Efficient Enantioselective Synthesis of (R)-(-)-Carnitine from Glycerol

Full text of DOI:10.1021/jo000503n

6766
J . Org. Chem. 2000, 65, 6766-6769
Sch em e 1. Syn th esis of En a n tiop u r e
Efficien t En a n tioselective Syn th esis of
(R)-(-)-Ca r n itin e fr om Glycer ola
(R)-(-)-Ca r n itin e fr om Glycer ol
Mauro Marzi,*,† Patrizia Minetti,† Giampiero Moretti,†
Maria Ornella Tinti,† and Francesco De Angelis*,‡
Dipartimento Ricerca Chimica, Sigma-Tau,
Via Pontina Km 30.400, I-00040 Pomezia (Roma), Italy,
and Dipartimento di Chimica, Ing. Chimica e Materiali,
Universita` dell’Aquila, Coppito, I-67010 L’Aquila, Italy
mauro.marzi@sigma-tau.it
Received April 3, 2000
In biochemical pathways, (R)-(-)-carnitine 1 plays an
important role in the â-oxidation of fatty acids and is also
involved in other important metabolic roles, both as free
carnitine and as acylcarnitines.1,2 The increasing demand
for this compound has led to the development of numer-
ous procedures for (R)-(-)-carnitine synthesis, involving
asymmetric synthesis,3 resolution through diasteroiso-
meric derivatives,4 microbiological or enzymatic tec-
niques,5 and the use of chiral starting materials;6 how-
ever, few of these procedures are of practical use.
In this paper, we report a convenient, high yielding
and easy synthesis of the four carbon-atom molecule,
(R)-(-)-carnitine 1, starting from glycerol 2 (Scheme 1).
Glycerol was first desymmetrized according to a proce-
dure described by Uang,7a making use of a (1R)-(-)-10-
camphorsulfonamide 3 derivative as the chiral auxiliary.8
The stereochemistry of camphorsulfonamide was obvi-
ously chosen on the basis of the chirality of the carnitine
isomer to be synthesized. The overall process is described
in Scheme 1 while the yields of each step is given in Table
1.
a
Reagents and conditions: (i) TsOH (cat.), toluene, reflux; (ii)
MsCl, Et3N, CH2Cl2, rt; (iii) Me3N, EtOH, 50 °C; (iv) HCl (1 N),
rt; (v) CH3COOH, HBr (48%), rt, then MeOH, reflux; (vi) NaCN,
H2O, 70 °C; (vii) HCl (37%), 90 °C.
Ta ble 1. Syn th esis of (R)-(-)-Ca r n itin e fr om Glycer ol:
P r od u ct Yield s
The chiral information was introduced into glycerol by
reaction with a selected (3c, vide infra) sulfonamide
derivative.7 Only one spiro-acetal, 4c, of the four possible
stereoisomers, formed in 60% yield based on 3c. The
correct (S)-configuration of the glycerol derivative 4c
was established on the basis of its final conversion to (R)-
(-)-carnitine 1. 4c was then converted, in almost quan-
titative yield, into the corresponding mesylate 5c by
product
yielda (%)
product
yielda (%)
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
72b
80b
82b
63b
50
43
60
33
90
5c
5d 7b
6a
6b
6c
6d
7
8
9
1
90
95
98
97
99
97
99c
92
99
80
* To whom correspondence should be addressed. (M.M.) Fax:
+39.06.91393638. (F.D.A.) Fax: +39.0862.433753. E-mail: deangelis@
aquila.infn.it.
(1) Ferrari, R.; Di Mauro, S.; Sherwood, G. L-Carnitine and its role
in medicine: from function to therapy; Academic Press: San Diego,
1992.
95
a
Isolated; refer to Scheme 1 for the starting compounds.
b
Reactions were performed on 100 mmol scale. Based on (1R)-
(-)-10-camphorsulfonyl chloride. c Yields are always g99%, inde-
pendently on the starting material (6a -d ).
(2) De Simone, C.; Famularo, G. Carnitine Today; Springer-Verlag:
Heidelberg, 1997.
