Regio- and diastereoselectivity in TiCl4-promoted reduction of 2-aryl-substituted cis-4-methyl-5-trifluoromethyl-1,3-dioxolanes

Article abstract of DOI:10.1016/S0957-4166(02)00687-0

TiCl₄-mediated reduction of both syn- and anti-(4S,5S)-2-aryl-4-methyl-5-trifluoromethyl-1,3-dioxolanes with Et₃SiD furnished monodeuterated hydroxy ethers resulting from the same regio- and stereoselective C-O bond cleavage (yields >80%; 82-92% de). Deuteride addition to the benzylidene acetal and removal of the alkyl moiety from the reaction product gave (R)-(α-²H)benzyl alcohol (90% ee), thus suggesting a new route to chiral 1-deuteriobenzyl alcohols. A mechanistic rationale is proposed and supported by theoretical calculations.

Full text of DOI:10.1016/S0957-4166(02)00687-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2609–2618
Regio- and diastereoselectivity in TiCl4-promoted reduction of
2-aryl-substituted cis-4-methyl-5-trifluoromethyl-1,3-dioxolanes
Carlo F. Morelli,a Arianna Fornili,b Maurizio Sironi,b Lavinia Dur`ı,a Giovanna Speranzaa and
Paolo Manittoaa,*
aDipartimento di Chimica Organica e Industriale, Universita` degli Studi di Milano, via Venezian 21, I-20133 Milano, Italy
bDipartimento di Chimica Fisica ed Elettrochimica, Universita` degli Studi di Milano, via Golgi 19, I-20133 Milano, Italy
Received 16 October 2002; accepted 23 October 2002
Abstract—TiCl4-mediated reduction of both syn- and anti-(4S,5S)-2-aryl-4-methyl-5-trifluoromethyl-1,3-dioxolanes with Et3SiD
furnished monodeuterated hydroxy ethers resulting from the same regio- and stereoselective CꢀO bond cleavage (yields >80%;
82–92% de). Deuteride addition to the benzylidene acetal and removal of the alkyl moiety from the reaction product gave
(R)-(a-2H)benzyl alcohol (90% ee), thus suggesting a new route to chiral 1-deuteriobenzyl alcohols. A mechanistic rationale is
proposed and supported by theoretical calculations. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
toluene (Scheme 1). The relative configurations of syn-
and anti-2a were proved by H NOESY experiments.
When compound syn-2a was treated with TiCl4 and
1
The exploitation of cyclic acetals as chiral templates
that temporarily modify the environment and reactivity
of carbonyl groups continues to attract the attention of
organic chemists.1 Main interests are the applications of
Lewis acid-promoted nucleophilic substitution at the
acetal carbon to asymmetric synthesis1b as well as the
relationship between mechanism and stereoselectivity.2
A number of di- and trisubstituted 1,3-dioxolanes, 1,3-
dioxanes, and 1,3-dioxepanes have been examined as
chiral templates.1,2a The recent synthesis of the four
stereoisomers of 1,1,1-trifluorobutane-2,3-diol in enan-
tiomeric pure form3 prompted us to examine them as
auxiliaries for stereoselective nucleophilic additions to
aldehydes via acetal intermediates. We report herein the
results of TiCl4-mediated reductive ring cleavage of
dioxolane acetals derived from (2S,3S)-1,1,1-trifluoro-
butane-2,3-diol 1 with substituted benzaldehydes. A
mechanistic interpretation is also suggested.
2. TiCl4-mediated reduction of dioxolanes
The diastereomeric trisubstituted 1,3-dioxolanes syn-
and anti-2a were prepared by reaction of benzaldehyde
with 1 (95% ee) and a catalytic amount of p-TsOH in
Scheme 1. Reagents and conditions: (a) TiCl4, Et3SiH(D),
CH2Cl2, −78°C; (b) Swern oxidation; (c) NaH, THF, reflux;
(d) TEA, diphenyl phosphoroazidate (DPPA); 1 M HCl,
reflux. See Table 1 for aryl residues.
* Corresponding
author.
Fax:
+39-02-503-14072;
e-mail:
paolo.manitto@unimi.it
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00687-0

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C. F. Morelli et al. / Tetrahedron: Asymmetry 13 (2002) 2609–2618
3. Mechanistic hypotheses and theoretical calculations
Et3SiH in CH2Cl2 at −78°C the monobenzyl ether 3a
was produced as the only reaction product (isolated
yield: 95%).
A possible mechanistic rationale for our findings is
outlined in Scheme 2 and is based on the following
considerations. It is likely that the reduction of acetal
carbon atoms occurs via oxocarbenium ions, as
reported for Lewis acid-catalyzed ring opening of cyclic
acetals.10,11 Thus, the regioselectivity in the 1,3-diox-
olane ring cleavage can be explained in terms of a
stronger destabilizing effect exerted by the CF3 group
on those ions in which such an electron-withdrawing
group is closer to the positive charge. In other words,
the ring opening of an O1ꢀTiCl4 complex (syn- and
anti-IA in Scheme 2) is expected to be preferred to one
involving C2ꢀO3 bond breaking in the O3ꢀTiCl4 com-
plexes syn- and anti-IB (Scheme 2).
Compound 3a was identified by comparison with an
authentic sample obtained as an intermediate in the
synthesis of 1.3 The formation of the regioisomer 4
(Ar=C6H5) was not detected by GC analysis of the
reaction mixture.
The TiCl4-catalyzed ring opening of syn-2a in the pres-
ence of Et3SiD (isotopic purity >99% D)4 gave the
expected reaction product which was shown to be
stereospecifically monodeuterated at the benzylic posi-
1
tion, i.e. 3a (HR=D). In fact, the H NMR spectrum
exhibited two broad singlets at l 4.52 and 4.67 having
an intensity ratio 15.5:1, instead of the typical AB
pattern due to the diastereotopic benzylic protons. In
conjunction with this, the R configuration of the O-
CHD-C6H5 group was deduced from chemical correla-
tion (Scheme 1) of the monodeuterated hydroxy ether
with (R)-(a-2H)benzyl alcohol (5, 90% ee) via Swern
oxidation,5 subsequent haloform reaction,6 and Curtius
rearrangement.7 The absolute configuration and ee of 5
were determined by comparison with an authentic sam-
ple of (S)-(a-2H)benzyl alcohol8 through 1H NMR
analysis of MTPA esters.9 The ee of the benzyl alcohol
was in accord with the ee of 13 and the observed
diastereoselectivity of the CꢀO bond cleavage of syn-2a.
The fact that the same stereochemical outcome results
from the deuteride substitution of O1 in both
diastereomers syn-2a–h and anti-2a–h (Table 1) is con-
sistent with a predominance of attack of Et3SiD on the
contact ion pair syn-IIA. As shown in Scheme 2, a fast
conversion of anti-IIA into syn-IIA should occur,
involving rotation about the C4ꢀC3 bond in the exter-
nal ion pair anti-IIIA, in competition with a much
slower nucleophilic substitution reaction. Analogously
syn-IIA would produce anti-IA giving rise to an equi-
librium between diastereomeric Lewis acid complexes,
largely displaced toward syn-IA and the corresponding
contact ion pair.
The dioxolane anti-2a afforded compound 3a (HR=D)
under the same reaction conditions (TiCl4 and Et3SiD)
as for its syn-isomer. A number of TiCl4-promoted
deuteride substitutions at the acetal carbon of 2b–h
prepared from different benzaldehydes were performed
with both syn- and anti-isomers (Table 1).
