Formal and improved synthesis of enantiopure chiral methanol

Article abstract of DOI:10.1016/j.tet.2008.05.091

[D₂]Methanol was converted to the carbamate derived from 2,2,6,6-tetramethylpiperidine. It was metalated with s-BuLi/TMEDA at -78 °C with a high primary kinetic isotope effect to give an α-oxymethyllithium, which was silylated with chlorodimethylphenylsilane. The silylmethyl carbamate formed was lithiated and borylated with the borate derived from tert-butanol and (R,R)-1,2-dicyclohexylethane-1,2-diol to give diastereomeric boronates, which were separated by preparative HPLC and can in principle be converted to enantiopure chiral methanols. Thus, both enantiomers are easily accessible in nine linear steps.

Full text of DOI:10.1016/j.tet.2008.05.091

Tetrahedron 64 (2008) 7605–7610
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formal and improved synthesis of enantiopure chiral methanol
*
Anna Schweifer, Friedrich Hammerschmidt
Institute of Organic Chemistry, University of Vienna, Wa¨hringerstrasse 38, A-1090 Wien, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
[D2]Methanol was converted to the carbamate derived from 2,2,6,6-tetramethylpiperidine. It was
metalated with s-BuLi/TMEDA at ꢀ78 ꢁC with a high primary kinetic isotope effect to give an
a-oxy-
Received 11 March 2008
Received in revised form 19 May 2008
Accepted 19 May 2008
methyllithium, which was silylated with chlorodimethylphenylsilane. The silylmethyl carbamate formed
was lithiated and borylated with the borate derived from tert-butanol and (R,R)-1,2-dicyclohexylethane-
1,2-diol to give diastereomeric boronates, which were separated by preparative HPLC and can in principle
be converted to enantiopure chiral methanols. Thus, both enantiomers are easily accessible in nine linear
steps.
Available online 23 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
which were oxidized to the D- and T-labeled (dimethylphenyl-
silyl)methanols 6. Base-induced Brook rearrangement, the key step
The synthesis of chiral acetic acid by two independent groups
led by Cornforth1 and Arigoni2,3 marked the beginning of the use
of the chiral methyl group for the elucidation4 of chemical and
enzymatic reaction mechanisms. We have recently reported the
synthesis of the tosylates of enantiopure chiral methanols
(CHDTOH) in a total of 12 steps for both enantiomers, starting from
commercially available starting materials.5 These tosylates are
a much more convenient source for chiral methyl groups than the
N,N-ditosylmethylamines derived from the respective chiral acetic
acids. We have already used these tosylates of chiral methanol for
the alkylation of homocysteine to prepare methionines with chiral
CHDT groups at sulfur.
of the synthesis, furnished chiral methanols 7, which were isolated
in high yield as their respective tosylates. Their enantiomeric
excesses of 98% were determined by 3H NMR spectroscopy after
transfer of the methyl groups to the nitrogen of (S)-2-
methylpiperidine.
Scheme 1. Synthesis of dideuterated carbamate 1.
To shorten and improve the synthesis, we wanted to replace the
laborious deuteration of 1 by the use of methanol CD3OD, necessi-
tating a change of strategy at the beginning. Furthermore, we were
looking for a deuterated substrate derived from an achiral precursor
to additionally save (S,S)-bis(1-phenylethyl)amine as a chiral aux-
iliary. As the experiments with chiral methyl groups are performed
with both enantiomers routinely for complementarity, the diaster-
eoselectivity of the borylation is not critical. Preferably, it should be
close to 1. Naturally, the boronates should be stable for storage.
We envisaged three achiral substrates for borylation, triphenyl-
acetate [1,1-D2]9, and carbamates [1,1-D2]10 as well as [1,1-D2]11
prepared from the corresponding methyl esters by metalation and
silylation (Fig. 1). Methyl carbamate [1,1,1-D3]8 was not considered
a suitable precursor for [1,1-D2]1, as metalation would very likely
occur at the benzylic position preferably.
2. Results and discussion
For the sake of clarity and in order to pinpoint the steps in the
synthesis of the chiral methanols amenable to improvement, their
synthesis is given here.5 Carbamate 1 prepared from (dimethyl-
phenylsilyl)methanol and homochiral (S,S)-bis(1-phenylethyl)-
amine had to be deuterated by four cycles of metalation with
s-BuLi/TMEDA and quenching with D2O, with purification of
product after every two cycles (Scheme 1). Lithiation of [1,1-D2]1
and borylation with the mixed boric acid ester 2 derived from (R,R)-
1,2-dicyclohexylethane-1,2-diol and tert-butanol gave a mixture of
deuterated diastereomeric boronates 3 and 4 in a ratio of 1.2:1
(Scheme 2). They were separated and stereospecifically reduced
with LiBEt3T with inversion of configuration to give boronates 5,
It was found by Beak et al.6 and Seebach et al.7 that the methyl
esters and secondary amides derived from substituted benzoic acids
and triphenylacetic acid, having shielded carbonyl groups, could
be metalated using s-BuLi/TMEDA and that the intermediate
* Corresponding author.
