Stereoselective TiCl4-promoted nucleophilic substitution at C-2 of (45,5S)-2-alkyl-4-methyl-5-trifluoromethyl-1,3-dioxolanes

Article abstract of DOI:10.1055/s-2004-834884

TiCl₄-mediated nucleophilic ring-opening reactions of chiral acetals derived from (2S,3S)-1,1,1-trifluorobutane-2,3-diol proceed in a completely regioselective manner, leading to the break of the O1-C2 bond accompanied by a high degree of stereoselectivity. The use of triethylsilyl deuteride or allyltributyltin as nucleophiles gives access, after removal of the chiral auxiliary, to stereoselectively deuterated primary alcohols or homoallylic secondary alcohols, respectively, with high enantiomeric excesses.

Full text of DOI:10.1055/s-2004-834884

PAPER
3005
Stereoselective TiCl4-Promoted Nucleophilic Substitution at C-2 of (4S,5S)-2-
Alkyl-4-methyl-5-trifluoromethyl-1,3-dioxolanes
N
ucleophilic Sub
a
stitution at
r
C-2 of
(
l
4
S
,5
S
)-
o
2-Alkyl-4-methyl-5
F
-trifluorometh
.
yl-1,3-dioxo
M
lanes orelli,* Lavinia Durì, Alberto Saladino, Giovanna Speranza, Paolo Manitto
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, via Venezian, 21, 20133 Milano, Italy
Fax +39(02)50314072; E-mail: carlo.morelli@unimi.it
Received 23 June 2004
ring-opening reactions only in the case of dioxolane 3c.
Abstract: TiCl4-mediated nucleophilic ring-opening reactions of
chiral acetals derived from (2S,3S)-1,1,1-trifluorobutane-2,3-diol
proceed in a completely regioselective manner, leading to the break
of the O1-C2 bond accompanied by a high degree of stereoselectiv-
Attempts to provide the anti-isomer of dioxolane 3a by
acid-catalyzed equilibration of the corresponding syn-di-
astereomeric compound, under various experimental con-
ity. The use of triethylsilyl deuteride or allyltributyltin as nucleo- ditions, were unsuccessful.
philes gives access, after removal of the chiral auxiliary, to
stereoselectively deuterated primary alcohols or homoallylic sec-
ondary alcohols, respectively, with high enantiomeric excesses.
F3C
Me
O
R
R
Key words: Acetals, ring opening, chiral auxiliary, allylations, ste-
reoselectivity
O
CF3
O
anti-3a–e
and/or
HO
HO
H
H
a
+
R
CH
1
CH3
F3C
Me
The Lewis acid-promoted reactions of acetals derived
from optically active diols are a powerful method for the
stereoselective addition of nucleophiles to aldehydes.1
These reactions have been deeply investigated as a tool
for asymmetric synthesis2 and a number of mechanistic
features are now well established.3
O
2
O
CF3
syn-3a–e
Me
CH2(CH2)6CH3
O
b
OH
5
We recently reported3e that the reductive ring-opening re-
action of both 2-epimers of 1,3-dioxolanes 3 prepared
from aromatic aldehydes (1, R = aryl) and (2S,3S)-1,1,1-
trifluorobutane-2,3-diol (2),4 when carried out with trieth-
ylsilyl deuteride in the presence of TiCl4, proceeds with an
almost complete regioselectivity and a high degree of ste-
reoselectivity (see 4 in Scheme 1, where R = aryl and
HR = D).
if R = CH3(CH2)7
c, d, e
Me
HS
HR
R
D
H
F3C
O
1'
OH
OH
6
4a–e
Scheme 1 Reagents and conditions: (a) p-TsOH (cat. amount), to-
luene, reflux; (b) TiCl4, Et3SiH(D), CH2Cl2, –78 °C; (c) Swern oxida-
tion; (d) NaH, wet THF, reflux; (e) TEA, diphenyl phopsphoroazidate
(DPPA), THF, 1 M HCl, reflux. See Table 1 for alkyl residues.
We report here that such procedure can be extended to
deuteride reduction as well as to allylic substitution at the
acetal carbon of trisubstituted 1,3-dioxolanes syn- and
anti-3 where R = alkyl, with maintenance of the selectiv-
ity previously observed.
Dioxolane syn-3a was subjected to reductive ring-open-
ing reaction with Et3SiH and TiCl4 in dichloromethane at
–78 °C to give compound 4a as the only reaction product
(Scheme 1). Its structure was confirmed by comparison
with both the regioisomers 4a and 5 prepared through in-
dependent routes. The former was obtained via protection
of the hydroxyl group in 2-position of 2 as benzyl ether,3e
subsequent alkylation of the remaining hydroxyl group
with 1-bromooctane, and final hydrogenolysis to remove
the protecting group. The latter was synthesized from
(2S,3S)-3-benzyloxy-4,4,4-trifluorobutan-2-ol, an inter-
mediate in the preparation of 2,4 by treatment with 1-bro-
mooctane and NaH in DMF at 60 °C followed by removal
of the benzyl group by hydrogenolysis.
Acetals syn- and anti-3a–e (see Table 1 for R) were ob-
tained by refluxing the diol 2 with the appropriate alde-
hyde in toluene in the presence of a catalytic amount of p-
toluenesulfonic acid with azeotropic removal of water.
Basic aqueous workup followed by flash column chroma-
tography gave the dioxolanes 3a–e as single syn- and anti-
diastereomers. The configuration at the acetal carbon in
1
each of them was assigned by H NOESY experiments.
The syn-diastereomer was obtained as major product in
every case. The isolated quantities of anti- isomer, al-
though enough for a complete NMR characterization of
compounds anti-3b,c,e, were suitable for the subsequent
Replacement of Et3SiH with Et3SiD (isotopic purity
>99% D)5 in the reduction of syn-3a furnished 4a showing
in the 1H NMR spectrum a peak ratio of 96:4 for the two
diastereotopic protons at C1¢ (Scheme 1 and Table 1). The
R configuration at the deuterated carbon in 4a (HR = D)
SYNTHESIS 2004, No. 18, pp 3005–3010
x
x.
x
x
.
2
0
0
4
Advanced online publication: 21.10.2004
DOI: 10.1055/s-2004-834884; Art ID: P06804SS
© Georg Thieme Verlag Stuttgart · New York

3006
C. F. Morelli et al.
PAPER
was assigned on the basis of chemical degradation accord- equivalent of allyltributyltin was added to a premixed so-
ing to the procedure previously reported3e (Swern oxida- lution of TiCl4 and syn-3b, the isolated yield of 7b in-
tion, subsequent haloform reaction and Curtius creased to ca. 90% (Scheme 2).
rearrangement; ca. 20% overall yield) and comparison of
Removal of the chiral auxiliary from 7b as mentioned
above (see Scheme 1 and ref. 3e), led to the homoallylic
the resulting monodeuterated alcohol 6 with a sample of
enantiopure (S)-(1-2H)-octan-1-ol prepared enzymatical-
alcohol 8 (ca. 20% overall yield) which was shown to
ly.6 1H NMR spectra of (+)-MPTA esters7 of the two enan-
have the expected S configuration and 93% ee on the basis
tiopure alcohols, together with that of the racemic
monodeuterated alcohol, were used for comparison. The
ee (85%) of 6 derived from dioxolane ring-opening was
1
of its optical rotation8 and H NMR analysis in the pres-
ence of Eu(hfc)3.
consistent with the diastereoselectivity in the deuteride re-
Me
duction of the cyclic acetal 3a (Table 1) in combination
with the optical purity (ca. 95%) of the auxiliary used.4
F3C
a
3a,b,d
O
R
OH
In analogous experiments, summarized in Table 1, com-
pounds 4b–e (HR = D) were obtained in good or moderate
yields and high diastereoselectivity.
