Diastereoselective synthesis of γ-hydroxy-β-amino alcohols and (2S,3S)-β-hydroxyleucine from chiral D-(N,N-dibenzylamino) serine (TBDMS) aldehyde

Full text of DOI:10.1021/jo971468w

J . Org. Chem. 1998, 63, 1709-1713
1709
Dia ster eoselective Syn th esis of
γ-Hyd r oxy-â-a m in o Alcoh ols a n d
(
2S,3S)-â-Hyd r oxyleu cin e fr om Ch ir a l
D-(N,N-Diben zyla m in o)ser in e (TBDMS)
Ald eh yd e
F igu r e 1.
Taoues La ¨ı b, J acqueline Chastanet, and J ieping Zhu*
condensation,11 and chiral pool approach12 among others13
have been developed. All exhibit good levels of stereo-
control.14 Leucine dehydrogenase from Bacillus species
has also been employed for the enzymatic synthesis of
L-â-hydroxyvaline.15
Institut de Chimie des Substances Naturelles, CNRS,
9
1198 Gif-sur-Yvette, France
Received August 6, 1997
As chiral building blocks, N-protected amino aldehydes
have found numerous applications in the synthesis of a
wide variety of compounds.16 In this respect, N-protected
serinal has special importance as the presence of a
â-hydroxy group in the side chain of serine affords direct
access to γ-hydroxy-â-amino alcohols and, moreover,
provides a handle for further transformations. Several
chiral serine aldehydes, in which the aldehyde group
originates from the acid function of the amino acid, have
been prepared. Thus, Garner and co-workers have
In tr od u ction
Amino diols and â-hydroxy-R-amino acids are fre-
quently found as key structural units in bioactive natural
products. For instance, D-erythro-sphingosine (1) (Fig-
ure 1) and its derivatives were shown to be important
inhibitors of protein kinase C, a pivotal enzyme in cell
regulation and signal transduction, while (2S,3S)-â-
hydroxyleucine (2) is a key constituent of a range of
1
2
17
natural peptide antibiotics such as telomycin, azinothri-
developed a cyclic oxazolidine aldehyde (3), (Figure 2)
3
4
5
5
6
while Rapoport reported both an acyclic N-(phenylsulfo-
cin, A83586C, citropeptin, variapeptin, L-156602, and
1
8
7
nyl)- protected aldehyde (4) and an N-(9-phenylfluoren-
verucopeptin as well as a family of cyclopeptide alka-
loids.8 Amino alcohols in general also play an important
9-yl) cyclic carbamate (5).19
Alternatively, Lajoie et al.
20
have disclosed an acyclic N-Fmoc serine aldehyde (6) in
which the carboxylic function of serine is masked as an
ortho ester and the hydroxy group is oxidized to an
aldehyde function. These protected serine aldehydes are
reactive toward a variety of classic reagents used for
addition to the aldehyde function, and their synthetic
role in modern organic chemistry as a class of versatile
chiral ligands.9 A number of elegant chemical syntheses
including Sharpless asymmetric epoxidation (AE)/dihy-
droxylation (AD) methodology,10 diastereoselective aldol
(
1) Hannun, Y. A.; Bell, R. M. Science 1989, 243, 500-507.
16
potential has been amply demonstrated. Among them,
(2) Sheehan, J . C.; Maeda, K.; Sen, A. K.; Stock, J . A. J . Am. Chem.
Soc. 1962, 84, 1303-05.
3) Maehr, H.; Liu, C. M.; Palleroni, N. J .; Smallheer, J .; Todaro,
L.; Williams, T. H.; Blount, J . F. J . Antibiot. 1986, 39, 17-25.
4) Smitka, T. A.; Deeter, J . B.; Hunter, A. H.; Mertz, F. P.; Ellis,
R. M.; Boeck, L. D.; Yao, R. C. J . Antibiot. 1988, 41, 726-733.
5) Nakagawa, M.; Hayakawa, Y.; Furihata, K.; Seto, H. J . Antibiot.
990, 43, 477-484.