E-mail address: friedrich.hammerschmidt@univie.ac.at (F. Hammerschmidt).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.091

7606
A. Schweifer, F. Hammerschmidt / Tetrahedron 64 (2008) 7605–7610
Scheme 3. Preparation of boronates 15 and 16 from silylmethyl ester 9.
deuterated silylmethanol (1R)-[1-D1]6 (Scheme 4).5 Its (R) configu-
ration was secured by recording the 1H NMR spectrum of the cor-
responding (R)-Mosher ester5 and comparing it with the spectra of
authentic samples of (1R)- and (1S)-[1-D1]6. The enantiopurity (99%
ee) proved that reduction of 15 with LiAlD4 and oxidative cleavage of
the B–C bond followed stereospecifically an invertive and retentive
course, respectively.5 Unfortunately, the triphenylacetic acid de-
rivatives were chemically somewhat labile, especially toward s-BuLi,
so that their use had to be abandoned. Therefore, we returned to the
two left precursors [1,1-D2]10 and [1,1-D2]11 in Figure 1. A literature
search revealed that Boche et al. had metalated methyl N,N-diiso-
propylcarbamate with s-BuLi/TMEDA for 5 h at ꢀ78 ꢁC and
quenched the intermediate oxymethyllithium with tributyl-
chlorostannane to give the corresponding tributylstannylmethyl
carbamate in 43% yield.9 We were anticipating a similar low yield for
the silylation with chlorodimethylphenylsilane. Furthermore, we
feared that the diastereomeric boronates obtained from the lithiated
silylmethyl carbamate could not be separated, as the N,N-diisopro-
pylcarbamoyl group seemed to be too small to allow that, based on
previous experience. Carbamate [1,1-D2]11 derived from 2,2,6,6-
tetramethylpiperidine (TMPH) and reminiscent of the carbamates10
used by Hoppe et al. to protect primary alcohols for metalation
seemed to be a feasible alternative to [1,1-D2]10. Unlabeled carba-
mate 11 has recently been metalated and stannylated to access (R)-
and (S)-(tributylstannyl)-[D1]methanol.11
Scheme 2. Synthesis of chiral methanols from dideuterated carbamate 1.
a
-heteroatom-substituted alkyllithiums reacted with electrophiles.
With this information in mind, we performed experiments in the
unlabeled series first. (Dimethylphenylsilyl)methanol and triphe-
nylacetic acid were converted to the silylmethyl ester 9 in 91% yield
by the Mitsunobu reaction using triphenylphosphine/diisopropyl
azodicarboxylate (DIAD) in toluene (Scheme 3).8 The lithiation
of ester 9 proceeded more slowly (90 min) than that of carbamate
[1-D]1 (15 min). Borylation of the intermediate oxymethyllithium
(ꢂ)-14 was borylated withmixed borate 2.5 As the oxymethyllithium
was configurationally labile, even at ꢀ95 ꢁC, and enantiomerization
was faster than borylation, one of the diastereomeric boronates was
formed selectively (combined yield: 52%, 15/16 3.3:1). Two
flash chromatographies were necessary to get homogenous dia-
stereomers, as starting ester and minor diastereomer 16 were of
similar polarity. The (R) configuration at the newly formed stereo-
genic center of the major diastereomer 15 was determined by
chemicalcorrelation. It was reduced withLiAlD4 toboronate (1R)-[1-
D1]5, followed by oxidative cleavage of the C–B bond to give
As before, the transformations were performed first in the un-
labeled series to optimize the reaction conditions, starting from
methyl carbamate12 17 a known compound easily accessible from
methyl chloroformate and TMPH. Thus, 17 was metalated11 with
s-BuLi/TMEDA in dry Et2O at ꢀ78 ꢁC for 4 h and the intermediate
oxymethyllithium was reacted with chlorodimethylphenylsilane to
Scheme 4. Determination of configuration at C-1 (boron bearing carbon atom) of
major diastereomer 15.
Figure 1. Envisaged precursors for the synthesis of chiral methanols.

A. Schweifer, F. Hammerschmidt / Tetrahedron 64 (2008) 7605–7610
7607
Scheme 7. Preparation of methyl carbamates [1,1,1-D3]17 and [1,1-D2]17.
mixture containing carbamoyl chloride13 20 was treated with
2 equiv of CD3OLi prepared from CD3OD and n-BuLi in dry THF.
Work up furnished the desired carbamate [1,1,1-D3]17 purified by
bulb-to-bulb distillation. The next step on the way to chiral silyl-
methanol was the silylation of the carbamate, which did not give
the required [1,1-D2]13 in satisfactory yield, unfortunately (see
Scheme 5). The primary kinetic isotope effect, known to be very
high in such a case, was detrimental for the yield.14 It was at best
18% after metalation for 72 h at ꢀ78 ꢁC using the conditions as used
for the preparation of the unlabeled species.
Scheme 5. Metalation of carbamates 17 and borylation with borate 2.
Therefore, we prepared the doubly deuterated methyl carba-
mate [1,1-D2]17 from commercially available CHD2OH similarly.
Metalation of [1,1-D2]17 with 1.3 equiv of s-BuLi/TMEDA at ꢀ78 ꢁC
for 18 h, followed by silylation, furnished carbamate [1,1-D2]11 in
74% yield (Scheme 5), containing monodeuterated species (3.3%,
corresponding to a kH/kD>30 assuming a CD2HOH with D2 of 100%,
it was however only 98%) as determined by 1H NMR spectroscopy
(400 MHz). Metalation and borylation as in the unlabeled series,
afforded a mixture of [1-D1]18 and [1-D1]19 (ratio in crude product
by 1H NMR spectroscopy: 1.7:1), which were separated by HPLC
(yield of [1-D1]18: 44%; yield of [1-D1]19: 26%). Each of the two
diastereomers contained less than 0.2% of the unlabeled species,
demonstrating that the deprotonation of the silylmethyl carbamate
showed an estimated primary kinetic isotope effect of 20–30. Fi-
nally, major boronate [1-D1]18 was exemplarily reduced with
LiBEt3H to (1S)-[1-D1]5 in 79% yield, compared to 62% when using
LiAlD4 (Scheme 8). Oxidative cleavage of the the B–C bond fur-
nished silylmethanol (S)-[1-D1]6 in again 79% yield with an ee>99%
as determined by 1H NMR spectroscopy of the (R)-Mosher ester.