7a,b,d
if R = C6H5CH2CH2
b, c, d
It can be noted that, as reported for benzylidene acetals,3e
both epimers of 3c gave the same absolute configuration
at the deuterated carbon as well as comparable diastereo-
selectivity and chemical yield. The results presented here,
together with those previously described, indicate that
TiCl4-catalyzed deuteride reductions of cyclic acetals de-
rived from (2S,3S)-1,1,1-trifluorobutane-2,3-diol are
characterized by complete regioselectivity, high diaste-
reoselectivity and satisfactory yields independent of the
‘activated’ aldehyde (aromatic, aliphatic or a,b-unsaturat-
ed). Thus, a common mechanistic rationale can be as-
sumed as described in the literature.3e
OH
8
Scheme 2 Reagents and conditions: (a) TiCl4, allyltributylstannane
CH2Cl2, –78 °C; for (b)–(d) see reagents (c)–(e) of Scheme 1. See Ta-
ble 1 for R.
In a similar manner, compounds 7a,d were obtained in
good yields starting from the corresponding syn-diox-
olanes 3a,d. It is to note that compounds 7a,b,d were ob-
tained in their diastereomeric pure form as the only
reaction products. Only in the case of dioxolane 3d, a
small amount (<5% yield) of the diastereomeric allylated
ether was isolated from the reaction mixture. This find-
ings confirm that the reaction proceeds in a almost com-
pletely regio- and stereoselective fashion; minor
diastereomeric allylic derivatives, if present, could be re-
moved by chromatographic purification, affording the
main reaction product in a diastereomerically pure form
and in good chemical yields. Thus, the ee of the product
depends entirely on the ee of the chiral auxiliary.4
Table 1 TiCl4-Mediated Reaction of Compounds syn-3 with Et3SiD
to Give Compounds 4
1,3-Dioxolane (syn-3)
Compound 4
Entry
R
Isolated yields Diastereomeric
(%)
ratio (at C-1¢)a
R:S
a
b
c
CH3(CH2)6
86
96:4
C6H5CH2CH2
C6H5CH2
84
97:3
89 (85)b
67
97:3 (92:8)b
97:3
d
e
Cyclohexyl
(E)-C6H5CH=CH
TLC was performed on silica gel F254 precoated aluminum sheets
(0.2 mm layer, Merck, Darmstadt, Germany); components were de-
tected by spraying a ceric sulfate ammonium molybdate solution,
followed by heating to ca. 150 °C. Silica gel (Merck, 40–63 mm)
was used for flash chromatography (FC). 1H and 13C NMR spectra
were recorded at 400.132 and 100.613 MHz on a Bruker AVANCE
400 spectrometer using a Xwin-NMR software package and at
300.133 and 75.469 on a Bruker AC 300 (Bruker, Karlsruhe, Ger-
many) equipped with an ASPECT 3000 data system. Chemical
shifts (d) are given in ppm and were referenced to the signals of
CDCl3 (dH 7.25 and dC 77.00 ppm). 13C NMR signal multiplicities
were based on APT spectra. All reagents were of commercial qual-
ity or purified prior to use by standard methods.
62
93:7c
a Determined by integration of the two C-1¢ protons in the 1H NMR
spectra on the assumption, based on the configuration of 6, that the
downfield signal was due to Hs and the isotopic abundance of every
examined compound was >99% (as in Et3SiD, compare ref. 5).
b Referred to the reaction of anti-3.
c Determined after conversion to compound 4b by catalytic hydroge-
nation.
This conclusion prompted us to explore the synthetic po-
tential of the regio- and stereoselectivity of ring-opening
reactions of trifluoromethyl-substituted 1,3-dioxolanes
with the involvement of C-nucleophiles. In this regard, the
reaction of syn-3b with equimolar amounts of TiCl4 and
allyltriethylsilane under usual conditions afforded com-
pound 7b in 73% chemical yield. However, when an
Preparation of Dioxolanes syn- and anti-3a–e; General Proce-
dure
A solution of (2S,3S)-1,1,1-trifluorobutane-2,3-diol (2, 1.5 mmol),
the appropriate aldehyde (1.6 mmol) and a catalytic amount of p-
toluenesulfonic acid in toluene (3 mL), was refluxed for 1 h with re-
Synthesis 2004, No. 18, 3005–3010 © Thieme Stuttgart · New York

PAPER
Nucleophilic Substitution at C-2 of (4S,5S)-2-Alkyl-4-methyl-5-trifluoromethyl-1,3-dioxolanes
3007
moval of water from the reaction mixture by means of a Dean–Stark
apparatus. The mixture was cooled to r.t., diluted with EtOAc (10
mL), washed with sat. NaHCO3 (2 × 10 mL), with a 10% solution
of NaHSO3 (2 × 10 mL) and with sat. NaCl solution (1 × 10 mL).
After drying (Na2SO4), the solution was evaporated under reduced
pressure and the residue was chromatographed by flash column
chromatography with the appropriate eluent mentioned below.
(2S,4S,5S)-2-Benzyl-4-methyl-5-(trifluoromethyl)-1,3-diox-
olane (syn-3c) and (2R,4S,5S)-2-Benzyl-4-methyl-5-(trifluoro-
methyl)-1,3-dioxolane (anti-3c)
syn-3c
Pale yellow liquid, obtained from (2S,3S)-1,1,1-trifluorobutane-
2,3-diol (2) and phenylacetaldehyde in 49% yield.
FC: EtOAc–hexane, 1:15; [a]D +15.76 (c 0.59, EtOH).
1H NMR (300 MHz, CDCl3): d = 1.49 (dq, 3 H, JHH = 6.0 Hz,
JHF = 1.7 Hz, Me), 3.04 (d, 2 H, J = 5.1 Hz, CH2Ph), 4.16 (dq, 1 H,
JHH = JHF = 7.0 Hz, H-5), 4.23–4.29 (m, 1 H, H-4), 5.16 (t, 1 H,
J = 5.1 Hz, H-2), 7.19–7.42 (m, 5 H, aromatic H).
(2S,4S,5S)-2-Heptyl-4-methyl-5-(trifluoromethyl)-1,3-diox-
olane (syn-3a)
Pale yellow liquid, obtained from (2S,3S)-1,1,1-trifluorobutane-
2,3-diol (2) and octanal in 89% yield.
