Synthesis of dideuterated and enantiomers of monodeuterated tridecanoic acids at C-9 and C-10 positions

Article abstract of DOI:10.1021/jo000957k

We report a route for the preparation of mono and dideuterated tridecanoic acids: (R)-[9-²H₁]-,(S)-[9-²H₁]-,(R)-[10-²H₁]-,(S)-[10-²H₁]-,[9,9-²H₂]-, and [10,10-²H₂]-tridecanoic acids required as probes for biochemical studies on desaturases. The key intermediates in the synthesis of all these probes are ketones 9, which give rise to the corresponding alcohols 10 and 13 by reduction with LiAlD₄ and LiAlH₄, respectively. Derivatization of nondeuterated racemic alcohols 13 with (S)-(+)-9-anthranylmethoxyacetic acid ((S)-(+)-9-AMA) and chromatographic resolution of both diastereoisomers allowed us to determine the absolute configuration of the stereogenic centers by ¹H NMR using an adaptation of the model proposed by Riguera and co-workers which was validated with alcohols of known absolute configuration. Both enantiomeric alcohols (R)- and (S)-13 were recovered by reduction of each diastereomeric ester with LiAlH₄. Mesylation of alcohols 10 and 13 followed by nucleophilic substitution by LiAlD₄ generated the saturated methoxymethyl derivatives 12 and 16, respectively. Final deprotection and Jones oxidation of the resulting alcohols afforded the above deuterated tridecanoic acids.

Full text of DOI:10.1021/jo000957k

8582
J . Org. Chem. 2000, 65, 8582-8588
Syn th esis of Did eu ter a ted a n d En a n tiom er s of Mon od eu ter a ted
Tr id eca n oic Acid s a t C-9 a n d C-10 P osition s
J ose´-Luis Abad, Gemma Fabria´s, and Francisco Camps*
Department of Biological Organic Chemistry, IIQAB-CSICJ ordi Girona 18-26, 08034 Barcelona, Spain
fcdqob@iiqab.csic.es
Received J une 23, 2000
We report a route for the preparation of mono and dideuterated tridecanoic acids: (R)-[9-2H1]-,
(S)-[9-2H1]-, (R)-[10-2H1]-, (S)-[10-2H1]-, [9,9-2H2]-, and [10,10-2H2]-tridecanoic acids required as probes
for biochemical studies on desaturases. The key intermediates in the synthesis of all these probes
are ketones 9, which give rise to the corresponding alcohols 10 and 13 by reduction with LiAlD4
and LiAlH4, respectively. Derivatization of nondeuterated racemic alcohols 13 with (S)-(+)-9-
anthranylmethoxyacetic acid ((S)-(+)-9-AMA) and chromatographic resolution of both diastereo-
1
isomers allowed us to determine the absolute configuration of the stereogenic centers by H NMR
using an adaptation of the model proposed by Riguera and co-workers which was validated with
alcohols of known absolute configuration. Both enantiomeric alcohols (R)- and (S)-13 were recovered
by reduction of each diastereomeric ester with LiAlH4. Mesylation of alcohols 10 and 13 followed
by nucleophilic substitution by LiAlD4 generated the saturated methoxymethyl derivatives 12 and
16, respectively. Final deprotection and J ones oxidation of the resulting alcohols afforded the above
deuterated tridecanoic acids.
In tr od u ction
acid using the moth Spodoptera littoralis as biological
model.9 This particular ∆9 monoene desaturase is spe-
cially interesting because it catalyzes the formation of a
conjugated dienoic fatty acid, but it does not desaturate
tetradecanoic acid.9 Therefore, comparing the reaction
features of this (Z)-9 desaturase with those reported for
the general (Z)-9 stearoylCoA desaturase was appealing.
To perform these investigations, we first undertook the
synthesis of selected deuterated fatty acids to be used
as probes. Although tetradecanoic acid is the natural
precursor of the (Z9,E11)-9,11-tetradecadionate, in a
previous paper we reported that tridecanoic acid is also
a suitable substrate.11
Biosynthesis of unsaturated fatty acids in living organ-
isms occurs by the direct introduction of double bonds
into a saturated precursor in an outstanding reaction that
is catalyzed by specific desaturases.1 In addition to the
enzymes that transform saturated fatty acids, other
desaturases that use unsaturated substrates to give
dienes do also occur in nature. The most ubiquitous
monoene desaturase is ∆12 oleoyl CoA desaturase, which
convert oleic acid into linoleic acid, a methylene-inter-
rupted dienoic fatty acid, and for which several mecha-
nistic studies have been reported.2-4 No mechanistic
investigations have been conducted, however, on other
monoene desaturases that give rise to conjugated dienoic
fatty acids.5-10 To gain insight into general desaturase
enzyme catalysis, research on the latter enzymes is also
desirable. Our ongoing interest in the mechanism of
desaturase enzymes has led us to undertake a mecha-
nistic study on a ∆9 monoene desaturase that produces
(Z,E)-9,11-tetradecadienoic acid from (E)-11-tetradecenoic
In this paper, we describe the preparation of dideu-
terated tridecanoic acids at C-9 and C-10 (1a ,b), useful
to investigate the site of initial oxidation in the desatu-
ration reaction (cryptoregiochemistry), and the synthesis
of the enantiomerically pure monodeuterated probes (R)-
and (S)- at C-9 and C-10 (2a ,b) to be used in the stereo-
specificity studies. Determination of the absolute config-
uration of key intermediates, enantiomerically pure
1
alcohols 13a ,b by H NMR studies on the corresponding
* To whom correspondence should be addressed. Tel: Int + 343 400
6116. Fax: Int + 343 204 5904.
diastereomeric esters of (S)-(+)-9-anthranylmethoxyace-
tic acid ((S)-(+)-9-AMA) is also described.
(1) Shanklin, J .; Cahoon, E. B. Annu. Rev. Plant Physiol. Mol. Biol.
1998, 49, 611-641.
(2) Buist, P. H.; Behrouzian, B. J . Am. Chem. Soc. 1998, 120, 871-
876.
(3) Morris, L. J . Biochem. Biophys. Res. Commun. 1964, 29, 311-
315.
(4) Morris, L. J .; Harris, R. V.; Kelly, W.; J ames, A. T. Biochem. J .
1968, 109, 673-678.
(5) Ando, T.; Hase, T.; Arima, R.; Uchiyama, M. Agric. Biol. Chem.
1988, 52, 473-478.
(6) Foster, S. P.; Roelofs, W. L. Experientia 1990, 46, 269-273.
(7) Arsequell, G.; Fabria´s, G.; Camps, F. Arch. Insect Biochem.
Physiol. 1990, 14, 47-56.
(8) Lofstedt, C.; Bengtsson, M. J . Chem. Ecol. 1988, 14, 903-915.
(9) Martinez, T.; Fabria´s, G.; Camps, F. J . Biol. Chem. 1990, 265,
1381-1387.
(10) Fang, N. B.; Teal, P. E. A.; Doolittle, R. E.; Tumlinson, J . H.
Insect Biochem. Mol. Biol. 1995, 25, 39-48.
Resu lts a n d Discu ssion
P r ep a r a tion of Deu ter a ted Tr id eca n oic Acid s.
