Asymmetric synthesis of (S)-(+)-carnitine and analogs

Article abstract of DOI:10.1016/S0040-4020(01)00542-7

A general asymmetric route to enantiomerically pure (S)-(+)-carnitine and analogs has been investigated that involves mono-addition of organometallic reagents to the lactone carbonyl group of (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin- 2-one and Lewis acid promoted stereoselective allylation of the resulting hemiacetals. The diastereomerically pure allyl oxazines thus obtained were readily converted into enantiomerically pure (S)-(+)-carnitine and two substituted analogs.

Full text of DOI:10.1016/S0040-4020(01)00542-7

TETRAHEDRON
Pergamon
Tetrahedron 57 #2001) 6505±6509
Asymmetric synthesis of ꢀS)-ꢀ1)-carnitine and analogs
Rajendra P. Jain and Robert M. Williamsp
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 12 February 2001; revised 23 March 2001; accepted 13 April 2001
AbstractÐAgeneral asymmetric route to enantiomerically pure #S)-# 1)-carnitine and analogs has been investigated that involves mono-
addition of organometallic reagents to the lactone carbonyl group of #5R,6S)-4-#benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-
1,4-oxazin-2-one and Lewis acid promoted stereoselective allylation of the resulting hemiacetals. The diastereomerically pure allyl oxazines
thus obtained were readily converted into enantiomerically pure #S)-#1)-carnitine and two substituted analogs. q 2001 Elsevier Science Ltd.
All rights reserved.
The asymmetric synthesis of carnitine and its analogs has
attracted considerable interest in recent years due to their
important biological activities. #R)-#2)-carnitine plays an
important role in biochemical pathways for 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, it has been found that this substance has clinical
applications as a hypolipidemic agent in hemodialysis
patients3 as well as in the treatment of myocardial
ischemia4 and seizure.5 Interestingly, the antipode,
#S)-#1)-carnitine acts as a competitive inhibitor of carnitine
acyltransferase6 causing depletion of carnitine.
The approach that was examined involved the sequential
nucleophilic addition of organometalic agents to the lactone
carbonyl group of 1, with the objective of creating a quater-
nary stereogenic center with high diastereoselectivity.
Initial investigations were conducted with MeLi as the
®rst nucleophile. Thus, reaction of 1 with MeLi at 2788C
in a variety of etheral solvents #Et2O, THF, DME) resulted
in the formation of the desired monoaddition product 2b as a
minor product #,25%) with recovery of a signi®cant
amount of unreacted starting material #Scheme 1). This
was rationalized due to the competing enolization of 1 as
a result of abstraction of the a-hydrogen by the alkyl
lithium. However, addition of anhydrous CeCl3 proved
13
Several approached have been reported in the literature for
the synthesis of carnitine and its analogs including asym-
metric syntheses,7 utilization of chiral starting materials,8
chemical resolution,9 enzymatic or microbial techniques10
and others.11 Herein, we report a general method for the
synthesis of #S)-#1)-carnitine and its analogs using
commercially available #5R,6S)-4-#benzyloxycarbonyl)-
5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one #1)12
as a starting material.
bene®cial and the reaction of 1 with MeLi/CeCl3 #THF,
2788C, 4 h) generated the desired hemiacetal 2b in 73%
yield as a mixture of diastereomers at C2. Reaction of 1
with n-BuLi under identical conditions generated 2c in
45% yield #74% yield of 2c on the basis of recovered start-
ing material) obtained as a mixture of diastereomers at C2.
Conversion of 1 into the unsubstituted acetoxy hemiacetal
2a was achieved by reaction with DIBAL-H #CH2Cl2,
2788C, 30 min) followed by acetylation of the intermediate
Scheme 1.
Keywords: amino acids; carnitine; asymmetric synthesis.
Corresponding author. Tel.: 11-970-491-6747; fax: 11-970-491-5610; e-mail: rmw@chem.colostate.edu
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020#01)00542-7

6506
R. P. Jain, R. M. Williams / Tetrahedron 57 +2001) 6505±6509
Scheme 2.
hemiacetal #Ac2O, Et3N, DMAP, CH2Cl2, 08C-rt, 12 h), as
face of this intermediate thus suffers nucleophilic attack
by the allyl group to furnish the anti-isomers 3b and 3c
#Fig. 1).
reported previously by our group14 #Scheme 1).