6) Hensens, O. D.; Borris, R. P.; Koupal, L. R.; Caldwell, C. G.;
(
(11) (a) Seebach, D.; J uaristi, E.; Miller, D. D.; Schickli, C.; Weber,
T. Helv. Chim. Acta 1987, 70, 237-261. (b) Sch o¨ llkopf, U.; Beulshaus-
en, T. Liebigs Ann. Chem. 1989, 223-225. (c) Kanemasa, S.; Mori, T.;
Tatsukawa, A. Tetrahedron Lett. 1993, 34, 8293-8296. (d) Evans, D
A.; Weber, A. E. J . Am. Chem. Soc. 1986, 108, 6757-6761. (e) Zhu, J .;
Bouillon, J . P.; Singh, G. P.; Chastanet, J .; Beugelmans, R. Tetrahedron
Lett. 1995, 36, 7081-7084. (f) Soloshonok, V. A.; Kacharov, A. D.;
Avilov, D. V.; Ishikawa, K.; Nagashima, N.; Hayashi, T. J . Org. Chem.
1997, 62, 3470-3479 and references therein.
(12) (a) Garner, P.; Park, J . M.; Malecki, E. J . Org. Chem. 1988,
53, 4395-4398. (b) Reetz, R. M.; Drewes, M. W.; Lennick, K.; Schmidt,
A.; Holdgr u¨ n, X. Tetrahedron: Asymmetry 1990, 1, 375-378. (c)
Murakami, T.; Minamikawa, H.; Hato, M. Tetrahedron Lett. 1994, 35,
745-748. Kozikowski, A. P.; Ding, Q. J .; Spiegel, S. Tetrahedron Lett.
1996, 37, 3279-3282.
(
(
1
(
Currie, S. A.; Haidri, A. A.; Homnick, C. F.; Honeycutt, S. S.;
Lindenmayer, S. M.; Schwartz, C. D.; Weissberger, B. A.; Woodruff,
H. B.; Zink, D. L.; Zitano, L.; Fieldhouse, J . M.; Rollins, T.; Springer,
M. S.; Springer, J . P. J . Antibiot. 1991, 44, 249-254.
(7) (a) Nishiyama, Y.; Sugawara, K.; Tomita, K.; Yamamoto, H.;
Kamei, H.; Oki, T. J . Antibiot. 1993, 46, 921-927. (b) Sugawara, K.;
Toda, S.; Moriyama, T.; Konishi, M.; Oki, T. J . Antibiot. 1993, 46, 928-
9
35.
(8) (a) J oulli e´ , M. J .; Nutt, R. E. In Alkaloids: Chemical and
(13) (a) Corey, E, J .; Lee, D.-H.; Choi, S. Tetrahedron Lett. 1992,
33, 6735-38. (b) Greck, C.; Bischoff, L.; Ferreira, F.; Pinel, C.; Piveteau,
E.; Gen eˆ t, J . P. Synlett 1993, 475-477. (c) J ackson, R. F.; Palmer, N.
J .; Wythes, M. J .; Clegg, W.; Elsegood, M. R. J . J . Org. Chem. 1995,
60, 6431-6440. (d) Ciufolini, M. A.; Shimizu, T.; Swaminathan, S.;
Xi, N. Tetrahedron Lett. 1997, 38, 4947-4950.
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1985,
Vol. 3, p 113-168. (b) Schmidt, U.; Lieberknecht, A.; Haslinger, E. In
The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1985; Vol.
2
6, p 299-326.
(
9) For recent reports on γ-hydroxy-â-amino alcohols, see: (a)
Katsumura, S.; Yamamoto, N.; Morita, M.; Han, Q. Tetrahedron:
Asymmetry 1994, 5, 161-164. (b) Vidal-Ferran, A.; Moyano, A.; Pericas,
M. A.; Riera, A. J . Org. Chem. 1997, 62, 4970-82. For recent reviews,
see: (c) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
(14) For recent general reviews, see: (a) Duthaler, R. O. Tetrahedron
1994, 50, 1539-1650. (b) Durand, J . O.; Gen eˆ t, J . P. Bull. Soc. Chim.
Fr. 1994, 131, 612-619.
(15) Hanson, R. L.; Singh, J .; Kissick, T. P.; Patel, R. N.; Szarka, L.
J .; Mueller, R. H. Biorg. Chem. 1990, 18, 116-130.
3
0, 49-69. (d) Ajer, D. J .; Prakash, I.; Schaad, D. R. Chem. Rev.
(Washington, D.C.) 1996, 96, 835-875.
(16) (a) J urczak, J .; Golebiowski, A. Chem. Rev. (Washington, D.C.)
1989, 89, 149-164. (b) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991,
30, 1531-1546.
(10) (a) J ung, M. E.; J ung, Y. H. Tetrahedron Lett. 1989, 30, 6637-
6
640. (b) Schmidt, U.; Respondek, M.; Lieberknecht, A.; Werner, J .;
Fischer, P. Synthesis 1989, 256-261. (c) Caldwell, C. G.; Bondy, S, S.