Double deuterated products 1 were prepared following
10.1021/jo000957k CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/15/2000

Synthesis of Deuterated Tridecanoic Acids
J . Org. Chem., Vol. 65, No. 25, 2000 8583
Sch em e 1
Sch em e 2
the reactions depicted in Scheme 1. Thus, properly
functionalized dithianes 8 were obtained by coupling
reaction of bromoalkylderivatives 5 with the anion of
dithiane 7, generated by reaction with BuLi. Dithiane 8
cleavage with NBS afforded ketone 9 and deuterated
alcohol 10 could be obtained by reduction of 9 with
LiAlD4. Mesylation of the hydroxyl group and nucleo-
philic substitution with LiAlD4 produced dideuterated
compound 12. Protective group cleavage in acidic media
and final J ones oxidation of the resulting alcohol gave
the corresponding gem-dideuterated tridecanoic acids 1.
As shown in Scheme 2, enantiomerically pure deuter-
ated tridecanoic acids 2 were prepared from ketones 9.
Reduction of these ketones with LiAlH4 afforded alcohols
13, which were submitted to kinetic enantiomeric resolu-
tion with different lipases (Candida cylindracea, Chro-
mobacterium viscosum, triacylglycerol lipase, LPS, CAL),
through the acetate formation with vinyl acetate.12
Although CAL and LPS showed conversions of around
50%, we did not get good enantiomeric excesses probably
because both substituents of the ketone were sterically
too similar for enzymatic differentiation. As an alterna-
tive, we investigated a way to separate both enantiomers
of alcohols 13 and later to determine the corresponding
absolute configurations. For this purpose, we decided to
explore the alcohol derivatization with different known
chiral acids such as R-methoxy-R-trifluoromethylphenyl-
acetic acid (MTPA)13 or R-methoxy-R-(9-anthryl)-acetic
acid (9-AMA)14 that have been recently proposed to
1
determine the absolute configuration by H NMR. Thus,
we decided to use this strategy for synthesizing both
stereoisomers of each one of the corresponding monodeu-
terated tridecanoic acids 2.
Initial reversed-phase-HPLC separation trials with the
diastereomeric Mosher esters resulting from (R)-MTPA
were unsuccessful. Resolution was slightly improved by
using (S)-(+)-acetoxyphenylacetic acid ((S)-(+)-APA) as
a derivatizing agent, but in this case, the unambiguous
1
assignment of most of the H NMR chemical shifts was
not possible. For this reason, we decided to use a stronger
shielding derivatizing agent, such as 9-anthranylmethoxy-
acetic acid (9-AMA).14
Synthesis of (S)-(+)-9-AMA esters 14 was accomplished
by reaction of carbinols 13 with the freshly prepared acid
chloride of (S)-(+)-9-anthranylmethoxyacetic acid. In this
case, the two resulting diastereomers (R)- and (S)-14a ,b
were well separated by HPLC (direct and reversed phase)
and appreciable chemical shift changes were observed in
1
the H NMR spectra corresponding to each diastereomer
that allowed, as described below, the unequivocal deter-
(11) Pinilla, A.; Camps, F.; Fabria´s, G. Biochemistry 1999, 38,
15272-15277.
(12) Petschen, I.; Malo, E. A.; Bosch, M. P.; Guerrero, A. Tetrahe-
dron: Asymmetry 1996, 7, 2135-2143.
(13) Mosher, H. S.; Dale, J . A. J . Am. Chem. Soc. 1973, 95, 512-
519.
(14) Seco, J . M.; Quin˜oa´, E.; Riguera, R. Tetrahedron 1999, 55, 569-
584.

8584 J . Org. Chem., Vol. 65, No. 25, 2000
Abad et al.
F igu r e 1. 1H NMR chemical shifts (in ppm) and differences
(∆δRS) for all positions of both (S)-(+)-AMA esters of (S)-(+)-
and (R)-(-)-2-octanol skeleton.
mination of the absolute configuration of the stereogenic
centers present in the tridecanoic acid skeleton.
Deter m in a tion of Absolu te Con figu r a tion of In -
ter m ed ia te Alcoh ols 13. Seco et al.15 have reported that
it is possible to determine the absolute configuration of
1
one enantiomer of secondary alcohols from the H NMR
chemical shifts differences between both diastereoiso-
meric esters of (R)- and (S)-9-anthranylmethoxyacetic
acids. Such differences are originated by the anisotropy
effect of the aromatic ring in a preferred conformation.
However, we were interested in the absolute configura-
tion determination of both enantiomers of 13a ,b by using
only one chiral acid ((S)-(+)-9-AMA). In this context, (S)-
(+)-9-AMA esters 14 are long-chain molecules with a high
conformational mobility that could lead to erratic chemi-
cal shift differences between both diastereoisomers, thus
precluding the application of the Riguera’s model. For
this reason, we decided to test our modified method by
using the (S)-(+)-9-AMA esters of (S)-(+)- (17a ) and (R)-
(-)-2-octanol (17b). Since these alcohols were com-
mercially available and its absolute configuration was
already known, they would offer a clear validation of the
applied model.
F igu r e 2. 1H NMR chemical shifts (in ppm) and differences
(∆δRS) for both (S)-(+)-AMA diasteromeric esters 14a and 14b.
LiAlD4 (inversion of configuration) gave each enantio-
merically pure monodeuterated products 16. The final
acids were obtained as showed above for the double
deuterated tridecanoic acids (Scheme 2).
For this purpose, 1H, 13C, DQFCOSY, and XH-CORFE
NMR spectra for both (S)-(+)-9-AMA diastereomeric
esters 17 were recorded. As shown in Figure 1, ∆δRS
)
1
δR - δS calculations from the H NMR chemical shifts
of the corresponding diastereoisomeric esters of 2-octanol
gave the opposite sign at each site of the substituted ester
function and in the proper position for the corresponding
absolute configuration determination in the model pro-
posed by Seco et al.14 Consequently, these results validate
that application of the modified Riguera’s procedure
would allow the assignment of the absolute configuration
to both enantiomeric alcohols 13.
Thus, spectra for (S)-(+)-9-AMA diastereomeric esters
14 were recorded and the chemical shifts for most of the
hydrogen atoms of each diastereomer were assigned. As
depicted in Figure 2, arrangement of ∆δ differences for
14 diastereomeric pairs allowed us to determine the
absolute configuration of each one of the alcohol stereo-
genic centers. For both studied cases, those products with
HPLC shorter retention times showed (S)-configuration
((S)-14a ,b), whereas those compounds with longer reten-
tion time showed (R)-configuration ((R)-14a ,b).
Con clu sion s
Preparation of tridecanoic acids mono- and dideuter-
ated at C-9 and C-10 is described. The pure enantiomers
of the monodeuterated acids were obtained from HPLC
purified (S)-(+)-9-AMA diastereoisomers 14 which were
also used to determine the absolute configuration at the
stereogenic centers of the tridecanoic acid skeleton by 1H
NMR spectroscopy. This novel adaptation of the previ-
ously reported Riguera’s model is another example of
absolute configuration determination in acyclic com-
pounds with high conformational mobility.