(3) (a) Kolb, H. C.; Bennani, Y. L.; Sharpless, K. B. Tetrahedron:
Asymmetry 1993, 33, 133-136. (b) Kitamura, M.; Ohkuma, T.; Tayaka,
H.; Noyori, R. Tetrahedron Lett. 1988, 29, 1555-1556.
(4) (a) Cavazza, C., BE-B 877609, 1979 (CAN 93: 114973). (b)
Voeffray, R.; Perlberger, J .-C.; Tenud, L.; Gosteli, J . Helv. Chim. Acta
1987, 70, 2058.
treatment with metanesulfonyl chloride and triethy-
lamine, and the newly created leaving group was finally
displaced by trimethylamine to form 6, carrying the
trimethylammonium moiety characteristic of carnitine.
The chiral auxiliary was then cleaved off by HCl treat-
ment, and thoroughly recovered from the organic layer
after the reaction mixture workup, while the dihydroxy-
propyltrimethylammonium mesylate 7 was obtained by
evaporation of the aqueous solution. 7 was then treated
with HBr in acetic acid to form, exclusively, the primary
bromide 8.9 8 was in turn converted into the required
four carbon atoms skeleton by nucleophilic substitution
of bromine with potassium cyanide: 9 formed, which,
(5) (a) J ung, H.; J ung, K.; Kleber, H.-P. Adv. Biochem. Eng. Biotech.
1993, 50, 21-43. (b) Kasai, N.; Sagaguchi, K. Tetrahedron Lett. 1992,
33, 1211-1213. (c) Hashiguchi, S.; Kawada, A.; Natsugari, H. Synthesis
1992, 403-408.
(6) (a) Bols, M.; Lundt, L.; Pedersen, C.Tetrahedron, 1992, 48, 319-
323. (b) Takano, S.; Yanase, M.; Sekiguchi, Y.; Ogasawara, K.
Tetrahedron Lett. 1987, 28, 1784-1785.
(7) (a) Hsu, C.-Y.; Lin, Y.-S.; Uang, B.-J . Tetrahedron: Asymmetry
1990, 1, 219-220. (b) Buser, P.; Splinder, F. Tetrahedron: Asymmetry
1993, 1, 2451-2460.
(8) Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Tetrahedron Lett.
1984, 25, 5885-5888.
10.1021/jo000503n CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

Notes
J . Org. Chem., Vol. 65, No. 20, 2000 6767
which means that always enantioselectivity in favor of
the required stereoisomer was practically complete. The
relatively low yields in the formation of dibenzyl and
diisopropyl derivatives 4b and 4d respectively, indicate
that the steric factor is partially involved in the spiro-
ketal formation. This result, besides confirming hydrogen
bonding as the only driving force for the observed
diastereoselectivity, indicated that the bulkiness of the
sulfonamide moiety played a secondary role. Since the
yield of 4c was the highest yields, with respect to 4a ,
4b, and 4d , it is likely that a conformationally con-
strained amide like 3c could favor the acetal formation.
In any case yields were far from being quantitative: the
starting sulfonamide always partially survives even after
very long reaction times; on the other hand, no competing
pathways have been revealed by examining the reaction
mixtures.
In summary, new enantioselective synthesis of (R)-
(-)-carnitine has been disclosed, which exploits the
merits of the “Oppolzer” chiral auxiliary 10-camphorsul-
fonamide.8 The synthesis fulfills also the requirements
for a large scale process,11 for the overall high yield of
the process, for the low costs of the starting material and
reagents, and also for the possibility of complete recovery
of the chiral auxiliary.
F igu r e 1.
without purification, was then hydrolyzed to (R)-(-)-
carnitine 1 by concentrated HCl. The overall yield,
starting from glycerol, was 40%, and the final product
was synthesized with >98% ee.10 The optical purity of 1
also serves as a criterion to evaluate the stereochemical
progress of the entire synthetic route.
Each step of the reaction sequence is high yielding,
with the exception of the first one, where the new
stereocenter is created. The limiting factor of this passage
appears to be the very low solubility of glycerol in toluene,
which is the solvent necessary for azeotropic water
removal; this also appears the reason for the very long
reaction time (3 days). It is worth considering that the
use of N,N-diisopropyl-10-camphorsulfonamide (3d) chiral
auxiliary, as described in the literature,7a gave 4d 7a,b in
only 33% yield (best result over 10 experiments), which
is much less with respect to what reported (73%).