13C NMR (75 MHz, CDCl3): d = 13.48 (Me), 40.67 (CH2Ph), 74.28
FC: EtOAc–hexane, 1:20; [a]D +30.83 (c 1.08, CHCl3).
2
(C-4), 74.95 (q, JCF = 30.9 Hz, C-5), 105.30 (C-2), 123.56 (q,
1H NMR (400 MHz, CDCl3): d = 0.90 (t, 3 H, J = 6.8 Hz, Me),
1.25–1.38 (m, 8 H, 4 CH2), 1.42–1.48 (m, 2 H, CH2), 1.49 (dq, 3 H,
JHH = 6.6 Hz, JHF = 2.0 Hz, Me-4), 1.71–1.78 (m, 2 H, CH2), 4.19
(dq, 1 H, JHH = JHF = 6.6 Hz, H-5), 4.25 (dqq, 1 H, JHH = 6.6 Hz,
JHF = 2.0 Hz, H-4), 4.99 (t, 1 H, J = 4.8 Hz, H-2).
13C NMR (75 MHz, CDCl3): d = 13.48 (Me), 14.03 (Me), 22.58,
23.79, 29.11, 29.39, 31.71, 33.55 (7 CH2), 74.07 (C-4), 74.83 (q,
2JCF = 30.5 Hz, C-5), 105.24 (C-2), 123.59 (q, JCF = 280.5 Hz, CF3).
JCF = 279.0 Hz, CF3), 126.85, 128.41, 129.68, 135.40 (aromatic C).
Anal. Calcd for C12H13F3O2 (246.23): C, 58.54; H, 5.32. Found: C,
58.19; H, 5.51.
anti-3c
Pale yellow liquid, obtained from (2S,3S)-1,1,1-trifluorobutane-
2,3-diol (2) and phenylacetaldehyde in 20% yield.
FC: EtOAc–hexane, 1:15.
Anal. Calcd for C12H21F3O2 (254.29): C, 56.68; H, 8.32. Found: C,
56.87; H, 8.03.
1H NMR (300 MHz, CDCl3): d = 1.35 (d, 3 H, J = 5.8 Hz, Me), 2.94
(d, 2 H, J = 4.4 Hz, CH2Ph), 4.16–4.27 (m, 2 H, H-4 and H-5), 5.56
(t, 1 H, J = 4.4 Hz, H-2), 7.21–7.39 (m, 5 H, aromatic H).
(2S,4S,5S)-4-Methyl-2-(2-phenylethyl)-5-(trifluoromethyl)-1,3-
dioxolane (syn-3b) and (2R,4S,5S)- 4-Methyl-2-(2-phenylethyl)-
5-(trifluoromethyl)-1,3-dioxolane (anti-3b)
13C NMR (75 MHz, CDCl3): d = 13.93 (Me), 41.29 (CH2Ph), 72.55
2
(C-4), 75.73 (q, JCF = 31.5 Hz, C-5), 105.36 (C-2), 123.81 (q,
syn-3b
JCF = 281.2 Hz, CF3), 126.79, 128.35, 129.96, 135.23 (aromatic C).
Pale yellow liquid, obtained from (2S,3S)-1,1,1-trifluorobutane-
2,3-diol (2) and 3-phenylpropanal in 70% yield.
Anal. Calcd for C12H13F3O2 (246.23): C, 58.54; H, 5.32. Found: C,
58.31; H, 5.44.
FC: EtOAc–hexane, 1:20; [a]D +25.05 (c 1.01, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.50 (dq, 3 H, JHH = 6.5 Hz,
JHF = 1.8 Hz, Me), 2.03–2.08 (m, 2 H, CH2), 2.76–2.80 (m, 2 H,
CH2Ph), 4.19 (dq, 1 H, JHH = JHF = 6.5 Hz, H-5), 4.26 (dqq, 1 H,
JHH = 6.5 Hz, JHF = 1.9 Hz, H-4), 5.00 (t, 1 H, J = 4.7 Hz, H-2),
7.19–7.22 (m, 3 H, aromatic H), 7.26–7.30 (m, 2 H, aromatic H).
(2S,4S,5S)-2-Cyclohexyl-4-methyl-5-(trifluoromethyl)-1,3-di-
oxolane (syn-3d)
Pale yellow liquid, obtained from (2S,3S)-1,1,1-trifluorobutane-
2,3-diol (2) and cyclohexanecarboxaldehyde in 63% yield.
FC: EtOAc–hexane, 1:16; [a]D +32.90 (c 1.00, CHCl3).
13C NMR (100 MHz, CDCl3): d = 13.50 (Me), 29.76 (CH2), 34.95
(CH2Ph), 74.23 (C-4), 74.99 (q, 2JCF = 32.6 Hz, C-5), 104.27 (C-2),
123.59 (q, JCF = 281.7 Hz, CF3), 125.95, 128.38, 141.18 (aromatic
C).
1H NMR (400MHz, CDCl3): d = 1.06–1.28 (m, 5 H, cyclohexyl),
1.47 (dq, 3 H, JHH = 6.6 Hz, JHF = 1.8 Hz, Me), 1.58–1.70 (m, 2 H,
cyclohexyl), 1.73–1.86 (m, 4 H, cyclohexyl), 4.17 (dq, 1 H,
JHH = JHF = 6.6 Hz, H-5), 4.22 (dqq, 1 H, JHH = 6.6 Hz, JHF = 2.0
Hz, H-4), 4.69 (d, 1 H, J = 5.1 Hz, H-2).
13C NMR (100 MHz, CDCl3): d = 13.85 (Me), 25.98, 26.00, 26.67,
27.41, 27.54, 41.40 (cyclohexyl), 74.33 (C-4), 75.11 (q, 2JCF = 31.2
Hz, C-5), 108.37 (C-2), 124.00 (q, JCF = 282.6 Hz, CF3).
Anal. Calcd for C13H15F3O2 (260.25): C, 60.00; H, 5.81. Found: C,
59.85; H, 5.62.
anti-3b
Pale yellow liquid, obtained from (2S,3S)-1,1,1-trifluorobutane-
2,3-diol (2) and 3-phenylpropanal in 10% yield.
Anal. Calcd for C11H17F3O2 (238.25): C, 55.45; H, 7.19. Found: C,
55.60; H, 6.98.
FC: EtOAc–hexane, 1:20.
1H NMR (400 MHz, CDCl3): d = 1.41–1.43 (m, 3 H, Me), 1.88–2.04
(m, 2 H, CH2), 2.75 (t, 2 H, J = 8.5 Hz, CH2Ph), 4.32 (dq, 1 H,
JHH = JHF = 6.4 Hz, H-5), 4.47 (br dq, 1 H, J = 6.4 Hz, H-4), 5.36 (t,
1 H, J = 5.0 Hz, H-2), 7.17–7.20 (m, 3 H, aromatic H), 7.26–7.30
(m, 2 H, aromatic H).