Exp er im en ta l Section
Gen er a l Meth od s. The HPLC analysis and semiprepara-
tive separations were performed by using Spherisorb ODS-2
(5 µm) columns (10 × 0.6 cm and 15 × 1 cm, respectively) and
eluting with MeOH-H2O mixtures. All 1H NMR spectra were
acquired at 300 MHz, and 13C NMR spectra, at 75 MHz in
freshly neutralized CDCl3 solutions, and chemical shifts are
Once we had determined the absolute configuration,
reduction of the diastereomeric esters with LiAlH4 re-
generated the enantiomerically pure alcohols without
racemization. Mesylation of (R)- and (S)-13 in the pres-
ence of Et3N and further treatment of the mesylates with
1
given in ppm using as internal standards Si(CH3)4 for H, and
CDCl3 for 13C. The standard 1H DQFCOSY and XH-CORFE
spectra for the determination of the absolute configuration of
(S)-(+)-9-AMA esters were recorded at 25 °C using the same
concentration for both diastereomeric pairs as described
(15) Seco, J . M.; Latypov, S. K.; Quin˜oa´, E.; Riguera, R. Tetrahedron
1997, 53, 8541-8564.

Synthesis of Deuterated Tridecanoic Acids
J . Org. Chem., Vol. 65, No. 25, 2000 8585
elsewhere.16 Gas chromatography coupled to mass spectrom-
etry (GC/MS) analysis was performed by electron impact (EI)
setting the source at 20 eV, using a nonpolar HP-1 capillary
column (30 m × 0.20 mm i.d.).
J ) 7 Hz, 2H), 1.86 (q, J ) 7 Hz, 2H), 1.57 (m, 2H), 1.50-1.24
(10H); 13C NMR δ 96.4, 67.8, 55.1, 34.0, 32.8, 29.7, 29.2, 28.7,
28.1, 25.6.
P r ep a r a t ion of Der iva t ives 5. Gen er a l P r oced u r e.
These compounds were prepared using the procedure reported
by Gras et al.18 To a stirred solution of the bromo alcohol 4
(15 mmol) in 60 mL of dimethoxymethane were added LiBr
(435 mg, 5 mmol) and p-toluenesulfonic acid (190 mg, 1 mmol)
at room temperature. Stirring was continued overnight. Brine
was added (50 mL), and the reaction mixture was extracted
with hexane, dried, and concentrated at reduced pressure to
give an oil that was purified by flash chromatography on silica
gel using hexane/MTBE 85:15 to afford the expected product
in 95-98% yields.
1-Br om o-9,11-d ioxa d od eca n e (5a ). This compound was
obtained in 96% yield (3.64 g): 1H NMR δ 4.62 (s, 2H), 3.52 (t,
J ) 6.5 Hz, 2H), 3.41 (t, J ) 7 Hz, 2H), 3.36 (s, 3H), 1.86 (q,
J ) 7 Hz, 2H), 1.59 (m, 2H), 1.52-1.24 (8H); 13C NMR δ 96.4,
67.8, 55.1, 34.0, 32.8, 29.7, 29.2, 28.7, 28.1, 26.1.
1-Br om o-10,12-d ioxa tr id eca n e (5b). This compound was
obtained in 98% yield (3.92 g): 1H NMR δ 4.62 (s, 2H), 3.52 (t,
J ) 6.5 Hz, 2H), 3.41 (t, J ) 7 Hz, 2H), 3.36 (s, 3H), 1.86 (q,
J ) 7 Hz, 2H), 1.59 (m, 2H), 1.52-1.22 (10H); 13C NMR 96.4,
67.8, 55.1, 34.0, 32.8, 29.7, 29.3, 29.3, 28.7, 28.1, 26.1.
Syn th esis of Dith ia n es 8. Gen er a l P r oced u r e. These
products were obtained using the procedure reported by
Seebach and Corey.19 To a solution of the dithiane 7 (10 mmol)
in 15 mL of dry THF and kept at -20 °C was added 12 mmol
of an hexane BuLi solution (7.5 mL, 1.6 M). The pale colored
reaction mixture was stirred for 30 min, cooled at -78 °C, and
kept for 10 min, and then product 5 (8 mmol) was added
dropwise and stirring was continued at -78 °C for 2 h. The
resulting solution was allowed to warm to room temperature
and the solvent was then evaporated. The residue was
suspended in 50 mL of H2O, extracted with CH2Cl2, dried, and
concentrated to dryness. The residue was purified by flash
chromatography on silica gel using a gradient of 0-10% MTBE
in hexane to give the pure dithianes 8.
2-Bu tyl-2-(9,11-d ioxa d od ecyl)-1,3-d ith ia n e (8a ). This
compound was obtained in 80% yield (2.22 g): IR 2935, 2860,
1465, 1150, 1110, 1050, 920 cm-1; 1H NMR δ 4.62 (s, 2H), 3.52
(t, J ) 6.5 Hz, 2H), 3.36 (s, 3H), 2.80 (m, 4H), 2.02-1.90 (m,
2H), 1.90-1.80 (4H), 1.66-1.52 (3H), 1.48-1.23 (13H), 0.93
(t, J ) 7 Hz, 3H); 13C NMR δ 96.3, 67.8, 55.0, 53.3, 38.1, 37.8,
29.7, 29.7, 29.4, 29.3, 26.2, 26.1, 25.9, 25.5, 23.9, 22.9, 14.0;
MS m/z (relative intensity) 348 (M+, 22), 175 (100). Anal. Calcd
for C18H36O2S2: C, 62.01; H, 10.40; S, 18.39. Found: C, 62.13;
H, 10.37; S, 18.26.
All IR spectra were run in CCl4 solutions. Elemental
analyses were obtained in the Microanalysis Service of IIQAB-
CSIC and they were conventional combustion analyses without
discrimination between hydrogen and deuterium contents.
LiAlD4 (Deuterium content 98%) was obtained from Aldrich
Chemical Co. The final deuterium contents of the labeled
substrates were determined by GC-MS analysis of their
respective methyl esters and were found to be as follows: 1a ,
2
2
2
2
2
89.0% H2, 8.7% H1 and 1.1% H0; 1b, 88.2.% H2, 8.7% H1
2
2
and 3.1% H0; (R)-2a , 92.0% 2H1 and 6.7% H0; (S)-2a , acid:
93.2% 2H1 and 5.9% 2H0; (R)-2b, 92.0% 2H1 and 7.7% 2H0; (S)-
2b, 92.2% 2H1 and 6.7% 2H0. Unless otherwise stated, organic
solutions obtained from workup of crude reaction mixtures
were dried over MgSO4. The purification procedures were
carried out by flash chromatography on silica gel (230-400
mesh) and products were mostly obtained as oils unless
otherwise specified. Visualization of UV-inactive materials was
accomplished by soaking the TLC plates in an ethanolic
solution of anisaldehyde and sulfuric acid (v/v/v, 96:2:2).
Optical rotations were determined at 25° in CHCl3 solution
at the specified concentration (g/100 mL). Enantiomeric and
diasteromeric excesses (ee and de) values were calculated by
HPLC or NMR analysis of the corresponding (S)-(+)-9-AMA
or MTPA diastereomeric esters.
P r ep a r a tion of 1,3-Dith ia n es 7. Gen er a l P r oced u r e. To
a refluxing mixture of 12 mL of BF3‚Et2O, 24 mL of acetic acid
and 40 mL of CHCl3 in a dry three-necked round-bottom flask
was added dropwise a 100 mL CHCl3 solution containing 40
mmol of the appropriate aldehyde and 6.5 g (60 mmol) of 1,3-
propanedithiol. Reflux was continued for 16 h; the reaction
mixture was cooled at room temperature and washed sequen-
tially with a 10% aqueous KOH solution and with a saturated
aqueous NaCl solution; and the organic layer was dried,
filtered, and concentrated at reduced pressure. The residue
was purified by flash chromatography on silica gel using a
gradient of 0-10% MTBE (methyl tert-butyl ether) in hexane
to give the expected dithianes in 90-95% yields.