Reaction of 2b and 2c with allyltrimethylsilane/TiCl4
#CH2Cl2, 2788C, 1 h) proceeded with a high degree of dia-
stereoselectivity to generate the desired coupling products
3b #67% yield) and 3c #65% yield) as single diastereomers
Oxidative cleavage of the allylic double bond in 3b and 3c
with O3 #MeOH/CH2Cl2, 2788C, then Me2S) followed by
treatment with PDC #DMF, rt, 24 h) cleanly generated
the carboxylic acids 4b and 4c in excellent yields #88±
91% over two steps). Conversion of 3a to 4a was achieved
in a similar way as reported previously.14 Removal of the
chiral auxiliary in 4a±c by hydrogenolysis #PdCl2, 120 psi
H2, THF/H2O, 75±808C, 3 h) followed by treatment with
DOWEXw 50WX2-100 ion-exchange resin generated the
desired b-hydroxy-g-amino acids 5a±c11a,15 in essentially
quantitative yields #Scheme 3).
1
#as evidenced by H NMR analysis of the crude reaction
products). The relative stereochemistry of the newly created
stereogenic center in 3b and 3c was determined as `S' by 1H
NMR NOE measurements on 3b and 3c. Conversion of 2a
to 3a was achieved by treatment with allyltrimethylsilane/
.
BF3 Et2O #CH3CN, 215 to 2208C, 30 min) as reported
previously14 #Scheme 2).
Modeling of the conformation of the putative oxocarbenium
ion intermediate that is presumed to result from Lewis-acid-
mediated removal of the acetoxy group from 2b and 2c,
reveals that the oxazine ring adopts a boat-like confor-
mation placing the phenyl ring adjacent to the ring nitrogen
atom in pseudo-equatorial disposition mandating that the
phenyl ring adjacent to the ring oxygen atom adopt an
axial orientation #Fig. 1). The signi®cantly less hindered
Reductive methylation of 5a±c with aqueous formaldehyde
#10% Pd/C, 80 psi H2, rt, 36 h) generated the desired
dimethylamino compounds 6a±c in essentially quantitative
yields. Quaternization of 6a±c with MeI #DMF, rt, 12 h)
followed by treatment with Amberlitew IRA-400 #HO-)
ion-exchange resin generated #S)-#1)-carnitine 7a
25
#[a]D ˆ128.1 #c 1, H2O); lit.9c [a]Dˆ230.9 #c 1, H2O)
for the enantiomer) and the carnitine analogs 7b11a
25
25
#[a]D ˆ118.3 #c 1, H2O)) and 7c #[a]D ˆ14.6 #c 1,
H2O)) in 68±85% yields #Scheme 4).
In summary, enantioselective syntheses of #S)-#1)-carnitine
and two analogs have been achieved by the sequential
mono-addition of organometallic reagents to the lactone
carbonyl of #5R,6S)-4-#benzyloxycarbonyl)-5,6-diphenyl-
2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one, followed by Lewis
acid-promoted stereoselective allylation of the resulting
hemiacetals. Since #5S,6R)-4-#benzyloxycarbonyl)-5,6-
diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one is also
commercially available,12 the methodology described here
provides convenient access to #R)-#2)-carnitine and the
corresponding analogs in the #R)-enantiomer series. Current
efforts in these laboratories are devoted to expanding this
Figure 1. PM3 geometry optimization of the putative oxocarbenium ion
intermediate using Spartan, C2 trivalent, overall molecular charge 11.
Scheme 3.

R. P. Jain, R. M. Williams / Tetrahedron 57 +2001) 6505±6509
6507
Scheme 4.
methodology to preparation of other amino acids, peptide
isosteres and alkaloids of biomedical signi®cance.
3409, 1678 cm21; HRMS #FAB1) Calcd for C25H26NO4
#m/z) 404.1861, found #m/z) 404.1865.
1.1.3. ꢀ5R,6S)-2-Hydroxy-2-butyl-5,6-diphenyl-morpho-
line-4-carboxylic acid benzyl ester ꢀ2c). Prepared from
anhydrous CeCl3 #0.99 g, 4 mmol) in 15 mL THF, n-BuLi
#2.3 M in hexane, 1.74 mL, 4 mmol) and 1 #1.28 g, 3.3
mmol) in 50 mL THF. Puri®cation of the crude product
by ¯ash chromatography on silica gel #8:2 petroleum ether:
ethyl acetate) furnished 0.663 g #45%) of 2c as a white foam
#mixture of diastereomers at C2) and 0.509 g of unreacted 1
as a white solid #74% yield of 2c on the basis of recovered
1. Experimental
All reactions requiring anhydrous conditions were
performed under a positive pressure of argon using oven
dried glassware #1208C) that was cooled under argon.