Different solvents or modified reaction conditions tar-
geted at water removal did not improve the reaction
efficiency. On the other hand, when we used diols soluble
in toluene, like 1,2-propanediol and 1,2-dihydroxy-3-
chloropropane, under the same conditions employed in
the reaction with glycerol (i.e., in large excess with
respect to the sulfonamide), we obtained the spiro-acetals
10 and 11 (Figure 1) in quantitative yields, after only 16
h of reaction time.
As expected in these cases, no diastereoselectivity was
observed and all the possible stereoisomers were formed
in variable amounts. It is, indeed, the hydrogen bond
between the free OH group in 4 and the sulfonamide
moiety, rather than a possible steric factor, which drives
the reaction stereochemistry.7a In the case of 10b, the
diastereoisomers mixture was in one step quantitatively
converted into diastereoisomeric propyltrimethylammo-
nium derivative 6d which, after chromatographic separa-
tion, could be a suitable precursor of both (R)- and (S)-
carnitine.
Exp er im en ta l Section
An a lytica l Meth od s. Melting points were determined by the
capillary method and are uncorrected. 1H NMR Spectra were
taken at 300 MHz. 13C NMR Spectra were taken at 75 or 50
MHz. Mass analyses were performed by using the fast atom
bombardment technique, using glycerol as the matrix. Sulfur
was determined by automatic titration. Optical rotation were
measured at 27 °C.
Ma ter ia ls. Anhydrous solvents were purchased from Aldrich.
Commercial reagents were purchased from Fluka or Aldrich and
were used as received. Thin-layer chromatography was per-
formed on 0.25 mm silica gel 60 F254 plates. Flash chromatog-
raphy was performed using silica gel 60 (40-63 mesh). Non-
aqueous reactions were carried out under nitrogen or argon
atmosphere.
Gen er a l Meth od s. Spectroscopic data of the compounds 3d ,
4d , and 5d correspond to those reported in the literature.7a,b,8
Syn th esis of th e Ca m p h or su lfon a m id es 3a -d . Gen er a l
P r oced u r es. To a solution of the amine (200 mmol) and DMAP
(26 g, 222 mmol) in anhydrous CH2Cl2 (10% w/v solution) was
added (-)-camphor-10-sulfonyl chloride (55.66 g, 222 mmol)
under stirring at 0 °C. After 1 h of stirring, the reaction solution
was diluted with ethyl acetate (1600 mL). The resulting solution
was washed with water, then 1 N HCl, and then water again.
The organic layer was dried over MgSO4 and filtered, and the
solvent was evaporated under reduced pressure. Camphorsul-
fonamides 3a -d were obtained as pure products after flash
chromatography.
The possible effect of steric factor was also evaluated.
We have, in fact, synthesized four (1R)-(-)-10-camphor-
sulfonamides (3a -d ), each one differing from the other
by the bulkiness of the amide moiety, the “Oppolzer” N,N-
diisopropyl-10-camphorsulfonamide 3d 8 being the refer-
ence reagent for the spiro-acetal formation reaction.
Yields for the sulfonamides syntheses ranged from 63%
(3d ) to 82% (3c). 3a -d were then reacted with glycerol
to give the corresponding 4a -d products, which were
then sequentially, finally converted into (R)-(-)-carnitine
1; in all cases, the ee of the final product was g98%,
(1R)-Ca m p h or -10-su lfon yld im eth yla m in e (3a ). 3a was
obtained as a colorless solid (72% yield): mp ) 62-63 °C. TLC
(n-hexane/ethyl acetate 7:3) Rf ) 0.38; [R]D ) -35.4° (c ) 1 in
CHCl3). Anal. Calcd for C12H21NO3S: C, 55.60; H, 8.10; N, 5.40;
S, 12.37. Found: C, 55.45; H, 8.20; N, 5.35; S 12.30.