2-Bu tyl-1,3-d ith ia n e (7a ). This compound was obtained
from valeraldehyde in 95% yield (6.67 g): 1H NMR δ 4.05 (t,
J ) 7 Hz, 1H), 2.98-2.76 (m, 4H), 2.13 (m, 1H), 1.86 (m, 1H),
1.75 (q, J ) 7 Hz, 2H), 1.49 (m, 2H), 1.33 (m, 2H), 0.91 (t, J )
7 Hz, 3H); 13C NMR δ 47.7, 35.2, 30.5, 28.8, 26.1, 22.3, 13.8.
2-P r op yl-1,3-d ith ia n e (7b). This compound was obtained
1
2-P r op yl-2-(10,12-d ioxa tr id ecyl)-1,3-d ith ia n e (8b). This
compound was obtained in 74% yield (2.06 g): IR 2935, 2855,
1465, 1150, 1110, 1050, 920 cm-1; 1H NMR δ 4.62 (s, 2H), 3.52
(t, J ) 6.5 Hz, 2H), 3.36 (s, 3H), 2.80 (m, 4H), 1.95 (m, 2H),
1.92-1.78 (4H), 1.66-1.54 (3H), 1.54-1.22 (13H), 0.94 (t, J )
7 Hz, 3H); 13C NMR 96.3, 67.7, 54.9, 53.2, 40.4, 38.1, 29.7, 29.6,
29.4, 29.3, 29.3, 26.1, 25.9, 25.5, 23.9, 17.4, 14.2; MS m/z
(relative intensity) 348 (M+, 22), 161 (100). Anal. Calcd for
from butyraldehyde in 90% yield (5.82 g). H NMR δ 4.06 (t,
J ) 7 Hz, 1H), 2.98-2.76 (m, 4H), 2.12 (m, 1H), 1.86 (m, 1H),
1.73 (q, J ) 7 Hz, 2H), 1.53 (m, 2H), 0.94 (t, J ) 7 Hz, 3H);
13C NMR δ 47.3, 37.5, 30.5, 26.1, 19.9, 13.7.
P r ep a r a tion of Br om o Alcoh ols 4. Gen er a l P r oced u r e.
The procedure reported by Camps et al.17 was used with minor
modifications. To a solution of diol (10 mmol) in 25 mL of
toluene cooled at 0 °C was added 14 mL of HBr (47%, 80
mmol), and then the mixture was refluxed in the dark for 5 h
(GC monitoring). The reaction was allowed to cool at room
temperature, and 25 mL of brine was added. The mixture was
extracted with hexane, dried, filtered, and concentrated at
reduced pressure. The residue was purified by flash chroma-
tography on silica gel using hexane/MTBE 5:1 to afford the
expected product.
C
18H36O2S2: C, 62.01; H, 10.40; S, 18.39. Found: C, 62.13; H,
10.38; S, 18.16.
Syn th esis of Keton es 9. Gen er a l P r oced u r e. To a
solution of NBS (10.9 g, 60 mmol) in 95 mL of acetone and 5
mL of H2O kept at -30 °C was added dropwise 3.5 g of dithiane
8 (10 mmol) dissolved in 100 mL of the same solvent mixture.
Stirring was continued for 5 min, and a 10% Na2S2O3 water
solution was added until the orange color of the solution
disappeared. Solvent was concentrated, extracted with CH2-
Cl2, dried, and concentrated to dryness. The residue was
purified by flash chromatography on silica gel using a gradient
of 0-10% MTBE in hexane to give 2.46 g (96% yield) of the
pure ketones.
8-Br om o-1-octa n ol (4a ). This compound was obtained in
85% yield (1.77 g): 1H NMR δ 3.64 (t, J ) 6.5 Hz, 2H), 3.41 (t,
J ) 7 Hz, 2H), 1.86 (q, J ) 7 Hz, 2H), 1.57 (m, 2H), 1.50-1.24
(8H); 13C NMR δ 62.8, 33.9, 32.7, 32.6, 29.1, 28.6, 28.0, 25.6.
9-Br om o-1-n on a n ol (4b). This compound was obtained in
90% yield (2.01 g): 1H NMR δ 3.64 (t, J ) 6.5 Hz, 2H), 3.41 (t,
14,16-Dioxa -5-h ep ta d eca n on e (9a ): IR 1715 cm-1 1H
;
NMR δ 4.62 (s, 2H), 3.51 (t, J ) 6.5 Hz, 2H), 3.36 (s, 3H), 2.39
(16) Abad, J .-L.; Casas, J .; Sa´nchez-Baeza, F.; Messeguer, A. J . Org.
Chem. 1995, 60, 3648-3656.
(17) Camps, F.; Casamor, J . M.; Coll, J .; Guerrero, A.; Riba, M. Org.
Prep. Proced. Int. 1983, 15, 63-70.
(18) Gras, J .-L.; Kong, Y.-Y.; Chang, W.; Guerin, A. Synthesis 1985,
74-75.
(19) Seebach, D.; Corey, E. J . J . Org. Chem. 1975, 40, 231-237.

8586 J . Org. Chem., Vol. 65, No. 25, 2000
Abad et al.
(t, J ) 7 Hz, 4H), 1.66-1.46 (6H), 1.40-1.18 (10H), 0.90 (t, J
) 7 Hz, 3H); 13C NMR 211.5, 96.3, 67.8, 55.0, 42.7, 42.5, 29.7,
29.3, 29.2, 29.1, 26.1, 25.9, 23.8, 22.3, 13.8; MS m/z (relative
intensity) 227 (M+-31, 30), 85 (100). Anal. Calcd for C15H30O3:
C, 69.72; H, 11.70. Found: C, 69.67; H, 11.69.
(S)-(+)-2-Oct yl-(S)-(+)-r-O-m e t h yl-r-(9-a n t h r yl)a ce -
ta te (17a ). This ester was isolated as a waxy solid (32 mg,
85%) starting from 13 mg of (S)-(+)-2-octanol: IR 1745 cm-1
;
1H NMR δ 8.58 (d, J ) 9 Hz, 2H), 8.47 (s, 1H), 8.01 (m, 2H),
7.60-7.40 (4H), 6.24 (s, 1H), 4.88 (sext, J ) 6.5 Hz, 1H), 3.43
(s, 3H), 1.15 (d, J ) 6 Hz, 2H), 1.12-1.02 (m, 2H), 0.98-0.78
(m, 2H), 0.72 (t, J ) 6.5 Hz, 3H), 0.72-0.54 (4H), 0.38-0.24
(m, 2H); 13C NMR δ 171.1, 131.4, 130.6, 129.1, 129.0, 127.7,
126.3, 124.9, 124.5, 77.2, 72.1, 57.4, 55.1, 35.4, 31.3, 28.4, 24.1,
22.3, 20.0, 14.0; MS m/z (relative intensity) 378 (M+, 12), 221
(100); [R]D ) +140 (c 1.0, 96% de).