13C NMR (100 MHz, CDCl3): d = 14.46 (Me), 30.19 (CH2), 36.59
(CH2Ph), 72.93 (C-4), 76.12 (q, 2JCF = 31.1 Hz, C-5), 105.20 (C-2),
124.34 (q, JCF = 283.3 Hz, CF3), 126.41, 128.74, 128.78, 141.52
(aromatic C).
(2S,4S,5S)-4-Methyl-2-[(E)-2-styryl]-5-(trifluoromethyl)-1,3-
dioxolane (syn-3e) and (2R,4S,5S)- 4-methyl-2-[(E)-2-styryl]-5-
(trifluoromethyl)-1,3-dioxolane (anti-3e)
syn-3e
Pale yellow liquid, obtained from (2S,3S)-1,1,1-trifluorobutane-
2,3-diol (2) and cinnamaldehyde in 65% yield.
FC: EtOAc–hexane, 1:16; [a]D +11.73 (c 1.04, EtOH).
1H NMR (300 MHz, CDCl3): d = 1.52–1.56 (m, 3 H, Me), 4.28 (dq,
1 H, JHH = JHF = 7.1 Hz, H-5), 4.29–4.40 (m, 1 H, H-4), 5.50 (d, 1
H, J = 6.7 Hz, H-2), 6.16 (dd, 1 H, J = 16.0, 6.7 Hz, H-1¢), 6.82 (d,
1 H, J = 16.0 Hz, H-2¢), 7.29–7.38 (m, 3 H, aromatic H), 7.40–7.46
(m, 2 H, aromatic H).
Anal. Calcd for C13H15F3O2 (260.25): C, 60.00; H, 5.81. Found: C,
59.79; H, 5.95
13C NMR (75 MHz, CDCl3): d = 13.50 (Me), 66.48 (C-4), 72.43 (q,
2JCF = 30.1 Hz, C-5), 104.84 (C-2), 123.67 (C-1¢), 124.15 (q,
JCF = 281.0 Hz, CF3), 128.36, 129.98, 134.01 (aromatic C), 136.90
(C-2¢).
Synthesis 2004, No. 18, 3005–3010 © Thieme Stuttgart · New York

3008
C. F. Morelli et al.
PAPER
Anal. Calcd for C13H13F3O2 (258.24): C, 60.46; H, 5.07. Found: C,
60.51; H, 5.12.
74.10 (CHCH3), 125.05 (q, JCF = 282.0 Hz, CF3), 126.59, 129.10,
142.38 (aromatic C).
anti-3e
(2S,3S)-1,1,1-Trifluoro-3-[(1R)-2-phenylethoxy]butan-2-ol (4c)
Obtained from (2S,4S,5S)-2-benzyl-4-methyl-5-(trifluoromethyl)-
1,3-dioxolane (syn-3c) in 89% yield.
Pale yellow liquid, obtained from (2S,3S)-1,1,1-trifluorobutane-
2,3-diol (2) and cinnamaldehyde in 15% yield.
FC: EtOAc–hexane, 1:15.
Pale yellow liquid; FC: EtOAc–hexane, 1:9; [a]D +9.13 (c 1.04,
EtOH).
1H NMR (400 MHz, CDCl3): d = 1.51 (dq, 3 H, JHH = 6.6 Hz,
JHF = 1.8 Hz, Me), 4.42 (dq, 1 H, JHF = 7.6 Hz, JHH = 6 Hz, H-5),
4.51–4.52 (m, 1 H, H-4), 5.90 (d, 1 H, J = 5.6 Hz, H-2), 6.16 (dd, 1
H, J = 15.6, 5.6 Hz, H-1¢), 6.79 (d, 1 H, J = 15.6 Hz, H-2¢), 7.28–
7.38 (m, 3 H, aromatic H), 7.41–7.46 (m, 2 H, aromatic H).
1H NMR (400 MHz, CDCl3): d = 1.26 (d, 3 H, J = 6.6 Hz, Me), 2.50
(br s, 1 H, OH), 2.90 (d, 2 H, J = 7.2 Hz, CH2Ph), 3.59 (br t, 0.97 H,
J = 7.2 Hz, CHD), 3.69 (dq, 1 H, J = 4.0, 6.6 Hz, CHCH3), 3.83 (br
t, 0.03 H, J = 7.2 Hz, CHD), 3.99 (dq, 1 H, JHH = 4.0 Hz, JHF = 7.2
Hz, CHCF3), 7.23–7.27 (m, 3 H, aromatic H), 7.31–7.34 (m, 2 H,
aromatic H).
13C NMR (100 MHz, CDCl3): d = 14.22 (Me), 72.83 (C-4), 76.00
2
(q, JCF = 30.9 Hz, C-5), 104.69 (C-2), 124.20 (q, JCF = 281.4 Hz,
CF3), 125.12 (C-1¢), 127.36, 129.06 (aromatic C), 134.94 (C-2¢),
135.89 (aromatic C).
13C NMR (75 MHz, CDCl3): d = 14.13 (Me), 36.32 (CH2Ph), 69.91
2
(JCD = 22.0 Hz, CHD), 71.71 (q, JCF = 30.0 Hz, CHCF3), 73.99
(CHCH3), 124.29 (q, JCF = 280.6 Hz, CF3), 126.47, 128.48, 128.87,
138.58 (aromatic C).
Anal. Calcd for C13H13F3O2 (258.24): C, 60.46; H, 5.07. Found: C,
60.38; H, 4.97.
Obtained from (2R,4S,5S)-2-benzyl-4-methyl-5-(trifluoromethyl)-
1,3-dioxolane (anti-3c) in 85% yield.
Reductive Ring-Opening Reactions of Acetals with TiCl4/
Et3SiH(D); General Procedure
1H NMR (400 MHz, CDCl3): d = 1.27 (d, 3 H, J = 6.6 Hz, Me), 2.60
(br s, 1 H, OH), 2.90 (d, 2 H, J = 7.2 Hz, CH2Ph), 3.56 (br t, 0.92 H,
J = 7.2 Hz, CHD), 3.71 (dq, 1 H, J = 4.0, 6.6 Hz, CHCH3), 3.83 (br
t, 0.08 H, J = 7.2 Hz, CHD), 3.99 (dq, 1 H, JHH = 4.0 Hz, JHF = 7.2
Hz, CHCF3), 7.22–7.27 (m, 3 H, aromatic H), 7.30–7.34 (m, 2 H,
aromatic H).
A 1 M solution of TiCl4 in CH2Cl2 (0.26 mL) was added dropwise
over ca. 2.5 min to a solution of the 1,3-dioxolane (0.50 mmol) and
Et3SiH(D) (0.55 mmol) in anhyd CH2Cl2 (2.5 mL) at –78 °C under
N2, and the mixture was stirred for 15 min. After quenching with
MeOH (0.20 mL) and further stirring for 5 min while warming to
r.t., the reaction mixture was diluted with CH2Cl2 (5 mL), washed
with 1 M HCl (2 × 5 mL) and with sat. NaCl solution (1 × 5 mL),
and dried (Na2SO4). Removal of the solvent under reduced pressure
gave the reaction product which was purified by flash chromatogra-
phy with the eluents mentioned below.