THF was distilled from sodium benzophenone ketyl and
dichloromethane was distilled from CaH2. Column chroma-
tography was performed on Merck silica gel Kieselgel 60
#230±400 mesh).1H NMR and 13C NMR spectra were
recorded on a Varian 300 or 400 MHz spectrometer. Mass
spectra were obtained on Fisons VG Autospec. IR spectra
were recorded on a Perkin-Elmer 1600 series FT-IR spec-
trometer. Optical rotations were obtained on a Rudolph
Research automatic polarimeter Autopol III. Compounds
2a, 3a, and 4a were prepared according to the reported
procedures.14
1
1). H NMR #300 MHz, CDCl3, 300K) d 7.50±7.10 #m,
15H), 5.75±5.10 #m, 4H), 4.13 and 4.03 #d, 1H, Jˆ
13.5 Hz), 3.23 #d, 1H, Jˆ13.5 Hz), 2.81 and 2.65 #s, 1H),
2.00±0.80 #m, 6H), 1.04 #t, 3H, Jˆ7.2 Hz); IR #CHCl3)
3416, 1679, 1604, 1585 cm21; HRMS #FAB1) Calcd for
C28H32NO4 #m/z) 446.2331, found #m/z) 446.2331.
1.1.4. General procedure for allylation of hemiacetals 2b
and 2c. To a solution of 2b and 2c in anhydrous CH2Cl2 was
added allyltrimethylsilane at 2788C followed by TiCl4 #1 M
solution in CH2Cl2) over a period of 15 min and the solution
was stirred at 2788C for 1 h, after which it was quenched
with saturated aq. NH4Cl and warmed to ambient tempera-
ture. Water was added to dissolve the precipitated solids,
and the solution was extracted with CH2Cl2. The combined
organic phase was dried and concentrated to furnish the
crude product which was puri®ed by ¯ash chromatography
on silica gel using petroleum/ethyl acetate mixtures as
eluents.
1.1. General
1.1.1. General procedure for addition of alkyl lithium
reagents to of ꢀ5R,6S)-4-ꢀbenzyloxycarbonyl)-5,6-di-
phenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one. To anhy-
drous cerium chloride13 #1.2 equiv.) at 08C was added
anhydrous THF with vigorous stirring and the resulting
suspension was warmed to and stirred at ambient tempera-
ture for 12 h after which the mixture was cooled to 2788C
and the alkyl lithium was added over a period of 5 min. The
resulting yellow suspension was stirred at the same tempera-
ture for 30 min after which a solution of 1 in anhydrous THF
was added dropwise over a period of 15 min. The mixture
was stirred at the same temperature for 4 h, quenched with
saturated aq. NH4Cl and warmed to ambient temperature.
Dilute HCl was added and the mixture was extracted with
ethyl acetate. The combined organic layer was dried
#Na2SO4) and evaporated under reduce pressure to furnish
the crude product which was puri®ed by ¯ash chroma-
tography on silica gel using petroleum ether/ethyl acetate
mixtures as eluents.
1.1.5. ꢀ2S,5R,6S)-2-Methyl-2-ꢀ2-propenyl)-5,6-diphenyl-
morpholine-4-carboxylic acid benzyl ester ꢀ3b). Prepared
from 2b #1 g, 2.48 mmol), allyltrimethylsilane #3.94 mL,
24.8 mmol) TiCl4 #1 M solution in CH2Cl2, 9.92 mL,
9.92 mmol) in dichloromethane #10 mL). Puri®cation of
the crude product by ¯ash chromatography on silica gel
#9:1 petroleum ether:ethyl acetate) furnished 0.710 g
25
#67%) of 3b as a clear colorless gum. [a]D ˆ2133.78 #c
1.9, CHCl3); 1H NMR #300 MHz, DMSO-d6, 393K) d
7.35±7.02 #m, 15H), 5.84±5.70 #m, 1H), 5.45 #d, 1H, Jˆ
3.6 Hz), 5.32 #d, 1H, Jˆ3.6 Hz), 5.20 #d, 1H, Jˆ12.6 Hz),),
5.12 #d, 1H, Jˆ12.6 Hz), 5.14±5.03 #m, 2H), 3.79 #d, 1H,
Jˆ13.5 Hz), 3.02 #d, 1H, Jˆ13.5 Hz), 2.71 #dd, 1H, Jˆ7.2,
14.7 Hz), 2.37 #dd, 1H, Jˆ7.5, 14.7 Hz), 1.33 #s, 3H); IR
#CHCl3) 1697 cm21; HRMS #FAB1) Calcd for C28H30NO3
#m/z) 428.2225; found #m/z) 428.2208.