14,16-Dioxa -4-h ep ta d eca n on e (9b): IR 1715 cm-1 1H
;
NMR δ 4.62 (s, 2H), 3.51 (t, J ) 6.5 Hz, 2H), 3.36 (s, 3H), 2.38
(t, J ) 7 Hz, 2H), 2.37 (t, J ) 7 Hz, 2H), 1.68-1.45 (6H), 1.43-
1.18 (10H), 0.91 (t, J ) 7 Hz, 3H); 13C NMR 211.5, 96.3, 67.8,
55.0, 44.7, 42.8, 29.7, 29.4, 29.3, 29.3, 29.2, 26.2, 23.8, 17.3,
13.7; MS m/z (relative intensity) 227 (M+ - 31, 35), 71 (100).
Anal. Calcd for C15H30O3: C, 69.72; H, 11.70. Found: C, 69.77;
H, 11.68.
P r ep a r a tion of Alcoh ols 13 by Red u ction of Keton es.
A solution of the corresponding ketone 9 in Et2O, maintained
under argon and at room temperature, was treated with 5
molar equiv of LiAlH4, and the mixture was stirred until the
reaction was completed (TLC monitoring). After the usual
workup, the residue obtained was purified by flash chroma-
tography on silica gel using hexane/MTBE 80:20 to give the
corresponding pure alcohols 13 in 98% yields.
(R)-(-)-2-Oct yl-(S)-(+)-r-O-m et h yl-r-(9-a n t h r yl)a ce-
ta te (17b). This ester was isolated as a waxy solid (23 mg,
84%) starting from 10 mg of (R)-(-)-2-octanol: IR 1745 cm-1
;
1H NMR δ 8.56 (d, J ) 9 Hz, 2H), 8.48 (s, 1H), 8.02 (m, 2H),
7.60-7.42 (4H), 6.24 (s, 1H), 4.94 (m, 1H), 3.40(s, 3H), 1.58-
1.04 (10H), 0.86 (t, J ) 7 Hz, 3H), 0.80 (d, J ) 6.5 Hz, 2H);
13C NMR δ 171.1, 131.4, 130.5, 129.1, 129.1, 127.6, 126.3,
124.9, 124.5, 77.3, 72.5, 57.5, 35.5, 31.6, 29.0, 25.2, 22.5, 19.4,
14; MS m/z (relative intensity) 378 (M+, 10), 221 (100); [R]D
+102 (c 0.7, 96% de).
)
14,16-Dioxa -5-h ep ta d eca n ol (13a ). This alcohol was iso-
lated (254 mg, 98%) starting from 260 mg of ketone 9a : IR
Starting from alcohol 13a (130 mg, 0.5 mmol) and 13b (120
mg, 0.46 mmol), 229 mg (90% yield), and 208 mg (89% yield)
of the expected mixture of diastereoisomers 14a and 14b were
isolated, respectively. These (S)-(+)-AMA diastereomeric mix-
tures were separated by semipreparative reversed-phase
HPLC using an isocratic flow rate (MeOH/H2O, 75:25) of 4 mL/
min to afford, after flash chromatography on silica gel of the
collected compound, (S)-14a (94 mg) and (R)-14a (88 mg); (S)-
14b (89 mg) and (R)-14b (83 mg).
1
3505 cm-1; H NMR δ 4.62 (s, 2H), 3.58 (bs, 1H), 3.52 (t, J )
6.5 Hz, 2H), 3.36 (s, 3H), 1.59 (m, 2H), 1.52-1.22 (19H), 0.91
(t, J ) 7 Hz, 3H); 13C NMR δ 96.4, 72.0, 67.8, 55.1, 37.5, 37.2,
29.7, 29.6, 29.5, 29.4, 27.8, 26.2, 25.6, 22.8, 14.1; MS m/z
(relative intensity) 211 (M+ - 49, 18), 171 (100). Anal. Calcd
for C15H32O3: C, 69.18; H, 12.39. Found: C, 69.16; H, 12.48.
14,16-Dioxa -4-h ep ta d eca n ol (13b). This alcohol was iso-
lated (250 mg, 98%) starting from 256 mg of ketone 9b: IR
(S)-14,16-Dioxa -5-h ep t a d ecyl-(S)-(+)-r-m et h oxy-r-(9-
1
3505 cm-1; H NMR δ 4.62 (s, 2H), 3.58 (bs, 1H), 3.52 (t, J )
a n th r yl)a ceta te ((S)-14a ) (shorter tR in HPLC separation,
1
42.5 min): IR 1745 cm-1; H NMR δ 8.58 (d, J ) 9 Hz, 2H),
6.5 Hz, 2H), 3.36 (s, 3H), 1.59 (m, 2H), 1.52-1.22 (19H), 0.93
(t, J ) 6.5 Hz, 3H); 13C NMR δ 96.4, 71.7, 67.8, 55.1, 39.7,
37.5, 29.7, 29.7, 29.5, 29.5, 29.4, 26.2, 25.6, 18.8, 14.1; MS m/z
(relative intensity) 211 (M+-49, 11), 185 (75). Anal. Calcd for
8.47 (s, 1H), 8.01 (m, 2H), 7.60-7.40 (4H), 6.26 (s, 1H), 4.86
(m, 1H), 4.64 (s, 2H), 3.49 (t, J ) 6.5 Hz, 2H), 3.42 (s, 3H),
3.38 (s, 3H), 1.50 (m, 2H), 1.42 (m, 2H), 1.32-1.10 (6H), 1.04
(m, 2H), 0.92 (m, 2H), 0.85 (t, J ) 7 Hz, 3H), 0.72-0.52 (4H),
0.29 (m, 2H); 13C NMR δ 171.1, 131.4, 130.6, 129.0, 129.0,
127.7, 126.3, 124.9, 124.6, 96.4, 77.2, 75.4, 67.9, 57.4, 55.1, 33.6,
33.4, 29.7, 29.1, 29.0, 28.9, 27.5, 26.1, 24.0, 22.5, 14.0; MS m/z
(relative intensity) 508 (M+, 10), 221 (100); [R]D ) +95 (c 1.0,
96% de). Anal. Calcd for C32H44O5: C, 75.54; H, 8.72. Found:
C, 75.55; H, 8.80.
C
15H32O3: C, 69.18; H, 12.39. Found: C, 68.99; H, 12.35.
P r ep a r a tion of Deu ter a ted Alcoh ols 10a a n d 10b. The
same procedure described above was followed using LiAlD4.
[5-2H]-14,16-Dioxa -5-h ep ta d eca n ol (10a ). This alcohol
was isolated (126 mg, 97%) starting from 130 mg of ketone
9a : IR 3630 cm-1; 1H NMR δ 4.62 (s, 2H), 3.52 (t, J ) 6.5 Hz,
2H), 3.36 (s, 3H), 1.59 (m, 2H), 1.52-1.22 (19H), 0.91 (t, J )
7 Hz, 3H) 13C NMR δ 96.3, 71.4 (t, J ) 21.5 Hz), 67.8, 55.0,
37.3, 37.0, 29.7, 29.6, 29.5, 29.3, 27.8, 26.1, 25.5, 22.7, 14.0;
MS m/z (relative intensity) 212 (M+ - 49, 5), 172 (55), 82 (100).
Anal. Calcd for C15H312HO3: C, 68.92; H, 12.34. Found: C,
68.80; H, 12.33.