Similarly, boronate [1-D1]19 will yield the (S)-silyl-[D1]methanol.
To obtain the enantiopure chiral methanols, the diastereomeric
boronates [1-D1]18 and [1-D1]19 will have to be reduced with
LiBEt3T and oxidized to deuterated and tritiated silylmethanols
undergoing Brook rearrangement to chiral methanols as described
recently.5
give silylmethyl carbamate 11 in 67% yield (Scheme 5). It was
metalated again with s-BuLi/TMEDA in dry Et2O at ꢀ78 ꢁC for
45 min and the
a-oxy-a-silylmethyllithium was borylated with
borate 2. The mixture of boronates was separated easily by pre-
parative HPLC to give diastereomers 18 (tR 8.8 min), the major and
more polar one, and 19 (tR 5.4 min), in yields of 57% and 31% (cor-
responding to a ratio of 1.8:1), respectively. When the
a-oxy-a-
silylmethyllithium was borylated at ꢀ40 ꢁC, the ratio decreased to
1.5:1 suffient for the labeled series. To determine the configuration
at the new stereogenic center, both boronates were reduced with
LiAlD4 in an SN2 type reaction to deuterated boronates (1R)- and
(1S)-[1-D1]5 in yields of 62% and 48%, respectively (Scheme 6).5
Oxidation with H2O2/NaHCO3 at 50 ꢁC furnished the respective
(dimethylphenylsilyl)methanols (S)- and (R)-[1-D1]6 in high yields
with enantiomeric excesses of 99% as proven by 1H NMR spec-
troscopy of their (R)-Mosher esters.5
Now we wanted to repeat the sequence with the triply deuter-
ated methyl carbamate [1,1,1-D3]17, derived from CD3OD. Its
synthesis was performed as given in Scheme 7. The reaction
Scheme 6. Determination of configuration of boronates 18 and 19 and of ee of
silylmethanols 6.
Scheme 8. Conversion of boronate [1-D1]18 to silylmethanol (S)-[1-D1]6.

7608
A. Schweifer, F. Hammerschmidt / Tetrahedron 64 (2008) 7605–7610
3. Conclusions
2 mmol) and TMEDA (0.349 g, 0.45 mL, 3 mmol) in dry Et2O (10 mL)
at ꢀ78 ꢁC under argon. After stirring for 90 min at ꢀ78 ꢁC, the re-
action mixture was cooled to ꢀ95 ꢁC and a solution of the mixed
borate5 2 [prepared from 0.747 g (3.3 mmol, crystallized from 1,2-
dichloroethane, ee 99%) of (R,R)-1,2-dicyclohexylethane-1,2-diol
and (t-BuO)3B (0.868 g, 1.07 mL, 3.77 mmol)] dissolved in dry Et2O
(5 mL). After stirring for 2 h at ꢀ95 ꢁC, the reaction was quenched
with a saturated aqueous solution of NH4Cl (10 mL) and Et2O
(20 mL). The phases were separated and the aqueous phase was
extracted with Et2O (3ꢃ10 mL). The combined organic layers were
dried (MgSO4) and concentrated under reduced pressure. The
crude product [15/16/9 3.3:1:0.5 by 1H NMR; CHSi: 4.25 (15), 4.19
(16), and 4.05 (9)] was flash chromatographed [hexanes/CH2Cl2
2:1; for TLC 2:1: Rf 0.53 for 16, 0.49 for 9, and 0.42 for 15] to give
a mixture of boronate 16 and ester 9 (0.12 g) and boronate 15
In summary, we have shown that CD2HOH can be used effi-
ciently to prepare the carbamate derived from TMPH, amenable to
lithiation and silylation. The resulting dideuterated silylmethyl
carbamate was converted to diastereomeric boronates, which can
be easily converted to chirally deuterated silylmethanols. Two high
primary kinetic isotope effects ensure complete removal of protium
from the boron bearing carbon atom. This approach represents
a formal synthesis of enantiopure chiral methanols in a total of nine
linear steps, starting from CD2HOH.
4. Experimental
4.1. General information
(0.62 g, 46%), which was crystallized from hexanes; mp 140–
1H and 13C NMR (J modulated) spectra were measured in CDCl3
at 300 K on a Bruker Avance DRX 400 at 400.13 MHz and
100.61 MHz, respectively. Chemical shifts, given in parts per mil-
142 ꢁC; [
a
]
þ13.1 (c 1.01, acetone). The mixture of 16 and 9 was
20
D
separated by flash chromatography (hexanes/CH2Cl2 3:1) to give 16
as a colorless gum; [
20
a
]
þ32.1 (c 2.0, acetone).