(1R)-Ca m p h or -10-su lfon yld iben zyla m in e (3b). 3b was
obtained as a colorless solid (80% yield): mp ) 73-75 °C; TLC
(n-hexane/ethyl acetate 7:3) Rf ) 0.58; [R]D ) -24.7° (c ) 0.6 in
CH3OH). Anal. Calcd for C24H29NO3S: C, 70.07; H, 7.05; N, 3.40;
S, 7.79. Found: C, 69.90; H, 7.25; N, 3.28; S 7.70.
(1R)-Ca m p h or -10-su lfon ylp yr r olid in e (3c). 3c was ob-
tained as a colorless solid (82% yield): mp ) 76-77 °C; TLC
(n-hexane/ethyl acetate 7:3) Rf ) 0.29; [R]D ) -34.8° (c ) 1 in
(9) Bock, K.; Lundt, I.; Pedersen, C. Acta Chem. Scand. B 1983, 37,
341-344.
(10) The optical purity of 1 was determined by standard HPLC
separation of a diastereoisomeric fluorenyl derivative: De Witt, P.;
Dejas R.; Muck, S. J . Chrom. Biomed. Appl. 1994, 657, 67-73.
(11) De Angelis, F.; Marzi, M.; Tinti, WO996286A, 1999 (CAN 132:
23188).

6768 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
CHCl3). Anal. Calcd for C14H23NO3S: C, 62.01; H, 8.40; N, 5.16;
S, 11.8. Found: C, 62.00; H, 8.42; N, 5.14; S 11.70.
(90% yield): TLC (n-hexane/ethyl acetate 7:3) Rf ) 0.25; [R]D
)
+13.5° (c ) 1 in CHCl3). Anal. Calcd for C16H29NO7S2: C, 46.72;
H, 7.05; N, 3.40; S, 15.56. Found: C, 46.74; H, 7.00; N, 3.45; S,
15.60.
Syn th esis of th e Sp ir o-Keta ls 4a -d . Gen er a l P r oced u r e.
Glycerol (6.6 g, 200 mmol) was suspended into a solution of (1R)-
camphor-10-sulfonamide 3(a -d according to cases) (100 mmol)
with p-toluenesulfonic acid monohydrate (1 g) in 200 mL of
anhydrous toluene. The mixture was heated under reflux for 3
h with azeotropic removal of produced water. Diluting with ethyl
acetate (300 mL) quenched the reaction and the organic solution
was washed with saturated NaHCO3. Organic layer was dried
over Na2SO4 and concentrated under reduced pressure. The
residue oil was then separated by flash chromatography.
(1R)-Ca m p h or -2-glycer ol-sp ir o-k et a l-10-su lfon yld im e-
th yla m in e (4a ). 4a was obtained as an oil (50% yield): TLC
(n-hexane/ethyl ether 6:4) Rf ) 0.18; [R]D ) +13.1° (c ) 2 in
CHCl3). Anal. for C15H27NO5S: C, 54.06; H, 8.10; N, 4.20; S, 9.62.
Found: C, 53.85; H, 8.20; N, 4.30; S 9.60.
(1R)-Ca m p h or -2-(1-m eth a n su lfon yl)glycer ol-sp ir o-keta l-
10-su lfon yld iben zyla m in e (5b). 5b was obtained as an oil
(95% yield): TLC (n-hexane/ethyl acetate 8.5:1.5) Rf ) 0.15; [R]D
) +2.7° (c ) 2 in CHCl3). Anal. Calcd for C28H37NO7S2: C, 59.70;
H, 6.57; N, 2.48; S, 11.36. Found: C, 59.62; H, 6.60; N, 2.44; S
11.40.
(1R)-Ca m p h or -2-(1-m eth a n su lfon yl)lycer ol-sp ir o-k eta l-
10-su lfon ylp yr r olid in e (5c). 5c was obtained as oil (90%
yield): TLC (n-hexane/ethyl acetate 7:3) Rf ) 0.19; [R]D ) + 12.5°
(c ) 1 in CHCl3). Anal. Calcd for C18H31NO7S2: C, 49.45; H, 7.09;
N, 3.20; S, 14.63. Found: C, 49.52; H, 7.20; N, 3.30; S, 14.64.
