Stereoselective synthesis of the nonproteinogenic amino acid (2S,3R)-3-amino-2-hydroxydecanoic acid from (4S,5S)-4-formyl-5-vinyl-2-oxazolidinone

Article abstract of DOI:10.1021/jo034334t

(4S,5S)-4-Formyl-5-vinyl-2-oxazolidinone (4b), which is readily obtained via a zinc-silver-mediated reductive elimination of α-D-lyxofuranosyl phenyl sulfone (3b), is successfully converted to the naturally occurring, nonproteinogenic amino acid (2S,3R)-3-amino-2-hydroxydecanoic acid (2). Also in this study, a facile "oxazolidinone rearrangement" reaction is uncovered during the attempted formation of the (methylthio)thiocarbonate derivative of the oxazolidinone alcohol 7.

Full text of DOI:10.1021/jo034334t

Ster eoselective Syn th esis of th e Non p r otein ogen ic Am in o Acid
(2S,3R)-3-Am in o-2-h yd r oxyd eca n oic Acid fr om
(4S,5S)-4-F or m yl-5-vin yl-2-oxa zolid in on e
Andrew G. H. Wee* and Douglas D. McLeod
Department of Chemistry and Biochemistry, University of Regina,
Regina, Saskatchewan, S4S 0A2, Canada
andrew.wee@uregina.ca
Received March 12, 2003
(4S,5S)-4-Formyl-5-vinyl-2-oxazolidinone (4b), which is readily obtained via a zinc-silver-mediated
reductive elimination of R-D-lyxofuranosyl phenyl sulfone (3b ), is successfully converted to the
naturally occurring, nonproteinogenic amino acid (2S,3R)-3-amino-2-hydroxydecanoic acid (2). Also
in this study, a facile “oxazolidinone rearrangement” reaction is uncovered during the attempted
formation of the (methylthio)thiocarbonate derivative of the oxazolidinone alcohol 7.
CHART 1. Micr ogin in (1) a n d (2S,3R)-AHDA (2)
The secondary metabolites isolated from the cyano-
bacterium Microcystis aeruginosa are linear peptides that
consist of either four, five, or six amino acids.1 These
peptides are biologically active and exhibit inhibitory
activities against protease enzymes. Microginin (1) was
the first of these linear peptides,1 which was isolated from
cultures of the cyanobacterium, and its structure was
assigned on the basis of degradation studies, spectro-
scopic data, and total synthesis.1,2 It is a linear pentapep-
tide wherein the N-terminal unit is a nonproteinogenic
amino acid, (2S,3R)-3-amino-2-hydroxydecanoic acid (2,
AHDA). Subsequently, it was found that (2S,3R)-AHDA
is common to many other linear peptides isolated from
the same species.1b,c Microginin possesses inhibitory
activities against angiotensin-converting enzyme (ACE),1
an enzyme that is involved in the vasoconstriction of
blood vessels. Compounds that are structurally related
to microginin are, therefore, of immense medicinal inter-
est because of their potential use in the treatment of
hypertension.3
nonracemic vic-amino alcohols or their 2-oxazolidinone
derivatives, which were prepared via the asymmetric
functionalization of appropriately constituted alkenes.2,4c-e
The third strategy involved the Lewis acid-mediated
nucleophilic addition of ketene acetals to chiral, non-
racemic imines.4f
Chemodifferentiated, bifunctionalized oxazolidinones
are useful synthetic intermediates, and their use in the
synthesis of amino alcohols and amino acids has not been
fully investigated. In this vein, we have developed the
use of chiral, nonracemic 4-formyl-5-vinyl-2-oxazolidino-
nes (4, eq 1) as advanced building blocks for the synthesis
of natural products.5
The synthesis of (2S,3R)-AHDA (2) has been reported
by several groups, and three key strategies4 have emerged.
The first strategy entailed the use of a “chiral pool”
starting material.4a,b The second strategy employed chiral,
(1) (a) Ekino, T.; Matsuda, H.; Murakami, Y.; Yamaguchi, K.
Tetrahedron Lett. 1993, 34, 501. (b) Ishida, K.; Kato, T., Murakami,
M.; Watanabe, M.; Watanabe, M. F. Tetrahedron 2000, 56, 8643. (c)
Ishida, K.; Matsuda, H.; Murakami, M. Tetrahedron 1998, 54, 13475.
(d) Reshef, V.; Carmeli, S. Tetrahedron 2001, 57, 2885. Linear peptides
from other algae species: (e) Sano, T.; Kaya, K. Phytochemistry 1997,
44, 1503. (f) Neumann, U.; Forchert, A.; Flury, T.; Weckesser, J . FEMS
Microbiol. Lett. 1997, 153, 475.
(2) (a) Matsumura, F.; Hamada, Y.; Shiori, T. Tetrahedron 1994,
50, 11303. (b) Bunnage, M. E.; Burke, A. J .; Davies, S. G.; Goodwin,
C. J . Tetrahedron: Asymmetry 1995, 6, 165.
(3) Wyvratt, M. J .; Patchett, A. A. Med. Res. Rev. 1985, 5, 483.