1.1.2. ꢀ5R,6S)-2-Hydroxy-2-methyl-5,6-diphenyl-morpho-
line-4-carboxylic acid benzyl ester ꢀ2b). Prepared from
anhydrous CeCl3 #1.65 g, 6.7 mmol) in 20 mL THF, MeLi
#1.4 M in Et2O, 4.78 mL, 6.7 mmol) and 1 #2.12 g,
5.5 mmol) in 100 mL THF. Puri®cation of the crude product
by ¯ash chromatography on silica gel #8:2 petroleum ether:
ethyl acetate) furnished 1.6 g #73%) of 2b as a white foam
#mixture of diastereomers at C2). 1H NMR #300 MHz,
CDCl3, 300K) d 7.50±7.00 #m, 15H), 5.80±5.00 #m, 4H),
4.13 and 4.03 #d, 1H, Jˆ13.5 Hz), 3.22 #d, 1H, Jˆ13.5 Hz),
2.69 and 2.57 #s, 1H), 1.68 and 1.64 #s, 3H); IR #CHCl3)
1.1.6. ꢀ2S,5R,6S)-2-Butyl-2-ꢀ2-propenyl)-5,6-diphenyl-
morpholine-4-carboxylic acid benzyl ester ꢀ3c). Prepared
from 2c #0.250 g, 0.56 mmol), allyltrimethylsilane #0.89
mL, 5.6 mmol), TiCl4 #1 M solution in CH2Cl2, 2.24 mL,
2.24 mmol) in dichloromethane #3 mL). Puri®cation of the

6508
R. P. Jain, R. M. Williams / Tetrahedron 57 +2001) 6505±6509
crude product by ¯ash chromatography on silica gel #9:1
petroleum ether:ethyl acetate) furnished 0.173 g #65%) of
#m, 4H), 0.95 #t, 3H, Jˆ7.5); IR #CHCl3) 3400±2800 #br),
1704, 1604, 1581 cm21; HRMS #FAB1) Calcd for
C30H34NO5 #m/z) 488.2436; found #m/z) 488.2433.
3c as a clear colorless gum. [a]D ˆ294.3 #c 1, CHCl3); 1H
25
NMR #300 MHz, DMSO-d6, 393K) d 7.37±7.05 #m, 15H),
5.85±5.71 #m, 1H), 5.51 #d, 1H, Jˆ3.6 Hz), 5.38 #d, 1H,
Jˆ3.6 Hz), 5.23 #d, 1H, Jˆ12.3 Hz),), 5.16 #d, 1H, Jˆ
12.3 Hz), 5.14±5.05 #m, 2H), 3.77 #d, 1H, Jˆ13.8 Hz),
3.06 #d, 1H, Jˆ13.8 Hz), 2.70 #dd, 1H, Jˆ6.6, 14.7 Hz),
2.47 #dd, 1H, Jˆ7.2, 14.7 Hz), 1.73±1.65 #m, 2H), 1.54±
1.34 #m, 4H), 0.95 #t, 3H, Jˆ7.5 Hz); IR #CHCl3) 1693,
1639, 1604, 1585 cm21; HRMS #FAB1) Calcd for
C31H36NO3 #m/z) 470.2695; found #m/z) 470.2628.