(R)-14,16-Dioxa -5-h ep t a d ecyl-(S)-(+)-r-m et h oxy-r-(9-
a n th r yl)a ceta te ((R)-14a ) (longer tR in HPLC separation,
1
47.3 min): IR 1745 cm-1; H NMR δ 8.58 (d, J ) 9 Hz, 2H),
8.47 (s, 1H), 8.01 (m, 2H), 7.60-7.40 (4H), 6.26 (s, 1H), 4.85
(m, 1H), 4.63 (s, 2H), 3.52 (t, J ) 6.5 Hz, 2H), 3.43 (s, 3H),
3.37 (s, 3H), 1.59 (m, 2H), 1.52-1.12 (12H), 1.04 (m, 2H), 0.64
(m, 2H), 0.32 (t, J ) 7 Hz, 3H), 0.29 (m, 2H); 13C NMR δ 171.1,
131.4, 130.6, 129.0, 129.0, 127.7, 126.3, 124.9, 124.6, 96.4, 77.2,
75.4, 67.8, 57.4, 55.1, 33.8, 33.1, 29.7, 29.4, 29.4, 29.3, 26.2,
26.2, 25.3, 22.0, 13.4; MS m/z (relative intensity) 508 (M+, 10),
221 (100); [R]D ) +72 (c 1.0, 97% de). Anal. Calcd for
[4-2H]-14,16-Dioxa -4-h ep ta d eca n ol (10b). This alcohol
was isolated (97 mg, 97%) starting from 100 mg of ketone 9b:
IR 3630 cm-1; 1H NMR δ 4.62 (s, 2H), 3.52 (t, J ) 6.5 Hz, 2H),
3.36 (s, 3H), 1.59 (m, 2H), 1.52-1.22 (19H), 0.93 (t, J ) 6.5
Hz, 3H); 13C NMR δ 96.3, 71.1 (t, J ) 21.5 Hz), 67.8, 55.0,
39.5, 37.3, 29.7, 29.7, 29.6, 29.5, 29.4, 26.1, 25.5, 18.7, 14.1;
MS m/z (relative intensity) 212 (M+ - 49, 7), 186 (40), 82 (100).
Anal. Calcd for C15H312HO3: C, 68.92; H, 12.34. Found: C,
68.99; H, 12.30.
Acid Ch lor id e a n d 9-AMA Ester s P r ep a r a tion . Gen er a l
P r oced u r e. The procedure of Ward and Rhee20 was used with
minor modifications. Oxalyl chloride (5 mmol) was added to a
mixture of (S)-(+)-AMAA (0.5 mmol) and DMF (0.05 mmol) in
hexane at room temperature. After 2 days, the solvent was
evaporated to dryness at reduced pressure. This residue was
dissolved in 5 mL of CH2Cl2 and added to a solution of racemic
alcohol 13 (105 mg, 0.40 mmol), Et3N (175 µL, 1.2 mmol), and
DMAP (12 mg, 0.1 mmol) in 10 mL of CH2Cl2. After 15 min
TLC monitoring revealed a complete conversion, the solution
was washed with H2O (2 × 5 mL), dried and concentrated to
a residue which was purified by flash chromatography on silica
gel using a gradient of 0-10% MTBE in hexane to give the
expected diastereomeric (S)-(+)-AMA esters 14 and 17 (85-
90% yields).
C
32H44O5: C, 75.54; H, 8.72. Found: C, 75.55; H, 8.80.
(S)-14,16-Dioxa -4-h ep t a d eca n yl-(S)-(+)-r-m et h oxy-r-
(9-a n th r yl)a ceta te ((S)-14b) (shorter tR in HPLC separation,
1
40.7 min): IR 1745 cm-1; H NMR δ 8.58 (d, J ) 9 Hz, 2H),
8.47 (s, 1H), 8.01 (m, 2H), 7.60-7.40 (4H), 6.25 (s, 1H), 4.88
(m, 1H), 4.64 (s, 2H), 3.52 (t, J ) 6.5 Hz, 2H), 3.42 (s, 3H),
3.38 (s, 3H), 1.51 (m, 2H), 1.46-0.9 (8H), 0.92 (m, 2H), 0.87
(t, J ) 7 Hz, 3H), 0.60 (4H), 0.27 (m, 2H); 13C NMR δ 171.1,
131.4, 130.5, 129.0, 129.0, 127.6, 126.3, 124.9, 124.5, 96.3, 77.1,
75.1, 67.8, 57.3, 55.0, 36.0, 33.4, 29.7, 29.3, 29.2, 28.9, 28.9,
26.1, 24.0, 18.5, 13.9; MS m/z (relative intensity) 508 (M+, 10),
221 (100); [R]D ) +95 (c 1.0, 95% ee). Anal. Calcd for
C
32H44O5: C, 75.54; H, 8.72. Found: C, 75.55; H, 8.80.
(R)-14,16-Dioxa -4-h ep t a d eca n yl-(S)-(+)-r-m et h oxy-r-
(9-a n th r yl)a ceta te ((R)-14b) (longer tR in HPLC separation,
1
44.8 min): IR 1745 cm-1; H NMR δ 8.57 (d, J ) 9 Hz, 2H),
8.47 (s, 1H), 8.01 (m, 2H), 7.58-7.42 (4H), 6.25 (s, 1H), 4.87
(m, 1H), 4.63 (s, 2H), 3.52 (t, J ) 6.5 Hz, 2H), 3.43 (s, 3H),
3.37 (s, 3H), 1.60 (m, 2H), 1.50-1.12 (12H), 1.05 (m, 2H), 0.60-
0.20 (6H), 0.29 (t, J ) 6.5 Hz, 3H); 13C NMR δ 171.1, 131.4,
130.6, 129.0, 129.0, 127.7, 126.3, 124.9, 124.5, 96.4, 77.2, 75.3,
(20) Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 42, 7165-
7166.

Synthesis of Deuterated Tridecanoic Acids
J . Org. Chem., Vol. 65, No. 25, 2000 8587
67.8, 57.4, 55.1, 35.4, 33.8, 29.7, 29.4, 29.4, 26.2, 25.3, 17.3,
13.3; MS m/z (relative intensity) 508 (M+, 10), 221 (100); [R]D
) +72 (c 1.0, 95% de). Anal. Calcd for C32H44O5: C, 75.54; H,
8.72. Found: C, 75.55; H, 8.80.
P r ep a r a tion of Alcoh ols (S)- a n d (R)-13 by Red u ction
of (S)-(+)-AMA Ester s. A solution of the corresponding (S)-
(+)-AMA ester 14 in Et2O, maintained under argon and at
room temperature was treated with 5 molar equiv of LiAlH4,
and the mixture was stirred until the reaction was completed
(TLC monitoring). After the usual work up, the residue
obtained was purified by flash chromatography on silica gel
using hexane/MTBE 85:15 to give the corresponding pure
alcohols.
(S)-14,16-Dioxa -5-h ep ta d eca n ol ((S)-13a ). This alcohol
was isolated (22 mg, 97%) starting from 45 mg of (S)-14a : [R]D
) +1.3 (c 1.0, 96% ee).
(R)-14,16-Dioxa -5-h ep ta d eca n ol ((R)-13a ). This alcohol
was isolated (21 mg, 97%) starting from 43 mg of (R)-14a : [R]D
) -1.4 (c 1.0, 97% ee).
mL) and treated with LiAlD4 (8 molar equiv.) for 16 h at 20
°C (TLC monitoring). H2O was added dropwise to the crude
reaction mixture and the resulting white precipitate was
filtered through Celite and concentrated to give a residue that,
after purification by flash chromatography on silica gel using
a gradient of 0-10% MTBE in hexane, afforded the corre-
sponding pure deuterated products.
