Convenient synthesis of optically active deuterated primary alcohols via deuteride reduction of acetals derived from homochiral (1R*,2R*)-3,3,3-trifluoro-1-phenylpropane-1,2-diols

Article abstract of DOI:10.1016/j.tetasy.2009.01.020

(1R)-1-Deuterated alcohols with high enantiomeric excess were prepared via TiCl₄/Et₃SiD reduction of acetals arising from the reaction of aldehydes with (1S,2S)-3,3,3-trifluoro-1-phenylpropane-1,2-diol 9. Such a chiral auxiliary was

Full text of DOI:10.1016/j.tetasy.2009.01.020

Tetrahedron: Asymmetry 20 (2009) 351–354
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Convenient synthesis of optically active deuterated primary alcohols
via deuteride reduction of acetals derived from homochiral
*
*
(1R ,2R )-3,3,3-trifluoro-1-phenylpropane-1,2-diols
*
Carlo F. Morelli , Paola Cairoli, Tiziana Marigolo, Giovanna Speranza, Paolo Manitto
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, via Venezian 21, I-20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
(1R)-1-Deuterated alcohols with high enantiomeric excess were prepared via TiCl4/Et3SiD reduction of
acetals arising from the reaction of aldehydes with (1S,2S)-3,3,3-trifluoro-1-phenylpropane-1,2-diol 9.
Received 8 December 2008
Accepted 21 January 2009
Available online 13 February 2009
Such a chiral auxiliary was synthesized in an enantiomerically pure form starting from
L-mandelic acid.
Due to its benzylic nature, it was easily removed from the reaction product of the reductive 1,3-dioxolane
ring-cleavage to afford the desired
a-deuterated alcohol.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
CF3
OH
Me
OH
CF3
L.A.
O
R
Chiral deuterated primary alcohols are used extensively for
investigating mechanisms in chemical and biological processes.1
To obtain enantiomerically pure R–CHD–OH compounds, two
chemical approaches are usually adopted; either the stereoselective
hydrogenation of the previously deuterated formyl group2 or the
deuteride reduction of the non-deuterated aldehyde precursor.3
The latter route appears to be more advantageous since it does not
require a synthetic step for preparing the –CD@O group. Neverthe-
less, it also entails some difficulties such as the synthesis of the deu-
terated chiral reducing agent3d and the availability of the chiral
catalyst for the enantioselective deuteride transfer from a common
donor (e.g., NaBD4).3a–c It should be noted that some alternative iso-
topic labelling strategies to prepare chiral 1-deuterated alcohols
have already been reported, for example, the use of Pd(II)-catalyzed
rearrangement of allylic acetates4a and Zn/Li transmetallation on
O
F3C
Me
O
Nu
Me Nu
OH
R
3
1
2
Nu
OH
R
4
Scheme 1. Stereoselective nucleophilic ring-opening of 2-substituted cis-4-methyl-
6a
5-trifluoromethyl dioxolanes 2.
In previous papers,6a–c we have reported that 1,3-dioxolanes 2
(Scheme 1), derived by reaction of aldehydes with (2S,3S)-1,1,1-
trifluorobutane-2,3-diol 1, undergo Lewis acid-promoted nucleo-
philic ring-opening reactions with the same regio- and stereo-
selectivities independent of the configuration of the acetal
carbon atom. In spite of the good yields and the high stereoselec-
tivity observed in the ring-cleavage of 2, the removal of the chiral
auxiliary from 3 to obtain enantiomerically enriched alcohols 4
required a laborious three-step procedure which greatly limited
the use of the reaction sequence shown in Scheme 1 for synthetic
purposes.
Taking this into account, we thought that the use of a properly
1-substituted 3,3,3-trifluoropropane-1,2-diol could offer an easier
way to liberate the alcohol from the product of the 1,3-dioxolane
reduction. Herein, we report the synthesis of (1S,2S)-3,3,3-
trifluoro-1-phenylpropane-1,2-diol 9 and its application for pre-
chiral
a-carbamoyloxy organolithiums followed by treatment with
D2O.4b
In principle, the use of a chiral auxiliary capable of forming an
aldehyde adduct, which then undergoes regio- and diastereoselec-
tive deuteride reduction, can be envisaged as an alternative to ob-
tain optically active (1-2H)alcohols. However, to the best of our
knowledge, only one example5 of such strategy has been reported
so far.