The intrinsic instability and the dual behavior (isomer-
ization versus nucleophilic substitution) of the contact
ion pairs generated by the complexes anti-IA might
explain the significantly lower yields and R/S ratios
observed for the reaction products 3 of anti-1,3-diox-
olanes (Table 1). The displacement of the configura-
tional equilibrium toward syn-species implies a marked
difference in energy between the anti and syn O1ꢀTiCl4
complexes IA (not necessarily between anti- and syn-2).
To validate this assumption, theoretical calculation of
energies and geometries of syn-2a and anti-2a, and their
TiCl4 complexes, syn-IA (Ar=C6H5) and anti-IA (Ar=
C6H5), were performed.
Some features of these reactions are worthy of note: (i)
isolated yields in benzyl ethers are generally good and
reflect a regioselectivity of ca. 100% corresponding to
C2ꢀO1 bond cleavage in all dioxolanes; (ii) diastereose-
lectivity is also very high and independent of the rela-
tive configuration of the 2-substituted 1,3-dioxolanes.
Table 1. TiCl4-mediated reaction of compounds 2 (syn and anti ) with Et3SiD to give compounds 3
Compound 3 (a-2H)
Diastereoisomeric ratioa R-Ca:S-Ca
1,3-Dioxolane (syn-2 or anti-2)
Isolated yields (%)
Entry
Ar=
From syn
From anti
From syn
From anti
a
b
c
d
e
f
g
h
C6H5
95
93
84
80
93
92
89
84
75
81
84
64
63
71
73
67
94:6
93:7
96:4
95:5
91:9
92:8
91:9
91:9
93:7
92:8
94:6
93:7
88:12
87:13
89:11
88:12
p-Me-C6H4
2-Naphthyl
p-Br-C6H4
m-NO2-C6H4
p-NO2-C6H4
m-OMe-C6H4
p-OMe-C6H4
a Determined by integration of the two benzylic (Ca) proton signals in the 1H NMR spectra on the assumption, based on the configuration of 5,
that the upfield singlet was due to HS (cf. 3) and the isotopic abundance of the examined compound was >99% D (cf. Ref. 4).

C. F. Morelli et al. / Tetrahedron: Asymmetry 13 (2002) 2609–2618
2611
Scheme 2. Proposed mechanism of configurational isomerization at C-2 of 1,3-dioxolanes via TiCl4 complexes.
Figure 1. Calculated geometries and relative energies (in parentheses, in kcal mol−1) of global minima of diastereomeric
benzaldehyde acetals (above) and their TiCl4 complexes (below). Structures syn-IA and anti-IA represent O1ꢀTiCl4 complexes of
compounds syn-2a and anti-2a. See Table 2 for bond lengths.

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C. F. Morelli et al. / Tetrahedron: Asymmetry 13 (2002) 2609–2618
,
Table 2. Calculated bond lengths (A) of syn and anti-2a
C2 epimers of 1,3-dioxolanes (Table 1). This feature,
which eliminates the chromatographic separation of
diastereomeric acetals 2, together with the availability
of enantiomerically pure (R,R)- and (S,S)-1,1,1-tri-
fluorobutane-2,3-diols 13 makes the procedure summa-
rized in Scheme 1 an alternative route to chiral benzylic
alcohols with good enantiomeric excess.16 Work is in
progress to explore mechanistic aspects and synthetic
potentialities of nucleophilic substitution at acetal car-
bons having the CF3 group b-positioned with respect to
the ethereal oxygen.
and their complexes with TiCl4 at the LANL2DZ level
Compounda
C2–O1 (Dr)b
C2–O3 (Dr)b
syn-2a
anti-2a
syn-IA
anti-IA
1.505
1.486
1.638 (0.133)
1.563 (0.077)
1.448
1.451
1.412 (−0.036)
1.444 (−0.007)
a Structures in Fig. 1.
b Dr values reported in parentheses indicate lengthening (Dr >0) or
shortening (Dr <0) of the bonds with respect to the uncomplexed
dioxolanes.
5. Experimental
5.1. General
The structures of the global minima of the configura-
tional isomers of 2a are reported in Fig. 1. For both of
them the TiCl4 molecule was then placed in proximity
of O1 and the geometries of the two complexes were
optimized at the DFT level using the B3LYP functional
and the LANL2DZ basis set. All the calculations were
carried out using the Gaussian G98 package12 (see
Section 5). The complex resulting from the syn-isomer
was found to be thermodynamically more stable by ca.
5 kcal/mol. Inspection of Fig. 1 reveals that in this
complex the aromatic ring substantially maintains the
‘perpendicular’ orientation relative to the heterocyclic
ring as in the uncomplexed syn-dioxolane.
TLC was performed on silica gel F254 precoated alu-
minum sheets (0.2 mm layer, Merck, Darmstadt, Ger-
many); components were detected by spraying with
ceric sulphate ammonium molybdate solution, followed
by heating to ca. 150°C. Silica gel (Merck, 40–63 mm)
was used for flash chromatography (FC). GC analyses
were carried out on a DANI 3800 gas chromatograph
(DANI, Monza, Italy) using a home made glass column
(2 m× 2 mm i.d.) packed with 10% FFAP on Chromo-
sorb W (60–80 mesh); GC parameters: injector, 220°C;
detector (FID), 220°C; carrier, N2 (30 ml/min); oven,
1
isothermal analysis at 200°C. H and 13C NMR spectra
In contrast, the attachment of the TiCl4 molecule to O1
of the anti-isomer causes rotation of the phenyl group
by ca. −75° from the ‘parallel’ orientation, which was
found to be the favored one in the anti-dioxolanes
(compare anti-2a and complex anti-IA in Fig. 1). In
addition, as a consequence of the modification in the
dioxolane conformation, the hydrogen atom at C2
becomes quasi-axial giving rise to a steric interaction
with the CF3 group. A rotation about the C4ꢀO3 bond
via intermediate ion pair (Scheme 2) should relieve the
above steric interactions (compare syn-IA and anti-IA
in Fig. 1).
were acquired at 400.132 and 100.613 MHz on a
Bruker AVANCE 400 Spectrometer using a Xwin-
NMR software package and at 300.133 and 75.47 on a
Bruker AC 300 (Bruker, Karlsruhe, Germany)
equipped with an ASPECT 3000 data system. Chemical
shifts (l) are given in ppm and were referenced to the
signals of CDCl3 (lH 7.25 and lC 77.00 ppm). 13C
NMR signals multiplicities were based on APT spectra.
All reagents were of commercial quality or purified
prior to use by standard methods.
5.2. General procedure for the synthesis of 2-aryl-4-
It can be noted that the Lewis acid complexation causes
lengthening of the bond between C2 and the complexed
oxygen atom, whilst the other CꢀO bond shortens
(Table 2). This fact can be interpreted in terms of
anomeric effect,13 as suggested by Yamamoto for 1,3-
dioxanes.14 The CꢀO bond lengthening is particularly
marked in complex syn-A which thus appears to be the
most likely candidate on the basis of relative popula-
tion/reactivity for the nucleophilic substitution reaction,
as shown in Scheme 2.
methyl-5-trifluoromethyl-1,3-dioxolanes, syn- and anti-2
A solution of diol 1, arylaldehyde (1.2 equiv.) and a
catalytic amount of p-toluenesulfonic acid in dry tolu-
ene (0.3 mmol of 1/ml) was heated under reflux with
removal of water by means of a Dean–Stark apparatus
until disappearance of the starting diol (GC). The solu-
tion was diluted with ethyl acetate, washed with satu-
rated hydrogencarbonate, 10% sodium hydrogensulfite
solution and saturated NaCl. The organic layer was
separated and dried (Na2SO4). The diastereomeric diox-
olanes syn and anti 2 were separated by flash column
chromatography.