(4) Chiral pool: (a) J efford, C. W.; McNulty, J .; Lu, Z.-H.; Wang,
J .-B. Helv. Chim. Acta 1996, 79, 1203. (b) Tuch, A.; Saniere, M.; Merrer,
Y. L.; Depezay, J . C. Tetrahedron: Asymmetry 1996, 7, 2901. Asym-
metric functionalization of alkenes: (c) Sugimura, H.; Miura, M.;
Yamada, N. Tetrahedron: Asymmetry 1997, 8, 4089. (d) Righi, C.;
Chionne, A.; D’Achille, R.; Bonini, C. Tetrahedron: Asymmetry 1997,
8, 903. (e) Bergmeier, S. C.; Stanchina, D. M. J . Org. Chem. 1999, 64,
2852. Nucleophilic addition to chiral imines: (f) Ha, H. J .; Ahn, Y.-G.;
Woo, J .-S.; Lee, G. S.; Lee, W. K. Bull. Chem. Soc. J pn. 2001, 74, 1667.
10.1021/jo034334t CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/15/2003
6268
J . Org. Chem. 2003, 68, 6268-6273

Synthesis of (2S,3R)-3-Amino-2-hydroxydecanoic Acid
SCHEME 1. Retr osyn th etic An a lysis of
SCHEME 2 a
(2S,3R)-AHDA
In previous reports, we showed5 that (a) these versatile
enantiomeric aldehydes 4 were readily generated via the
Zn-Ag couple-mediated reductive elimination of the
appropriate iodo phenyl sulfones 3 and (b) the in situ
reaction of the aldehydes 4 with organocerium reagents
proceeded efficiently and with high diastereoselectivity
to give the corresponding secondary alcohols. We have
employed aldehydes 4 as advanced chiral, nonracemic
intermediates in the total synthesis of C-18-D-ribo-
phytosphingosine5b and (2R,3S)-3-hydroxy-2-(hydroxy-
methyl)pyrrolidine.5c We now demonstrate the use of
chiral, nonracemic aldehyde 4b in the synthesis of
(2S,3R)-AHDA (2) and report, herein, the details of our
work.
a
Reagents: (a) (i) Zn/Ag, glacial AcOH; (ii) 4b, THF, C6H13CeCl2,
-78 °C, 78%. (b) Ph3P, I2, imidazole, PhMe, 120 °C, 64%. (c)
Bu3SnH, cat. AIBN, PhMe, 110 °C, 85%. (d) Route a: (i) O3,
CH2Cl2, - 78 °C, Me2S; (ii) J ones’ reagent; CH2N2, 47% (over three
steps). Route b: O3, 2.5 M aq NaOH, MeOH, - 78 °C, 69%. (e)
NaOMe (4 mol equiv), MeOH; then 1 M aq HCl, 99%. (f) 2 M aq
KOH, 95% EtOH, reflux, quant. (g) 20% Pd(OH)2, H2, MeOH, 94%.
We chose to employ free-radical technology for the
removal of the hydroxyl group in 7. The Robins’ method6b,c
was first explored, which required the preparation of the
secondary phenyl thionocarbonate derivative. Thus, the
alcohol 7 was treated with phenyl chlorothioformate in
the presence of DMAP according to the literature
procedure.6b,c However, no phenyl thionocarbonate prod-
uct was formed in this case, even after a prolonged
reaction time (22 h, rt), and starting alcohol 7 (and 3c)
was recovered in 90% yield. The difficulty encountered
in the acylation of the secondary hydroxyl group was
somewhat unexpected. We reasoned that the hydroxyl
moiety may be in a sterically encumbered environment
and that approach of the bulky 4-(N,N-dimethyl)-1-
(phenoxythiocarbonyl)pyridinium chloride to the hydroxyl
group may be sterically hindered. Furthermore, if acy-
lation had occurred, the corresponding tetrahedral in-
termediate would be energetically disfavored for steric
reasons.
Resu lts a n d Discu ssion
The retrosynthetic analysis of (2S,3R)-AHDA (2) is
summarized in Scheme 1. Amino acid 2 could be envi-
sioned to be derived from 5, which in turn, should be
accessible from the olefin 6. Olefin 6 should be obtainable
from the secondary alcohol 7, which is prepared via the
nucleophilic addition reaction of the organocerium re-
agent “C6H13CeCl2” and the known 2-oxazolidinone-
carbaldehyde 4b,5c readily accessible from the iodo phenyl
sulfone 3b.
Thus, the readily prepared iodo phenyl sulfone 3b5c
was subjected to the previously described5 reductive
elimination to obtain the aldehyde 4b which, without
isolation, was reacted with preformed C6H13CeCl2 at -78
°C. This provided an inseparable mixture of the syn-
alcohol 75a,b and the known5c deiodinated compound 3c
in a 6.3:1 ratio (Scheme 2). To facilitate in the further
characterization of 7, a small amount of the mixture was
treated with acetic anhydride to obtain the acetate
derivative 7 (X ) OAc), which was readily separated from
3c. The next step in our synthesis of AHDA (2) required
the removal of the hydroxyl group in 7 in order to
complete the installation of the heptyl substituent. The
mixture of alcohol 7 and 3c was employed in the
subsequent studies because compound 3c was deemed
to be chemically insert under the reaction conditions that
would be used.
(5) (a) Wee, A. G. H.; Tang, F. Tetrahedron Lett. 1996, 37, 6677. (b)
Wee, A. G. H.; Tang, F. Can. J . Chem. 1998, 76, 1070. (c) Wee, A. G.
H.; McLeod, D. D.; Rankin, T. R. Heterocycles 1998, 48, 2263.
J . Org. Chem, Vol. 68, No. 16, 2003 6269

Wee and McLeod
SCHEME 3. Rea ction P a th w a y for th e F or m a tion
of 13 a n d 14
Therefore, we investigated the preparation of the
(methylthio)thiocarbonate6a,7 from the alcohol 7 (eq 2).
