Asymmetric synthesis of (R)-(-)-carnitine

Article abstract of DOI:10.1016/S0040-4039(01)00780-8

A TiCl₄-promoted Mukaiyama-type aldol reaction of the ketenesilyl acetal of ethyl acetate with the lactone carbonyl of (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin- 2-one (1) proceeds with a high degree of diastereoselectivity. The TBDMS-protected hemiketal thus obtained was efficiently converted into highly enantiomerically enriched (R)-(-)-carnitine by following an elimination-reduction protocol. This approach further demonstrates the utility of commercially available glycine template 1 as a potential substrate for the asymmetric synthesis of both enantiomers of carnitine.

Full text of DOI:10.1016/S0040-4039(01)00780-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4437–4440
Asymmetric synthesis of (R)-(−)-carnitine
Rajendra P. Jain and Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 15 March 2001; revised 28 March 2001; accepted 10 May 2001
Abstract—A TiCl4-promoted Mukaiyama-type aldol reaction of the ketenesilyl acetal of ethyl acetate with the lactone carbonyl
of (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one (1) proceeds with a high degree of
diastereoselectivity. The TBDMS-protected hemiketal thus obtained was efficiently converted into highly enantiomerically
enriched (R)-(−)-carnitine by following an elimination–reduction protocol. This approach further demonstrates the utility of
commercially available glycine template 1 as a potential substrate for the asymmetric synthesis of both enantiomers of carnitine.
© 2001 Elsevier Science Ltd. All rights reserved.
The asymmetric syntheses of carnitine and its analogs
have attracted considerable interest in recent years due
to their potential biological activity. (R)-(−)-Carnitine
plays an important role in biochemical pathways for
the b-oxidation of fatty acids and is involved in other
important metabolic functions, both as free carnitine
and as acyl carnitines.1,2 In addition, clinical applica-
Several approaches have been reported in the literature
for the synthesis of carnitine and its analogs including
asymmetric syntheses,7 utilization of chiral, non-
racemic starting materials,8 chemical resolution,9 enzy-
matic or microbial techniques10 and others.11
We have recently reported12 the asymmetric synthesis of
(S)-(+)-carnitine from (5R,6S)-4-(benzyloxycarbonyl)-
5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one
(1)13 by conducting a stereoselective allylation on the
protected hemiacetal (2) derived from 1 (Scheme 1).
The allyl oxazine 3 thus obtained was readily converted
into (S)-(+)-carnitine.12 Herein, we report an efficient
tions as
a hypolipidemic agent in hemodialysis
patients,3 as well as in the treatment of myocardial
ischaemia4 and seizure5 have been developed. The
antipode, (S)-(+)-carnitine acts as competitive inhibitor
of carnitine acyltransferase6 causing depletion of
carnitine.
Scheme 1.
Scheme 2.
* Corresponding author. E-mail: rmw@chem.colostate.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00780-8