D
lion, were referenced to residual CHCl3
(
dH¼7.24) and CDCl3
(dC¼77.00). The signal of the boron bearing carbon atom in boro-
4.3.1. Compound 15
nates was normally not detected in the 13C NMR spectra.15 IR
spectra were run on a Perkin–Elmer 1600 FT-IR spectrometer; liq-
uid samples were measured as films on a silicon disc.16 Analytical
HPLC was performed on a Jasco System (PU-980 pump, UV 975 and
IR (Si): nmax 2925, 2852, 1726, 1448, 1352, 1262, 1185 cmꢀ1
;
1H
7.35–7.16 (m, 20H), 4.19 (s, H), 3.80 (m,
2H),1.74–1.49 (m,10H),1.24–1.02 (m, 8H),1.02–0.78 (m, 4H), 0.18 (s,
6H); 13C NMR (100.6 MHz, CDCl3):
174.6, 143.2, 136.3, 134.0, 130.4,
NMR (400.1 MHz, CDCl3):
d
d
RI 930) using a Superspher Si 60 (4
m
m) column (B 0.4ꢃ25 cm), 5%
129.1, 127.6, 127.5, 126.5, 84.3, 67.3, 42.9, 28.7, 27.6, 26.4, 26.0, 25.8,
ꢀ4.3, ꢀ4.5. Anal. Calcd for C43H51BO4Si: C, 77.00; H, 7.66. Found:
76.78; H, 7.63.
EtOAc/hexanes, 2 mL/min, 20 ꢁC, UV 254 nm; tR¼5.4 min (18) and
8.8 min (19). Preparative HPLC was performed on a Dynamax
Model SD-1 equipped with a Model UV-1 absorbance detector us-
ing a Superspher Si 60 (4
m
m) column (B 3.2ꢃ23.7 cm), 5% EtOAc/
4.3.2. Compound 16
hexanes, 80 mL/min, 20 ꢁC; tR¼9.0 and 12.0 min. Optical rotations
were measured at 20 ꢁC on a Perkin–Elmer 351 polarimeter in
a 1 dm cell. TLC was carried on 0.25 mm thick Merck plates, silica
gel 60 F254. Flash chromatography was performed with Merck silica
gel 60 (230–400 mesh). Spots were visualized by UV and/or dipping
the plate into a solution of (NH4)6Mo7O24$4H2O (23.0 g) and of
Ce(SO4)2$4H2O (1.0 g) in 10% aqueous H2SO4 (500 mL), followed by
heating with a heat gun. Melting points were determined on
a Reichert Thermovar instrument and were uncorrected.
IR (Si): nmax 2925, 2853, 1728, 1448, 1354, 1259, 1182 cmꢀ1
;
1H
7.34–7.16 (m, 20H), 4.26 (s, H), 3.78 (m,
2H), 1.70 (m, 8H), 1.56 (m, 2H), 1.17 (m, 8H), 1.00 (m, 2H), 0.88 (m,
2H), 0.24 (s, 3H), 0.13 (s, 3H); 13C NMR (100.6 MHz, CDCl3):
174.5,
NMR (400.1 MHz, CDCl3):
d
d
143.4, 136.4, 134.0, 130.5, 129.1, 127.5, 126.4, 84.1, 67.5, w60 (very
broad, BCH?), 42.8, 28.7, 27.5, 26.4, 26.0, 25.8, ꢀ3.8, ꢀ5.0. Anal.
Calcd for C43H51BO4Si: C, 77.00; H, 7.66. Found: 77.02; H, 7.78.
4.4. (R,R)-1,2-Dicyclohexylethane-1,2-diol (1R)-
(dimethylphenylsilyl)-[1-D1]methylboronate {(1R)-[1-D1]5}
from 15
As the nomenclature of boronates is complex, the practical
system of Matteson et al. was adopted.17
4.2. (Dimethylphenylsilyl)methyl triphenylacetate (9)
Boronate 15 (0.671 g, 1 mmol) was reduced with LiAlD4
according to General Procedure A given in Ref. 5 to give (1R)-[1-
D1]5 (0.275 g, 71%). The 1H NMR spectrum was identical with that
of an authentic sample.
Diisopropyl azodicarboxylate (1.18 mL, 1.212 g, 6 mmol) was
added dropwise to
a stirred mixture of triphenylphosphine
(1.574 g, 6 mmol), triphenylacetic acid (13) (1.586 g, 5.5 mmol), and
(dimethylphenylsilyl)methanol (12) (0.831 g, 5 mmol) in dry tolu-
ene (12.5 mL) under argon at ꢀ30 ꢁC. The cooling bath was re-
moved and the mixture was stirred at ambient temperature until
completion of the reaction (2 h). The reaction mixture was con-
centrated. The residue was purified by flash chromatography
(hexanes/CH2Cl2 1:1; Rf 0.24 for hexanes/CH2Cl2 2:1) to afford ester
9 (1.98 g, 91%), which was crystallized from hexanes; mp 61–62 ꢁC.
IR (Si): 3058, 2958, 1731, 1494, 1446, 1282, 1251, 1182, 1116 cmꢀ1; 1H
4.5. (R)-(Dimethylphenylsilyl)-[1-D1]methanol {(R)-[1-D1]6}
Boronate (1R)-[1-D1]5 (0.190 g, 0.493 mmol) was oxidized by
General Procedure B given in Ref. 5 to yield silylmethanol (R)-[1-
D1]6 (80 mg, 97%) as a colorless liquid.