4. Conclusions
Our findings indicate that the CF3 group as a sub-
stituent of 2-aryl-1,3-dioxolanes determines the regiose-
lectivity of the TiCl4/Et3SiH ring opening at the level of
the benzylic carbon. The reductive cleavage of the CꢀO
bond closer to the electron withdrawing group occurs
to the extent of practically 100%.15 Interestingly, the
stereochemical outcome of the deuteride substitution of
the oxygen of the acetal carbon is the same for both the
5.2.1. (2S,4S,5S)-4-Methyl-2-phenyl-5-trifluoromethyl-
1,3-dioxolane, syn-2a and (2R,4S,5S)-4-methyl-2-phenyl-
5-trifluoromethyl-1,3-dioxolane, anti-2a. Obtained from
1 and benzaldehyde in 55 and 30% yield, respectively;
eluent for FC: EtOAc/hexane, 1/12.
1
syn-2a: Pale yellow liquid. GC tR 1.9 min. H NMR
(CDCl3, 400 MHz): l=1.60 (dq, JHH=6.6 Hz, JHF
=

C. F. Morelli et al. / Tetrahedron: Asymmetry 13 (2002) 2609–2618
2613
1.8 Hz, 3H, Me), 4.37 (dq, JHH=JHF=6.6 Hz, 1H, H-5),
4.46 (dqq, JHH=6.6 Hz, JHF=1.7 Hz, 1H, H-4), 5.86 (s,
1H, H-2), 7.41–7.57 (m, 5H, aromatic H). Associations
3H) and 7.99 (s, 1H) (aromatic H). 13C NMR (75 MHz):
l=13.54 (Me), 74.80 (C-4), 75.74 (q, 2JCF=30 Hz, C-5),
1
104.63 (C-2), 123.75 (q, JCF=280 Hz, CF3), 123.85,
between H-2 and H-4/H-5 in the NOESY spectrum. 13
C
126.33, 126.83, 127.30, 127.83, 128.42, 128.63, 132.92 and
134.30 (aromatic C); [h]D +15.3 (c 0.77, CHCl3). Anal.
calcd for C15H13O2F3: C, 63.83; H, 4.64 Found: C, 63.66;
H, 4.81%.
NMR (100 MHz): l=13.47 (Me), 74.68 (C-4), 75.22 (q,
2JCF=31 Hz, C-5), 104.43 (C-2), 123.60 (q, JCF=282
1
Hz, CF3), 127.04, 128.45, 129.94 and 135.43 (aromatic
C); [h]D +25.4 (c 1.12, CHCl3). Anal. calcd for
C11H11O2F3: C, 56.89; H, 4.77. Found: C, 56.85; H,
4.81%.
anti-2c: Colorless liquid which solidifies on standing. GC
tR 12.2 min. 1H NMR (400 MHz): l=1.55–1.59 (m, 3H,
Me), 4.49–4.57 (m, 2H, H-4 and H-5), 6.50 (s, 1H, H-2),
7.53–7.56 (m, 2H), 7.58 (dd, 1H, J=8.5 and 1.6 Hz),
7.85–7.93 (m, 3H) and 7.97 (brs, 1H) (aromatic H). 13C
NMR (100 MHz): l=14.23 (Me), 72.94 (C-4), 76.35 (q,
1
anti-2a: Pale yellow liquid. GC tR 1.6 min. H NMR
(CDCl3, 400 MHz): l=1.54 (m, 3H, Me), 4.45–4.53 (m,
2H, H-4, H-5), 6.33 (s, 1H, H-2), 7.41–7.51 (m, 5H,
aromatic H). Associations between Me-4 and H-2 in the
NOESY spectrum. 13C NMR (100 MHz): l=14.18 (Me),
1
2JCF=31 Hz, C-5), 104.44 (C-2), 124.31 (q, JCF=282
Hz, CF3), 123.76, 125.74, 126.84, 127.02, 128.18, 128.71,
128.92, 133.30, 134.14 and 135.87 (aromatic C); [h]D
+23.0 (c 1.07, CHCl3). Anal. calcd for C15H13O2F3: C,
63.83; H, 4.64 Found: C, 63.72; H, 4.78%.
2
72.87 (C-4), 76.28 (q, JCF=32 Hz, C-5), 104.28 (C-2),
1
124.27 (q, JCF=281 Hz, CF3), 126.38, 128.86, 129.61
and 138.56 (aromatic C); [h]D +20.5 (c 1.04, CHCl3).
Anal. calcd for C11H11O2F3: C, 56.89; H, 4.77. Found:
C, 56.93; H, 4.84%.
5.2.4.
(2S,4S,5S)-2-(4-Bromophenyl)-4-methyl-5-tri-
fluoromethyl-1,3-dioxolane, syn-2d and (2R,4S,5S)-2-(4-
bromophenyl)-4-methyl-5-trifluoromethyl-1,3-dioxolane,
anti-2d. Obtained from 1 and 4-bromo-benzaldehyde in
48 and 22% yield, respectively; eluent for FC: Et2O/hex-
ane, 15/85.
5.2.2. (2S,4S,5S)-4-Methyl-2-p-tolyl-5-trifluoromethyl-
1,3-dioxolane, syn-2b and (2R,4S,5S)-4-methyl-2-p-tolyl-
5-trifluoromethyl-1,3-dioxolane, anti-2b. Obtained from 1
and p-tolualdehyde in 48 and 7% yield, respectively.
Eluent for FC: EtOAc/petroleum ether, 1/18.
syn-2d: White solid. GC tR 4.6 min. 1H NMR (400 MHz):
l=1.59 (dq, 3H, JHH=6.6 Hz, JHF=1.8 Hz, Me), 4.37
syn-2b: Pale yellow liquid. GC tR 2.60 min. 1H NMR (400
MHz): l=1.59 (dq, 3H, JHH=6.7 Hz, JHF=1.8 Hz, Me),
2.39 (s, 3H, Me), 4.37 (dq, 1H, JHH=JHF=6.7 Hz, H-5),
4.46 (dqq, 1H, JHH=6.7 Hz, JHF=1.8 Hz, H-4), 5.84 (s,
1H, H-2), 7.23 (d, 2H, J=8.1 Hz) and 7.43 (d, 2H, J=8.1
Hz) (aromatic H). 13C NMR (75 MHz): l=13.46 (Me),
(dq, 1H, JHH=JHF=6.6 Hz, H-5), 4.47 (dqq, 1H, JHH
6.6 Hz, JHF=1.8 Hz, H-4), 5.82 (s, 1H, H-2), 7.41 (d, 2H,
J=8.4 Hz) and 7.56 (d, 2H, J=8.4 Hz) (aromatic H). 13
=
C
NMR (75 MHz): l=13.44 (Me), 74.80 (C-4), 75.23 (q,
2JCF=30 Hz, C-5), 103.66 (C-2), 123.52 (q, JCF=280
1
2
21.20 (Me), 74.62 (C-4), 75.27 (q, JCF=32 Hz, C-5),
Hz, CF3), 124.13, 128.70, 131.65 and 134.60 (aromatic
C); [h]D +16.7 (c 1.16, CHCl3). Anal. calcd for
C11H10O2BrF3: C, 42.47; H, 3.23. Found: C, 42.59; H,
3.18%.