Synthesis 1990, 34-36. (d) Sunazuka, T.; Nagamitsu, T.; Tanaka, H.;
Omura, S.; Sprengeler, P. A. Smith, A. B. Tetrahedron Lett. 1993, 34,
(17) (a) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361-2364.
(b) Garner, P.; Park, J . M. Org. Synth. 1991, 70, 18-26.
(18) (a) Maurer, P. J .; Takahata, H.; Rapoport, H. J . Am. Chem.
Soc. 1984, 106, 1095-1098. (b) Roemmele, R. C.; Rapoport, H. J . Org.
Chem. 1989, 54, 1866-1875.
4
1
6
447-4448. (e) Hale, K. J .; Manaviazar, S.; Delisser, V. M. Tetrahedron
994, 50, 9181-9188. (f) Shao, H.; Goodman, M. J . Org. Chem. 1996,
1, 2582-2583. (g) For a recent comprehensive review on AD, see:
(19) Lubell, W.; Rapoport, H. J . Org. Chem. 1989, 54, 3824-3831.
(20) Blaskovich, M. A.; Lajoie, G. A. J . Am. Chem. Soc. 1993, 115,
5021-5030.
Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994,
9
4, 2483-2547.
S0022-3263(97)01468-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/14/1998

1
710 J . Org. Chem., Vol. 63, No. 5, 1998
Notes
Sch em e 2
useful chiral building blocks. Curiously, application of
N,N-dibenzylserine aldehyde of type 7 (Figure 2) in
F igu r e 2.
asymmetric synthesis has scarcely been reported in the
Sch em e 1
literature.2
5,26
We report herein our studies concerning
the synthesis of (2R)-2-(N,N-dibenzylamino)-3-O-[(tert-
butyldimethylsilanyl)oxy]propionaldehyde (7) and its use
for the asymmetric synthesis of amino diols and â-hy-
droxy-R-amino acids.27
Resu lts a n d Discu ssion
D-N,N-Dibenzylserine (TBDMS) aldehyde (7) was pre-
pared as described in Scheme 2. Chemoselective bis
N-benzylation of D-serine methyl ester (10) with benzyl
Garner’s aldehyde (3) is probably the most popular
synthon and has been used as the starting material in
the synthesis of a wide range of bioactive compounds.16,21
3
bromide (DMSO-THF, NaHCO ) gave the desired amino
ester 11, which was converted to TBDMS ether 12 under
conventional conditions. Transformation of the ester to
an aldehyde function was best realized in a two-step
Though moderate to good selectivities are generally
obtained, the facial selectivity of addition of Grignard
reagents and other organometallic species to this alde-
hyde has been shown to be reagent dependent. Moreover,
both chelated and nonchelated processes can occur
concomitantly, leading to diminished diastereoselectivity
4
sequence. Thus, reduction of ester 12 with LiBH in
ether in the presence of methanol28 gave the amino
alcohol 13 in quantitative yield. No racemization due to
silyl group migration was observed in the reduction step
in accord with Meyers’s observation.29 Swern oxidation
of 13 then gave the desired amino aldehyde 7. Though
the oxidation proceeded cleanly, degradation of the
aldehyde occurred during chromatographic purification
leading to only moderate isolated yield (45-50%). That
silica gel can catalyze the decomposition of N,N-diben-
zylamino aldehyde has very recently been reported by
Whiting, and a possible mechanism was proposed by the
same group.31 Thus, in the following studies, the crude
aldehyde 7 obtained after conventional aqueous workup
of the Swern oxidation reaction mixture was submitted
directly to reaction with organometallic reagents.
or even reversed facial selectivity such that prediction
30
of stereochemical outcome is tenous (Scheme 1).22
In connection with our work on the total synthesis of
cyclopeptide alkaloids,23 we required an efficient and
general synthesis of erythro-(2S,3S)-â-hydroxy-R-amino
acids. Several years ago, Reetz1
6b,24,25
introduced the
concept of protecting-group tuning as a means of realizing
high levels of asymmetric control in organometallic
additions involving N,N-dibenzylamino aldehydes. Their
configurational stability at room temperature and the
reliable and predictable high diastereoselectivity (ds
>
90% is a rule) observed with a battery of different
organometallics have made them a family of extremely
Treatment of crude amino aldehyde 7 with 2 equiv of
isopropylmagnesium chloride (Scheme 3) in THF gave
the anti amino alcohol 14a in 75% overall yield (two
steps, 85-90% based on reacted starting material) to-
gether with the reduced product 13. The Grignard
addition is highly diastereoselective affording the anti
product with a de greater than 95%. The stereochemistry
(
21) For a recent application, see: Kumar, J . S. R.; Datta, A.