(2S,3S)-3-[(R)-Cyclohexylmethoxy]-1,1,1-trifluorobutan-2-ol
(4d)
Obtained from (2S,4S,5S)-2-cyclohexyl-4-methyl-5-(trifluoro-
methyl)-1,3-dioxolane (syn-3d) in 67% yield.
Pale yellow liquid; FC: EtOAc–hexane, 1:10; [a]D +22.4 (c 1.12,
(2S,3S)-1,1,1-Trifluoro-3-(octyloxy)butan-2-ol (4a)
Obtained from (2S,4S,5S)-2-heptyl-4-methyl-5-(trifluoromethyl)-
1,3-dioxolane (syn-3a) in 86% yield.
EtOH).
1H NMR (400 MHz, CDCl3): d = 0.86–0.95 (m, 2 H, cyclohexyl),
1.14–1.21 (m, 2 H, cyclohexyl), 1.25 (d, 3 H, J = 6.4 Hz, Me), 1.51–
1.57 (m, 2 H, cyclohexyl), 1.65–1.70 (m, 1 H, cyclohexyl), 1.69–
1.80 (m, 4 H, cyclohexyl), 2.58–2.65 (br s, 1 H, OH), 3.17 (d, 0.97
H, J = 6.5 Hz, CHD), 3.35 (d, 0.03 H, J = 6.5 Hz, CHD), 3.64 (dq,
1 H, J = 6.4, 4.3 Hz, CHCH3), 4.03 (dq, 1 H, JHF = 7.3 Hz, JHH = 4.3
Hz, CHCF3).
13C NMR (100 MHz, CDCl3): d = 14.27 (Me), 25.91, 26.66, 29.78
(CH2 cyclohexyl), 38.18 (CH cyclohexyl), 72.01 (q, 2JCF = 29.6 Hz,
CHCF3), 73.88 (CHCH3), 74.95 (t, JCD = 21.5 Hz, CHD), 125.54 (q,
JCF = 282.5 Hz, CF3).
Pale yellow liquid; FC: EtOAc–hexane, 1:9; [a]D +2.25 (c 1.12,
EtOH).
1H NMR (400 MHz, CDCl3): d = 0.89 (t, 3 H, J = 7.0 Hz, Me), 1.27
(d, 3 H, J = 6.4 Hz, Me), 1.28–1.38 (m, 10 H, 5 CH2 octyl), 1.58 (dt,
2 H, J = 7.2 Hz, CH2 octyl), 2.60 (d, 1 H, J = 5.2 Hz, OH), 3.36 (br
t, 0.96 H, J = 7.2 Hz, CHD), 3.53 (br t, 0.04 H, J = 7.2 Hz, CHD),
3.67 (dq, 1 H, J = 6.4, 4.1 Hz, CHCH3), 4.03–4.07 (m, 1 H, CHCF3).
13C NMR (75 MHz, CDCl3): d = 13.94 (Me), 13.96 (Me), 22.53,
25.89, 29.12, 29.25, 29.56, 31.71 (CH2), 69.08 (t, JCD = 22.0 Hz,
2
CHD), 71.75 (q, JCF = 29.5 Hz, CHCF3), 73.60 (CHCH3), 124.29
(q, JCF = 281.2 Hz, CF3).
(2S,3S)-1,1,1-Trifluoro-3-{[(1R,2E)-3-phenylprop-2-en-1-
yl]oxy}butan-2-ol (4e)
Obtained from (2S,4S,5S)-4-methyl-2-[(E)-2-styryl]-5-(trifluoro-
methyl)-1,3-dioxolane (syn-3e) in 62% yield.
(2S,3S)-1,1,1-Trifluoro-3-{[(1R)-3-phenylpropyl]oxy}butan-2-
ol (4b)
Obtained from (2S,4S,5S)-4-methyl-2-(2-phenylethyl)-5-(trifluo-
romethyl)-1,3-dioxolane (syn-3b) in 84% yield.
Pale yellow liquid; FC: EtOAc–hexane, 1:8; [a]D +8.24 (c 1.03,
EtOH).
Pale yellow liquid; FC: EtOAc–hexane, 1:12; [a]D +22.36 (c 1.06,
EtOH).
1H NMR (400 MHz, CDCl3): d = 1.32 (d, 3 H, J = 6.4 Hz, Me), 2.60
(d, 1 H, J = 5.6 Hz, OH), 3.84 (dq, 1 H, J = 4.0, 6.4 Hz, CHCH3),
4.08–4.15 (m, 1 H, CHCF3), 4.14 (dd, >0.90 H, J = 6.0, 1.4 Hz,
CHD), 4.26 (dd, <0.10 H, J = 6.0, 1.4 Hz, CHD), 6.26 (dd, 1 H,
J = 15.8, 6.0 Hz, vinylic H), 6.62 (dd, 1 H, J = 15.8, 1.4 Hz, vinylic
H), 7.24–7.35 (m, 3 H, aromatic H), 7.38–7.40 (m, 2 H, aromatic
H).
1H NMR (400 MHz, CDCl3): d = 1.28 (d, 3 H, J = 6.4 Hz, Me), 1.92
(dt, 2 H, J = 7.2 Hz, CH2), 2.56 (d, 1 H, J = 5.6 Hz, OH), 2.72 (t, 2
H, J = 7.2 Hz, CH2Ph), 3.40 (br t, 0.97 H, J = 7.2 Hz, CHD), 3.58
(br t, 0.03 H, J = 7.2 Hz, CHD), 3.69 (dq, 1 H, J = 4.0, 6.4 Hz,
CHCH3), 4.05 (ddq, 1 H, JHH = 5.6, 4.0 Hz, JHF = 7.4 Hz, CHCF3),
7.20–7.23 (m, 2 H, aromatic H), 7.29–7.31 (m, 3 H, aromatic H).
13C NMR (100 MHz, CDCl3): d = 14.20 (Me), 69.44 (t, JCD = 21.5
13C NMR (75 MHz, CDCl3): d = 14.15 (Me), 31.25, 32.31 (CH2),
68.39 (t, JCD = 22.5 Hz, CHD), 72.23 (q, JCF = 30.1 Hz, CHCF3),
2
Hz, CHD), 71.96 (q, JCF = 30.0 Hz, CHCF3), 72.90 (CHCH3),
2
124.32 (q, JCF = 282.3 Hz, CF3), 125.12 (vinylic C), 126.50, 127.88,
128.56 (aromatic C), 133.11 (vinylic C), 136.35 (aromatic C).
