Direct chemical synthesis of chiral methanol of 98% ee and its conversion to [2H1,3H]methyl tosylate and [ 2H1,3H-methyl]methionine

Article abstract of DOI:10.1021/ja051568g

This paper describes the synthesis of chiral methanols [(R)- and (S)-CHDTOH] in a total of 12 steps starting from (chloromethyl) dimethylphenylsilane. The metalated carbamates derived from (dimethylphenylsilyl)methanol and secondary amines were borylated at low temperatures (-78 or -94°C) using borates derived from fert-butyl alcohol and (+)-pinane-2,3-diol or (R,R)-1,2-dicyclohexylethane-1,2-diol to give diastereomeric boronates (dr 1:1 to 5:1). The carbamoyloxy group could be replaced smoothly with inversion of configuration by an isotope of hydrogen using LiAIH(D)₄ [or LiBEt₃H(D,T)]. If the individual diastereomeric boronates were reduced with LiAID₄ and oxidized with H₂O₂/NaHCO₃, monodeuterated (dimethylphenylsilyl)methanols of ee > 98% resulted. The absolute configurations of the boronates were based on a single-crystal X-ray structure analysis. Brook rearrangement of the enantiomers of (dimethylphenylsilyl)-[ ²H₁,³H]methanol prepared similarly furnished the chiral methanols which were isolated as 3,5-dinitrobenzoates in 81% and 90% yield, respectively. For determination of the enantiomeric excesses (98%), the methyl groups were transferred to the nitrogen of (S)-2-methylpiperidine and ³H{¹H} NMR spectra were recorded. The Brook rearrangement is a stereospecific process following a retentive course. The chiral methanols were also transformed into methyl tosylates used to prepare [²H ¹,³H-methyl]methionines in high overall yields (>80%).

Full text of DOI:10.1021/ja051568g

Published on Web 09/20/2005
Direct Chemical Synthesis of Chiral Methanol of 98% ee and
Its Conversion to [2H1,3H]Methyl Tosylate and
[2H1,3H-Methyl]Methionine
Biljana Peric Simov,† Frank Wuggenig,† Kurt Mereiter,‡ Hendrik Andres,§
Julien France,§ Peter Schnelli,§ and Friedrich Hammerschmidt*,†
Contribution from the Institut fu¨r Organische Chemie der UniVersita¨t Wien,
Wa¨hringerstrasse 38, A-1090 Wien, Austria; Institute of Chemical Technologies and Analytics,
Vienna UniVersity of Technology, Getreidemarkt 9/164SC, A-1060 Vienna, Austria, and
NoVartis Pharma AG, Lichtstrasse 35, CH-4056 Basel, Switzerland
Received March 30, 2005; E-mail: friedrich.hammerschmidt@univie.ac.at
Abstract: This paper describes the synthesis of chiral methanols [(R)- and (S)-CHDTOH] in a total of 12
steps starting from (chloromethyl)dimethylphenylsilane. The metalated carbamates derived from (dimethyl-
phenylsilyl)methanol and secondary amines were borylated at low temperatures (-78 or -94 °C) using
borates derived from tert-butyl alcohol and (+)-pinane-2,3-diol or (R,R)-1,2-dicyclohexylethane-1,2-diol to
give diastereomeric boronates (dr 1:1 to 5:1). The carbamoyloxy group could be replaced smoothly with
inversion of configuration by an isotope of hydrogen using LiAlH(D)4 [or LiBEt3H(D,T)]. If the individual
diastereomeric boronates were reduced with LiAlD4 and oxidized with H2O2/NaHCO3, monodeuterated
(dimethylphenylsilyl)methanols of ee > 98% resulted. The absolute configurations of the boronates were
based on a single-crystal X-ray structure analysis. Brook rearrangement of the enantiomers of (dimeth-
ylphenylsilyl)-[2H1,3H]methanol prepared similarly furnished the chiral methanols which were isolated as
3,5-dinitrobenzoates in 81% and 90% yield, respectively. For determination of the enantiomeric excesses
(98%), the methyl groups were transferred to the nitrogen of (S)-2-methylpiperidine and 3H{1H} NMR spectra
were recorded. The Brook rearrangement is a stereospecific process following a retentive course. The
chiral methanols were also transformed into methyl tosylates used to prepare [2H1,3H-methyl]methionines
in high overall yields (>80%).
3
use of H NMR spectroscopy.6 Recently, chiral N,N-ditosyl-
Introduction
methylamine was prepared in a short synthesis directly, albeit
1
2
The chiral methyl group carrying one atom each of H, H,
and 3H has captured the imagination of chemists since the first
syntheses of the enantiomers of chiral acetic acid and the
determination of their configuration by Cornforth’s1 and Ari-
goni’s2 groups.3,4 The chiral methyl group was used to analyze
stereochemical problems in chemistry and biochemistry, par-
ticularly of methylations.4,5 To do that the chiral acetate was
converted to N,N-ditosylmethylamine and used to methylate
L-homocysteine to give L-methionine with a chiral methyl group.