It was hypothesized that (a) the alkoxide oxyanion would
be more nucleophilic and (b) acylation by carbon disulfide
(CS2) would occur more efficiently compared to the use
of the bulkier 4-(N,N-dimethyl)-1-(phenoxythiocarbonyl)-
pyridinium chloride. Thus, the alcohol 7 was treated with
NaH (0 °C, THF) in the presence of a catalytic amount
of imidazole, according to the literature procedure,7 and
followed subsequently by the addition of CS2 and io-
domethane to afford two new compounds as revealed by
TLC analysis of the reaction mixture. The two compo-
nents were readily separated from 3c and purified by
flash chromatography: the less polar (Rf ) 0.54, 3:1
petroleum ether/EtOAc) component was assigned struc-
ture 13, and the more polar compound (Rf ) 0.31, 3:1
petroleum ether/EtOAc) was assigned structure 14 on the
basis of spectroscopic data. The ratio of 13:14 was 6:1;
however, upon standing, compound 13 was found to
slowly convert to 14 (72 h, rt).
The IR spectra of compounds 13 and 14 exhibited the
characteristic absorptions for the thiocarbonyl group at
ν
max 1058 cm-1 and the carbonyl moiety at νmax 1647 cm-1
,
to participate in a facile intramolecular nucleophilic
substitution reaction with the 2-oxazolidinone moiety,
which would result in the formation of the isomeric trans-
2-oxazolidinone 17. The driving force for this rearrange-
ment is the relief of steric strain. The rearranged alkoxide
17 is intercepted by CS2 followed by methyl iodide to form
the corresponding (methylthio)thiocarbonate (13).
Compound 14 is formed from 13 via a thermally and
orbital-symmetry-allowed thio-Claisen rearrangement
reaction.8a The tendency for 13 to rearrange to 14
suggests that the former compound is thermodynamically
less stable than 14.8b The formation of the trans double
bond in 14 indicates that the rearrangement had pro-
ceeded via a highly ordered chairlike transition state
in which the bulky 2-oxazolidinonyl unit occupied a
pseudoequatorial position.
Since the Robins and Barton-McCombie methods for
deoxygenation were not suitable for use in the conversion
of 7 to 9, alternative methods based on the free-radical-
mediated reduction of halides9 were investigated. There-
fore, the secondary iodide 8 was prepared from 7 (and
3c) (Scheme 2), and we chose to use an iodination
procedure based on the Mitsunobu reaction.5,10 Initially,
we were concerned that the sterically hindered hydroxyl
group in 7 may prove to be resistant to conversion to the
iodide. We were pleased that reaction of 7 with a mixture
of Ph3P, I2, and imidazole in toluene at reflux afforded a
64% yield of the desired iodide 8, which was easily
separated from the deiodinated compound 3c. Subse-
quent reduction of the secondary iodide 8 with tributyl-
stannane under free-radical reaction conditions afforded
the olefin 9 in 85% yield.
respectively. For compound 13, the salient features in
its 1H NMR spectrum were the set of multiplets at δ
5.32-5.49 and 5.58-5.79, which were ascribed to the
terminal olefinic hydrogens, and a low-field multiplet at
δ 6.25-6.33, which was due to the allylic hydrogen
adjacent to the xanthate moiety. The characteristic
1
resonances in the H NMR spectrum of 14 were the set
of double doublets, due to the allylic methylene hydro-
gens, one centered at δ 3.50 and the other at δ 3.58 and
the multiplet at δ 5.32-5.55, which were attributed to
1
the internal olefinic hydrogens. A comparison of the H
NMR spectra of 13 and 14 also revealed significant
chemical shift differences in the resonances of the H-5
multiplet and the benzylic methylene hydrogens. In 13,
H-5 was deshielded and resonated at δ 4.32-4.45,
whereas in 14, H-5 appeared at δ 3.92-4.08. The benzylic
methylene hydrogens in 13 resonated at δ 4.91 and 4.95,
but in 14, these hydrogens were shielded and occurred
at δ 3.85 and 4.67.
For further structural confirmation, compound 14 was
reduced with tributylstannane (catalytic AIBN) to pro-
vide the olefin 15 (eq 2). The H NMR spectrum showed
1
the absence of the characteristic set of double doublets
of the allylic methylene hydrogens and the presence of a
new signal (double doublet, J ) 6.6, 1.3 Hz) centered at
δ 1.74 due to the allylic methyl group. Furthermore, the
H-1′ resonance centered at δ 5.62 revealed a vicinal
coupling constant of J 1′,2′ ) 15.1 Hz, which indicated a
trans geometry for the double bond in 15 and hence also
in compound 14.
A plausible mechanism to explain the formation of 13
and 14 from 7 under the reaction conditions used for
(methylthio)thiocarbonate formation is shown in Scheme
3. The initially formed alkoxide 16 (from 7) is envisaged
(2S,3R)-AHDA. With the olefin 9 successfully pre-
pared, the next step in the synthesis entailed the conver-
(8) (a) Compared with: Martin, S. F.; Daniel, D.; Cherney, R. T.;
Liras, S. J . Org. Chem. 1992, 57, 2523. (b) Semiempirical AM1
calculations (PC Spartan, version 6) of compounds 13 and 14 gave ∆Hf
(13) ) - 71.242 kcal/mol and ∆Hf (14) ) - 99.755 kcal/mol.
(9) Review: Neumann, W. P. Synthesis 1987, 665.
(10) (a) Garegg, P. J .; Samuelsson, B. J . Chem. Soc., Perkin Trans.