Synthesis 2004, No. 18, 3005–3010 © Thieme Stuttgart · New York

PAPER
Nucleophilic Substitution at C-2 of (4S,5S)-2-Alkyl-4-methyl-5-trifluoromethyl-1,3-dioxolanes
3009
Allylation Reactions of Dioxolanes with TiCl4/Allyltributyltin;
General Procedure
d, 1 H, J = 5.8 Hz, OH), 3.19 (m, 1 H, CHO), 3.78 (dq, 1 H, J = 6.4,
3.0 Hz, CHCH3), 4.05–4.13 (m, 1 H, CHCF3), 5.05–5.12 (m, 2 H,
vinylic CH2), 5.82 (ddt, 1 H, J = 17.0, 10.4, 7.1 Hz, vinylic CH).
To a solution of the 1,3-dioxolane (0.5 mmol) in CH2Cl2 (2.5 mL),
cooled to –78 °C, 1M TiCl4 solution in CH2Cl2 (0.52 mL) was add-
ed dropwise over ca. 2.5 min. After 5 min, allyltributylstannane was
added dropwise over 2 min and the mixture was stirred at –78 °C for
15 min. The reaction was quenched with MeOH (0.5 mL) and
warmed to r.t. The mixture was diluted with CH2Cl2 (5 mL), washed
with 1 M HCl (2 × 5 mL) and with sat. NaCl solution (1 × 5 mL)
and dried (Na2SO4). The solvent was evaporated under reduced
pressure and the product was purified by flash column chromatog-
raphy with the eluents mentioned below.
13C NMR (100 MHz, CDCl3): d = 14.90 (Me), 26.67, 26.92, 29.11
(CH2 cyclohexyl), 36.09 (allylic CH2), 41.25 (CH cyclohexyl),
2
72.34 (q, JCF = 29.8 Hz, CHCF3), 72.40 (CHCH3), 82.80 (CHO),
117.36 (vinylic CH2), 124.60 (q, JCF = 281.9 Hz, CF3), 135.43 (vi-
nylic CH).
Anal. Calcd for C14H23F3O2 (280.33): C, 59.98; H, 8.27. Found: C,
59.77; H, 8.11.
Alternative Synthesis of (2S,3S)-1,1,1-Trifluoro-3-(octyloxy)bu-
tan-2-ol (4a)
(2S,3R)-1,1,1-Trifluoro-3-{[(1S)-1-heptylbut-3-en-1-yl]oxy}bu-
tan-2-ol (7a)
Obtained from (2S,4S,5S)-2-heptyl-4-methyl-5-(trifluoromethyl)-
To a solution of (2S,3S)-1,1,1-trifluorobutane-2,3-diol (2, 302 mg,
2.09 mmol) in freshly distilled THF (10 mL), tBuOK (236 mg, 2.10
mmol) was added and the mixture was refluxed for 15 min. Benzyl
bromide (0.25 mL, 2.10 mmol) was then added, the mixture was re-
fluxed for 3 h, cooled to r.t., diluted with EtOAc (15 mL), washed
with H2O (2 × 10 mL), 1 M HCl (1 × 10 mL), and sat. NaCl (1 × 10
mL). The separated organic layer was dried (Na2SO4) and evaporat-
ed under reduced pressure. The residue was purified by flash chro-
matography (EtOAc–hexane, 1:5) to give (2S,3R)-3-benzyloxy-
4,4,4-trifluorobutan-2-ol as pale yellow liquid, 250 mg (51% yield).
1H NMR (300 MHz, CDCl3): d = 1.27 (d, 3 H, J = 6.5 Hz, Me), 1.85
(br s, 1 H, OH), 3.81 (dq, 1 H, J = 7.1, 4.4 Hz, CHCF3), 4.05 (dq, 1
H, J = 6.5, 4.4 Hz, CHCH3), 4.63 (d, 1 H, J = 11.2 Hz, CH2Ph), 4,90
(d, 1 H, J = 11.2 Hz, CH2Ph), 7.36–7.40 (m, 5 H, aromatic H).
1,3-dioxolane (3a) in 80% yield.
Pale yellow liquid; FC: CH2Cl2; [a]D +1.11 (c 1.02, EtOH).
1H NMR (300 MHz, CDCl3): d = 0.89 (t, 3 H, J = 7.0 Hz, Me),
1.30–1.45 (m, 13 H, 5 CH2 octyl and Me), 1.57–1.67 (m, 2 H, CH2
octyl), 2.17–2.28 (m, 2 H, allylic CH2), 2.93 (br, 1 H, OH), 3.38 (tt,
1 H, J1 = J2 = 5.7 Hz, CHO), 3.75 (dq, 1 H, J = 6.4, 3.4 Hz,
CHCH3), 3.98–4.07 (m, 1 H, CHCF3), 5.02–5.08 (m, 2 H, vinylic
H), 5.71–5.82 (m, 1 H, vinylic H).
13C NMR (75 MHz, CDCl3): d = 13.56 (Me), 14.03 (Me), 22.60,
25.31, 29.20, 29.68, 31.77, 33.79, 38.81 (CH2), 71.59 (CHCH3),
2
72.05 (q, JCF = 30.1 Hz, CHCF3), 78.07 (CHO), 117.19 (vinylic
CH2), 124.38 (q, JCF = 281.1 Hz, CF3), 134.56 (vinylic CH).
13C NMR (75 MHz, CDCl3): d = 17.97 (Me), 66.32 (CHCH3), 75.20
(CH2Ph), 80.17 (q, 2JCF = 26.2 Hz, CHCF3), 124.73 (q, JCF = 283.5
Hz, CF3), 128.14, 128.34, 128.59, 136.79 (aromatic C).
Anal. Calcd for C15H27F3O2 (296.37): C, 60.79; H, 9.18. Found: C,
60.63; H, 8.98.
To a suspension of NaH (190 mg, 50% dispersion in mineral oil,
3.96 mmol) in DMF (5 mL), (2S,3R)-3-benzyloxy-4,4,4-trifluoro-
butan-2-ol prepared as above (250 mg, 1.05 mmol) was added, fol-
lowed by bromooctane (0.28 mL, 1.60 mmol). The mixture was
stirred at 60 °C for 1.5 h, cooled to r.t. and treated cautiously with
H2O until evolution of H2 ceased. The solution was concentrated
under reduced pressure, the residue was taken up in EtOAc (5 mL),
washed with 1 M HCl (2 × 5 mL), with sat. NaCl solution (1 × 5
mL), and dried (Na2SO4). The solvent was removed under reduced
pressure affording 580 mg of a chromatographically homogeneous
yellow oil which was used in the subsequent step without further
purification.
(2S,3R)-1,1,1-Trifluoro-3-{[(1S)-1-(2-phenylethyl)but-3-en-1-
yl]oxy}butan-2-ol (7b)
Obtained from (2S,4S,5S)-4-methyl-2-(2-phenylethyl)-5-(trifluo-
romethyl)-1,3-dioxolane (3b) in 85% yield.
Pale yellow liquid; FC: CH2Cl2–light petroleum, 1:1; [a]D +1.04 (c
1.55, EtOH).
