzoxazolidin-2-ones (1a–d), see
Ref. 4. N-(Propionyl)hexahydrobenzoxazolidin-2-ones
(2a–d), see Ref. 4. N-(Hydrocinnamoyl)hexahydro-
benzoxazolidin-2-ones (3a–d); general procedure
A dry two-necked flask fitted with a magnetic stirrer, a
dropping funnel and a low-temperature thermometer,
was charged with a mixture of 1 (0.14 g, 1 mmol) in THF
(20 mL) under argon. The solution was cooled to 0°C in
an ice bath before the dropwise addition of a precooled
solution on n-BuLi (0.65 mL, 1.6 M in hexane). After 30
min the mixture was cooled to −78°C with an acetone/
dry ice bath, and then a precooled solution of hydrocin-
namoyl chloride (0.17 g, 1.0 mmol) in THF (5 mL) was
added dropwise. The reaction mixture was stirred and
allowed to warm to rt and quenched with a saturated
aqueous solution of NH4Cl (5 mL). Water (25 mL) was
added and the organic material was extracted with
CH2Cl2 (3×25 mL), dried with anhydrous Na2SO4,
filtered and evaporated. The crude product was purified
by flash chromatography (hexane/ethyl acetate, 5:1) to
give compounds 3.
4.2.1. (4S,5S,2%R)-4. 0.057 g (41% yield) as white crys-
tals, mp 62–63°C, [h]2D5=−53.3 (c=1, CHCl3). 1H NMR
(400 MHz, CDCl3) l 0.9 (m, 1H), 1.0 (m. 1H), 1.1 (d,
3J=7.0 Hz, 3H), 1.8 (m, 2H), 2.2 (m, 1H), 2.6 (m, 1H),
2.8 (dd, 2J=13.56 Hz, 3J=8.44 Hz, 1H), 2.9 (dd,
2J=13.56 Hz, 3J=8.4 Hz, 1H), 3.4 (m, 2H), 4.0 (m, 1H),
7.2–7.3 (m, 5H). 13C NMR (100 MHz, CDCl3/TMS) l
17.1, 23.6, 23.8, 28.2, 40.5, 41.5, 63.0, 63.8, 81.2, 126.5,
128.0, 129.0, 139.9, 154.3, 178.5. IR (cm−1): 1784.3,
1701.3. Mass (m/z): 287 (molecular ion), 243, 228, 174,
142, 118 (base peak), 91, 74, 55, 41. C17H21NO3 (287.4)
calc. 71.05% C, 7.37% H; found 70.97% C, 7.40% H.
4.1.1. (4S,5S)-3a. 0.26 g (99% yield) as white crystals, mp
1
135–136°C, [h]2D5=−77.3 (c=1, CHCl3). H NMR (400
3
MHz, CDCl3/TMS) l 1.40 (m, 3H), 1.64 (dq, J=7.00
2
Hz, J=4.40 Hz, 1H), 1.83 (m, 1H), 1.92 (m, 1H), 2.21
3
(dd, J=2.16 Hz, 1H), 2.80 (m, 1H), 3.0 (m, 2H), 3.15
3
2
(m, 1H), 3.27 (m, 1H), 3.53 (dt, J=3.28 Hz, J=10.96
Hz, 1H), 3.81 (dt, 3J=3.68 Hz, 2J=11.30 Hz, 1H),
7.21–7.27 (m, 5H). 13C NMR (100 MHz, CDCl3/TMS)
l 23.6, 23.8, 28.5, 28.8, 30.5, 38.0, 63.2, 77.4, 126.3,
128.5, 128.6, 140.6, 155.0, 174.6. IR (cm−1): 1793.9,
1687.2. Mass (m/z): 197 (molecular ion), 169, 152, 142,
4.2.2. (4R,5R,2%S)-4. 0.056 g (40% yield) as white crys-
tals, mp 59–60°C, [h]2D5=+53.9 (c=1, CHCl3). 1H NMR,
13C NMR, IR and mass spectra similar to those
described for (4S,5S,2R)-4.