1 1980, 2866. (b) Coleman, R. S.; Carpenter, A. J . J . Org. Chem. 1992,
57, 5813.
(6) (a) Hartwig, W. Tetrahedron 1983, 29, 2609-2645. (b) Robins,
M. J .; Wilson, J . S. J . Am. Chem. Soc. 1981, 103, 932. (c) Martin, S.
F.; Dapper, M. S.; Dupre, S.; Murphy, C. J . J . Org. Chem. 1987, 52,
3708.
(7) (a) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin
Trans. 1 1975, 1574. (b) Barton, D. H. R.; Subramanian, R. J . Chem.
Soc., Perkin Trans. 1 1977, 1718.
6270 J . Org. Chem., Vol. 68, No. 16, 2003

Synthesis of (2S,3R)-3-Amino-2-hydroxydecanoic Acid
sion of the C5-ethenyl unit to an ester group. Two
pathways were investigated. The first was a three-step
procedure (route a, Scheme 2) that consisted of the
ozonolysis of the ethenyl group to generate the aldehyde,
J ones’ oxidation of the aldehyde, and methylation of the
corresponding carboxylic acid with ethereal diazomethane.
Although this route afforded the methyl ester 10 in an
overall (three steps) yield of 47%, a more concise route
for the preparation of 10 was desired.
(balloon)] to yield synthetic 2 in 94% yield after purifica-
tion via ion-exhange chromatography. The melting point
of our synthetic 2 matched the reported literature melting
point for (2S,3R)-AHDA.2 The 1H NMR data for synthetic
2 are also in accord with the data reported2 in the
literature.
Con clu sion s
In 1993, Marshall and Garofalo reported11 the direct
conversion of alkenes to methyl esters via ozonolysis of
the double bond in 2.5 M methanolic sodium hydroxide.
Therefore, we decided to prepare 10 using this method
(route b, Scheme 2). We were also aware that potential
complications, resulting from base-mediated hydrolysis
of the 2-oxazolidinone moiety, could arise. However, it
was reasoned that since the oxidation was conducted at
-78 °C, the 2-oxazolidinone moiety may be tolerated
under the basic reaction conditions. Our line of reasoning
was confirmed: the ozonolysis of olefin 9, employing the
prescribed conditions,11 yielded the cis methyl ester 10
in a respectable yield of 69%. It is useful to note that
trans-10, which could have arisen from an epimerization
at the C-5 stereocenter under the basic reaction condi-
tions, was not detected. The 1H NMR spectrum of the
crude product only showed the signals corresponding to
cis-10.
The readily accessible 2-oxazolidinone-4-carbaldehyde
(4b) has proven to be an excellent and practical building
block for the synthesis of (2S,3R)-AHDA (2, overall yield
27%). Besides 2-oxazolidinone’s role as a masked vic-
amino alcohol, its chemical stability to a variety of
reagents is noteworthy, which permitted further syn-
thetic manipulations to be applied to the C-4 and C-5
substituents culminating in the synthesis of 2. Moreover,
the “oxazolidinone rearrangement” reaction (7 f 14),
which occurred during the attempted formation of the
(methylthio)thiocarbonate derivative of alcohol 7, pro-
vides a potential new route for the preparation of
â-hydroxy-R-amino acids from oxazolidinone derivatives
of type 7. Studies directed at developing the “oxazolidi-
none rearrangement” reaction are ongoing.
Exp er im en ta l Section
(4R,5S)-3-Ben zyl-4-(1-h yd r oxyh ep tyl)-5-vin yl-2-oxa zo-
lid in on e (7). The organocerium reagent, C6H13CeCl2, was
prepared by treating a suspension of anhydrous CeCl3 (3.00
g, 12.2 mmol)5a,c in THF (27 mL) with 0.5 M C6H13MgBr (24
mL) [prepared from 1-bromohexane (3.50 mL, 4.13 g, 25.0
mmol) and Mg turnings (0.945 g, 39.6 mmol) in THF (25 mL)]
at 0 °C. The mixture was stirred at 0 °C for 1 h and then cooled
to -78 °C.
With the cis-ester 10 in hand, we investigated a “one-
pot” procedure,12 for the preparation of the trans acid 11,
via the epimerization of the C-5 stereocenter and hy-
drolysis of the carbomethoxy group (Scheme 2). It was
expected that epimerization would be facile because of
the relief of steric strain in the conversion of cis-10 to
trans-11. When cis-10 was treated with KOH in refluxing
ethanol,12 a 1:1 cis and trans mixture of the acid 11 was
obtained. These results suggested that hydrolysis of the
carbomethoxy group in cis-10 was competitive with
epimerization of the C-5 stereocenter; the hydrolysis of
the ester group in cis-10 would yield the corresponding
carboxylate anion, which, in turn, would suppress further
epimerization at C-5 by attenuating the acidity of the C-5
R-hydrogen.
It is clear from the above studies that epimerization
at C-5 must precede the hydrolysis of the ester moiety,
and we therefore examined the reaction using NaOMe
in MeOH under anhydrous conditions. Initial studies
quickly revealed that the use of neither catalytic amounts
(30 mol %) nor 1 mol equiv of NaOMe was effective for
causing epimerization; in fact, starting material was
consumed and an unidentified product was obtained. It
was found that the desired epimerization was best
achieved using 4 equiv of NaOMe in methanol at room
temperature (24 h) and that subsequent processing of the
reaction mixture with 1 M aqueous HCl led directly to
the desired trans acid 11 in quantitative yield.