Floss et al. demonstrated that the ee and absolute configuration
of the chiral methyl group can also be determined by transfer
to the nitrogen of chiral, nonracemic 2-methylpiperidine and
of low ee (66%).7
We reasoned that chiral methanol would be the smallest and
most versatile compound with a chiral methyl group so far not
prepared directly, that is, without involving cleavage of a C-C
bond. The chiral methyl tosylate would be a strong methylating
agent, contrary to N,N-ditosylmethylamine used to methylate
potassium 4-methoxybenzoate to prepare CHDTOH8b of low
enantiomeric excess (ee 44-58%). Chiral methanol was formed
during the degradation of natural products containing a chiral
methoxy group. Arigoni’s group obtained [2H1,3H]methyl tosyl-
ate by thermal decomposition of N-[2H1,3H]methyl-N-nitroso-
p-toluenesulfonamide.9
† Universita¨t Wien.
Results and Discussion
We thought that the [1,2]-Brook rearrangement10 could form
the basis for the synthesis of chiral methanol. This 1,2-silyl
‡ Vienna University of Technology.
§ Novartis Pharma AG.
(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, 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) 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) Glasenapp-Breiling, M.; Montforts, F.-P. Angew. Chem., Int. Ed. Engl. 2000,
39, 721-723.
(6) Anet, F. A. L.; O’Leary, D. J.; Beale, J. M.; Floss, H. G. J. Am. Chem.
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N.; Berthault, P.; Rousseau, B.; O’Leary, D. J. J. Am. Chem. Soc. 2005,
127, 412-420.
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Ed. Engl. 2002, 41, 497-498.
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(b) Zydowsky, L. D.; Zydowsky, T. M.; Haas, E. S.; Brown, J. W.; Reeve,
J. N.; Floss, H. G. J. Am. Chem. Soc. 1987, 109, 7922-7923.
9
13934
J. AM. CHEM. SOC. 2005, 127, 13934-13940
10.1021/ja051568g CCC: $30.25 © 2005 American Chemical Society

Direct Chemical Synthesis of Chiral Methanol
A R T I C L E S
Scheme 1. [1,2]-Brook Rearrangement of a Labeled Silylmethanol
Scheme 3. Replacing the B-C or Si-C Bond in Boronate 5 by
H-C Bondsa
Scheme 2. Synthesis of Boronates from Carbamatesa
a (a) s-BuLi/TMEDA/Et2O, -78 °C; (b) mixed borate of (+)-pinane-
2,3-diol and tert-butyl alcohol.
a (a) EtCO2H, diglyme, 150 °C; (b) Bu4NF‚3H2O, THF, 50 °C (73%);
(c) Bu4NF‚xD2O, THF, 50 °C (80%).
migration occurs with partial or complete inversion of config-
uration for secondary and tertiary R-silyl benzyl alcohols,
respectively, but with retention (>97%) of configuration if the
phenyl substituent is replaced by an alkyl group.10-12 Thus,
labeled silylmethanol 1 seemed to be a suitable precursor for
the desired chiral methanol 3 (Scheme 1). Labeled silylmethanol
(S)-1 will give chiral methanol (R)-3 if the silyl group is replaced
by protium with retention of configuration. The stereochemical
outcome of this transformation was open, as the intermediate
carbanionic species would probably be less stable than that
bearing an alkyl group. The synthesis of the enantiomers of 1
by enantioselective reduction of unstable formylsilanes13,14 did
not seem to be possible. Therefore, we developed a new method
involving manipulation of a sp3-hybridized carbon bearing a
silyl group. Recently, boronates 5 and 6 were obtained by
diastereoselective borylation15 (dr up to 17:1 in favor of 5) of
metalated (trimethylsilyl)methyl carbamate 4 derived from
(R,R)-bis(1-phenylethyl)amine with mixed borates containing
(+)-pinane-2,3-diol (Scheme 2). The very stable N,N-diisopro-
pylcarbamoyloxy group was tolerated in the first place as labile
alternatives are known.16 We envisaged transforming these
compounds into the enantiomers of labeled (trimethylsilyl)-
methanol and finally chiral methanol. Heating boronate 5 with
propanoic acid in diglyme at 150 °C did not replace the B-C
by a H-C bond as found for trialkylboranes17 (Scheme 3).
Hoping that 5 could first be desilylated and then deborylated
to give a chiral methyl carbamates, in the isotopic series, 5 was
treated with Bu4NF‚3H2O and Bu4NF‚xD2O in THF to furnish
boronates 7 (73%) and [1-2H1]7 (80%, 25% of 7, 75% of a 1:1
mixture of monodeuterated diastereomers), respectively. The
intermediate carbanion with a boron substituent is evidently
configurationally labile and racemized prior to deuteriation/
protonation.
a
Scheme 4. Reduction of Boronate 5 with LiAlH4
a (a) LiAlH4 (5.7 mol equiv)/Et2O, 1 h reflux (12: 84%); (b) LiAlH4
(7.4 mol equiv)/THF, 21 h reflux (12: 79%, (R,R)-13: 91%).