4.6. Preparation of methyl 2,2,6,6-tetramethylpiperidine-1-
carboxylates {17, [1,1,1-D3]17 and [1,1-D2]17}
NMR (400.1 MHz, CDCl3):
d
7.40–7.12 (m, 20H), 4.07 (s, 2H), 0.19 (s,
174.5, 143.0, 136.0, 133.8, 130.3,
6H); 13C NMR (100.6 MHz, CDCl3):
d
4.6.1. Improved preparation of 17
129.4,127.8, 127.6,126.7, 67.6, 58.0, ꢀ4.7. Anal. Calcd for C29H28O2Si:
A mixture of TMPH (7.4 mL, 43.86 mmol) and methyl chloro-
formate (3.7 mL, 43.86 mmol) in dry THF (20 mL) was heated at
40 ꢁC (48 h). Water (40 mL) was added and the mixture was stirred
for 5 min. The organic phase was separated and the aqueous one
extracted with EtOAc (3ꢃ15 mL). The combined organic layers were
washed with HCl (40 mL, 2 M), a saturated aqueous solution of
NaHCO3 (40 mL), dried (MgSO4), and concentrated under reduced
pressure. The residue was purified by bulb-to-bulb distillation
(110–120 ꢁC/13 mbar) to yield carbamate (3.00 g, 73% compared to
C, 79.77; H, 6.46. Found: C, 79.72; H, 6.63.
4.3. (R,R)-1,2-Dicyclohexylethane-1,2-diol (1R)- and (1S)-
[triphenylacetoxy-(dimethylphenylsilyl)methyl]-boronate
(15 and 16)
s-BuLi (2.31 mL, 3 mmol, 1.3 M in cyclohexane) was added
dropwise to a stirred solution of triphenylacetate 9 (0.873 g,

A. Schweifer, F. Hammerschmidt / Tetrahedron 64 (2008) 7605–7610
7609
30–40% in Et2O according to the literature procedure12) as a color-
less liquid.
4.7.2. (Dimethylphenylsilyl)-[D2]methyl 2,2,6,6-
tetramethylpiperidine-1-carboxylate {[1,1-D2]11} from [1,1,1-D3]17
s-BuLi (4.24 mL, 5.93 mmol, 1.5 equiv, 1.4 M solution in cyclo-
hexane) was added dropwise to a stirred solution of methyl
carbamate [1,1,1-D3]17 (0.787 g, 3.95 mmol) and TMEDA (0.689 g,
0.89 mL, 5.93 mmol, 1.5 equiv) in dry Et2O (3.1 mL) at ꢀ78 ꢁC under
argon. After stirring for 72 h at ꢀ78 ꢁC, chlorodimethylphenylsilane
(1.012 g, 1.0 mL, 5.93 mmol, 1.5 equiv) was added, and the reaction
mixture was allowed to warm to room temperature for 18 h. Work
up and purification as for the unlabeled compound gave deuterated
silylmethyl carbamate [1,1-D2]11 (0.237 g, 18%).
1H NMR (400.1 MHz, CDCl3):
d 3.61 (s, 3H), 1.67–1.56 (m, 6H),
1.37 (s, 12H); 13C NMR (100.6 MHz, CDCl3): 157.9, 56.0 (2C), 50.9,
39.4 (2C), 29.8 (4C), 15.5.
4.6.2. [D3]Methyl 2,2,6,6-tetramethylpiperidine-1-carboxylate
{[1,1,1-D3]17}
A solution of 2,2,6,6-tetramethylpiperide-1-carbonyl chloride
was prepared from phosgene (4.85 mL, 9.37 mmol, approx. 20% so-
lution in toluene) according to General Procedure given in Ref.13 for
the ‘‘Synthesis of 2,2,6,6-Tetramethylpiperidine Urethanes’’ in the
literature, except that a two-necked round-bottomed flask fitted
with an argon balloon was used. Instead of filtering the mixture it
was cooled to ꢀ50 ꢁC and a solution of CD3OLi in THF was added. It
had been prepared by addition of n-BuLi (11.7 mL,18.72 mmol,1.6 M
in hexanes) to a stirred solution of CD3OD (0.675 g, 18.72 mmol,
0.68 mL) in dry THF (20 mL) under argon at ambient temperature.
Stirring was continued for 30 min at ꢀ50 ꢁC and 1 h at ambient
temperature. Water (25 mL) and HCl (5 mL, 2 M) were added. The
organic phase was separated and the aqueous one extracted twice
withCH2Cl2 (20 mL). Thecombinedorganiclayerswerewashed with
water (3ꢃ20 mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude product was bulb-to-bulb distilled (100–105 ꢁC/
9 mbar) to give methyl carbamate [1,1,1-D3]17 (1.547 g, 82%).
The 1H and 13C NMR spectra were identical with that of the
unlabeled species, except for the missing signals for OCH3.
1H and 13C NMR spectra were identical with that of the un-
labeled species, except for the missing signals for OCH2Si.
4.7.3. (Dimethylphenylsilyl)-[D2]methyl 2,2,6,6-
tetramethylpiperidine-1-carboxylate {[1,1-D2]11} from [1,1-D2]17
s-BuLi (2.01 mL, 2.82 mmol, 1.3 equiv, 1.4 M solution in cyclo-
hexane) was added dropwise to a stirred solution of dideuterated
methyl carbamate [1,1-D2]17 (0.437 g, 2.17 mmol) and TMEDA
(0.328 g, 0.43 mL, 2.82 mmol, 1.3 equiv) in dry Et2O (2.17 mL) at
ꢀ78 ꢁC under argon. After stirring for 18 h at ꢀ78 ꢁC, chloro-
dimethylphenylsilane (0.47 mL, 2.82 mmol, 1.3 equiv) was added
and the reaction mixture was stirred while warming up to room
temperature within 3 h. Work up and purification as for the
unlabeled compound gave deuterated silylmethyl carbamate [1,1-
D2]11 (0.540 g, 74%).