The iodo phenyl sulfone 3b (1.0 g, 2.0 mmol) was dissolved
in THF (20 mL), and the solution was added, via cannula, to
a suspension of Zn/Ag couple in dry THF.8 The mixture was
refluxed for 1 h, and the reaction mixture was cooled to room
temperature. The filtered solution of aldehyde 4b was trans-
ferred, via cannula, to the preformed C6H13CeCl2 at -78 °C.
The reaction mixture was stirred at -78 °C for 5 h and then
slowly warmed to room temperature and stirred at room
temperature for 1 h. The reaction was quenched at -78 °C
with saturated aqueous NH4Cl (5 mL), and the organic phase
was extracted, dried, filtered, and evaporated. Purification of
the crude oily residue by flash chromatography (5:1 petroleum
ether/EtOAc) gave 577 mg of an inseparable mixture of the
secondary alcohol 7 and the known5c bicyclic oxazolidinone 3c.
The ratio of 7:3c was 6.3:1 on the basis of the relative ratio of
the integration of the multiplet due to the internal olefinic
proton (δ 6.10) of 7 to the integration of the multiplets due to
the protons of the phenyl sulfone moiety (δ 7.52-7.95) in 3c.
1
ν
max: 3426(br), 1744, 1496 cm-1. H NMR (discernible signals
for 3c in square brackets): δ 0.89 (t, 3H, J ) 7.3 Hz), 1.02-
1.69 (m, 10H), [1.38, d, J ) 6.7 Hz], 2.00-2.19 (br. s, 1H), 3.57
(dd, 1H, J ) 4.6, 8.6 Hz), 3.62-3.78 (m, 1H), 4.36 (d, 1H, J )
15.9 Hz), [4.38, d, J ) 13.9 Hz], [4.63, s], [4.65, d, J ) 13.9
Hz], 4.80-4.98 (m, 1H), 4.98 (d, 1H, J ) 15.9 Hz), 5.40-5.52
(m, 2H), 6.10 (ddd, 1H, J ) 18, 12, 6.7 Hz), 7.15-7.49 (m, 5H),
[7.52-7.95, m].
To complete the synthesis of (2S,3R)-AHDA, acid 11
was treated with 2 M aqueous KOH in refluxing ethanol5c
to give the crystalline N-benzyl amino acid 12 (Scheme
2) in quantitative yield. The N-benzyl protecting group
in 12 was removed by hydrogenolysis [20% Pd(OH)2, H2
A small amount of 7 (23.5 mg, 0.074 mmol, based on 7) was
reacted with Ac2O (12.0 µL, 0.128 mmol) in dry pyridine (1
mL) containing a catalytic amount of DMAP (8.00 mg, 0.066
mmol). After 2 h at room temperature, the reaction mixture
was concentrated and ethyl acetate was added. The mixture
was washed several times with saturated CuSO4, water, and
then brine. The organic layer was dried, filtered, and evapo-
rated. The residual oil was purified by flash chromatography
(11) Marshall, J . A.; Garofalo, A. W. J . Org. Chem. 1993, 58, 3675.
(12) Sunazuka, T.; Nagamitsu, T.; Tanaks, H.; Omura, S. Tetra-
hedron Lett. 1993, 34, 4447.
J . Org. Chem, Vol. 68, No. 16, 2003 6271

Wee and McLeod
(6:1 petroleum ether/EtOAc and then 2:1 petroleum ether/
EtOAc) to afford the acetate 7 (X ) OAc, 91%, 20.9 mg) and
the known5c bicyclic oxazolidinone 3c (3 mg). Com p ou n d 7
toluene (5 mL) at 80 °C, and to this was added Ph3P (724 mg,
2.76 mmol) in toluene (3 mL) via cannula. Then, the alcohol 7
(283 mg, 0.892 mmol) in toluene (3 mL) was added, followed
by I2 (454 mg, 1.79 mmol) in toluene (14 mL). After all the
additions were complete, the temperature was raised to 120
°C and the reaction was stirred overnight. The reaction was
cooled to room temperature, and then EtOAc (15 mL) and
Florisil were added. The mixture was stirred for 30 min. The
organic layer was washed with sodium thiosulfate (to remove
excess I2) and brine, dried, filtered, and concentrated. This
compound required a number of filtrations to remove the Ph3-
PO. The residue was subject to column chromatography (8:1
petroleum ether/EtOAc and then 4:1 petroleum ether/EtOAc)
1
(X ) OAc). νmax: 1744 cm-1. H NMR: δ 0.82 (t, 3H, J ) 6.6
Hz), 0.87-1.72 (m, 10H), 1.97 (s, 3H), 3.65 (dd, 1H, J ) 3.1,
7.9 Hz), 4.14 (d, 1H, J ) 15.6 Hz), 4.76-4.99 (m, 3H), 5.37
(dd, 2H, J ) 11.4, 16.9 Hz), 5.74-5.96 (m, 1H), 7.12-7.40 (m,
5H). 13C NMR: δ 13.9, 22.4, 25.6, 28.9, 31.2, 31.5, 47.9, 58.3,
71.6, 78.1, 120.4, 127.9, 128.0, 128.9, 130.4, 135.9, 158.1, 170.0.
HRMS: calcd for C21H30NO4 (M + 1), 360.2175; found,
360.2175.