1
104.49 (C-2), 123.70 (q, JCF=282 Hz, CF3), 126.97,
129.10, 132.73 and 139.88 (aromatic C); [h]D +14.8 (c
0.89, CHCl3). Anal. calcd for C12H13O2F3: C, 58.53; H,
5.32. Found: C, 58.61; H, 5.14%.
anti-2d: Pale yellow liquid. GC tR 3.5 min. 1H NMR (400
MHz): l=1.51 (m, 3H, Me), 4.41–4.48 (m, 2H, H-4 and
H-5), 6.26 (s, 1H, H-2), 7.35 (d, 2H, J=8.4 Hz) and 7.54
(d, 2H, J=8.4 Hz) (aromatic H). 13C NMR (100 MHz):
l=14.14 (Me), 72.96 (C-4), 76.26 (q, 2JCF=31 Hz, C-5),
1
anti-2b: Pale yellow liquid. GC tR 2.20 min. H NMR
(400 MHz): l=1.51 (brd, 3H, J=6.3 Hz, Me), 2.39 (s,
3H, Me), 4.42–4.52 (m, 2H, H-4 and H-5), 6.29 (s, 1H,
H-2), 7.22 (d, 2H, J=7.9 Hz) and 7.37 (d, 2H, J=7.9 Hz)
(aromatic H). 13C NMR (100 MHz): l=14.23 (Me),
21.62 (Me), 72.77 (C-4), 76.23 (q, JCF=31 Hz, C-5),
104.35 (C-2), 124.25 (q, JCF=281 Hz, CF3), 126.26,
129.53, 135.58 and 139.52 (aromatic C); [h]D +21.2 (c
0.44, CHCl3). Anal. calcd for C12H13O2F3: C, 58.53; H,
5.32. Found: C, 58.66; H, 5.16%.
1
103.59 (C-2), 124.11 (q, JCF=281 Hz, CF3), 123.73,
2
127.98, 132.04, and 137.59 (aromatic C); [h]D +21.1 (c
0.81, CHCl3). Anal. calcd for C11H10O2BrF3: C, 42.47;
H, 3.23. Found: C, 42.55; H, 3.15%.
1
5.2.5.
(2S,4S,5S)-2-(3-Nitrophenyl)-4-methyl-5-tri-
5.2.3.
methyl-1,3-dioxolane, syn-2c and (2R,4S,5S)-4-methyl-2-
(2%-naphtyl)-5-trifluoromethyl-1,3-dioxolane, anti-2c.
Obtained from 1 and 2-naphtylaldehyde in 53 and 39%
yield, respectively; eluent for FC: EtOAc/petroleum
ether, 1/12.
(2S,4S,5S)-4-Methyl-2-(2%-naphtyl)-5-trifluoro-
fluoromethyl-1,3-dioxolane, syn-2e and (2R,4S,5S)-2-(3-
nitrophenyl)-4-methyl-5-trifluoromethyl-1,3-dioxolane,
anti-2e. Obtained from 1 and 3-nitro-benzaldehyde in 40
and 22% yield, respectively; eluent for FC: EtOAc/hex-
ane, 1/5.
syn-2e: Yellow liquid. TLC (eluent as above) Rf 0.29. 1H
NMR (400 MHz): l=1.62 (dq, 3H, JHH=6.6 Hz,
JHF=1.8 Hz, Me), 4.43 (dq, 1H, JHH=JHF=6.6 Hz,
H-5), 4.54 (dqq, 1H, JHH=6.6 Hz, JHF=1.8 Hz, H-4),
5.96 (s, 1H, H-2), 7.62 (t, 1H, J=7.9 Hz), 7.89 (dt, 1H,
J=7.9 and 2.0 Hz), 8.30 (dt, 1H, J=7.9 and 2.0 Hz)
1
syn-2c: White solid. GC tR 15.5 min. H NMR (400
MHz): l=1.64 (dq, 3H, JHH=6.6 Hz, JHF=1.8 Hz, Me),
4.44 (dq, 1H, JHH=JHF=6.7 Hz, H-5), 4.55 (dqq, 1H,
JHH=6.6 Hz, JHF=1.8 Hz, H-4), 6.04 (s, 1H, H-2), 7.53
(m, 2H), 7.66 (dd, 1H, J=8.5 and 1.6 Hz), 7.87–7.92 (m,

2614
C. F. Morelli et al. / Tetrahedron: Asymmetry 13 (2002) 2609–2618
and 8.39 (t, 1H, J=2.0 Hz) (aromatic H). 13C NMR (75
MHz): l=13.32 (Me), 75.09 (C-4), 75.30 (q, 2JCF=31 Hz,
C-5), 102.69 (C-2), 123.42 (q, 1JCF=281 Hz, CF3), 122.17,
124.60, 129.61, 132.92, 137.88 and 148.24 (aromatic C);
[h]D +16.4 (c 1.08, CHCl3). Anal. calcd for C11H10NO4F3:
C, 47.66; H, 3.63; N, 5.05. Found: C, 47.52; H, 3.71; N,
5.12%.
1H, J=8.0 and 1.6 Hz), 7.11 (d, 1H, J=1.6 Hz), 7.12 (d,
1H, J=8.0 Hz) and 7.33 (t, 1H, J=8.0) (aromatic H).
13C NMR (75 MHz): l=13.47 (Me), 55.23 (OMe), 74.72
2
(C-4), 75.70 (q, JCF=31 Hz, C-5), 104.26 (C-2), 123.58
1
(q, JCF=283 Hz, CF3), 111.94, 115.99, 119.45, 129.56,
136.90 and 159.72 (aromatic C); [h]D +13.7 (c 1.12,
CHCl3). Anal. calcd for C12H13O3F3: C, 54.96; H, 4.99.
Found: C, 55.08; H, 4.77%.
anti-2e: Pale yellow liquid TLC (eluent as above) Rf 0.43.
1H NMR (400 MHz): l=1.55 (dq, 3H, JHH=8.2 Hz,
anti-2g Pale yellow liquid. GC tR 3.7 min. 1H NMR (400
MHz): l=1.52 (dm, 3H, J=6.6 Hz, Me), 3.84 (s, 3H, Me),
4.46 (dq, 1H, JHH=JHF=6.6 Hz, H-5), 4.47 (m, 1H, H-4),
6.29 (s, 1H, H-2), 6.92 (dd, 1H, J=7.8 and 2.3 Hz), 7.01
(d, 1H, J=2.3 Hz), 7.06 (d, 1H, J=7.8 Hz) and 7.32 (t,
1H, J=7.8 Hz) (aromatic H). 13C NMR (75 MHz):
l=13.70 (Me), 55.22 (OMe), 72.38 (C-4), 75.76 (q,
2JCF=30 Hz, C-5), 103.63 (C-2), 123.81 (q, 1JCF=281 Hz,
CF3), 111.20, 114.79, 118.07, 129.62, 135.73 and 159.75
(aromatic C); [h]D +22.6 (c 0.84, CHCl3). Anal. calcd for
C12H13O3F3:C, 54.96;H, 4.99. Found:C, 55.14;H, 4.81%.