Tetrahedron Lett. 1997, 38, 473-476. For a recent review concerning
the use of amino acids as chiral pools, see: Sardina, F. J .; Rapoport,
H. Chem. Rev. 1996, 96, 1825-1872.
(22) (a) Williams, L.; Zhang, Z.; Ding, X.; J oulli e´ , M. M. Tetrahedron
Lett. 1995, 36, 7031-7034. (b) Han, B. H.; Kim, Y. C.; Park, M. K.;
Park, J . H. Heterocycles 1995, 1909-1914. (c) Williams, L.; Zhang, Z.;
Shao, F.; Carroll, P. J .; J oulli e´ , M. M. Tetrahedron 1996, 52, 11673-
1
1694.
(
23) Zhu, J .; La ¨ı b, T.; Chastanet, J .; Beugelmans, R. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2517-2519.
24) (a) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem.,
(26) N,N-Dibenzylserine (TBDMS) aldehyde (7) was mentioned in
Reetz’s review (ref 16b) on the basis of his unpublished results. Serine
aldehydes wherein the side-chain hydroxy group was protected as a
benzyl ether and a MOM ether were described in refs 12b and 25,
respectively. See references therein.
(
Int. Ed. Engl. 1987, 26, 1141-1143. For recent applications of Reetz’s
aldehydes, see: (b) Barluenga, J .; Baragana, B.; Concellon, J . M. J .
Org. Chem. 1995, 60, 6696-6699. (c) Beaulieu, P. L.; Wernic D. J . Org.
Chem. 1996, 61, 3635-3645. (d) Hanessian, S.; Park, H.; Yang, R. Y.
Synlett 1997, 351-352. (e) Hanessian, S.; Park, H.; Yang, R. Y. Synlett
(27) Part of this work has been published as
a preliminary
communication: La ¨ı b, T.; Chastanet, J .; Zhu, J . Tetrahedron Lett. 1997,
38, 1771-1772.
1
2
997, 353-354. (f) Hoffman, R. V.; Tao, J . J . Org. Chem. 1997, 62,
292-2297. (g) Paquette, L. A.; Mitzel, T. M.; Isaac, M. B.; Crasto, C.
(28) Soai, K.; Ookawa, A.; Hayashi, H. J . Chem. Soc., Chem.
Commun. 1983, 668-669.
F.; Schomer, W. W. J . Org. Chem. 1997, 62, 4293-4301 and references
(29) Novachek, K. A.; Meyers, A. I. Terahedron Lett. 1996, 37, 1743-
therein.
1746.
(
25) For syn selective addition with diethylzinc see: Andr e´ s, J . M.;
Barrio, R.; Martinez M. A.; Pedrosa, R.; P e´ rez-Encabo, A. J . Org. Chem.
996, 1, 4210-4213.
(30) Omura, K.; Swern, D. Tetrahedron 1978, 1651-1660.
(31) Adia, M.; H e´ naff, N.; Whiting, A. Tetrahedron Lett. 1997, 38,
3101-3102.
1

Notes
J . Org. Chem., Vol. 63, No. 5, 1998 1711
Sch em e 3
F igu r e 3.
amino alcohols 14b and 14c in 85% and 88% yields,
respectively. No reduced product 13 was isolated in these
two cases as both reagents lack hydrogen atoms at the â
position. The reaction of amino aldehyde 7 with alkyl-
lithium gave a more complex reaction mixture from
which the anti amino alcohol could be isolated, but only
in less than 30% yield. However, when the organo-
lithium reagent was transformed into an organocerium
reagent,34 the efficiency of the desired transformation was
recovered to give the adduct 14d in good chemical yield
and with excellent anti diastereoselectivity. Reaction of
Sch em e 4
7
with the organocuprate reagent Bu
2
CuLi was also
3
5
attempted but results were less than satisfactory.