1
Com p ou n d 3c.5c
ν
max: 1754, 1672 cm-1. H NMR: δ 1.37
(d, 3H, J ) 6.7 Hz), 4.38 (d, 1H, J ) 13.3 Hz), 4.59-4.63 (m,
1H), 4.64 (d, 1H, J ) 13.3 Hz), 4.80-5.00 (m, 3H), 7.30-7.50
(m, 5H), 7.52-7.88 (m, 5H).
to give the oily iodide 8 (64%, 267 mg) and 3c5c (21 mg). νmax
:
1756 cm-1. 1H NMR: δ 0.88 (t, 3H, J ) 8.1 Hz), 1.03-2.15 (m,
10H) 3.85-4.04 (m, 1H), 4.12 (dt, 1H, J ) 4.6, 11.3 Hz), 4.47
(d, 1H, J ) 16.3 Hz), 4.82 (dd, 1H, J ) 7.3, 9.0 Hz), 5.03 (d,
1H, J ) 16.3 Hz), 5.38-5.63 (m, 2H), 5.86-6.17 (m, 1H), 7.12-
7.48 (m, 5H). 13C NMR: δ 14.0, 22.6, 28.2, 29.7, 31.1, 31.6,
34.3, 46.6, 62.5, 79.6, 121.6, 128.1, 128.2, 128.9, 129.3, 135.8,
157.8.
F or m a tion of (4R,5S)-3-Ben zyl-5-h exyl-4-[(1S)-1-(S-m e-
th yld ith ioca r bon yloxy)-2-p r op en yl]-2-oxa zolid in on e (13)
a n d (4S,5S)-3-Ben zyl-5-h exyl-4-[3-(m eth ylth io)th ioca r -
bon yloxy]-(1-p r op en yl)-2-oxa zolid in on e (14). The alcohol
7 (218 mg, 0.688 mmol) and imidazole (2.74 mg, 0.0403 mmol)
were dissolved in THF (8 mL). Then, the solution was added
to a suspension of NaH (50% in mineral oil, 38.3 mg, 0.799
mmol) in THF (2 mL) at 0 °C and stirred for 3 h. Carbon
disulfide (0.42 mL, 6.98 mmol) was added to the reaction
mixture, causing a bright yellow color to appear. After 1 h,
methyl iodide (0.45 mL, 7.23 mmol) was added and the mixture
was stirred for an additional 1 h and then slowly warmed to
room temperature. Brine was added to the reaction mixture;
the organic layer was separated and washed, and the aqueous
layer was thoroughly extracted with CH2Cl2. The combined
organic phases were dried, filtered, and evaporated. The
residue was subjected to flash chromatography (8:1 petpetro-
leum ether/EtOAc and then 1:1 petroleum ether/EtOAc) to give
a 6:1 ratio of products 13 (55%, 168 mg) and 14 (9.5%, 38.7
mg). Compound 3c5c (28 mg) was also isolated. Com p ou n d
(4R,5S)-3-Ben zyl-4-h ep tyl-5-vin yl-2-oxa zolid in on e (9).
The iodide 8 (145 mg, 0.339 mmol) and AIBN (11.4 mg, 0.0694
mmol) were dissolved in toluene (3 mL), and then added to a
solution of n-Bu3SnH (247 mg, 0.849 mmol) in toluene (6 mL)
at 80 °C. The reaction temperature was raised to 110 °C after
the addition was complete. After 6 h, the cooled reaction
mixture was quenched with the addition of Et2O (15 mL) and
10% aqueous KF25 (10 mL); the mixture was stirred for 1 h.
The layers were separated, and the aqueous layer was washed
with Et2O. The organic layers were combined, dried, and
concentrated, and the crude product was subjected to column
chromatography (8:1 petroleum ether/EtOAc and then 4:1
petroleum ether/EtOAc) to give the product 9 (85%, 86.7 mg).
ν
max: 1754, cm-1 1H NMR: δ 0.77-1.70 (m, 15H), 3.58 (dt,
.
1
13. νmax: 1756, 1650, 1058, 912 cm-1. H NMR: δ 0.88 (t, 3H,
1H, J ) 7.6, 3.1 Hz), 4.04 (d, 1H, J ) 15.1 Hz), 4.83 (d, 1H, J
) 15.1 Hz), 4.87 (t, 1H, J ) 6.9 Hz), 5.38 (d, 1H, J ) 10.5 Hz),
5.46 (d, 1H, J ) 16.8 Hz), 5.80-6.00 (m, 1H). 13C NMR: δ
14.1, 22.6, 24.7, 27.0, 28.9, 29.5, 29.7, 31.7, 46.2, 57.5, 78.3,
120.5, 127.9, 128.0, 128.4, 128.8, 130.9, 136.1, 152.1.
J ) 8.4 Hz), 1.04-1.68 (m, 10H), 2.61 (s, 3H), 3.40 (dd, 1H, J
) 2.4, 4.1 Hz,), 4.07 (d, 1H, J ) 15.3 Hz), 4.32-4.44 (m, 1H),
4.96 (d, 1H, J ) 15.3 Hz), 5.32-5.49 (m, 2H), 5.58-5.79 (m,
1H), 6.24-6.35 (m, 1H), 7.23-7.50 (m, 5H). 13C NMR: δ 14.6,
19.8, 22.5, 24.6, 29.4, 32.1, 36.0, 47.1, 61.6, 75.1, 80.8, 121.7,
126.1, 128.7, 128.9, 129.5, 130.0, 135.4, 157.8, 215.1. Com -
(4R,5R)-3-Ben zyl-4-h ep tyl-5-m eth oxyca r bon yl-2-oxa zo-
lid in on e (10): Rou te A. Compound 9 (24.0 mg, 0.0797 mmol)
was dissolved in CH2Cl2 and cooled to -78 °C. Ozone was
bubbled through the solution until it turned blue and TLC
indicated that the reaction was complete. Ph3P (23.7 mg, 0.120
mmol) was added to the solution at -78 °C, and the mixture
was slowly warmed to room temperature. After 1 h of stirring,
the solvent was evaporated and the aldehyde was dissolved
in redistilled acetone (2 mL) and cooled to 0 °C. J ones’ reagent
(0.15 mL) was added to the solution, and the mixture was
stirred at 0 °C until the orange color persisted for 20 min. After
20 min, 2-propanol was added to destroy excess J ones’ reagent.