IR (Si): nmax 2964, 1689, 1366, 1331, 1298, 1250, 1116, 1082 cmꢀ1
.
The 1H NMR spectrum was identical with that of the unlabeled
species, except for the missing signal for OCH2Si. It contained 3.3%
of mondeuterated species: 3.90 (t, J¼1.5 Hz, OCDHSi); 13C NMR
spectrum was identical with that of unlabeled species, except for
the signal for OCH2Si, which was replaced by the resonance for
OCDHSi: 55.5 (quint, J¼20.6 Hz).
4.6.3. [D2]Methyl 2,2,6,6-tetramethylpiperidine-1-carboxylate
{[1,1-D2]17}
It was prepared similarly to the trideuterated species, starting
from the same amount of phosgene in toluene, but using CD2HOH
(0.638 g, 18.72 mmol, 0.76 mL; 98% D2) instead of CD3OD, to yield
dideuterated carbamate [1,1-D2]17 (1.46 g, 78%).
1H NMR (400.1 MHz, CDCl3):
d
3.73 (t, J¼1.5 Hz, OCDH2, 1%), 3.58
(quint, J¼1.5 Hz, 1H, OCD2H, 99%), 1.68–1.55 (m, 6H), 1.37 (s, 12H);
13C NMR (100.6 MHz, CDCl3):
157.9, 56.0 (2C), 50.4 (quint,
4.8. (R,R)-1,2-Dicyclohexylethane-1,2-diol [(1S)- and (1R)-
(2,2,6,6-tetramethylpiperidine-1-carbonyloxy)-(dimethyl-
phenylsilyl)methyl]boronates {18 and 19, [1-D1]18
and [1-D1]19}
d
J¼22.2 Hz, OCD2H), 39.4 (2C), 29.8 (4C), 15.5.
4.8.1. Preparation of 18 and 19
4.7. Preparation of (dimethylphenylsilyl)methyl 2,2,6,6-
tetramethylpiperidine-1-carboxylates {11 and [1,1-D2]11}
A solution of silylmethyl carbamate 11 (1.004 g, 3.01 mmol) and
dry TMEDA (0.419 g, 0.54 mL, 3.61 mmol) in dry Et2O (9 mL) was
cooled to ꢀ78 ꢁC under argon. s-BuLi (2.58 mL, 3.61 mmol, 1.4 M
solution in cyclohexane) was added and after stirring for 1 h, the
freshly prepared5 boric acid ester 2 (3.61 mmol) dissolved in dry
Et2O (4.5 mL) was added. Stirring was continued for 1 h at ꢀ78 ꢁC.
The reaction was quenched with a mixture of saturated aqueous
solutions of NH4Cl and NaHCO3 (1:1, 40 mL). The organic phase was
separated and the aqueous layers were extracted with Et2O
(3ꢃ40 mL). The combined organic phase were dried (MgSO4),
concentrated, and purified by flash chromatography (hexanes/
EtOAc 10:1, Rf 0.45/0.33) to give a mixture of diastereomers 18 and
19 in a ratio of 1.8:1 (1H NMR), which were separated by pre-
parative HPLC (EtOAc/hexanes 1:19; 19: tR 5.5 min; 18: tR 8.8 min)
to give boronate 18 (0.527 g, 31%) and 19 (0.973 g, 57%) as colorless
oils.
4.7.1. (Dimethylphenylsilyl)methyl 2,2,6,6-tetramethylpiperidine-1-
carboxylate (11)
s-BuLi (4.28 mL, 6 mmol, 1.4 M solution in cyclohexane) was
added dropwise to a stirred solution of methyl carbamate 17
(0.996 g, 5 mmol) and dry TMEDA (0.697 g, 0.91 mL, 6 mmol) in dry
Et2O (10 mL) at ꢀ78 ꢁC under argon. After stirring for 4 h at ꢀ78 ꢁC,
chlorodimethylphenylsilane (1.024 g, 1.0 mL, 6 mmol) was added,
and the reaction mixture was stirred and allowed to warm to room
temperature in the cooling bath. After addition of a saturated
aqueous solution of sodium bicarbonate (20 mL), the organic phase
was separated and the aqueous layer was extracted with Et2O
(3ꢃ20 mL). The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure. The crude product was first
purified by flash chromatography (CH2Cl2/hexanes 15:1, Rf 0.35)
and finally bulb-to-bulb distilled (110–112 ꢁC/0.3 mbar) to give
silylmethyl carbamate 11 (1.118 g, 67%) as a colorless oil.