* Corresponding author. Tel.: +39 02 50314099; fax: +39 02 50314072.
E-mail address: carlo.morelli@unimi.it (C.F. Morelli).
Biochemical enzymatic methods suffer the limitation that the deuterated
stereocentre is obtained in one enantiomeric form with the result that a chemical
multistep process (configuration inversion) is necessary to provide the other
enantiomer (e.g., Ref. 15).
paring
excess.
a-deuterated primary alcohols with high enantiomeric
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.01.020

352
C. F. Morelli et al. / Tetrahedron: Asymmetry 20 (2009) 351–354
Table 1
2. Results and discussion
Aldehyde 6,7 prepared from
Isolated yields of products from reactions of Scheme 3
L-mandelic acid 5 (enantiomeric
Entry
13 (R=)
14a
15
17b (% ee)
706b (90)
7612 (88)
7413 (84)
7214 (92)
purity = 99%), was allowed to react with (trifluoromethyl)trimeth-
ylsilane in the presence of a catalytic amount of tetra(n-butyl)-
ammonium fluoride (TBAF)6d,8 to give a mixture of the fully
protected 3,3,3-trifluoro-1-phenylpropane-1,2-diols 7 and 8 in ca.
55:45 ratio (Scheme 2). After chromatographic separation of the
two diastereoisomers, their quantitative deprotection furnished
the pure diols 9 and 10 in satisfactory overall yields (ca. 40% each
of them from aldehyde 6).
a
b
c
nC7H15
C6H5CH2CH2
C6H5CH2
72 (80:20)
63 (76:24)
35 (63:37)
37 (60:40)
89 (95:5)
87 (94:6)
85 (92:8)
97 (96:4)
d
Cyclohexyl
a
The syn/anti ratios of the dioxolane mixture giving 14 are in parentheses.
The (R)-configuration proved by 1H NMR analysis of the corresponding MPTA
b
esters.
Ph
15a was obtained as the only reaction product in agreement with a
high regioselectivity of the nucleophilic dioxolane cleavage. The 1H
NMR spectrum of 15a exhibited two broad triplets at 3.29 and
3.37 ppm (corresponding to protons HS and HR of O–CHD–R,
respectively)6 with relative intensities 95:5, which were indicative
of high diastereoselectivity in the invertive attack of the formal
deuteride anion to the acetalic carbon. The reductive ring-opening
of the anti-dioxolane under the above reaction conditions fur-
nished the same product 15a as in the case of the syn-isomer,
the yield and diastereomeric excess being practically identical for
both dioxolanes. Such behaviour of the C-2 epimeric 1,3-dioxol-
anes (mentioned above with regard to the nucleophilic cleavage
of acetals derived from the diol 1, Scheme 1) has been explained
on the basis of kinetics and reactivity considerations.6a It suggests
the use of the diastereomeric mixture of acetals to obtain the ring-
opening product suited for the next synthetic steps. Finally, the
removal of the chiral auxiliary from 15a was accomplished by its
conversion into acetate 16a which in turn was treated with boron
CF3
Ph
CF3
O
O
O
O
O
11
O
12
The relative configurations of 9 (1S,2S) and 10 (1S,2R) were estab-
lished on the basis of 1H NMR data (1H–1H coupling constants
and NOESY of their cyclic carbonates, that is, 11 and 12, respec-
tively).6d,9 Taking into account that the stereocentre of the starting
L
-mandelic acid was not involved in the reactions leading to both
diastereomeric diols, the absolute (1S,2S)-configuration was
assigned to 9. The enantiomeric purity of this compound was con-
firmed to be P99% by inspection of the 1H NMR spectrum of its
MTPA diester in comparison with that of rac-9 diester prepared
from (D,L)-mandelic acid.
Compound 9 was reacted with octanal 13a (Scheme 3) in
refluxing toluene in the presence of catalytic amount of p-toluene-
sulfonic acid to provide a syn/anti mixture of the two diastereo-
meric 1,3-dioxolanes,6 that is, 14a (syn) and its epimer at C-2
(anti), in 90% global yield.