As it was not possible to replace the dioxyboryl group of
boronate 5 at all or the silyl group stereospecifically by isotopes
of hydrogen, we decided to reduce it to a monoalkylborane.
This should then be transformed into a trialkylborane which
would possibly give the desired carbamate without a boron
substituent on exposure to propanoic acid at 150 °C. Thus, a
mixture of 5 and excess LiAlH4 was refluxed in diethyl ether
for 1 h (Scheme 4). The crude product consisted of N,N-bis-
(1-phenylethyl)amine (R,R)-11 and a compound (84%) having,
surprisingly, structure 12. Similarly, diastereomer 6 was reduced
to the same boronate in 74% yield. When boronate 5 was
reduced with a large excess of LiALH4 in refluxing THF for
21 h, (trimethylsilyl)methylboronate 12 and (R,R)-13, the
N-methyl derivative of (R,R)-11, were obtained. It was found
later that boronates were smoothly reduced already at 0 °C in
1 h with 1.05-1.1 mol equiv of LiAlH4 or LiBEt3H in high
yield. Surprisingly, boronate 5 was transformed into 12 in low
yield by a large excess (15 mol equiv) of even NaBH4 sluggishly
in dry ethanol at ambient. We assume that the hydride ion is
first transferred from the reducing agent to the boron18 and from
there to the neighboring carbon atom with concomitant substitu-
tion of the carbamoyloxy group under inversion of configuration.
The reductive removal of the carbamoyloxy group was a
marvelous discovery and eventually paved the way to chiral
silylmethanol.
(9) Gautier, A. E. Dissertation, ETH Zu¨rich nr. 6583, 1980, pp 69-76.
(10) Reviews: (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77-84. (b) West, R.
AdV. Organomet. Chem. 1977, 16, 1-31. (c) Moser, W. H. Tetrahedron
2001, 57, 2065-2084.
(11) (a) Wilson, S. R.; Hague, M. S.; Misra, R. N. J. Org. Chem. 1982, 47,
747-748. (b) Hoffmann, R.; Bru¨ckner, R. Chem. Ber. 1992, 125, 2731-
2739.
(12) Hudrlik, P. F.; Hudrlik, A. M.; Kulkarni, A. K. J. Am. Chem. Soc. 1982,
104, 6809-6811.
(13) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198-2200.
(14) Soderquist, J. A.; Miranda, E. I. J. Am. Chem. Soc. 1992, 114, 10078-
10079.
(15) Peric Simov, B.; Rohn, A.; Brecker, L.; Giester, G.; Hammerschmidt, F.
Synthesis 2004, 2704-1710.
Silylmethylboronate 12, which was quite stable, was oxidized
slowly by H2O2/NaHCO3 (Scheme 5). To circumvent isolation
(16) (a) Hintze, F.; Hoppe, D. Synthesis 1992, 1216-1218. Hoppe, D.; Hintze,
F.; Tebben, P. Angew. Chem., Int. Ed. Engl. 1990, 29, 1422-1424. (b)
Derwing, C.; Hoppe, D. Synthesis 1996, 149-154.
(17) Murray, K.; Brown, H. C. J. Am. Chem. Soc. 1959, 81, 4108-4109.
(18) Matteson, D. S.; Mah, R. W. H. J. Am. Chem. Soc. 1963, 85, 2599-2603.
9
J. AM. CHEM. SOC. VOL. 127, NO. 40, 2005 13935

A R T I C L E S
Peric Simov et al.
Scheme 5. Oxidation of (Trimethylsilyl)methylboronates and
Scheme 7. Lithiation and Borylation of (Dimethylphenylsilyl)methyl
Carbamates 17a
Preparation of Mosher Estersa
a (a) H2O2/NaHCO3/H2O/THF, ambient, 65 h; (b) (S)-MTPACl/pyridine
(2 steps: 27%); (c) LiAlD4 (5 mol equiv)/Et2O, reflux (85%); (a,b) (15%).
a (a) s-BuLi/TMEDA/Et2O/-78 °C, 15 min; (b) mixed borate of (+)-
pinane-2,3-diol and tert-butyl alcohol; yields and ratios of diastereomers
19/20 in Table 1.