Syn t h esis of t h e Tr im et h yla m m on iu m Der iva t es 6a -
d . Gen er a l P r oced u r e. 5a -d (or 10b) (100 mmol) was added
to 500 mL of a 33% ethanolic solution of trimethylamine and
heated at 50 °C for 48 h. The solvent and excess base were then
removed under reduced pressure. All crude products were
separated by flash chromatography using ethyl acetate/methanol
(1:1) as the solvent.
(1R)-Ca m p h or -2-(1-tr im eth yla m m on iu m )glycer ol-sp ir o-
k et a l-10-su lfon yld im et h yla m in e Met h a n esu lfon a t e (6a ).
6a was obtained as hygroscopic solid (98% yield): TLC (CHCl3/
i-PrOH/MeOH/H2O/CH3COOH 4.2:0.7:2.8:1.05:1.05) Rf ) 0.60;
[R]D ) -8.85° (c ) 1 in MeOH). Anal. Calcd for C19H38N2O7S2:
C, 48.53; H, 8.08; N, 5.95; S, 13.61. Found: C, 48.32; H, 8.30; N,
5.87; S, 13.58.
(1R)-Ca m p h or -2-(1-tr im eth yla m m on iu m )glycer ol-sp ir o-
k eta l-10-su lfon yld iben zyla m in e Meth a n esu lfon a te (6b). 6b
was obtained as hygroscopic solid (97% yield): TLC (CHCl3/i-
PrOH/MeOH/H2O/CH3COOH 4.2:0.7:2.8:1.05:1.05) Rf ) 0.95;
[R]D ) -7.3° (c ) 1 in MeOH). Anal. Calcd for C31H46N2O7S2:
C, 59.82; H, 7.39; N, 4.50; S, 10.28. Found: C, 59.62; H, 7.60; N,
4.44; S, 10.00.
(1R)-Ca m p h or -2-glycer ol-sp ir o-k eta l-10-su lfon yld iben -
zyla m in e (4b). 4b was obtained as a colorless solid (43%
yield): mp ) 74-75 °C; TLC (n-hexane/ethyl acetate 7:3) Rf )
0.46; [R]D ) +1.2° (c ) 1 in CHCl3). Anal. Calcd for C28H37
-
NO5S: C, 67.34; H, 7.40; N, 2.80; S, 6.42. Found: C, 67.29; H,
7.50; N, 2.80; S 6.38.
(1R)-Ca m p h or -2-glycer ol-sp ir o-k eta l-10-su lfon ylp yr r o-
lid in e (4c). 4c was obtained as an oil (60% yield): TLC
(n-hexane/ethyl acetate 7:3) Rf ) 0.15; [R]D ) -11.8° (c ) 1 in
CHCl3). Anal. Calcd for C17H29NO5S: C, 56.84; H, 8.07; N, 3.89;
S, 8.90. Found: C, 56.76; H, 8.10; N, 3.82; S 8.85.
Syn th esis of th e Sp ir o-Keta ls 10a ,b a n d 11a ,b. Gen er a l
P r oced u r e. Racemic 3-chloro-1,2-propanediol (1.1 g, 10 mmol)
or racemic propanediol (1.55 gr, 10 mmol) was dissolved into a
solution of (1R)-camphor-10-sulfonamide 3a or 3d (5 mmol) with
p-toluenesulfonic acid monohydrate (200 mg) in 100 mL of
anhydrous benzene. The mixture was heated under reflux for
16 h with azeotropic removal of produced water. Diluting with
ethyl acetate (300 mL) quenched the reaction and the organic
solution was washed with saturated NaHCO3. Organic layer was
dried over Na2SO4 and concentrated under reduced pressure.
The residue oil was then separated by flash chromatography to
give pure 10a ,b and 11a ,b.
(R,S)-Cam ph or -2-(1,2-dih ydr oxy-3-ch lor o)pr opan e-spir o-
k eta l-10-su lfon yld im eth yla m in e (10a ). 10a , as a mixture of
diastereoisomers, was obtained as an oil (98% yield): TLC (n-
hexane/ethyl acetate 8:2) from Rf ) 0.31 to Rf ) 0.22. Anal. Calcd
for C15H26ClNO4S: C, 51.28; H, 7.40; Cl, 10.11; N, 3.98; S, 9.11.
Found: C, 51.20; H, 7.45; Cl, 10.00; N, 3.70; S 9.10.