1.1.10. General procedure for the hydrogenolysis of
carboxylic acids 4a±c. Asolution of 4a±c in THF: water
#6:4, v/v) was hydrogenated with PdCl2 #3 equiv.) at 75±
808C and 120 psi of H2 for 3 h. The mixture was then cooled
to ambient temperature, the catalyst was removed by ®l-
tration through a plug of Celite and the ®ltrate concentrated
and triturated with Et2O. The residue thus obtained was
dissolved in water and passed through DOWEXw 50WX2-
100 ion exchange resin and the resin was washed with
distilled water. Elution of the resin with 2% aq. NH4OH
1.1.7. General procedure for the oxidation of allyl
oxazines 3b and 3c. To a solution of 3a and 3b in anhydrous
MeOH and anhydrous CH2Cl2 was bubbled O3 at 2788C
until the solution turned blue. At this point Ar gas was
bubbled through the solution for 5 min to remove excess
of O3. Me2S was added and the mixture was warmed to
and stirred at ambient temperature overnight. The residue
obtained after the evaporation of solvent was taken up in
water and extracted with CH2Cl2. The combined extracts
were dried #Na2SO4) and evaporated to provide the crude
aldehyde which was treated with PDC #3.5 equiv.) in anhy-
drous DMF for 24 h. Water was added followed by brine
and the mixture was extracted with ethyl acetate. The
combined organic extracts were washed with brine, dried
#Na2SO4), and concentrated to furnish the crude product
which was puri®ed by ¯ash chromatography on silica gel
using petroleum ether/ethyl acetate mixtures as eluents.
1
furnished the amino acids 5a±c which were pure by H
nmr analysis.
1.1.11. ꢀS)-4-Amino-3-hydroxybutanoic acid ꢀ5a).15 Pre-
pared by hydrogenolysis of 4a #0.12 g, 0.28 mmol) with
PdCl2 #0.15 g, 0.84 mmol) in THF #6 mL): water #4 mL)
to provide 0.031 g #93%) of 5a as a white amorphous
25
solid after ion exchange chromatography. [a]D 1 ˆ119.1
#c 1, H2O); lit.10d [a]D ˆ120.7 #c 1.9, H2O); H NMR
25
#300 MHz, D2O) d 4.24±4.10 #m, 1H), 3.15±3.10 #m,
1H), 2.94±2.87 #m, 1H), 2.39 #d, 2H, Jˆ8.0 Hz).
1.1.12. ꢀS)-4-Amino-3-methyl-3-hydroxybutanoic acid
ꢀ5b).11a Prepared by hydrogenolysis of 4b #0.13 g,
0.29 mmol) with PdCl2 #0.16 g, 0.9 mmol) in THF #6 mL):
water #4 mL) to provide 0.038 g #97%) of 5b as a white
amorphous solid after ion exchange chromatography.
25
1
1.1.8.
ꢀ2S,5R,6S)-2-Methyl-2-ꢀ2-carboxyethyl)-5,6-di-
[a]D ˆ18.4 #c 1, H2O); H NMR #300 MHz, D2O) d
3.06 #d, 1H, Jˆ12.9 Hz), 3.00 #d, 1H, Jˆ12.9 Hz), 2.46
#s, 2H), 1.29 #s, 3H); 13C NMR #75 MHz, D2O) d 174.4,
64.4, 43.5, 41.8, 19.8; IR #KBr) 3700±2500 #br), 1638,
1561 cm21; HRMS #FAB1) Calcd for C5H12NO3 #m/z)
134.0817; found #m/z) 134.0822.
phenyl-morpholine-4-carboxylic acid benzyl ester ꢀ4b).
Prepared from 3b #0.5 g, 1.17 mmol) in dichloromethane
#10 mL) and MeOH #20 mL) to obtain 0.486 g of crude
aldehyde which was treated with PDC #1.5 g, 3.98 mmol)
in anhydrous DMF #4 mL) to obtain crude 4b which on
puri®cation by ¯ash chromatography on silica gel #1:1
petroleum ether:ethyl acetate) furnished 0.46 g of 4b as a
1.1.13. ꢀS)-4-Amino-3-butyl-3-hydroxybutanoic acid
ꢀ5c). Prepared by hydrogenolysis of 4c #0.13 g,
0.26 mmol) with PdCl2 #0.15 g, 0.84 mmol) in THF
#6 mL): water #4 mL) to provide 0.047 g #99%) of 5c as a
white amorphous solid after ion exchange chromatography.