1H NMR (400 MHz, CDCl3): d = 1.25 (d, 3 H, J = 6.4 Hz, Me), 1.85
(dt, 2 H, J = 7.9, 5.8 Hz, PhCH2CH2), 2.32–2.36 (m, 2 H, allylic
CH2), 2.65 (br d, 1 H, J = 5.0 Hz, OH), 2.65 (dt, 1 H, J = 13.8, 7.9
Hz, CH2Ph), 2.72 (dt, 1 H, J = 13.8, 7.9 Hz, CH2Ph), 3.50 (tt, 1 H,
J1 = J2 = 5.8 Hz, CHO), 3.80 (dq, 1 H, J = 6.4, 3.6 Hz, CHCH3),
3.97–4.05 (m, 1 H, CHCF3), 5.10–5.15 (m, 2 H, vinylic CH2), 5.83
(ddt, 1 H, J = 18.0, 10.1, 7.1 Hz, vinylic H), 7.19–7.23 (m, 2 H, ar-
omatic H), 7.28–7.33 (m, 3 H, aromatic H).
({[(1R,2S)-2-(Octyloxy)-1-(trifluoromethyl)propyl]oxy}meth-
yl)benzene
1H NMR (300 MHz, CDCl3): d = 0.86 (t, 3 H, J = 6.8 Hz, Me),
1.15–1.40 (m, 13 H, 5 CH2 and Me), 1.42–1.60 (m, 2 H, CH2), 3.29
(dt, 1 H, J = 8.9, 6.4 Hz, CH2O), 3.44 (dt, 1 H, J = 8.9, 6.4 Hz,
CH2O), 3.63 (dq, 1 H, J = 6.8, 4.1 Hz, CHCH3), 3.80 (dq, 1 H,
JHH = 4.1, JHF = 7.4 Hz, CHCF3), 4.69 (d, 1 H, J = 11.3 Hz,
PhCH2O), 4.79 (d, 1 H, J = 11.3 Hz, PhCH2O), 7.24–7.47 (m, 5 H,
aromatic H).
13C NMR (100 MHz, CDCl3): d = 15.24 (Me), 31.92, 35.70, 39.25
2
(CH2), 72.06 (CHCH3), 72.54 (q, JCF = 30.2 Hz, CHCF3), 77.64
(CHO), 117.94 (vinylic CH2), 124.64 (q, JCF = 282.3 Hz, CF3),
126.39, 128.65, 128.89 (aromatic C), 134.64 (vinylic CH), 142.11
(aromatic C).
Anal. Calcd for C16H21F3O2 (302.33): C, 63.56; H, 7.00. Found: C,
63.42; H, 6.92.
To a suspension of Pd/C (210 mg, 10% Pd) in MeOH (15 mL) under
an atmosphere of H2, a solution of crude ({[(1R,2S)-2-(octyloxy)-1-
(trifluoromethyl)propyl]oxy}methyl)benzene prepared as above
(550 mg, 1.05 mmol) in MeOH (5 mL) was added and the reaction
mixture was stirred overnight at r.t. The catalyst was filtered off, the
methanolic solution was evaporated under reduced pressure and the
residue was purified by flash chromatography (EtOAc–hexane, 1:9)
to give the title compound 4a.
(2S,3R)-3-{[(1R)-1-cyclohexylbut-3-en-1-yl]oxy}-1,1,1-trifluo-
robutan-2-ol (7d)
Obtained from (2S,4S,5S)-2-cyclohexyl-4-methyl-5-(trifluoro-
methyl)-1,3-dioxolane (3d) in 62% yield.
Pale yellow liquid; FC: EtOAc–light petroleum, 1:16; [a]D +10.4 (c
1.00, EtOH).
1H NMR (400 MHz, CDCl3): d = 0.95–1.10 (m, 2 H, cyclohexyl),
1.10–1.30 (m, 3 H, cyclohexyl), 1.23 (d, 3 H, J = 6.4 Hz, Me), 1.44–
1.53 (m, 1 H, cyclohexyl), 1.65–1.72 (m, 2 H, cyclohexyl), 1.73–
1.81 (m, 3 H, cyclohexyl), 2.20–2.34 (m, 2 H, allylic CH2), 2.56 (br
Pale yellow liquid, 190 mg (68% yield); [a]D +2.18 (c 0.55, EtOH).
1H NMR (400 MHz, CDCl3): d = 0.89 (t, 3 H, J = 6.8 Hz, Me), 1.27
(d, 3 H, J = 6.4 Hz, Me), 1.28–1.37 (m, 10 H, 5 CH2 octyl), 1.55–
1.60 (m, 2 H, CH2 octyl), 2.63 (d, 1 H, J = 5.4 Hz, OH), 3.41 (dt, 1
Synthesis 2004, No. 18, 3005–3010 © Thieme Stuttgart · New York

3010
C. F. Morelli et al.
PAPER
H, J = 9.0, 6.4 Hz, CH2O), 3.57 (dt, 1 H, J = 9.0, 6.8 Hz, CH2O),
3.70 (dq, 1 H, J = 6.4, 4.0 Hz, CHCH3), 4.07 (ddq, 1 H, JHH = 5.4,
4.0 Hz, JHF = 7.4 Hz, CHCF3).
1H NMR (300 MHz, CDCl3): d = 0.87 (t, 3 H, J = 6.7 Hz, Me),
1.22–1.35 (m, 10 H, 5 CH2 octyl), 1.51–1.62 (m, 3 H, CH2 octyl and
OH), 3.61 (br t, 1 H, J = 6.6 Hz, CHD).
13C NMR (100 MHz, CDCl3): d = 14.43 (Me), 14.50 (Me), 23.02,
26.43, 29.60, 29.74, 30.18, 32.18 (CH2 octyl), 69.92 (CH2O), 72.26
(q, 2JCF = 29.6 Hz, CHCF3), 74.05 (CHCH3), 124.77 (q, JCF = 282.2
Hz, CF3).
Removal of the Chiral Auxiliary from Compound 7b: Synthesis
of (3S)-1-Phenylhex-5-en-3-ol (8)
2-{[(1S)-1-(2-Phenylethyl)but-3-en-1-yl]oxy}propanoic Acid
Obtained from (2S,3R)-1,1,1-trifluoro-3-{[(1S)-1-(2-phenyleth-
yl)but-3-en-1-yl]oxy}butan-2-ol (7b) in 58% yield following the
procedure described in ref. 3e.
(2S,3S)-4,4,4-Trifluoro-3-(octyloxy)butan-2-ol (5)
To a suspension of NaH (193 mg, 50% dispersion in mineral oil, 4
mmol) in DMF (5 mL), (2S,3S)-3-benzyloxy-4,4,4-trifluorobutan-
2-ol4 (252 mg, 1.05 mmol) was added, followed by bromooctane
(0.28 mL, 1.6 mmol). The mixture was stirred at 60 °C for 1.5 h,
cooled to r.t. and treated cautiously with H2O until evolution of H2
ceased. The solution was concentrated under reduced pressure, then
the residue was taken up in EtOAc (10 mL), washed with 1 M HCl
(2 × 8 mL) and with sat. NaCl solution (1 × 8 mL). After drying
(Na2SO4) the solvent was removed under reduced pressure afford-
ing 580 mg of ({[(1S,2S)-2-octyloxy-1-(trifluoromethyl)pro-
pyl]oxy}methyl)benzene as chromatographically homogeneous
yellow oil which was used in the subsequent step without further
purification.