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R. P. Jain, R. M. Williams / Tetrahedron Letters 42 (2001) 4437–4440
method for the synthesis of (R)-(−)-carnitine by
employing the same glycine template 1 as a starting
material but using distinctly different chemistry.
the double bond from the sterically less hindered face
of the molecule.
Hydrolysis of ester group in 6 (1 M NaOH, THF, rt, 12
h) and subsequent neutralization of the reaction mix-
ture with 1 M HCl followed by hydrogenolysis (2.2
equiv. PdCl2, 120 psi of H2, 75–80°C, 3 h) and treat-
ment with DOWEX 50WX2-100 ion-exchange resin
generated the desired b-hydroxy-g-aminobutyric acid
715 ([h]2D5=−18.0 (c 1, H2O); lit.15a [h]2D5=−20.5 (c 1.75,
H2O)) in a one pot reaction (91% yield from 6).
We envisaged that reversal of stereochemistry at C2 in
3 could result into the formation of (R)-(−)-carnitine.
This led us to investigate the asymmetric Mukaiyama-
type aldol reaction14 on the lactone carbonyl of 1.
Thus, reaction of 1 with the t-butyldimethylsilylketene
acetal of ethyl acetate in the presence of TiCl4 at −50°C
(CH2Cl2, 12 h) resulted in the formation of the TBDMS
1
protected hemiketal 4 as a single diastereomer (by H
NMR analysis of the crude product) in moderate yield
(57%). The yield of the reaction was further improved
by reducing the reaction time (−20°C, 30 min, 85%
yield, Scheme 2).
Although a one-pot conversion of 7 to (R)-(−)-carnitine
(9) has been reported in literature, the yield of the
reaction was very low (<10%)10a and hence, we adopted
a more efficient two step procedure which we have
recently reported for the synthesis of (S)-(+)-carnitine.12
Thus, reductive methylation of 7 with aq. CH2O (10%
Pd/C, 80 psi of H2, rt, 36 h) generated the desired
dimethylamino compound 8 in quantitative yield. Quat-
ernization of 8 with CH3I (DMF, rt, 24 h) followed by
treatment with Amberlite IRA-400 (OH) ion-exchange
resin generated (R)-(−)-carnitine 97–10 ([h]D25=−29.2 (c 2,
H2O); lit.9a [h]D=−31.3 (c 10, H2O)) in 83% yield
(Scheme 3). Experimental data is provided for all new
compounds.16
The stereochemistry of the newly created stereogenic
1
center in 4 was determined as ‘R’ by H NMR NOE
measurements that revealed a syn-relationship for the
C5 and C6 protons of the oxazine ring with the protons
a to ester carbonyl group. The stereochemical outcome
of the Mukaiyama-type aldol reaction is presumed to
be a manifestation of a transition state (A) where
nucleophilic addition occurs on the less hindered face of
1, as shown in Scheme 2.
Treatment of 4 with BF3·Et2O (CH2Cl2, 0°C, 8 h)
cleanly generated the elimination product 5 in 95%
yield (no elimination product with an exocyclic double
In summary, we have demonstrated an efficient method
for the synthesis of (R)-(−)-carnitine by employing an
asymmetric Mukaiyama type aldol reaction on lactone
carbonyl of commercially available (5R,6S)-4-(benzyl-
oxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-
oxazin-2-one (1)13 and subsequent elimination–
reduction protocol. Since, oxazinone (1) has also been
used as a starting material for the synthesis of (S)-(+)-
carnitine,12 this further demonstrates the utility of this
glycine template as a potential substrate for the
stereodivergent synthesis of both enantiomers of car-
nitine. Current efforts are focused on synthesis of other
peptide isosteres of biological importance, based on this
methodology.
1
bond was detected by H NMR at this reaction temper-
ature). Hydrogenation of 5 to the all syn-substituted
oxazine 6 could not be achieved with 10% Pd/C (20
mol%, 80 psi of H2, EtOH, rt, 12 h) and resulted in the
recovery of starting material (no Cbz-deprotection was
observed under these reaction conditions either). How-
ever, hydrogenation of 5 with PdCl2 (20 mol%, 100 psi
of H2, EtOH, 2 equiv. conc. HCl, rt, 18 h) resulted in
the formation of the desired all syn-substituted oxazine
6 in quantitative yield and with a 94:6 diastereomeric
1
ratio (by H NMR, Scheme 3).
The stereochemistry of newly created stereogenic center
in the major diastereomer of 6 was determined as ‘R’
1
Acknowledgements
by H NMR NOE measurements that revealed a syn-
relationship of the protons at C2, C5 and C6 of the
oxazine ring. The high degree of asymmetric induction
in the reduction step can be explained by adsorption on
the catalyst surface and subsequent hydrogenation of
This work was supported by National Science Founda-
tion (Grant No. CHE 9731947).
Scheme 3.

R. P. Jain, R. M. Williams / Tetrahedron Letters 42 (2001) 4437–4440
4439
Poisson, J. E. Tetrahedron: Asymmetry 1993, 4, 893.
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16. (2R,5R,6S)-2-(tert-Butyldimethylsilyloxy)-2-ethoxycarbon-
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anhydrous CH2Cl2 (40 mL) was added at −20°C the
t-butyldimethylsilylketene acetal of ethyl acetate (5.05 g,
25 mmol) which was followed by a dropwise addition of
TiCl4 (2.74 mL, 25 mmol) over a period of 10 min. The
reaction mixture was stirred at −20°C for 30 min after
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The mixture was warmed to ambient temperature and
extracted with CH2Cl2. The combined organic layer was
washed with brine, dried (anhydrous Na2SO4) and con-
centrated to provide crude 4 which on purification by
flash chromatography on silica gel (95:5 petroleum
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gum; [h]2D5=−85.8 (c 1, CHCl3); 1H NMR (300 MHz,
DMSO-d6, 393 K): l 7.38–7.07 (m, 15H), 5.51 (d, 1H,
J=4.2 Hz), 5.46 (d, 1H, J=4.2 Hz), 5.23 (d, 1H, J=
12.6 Hz), 5.15 (d, 1H, J=12.6 Hz), 4.45 (d, 1H, J=13.5
Hz), 4.13–3.97 (m, 2H), 3.23 (d, 1H, J=13.5 Hz), 3.04
(d, 1H, J=13.5 Hz), 2.77 (d, 1H, J=13.5 Hz), 1.14 (t,
3H, J=7.2 Hz), 0.93 (s, 9H), 0.27 (s, 3H), 0.26 (s, 3H);
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137.5, 136.0, 135.7, 128.8, 127.6, 127.1, 126.9, 126.6,
126.2, 124.9, 97.1, 74.9, 66.4, 59.2, 55.5, 46.3, 24.9, 16.9,
13.1, −3.0, −3.4; IR (CHCl3): 1737, 1700, 1604, 1585
cm−1; HRMS (FAB+) calcd for C34H44NO6Si (m/z):
590.2937, found (m/z): 590.2931.
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(5R,6S)-2-Ethoxycarbonylmethyl-5,6-diphenyl-5,6-dihydro-
[1,4]oxazine-4-carboxylic acid benzyl ester (5): To
a
stirred solution of 4 (1.762 g, 3 mmol) in CH2Cl2 (40
mL) was added at 0°C BF3·Et2O (0.76 mL, 6 mmol)
dropwise over a period of 10 min and the resulting
solution was stirred at 0°C for 8 h. It was then
quenched with water at 0°C, warmed to ambient tem-
perature and extracted with CH2Cl2. The combined
organic layer was dried (Na2SO4) and concentrated to
provide crude 5 which on purification by flash chro-
matography on silica gel (9:1 petroleum ether:ethyl ace-
tate, followed by 8:2 petroleum ether:ethyl acetate)
furnished 1.3 g (95%) of 5 as a clear colorless gum;
[h]2D5=+235.1 (c 1, CHCl3); 1H NMR (300 MHz,
DMSO-d6, 373 K): l 7.30–6.97 (m, 15H), 6.74 (s, 1H),
5.37 (d, 1H, J=3.0 Hz), 5.32 (d, 1H, J=3.0 Hz), 5.19
(d, 1H, J=12.6 Hz), 5.12 (d, 1H, J=12.6 Hz), 4.17 (q,
2H, J=7.5 Hz), 3.39 (d, 1H, J=16.2 Hz), 3.31 (d, 1H,
J=16.2 Hz), 1.22 (t, 3H, J=7.5 Hz); 13C NMR (75
MHz, DMSO-d6, 373 K): l 168.6, 150.6, 136.2, 136.1,
135.7, 133.5, 127.6, 127.2, 127.0, 126.8, 126.5, 125.7,
104.4, 77.4, 66.5, 59.6, 58.5, 37.0, 13.3; IR (CHCl3):
1737, 1707, 1605, 1585 cm−1; HRMS (FAB+) calcd for
C28H27NO5 (m/z): 457.1889, found (m/z): 457.1896.
(2R,5R,6S)-2-Ethoxycarbonylmethyl-5,6-diphenyl-morpho-
line hydrochloride (6): To a solution of 5 (0.3 g, 0.65
mmol) in EtOH (30 mL) was added 10 M HCl (130 mL,
1.3 mmol) and PdCl2 (0.023 g, 0.13 mmol) and the
mixture was hydrogenated at 100 psi of H2 and at
ambient temperature for 18 h. Removal of catalyst by
14. Mukaiyama, T. In Organic Reactions; Dauben, W. G.,
Ed.; Wiley-Interscience: New York, 1982; Vol. 28, pp.
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thesis 1992, 403; (f) Lu, Y.; Miet, C.; Kunesch, N.;