Scheme 6. Synthesis of (Dimethylphenylsilyl)methanol and Its
Carbamatesa
Table 1. Borylation of (Dimethylphenylsilyl)methyl Carbamates
17a-c with the Mixed Borate Derived from (+)-Pinane-2,3-diol
and tert-Butyl Alcohol
carbamate
temp.
boronates/ratioa
yield
17a
17b
17b
(R,R)-17c
(R,R)-17c
(S,S)-17c
(S,S)-17c
-78 °C
-78 °C
-95 °C
-78 °C
-95 °C
-78 °C
-95 °C
19a:20a/1.4:1
19b:20b/4:1
19b:20b/4.3:1
19c:20c/5:1
19c:20c/7:1
19d:20d/3:1
19d:20d/5:1
68%
77%
67%
83%
68%
71%
60%
a (a) CH3CO2Na/NaI/DMF/reflux, 2 h; (b) LiAlH4/Et2O (combined
yield: 87%); (c) for 17a: Me2NC(O)Cl/Et2Ni-Pr/DMAP/toluene, reflux
(83%); (c) for 17b: i-Pr2NC(O)Cl/Et2Ni-Pr/DMAP/toluene, reflux (86%);
(c) for (R,R)-17c: (R,R)-(PhMeCH)2NH/COCl2/Et2Ni-Pr/toluene, 0 °C, then
DMAP and 16, reflux, 79%; (S,S)-17c: (S,S)-(PhMeCH)2NH/COCl2/Et2Ni-
Pr/toluene, 0 °C, then DMAP and 16, reflux, 63%.
a All reactions were performed in Et2O using s-BuLi/TMEDA for
metalation at -78 °C; the ratios were determined by 1H NMR spectroscopy
of the crude products.
of the volatile (trimethylsilyl)methanol19 (bp 120-122 °C), the
crude product was dissolved in CH2Cl2, dried, and treated with
(S)-Mosher chloride [(S)-MTPACl]/pyridine. The ester20 could
be isolated easily but in low yield (27%). Similarly, boronate 6
was transformed into ester (R)-[1-2H1]14-MTPA-(R), except that
LiAlH4 was replaced by LiAlD4. The low combined yield was
mitigated by the high enantiomeric excess (>98%), reflecting
the ee of (+)-pinane-2,3-diol (98-99% ee).21 Oxidative cleavage
of the B-C bond follows a mechanism with retention of
configuration.22 Therefore, replacement of the carbamoyloxy
group has to occur stereospecifically with (very likely) inversion
of configuration.
To lower the volatility of the silylmethanol we switched from
the trimethylsilyl to the dimethylphenylsilyl group. (Dimeth-
ylphenylsilyl)methanol (16, bp 58 °C/0.1 mbar) was prepared
in 87% overall yield from the commercially available chloro-
methylsilane 15 (Scheme 6).15,23 To study the influence of the
replacement of a methyl by a phenyl group on the diastereo-
selectivity of the borylation and find a pair of diastereomers
which can be separated easily by flash chromatography,
carbamates 17a-c were prepared by esterification of (dimeth-
ylphenylsilyl)methanol (16) with four carbamoyl chlorides. The
carbamates were borylated by the conditions optimized for the
(trimethylsilyl)methyl carbamates (Scheme 7). They were
deprotonated with s-BuLi/TMEDA in diethyl ether or THF at
-78 °C in less than 5 min (with n-BuLi/TMEDA in 15 min).
However, routinely 15 min were used with s-BuLi to generate
lithiated carbamates 18a-c, which were borylated with the
mixed borate of tert-butyl alcohol and (+)-pinane-2,3-diol [(S)-
pinane-2,3-diol] (Table 1). The configurations at the boron-
bearing carbon atoms are already given here, but the determi-
nations are dealt with later. Compared to boronates with the
trimethylsilyl group, the differences in the polarities of 19/20
became smaller. Boronates 19a-c/20a-c could be separated
by flash chromatography with increasing difficulty. Separation
of 19c/20c by HPLC could be done easily, and homogeneous
19d could be obtained only by HPLC. The ratio of diastereomers
increased from 1.4:1 (R ) Me) to 7:1 [R ) (R)-PhMeCH]. The
diastereoselectivity was higher for (R,R)-17c (19c/20c 5:1,
matched pair) than for (S,S)-17c (19d/20d 3:1, mismatched pair).
Lowering the reaction temperature for the borylation from -78
to -94 °C increased the diastereoselectivity marginally.
Finally, (S,S)-17c was borylated with the mixed borate 22
derived from (R,R)-1,2-dicyclohexylethane-1,2-diol (20)24,25
(Scheme 8). The use of this C2-symmetric diol was inspired by
the work of Hoffmann25 and Matteson et al.,26 who found that
it is a superior director for syntheses with boronic acid esters.
The lithiated carbamate 18c [R ) (S,S)-PhMeCH] furnished
diastereomers 23/24 in a ratio of 1.2:1, which could be separated
easily by flash chromatography (TLC: Rf ) 0.40 and 0.24 for
hexanes/EtOAc 10:1). The (R)-configuration at the boron-
bearing carbon atom of the more polar and crystalline 24 was
(19) Ambasht, S.; Chiu, S. K.; Peterson, P. E.; Queen, J. Synthesis 1980, 318-
320.