25
white foam #88% yield over two steps). [a]D ˆ2118.3 #c
1
1, CHCl3); H NMR #300 MHz, DMSO-d6, 373K) d 11.80
#br, 1H), 7.37±7.07 #m, 15H), 5.48 #d, 1H, Jˆ3.6 Hz), 5.43
#d, 1H, Jˆ3.6 Hz), 5.21 #d, 1H, Jˆ12.9 Hz),), 5.14 #d, 1H,
Jˆ12.9 Hz), 4.01 #d, 1H, Jˆ14.1 Hz), 3.04 #d, 1H, Jˆ
14.1 Hz), 2.85 #d, 1H, Jˆ14.4 Hz), 2.72 #d, 1H, Jˆ
14.4 Hz), 1.54 #s, 3H); IR #CHCl3) 3500±2700 #br), 1704,
1603, 1585 cm21; HRMS #FAB1) Calcd for C27H28NO5
#m/z) 446.1967; found #m/z) 446.1969.
25
1
[a]D ˆ13.1 #c 1.4, H2O); H NMR #300 MHz, D2O) d
3.13 #d, 1H, Jˆ9.9 Hz), 3.06 #d, 1H, Jˆ9.9 Hz), 2.48 #s,
1H), 1.60±1.56 #m, 2H), 1.34±1.29 #m, 4H), 0.88 #t, 3H,
Jˆ5.4 Hz); 13C NMR #75 MHz, D2O) d 173.7, 65.4, 41.2,
38.2, 32.3, 19.5, 17.1, 7.8; IR #KBr) 3500±2400 #br), 1628,
1560 cm21; HRMS #FAB1) Calcd for C8H18NO3 #m/z)
176.1286; found #m/z) 176.1285.
1.1.9. ꢀ2S,5R,6S)-2-Butyl-2-ꢀ2-carboxyethyl)-5,6-diphenyl-
morpholine-4-carboxylic acid benzyl ester ꢀ4c). Prepared
from 3c #0.5 g, 1.06 mmol) in dichloromethane #10 mL) and
MeOH #20 mL) to obtain 0.482 g of crude aldehyde which
was treated with PDC #1.5 g, 3.98 mmol) in anhydrous
DMF #4 mL) to obtain crude 4c which on puri®cation by
¯ash chromatography on silica gel #1:1 petroleum ether:
ethyl acetate) furnished 0.47 g of 4c as a white foam #91%
1.1.14. General procedure for conversion of amino acids
5a±c into 7a±c. Asolution of amino acids 5a±c in distilled
water was hydrogenated over 10% Pd/C in the presence of
excess of 37% aq. formaldehyde at 80 psi of H2 and ambient
temperature for 36 h. The catalyst was removed by ®ltration
through Celite and was washed with hot distilled water. The
combined aqueous layer was passed through DOWEXw
50WX2-100 ion exchange resin and the resin was washed
with distilled water. Elution of the resin with 2% aq.
NH4OH furnished the amino acids 6a±c which were pure
25
1
yield over two steps). [a]D ˆ2127.8 #c 1, CHCl3); H
NMR #300 MHz, DMSO-d6, 373K) d 11.80 #br, 1H),
7.37±7.07 #m, 15H), 5.51 #d, 1H, Jˆ4.2 Hz), 5.45 #d, 1H,
Jˆ4.2 Hz), 5.21 #d, 1H, Jˆ12.3 Hz),), 5.14 #d, 1H,
Jˆ12.3 Hz), 4.01 #d, 1H, Jˆ13.5 Hz), 3.06 #d, 1H,
Jˆ13.5 Hz), 2.79 #s, 2H), 1.94±1.87 #m, 2H), 1.60±1.34
1
by H NMR analysis. The amino acids 6a±c were stirred
with MeI in anhydrous DMF for 12 h at ambient temperature.

R. P. Jain, R. M. Williams / Tetrahedron 57 +2001) 6505±6509
6509
The solvent was removed under reduced pressure #2 mm) at
ambient temperature to obtain the crude product which was
dissolved in distilled water and passed through Amberlitew
IRA-400 #OH) ion exchange resin eluting with water to
furnish the amino acids 7a±c.
2.52 #s, 2H), 1.80±1.64 #m, 2H), 1.36±1.26 #m, 4H), 0.87
#t, 3H, Jˆ6.9 Hz); 13C NMR #75 MHz, D2O) d 173.4, 67.6,
65.0, 50.1, 38.8, 34.5, 19.8, 17.0, 7.8; IR #KBr) 1587 cm21
;
HRMS #FAB1) Calcd for C11H24NO3 #m/z) 218.1756;
found #m/z) 218.1753.