[13,13-2H2]-2,4-Dioxa h ep ta d eca n e (12a ). This compound
1
(22 mg, 90%) was obtained from 34 mg (0.1 mmol) of 11a : H
NMR δ 4.62 (s, 2H), 3.52 (t, J ) 6.5 Hz, 2H), 3.36 (s, 3H), 1.59
(m, 2H), 1.42-1.20 (18H), 0.88 (t, J ) 6.5 Hz, 3H); 13C NMR
δ 96.3, 67.8, 55.0, 31.8, 29.7, 29.6, 29.5, 29.4, 29.1, 28.8 (quint,
J ) 19 Hz), 26.2, 22.7, 14.1; MS m/z (relative intensity) 245
(M+ - 1, 5), 213 (20), 182 (30), 98 (100). Anal. Calcd for C15H30
-
2H2O2: C, 73.17; H, 13.00. Found: C, 73.15; H, 13.04.
[14,14-2H2]-2,4-Dioxa h ep ta d eca n e (12b). This compound
(21 mg, 86%) was obtained from 34 mg (0.1 mmol) of 11b: 1H
NMR δ 4.62 (s, 2H), 3.52 (t, J ) 6.5 Hz, 2H), 3.36 (s, 3H), 1.59
(m, 2H), 1.42-1.18 (18H), 0.88 (t, J ) 7 Hz, 3H); 13C NMR δ
96.3, 67.8, 55.0, 31.7, 29.7, 29.6, 29.6, 29.4, 28.5 (quint, J )
(S)-14,16-Dioxa -4-h ep ta d eca n ol ((S)-13b). This alcohol
was isolated (21 mg, 97%) starting from 43 mg of (S)-14b: [R]D
) +0.9 (c 1.0, 95% ee).
(R)-14,16-Dioxa -4-h ep ta d eca n ol ((R)-13b). This alcohol
was isolated (20 mg, 98%) starting from 40 mg of (R)-14b: [R]D
) -0.9 (c 1.0, 95% ee).
19 Hz), 26.2, 22.6, 14.1; MS m/z (relative intensity) 245 (M+
-
-
1, 5), 213 (12), 182 (15), 82 (100). Anal. Calcd for C15H30
2H2O2: C, 73.17; H, 13.00. Found: C, 73.25; H, 12.99.
[13-2H]-2,4-Dioxa h ep ta d eca n e (16a ). Compounds (R)-
[13-2H]-2,4-d ioxa h ep ta d eca n e ((R)-16a ) (11 mg, 89%) and
(S)-[13-2H]-2,4-d ioxa h ep ta d eca n e ((S)-16a ) (10 mg, 87%)
were obtained from 17 mg of (S)-15a and 16 mg of (R)-15a ,
respectively: 1H NMR δ 4.62 (s, 2H), 3.52 (t, J ) 6.5 Hz, 2H),
3.36 (s, 3H), 1.59 (m, 2H), 1.42-1.18 (18H), 0.88 (t, J ) 6.5
Hz, 3H); 13C NMR δ 96.4, 67.9, 55.0, 31.9, 29.7, 29.6, 29.6, 29.4,
29.2, 29.2 (t, J ) 19 Hz), 26.2, 22.7, 14.1; MS m/z (relative
intensity) 244 (M+ - 1, 2), 212 (15), 181 (25), 97 (100). Anal.
Calcd for C15H312HO2: C, 73.47; H, 13.06. Found: C, 73.25;
H, 13.16.
P r ep a r a tion of Mesyl Ester s 11 a n d 15. Gen er a l P r o-
ced u r e. These products were prepared by the procedure
described by Abad et al.16 A solution of alcohol (26 mg, 0.1
mmol) and Et3N (45 µL, 0.3 mmol) in 5 mL of CH2Cl2 was
treated with CH3SO3Cl (11 µL, 0.14 mmol), and the mixture
was stirred under argon for 2 h at room temperature (TLC
monitoring). The reaction mixture was washed with H2O (2 ×
2 mL), dried, concentrated and purified by flash chromatog-
raphy on silica gel using hexane/MTBE 85:15 to give the
expected pure products.
[14-2H]-2,4-Dioxa h ep ta d eca n e (16b). Compounds (R)-
[14-2H]-2,4-d ioxa h ep ta d eca n e ((R)-16b) (10 mg, 92%) and
(S)-[14-2H]-2,4-d ioxa h ep ta d eca n e ((S)-16b) (11 mg, 89%)
were obtained from 15 mg of (S)-15b and 17 mg of (R)-15b,
respectively: 1H NMR δ 4.62 (s, 2H), 3.52 (t, J ) 6.5 Hz, 2H),
3.36 (s, 3H), 1.60 (m, 2H), 1.42-1.18 (18H), 0.88 (t, J ) 7 Hz,
3H); 13C NMR δ 96.4, 67.9, 55.0, 31.8, 29.7, 29.6, 29.6, 29.5,
29.4, 28.9 (t, J ) 19 Hz), 26.2, 22.6, 14.1; MS m/z (relative
intensity) 244 (M+ - 1, 2), 212 (12), 181 (18), 97 (96), 82 (100).
Anal. Calcd for C15H312HO2: C, 73.47; H, 13.06. Found: C,
73.45; H, 13.03.
Ca r b oxylic Acid s P r ep a r a t ion . Gen er a l P r oced u r e.
Products 12 and the proper enantiomers of 16 were depro-
tected to the corresponding alcohols by treatment with a
MeOH/HCl solution (0.5 M) for 16 h at room temperature.
Solvent was evaporated and the crude was treated with 2 mL
of water, extracted with CH2Cl2, dried, and concentrated to a
residue which was dissolved in a solution of 4 mL of acetone
and 350 µL of H2SO4 at -5 °C and then 350 mg of CrO3
dissolved in 700 µL of water was added dropwise. The reaction
mixture was stirred at -10 °C for 1 h and then allowed to
warm to room temperature and stirred overnight. At this time,
the reaction mixture was concentrated and 2 mL of HCl (1 M)
was added, extracted with CH2Cl2, dried, and concentrated to
a residue that was purified by flash chromatography on silica
gel using hexane/MTBE 85:15 to give the corresponding acid
as a solid.
[5-2H ]-14,16-Dioxa -5-h ep t a d ecyl
Met h a n esu lfon a t e
(11a ). This compound (64 mg, 95%) was obtained from 52 mg
1
(0.2 mmol) of alcohol 10a : IR 1360, 1340, 1180, 910 cm-1; H
NMR δ 4.62 (s, 2H), 3.52 (t, J ) 6.5 Hz, 2H), 3.36 (s, 3H), 3.00
(s, 3H), 1.69 (4H), 1.59 (m, 2H), 1.52-1.22 (15H), 0.92 (t, J )
7 Hz, 3H); 13C NMR δ 96.3, 83.8 (t, J ) 22.5 Hz), 67.7, 55.0,
38.6, 34.2, 33.9, 29.6, 29.3, 29.2, 26.9, 26.1, 24.8, 22.4, 13.8.