(20) Seco, J. M.; Quin˜oa´, E.; Riguera, R. Chem. ReV. 2004, 104, 17-117.
(21) Ray, R.; Matteson, D. S. Tetrahedron Lett. 1980, 21, 449-450.
(22) Zweifel, G.; Brown, H. C. Org. React. 1963, 13, 1-54.
(23) Boons, G. J. P. H.; Elie, C. J. J.; van der Marel, G. A.; van Boom, J. H.
Tetrahedron Lett. 1990, 31, 2197-2200.
(24) (a) Hiscox, W. C.; Matteson, D. S. J. Org. Chem. 1996, 61, 8315-8316.
(b) Wang, Z.-M.; Sharpless, K. B. J. Org. Chem. 1994, 59, 8302-8303.
(25) Hoffmann, R. W.; Ditrich, K.; Ko¨ster, G.; Stu¨rmer, R. Chem. Ber. 1989,
122, 1783-1789.
(26) (a) Matteson, D. J.; Man, H.-W. J. Org. Chem. 1993, 58, 6545-6547. (b)
Matteson, D. S.; Man, H.-W.; Ho, O. C. J. Am. Chem. Soc. 1996, 118,
4560-4566.
9
13936 J. AM. CHEM. SOC. VOL. 127, NO. 40, 2005

Direct Chemical Synthesis of Chiral Methanol
A R T I C L E S
Scheme 8. Borylation of (S,S)-17c with a Mixed Borate of
Scheme 9. Conversion of Boronates 23 and 24 to Mosher Esters
and of a Mixture of 19b/20b to 16a
(R,R)-1,2-Dicyclohexylethane-1,2-diola
a (a) (t-BuO)3B/PhMe/heat (100%); (b) s-BuLi/TMEDA/Et2O, -78 °C,
15 min, 22, (23/24 1.2:1, 78%).
a (a) 23: LiAlH4 (1.1 mol equiv/Et2O)/0 °C, 30 min [71% of 25 along
with 67% of (S,S)-11; 87% of 26]; (b) 23 or 24: LiBEt3H (1.1 mol equiv/
Et2O)/0 °C, 30 min (93% for 23, 81% for 24); (c) 24: LiAlH4 (5 mol equiv/
THF)/reflux, 21 h [62% of 25 along with 59% of (S,S)-13]; (d) H2O2/
NaHCO3/H2O/THF, 50 °C, pentaerythritol (86% for 25; 78% for 26); (e)
(S)-MTPACl/pyridine (90%).
Scheme 10. Transformation of Boronates 23 and 24 into
Deuteriated (Dimethylphenylsilyl)methanols and Determination of
Their Enantiomeric Excessesa
Figure 1. Molecular structure of 24 in the solid state (40% ellipsoids, all
hydrogen atoms except H(1) omitted for clarity).
secured by a single-crystal X-ray structure analysis (Figure 1).
Surprisingly, the diastereoselectivity is low.
To determine the configurations of boronates 19 and 20 they
were transformed into deuterated (dimethylphenylsilyl)metha-
nols and compared as their Mosher esters to those obtained from
boronates 23 and 24 of known configuration. Their optimized
reduction could be performed with 1.1 mol equiv of LiAlH-
(D)4 or LiBEt3H(D) under very mild conditions (Et2O, 0 °C,
30 min) (Scheme 9). If boronate 24 was reduced by a large
excess of LiAlH4 (5 mol equiv) in refluxing THF, the desired
25 was isolated in 71% yield along with 67% of (S,S)-13 formed
by reduction of the lithium carbamidate (see Scheme 4).
Boronate 25 could be oxidized with H2O2/NaHCO3 smoothly
in 86% yield, which became the standard procedure for cleavage
of the B-C bond. The workup was improved by stirring the
reaction mixture with pentaerythritol to remove boric acid, and
(dimethylphenylsilyl)methanol (16) was esterified with (S)-
Mosher chloride/pyridine to give ester 16-MTPA-(R) needed
for comparison. Reduction-oxidation of a mixture of 19b/20b
worked as well as that of 23 and 24. Reduction of the
homogeneous boronates 23 and 24 with LiAlD4 and oxidative
cleavage of the B-C bonds known to occur with retention of
configuration furnished silylmethanols (S)- and (R)-[1-2H1]16
assuming inversion of configuration for the substitution process
with the deuteride (Scheme 10). The SiCHD groups of the two
diastereomeric Mosher esters of 99% de resonated as well-
separated triplets in the 1H NMR spectrum {400.13 MHz; (S)-
[1-2H1]16-MTPA-(R): δ ) 4.11, J ) 1.5 Hz; [(R)-[1-2H1]16-
a (a) LiAlD4/Et2O, 0 °C (95% for 23; 91% for 24), (b) H2O2/NaHCO3/
H2O/THF, 50 °C (yield of (S)-[1-2H1]16: 88%; yields of (R)-[1-2H1]16:
79% for (R)-[1-2H1]25 from 24); (d) (S)-MTPACl/pyridine/CH2Cl2
(yields g90%).