J
HF=1.9 Hz, Me), 4.47–4.49 (m, 2H, H-4 and H-5), 6.30
(s, 1H, H-2), 7.56 (t, 1H, J=8.0 Hz), 7.77 (brd, 1H, J=8.0
Hz), 8.20 (brd, 1H, J=8.0 Hz), 8.30 (t, 1H, J=2.0 Hz),
(aromatic H). 13C NMR (100 MHz): l=13.64 (Me), 72.89
(C-4), 75.99 (q, JCF=31 Hz, C-5), 102.36 (C-2), 123.25
(q, JCF=280 Hz, CF3), 121.02, 124.04, 129.59, 132.10,
2
1
140.42, and 148.35 (aromatic C); [h]D +24.3 (c 0.97,
CHCl3). Anal. calcd for C11H10NO4F3: C, 47.66; H, 3.63;
N, 5.05. Found: C, 47.56; H, 3.68; N, 5.18%.
5.2.6.
(2S,4S,5S)-2-(4-Nitrophenyl)-4-methyl-5-tri-
fluoromethyl-1,3-dioxolane, syn-2f and (2R,4S,5S)-2-(4-
nitrophenyl)-4-methyl-5-trifluoromethyl-1,3-dioxolane,
anti-2f. Obtained from 1 and 4-nitro-benzaldehyde in 43
and 23% yield, respectively; eluent for FC: EtOAc/hex-
ane, 1/3.
5.2.8. (2S,4S,5S)-2-(4-Methoxyphenyl)-4-methyl-5-tri-
fluoromethyl-1,3-dioxolane, syn-2h and (2R,4S,5S)-2-(4-
methoxyphenyl)-4-methyl-5-trifluoromethyl-1,3-dioxolane,
anti-2h. Obtained from 1 and 4-methoxy-benzaldehyde
in 66 and 15% yield, respectively; eluent for FC: Et2O/hex-
ane, 2/8.
1
syn-2f: White solid. TLC (eluent as above) Rf 0.30. H
NMR (400 MHz): l=1.61 (dq, 3H, JHH=6.9 Hz,
syn-2h: Pale yellow solid. GC tR 5.2 min. 1H NMR (400
MHz): l=1.59 (dq, 3H, JHH=6.9 Hz, JHF=1.8 Hz, Me),
3.83 (s, 3H, OMe), 4.36 (dq, 1H, JHH=JHF=6.9 Hz, H-5),
4.45 (dqq, 1H, JHH=6.9 Hz, JHF=1.8 Hz, H-4), 5.83 (s,
1H, H-2), 6.94 (d, 2H, J=8.7 Hz) and 7.47 (d, 2H, J=8.7
Hz) (aromatic H). 13C NMR (100 MHz): l=13.87 (Me),
JHF=1.8 Hz, Me), 4.42 (dq, 1H, JHH=JHF=6.9 Hz, H-5),
4.54 (dqq, 1H, JHH=6.9 Hz, JHF=1.8 Hz, H-4), 5.96 (s,
1H, H-2), 7.71 (d, 2H, J=8.8 Hz) and 8.28 (d, 2H, J=8.8
Hz) (aromatic H). 13C NMR (75 MHz): l=13.37 (Me),
2
75.14 (C-4), 75.34 (q, JCF=30 Hz, C-5), 102.69 (C-2),
123.36 (q, 1JCF=280 Hz, CF3), 123.60, 127.89, 142.33 and
148.81 (aromatic C); [h]D +16.9 (c 0.26, CHCl3). Anal.
calcd for C11H10NO4F3: C, 47.66; H, 3.63; N, 5.05. Found:
C, 47.58; H, 3.65; N, 5.20%.
55.65 (OMe), 74.94 (C-4), 75.53 (q, JCF=30 Hz, C-5),
2
1
104.79 (C-2), 124.16 (q, JCF=280 Hz, CF3), 114.30,
128.11, 128.99 and 161.40 (aromatic C); [h]D +15.7 (c 0.48,
CHCl3). Anal. calcd for C12H13O3F3: C, 54.96; H, 4.99.
Found: C, 55.15; H, 4.84%.
anti-2f: Colorless liquid. TLC (eluent as above) Rf 0.55.
1H NMR (400 MHz): l=1.55 (m, 3H, Me), 4.42 (dqq,
1H, JHH=6.3 Hz, JHF=1.5 Hz, H-4), 4.48 (dq, 1H,
anti-2h: Pale yellow liquid. GC tR 4.1 min. 1H NMR (400
MHz): l=1.51 (m, 3H, Me), 3.82 (s, 3H, OMe), 4.42–4.54
(m, 2H, H-4 and H-5), 6.26 (s, 1H, H-2), 6.93 (d, 2H,
J
HH=JHF=6.3 Hz, H-5), 6.35 (s, 1H, H-2), 7.67 (d, 2H,
J=8.6 Hz) and 8.27 (d, 2H, J=8.6 Hz) (aromatic H). 13
C
J=8.5 Hz) and 7.39 (d, 2H, J=8.5 Hz) (aromatic H). 13
C
NMR (75 MHz): l=13.68 (Me), 72.89 (C-4), 75.97 (q,
2JCF=31 Hz, C-5), 102.47 (C-2), 123.52 (q, 1JCF=281 Hz,
CF3), 123.72, 126.92, 144.89 and 148.47 (aromatic C); [h]D
+20.6 (c 0.43, CHCl3). Anal. calcd for C11H10NO4F3: C,
47.66; H, 3.63; N, 5.05. Found: C, 47.70; H, 3.74; N,
5.09%.
NMR (100 MHz): l=14.30 (Me), 55.71 (OMe), 72.80
2
(C-4), 76.25 (q, JCF=31 Hz, C-5), 104.26 (C-2), 124.26
(q, 1JCF=281 Hz, CF3), 114.23, 127.77, 130.58 and 160.77
(aromatic C); [h]D +19.6 (c 0.56, CHCl3). Anal. calcd for
C12H13O3F3:C, 54.96;H, 4.99. Found:C, 55.04;H, 4.81%.
5.3. Reductive ring-opening reactions of acetals with
TiCl4/Et3SiH(D). General procedure
5.2.7. (2S,4S,5S)-2-(3-Methoxyphenyl)-4-methyl-5-tri-
fluoromethyl-1,3-dioxolane, syn-2g and (2R,4S,5S)-2-(3-
methoxyphenyl)-4-methyl-5-trifluoromethyl-1,3-dioxolane,
anti-2g. Obtained from 1 and 3-methoxy-benzaldehyde
in 61 and 26% yield, respectively; eluent for FC: EtOAc/
hexane, 1/8.
1 M TiCl4 solution in CH2Cl2 (0.26 mL) was added
dropwise over ca. 2.5 min to a solution of the 1,3-diox-
olane (0.5 mmol) and Et3SiH(D) (0.55 mmol) in dry
CH2Cl2 (2.5 mL) at −78°C under N2 and the mixture was
stirred for 15 min. After quenching with MeOH (0.2 mL)
and further stirring for 5 min, the reaction mixture was
diluted with CH2Cl2 (5 mL), washed with 1 M HCl and
with saturated NaCl, and dried (Na2SO4). Removal of the
solvent under reduced pressure gave the reaction product
which was purified by flash chromatography.
syn-2g: Colorless liquid which solidifies on standing. GC
tR 4.3 min. 1H NMR (400 MHz): l=1.60 (dq, 3H,
J
HH=6.6 Hz, JHF=1.8 Hz, Me), 3.84 (s, 3H, OMe), 4.37
(dq, 1H, JHH=JHF=6.6 Hz, H-5), 4.48 (dqq, 1H, JHH
6.6 Hz, JHF=1.8 Hz, H-4), 5.85 (s, 1H, H-2), 6.97 (dd,
=

C. F. Morelli et al. / Tetrahedron: Asymmetry 13 (2002) 2609–2618
2615
5.3.1. (2S,3S)-3-[(R)-a-2H]-Benzyl-1,1,1-trifluorobutan-
2-ol 3a. See Table 1 for yields from syn-2a and anti-
2a.