4440
R. P. Jain, R. M. Williams / Tetrahedron Letters 42 (2001) 4437–4440
filtration through a plug of Celite and removal of solvent
neutralized with 1 M HCl and diluted by adding 5 mL
water. The resulting solution was hydrogenated with
PdCl2 (0.216 g, 1.22 mmol) at 75–80°C and 120 psi of H2
for 3 h. The mixture was then cooled to ambient temper-
ature, the catalyst was removed by filtration through a
plug of Celite and the filtrate concentrated and triturated
with Et2O. The residue thus obtained was dissolved in
water and passed through DOWEX 50WX2-100 ion-
exchange resin and the resin was washed with distilled
water. Elution of the resin with 3% aq. NH4OH furnished
0.06 g (91%) of 7 which was pure by NMR; [h]2D5=−18.0
(c 1, H2O); lit.15a [h]D25=−20.5 (c 1.75, H2O); 1H NMR
(400 MHz, D2O, 300 K): l 4.21–4.15 (m, 1H), 3.14 (dd,
1H, J=3.2, 13.2 Hz), 2.93 (dd, 1H, J=9.2, 13.2 Hz), 2.41
(d, 2H, J=6.4 Hz); 13C NMR (75 MHz, D2O, 300 K): l
173.9, 61.0, 39.6, 37.9.
furnished 0.235 g (99%) of crude 6 (dr=94:6 by 1H
NMR) as a white solid which was pure by NMR; [h]2D5=
1
−8.4 (c 1, CHCl3); H NMR (400 MHz, CD3OD, 300 K):
l 7.64–7.10 (m, 10H), 5.36 (d, 1H, J=3.2 Hz), 4.98 (d,
1H, J=3.2 Hz), 4.60–4.53 (m, 1H), 4.24 (q, 2H, J=7.2
Hz), 3.43–3.27 (m, 2H), 2.93 (d, 2H, J=6.0 Hz), 1.30 (t,
3H, J=7.2 Hz); 13C NMR (75 MHz, CD3OD, 300 K): l
171.5, 137.9, 132.7, 132.3, 130.7, 129.8, 129.2, 128.7,
126.5, 78.9, 72.7, 62.2, 58.4, 41.6, 38.9, 14.7; IR (CHCl3):
1738, 1586 cm−1; HRMS (FAB+) calcd for C20H24NO3
(m/z): 326.1756, found (m/z): 326.1765.
(R)-4-Amino-3-hydroxybutanoic acid (7):15 To the solu-
tion of 6 (0.2 g, 0.55 mmol) in THF (10 mL) was added
1 M NaOH (2.75 mL, 2.75 mmol) and the mixture was
stirred at ambient temperature for 12 h after which it was
.