20
4.8.1.1. Compound 18. [
a
]
þ27.8 (c 1.3, acetone); IR (Si): nmax
D
2924, 2878, 1680, 1590, 1428, 1164 cmꢀ1
;
1H NMR (400.1 MHz,
IR (Si): nmax 2963, 2942, 1690, 1365, 1333, 1323, 1302, 1076 cmꢀ1
1H NMR (400.1 MHz, CDCl3):
7.53 (m, 2H), 7.32 (m, 3H), 3.92 (s,
2H), 1.59 (m, 6H), 1.32 (s, 12H), 0.36 (s, 6H); 13C NMR (100.6 MHz,
CDCl3): 158.4, 136.8, 133.8 (2C), 129.3, 127.8 (2C), 56.1, 56.0 (2C),
;
CDCl3): 7.63 (m, 2H), 7.29 (m, 3H), 3.80 (s, 1H), 3.50 (m, 2H), 1.86–
d
d
1.78 (m, 2H), 1.72–1.49 (m, 14H), 1.35 (s, 6H), 1.31 (s, 6H), 2.03–1.03
(m, 8H), 0.97–0.83 (m, 4H), 0.36 (s, 3H), 0.34 (s, 3H); 13C NMR
d
(100.6 MHz, CDCl3): d 163.8, 138.2, 134.4 (2C), 128.8, 127.4 (2C), 82.7
39.6 (2C), 29.7 (4C), 15.5, ꢀ4.0 (2C). Anal. Calcd for C19H31NO2Si
(2C), 58.2 (2C), 43.1 (2C), 40.7 (2C), 29.6 (2C), 29.5 (2C), 29.2 (2C),
28.6 (2C), 26.8 (2C), 26.3 (2C), 26.2 (2C), 15.6, ꢀ3.7, ꢀ3.9. Anal. Calcd
(333.55): C, 68.42; H, 9.37; N, 4.20. Found: C, 68.13; H, 9.21; N, 4.09.

7610
A. Schweifer, F. Hammerschmidt / Tetrahedron 64 (2008) 7605–7610
for C33H54BNO4Si (567.68): C, 69.82; H, 9.59; N, 2.47. Found: C,
69.60; H, 9.39; N, 2.33.
Boronate (1R)-[1-D1]5 (0.083 g, 0.215 mmol), derived from
boronate 18, yielded deuterated silylmethanol (R)-[1-D1]6 (0.033 g,
92%) as a colorless oil. Similarly, boronate (1S)-[1-D1]5 (0.067 g,
0.174 mmol), derived from boronate 19, gave (S)-[1-D1]6 (0.025 g,
20
4.8.1.2. Compound 19. [
a]
þ14.7 (c 1.1, acetone); IR (Si): nmax
D
2924, 2852, 1679, 1590, 1428, 1165 cmꢀ1
;
1H NMR (400.1 MHz,
86%). Similarly, boronate (1S)-[1-D1]5, derived from [1-D1]18, was
20
CDCl3): 7.59 (m, 2H), 7.29 (m, 3H), 3.88 (s, 1H), 3.52 (m, 2H), 1.98–
d
converted to (S)-[1-D1]6 (0.159 g, 79%; H<0.3%); [
a
]
þ0.57 (c 1.1,
D
1.90 (m, 2H), 1.74–1.50 (m, 14H), 1.35–1.22 (m, 2H), 1.33 (s, 6H), 1.30
(s, 6H), 1.29–1.03 (m, 6H), 1.02–0.85 (m, 4H), 0.39 (s, 3H), 0.32 (s,
acetone). Their 1H and 13C NMR spectra were identical with each
other and with those for these compounds reported in the
literature.5
3H); 13C NMR (100.6 MHz, CDCl3):
d 164.3, 138.8, 134.0 (2C), 128.7,
127.5 (2C), 82.7 (2C), 58.5 (2C), 43.1 (2C), 40.8 (2C), 29.7 (2C), 29.5
(2C), 29.3 (2C), 29.1 (2C), 26.7 (2C), 26.3 (2C), 26.1 (2C), 15.6, ꢀ3.8,
ꢀ4.1, BCHSi not detected. Anal. Calcd for C33H54BNO4Si (567.68): C,
69.82; H, 9.59; N, 2.47. Found: C, 69.70; H, 9.45; N, 2.32.
4.11. Esterification of deuterated silylmethanols (R)- and (S)-
[1-D1]6 to (R)-MTPA ester
Small samples (15–25 mg) of these alcohols were derivatized
with (S)-MTPACl according to General Procedure C given in Ref. 5.
The 1H NMR spectrum (400.1 MHz, CDCl3) of the (R)-MTPA ester of
the deuterated silylmethanol derived from boronate 18 showed
a significant resonance at 4.20 (t, J¼1.0 Hz; ee 99%) indicating (R)
configuration for the alcohol. The 1H NMR spectra of the (R)-MTPA
ester of the deuterated silylmethanols derived from boronates 19
and [1-D1]18 showed a significant resonance at 4.11 (t, J¼1.0 Hz; ee
99%) indicating (S) configuration for the alcohols.
4.8.2. Preparation of [1-D1]18 and [1-D1]19
Dideuterated silylmethyl carbamate [1,1-D2]11 (1.117 g,
3.33 mmol) was converted to
a mixture of deuterated dia-
stereomers by the procedure used for the nondeuterated species.
The crude product was purified with flash chromatography to give
a mixture of the diastereomers [1.466 g, ratio 1.8:1 (by 1H NMR)] as
a colorless oil. The mixture was separated by HPLC to give the
individual diastereomers {[1-D1]18: 0.899 g, 47%; [1-D1]19: 0.490 g,
26%}.
20
4.8.2.1. Compound [1-D1]18. [
a]
þ27.8 (c 1.3, acetone); H at boron
D
Acknowledgements
bearing carbon atom: <0.20% (1H NMR). The 1H NMR spectrum was
identical with that of the unlabeled species 18, except for the
missing signal for OCHB. The 13C NMR spectrum was identical with
that of 18.