[4-2H ]-14,16-Dioxa -4-h ep t a d ecyl
Met h a n esu lfon a t e
(11b). This compound (62 mg, 94%) was obtained from 52 mg
(0.2 mmol) of alcohol 10b: IR 1350, 1340, 1180, 910 cm-1; 1H
NMR δ 4.62 (s, 2H), 3.52 (t, J ) 6.5 Hz, 2H), 3.36 (s, 3H), 3.00
(s, 3H), 1.69 (4H), 1.59 (m, 2H), 1.52-1.22 (15H), 0.95 (t, J )
7 Hz, 3H); 13C NMR δ 96.3, 83.6 (t, J ) 22.5 Hz), 67.7, 55.0,
38.6, 36.3, 34.3, 29.6, 29.4, 29.3, 26.1, 24.8, 18.2, 13.8.
14,16-Dioxa -5-h ep ta d ecyl Meth a n esu lfon a te (15a ): IR
1
1360, 1340, 1175, 905 cm-1; H NMR δ 4.70 (quint, J ) 6.5
Hz, 1H), 4.62 (s, 2H), 3.52 (t, J ) 6.5 Hz, 2H), 3.36 (s, 3H),
3.00 (s, 3H), 1.69 (4H), 1.59 (m, 2H), 1.52-1.22 (15H), 0.92 (t,
J ) 7 Hz, 3H); 13C NMR δ 96.3, 84.3, 67.8, 55.1, 38.7, 34.2,
34.1, 29.7, 29.4, 29.3, 27.1, 26.1, 24.9, 22.4, 13.9. (S)-14,16-
Dioxa-5-h eptadecyl m eth an esu lfon ate ((S)-15a). This com-
pound (32 mg, 95%) was obtained from 26 mg (0.1 mmol) of
alcohol (S)-13a : [R]D ) -0.7 (c 1.0, 96% ee), (R)-14,16-Dioxa -
5-h ep ta d ecyl m eth a n esu lfon a te ((R)-15a ). This compound
(30 mg, 91%) was obtained from 26 mg (0.1 mmol) of alcohol
(R)-13a : [R]D ) +0.7 (c 1.0, 97% ee).
14,16-Dioxa -4-h ep ta d ecyl m eth a n esu lfon a te (15b): IR
[10,10-2H2]-Tr id eca n oic Acid (1a ). This product (12 mg,
70%) was isolated from 20 mg of 12a : mp 40-41 °C; IR 1710
cm-1; 1H NMR δ 2.35 (t, J ) 7.5 Hz, 2H), 1.63 (quint, J ) 7.5
Hz, 2H), 1.42-1.16 (16H), 0.88 (t, J ) 6.5 Hz, 3H); 13C NMR
δ 180.4, 34.1, 31.9, 29.5, 29.4, 29.2, 29.1, 29.0, 28.8 (quint, J
) 19 Hz), 24.7, 22.7, 14.1. Anal. Calcd for C13H252H2O2: C,
72.18; H, 12.11. Found: C, 72.22; H, 12.03.
1
1365, 1340, 1175, 910 cm-1; H NMR δ 4.71 (quint, J ) 6.5
Hz, 1H), 4.62 (s, 2H), 3.52 (t, J ) 6.5 Hz, 2H), 3.36 (s, 3H),
3.00 (s, 3H), 1.69 (4H), 1.59 (m, 2H), 1.52-1.22 (15H), 0.95 (t,
J ) 7 Hz, 3H); 13C NMR δ 96.3, 84.0, 67.7, 55.0, 38.6, 36.5,
34.4, 29.6, 29.4, 29.3, 26.1, 24.8, 18.2, 13.8. (S)-14,16-Dioxa -
4-h ep ta d ecyl m eth a n esu lfon a te ((S)-15b). This compound
(31 mg, 95%) was obtained from 26 mg (0.1 mmol) of alcohol
(S)-13b: [R]D ) -3.2 (c 1.0, 95% ee), (R)-14,16-Dioxa -4-
h ep ta d ecyl m eth a n esu lfon a te ((R)-15b). This compound
(30 mg, 94%) was obtained from 26 mg (0.1 mmol) of alcohol
(R)-13b: [R]D ) +3.2 (c 1.0, 95% ee).
[11,11-2H2]-Tr id eca n oic Acid (1b). This product (11 mg,
67%) was isolated from 19 mg of 12b: mp 40-41 °C; IR 1710
cm-1; 1H NMR δ 2.35 (t, J ) 7.5 Hz, 2H), 1.63 (quint, J ) 7.5
Hz, 2H), 1.40-1.18 (16H), 0.88 (t, J ) 6.5 Hz, 3H); 13C NMR
δ 180.5, 34.1, 31.7, 29.6, 29.4, 29.2, 29.0, 28.5 (quint, J ) 19
Hz) 24.7, 22.6, 14.1. Anal. Calcd for C13H252H2O2: C, 72.18;
H, 12.11. Found: C, 72.05; H, 12.01.
Rea ction of Mesyla tes 11 a n d 15 w ith LiAlD4. Gen er a l
P r oced u r e. The mesyl derivative was dissolved in Et2O (4

8588 J . Org. Chem., Vol. 65, No. 25, 2000
Abad et al.
[10-2H]-Tr id eca n oic Acid (2a ). Compounds (S)-[10-2H]-
tr id eca n oic a cid ((S)-2a ) (6.7 mg, 69%) and (R)-[10-2H]-
tr id eca n oic a cid ((R)-2a ) (5.9 mg, 67%) were obtained from
11 mg of (S)-16a and 10 mg of (R)-16a , respectively: mp 39-
41 °C; IR 1710 cm-1; 1H NMR δ 2.35 (t, J ) 7.5 Hz, 2H), 1.63
(quint, J ) 7.5 Hz, 2H), 1.42-1.16 (16H), 0.88 (t, J ) 6.5 Hz,
3H); 13C NMR δ 179.7, 34.0, 31.9, 29.5, 29.5, 29.4, 29.2, 29.0,
Ack n ow led gm en t. Financial support of this work
by CICYT (Grant AGF-98-0844), Comissionat per a
Universitats i Recerca from the Generalitat de Catalu-
nya (Grant 99SGR-00187) is gratefully acknowledged.
We thank Prof. R. Riguera for generous supply of
analytical (R)-(-)- and (S)-(+)-9-AMA samples. J .-L.A.
thanks the Spanish Ministry of Education and Culture
for a Postdoctoral Reincorporation Contract.
28.9, 29.2 (t, J ) 19 Hz), 24.7, 22.7, 14.1. Anal. Calcd for C13H25
-
2HO2: C, 72.51; H, 12.17. Found: C, 72.56; H, 12.09.
[11-2H]-Tr id eca n oic Acid (2b). Compounds (S)-[11-2H]-
Tr id eca n oic a cid ((S)-2b) (6.5 mg, 67%) and (R)-[11-2H]-
Tr id eca n oic a cid ((R)-2b) (5.8 mg, 66%) were obtained from
11 mg of (S)-16b and 10 mg of (R)-16b: mp 40-41 °C; IR 1710
cm-1; 1H NMR δ 2.35 (t, J ) 7.5 Hz, 2H), 1.63 (quint, J ) 7.5
Hz, 2H), 1.40-1.18 (16H), 0.88 (t, J ) 6.5 Hz, 3H); 13C NMR
δ 179.6, 33.9, 31.8, 29.6, 29.6, 29.5, 29.4, 29.2, 29.0, 28.9 (quint,
J ) 19 Hz), 24.7, 22.7, 14.1. Anal. Calcd for C13H252HO2: C,
72.51; H, 12.17. Found: C, 72.35; H, 12.10.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and DEPT spectra for compounds 1, 2, 8-17 and additional
DQFCOSY and HETCOR for compounds 14 and 17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O000957K