C. Anaya de Parrodi et al. / Tetrahedron: Asymmetry 12 (2001) 69–79
77
4.2.3. (4S,5S,2%S)-4. 0.11 g (80% yield) as white crystals,
mp 60–61°C, [h]D25=+68.8 (c=1, CHCl3). 1H NMR
was cooled to 0°C in an ice water bath before the
dropwise addition of precooled solution of
a
3
(400 MHz, CDCl3/TMS) l 1.15 (d, J=6.96 Hz, 3H),
(4S,5S,2%R)-4 (100 mg, 0.35 mmol) in THF (5 mL). The
reaction mixture was stirred and allowed to warm up to
rt for 3 h and quenched with a saturated solution of
NH4Cl (5 mL). Water (25 mL) was added and the
organic material was extracted with CH2Cl2 (3×25 mL),
dried with anhydrous Na2SO4, filtered and evaporated,
to afford (R)-5 in 95% crude yield. The crude product
was purified by flash chromatography (petroleum ether/
ethyl acetate, 6:1) to give (R)-5 (0.04 g, 90%), [h]2D5=+
10.9 (c=2.0, C6H6) [lit.16 [h]D25=+11.1 (c=1.25, C6H6)].
1.38 (m, 3H), 1.62 (d, 3J=11.7 Hz, 1H), 1.85 (dd,
2
3
3J=6.0 Hz, J=8.8 Hz, 1H), 1.92 (d, J=8.0 Hz, 1H),
2.22 (d, 3J=11.76 Hz, 1H), 2.55 (dd, 2J=13.56 Hz,
3J=8.40 Hz, 1H), 2.82 (m, 1H), 3.13 (dd, J=7.7 Hz,
3
2J=13.56 Hz, 1H), 3.52 (dt, 2J=10.96 Hz, 3J=1.64 Hz,
2
3
1H), 3.85 (dt, J=11.72 Hz, J=3.64 Hz, 1H), 3.99 (m,
1H), 7.17–7.29 (m, 5H). 13C NMR (100 MHz, CDCl3/
TMS) l 17.6, 23.6, 23.8, 28.5, 28.9, 38.5, 40.5, 63.2,
81.3, 126.2, 128.3, 129.4, 139.6, 154.0, 178.9. IR (cm−1):
1784.3, 1701.3. Mass (m/z): 287 (molecular ion), 243,
228, 174, 142, 118 (base peak), 91, 74, 55, 41.
C17H21NO3 (287.4) calc. 71.05% C, 7.37% H; found
71.08% C, 7.25% H.
4.2.10. (S)-2-Benzyl-1-propanol, (S)-5. Following the
same procedure described for the preparation of (R)-5,
100 mg (0.35 mmol) of (4R,5R,2%S)-4 was reduced with
LiAlH4 (13 mg, 0.70 mmol) to afford (S)-5 (40 mg, 90%
yield), [h]D25=−10.2 (c=1, C6H6) [lit.16 [h]2D5=+11.1 (c=
1.25, C6H6) for the (R) enantiomer]. 1H NMR (400
MHz, CDCl3/TMS) l 0.9 (d, J=6.6 Hz, 3H), 1.2
(broad, 1H), 2.0 (q, J=6.6 Hz, 1H), 2.4 (dd, J=8.1 Hz,
J1=13.2 Hz, 1H), 2.6 (dd, J=6.2 Hz, J1=13.6 Hz,
1H), 3.6 (m, 2H), 7.2 (m, 5H). 13C NMR (100 MHz,
CDCl3/TMS) l 16.5, 37.9, 39.8, 67.8, 125.9, 128.3,
129.2, 140.6. IR (cm−1): 3368.
4.2.4. (4R,5R,2%R)-4. 0.10 g (78% yield) as white crys-
tals, mp 63–64°C, [h]2D5=−68.3 (c=1, CHCl3). 1H
NMR, 13C NMR, IR and mass spectra similar to those
described for (4S,5S,2%S)-4.