(R ,S )-C a m p h o r -2-(1,2-d ih y d r o x y -3-c h lo r o )p r o p a n e -
sp ir ok eta l-10-su lfon yld iisop r op yla m in e (10b). 10b, as a
mixture of diastereoisomers, was obtained as an oil (98%
yield): TLC (n-hexane/ethyl acetate 8:2) from Rf ) 0.60 to Rf )
0.29. Anal. Calcd for C19H34ClNO4S: C, 56.01; H, 8.35; Cl, 8.72;
N, 3.44; S, 7.86. Found: C, 55.70; H, 8.24; Cl, 8.70; N, 3.50; S,
7.54.
(1R)-Ca m p h or -2-(1-tr im eth yla m m on iu m )glycer ol-sp ir o-
k eta l-10-su lfon ylp yr r olid in e Meth a n esu lfon a te (6c). Crude
6c was obtained as hygroscopic solid (99% yield): TLC (CHCl3/
i-PrOH/MeOH/H2O/CH3COOH 4.2:0.7:2.8:1.05:1.05) Rf ) 0.66;
[R]D ) -13.5° (c ) 1 in MeOH). Anal. Calcd for C21H40N2O7S2:
C, 50.83; H, 8.06; N, 5.64; S, 12.89. Found: C, 50.60; H, 8.25; N,
5.48; S, 12.70.
(1R)-Ca m p h or -2-(1-tr im eth yla m m on iu m )glycer ol-sp ir o-
k eta l-10-su lfon yld iisop r op yla m in e Meth a n esu lfon a te (6d ).
Crude 6d was obtained as a hygroscopic solid (97% yield): TLC
(CHCl3/i-PrOH/MeOH/H2O/CH3COOH 4.2:0.7:2.8:1.05:1.05) Rf
) 0.76; [R]D ) -5.5° (c ) 1 in CHCl3). Anal. Calcd for
C
23H46N2O7S2: C, 52.49; H, 8.74; N, 5.32; S, 12.16. Found: C,
52.39; H, 9.00; N, 5.48; S, 11.96.
(S)-3-Tr im eth ylam m on iu m -1,2-dih ydr oxypr opan e Meth -
a n esu lfon a te (7). A solution of 6a -d (100 mmol) in methanolic
HCl (75 mL of 3 N HCl in 500 mL of MeOH) was stirred at 70
°C for 18 h. The solvent was removed under reduced pressure.
The crude product was redissolved in water and washed with
ethyl acetate. Camphorsulfonamides 3a -d were recovered from
the organic layer, while the aqueous layer containing 7 was
decolorized by activated charcoal and then concentrated under
vacuum. Crude 7 was obtained as very hygroscopic colorless solid
(yield ) 99%): TLC (CHCl3/i-PrOH/MeOH/H2O/CH3COOH 4.2:
0.7:2.8:1.05:1.05) Rf ) 0.14; [R]D ) -18° (c ) 1 in H2O). Anal.
Calcd for C7H19NO5S (-2.5% H2O): C, 35.75; H, 8.42; N, 5.95;
S, 13.63. Found: C, 35.15; H, 8.84; N, 5.2; S, 13.03.
(S )-3-T r im e t h y la m m o n iu m -1-b r o m o -2-h y d r o x y p r o -
p a n e Br om id e (8). 7 (23.1 g, 100 mmol) was dissolved in 410
mL of 30% HBr in acetic acid and 64 mL of acetic anhydride.
The mixture was stirred at room temperature for 24 h. Then,
MeOH (1800 mL) was added and the resulting solution was
refluxed for 6 h. The solution was then concentrated under
vacuum and the resulting oil was solidified by treating with ethyl
ether. Crude 8 was crystallized from acetone giving hygroscopic
solid (yield ) 92%): TLC (CHCl3/i-PrOH/MeOH/H2O/CH3COOH
4.2:0.7:2.8:1.05:1.05) Rf ) 0.20; [R]D ) -18° (c ) 1 in H2O); FAB-
MS (+ve) m/z ) 196, 198. Anal. Calcd for C6H15Br2NO (-1%
H2O): C, 25.75; H, 5.51; N, 5.00. Found: C, 25.30; H, 5.80; N,
4.67.