1H NMR (300 MHz, CDCl3): d = 0.90 (t, 3 H, J = 6.8 Hz, Me),
1.28–1.42 (m, 13 H, 5 CH2 octyl and Me), 1.53–1.61 (m, 2 H, CH2
octyl), 3.59–3.83 (m, 4 H, CH2O, CHCH3 and CHCF3), 4.50 (d, 1
H, J = 11.4 Hz, PhCH2O), 4.59 (d, 1 H, J = 11.4 Hz, PhCH2O),
7.33–7.49 (m, 5 H, aromatic H).
1H NMR (300 MHz, CDCl3): d = 1.43 (d, 3 H, J = 6.8 Hz, Me),
1.85–1.87 (m, 2 H, PhCH2CH2), 2.35 (m, 2 H, allylic CH2), 2.69 (m,
2 H, PhCH2), 3.50 (m, 1 H, CHO), 3.93 (m, 1 H, CHCOOH), 5.10–
5.16 (m, 2 H, vinylic CH2), 5.78–5.80 (m, 1 H, vinylic CH), 7.15–
7.31 (m, 5 H, aromatic H), 9.20–9.80 (br, 1 H, COOH).
(3S)-1-Phenylhex-5-en-3-ol (8)
Obtained from the above mentioned 2-{[(1S)-1-(2-phenylethyl)but-
3-en-1-yl]oxy}propanoic acid in 33% yield following the procedure
described in ref. 3e.
[a]D – 19.24 (c 0.98, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.58 (br s, 1 H, OH), 1.74–1.86
(m, 2 H, PhCH2CH2), 2.10–2.14 (m, 2 H, allylic CH2), 2.62–2.90
(m, 2 H, PhCH2), 3.60–3.74 (m, 1 H, CHO), 5.08–5.22 (m, 2 H, vi-
nylic CH2), 5.72–5.93 (m, 1 H, vinylic CH), 7.13–7.34 (m, 5 H, ar-
omatic H).
To a suspension of Pd/C (210 mg, 10% Pd) in MeOH (15 mL) under
an atmosphere of H2, a solution of the crude product prepared as
above (550 mg, 1.05 mmol) in MeOH (5 mL) was added and the re-
action mixture was stirred overnight at r.t. The catalyst was filtered
off, the methanolic solution was evaporated under reduced pressure
and the residue was purified by flash column chromatography
(EtOAc–hexane, 1:6) giving 5.
Acknowledgment
We are grateful to MIUR for financial support.
References
(1) (a) Seebach, D.; Imwinkeheid, R.; Weber, T. In Modern
Synthetic Methods; Scheffold, R., Ed.; Vol. 4, Springer-
Verlag: Berlin, 1986, 125. (b) Mori, A.; Fujiwara, J.;
Yamamoto, H. J. Organomet. Chem. 1985, 285, 83.
(2) For example, see: (a) McNamara, J. M.; Kishi, Y. J. Am.
Chem. Soc. 1982, 104, 7371. (b) Sekizaki, H.; Jung, M.;
McNamara, J. M.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
7372. (c) Johnson, W. S.; Chan, M. F. J. Org. Chem. 1985,
50, 2598.
Pale yellow oil, 210 mg (77% yield); [a]D – 4.25 (c 0.40, EtOH).
1H NMR (400 MHz, CDCl3): d = 0.90 (t, 3 H, J = 6.6 Hz, Me),
1.29–1.38 (m, 13 H, 5 CH2 octyl and Me), 1.60–1.63 (m, 2 H, CH2
octyl), 2.07 (br s, 1 H, OH), 3.58–3.67 (m, 2 H, CH2O), 3.80–3.86
(m, 1,H, CHCH3), 4.04 (dq, 1 H, J = 6.4, 4.5 Hz, CHCF3).
13C NMR (100 MHz, CDCl3): d = 14.43 (Me), 18.35 (Me), 23.01,
26.25, 29.59, 29.68, 30.23, 32.18 (6 CH2 octyl), 66.70 (CHCH3),
2
74.46 (CH2O), 81.42 (q, JCF = 27.3 Hz, CHCF3), 125.13 (q,
(3) (a) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron 1990,
46, 4595. (b) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki,
K.; Yamamoto, H.; Bartlett, P. A.; Heathcock, C. H. J. Org.
Chem. 1990, 55, 6107. (c) Denmark, S. E.; Almstead, N. G.
J. Am. Chem. Soc. 1991, 113, 8089. (d) Harada, T.;
Nakamura, T.; Kinugasa, M.; Oku, A. J. Org. Chem. 1999,
64, 7594. (e) Morelli, C. F.; Fornili, A.; Sironi, M.; Durì, L.;
Speranza, G.; Manitto, P. Tetrahedron: Asymmetry 2002,
13, 2609.
JCF = 285.1 Hz, CF3).
Removal of the Chiral Auxiliary from Compound 4a
3-[(R)-(1-2H)Octyloxy]propanoic Acid
Obtained from (2S,3S)-1,1,1-Trifluoro-3-(octyloxy)butan-2-ol (4a)
in 64% yield following the procedure described in ref. 3e.
1H NMR (200 MHz, CDCl3): d = 0.86 (t, 3 H, J = 6.7 Hz, Me),
1.23–1.36 (m, 10 H, 5 CH2 octyl), 1.45 (d, 3 H, J = 6.9 Hz, Me),
1.60–1.63 (m, 2 H, CH2 octyl), 3.44 (br t, 0.5 H, J = 6.5 Hz, CHD),
3.55 (br t, 0.5 H, J = 6.5 Hz, CHD), 3.97 (q, 1 H, J = 6.9 Hz,
CHCOOH), 8.00–8.50 (br, 1,H, COOH).
(4) Morelli, C. F.; Speranza, G.; Durì, L.; Manitto, P. Org. Prep.
Proc. Int. 2002, 34, 103.
(5) Stein, J.; Lewis, L. N.; Gao, Y.; Scott, R. A. J. Am. Chem.
Soc. 1999, 121, 3693.
(6) Brosch, D.; Kirmse, W. J. Org. Chem. 1993, 58, 1118.
(7) Althouse, V. E.; Feigl, D. M.; Sanderson, W. A.; Mosher, H.
S. J. Am. Chem. Soc. 1966, 88, 3595.
(R)-(1-2H)Octan-1-ol (6)
Obtained from the above mentioned 3-[(R)-(1-2H)octyloxy]pro-
panoic acid in 32% yield following the procedure described in ref.
3e.
(8) Imwinkelried, R.; Seebach, D. Angew. Chem., Int. Ed. Engl.
1985, 24, 765.
Synthesis 2004, No. 18, 3005–3010 © Thieme Stuttgart · New York