5.3.5.
(2S,3S)-3-[(R)-a-2H]-(3-Nitrobenzyloxy)-1,1,1-
trifluorobutan-2-ol, 3e. See Table 1 for yields from syn-2e
and anti-2e.
Pale yellow liquid. GC tR 3.9 min. Eluent for FC:
EtOAc/petroleum ether, 1/7. 1H NMR (400 MHz):
l=1.34 (d, 3H, J=6.2 Hz, Me), 2.65 (brs, 1H, OH),
3.82–3.88 (m, 1H) and 4.10–4.15 (m, 1H) (H-2 and
H-3), 4.51 (brs, 0.94H, CHS-Ar), 4.64 (brs, 0.06H,
CHR-Ar), 7.31–7.40 (m, 5H, aromatic H). 13C NMR
(100 MHz): l=14.51 (Me), 71.28 (t, 1JCD=21 Hz,
CHD), 72.33 (q, 2JCF=29 Hz, C-2), 73.70 (C-3),
Pale yellow liquid. Eluent for FC: EtOAc/petroleum
ether, 1/2. 1H NMR (400 MHz): l=1.36 (d, 3H, J=6.3
Hz, Me), 2.47 (brd, 1H, J=4.8 Hz, OH), 3.86 (qd, 1H,
J=6.3 and 4.6 Hz, H-3), 4.06–4.14 (m, 1H, H-2), 4.58
(brs, 0.91H, CHS-Ar), 4.70 (brs, 0.09H, CHR-Ar), 7.52
(t, 1H, J=7.8 Hz), 7.66 (d, 1H, J=7.8 Hz), 8.15 (d, 1H,
J=7.8 Hz), and 8.21 (s, 1H) (aromatic H). 13C NMR (100
1
MHz): l=14.44 (Me), 69.49 (t, JCD=22 Hz, CHD),
1
124.79 (q, JCF=281 Hz, CF3), 128.29, 128.45, 128.96
and 137.82 (aromatic C); [h]D +20.6 (c 0.43, CHCl3).
72.20 (q, 2JCF=30 Hz, C-2), 74.07 (C-3), 124.33 (q,
1JCF=283 Hz, CF3), 122.17, 122.70, 129.41, 133.37,
139.91 and 148.32 (aromatic C); [h]D +8.3 (c 0.82, CHCl3).
5.3.2. (2S,3S)-3-[(R)-a-2H]-(4-Methylbenzyloxy)-1,1,1-
trifluorobutan-2-ol, 3b. See Table 1 for yields from syn-2b
and anti-2b.
5.3.6.
(2S,3S)-3-[(R)-a-2H]-(4-Nitrobenzyloxy)-1,1,1-
trifluorobutan-2-ol, 3f. See Table 1 for yields from syn-2f
and anti-2f.
Pale yellow liquid. Eluent for FC: EtOAc/hexane, 1/3. 1H
NMR (400 MHz): l=1.39 (d, 3H, J=6.4 Hz, Me), 2.59
(brd, 1H, J=5.1 Hz, OH), 3.89 (qd, 1H, J=6.4 and 4.6
Hz, H-3), 4.13 (qdd, 1H, J=6.9, 5.1, and 4.6 Hz, H-2),
4.62 (brs, 0.90H, CHS-Ar), 4.74 (brs, 0.10H, CHR-Ar),
7.52 (d, 2H, J=8.5 Hz) and 8.23 (d, 2H, J=8.5 Hz)
(aromatic H). 13C NMR (100 MHz): l=14.49 (Me), 69.49
(t, 1JCD=22 Hz, CHD), 72.14 (q, 2JCF=27 Hz, C-2), 74.22
Pale yellow liquid. GC tR 5.3 min. Eluent for FC:
EtOAc/petroleum ether, 1/6. 1H NMR (300 MHz):
l=1.29 (d, 3H, J=6.3 Hz, Me), 2.34 (s, 3H, Me), 2.58
(brs, 1H, OH), 3.76–3.84 (m, 1H) and 4.02–4.08 (m, 1H)
(H-2 and H-3), 4.43 (brs, 0.93H, CHS-Ar), 4.56 (brs,
0.07H, CHR-Ar), 7.15 (d, 2H, J=8.1 Hz) and 7.21 (d,
2H, J=8.1 Hz) (aromatic H). 13C NMR (75 MHz):
l=14.04 (Me), 21.08 (Me), 70.75 (t, 1JCD=21 Hz, CHD),
71.88 (q, 2JCF=31 Hz, C-2), 73.06 (C-3), 124.39 (q,
1JCF=281 Hz, CF3), 128.05, 129.22, 134.36 and 137.83
(aromatic C); [h]D +8.2 (c 1.12, CHCl3).
1
(C-3), 124.40 (q, JCF=281 Hz, CF3), 123.60, 127.77,
145.34 and 147.36 (aromatic C); [h]D +10.4 (c 0.72,
CHCl3).
5.3.7. (2S,3S)-3-[(R)-a-2H]-(3-Methoxybenzyloxy)-1,1,1-
trifluorobutan-2-ol, 3g. See Table 1 for yields from syn-2g
and anti-2g.
5.3.3. (2S,3S)-3-[(R)-a-2H]-3-(Naphtalen-2-ylmethoxy)-
1,1,1-trifluorobutan-2-ol, 3c. See Table 1 for yields from
syn-2c and anti-2c.
White solid. TLC: Eluent as above, Rf 0.32. 1H NMR (400
MHz): l=1.37 (d, 3H, J=6.4 Hz, Me), 2.62 (brd, 1H,
J=5.3 Hz, OH), 3.91 (qd, 1H, J=6.3 and 4.2 Hz, H-3),
4.12–4.19 (m, 1H, H-2), 4.68 (brs, 0.96H, CHS-Ar), 4.80
(brs, 0.04H, CHR-Ar), 7.47–7.52 (m, 3H), 7.79 (s, 1H),
7.77–7.88 (m, 3H) (aromatic H). 13C NMR (100 MHz):
Pale yellow liquid. GC tR 11.0 min (eluent for FC:
EtOAc/petroleum ether, 1/5). 1H NMR (400 MHz):
l=1.34 (d, 3H, J=6.4 Hz, Me), 2.59 (brd, 1H, J=5.0
Hz, OH), 3.81–3.88 (m, 1H, H-3), 3.84 (s, 3H, OMe),
4.11–4.15 (m, 1H, H-2), 4.49 (brs, 0.91H, CHS-Ar), 4.62
(brs, 0.09H, CHR-Ar), 6.87 (dd, 1H, J=8.1 and 2.5 Hz),
6.91(s, 1H), 6.92(d, 1H, J=8.1Hz)and7.29(t, 1H, J=8.1
Hz) (aromatic H). 13C NMR (100 MHz): l=14.15 (Me),
1
l=14.65 (Me), 71.33 (t, JCD=21 Hz, CHD), 72.49 (q,
2JCF=29 Hz, C-2), 73.45 (C-3), 124.72 (q, 1JCF=280 Hz,
CF3), 126.01, 126.49, 126.66, 127.03, 128.13, 128.28,
128.80, 133.50, 133.64 and 135.30 (aromatic C); [h]D +8.4
(c 0.45, CHCl3).