MTPA-(R): δ ) 4.20, J ) 1.5 Hz}. Determination of the
configurations of boronates derived from (+)-pinane-2,3-diol
was performed similarly and is detailed in the Supporting
Information.
In summary, lithiation of carbamates 17a-c gave configu-
rationally labile lithium-complexed carbanions which were
kinetically resolved by the borates. The mixed borate of (+)-
pinane-2,3-diol and tert-butyl alcohol preferentially induced the
(S)-configuration at the boron-bearing carbon atom irrespective
of the substituents at nitrogen. The low diastereoselectivity (1.2:
1) for carbamate (S,S)-17c with borate 22 was very likely the
9
J. AM. CHEM. SOC. VOL. 127, NO. 40, 2005 13937

A R T I C L E S
Peric Simov et al.
Scheme 11. Transfer of the Methyl Group from Methyl
3,5-Dinitrobenzoate to (S)-2-Methylpiperidine
Scheme 12. [1,2]-Brook Rearrangement of 16 and Isolation of
Methanol as 3,5-Dinitrobenzoatea
result of opposing induction (mismatched case). Formation of
virtually equal amounts of diastereomers 23 and 24 in the latter
case is advantageous for the preparation of chiral methanols
because both enantiomers are needed for complementary
stereochemical investigations.
[1,2]-Brook Rearrangement of (Dimethylphenylsilyl)-
methanol. Three challenges had to be overcome before the
conversion of (R)- and (S)-[1-2H1,3H]16 to the chiral methanols
could be addressed: (1) optimization of reaction conditions for
the rearrangement of (dimethylphenylsilyl)methanol; (2) isola-
tion of the formed methanol, possibly as a derivative; and (3)
optimization of the conditions for determination of the enan-
tiomeric excess of chiral methanol with unlabeled methanol.
Floss and Anet et al. found that the ee of the chiral methyl group
can be determined directly by 3H NMR spectroscopy after
transfer to the nitrogen of (R)- or (S)-2-methylpiperidine.6 We
envisaged preparing the 3,5-dinitrobenzoate of the chiral
methanol in the reaction mixture, which would hopefully
facilitate its isolation, and the subsequent transfer of the chiral
methyl group to commercial (S)-2-methylpiperidine (ee 94%).
To check whether the methyl group can be transferred, a deep
red colored mixture of methyl 3,5-dinitrobenzoate (27, 10 mg)
and (S)-2-methylpiperidine (28, 20 equiv) was heated under
argon in an NMR tube at 80 °C for 6 h (Scheme 11). One-half
of the reaction mixture was taken and diluted with CD2Cl2, and
a 1H NMR spectrum (400.13 MHz) was recorded. The ratio of
27/29/MeOH was 5:69:26, satisfactory for determination of the
ee of chiral methanol. Using the [2H1]methyl ester as electro-
a (a) t-BuOK/polar aprotic solvent/up to 6% of H2O; 20-25 °C, 16-18
h, then (b) 3,5-(O2N)2C6H3C(O)Cl/pyridine, 50 °C, 1 h (for both steps: 75-
90% of 27).
27; combined yield: 75-90%) and tert-butyl 3,5-dinitroben-
zoate (32). Monodeuterated (dimethylphenylsilyl)methanol yielded
monodeuterated benzoate (2H1: 99%), indicating that no
deuterium-hydrogen exchange took place under the strongly
basic conditions.
Preparation and Rearrangement of (R)- and (S)-(Dimeth-
ylphenylsilyl)-[1-2H1,3H]methanol. As both enantiomers of
chiral methanol were to be prepared, borylation of carbamate
(S,S)-17c with borate 22 derived from (R,R)-1,2-dicyclohexyl-
ethane-1,2-diol was used. To prepare chiral methanol of high
specific activity the tritium should be introduced via LiBEt3T.28
To make sure that all molecules contain one deuterium atom,
the dideuterated carbamate (S,S)-[1,1-2H2]17c was the appropri-
ate precursor obtained from (S,S)-17c by four cycles of
metalation and quenching with D2O in 92% yield (2H2 > 99%
by 1H NMR) (Scheme 13). The labeled carbamate was metalated
and borylated with the mixed borate 22. The two deuterated
diastereomeric boronates formed in a ratio of 1.25:1 in favor
of the less polar [1-2H1]23 in a combined yield of 72%.