4.2.5. (4S,5R,2%R)-4. 0.050 g (35% yield) as a colorless
1
oil, [h]2D5=+21.1 (c=1, CHCl3). H NMR (400 MHz,
3
CDCl3/TMS) l 1.13 (d, J=7.0 Hz, 3H), 1.42 (m, 2H),
2
3
1.58 (m, 4H), 2.15 (m, 2H), 2.59 (dd, J=8 Hz, J=6
2
3
Hz, 1H), 3.08 (dd, J=8 Hz, J=6 Hz, 1H), 4.06 (m,
1H), 4.34 (m, 1H), 4.52 (m, 1H), 7.16–7.29 (m, 5H). 13C
NMR (100 MHz, CDCl3/TMS) l 16.7, 19.0, 20.7, 26.3,
26.8, 39.3, 39.7, 53.8, 74.2, 126.3, 128.3, 129.7, 139.3,
153.5, 176.4. IR (cm−1): 1784.3, 1701.3. Mass (m/z): 287
(molecular ion), 243, 228, 174, 142, 118 (base peak), 91,
74, 55, 41. C17H21NO3 (287.4) calc. 71.05% C, 7.37% H;
found 71.14% C, 7.31% H.
4.3. General procedure for aldol condensation reactions
A dry two-necked flask fitted with magnetic stirrer and
low-temperature thermometer was charged with a mix-
ture of 2 (0.50 g, 2.53 mmol) in dry CH2Cl2 (5.8 mL)
under argon. The solution was cooled to −78°C with a
dry ice/acetone bath, and then 1.2 equiv. of di-n-butyl-
boron triflate was added dropwise, followed by a slow
addition of 2.0 equiv. of Et3N (0.7 mL) over 30 min.
The reaction mixture was stirred and allowed to warm
up to rt (15–20 min), then cooled again to −78°C before
the addition of 2.0 equiv. of the aldehyde. Stirring was
continued at −78°C for 5.5 h, and quenched by slow
addition of 30% aqueous H2O2 (0.5–1.0 mL). The
organic material was extracted with CH2Cl2 (3×25 mL),
dried with anhydrous Na2SO4, filtered and evaporated.
The crude product was purified by flash chromatogra-
phy (petroleum ether/ethyl acetate, 5:1) to give aldol
products 7.
4.2.6. (4R,5S,2%S)-4. 0.04 g (30% yield) as a colorless
1
oil, [h]2D5=−20.0 (c=1, CHCl3). H NMR, 13C NMR,
IR and mass spectra similar to those described for
(4S,5S,2%R)-4.
4.2.7. (4S,5R,2%S)-4. 0.12 g (82% yield) as white crys-
tals, mp 40–41°C, [h]2D5=+76.5 (c=1, CHCl3). 1H
NMR (400 MHz, CDCl3/TMS) l 1.17 (m, 5H), 1.41
(m, 1H), 1.62 (m, 3H), 2.15 (m, 1H), 2.30 (m, 1H), 2.69
2
3
2
(dd, J=7.32 Hz, J=6.96 Hz, 1H), 2.96 (dd, J=13.38
Hz, 3J=7.72 Hz, 1H), 4.05 (m, 1H), 4.18 (m, 2H),
7.16–7.28 (m, 5H). 13C NMR (100 MHz, CDCl3/TMS)
l 16.8, 19.1, 20.9, 26.3, 27.2, 39.5, 40.2, 53.8, 74.2,
126.3, 128.3, 129.1, 139.3, 153.4, 176.3. IR (cm−1):
1784.3, 1701.3. Mass (m/z): 287 (molecular ion), 243,
228, 174, 142, 118 (base peak), 91, 74, 55, 41.
C17H21NO3 (287.4) calc. 71.05% C, 7.37% H; found
71.15% C, 7.28% H.
4.3.1. (4S,5S,2%S,3%S)-7. 0.46 g (60% yield) as white
1
crystals, mp 101–102°C, [h]2D5=+20.1 (c=1, CHCl3). H
3
NMR (400 MHz, CDCl3/TMS) l 1.10 (d, J=6.96 Hz,
3H), 1.4 (m, 3H), 1.64 (m, 1H), 1.8–2.0 (m, 2H), 2.24
3
(d, J=11.72 Hz, 1H), 2.81 (m, 1H), 3.27 (br. s, 1H,
OH), 3.55 (dt, 3J=3.28 Hz, 3J=10.96 Hz, 1H), 3.86 (dt,
3
3
3J=3.64 Hz, 2H), 4.04 (dq, J=2.92 Hz, J=7.0 Hz,
1H), 5.2 (d, J=2.92 Hz, 1H), 7.22–7.43 (m, 5H). 13C
3
4.2.8. (4R,5S,2%R)-4. 0.11 g (75% yield) as white crys-
tals, mp 42–43°C, [h]2D5=−78.2 (c=1, CHCl3). 1H
NMR, 13C NMR, IR and mass spectra similar to those
described for (4S,5R,2%S)-4.