1.1.15. ꢀS)-ꢀ1)-Carnitine ꢀ7a). Prepared by hydrogenation
of 5a #0.03 g, 0.25 mmol) in distilled water #4 mL) and
formaldehyde #37 wt. % solution in water, 0.5 mL, excess)
with 10% Pd/C #0.01 g, 33% w/w) to provide 0.037 g #99%)
of 6a as a white amorphous solid after DOWEXw 50WX2-
Acknowledgements
This work was supported by National Science Foundation
#grant CHE 9731947).
1
100 ion exchange chromatography. H NMR #300 MHz,
D2O) d 4.40±4.26 #m, 1H), 3.22±3.10 #m, 2H), 2.90 #s,
6H), 2.39 #d, 2H, Jˆ6.3 Hz). Treatment of 6a #0.035 g,
0.23 mmol) with MeI #1 mL) and DMF #1 mL) followed
by ion exchange chromatography using Amberlitew IRA-
400 #OH) ion exchange resin furnished 0.03 g #78%) of 7a
References
1. Ferrari, R.; Di Mauro, S.; Sherwood, G. L-Carnitine and its
Role in Medicine: from Function to Therapy; Academic: San
Diego, 1992.
as a clear colorless gum. [a]D ˆ128.1 #c 1, H2O); lit.9c
25
2. De Simone, C.; Famularo, G. Carnitine Today; Springer
Verlag: Heidelberg, 1997.
[a]Dˆ230.9 #c 1, H2O) for the enantiomer; 1H NMR
#300 MHz, D2O) d 4.60±4.52 #m, 1H), 3.44±3.42 #m,
2H), 2.22 #s, 9H), 2.50±2.36 #m, 2H).
3. Guarnieri, G. F.; Ranieri, F.; Toigo, G.; Vasile, A.; Ciman, M.;
Rizzoli, V.; Moracchiello, M.; Campanacci, L.; Am J. Clin.
Nutr. 1980, 33, 1489.
1.1.16. ꢀS)-3-Hydroxy-3-methyl-4-ꢀtrimethylammonio)-
butanoic acid ꢀ7b).11a Prepared by hydrogenation of 5b
#0.03 g, 0.22 mmol) in distilled water #4 mL) and formalde-
hyde #37 wt. % solution in water, 0.5 mL, excess) with 10%
Pd/C #0.01 g, 33% w/w) to provide 0.036 g #99%) of 6b as a
white amorphous solid after DOWEXw 50WX2-100 ion
4. Woster, P. M.; Murray J. Med. Chem. 1986, 29, 865.
5. Cavazza, C. Eur. Pat. Appl. EP 637449, 1995; Chem. Abstr.
1995, 122, 205212.
6. #a) Vary, T. C.; Neely, J. R. Am. J. Physiol. 1982, 242, H585.
#b) Bressler, R.; Brendel, K. J. Biol. Chem. 1966, 241, 4092.
7. #a) Kitamura, M.; Ohkuma, T.; Takaya, H.; Noyori, R.
Tetrahedron Lett. 1988, 29, 1555. #b) Takeda, H.; Hosokawa,
S.; Aburatani, M.; Achiwa, K. Synlett 1991, 193. #c) Kolb,
H. C.; Bennani, Y. L.; Sharpless, K. B. Tetrahedron: Asym-
metry 1994, 4, 133.
1
exchange chromatography. H NMR #300 MHz, D2O) d
3.32 #d, 1H, Jˆ13.8 Hz), 3.23 #d, 1H, Jˆ13.8 Hz), 2.95
#s, 3H), 2.93 #s, 3H), 2.57 #s, 2H), 1.31 #s, 3H); 13C NMR
#75 MHz, D2O) d 173.8, 64.8, 61.9, 43.0, 4 1.0, 21.8. Treat-
ment of 6b #0.030 g, 0.18 mmol) with MeI #1 mL) and DMF
#1 mL) followed by ion exchange chromatography using
Amberlitew IRA-400 #OH) ion exchange resin furnished
0.028 g #85%) of 7b as a white amorphous solid.
8. #a) Bellamy, F. D.; Bondoux, M.; Dodey, P. Tetrahedron Lett.
1990, 31, 7323. #b) Bols, M.; Lundt, I.; Pedersen, C.