1
55.19 (OMe), 70.65 (t, JCD=21 Hz, CHD), 71.88 (q,
2JCF=30 Hz, C-2), 73.24 (C-3), 124.37 (q, 1JCF=276 Hz,
CF3), 113.27, 113.52, 120.03, 129.62, 139.02 and 159.78
(aromatic C); [h]D +9.8 (c 0.87, CHCl3).
5.3.4. (2S,3S)-3-[(R)-a-2H]-(4-Bromobenzyloxy)-1,1,1-
trifluorobutan-2-ol, 3d. See Table 1 for yields from syn-2d
and anti-2d.
5.3.8. (2S,3S)-3-[(R)-a-2H]-(4-Methoxybenzyloxy)-1,1,1-
trifluorobutan-2-ol, 3h. See Table 1 for yields from syn-2h
and anti-2h.
Pale yellow liquid. Eluent for FC: EtOAc/hexane, 1/6. 1H
NMR (400 MHz): l=1.34 (d, 3H, J=6.3 Hz, Me), 2.62
(brd, 1H, J=5.1 Hz, OH), 3.83 (qd, 1H, J=6.3 and 4.3
Hz, H-3), 4.06–4.15 (m, 1H, H-2), 4.46 (brs, 0.95H,
CHS-Ar), 4.58 (brs, 0.05H, CHR-Ar), 7.23 (d, 2H, J=8.3
Hz) and 7.50 (d, 2H, J=8.3 Hz) (aromatic H). 13C NMR
(100 MHz): l=14.63 (Me), 70.46 (t, 1JCD=22 Hz, CHD),
72.43 (q, 2JCF=29 Hz, C-2), 73.88 (C-3), 124.75 (q,
1JCF=280 Hz, CF3), 122.28, 129.81, 132.04 and 136.90
(aromatic C); [h]D +8.4 (c 1.01, CHCl3).
Pale yellow liquid. GC tR 11.0 min. Eluent for FC:
EtOAc/petroleum ether, 1/5.
1H NMR (400 MHz): l=1.31 (dd, 3H, J=6.4 and 0.9
Hz, Me), 2.65 (brd, 1H, J=5.1 Hz, OH), 3.79–3.83 (m,
4H, H-3 and OMe), 4.06–4.10 (m, 1H, H-2), 4.43 (brs,
0.91H, CHS-Ar), 4.56 (brs, 0.09H, CHR-Ar), 6.91 (d, 2H,
J=8.6 Hz) and 7.28 (d, 2H, J=8.6 Hz) (aromatic H). 13
C
NMR (100 MHz): l=14.14 (Me), 55.26 (OMe), 70.47 (t,

2616
C. F. Morelli et al. / Tetrahedron: Asymmetry 13 (2002) 2609–2618
1JCD=21 Hz, CHD), 71.84 (q, 2JCF=28 Hz, C-2), 72.81
(C-3), 124.38 (q, JCF=279 Hz, CF3), 113.92, 128.20,
Hz, H-2); 4.70 and 4.75 (br s, 0.5 H each, CHD); 5.65
(br, 1H, COOH); 7.33–7.39 (m, 5H, aromatic H).
1
129.12 and 159.43 (aromatic C); [h]D +8.8 (c 0.89, CHCl3).
A solution of 2-[(R-a-2H)benzyloxy]propanoic acid pre-
pared as above (70 mg, 0.38 mmol) in dry THF (1.2 ml)
was placed in a three necked round-bottom flask equipped
with a condenser, treated with Et3N (0.050 ml) and stirred
at rt under N2 for 15 min. Then diphenylphosphoazidate
(DPPA) (0.087 ml, 0.38 mmol) was added in one portion
and the reaction mixture was stirred for additional 30 min.
The temperature was quickly raised to 60°C using a
pre-heated water bath and water (0.80 ml) was added. The
reaction was stirred at 60°C for 30 min, cooled to rt,
diluted with ethyl acetate (5 ml) and washed with 1 M
HCl (2×4 ml), saturated NaCl (1×4 ml), saturated
NaHCO3 (2×4 ml) and saturated NaCl (1×4 ml). The
separated organic layer was dried (Na2SO4) and evapo-
rated under reduced pressure. The residue was purified
by flash column chromatography (eluent: EtOAc/hexane,
3/5) to give (R)-(a-2H)benzyl alcohol (5) as a pale yellow
liquid (10 mg, 24% yield).
5.4. 3-Benzyloxy-4,4,4-trifluorobutan-2-ol, 4
To a solution of 1 (302 mg, 2.1 mmol) in dry THF (10
ml) potassium tert-butoxide (236 mg, 2.1 mmol) was
added and the mixture was heated at reflux for 15 min
withstirring. Benzylbromide(0.25ml, 2.1mmol)wasthen
added and the mixture was refluxed for 2.5 h, cooled to
room temperature, diluted with ethyl acetate (15 ml),
washed with 1N HCl (2×20 ml) and saturated NaCl
(1×15ml). The organic layer was separated, dried
(Na2SO4)andconcentratedunderreducedpressure. Flash
column chromatography (silica gel, EtOAc/hexane, 1/5)
gave pure 4 as a pale yellow liquid (330 mg, 67% yield).
1H NMR (CDCl3, 300 MHz): l=1.28 (d, J=6.2 Hz, 3H,
Me), 2.00 (brs, 1H, OH), 3.80 (m, 1H) and 4.05 (m, 1H)
(H-2 and H-3), 4.64 and 4.90 (AB syst., J=11.3 Hz, 2H,
CH2Ph), 7.31–7.41 (m, 5H, aromatic H); 13C NMR
(CDCl3, 75 MHz): l=17.97 (Me), 66.32 (C-2), 75.20
(CH2); 80.17 (q, 2JCF=26 Hz, C-3), 124.73 (q, 1JCF=283
Hz, CF3), 128.14, 128.34, 128.59 and 136.79 (aromatic C);
[h]D −21.1 (c 1.14, CHCl3). Anal. calcd for C11H13O2F3:
C, 56.41; H, 5.59. Found: C, 56.16; H, 5.34%.
5: 1H NMR (400 MHz) l: 2.08 (brs, 1H, OH); 4.78 (brt,
1
1H, JHD=1.87 Hz, CHD); 7.37–7.39 (m, 5H, aromatic
H); 13C NMR (100 MHz) l: 65.33 (t, 1JCD=21 Hz, CHD);
127.42, 128.04, 128.95, 141.25 (aromatic C).
5.5. (R)-(a-2H)Benzyl alcohol, 5
,
5.6. Cartesian coordinates (in A) of the species
reported in Fig. 1, optimized at the B3LYP/LANL2DZ
To a solution of oxalyl chloride (0.049 ml, 0.62 mmol)
in dry CH2Cl2 (1 ml) at −78°C under N2, dimethyl
sulfoxide (0.08 ml, 1.25 mmol) was added, keeping the
temperature below −50°C. The mixture was stirred for
5 min and a solution of compound 3a (HR=D) (135 mg,
0.57 mmol) in CH2Cl2 (0.5 ml) was added over 10 min.