Each diastereomer was reduced with freshly prepared
LiBEt3T.28 To complete the reduction excess LiBEt3H was
added only to the reaction mixture containing [1-2H1]23 after
20 min. Workup and purification furnished (1S)- and (1R)-[1-
2H1,3H]25 in yields of 68% and 77% and of high specific
activity, 11.3 (306.0 mCi)/mmol and 15.3 GBq (412.9 mCi)/
mmol, respectively. The boronates (1S)- and (1R)-[1-2H1,3H]-
24 were oxidized to silylmethanols (S)- and (R)-[1-2H1,3H]16
obtained in 60% and 90% yield, respectively. After appropriate
dilution with unlabeled 16, samples of both silylmethanols were
rearranged to the chiral, nonracemic methanols isolated as their
3,5-dinitrobenzoates (R)- and (S)-[2H1,3H-methyl]27 in yields
of 81% [3.87 GBq (104.7 mCi)/mmol] and 90% [3.83 GBq
(103.6 mCi)/mmol], respectively.
1
phile, the H NMR spectrum showed the expected AB system
for the two diastereotopic protons of the CH2D group.27
Kinetic studies revealed that the reaction rate for the Brook
rearrangement was highest in DMSO and that considerable
negative charge develops on the silicon-bearing carbon atom.10a
To minimize possible partial racemization of the intermediate
silyloxymethylanion, we effected the rearrangement of (dimeth-
ylphenylsilyl)methanol (16) in solvents containing water.12 The
[1,2]-Brook rearrangement of 16 was finished (TLC) in DMSO-
d6 containing D2O (5%) and t-BuOK (50 mg/mL) after 3 h at
ambient temperature (Scheme 12). The formed CH2DOH could
1
be detected by H NMR spectroscopy. As the methanol could
not be isolated from DMSO, which was also not compatible
with 3,5-dinitrobenzoyl chloride, it was replaced by TMU
(N,N,N′,N′-tetramethylurea) selected from a series of aprotic
solvents (DMF, HMPTA, DMPU ) 1,3-dimethyl-2-oxo-
hexahydropyrimidine,TMU) tested. The best and reproducible
results were obtained using TMU (2 mL) containing up to 0.5
mmol of (dimethylphenylsilyl)methanol, D2O (0.12 mL, 6%),
and t-BuOK (0.100 g) as base at room temperature (20-25 °C).
After 16-18 h dry THF and excess pyridine and 3,5-dinitroben-
zoy1 chloride were added, which furnished methyl (27 or [1-2H1]-
A few milligrams of the benzoate (R)-[2H1,3H-methyl]27 were
reacted with a large excess (20 equiv) of commercial (S)-2-
methylpiperidine (ee 94%29) and heated to effect methylation
at nitrogen. The cooled reaction mixture was diluted with CD2-
Cl2 before recording the 3H{1H} NMR spectrum (A, Figure 2).
It shows that the N-[2H1,3H]methyl-2-methylpiperidine was a
(28) Andres, H.; Morimoto, H.; Williams, P. G. J. Chem. Soc., Chem. Commun.
1990, 627-628.
(29) Doller, D.; Davies, R.; Chackalamannil, S. Tetrahedron: Asymmetry 1997,
8, 1275-1278.
(27) Anet, F. A. L.; Kopelevich, M. J. Am. Chem. Soc. 1989, 111, 3429-3431.
9
13938 J. AM. CHEM. SOC. VOL. 127, NO. 40, 2005

Direct Chemical Synthesis of Chiral Methanol
A R T I C L E S
Scheme 13. Synthesis of Chiral Methanols and Determination of
Their Enantiomeric Excessa
Figure 2. Segments of the 3H{1H} NMR spectra recorded at 426.79 MHz
of reaction mixtures after heating (80 °C) for 6 h in a thick-walled NMR
tube under argon, cooling, diluting with CD2Cl2, and sealing; (A) (R)-
[2H1,3H-methyl]27 (6 mg) and commercial (S)-(+)-2-methylpiperidine
(0.063 mL, ee 94%, chemical purity 97%); (A and B) mixture of
(R)-[2H1,3H-methyl]27 (2.2 mg), (S)-[2H1,3H-methyl]27 (4.2 mg), and (S)-
(+)-2-methylpiperidine (0.067 mL prepared by resolution, ee g 99%); (B)
(S)-[2H1,3H-methyl]27 (6 mg) and (S)-(+)-2-methylpiperidine (0.063 mL,
ee g 99%).
Scheme 14. Synthesis of Chiral Methyl Tosylate and Its Use To
Methylate L-Homocysteinea
a (a) t-BuOK/TMU/6% H2O, ambient, 16-18 h, then pyridine/THF/t-
BuOK/p-toluenesulfonyl chloride (-50 °C), aqueous work up, 91% of (R)-
30 [94% of (S)-30]; (b) S-benzyl L-homocysteine/liquid NH3/Na; EtOH,
then (R)-30, 0 °C; 88% of [2H1,3H-methyl-(S)]31{96% of [2H1,3H-methyl-
(R)]31}.
of the methyl resonances are given in Figure 2 (B and A,B,
respectively). The reaction mixture of the benzoate (S)-[2H1,3H-
methyl]27 is stereochemically homogeneous (98% ee).