Tetrahedron 1992, 48, 319. #c) Kabat, M. M.; Daniewski,
A. R.; Burger, W. Tetrahedron: Asymmetry 1997, 8, 2663.
9. #a) Voeffray, R.; Perlberger, J.-C.; Tenud, L.; Gosteli, J. Helv.
Chim. Acta 1987, 70, 2058. #b) Marzi, M.; Minetti, P.; Moretti,
G.; Tinti, M. O.; De Angelis, F. J. Org. Chem. 2000, 65, 6766.
10. #a) Kaneko, T.; Yoshida, R. Bull. Chem. Soc. Jpn. 1962, 35,
1153. #b) Zhou, B.; Gopalan, A. S.; VanMiddlesworth, F.;
Shieh, W.-R.; Sih, C. J. J. Am. Chem. Soc. 1983, 105, 5925.
#c) Gopalan, A. S.; Sih, C. J. Tetrahedron Lett. 1984, 25, 5235.
#d) Fuganti, C.; Grasselli, P. Tetrahedron Lett. 1985, 26, 101.
#e) Bianchi, D.; Cabri, W.; Cesti, P.; Francalanci, F.; Ricc, M.
J. Org. Chem. 1988, 53, 104. #f) Kasai, N.; Sakaguchi, K.
Tetrahedron Lett. 1992, 33, 1211.
25
1
[a]D ˆ118.3 #c 1, H2O); H NMR #300 MHz, D2O) d
3.52 #d, 1H, Jˆ14.1 Hz), 3.47 ##d, 1H, Jˆ14.1 Hz), 3.25
#s, 9H), 2.45 #s, 2H), 1.46 #s, 3H); 13C NMR #75 MHz,
D2O) d 173.2, 66.5, 65.3, 50.0, 42.6, 21.7; IR #KBr) 1655,
1596 cm21; HRMS #FAB1) Calcd for C8H18NO3 #m/z)
176.1286; found #m/z) 176.1284.
1.1.17. ꢀS)-3-Hydroxy-3-butyl-4-ꢀtrimethylammonio)-
butanoic acid ꢀ7c). Prepared by hydrogenation of 5c
#0.03 g, 0.25 mmol) in distilled water #4 mL) and formalde-
hyde #37 wt. % solution in water, 0.5 mL, excess) with 10%
Pd/C #0.01 g, 33% w/w) to provide 0.034 g #97%) of 6c as a
white amorphous solid after DOWEXw 50WX2-100 ion
11. #a) Comber, R. N.; Hosmer, C. A.; Brouillette, W. J. J. Org.
Chem. 1985, 50, 3627. #b) Brouillette, W. J.; Saeed, A.;
Abuelyaman, A.; Hutchison, T. L.; Wolkowicz, P. E.;
McMillin, J. B. J. Org. Chem. 1994, 59, 4297.
1
exchange chromatography. H NMR #300 MHz, D2O) d
3.29 #d, 1H, Jˆ14.1 Hz), 3.17 #d, 1H, Jˆ14.1 Hz), 2.90
#s, 6H), 2.57 #s, 2H), 1.60±1.48 #m, 2H), 1.36±1.20 #m,
4H), 0.85 #t, 3H, Jˆ6.0 Hz); 13C NMR #75 MHz, D2O) d
173.9, 67.1, 61.2, 41.0, 40.4, 35.0, 20.1, 17.8, 8.7. Treatment
of 6c #0.030 g, 0.14 mmol) with MeI #1 mL) and DMF
#1 mL) followed by ion exchange chromatography using
12. The requisite diphenyloxazine and its antipode are commer-
cially available from Aldrich Chemical Co., Catalog #331856
#CAS Registry #105228464); the antipode: catalog #331872
#CAS Registry #100516549).
13. Takeda, N.; Imamoto, T. Organic Syntheses 1998, 76, 228.
14. Aoyagi, Y.; Williams, R. M. Tetrahedron 1998, 54, 10419.
15. Lu, Y.; Miet, C.; Kunesch, N.; Poisson, J. E. Tetrahedron:
Asymmetry 1993, 4, 893.
Amberlitew IRA-400 #OH) ion exchange resin furnished
ˆ
25
0.022 g #68%) of 7c as a clear colorless gum. [a]D
1
14.6 #c 1, H2O); H NMR #300 MHz, D2O) d 3.52 #d,
1H, Jˆ10.5 Hz), 3.46 #d, 1H, Jˆ10.5 Hz), 3.26 #s, 9H),