The mixture was stirred for 15 min, then treated with Et3N
(0.4 ml) and the stirring was continued for additional 15
min. The acetone-solid carbon dioxide bath was removed
and the reaction was quenched with water (2 ml). The
aqueous layer was extracted with CH2Cl2 (3×5 ml) and
the combined organic layers were dried (Na2SO4). Evap-
oration of the solvent under reduced pressure gave crude
3-[(R-a-2H)benzyloxy]-1,1,1-trifluorobutan-2-one (180
mg) which was used in the next step without further
purification.
level
5.6.1. syn-2a.
H
C
O
C
C
O
H
H
C
C
H
H
H
F
−0.386915
−0.386689
1.059449
1.436614
0.191991
−0.905997
2.323340
0.315204
−0.140704
−0.140804
−0.140914
1.217954
2.087154
1.111211
1.518926
2.367554
1.228077
3.314631
3.044397
3.776088
4.050706
0.958889
0.300810
2.489363
−1.324467
−3.572523
−2.353281
−1.419997
−2.540846
−3.478049
−2.280730
−0.622672
−2.614107
−4.270747
−4.439743
−2.415602
−1.315290
−0.899935
−0.534505
−0.908886
−0.806424
−1.103657
−1.967336
0.941731
−0.074117
0.967855
−0.482264
−0.105154
1.840339
1.200860
1.296669
−0.753486
0.271834
−1.618093
0.629775
1.138195
−1.107919
−2.685698
1.291938
2.204164
−1.779171
0.669548
1.854571
−0.154544
−0.345020
−1.059687
0.656467
0.815744
2.863022
The crude 3-[(R-a-2H)benzyloxy]-1,1,1-trifluorobutan-2-
one prepared as above (180 mg) was dissolved in THF
(0.5 ml) and carefully added to a suspension of NaH (296
mg, 50% dispersion in mineral oil) in THF (5 ml) with
stirring under N2. The mixture was stirred at rt for 15
min and then refluxed for 3 h. After cooling to rt the
reaction mixture was treated with MeOH (0.75 ml) and
extracted with water (3×3 ml). The combined aqueous
solutions were acidified with 10% HCl (pH ca. 1),
saturated with solid NaCl and extracted with ethyl acetate
(3×5 ml). The combined organic layers were dried over
Na2SO4 and evaporated under reduced pressure to afford
2-[(R-a-2H)benzyloxy]propanoic acid as a yellow liquid
(70 mg, 66% yield after two steps)
F
F
2.379585
C
C
C
C
C
C
H
H
H
H
H
−1.120265
−2.474300
−1.539835
−1.380559
−2.056870
−2.214944
−1.339036
−1.058518
−2.257693
−2.535643
−2.996301
2-[(R-a-2H)benzyloxy]propanoic acid: 1H NMR (400
MHz) l: 1.52 (d, 3H, J=6.9 Hz, Me); 4.14 (q, 1H, J=6.9

C. F. Morelli et al. / Tetrahedron: Asymmetry 13 (2002) 2609–2618
2617
5.6.2. anti-2a.
H
−4.252366
1.387286
2.762949
0.768449
0.068029
2.964307
−3.482851
−0.907795
−2.493654
−2.044262
−0.875513
0.689387
1.710147
Ti
Cl
Cl
Cl
Cl
−0.989652
−1.771004
0.816313
−2.812053
−0.935896
C
O
C
C
O
H
H
C
C
H
H
H
F
−0.682201
0.399421
0.407434
0.389595
0.085493
0.648705
−0.393763
−1.008689
1.721506
0.667422
1.760112
0.357791
0.301163
2.839821
1.949639
1.705617
1.262492
−0.921141
−3.306652
−1.370135
−1.665890
−2.856603
−2.561522
−0.793863
−1.317331
−3.429415
−2.906093
−4.226178
−0.695201
0.791163
1.260094
−0.014728
−1.083716
2.016818
−0.124025
1.969161
−0.147019
−0.114796
−1.108893
0.652790
1.135366
3.006725
−0.684102
0.696018
1.541837
0.693216
0.806480
1.565845
0.979840
2.944552
2.925714
3.366356
3.597686
0.932081
0.072946
2.259020
−1.266461
−1.225206
−2.304914
−0.837637
−2.157497
−2.693694
−1.374604
−0.115430
−2.447209
−3.410418
−1.069670
−2.721192
5.6.4. anti-A.
C
O
C
0.676809
−0.073213
−0.071741
−0.073178
−0.957031
−0.626476
−0.514097
−1.999214
1.367368
−0.793355
0.221305
−1.487119
−1.031439
2.019661
−1.626209
−0.063715
0.336949
−0.746629
−1.957448
1.331308
0.675772
2.089998
2.747465
1.968994
2.159644
2.530122
2.630663
4.233783
4.468662
4.504624
4.838564
2.725336
1.840303
3.915976
0.643236
−0.451588
−2.555807
−1.576031
−0.372412
−1.422658
−2.628381
−1.634004
0.510561
−1.362482
−3.495753
−3.369529
−1.194243
0.308367
−1.398995
−1.986897
−2.878007
F
F
C
2.564212
O
H
H
C
H
C
C
C
C
C
C
H
H
H
H
H
−1.027659
−1.220928
−2.271937
−2.501004
−0.470126
−0.995318
−3.022644
−3.073030
0.516605
−0.472854
0.434691
C
−1.048849
−1.379420
−1.851306
−0.166290
−0.802494
1.247404
H
H
H
F
F
F
H
C
C
C
C
2.177053
1.358297
0.984983
−0.411564
−4.007942
−2.676706
0.996346
−1.900091
−2.216619
−3.394121
−2.734169
−2.312727
−2.894793
−3.318385
−2.678846
−1.948830
−2.962537
−3.711198
−3.843977
1.374987
−0.866569
−2.322800
−0.192355
−2.272015
−2.997376
−0.919625
0.891838
−2.789197
−4.080482
−0.395943
−2.886305
0.305764
C
C
5.6.3. syn-A.
H
H
H
H
H
Ti
Cl
Cl
Cl
Cl
H
C
O
C
C
O
H
H
C
C
H
H
H
F
−1.640038
0.685598
0.687866
0.689044
2.032413
2.887112
1.926943
2.372204
3.088000
2.006773
4.170812
3.972577
4.640867
4.872434
1.801394
1.023753
3.240308
−0.466494
−2.640984
−1.525888
−0.491622
−1.578269
−2.611848
−1.507255
0.331218
−1.601307
−3.427507
−1.575920
−0.482531
−0.215567
0.259212
−0.133895
0.079776
−0.255275
−1.212617
1.760453
0.628103
1.685258
0.195578
0.548261
2.603164
2.073879
2.130374
0.141328
1.271224
−0.678497
1.529331
2.089516
−0.113616
−1.747944
2.154372
3.158211
−0.747060
−1.633088
−0.017088
0.324585
−0.912377
−2.008955
1.225121
−0.822846
0.661655
−1.211619
−1.405378
−2.100536
−0.374122
−0.437001
1.594736
−0.002942
2.095832
−1.634043
0.867646
3.007713
0.036756
0.682926
2.723047
Acknowledgements
F
We are grateful to MIUR for financial support.
F
1.228429
C
C
C
C
C
C
H
H
H
H
−2.338906
−3.722507
−2.782575
−2.599468
−3.287293
−3.472974
−2.589022
−2.270364
−3.483158
−3.810788
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2618
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