NMR (100 MHz, CDCl3/TMS) l 11.0, 23.6, 23.8, 28.5,
28.7, 45.2, 63.2, 72.2, 81.4, 126.1, 127.3, 128.2, 141.3,
154.3, 179.7. IR (cm−1): 3523, 1759, 1707. Mass (m/z):
303 (molecular ion), 286, 242, 206, 197 (base peak),
142, 105, 97, 77, 68, 57, 39. C17H21NO4 (303) calc.
67.32% C, 6.93% H; found 67.25% C, 6.80% H.
4.2.9. (R)-2-Benzyl-1-propanol, (R)-5. A dry two-necked
flask provided with a magnetic stirrer and a dropping
funnel was charged with a mixture of LiAlH4 (13 mg,
0.70 mmol) in THF (5 mL) under argon. The solution
4.3.2. (4R,5R,2%R,3%R)-7. 0.54 g (70% yield) as white
1
crystals, mp 101–102°C, [h]2D5=−20.1 (c=1, CHCl3). H

78
C. Anaya de Parrodi et al. / Tetrahedron: Asymmetry 12 (2001) 69–79
NMR, 13C NMR, IR and mass spectra similar to those
described for (4S,5S,2%S,3%R)-7.
MHz, CDCl3) l 1.36 (m, 3H), 1.57 (d, J=6.92 Hz, 3H),
1.61 (m, 1H), 1.87 (m, 2H), 2.14 (m, 2H), 2.17 (s, 3H),
3.29 (ddd, Jgauche=3.46 Hz, Janti=11.13 Hz, Janti=11.01
Hz, 1H), 3.83 (ddd, Jgauche=3.46 Hz, Janti=11.13 Hz,
4.3.3. (4S,5S,2%S,3%R)-7. 0.40 g (65% yield), as white
1
crystals, mp 61–62°C, [h]2D5=+51.0 (c=1, CHCl3). H
J
anti=11.31 Hz, 1H), 5.23 (q, J=6.92 Hz, 1H). 13C
3
NMR (400 MHz, CDCl3/TMS) l 1.17 (t, J=7.32 Hz,
NMR (25 MHz, CDCl3) l 11.0, 20.4, 23.5, 23.8, 28.1,
28.5, 64.5, 82.1, 112.0, 136.56, 168.3. IR (cm−1):
2360,1700,1772. Mass (m/z): 240 (molecular peak), 198,
180, 153, 136, 124, 109, 97, 82, 68, 56. C12H17NO4: calc.
60.25% C, 7.11% H; found 59.85% C, 7.01% H.
3H), 1.36 (m, 3H), 1.62 (m, 1H), 1.87 (m, 2H), 2.20 (d,
3
3J=11.76 Hz, 1H), 2.75 (d, J=2.56 Hz, 1H), 3.00 (br.
3
3
s, 1H, OH), 3.55 (dt, J=3.32 Hz, J=11.0 Hz, 1H),
3.66 (dq, 3J=6.96 Hz, 3J=3.28 Hz, 1H), 3.85 (dt,
3J=3.68 Hz, 3J=11.34 Hz, 1H), 4.16 (m, 1H). 13C
NMR (100 MHz, CDCl3/TMS) l 11.5, 19.5, 23.5, 23.6,
28.3, 28.6, 44.0, 63.0, 67.0, 81.2, 154.5, 179.5. IR (cm−1):
3456, 1780, 1698. Mass (m/z): 242 (molecular peak),
224, 198, 180, 154, 142, 124, 110, 97, 81, 69, 56, 39.
C17H19NO4 (241) calc. 59.75% C, 7.88% H; found
59.69% C, 7.75% H.
4.3.10. (4S,5S,2%R)-N-(2-Acetyl-1-propionyl)hexahydro-
benzoxazolidin-2-one, (4S,5S,2%R)-9. White crystals, mp
144–146°C, [h]2D5=−159.1 (c=1, CHCl3). 1H NMR (100
MHz, CDCl3) l 1.22 (d, J=7.32 Hz, 3H), 2.15 (s, 3H),
4.32 (q, J=7.32 Hz, 1H). 13C NMR (25 MHz, CDCl3)
l 12.8, 27.9, 53.7, 154.5, 172.3, 205.0. IR (cm−1): 1794,
1724, 1682. Mass (m/z): 240 (molecular peak), 222, 197,
169, 153, 142, 124, 112, 97, 88, 81, 74, 68, 56.