Both were isolated by flash chromatography (Table 1) after
which 14a was then subjected to reductive ring-opening reaction
using stoichiometric amount of TiCl4 and Et3SiD10 (D > 98%). Ether
tribromide in dichloromethane at 0 °C.11 The resultant
a-mono-
deuterated 1-octanol 17a was isolated in ca 70% overall yield. Its
configuration at C1 was proven to be (R) by the MTPA ester method
using racemic monodeuterated 1-octanol and an authentic sample
of (R)-(1-2H)octanol6b as reference compounds.
The procedure described here was validated by the experi-
ments reported in Table 1 as a general method for preparing
OH
TBDMSO
e
CF3
CF3
OH
OTMS
OH
TBDMSO
7
9
a, b, c
O
d
OH
O
5
6
OH
TBDMSO
e
CF3
CF3
OH
OTMS
8
10
Scheme 2. Reagents and conditions: (a) MeOH, TsOH, rt; (b) TBDMSCl, imidazole, DMF, rt; (c) DIBAL-H, Et2O, ꢀ78 °C; (d) Me3SiCF3, cat. TBAF, THF, 0 °C; (e) TBAF, THF, rt.
Ph
CF3
OX
H D
R OH
b
a
O
R
d
R
CHO
+ 9
F3C
O
O
D
Hs
Ph
13a-d
R
17a-d
14a-d
15a-d X = H
16a-d X = Ac
c
Scheme 3. Reagents and conditions: (a) TsOH, toluene, reflux; (b) Et3SiD, TiCl4, CH2Cl2, ꢀ78 °C; (c) Ac2O, Et3 N, CH2Cl2, 0 °C; (d) BBr3, CH2Cl2, 0 °C; see Table 1 for R residues
and single reaction yields.

C. F. Morelli et al. / Tetrahedron: Asymmetry 20 (2009) 351–354
353
(1-2H)-alcohols with high isotopic and enantiomeric excess start-
ing from either - or -mandelic acid, respectively.
3.3. Synthesis of dioxolanes 14a–d. General procedure
L
D
The preparation of dioxolane 14a is representative. A solution of
diol 9 (412 mg, 2.0 mmol), octanal 13a (0.375 mL, 2.4 mmol) and a
catalytic amount of p-toluenesulfonic acid (1–2 mol%) in toluene
(6 mL) was refluxed with azeotropic removal of water by means
of a Dean-Stark apparatus until the disappearance of diol 9
(45 min., TLC monitoring). The reaction mixture was diluted with
EtOAc (15 mL) and washed with saturated NaHCO3 (3 ꢁ 10 mL)
and saturated NaCl (10 mL). The separated organic layer was dried
over Na2SO4 and the solvent was evaporated under reduced pres-
sure. Flash column chromatography (silica gel, AcOEt–hexane
3:97) of the residue afforded dioxolane anti 14a (yellowish liquid,
114 mg, 18% yield) and dioxolane syn 14a (pale yellow liquid,
456 mg, 72% yield).
3. Experimental
3.1. General
TLC was performed on silica gel F254 precoated aluminum
sheets (0.2 mm layer, Merck, Darmstadt, Germany); components
were detected by spraying a Ceric sulfate ammonium molybdate
solution, followed by heating to ca. 150 °C. Silica gel (Merck, 40–
63 l
m) was used for flash chromatography (FC). 1H and 13C NMR
spectra were recorded at 400.133 and 100.613 MHz, respectively,
on a Bruker Avance 400 spectrometer using a Xwin-NMR software
package. Chemical shifts (d) are given in ppm and were referenced
anti 14a: ½a D
ꢂ
¼ þ79:1 (c 1.09, EtOH); 1H NMR: d 0.90 (t, 3H,
to the signals of the solvent (CDCl3, dH 7.27 and dC 77.00 ppm). 13
C
J = 6.8 Hz, Me); 1.31–139 (m, 8H, alkyl chain); 1.45–1.53 (m, 2H, al-
kyl chain); 1.72–1.78 (m, 2H, alkyl chain); 4.58–4.63 (m, 1H, H-5);
5.39 (d, 1H, J = 6.4 Hz, H-4); 5.65 (t, 1H, J = 5.2 Hz, H-2); 7.34–7.43
(m, 5H, aromatic H). 13C NMR: d 14.06 (Me); 22.63, 23.79, 29.17,
29.34, 31.71, 35.05 (CH2 of the alkyl chain); 76.58–77.41 (overlap-
signal multiplicities were based on APT spectra. Solvents were
dried by standard methods prior to use. -Mandelic acid, octanal,
L
3-phenylpropanal, phenylacetaldehyde, cyclohexane–carboxalde-
hyde, DIBAL-H 1 M solution in hexane and chlorotriethylsilane
were purchased from Aldrich; (trifluoromethyl)trimethylsilane,
was from Fluka. LiAlD4 (98% atom D), used to prepare deuterotri-
ethylsilane10 was from Aldrich. All reagents were used as received.