(R,S)-Ca m p h or -2-(1,2-d ih yd r oxy)p r op a n e-sp ir o-k et a l-
10-su lfon yld im eth yla m in e (11a ). 11a , as a mixture of dias-
tereoisomers, was obtained as an oil (98% yield): TLC (n-hexane/
ethyl acetate 8:2) from Rf ) 0.29 to Rf ) 0.22. Anal. Calcd for
C15H27NO4S: C, 56.90; H, 8.53; N, 4.42; S, 10.11. Found: C,
56.52; H, 8.42; N, 4.14; S, 10.00.
(R,S)-Ca m p h or -2-(1,2-d ih yd r oxy)p r op a n e-sp ir o-k et a l-
10-su lfon yld iisop r op yla m in e (11b). 11b, as a mixture of
diastereoisomers, was obtained as an oil (98% yield): TLC (n-
hexane/ethyl acetate 8:2) from Rf ) 0.60 to Rf ) 0.45. Anal. Calcd
for C19H35NO4S: C, 61.12; H, 9.38; N, 3.75; S, 8.58. Found: C,
61.20; H, 9.30; N, 3.50; S, 8.56.
Syn th esis of th e Mesyla tes 5a -d . Gen er a l P r oced u r e.
The spiro-acetals 4a -d (100 mmol) and triethylamine (21.2 mL,
150 mmol) were dissolved in CH2Cl2 (500 mL) and cooled to 0
°C, neat MsCl (10 mL, 150 mmol) was added, and the solution
was stirred at room temperature for 3 h. The reaction mixture
was then diluted with CH2Cl2 and washed with 1 N HCl. The
organic layer was then washed with NaHCO3 (5%) and dried
over Na2SO4. The organic solution was concentrated under
reduced pressure, and the residue oil was separated by flash
chromatography to give pure 5a -d .
(1R)-Ca m p h or -2-(1-m eth a n su lfon yl)glycer ol-sp ir o-k eta l-
10-su lfon yld im et h yla m in e (5a ). 5a was obtained as an oil

Notes
(R )-3-T r im e t h y la m m o n iu m -1-c y a n o -2-h y d r o x y p r o -
p a n e Br om id e (9). A solution of 8 (27.87 g, 100 mmol) and
sodium cyanide (6.50 g, 100 mmol) in 280 mL of water, was
stirred at 70 °C. When the reaction was complete (about 24 h,
by HPLC), water was removed under vacuum to give a colorless
solid (mixture of 9 and NaBr 1:1; yield ) 99%).
(R)-(-)-ca r n itin e In n er Sa lt (1). The mixture 9 (40 g, about
100 mmol) was added to 12 N HCl (50 mL), and the resulting
solution was heated at 90 °C for 4 h. The black solution was
then diluted with water (80 mL) and eluted through Amberlite
IRA-402 (OH- form) and successively through Amberlite IRC-
50 (HCl form). The water solution was concentrated under
vacuum to give a colorless syrup. By crystallization of the syrup
with i-PrOH, pure (R)-(-)-carnitine 1 inner salt was obtained:
mp 200 °C with dec (lit.12 mp 197 °C with dec); [R]D ) -30.9° (c
) 1 in H2O) (lit.13 [R]D ) -31.3° (c ) 10 in H2O)). Anal. Calcd
J . Org. Chem., Vol. 65, No. 20, 2000 6769
for C7H15NO3 (-0. 7% H2O): C, 51.79; H, 9.39; N, 8.62. Found:
C, 51.65; H, 9.50; N, 8.55.
Su p p or tin g In for m a tion Ava ila ble: Spectral data of all
1
the compounds synthesized; H and 13C NMR spectra of the
compounds 1, 3a -c, 4a -c, 5a -c, 6a -d , 7-9, 10a ,b, 11a ,b;
mass spectra of the compounds 1, 7, and 8; HPLC profiles of
the compounds 7-9. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O000503N
(12) The Merck Index, 12th ed.; Merck & Co Inc.: Whitehouse
Station, NJ , 1996.
(13) Voeffray, R.; Perlberger, J . C.; Tenud, L. Helv. Chim. Acta 1987,
70, 2058-2064.