C12H17NO4: calc. 60.25% C, 7.11% H; found 60.25% C,
7.21% H.
4.3.4. (4R,5R,2%R,3%S)-7. 0.37 g (60% yield), as white
1
crystals, mp 63–65°C, [h]2D5=−50.8 (c=1, CHCl3). H
NMR, 13C NMR, IR and mass spectra similar to those
described for (4S,5S,2%S,3%R)-7.
4.3.5. (4S,5R,2%S,3%S)-7. 0.54 g (70% yield) as white
Acknowledgements
1
crystals, mp 120–121°C, [h]2D5=+70.1 (c=1, CHCl3). H
3
NMR (400 MHz, CDCl3/TMS) l 1.16 (d, J=5 Hz,
1H), 1.42 (m, 1H), 1.55–1.72 (m, 3H), 2.15 (m, 1H),
2.31 (m, 1H), 3.22 (br. s, 1H, OH), 4.01 (m, 1H), 4.22
We thank CONACYT for financial support (Projects
No. 32202-E and No. L0006-E).
3
3
(m, 1H), 4.31 (d, J=2.56 Hz, 1H), 5.01 (d, J=3.24
Hz, 1H), 7.2–7.45 (m, 5H). 13C NMR (100 MHz,
CDCl3/TMS) l 10.9, 19.1, 20.9, 26.3, 27.0, 44.7, 53.8,
74.0, 74.5, 126.2, 127.6, 128.3, 141.5, 153.4, 176.5. IR
(cm−1): 3602, 1780, 1723. Mass (m/z): 303 (molecular
peak), 286, 206, 197 (base peak), 142, 129, 105, 97, 77,
68, 57, 39. C17H21NO4 (303) calc. 67.32% C, 6.93% H;
found 67.30% C, 6.75% H.
References
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4.3.6. (4R,5S,2%R,3%R)-7. 0.54 g (70% yield) as white
1
crystals, mp 122–123°C, [h]2D5=−71.2 (c=1, CHCl3). H
NMR, 13C NMR, IR and mass spectra similar to those
reported for (4S,5R,2%S,3%S)-7.
4.3.7. (4S,5R,2%S,3%R)-7. 0.37 g (60% yield) as white
1
crystals, mp 82–83°C, [h]2D5=+78.0 (c=1, CHCl3). H
3
NMR (400 MHz, CDCl3/TMS) l 1.17 (d, J=6.24 Hz,
3
3H). 1.2 (d, J=7 Hz, 3H), 1.45 (m, 1H), 1.65 (m, 4H),
2.19–2.32 (m, 2H), 2.91 (br. s, 1H, OH), 3.63 (dq,
3
3J=2.92 Hz, J=6.9 Hz, 1H), 4.11 (m, 1H), 4.35 (m,
1H), 4.55 (m, 1H). 13C NMR (100 MHz, CDCl3/TMS)
l 10.3, 11.0, 19.7, 20.8, 26.3, 27.0, 43.1, 53.7, 67.8, 74.5,
153.5, 177.3. IR (cm−1): 3468, 1780, 1687. Mass (m/z):
242 (molecular peak), 224, 197, 153, 142, 123, 110, 97,
81, 69, 56, 39. C17H21NO4: calc. 59.75% C, 7.88% H;
found 59.74% C, 7.85% H.
4.3.8. (4R,5S,2%R,3%S)-7. 0.37 g (60% yield) as white
1
crystals, mp 80–81°C, [h]2D5=−77.3 (c=1, CHCl3). H
NMR, 13C NMR, IR and mass spectra similar to those
reported for (4S,5R,2%S,3%R)-7.
4.3.9. (4S,5S)-N-[1-Acetoxy-(Z)-propenyl]hexahydro-
benzoxazolidin-2-one, (Z)-8. White crystals, mp 91–
1
92°C, [h]2D5=+25.98 (c=1.07, CHCl3). H NMR (100

C. Anaya de Parrodi et al. / Tetrahedron: Asymmetry 12 (2001) 69–79
79
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14. The vinylic proton in O-acylated products appears at
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