ping with solvent, C-5); 77.83 (C-4); 107.17 (C-2); 123.22 (q, 1JC–F
=
281 Hz, CF3); 126.62, 128.19, 128.43, 133.05 (aromatic C).
syn 14a: ½a D
ꢂ
¼ þ101:0 (c 1.00, EtOH); 1H NMR: d 0.92 (t, 3H,
J = 6.9 Hz, Me); 1.33–1.43 (m, 8H, alkyl chain); 1.52–1.60 (m, 2H,
alkyl chain); 1.88–1.93 (m, 2H, alkyl chain); 4.46–4.53 (m, 1H, H-
5); 5.21 (t, 1H, J = 4.9 Hz, H-2); 5.26 (d, 1H, J = 6.6 Hz, H-4); 7.36–
7.45 (m, 5H, aromatic H).13C NMR: d 14.46 (Me); 23.04, 24.17,
3.2. Synthesis of (1S,2S)-3,3,3-trifluoro-1-phenylpropane-
2,3-diol 9
29.53, 29.81, 32.14, 33.84 (CH2 of the alkyl chain); 76.54 (q, 2JC–F
29 Hz, C-5); 80.03 (C-4); 106.03 (C-2); 123.42 (q, JC–F = 281 Hz,
=
To a solution of (S)-O-(t-butyl)dimethylsilyl mandelaldehyde 6
(11.38 g, 45.44 mmol) in dry THF (50 mL) cooled to 0 °C, (trifluoro-
1
methyl)trimethylsilane (8.0 mL, 54.52 mmol) and
a catalytic
CF3); 127.10, 128.55, 128.93, 133.27 (aromatic C).
amount of tetra-(n-butyl)ammonium fluoride (50 mg) were added
and the solution was stirred at 0 °C for 45 min. The reaction mix-
ture was diluted with AcOEt (100 mL) and washed with water
(75 mL); the organic layer was separated and the aqueous layer
was extracted with AcOEt (2 ꢁ 50 mL). The combined organic lay-
ers were washed with saturated NaCl solution (100 mL) and dried
(Na2SO4). Evaporation of the solvent under reduced pressure gave a
viscous yellow liquid (19.63 g). Two consecutive separations by
flash column chromatography (silica gel, hexane) yielded the dia-
stereomeric protected diols 7 (6.84 g, 36% yield) and 8 (7.17 g,
40% yield), together with an unseparated fraction (2.85 g, 16%
yield).
3.4. Stereoselective reductive ring-opening reaction.
Preparation of compounds 15a–d. General procedure
The preparation of hydroxy ether 15a is representative. To a
solution of a syn-dioxolane 14a (167 mg, 0.53 mmol) and deut-
erotriethylsilane (65 mg, 0.55 mmol) in dry dichloromethane
(2.5 mL) cooled at ꢀ78 °C, a 1 M solution of TiCl4 in dichlorometh-
ane (0.55 mL) was added dropwise over 5 min. The reaction mix-
ture was stirred for an additional 10 min at the same
temperature and then quenched with methanol (0.25 mL). The
solution was warmed to rt, diluted with AcOEt (10 mL), washed
with 1 M HCl (3 ꢁ 7 mL) and saturated NaCl (7 mL). The organic
layer was dried (Na2SO4) and the solvent was removed under re-
duced pressure. Flash column chromatography (silica gel, AcOEt–
hexane 1:9) gave 15a as a colourless liquid (150 mg, 89% yield).