We gratefully acknowledge financial support of this research by
the Fonds zur Fo¨rderung der wissenschaftlichen Forschung (project
no. P19869-N19).
20
4.8.2.2. Compound [1-D1]19. [
a
]
þ14.3 (c 0.56, acetone); H at
D
boron bearing carbon atom: <0.20% (1H NMR). The 1H NMR spec-
trum was identical with that of the unlabeled species 19, except for
the missing signal for OCHB. The 13C NMR spectrum was identical
with that of 19.
References and notes
1. Cornforth, J. W.; Redmond, J. W.; Eggerer, H.; Buckel, W.; Gutschow, C. Nature
1969, 221, 1212–1213.
2. Lu¨thy, J.; Retey, J.; Arigoni, D. Nature 1969, 221, 1213–1215.
3. For the latest two syntheses of chiral acetic acid see: (a) Dehnhardt, C.;
McDonald, M.; Lee, S.; Floss, H. G.; Mulzer, J. J. Am. Chem. Soc. 1999, 121, 10848–
10849; (b) Mulzer, J.; Wille, G.; Bilow, J.; Arigoni, D.; Martinoni, B.; Roten, K.
Tetrahedron Lett. 1997, 38, 5469–5472.
4.9. Reductive removal of carbamoyloxy group from
boronates 18, 19, and [1-D1]18
4. Reviews: (a) Floss, H. G.; Lee, S. Acc. Chem. Res. 1993, 26, 116–122; (b) Floss,
H. G.; Tsai, M.-D.; Woodard, R. W. Top. Stereochem. 1984, 15, 253–321; (c)
Floss, H. G. Methods Enzymol. 1982, 87, 126–159.
5. Peric Simov, B.; Wuggenig, F.; Mereiter, K.; Andres, H.; France, J.; Schnelli, P.;
Hammerschmidt, F. J. Am. Chem. Soc. 2005, 127, 13934–13940.
6. (a) Beak, P.; McKinnie, B. G. J. Am. Chem. Soc. 1977, 99, 5213; (b) Beak, P.; Reitz,
D. B. Chem. Rev. 1978, 78, 275–316.
7. Schlecker, R.; Seebach, D.; Lubosch, W. Helv. Chim. Acta 1978, 61, 512–526.
8. (a) Reviews: Mitsunobu, O. Synthesis 1981, 1–28; (b) Hughes, D. L. Org. React.
1992, 42, 335–656; (c) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127–164.
9. Boche, G.; Bosold, F.; Lohrenz, J. C. W.; Opel, A.; Zulauf, P. Chem. Ber. 1993, 126,
1873–1885.
10. Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2282–2316.
11. Kapeller, D.; Barth, R.; Mereiter, K.; Hammerschmidt, F. J. Am. Chem. Soc. 2007,
129, 914–923.
12. Werchan, H. G.; Russew, R. I.; Held, P. J. Prakt. Chem. 1977, 319, 516–521.
13. Martina, S.; MacDonald, S. A.; Enkelmann, V. J. Org. Chem. 1994, 59, 3281–3283.
14. (a) Hoppe, D.; Paetow, M.; Hintze, F. Angew. Chem., Int. Ed. Engl. 1993, 32, 394–
396; (b) Wu, S.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1996, 118, 715–721; (c) Clayden,
J.; Pink, J. H.; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1998, 39, 8377–8380;
(d) Hammerschmidt, F.; Schmidt, S. Eur. J. Org. Chem. 2000, 2239–2245.
15. Wrackmeyer, B.; Ko¨ster, R. Houben-Weyl Methods of Organic Chemistry, 4th ed.;
Ko¨ster, R., Ed.; Thieme: Stuttgart, 1984; Vol. 13, 3c, pp 377–611.
16. Mikenda, W. Vib. Spectrosc. 1992, 3, 327–330.
These reactions were performed with LiAlD4 (1.2 equiv) or
LiBEt3H (1.1 equiv) in Et2O according to General Procedure A given
in Ref. 5.
Boronate 18 (0.290 g, 0.511 mmol) was reduced with LiAlD4 and
20
yielded silylmethylboronate (1R)-[1-D1]5 (0.112 g, 57%);
[a]
D
20
þ38.2 (c 0.9, acetone) {lit.5
[
a]
þ39.3 (c 2.0, acetone)} as a color-
D
less oil. Similarly, boronate 19 (0.212 g, 0.373 mmol) gave silylme-
20
thylboronate (1S)-[1-D1]5 (0.069 g, 48%);
[
a]
þ38.1 (c 0.9,
D
acetone). Boronate [1-D1]18 (0.899 g, 1.58 mmol) was reduced with
LiBEt3D and gave silylmethylboronate (1S)-[1-D1]5 (0.482 g, 79%);
[
a]
þ38.5 (c 1.5, acetone) {lit.5
[a
]
þ38.7 (c 1.54, acetone)}.
20
20
D
D
Their 1H and 13C NMR spectra were identical with each other
and with those for these compounds reported in the literature.5
4.10. Oxidative cleavage of B–C bond in boronates (1R)- and
(1S)-[1-D1]5
These reactions were performed with H2O2 in aqueous NaHCO3/
THF at 50 ꢁC according to General Procedure B given in Ref. 5.
17. Matteson, D. S.; Kandil, A. A.; Soundararajan, R. J. Am. Chem. Soc. 1990, 112,
3964–3969.