Anet and Floss et al. reported that the tritium of (7R)-[7-
2H1,3H]29 resonates at higher field than that of (7S)-[7-2H1,3H]-
29.6 The latter was obtained by the sequence given in Scheme
13 from [1-2H1]23 having an (S)-configuration at C-1. Conse-
quently, the intermediate chiral methanol was (R)-configured,
as an (S)-configured chiral methyl group resulted on methylation
of the nitrogen atom. Complementary results were obtained with
the chiral methanol derived from [1-2H1]24. These findings
coincide with the assumption that substitution of the carbam-
oyloxy group by hydride (deuteride or tritide) occurred with
inversion of configuration. Furthermore, this finding is un-
equivocal proof of the microscopic configurational stability of
the intermediate “silyloxymethylanion” of the Brook rearrange-
ment occurring with retention10-12 of configuration.
Preparation of Methyl Tosylate and L-Methionine with
Chiral Methyl Groups. Methyl 3,5-dinitrobenzoate is an
excellent derivative of chiral methanol for isolation but a weak
alkylating agent. After quite a while we found the appropriate
conditions to convert the chiral methanol formed in the reaction
mixture to the corresponding tosylate, which is a highly reactive
methyl donor superior to N,N-ditosylmethylamine (Scheme 14).
We demonstrated that the sodium salt of the homocysteine4 was
alkylated with chiral methyl tosylate to give L-methionine with
a chiral methyl group, which is the standard substrate for feeding
experiments to study methyl transfer in biosynthetic pathways.4
Furthermore, the chiral methyl tosylate transferred its methyl
a (a) 4 × (TMEDA (1.2 equiv)/s-BuLi (1.15 equiv)/THF, -78 °C, 10
min; then D2O in THF), 92%; (b) TMEDA (1.2 equiv)/s-BuLi (1.1 equiv)/
THF, -78 °C, 15 min, then borate 22 (1.3 equiv), 3 h, 40% of [1-2H1]23
and 32% of [1-2H1]24; (c) LiBEt3 H (68% for [1-2H1]23, 77% for [1-2H1]24);
3
(d) H2O2/THF/NaHCO3 (60% for (1S)-[1-2H1,3H]25, 90% for (1R)-[1-
2H1,3H]25); (e) t-BuOK/TMU/6% H2O, ambient, 16-18 h, then 3,5-
dinitrobenzoyl chloride/pyridine/THF (81% for (S)-[1-2H1,3H]16, 90% for
(R)-[1-2H1,3H]16); (f) (S)-2-methylpiperidine.
diastereomeric mixture consisting mainly of the species with a
(S)-configured chiral methyl group and an estimated 3-4% of
the species with the (R)-configured one. Consequently, the ee
of the chiral methyl benzoate was 92-94%, in agreement with
the ee of (S)-2-methylpiperidine. (S)-2-Methylpiperidine of
g99% ee obtained by resolution of the racemate29 (see also
Supporting Information) was reacted with (S)-[2H1,3H-methyl]-
27 and a mixture of (S)- and (R)-[2H1,3H-methyl]27 in a ratio
of 2:1, respectively. The segments of the 3H{1H} NMR spectra
9
J. AM. CHEM. SOC. VOL. 127, NO. 40, 2005 13939

A R T I C L E S
Peric Simov et al.
group to (S)-2-methylpiperidine at room temperature in a smooth
reaction (3H NMR, 98% ee). Methionine with the (R)-configured
methyl group was prepared similarly. The combined yields for
both steps were >80%.
to prepare L-methionines with chiral methyl groups. Further
work will focus on the use of these samples of methionine to
elucidate the methyl transfer in the biosynthesis of fosfomycin.
Acknowledgment. This work was supported by grant no.
P14985-N03 from the Fonds zur Fo¨rderung der wissenschaftli-
chen Forschung. We are grateful to S. Felsinger and C. Tyl for
recording the NMR spectra, S. Schneider for the separation of
boronate mixtures by preparative HPLC, and Dr. L. Brecker
for help with the interpretation of NMR spectra.
Conclusion
We have shown that metalated carbamates of (dimethylphen-
ylsilyl)methanol are configurationally labile and kinetically
resolved by borates derived from chiral, nonracemic diols. The
diastereomeric boronates are reduced stereospecifically with
complex hydrides by substitution of the carbamoyloxy group
with inversion of configuration by an isotope of hydrogen. This
extraordinary transformation enabled the preparation of the
homochiral (dimethylphenylsilyl)-[2H1,3H]methanols, which were
subjected to Brook rearrangement to furnish both enantiomers
of chiral methanol of ee 98% in a total of only 12 steps. The
methanols were also converted to chiral methyl tosylates used
Supporting Information Available: All experimental proce-
dures and spectroscopic data; X-ray crystallographic data of 24
in PDF as well as CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA051568G
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13940 J. AM. CHEM. SOC. VOL. 127, NO. 40, 2005