Then, Celite was added and the mixture was stirred for an
additional 15 min and then filtered through a Celite pad. The
filtrate was evaporated to give an oil, which was taken into
EtOAc; this solution was extracted with NaHCO3. The extract
was acidified with 10% HCl at 0 °C and extracted thoroughly
with CH2Cl2. The combined organic layers were dried, filtered,
and concentrated. The residual oil was taken into Et2O, and
ethereal CH2N2 (2 M in Et2O, 2 mL) was added at 0 °C. This
mixture was stirred overnight, and then the excess CH2N2 was
destroyed by careful addition of glacial acetic acid. The solution
was evaporated, and the residue was subjected to column
chromatography (5:1 petroleum ether/EtOAc) to give the ester
1
p ou n d 14. νmax: 1751, 1647 cm-1. H NMR: δ 0.89 (t, 3H, J
) 8.4 Hz), 1.00-1.40 (m, 8H), 1.40-1.60 (m, 2H), 2.37 (s, 3H),
3.47 (dd, 1H, J ) 7.5, 7.5 Hz), 3.50 (dd, 1H, J ) 12.3, 6.2 Hz),
3.58 (dd, 1H, J ) 12.3, 5.5 Hz), 3.85 (d, 1H, J ) 14.5 Hz), 3.94-
4.08 (m, 1H), 4.67 (d, 1H, J ) 14.5 Hz), 5.32-5.55 (m, 2H),
7.10-7.34 (m, 5H). 13C NMR: δ 13.2, 14.1, 22.5, 24.7, 28.9,
31.6, 31.7, 33.7, 45.9, 62.8, 79.2, 127.8, 128.6, 128.7, 130.4,
131.9, 135.8, 157.6, 188.9. HRMS: calcd for C19H26NO2 (M -
MeSC(dO)S), 300.1963; found, 300.1958.
(4S,5S)-3-Ben zyl-5-h exyl-4-(1-p r op en yl)-2-oxa zolid in o-
n e (15). A solution of n-Bu3SnH (176 mg, 0.603 mmol) in
toluene (8 mL) was heated to 80 °C. A mixture of compound
14 (98.2 mg, 0.241 mmol) and AIBN (8 mg, 0.0487 mmol) in
toluene (2 mL) was added to the hot n-Bu3SnH solution via
cannula. The mixture was heated at 80 °C for 16 h, and then
the solvent was removed in vacuo. The product 15 was isolated
by column chromatography, initially eluting with 20:1 petro-
leum ether/EtOAc to remove the tin residue and then with a
gradient elution starting with 6:1 petroleum ether/EtOAc to
3:1 petroleum ether/EtOAc to give 15 (85%, 111 mg). νmax
:
1753, 1603 cm-1. H NMR: δ 0.88 (t, 3H, J ) 8.3 Hz), 1.03-
1.66 (m, 10H), 1.73 (dd, 3H, J ) 7.1, 9.1 Hz), 3.54 (dd, 1H, J
) 9.1, 7.1 Hz), 3.97 (d, 1H, J ) 14.7 Hz), 3.97-4.14 (m, 1H),
4.72 (d, 1H, J ) 14.7 Hz), 5.17-5.36 (m, 1H), 5.62 (dq, 1H, J
) 15.1, 6.9 Hz), 7.12-7.44 (m, 5H). 13C NMR: δ 14.0, 17.8,
22.5, 22.8, 28.9, 31.6, 33.6, 45.7, 63.5, 79.6, 127.6, 127.7, 127.8,
128.4, 128.6, 133.1, 136.1, 157.7. HRMS: calcd for C19H27NO2,
301.2042; found, 301.2047.
1
1
10 (47%, 12.5 mg). The IR and H NMR spectra were identical
to the ester obtained using route B. Rou te B. Compound 9
(61.0 mg, 0.203 mmol) was dissolved in a mixture of CH2Cl2
(2 mL) and 2.5 M methanolic NaOH (0.45 mL). The mixture
was cooled to -78 °C, and ozone was bubbled into the solution.
The mixture initially turned a bright yellow and then went
clear and finally blue. Et2O (20 mL) and H2O (10 mL) were
added at -78 °C to prevent hydrolysis of the ester, and the
(4S,5S)-3-Ben zyl-4-(1-iod oh ep t yl)-5-vin yl-2-oxa zolid i-
n on e (8). Imidazole (164 mg, 2.40 mmol) was dissolved in
6272 J . Org. Chem., Vol. 68, No. 16, 2003

Synthesis of (2S,3R)-3-Amino-2-hydroxydecanoic Acid
mixture was warmed to room temperature. The organic layer
was separated, and the aqueous layer was washed several
times with Et2O. The combined organic layers were dried,
filtered, concentrated, and subjected to column chromatogra-
phy (6:1 petroleum ether/EtOAc and then 1:1 petroleum ether/
EtOAc) to give the ester 10 (69%, 46.8 mg). [R]23D: -27.9° (c
H
+ form), using 5% NH4OH as the eluent. The N-benzyl amino
acid 12 was obtained with a small amount of impurity present
(quantitative, 10.5 mg). Mp (MeOH/H2O): 206.8-209.2 °C.