1H NMR: d 0.89 (t, 3H, J = 6.4 Hz, Me); 1.25–1.34 (m, 10 H, alkyl
chain); 1.53–1.58 (m, 2H, alkyl chain); 2.21 (br, OH); 3.28 (t, 0.95
H, J = 6.4 Hz, CHD); 3.37 (t, 0.05 H, J = 6.4 Hz, CHD); 4.12–4.18
(m, 1H, H-2); 4.49 (d, 1H, J = 6.4 Hz, H-3); 7.36–7.42 (m, 5H, aro-
matic H). 13C NMR: d 14.45 (Me); 23.02, 26.34, 29.59, 29.69,
Compound 7: 1H NMR (400 MHz, CDCl3): d ꢀ0.24 (s, 3H, SiMe2t-
Bu); ꢀ0.21 (s, 9H, SiMe3); 0.04 (s, 3H, SiMe2tBu); 0.85 (s, 9H, Si-
Me2tBu); 3.90–3.97 (m, 1H, H-2); 4.71 (d, 1H, J = 8.0 Hz, H-1);
7.28–7.37 (m, 5H, aromatic H). 13C NMR: d ꢀ5.05 (SiMe2tBu);
ꢀ4.35 (SiMe2tBu); ꢀ0.29 (SiMe3); 18.36 (CMe3); 25.99 (SiMe2tBu);
74.83 (C-1); 75.71 (q, 2JC–F = 28.0 Hz, C-2); 125.16 (q, 1JC–F = 284 Hz,
CF3); 128.28, 128.38, 128.45, 141.76 (aromatic C).
A
solution of diol 7 (3.43 g, 8.7 mmol) and tetra-(n-
butyl)ammonium fluoride (TBAF, 5.00 g, 19.2 mmol) in dry THF
(9 mL) was stirred at rt for 30 min. The reaction mixture was di-
luted with AcOEt (100 mL) and washed with 0.1 M HCl (70 mL)
and saturated NaCl solution (70 mL). The separated organic layer
was dried over Na2SO4 and evaporated under reduced pressure.
Flash column chromatography of the residue (silica gel, AcOEt–
hexane 3:5) gave diol 9 as an amorphous white solid (1.77 g, 98%
yield). Recrystallization from hexane gave colourless crystals,
1
29.86, 32.19 (CH2 of the alkyl chain); 69.62 (t, JC–D = 21 Hz,
2
1
CHD); 73.39 (q, JC–F = 29 Hz, C-2); 80.45 (C-3); 124.74 (q, JC–F
=
281 Hz, CF3); 128.25, 128.96, 129.13, 137.07 (aromatic C).
3.5. Removal of the chiral auxiliary. Synthesis of (R)-[1-2H]-
primary alcohols 17a–d. General procedure
The preparation of (R)-1-[2H]1-octanol 17a is representative. To
a solution of compound 15a (35 mg, 0.11 mmol) in dry dichloro-
methane (1 mL) cooled to 0 °C, acetic anhydride (31
(1.54 g, 99% ee by the diester with MTPA), ½aꢂD ¼ þ14:1 (c 1.06,
MeOH); 1H NMR (400 MHz, CDCl3): d 2.29–2.31 (m, 2H, OH);
4.21 (qdd, 1H, JC–F = JH3–H2 = JH3–OH = 6.5 Hz, H-3); 4.97 (dd, 1H,
lL,
JH2–H3 = 6.5 Hz, JH2–OH = 4.2 Hz, H-2); 7.27–7.45 (m, 5H, aromatic
0.33 mmol), triethylamine (76 L, 0.55 mmol) and a catalytic
l
2
H). 13C NMR (400 MHz, CDCl3): d 73.16 (C-1); 73.66 (q, JC–F
=
amount of DMAP were added. The mixture was stirred for
30 min. at 0 °C, diluted with AcOEt (5 mL), washed with 1 M HCl
(3 ꢁ 3 mL), saturated NaHCO3 (3 ꢁ 3 mL) and saturated NaCl
1
30 Hz, C-2); 124.80 (q, JC–F = 281 Hz, CF3); 127.58, 129.04,
129.26, 138.87 (aromatic C).

354
C. F. Morelli et al. / Tetrahedron: Asymmetry 20 (2009) 351–354
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Acknowledgements
Thanks are due to MIUR (Italy) for financial support (FIRST). A
postgraduate fellowship from Consorzio CINMPIS (to T. M.) is
gratefully acknowledged.
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