[R]23D: +5.1° (c 4.9, MeOH). νmax (KBr): 3418-2300, 3313,
1
1734, 1636 cm-1. H NMR (DMSO-d6): δ 0.84 (t, 3H, J ) 6.5
Hz), 1.00-1.49 (m, 12H), 2.55-2.69 (m, 1H), 3.67 (d, 1H, J )
4.1 Hz), 3.74 (d, 1H, J ) 13.4 Hz), 3.94 (d, 1H, J ) 13.4 Hz).
13C NMR (DMSO-d6): δ 14.0, 22.1, 25.9, 29.2, 29.9, 31.3, 50.1,
58.8, 69.4, 126.8, 128.1, 128.4, 140.0, 175.1. FAB-HRMS: calcd
for C17H28NO3 (M + 1), 294.2069; found, 294.2063.
1
1.70, CHCl3). νmax: 1769, 1496 cm-1. H NMR: δ 0.87 (t, 3H,
J ) 6.8 Hz), 1.03-1.78 (m, 12H), 3.81 (s, 3H), 3.74-3.87 (m,
1H), 4.09 (d, 1H, J ) 15.3 Hz), 4.81 (d, 1H, J ) 15.4 Hz), 4.92
(d, 1H, J ) 8.3 Hz), 7.22-7.44 (m, 5H). 13C NMR: δ 14.1, 22.6,
24.5, 28.3, 28.9, 29.5, 31.6, 46.3, 52.5, 56.7, 74.8, 128.0, 128.1,
128.9, 135.5, 157.3, 168.0. HRMS: calcd for C19H27NO4, 333.1940;
found, 333.1940.
(2S,3R)-3-Am in o-2-h ydr oxydecan oic Acid (2). The amino
acid 12 (10.5 mg, 0.0358 mmol) was dissolved in MeOH (4 mL)
at room temperature, and Pearlman’s catalyst (20% Pd(OH)2/
C, 6.49 mg) was then added. The reaction mixture was stirred
under H2 gas (balloon, 1 atm). After 16 h, the mixture was
filtered through a Celite pad moistened with MeOH. The
solvent was evaporated under reduced pressure, and the
residue was subjected to ion-exchange chromatography (Dowex
50w × 8, 200-400 mesh) using 5% NH4OH as the eluent. The
amino acid 2, was obtained as the free base (94%, 6.84 mg).
[R]22D: +7.3 (c 0.34,1 M HCl). Lit.2b [R]25D: +5.4 (c 0.59, 1 M
HCl). Mp: 218.4-219.7 (dec). Lit.2b mp: 219-220 (dec). 1H
NMR (D2O): δ 0.80 (t, 3H, J ) 6.8 Hz), 1.20-1.70 (m, 12H),
3.30-3.39 (m, 1H), 4.03 (d, 1H, J ) 3.7 Hz). FAB-HRMS: calcd
for C10H22NO3 (M + 1), 204.1600; found, 204.1549.
(4R,5S)-3-Ben zyl-4-h ep t yl-5-ca r b oxyla t e-2-oxa zolid i-
n on e (11). A solution of the ester 10 (41.3 mg, 0.124 mmol)
in dry MeOH (2.4 mL, 100 mL distilled from 1.0 g Na) was
treated with 1 M NaOMe (0.248 mL, 0.248 mmol) in MeOH.
The mixture was stirred at room temperature, and after 6 h,
another portion of 1 M NaOMe (0.248 mL, 0.248 mmol) was
added. The reaction was stirred overnight and then quenched
with 1 M HCl (1 mL); the resulting mixture was evaporated
and subjected to column chromatography (4:1 CH2Cl2/MeOH)
to give the acid 11 (99%, 39.6 mg). [R]23D: +28.8° (c 1.0, CHCl3).
1
ν
max: 3530-2400, 1762, 1497 cm-1. H NMR: δ 0.86 (t, 3H, J
) 6.6 Hz), 1.05-1.85 (m, 12H)., 3.60-3.75 (m, 1H), 4.11 (d,
1H, J ) 15.2 Hz), 4.60 (d, 1H, J ) 4.5 Hz), 4.79 (d, 1H, J )
15.1 Hz), 7.18-7.43 (m, 5H), 8.37-8.74 (br. s, 1H). 13C NMR:
δ 14.0, 22.5, 23.2, 29.0, 29.1, 31.5, 31.6, 46.2, 58.1, 74.3, 127.8,
128.1, 128.9, 135.1, 156.9, 172.4. HRMS calcd for C18H25NO4
319.1783, found 319.1778.
Ack n ow led gm en t. We thank NSERC, Canada, and
the University of Regina for financial support. We would
also like to thank Mr. Ken Thoms, University of
Saskatchewan, for performing the high-resolution mass
spectral analysis.
(2S,3R)-N-Ben zyl-3-am in o-2-h ydr oxydecan oic Acid (12).
The acid 11 (11.5 mg, 0.0359 mmol) was dissolved in 96%
EtOH (1.5 mL), and 2 M KOH (1 mL) was added. The mixture
was refluxed for 40 h and cooled to room temperature, and
the solvent was removed in vacuo. The residue was taken into
10% HCl and stirred for 1 h, and the acidic solution was
evaporated to dryness. The residue was subjected to ion-
exchange chromatography (Dowex 50w × 8, 200-400 mesh,
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 3c and 7-15 and 1H NMR spectra of
the rearrangement of 13 to 14. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O034334T
J . Org. Chem, Vol. 68, No. 16, 2003 6273