One-pot Swern oxidation and in situ trapping of the
resulting aldehyde with nucleophilic reagents, as devel-
oped by Ireland,36 is known to be an excellent method to
circumvent the deleterious side reactions characteristic
of highly reactive carbonyl compounds. We applied this
technique to the Swern oxidation medium (CH
and found that addition of isopropylmagnesium chloride
5 equivalents) gave the desired amino alcohol 14a with
equal efficiency. A similar result was obtained when
2 2
Cl ) of 7
(
diethyl ether, instead of the usual CH
the solvent for the Swern oxidation.
2 2
Cl , was used as
of 14a was verified by its conversion into oxazolidinone
6 (Scheme 4, vide infra). The coupling constant (J H4-H5
6.5 Hz) together with the observation of an NOE cross-
peak between the H-4 and H-5 protons of 16 indicated a
cis relationship for these two protons and, thus, the anti
stereochemistry of adduct 14a .32 It is appropriate to
point out that the facial selectivity observed here is
complementary to J oulli e´ ’s observation that the syn
product is formed predominantly when the same Grig-
nard reagent is reacted with Garner’s aldehyde (Scheme
1
)
The tert-butyldimethyl silyl group was selected as the
protective group for the side-chain hydroxy group of
serine mainly for its easy of introduction, its relative
stability, and the nonchelating property of the resulting
TBDMS ether. However, it is reasonable to postulate
that the diastereoselectivity of the Grignard addition
would be sensitive to the nature of the â-hydroxy protec-
tive group in the aldehyde 7. We were thus concerned
at the outset of this work that the bulky TBDMS
protecting group would decrease the steric discrimination
1
). The formation of the reduced product 13 may be
explained by â-hydride elimination, frequently observed
as a side product when both the substrate and the
Grignard reagents are sterically hindered. We were able
to overcome to a great extent this undesirable reaction
pathway by simply running the reaction in diethyl ether
instead of THF at -78 °C. Under these conditions,
higher yields (88-95%) of desired product 14a could be
obtained. It is worth noting that in the case of Garner’s
aldehyde the stereochemical outcome is sensitive to the
reaction medium and that diethyl ether favors the Cram
2
between the R-N,N-dibenzyl and R-CH OTBDMS groups,
3
7
consequently decreasing the Felkin selectivity. Experi-
mentally, this was found not to be the case, and the
excellent anti diastereoselectivity observed coincides
nicely with the usual Felkin-Anh model (Figure 3).
The potential of this new chiral serine aldehyde
derivative 7 is demonstrated by a highly diastereoselec-
tive synthesis of (2S,3S)-â-hydroxyleucine (2) as shown
in Scheme 4. Hydrogenolysis of 14a on Pearlman’s
catalyst gave amino alcohol 15, which was transformed
into oxazolidinone 16 by treatment with carbonyl diimi-
chelating transition state leading to an increase in syn
adduct formation.2
2,33
However, in our case, the same
38
dazole (CDI). One-pot deprotection and J ones oxidation
degree of anti selectivity (within NMR detection limits)
was observed in both THF and diethyl ether, indicating
the strong preference for nucleophilic approach according
to the Felkin-Anh model (vide infra).
Other Grignard reagents such as MeMgBr and Ph-
MgBr reacted with 7 with equal efficiency to give the anti
(34) (a) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.;
Mita, T.; Hatanaka, Y. J . Org. Chem. 1984, 49, 3904-3912. (b)
Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y.
J . Am. Chem. Soc. 1989, 111, 4392-4398.
(35) The organolithium and organocuprate reagents are known to
react cleanly with N,N-dibenzylalanine aldehyde; see ref 16b and:
Reetz, M. T.; Reif, W.; Holdgr u¨ n, X. Heterocycles 1989, 28, 707-710.
(
36) Ireland, R. E.; Norbeck, D. W. J . Org. Chem. 1985, 50, 2198-
(
32) (a) Futagawa, S.; Inui, T.; Shiba, T. Bull. Chem. Soc. J pn. 1973,
6, 3308-3310. (b) Wagner, B.; Beugelmans, R. Zhu, J . Tetrahedron
Lett. 1996, 37, 6557-6560.
33) Coleman, R. S.; Carpenter, A. J . Tetrahedron Lett. 1992, 33,
697-1700.
2200.
(37) (a) Ch e´ rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
4
2199-2204. (b) Ch e´ rest, M.; Felkin, H. Tetrahedron Lett. 1968, 2204-
(
2208.
1
(38) Liu, H. T.; Han, I. S. Synth. Commun. 1985, 15, 759-764.

1
712 J . Org. Chem., Vol. 63, No. 5, 1998
Notes
led to the oxazolidinone carboxylic acid 17 in 72% yield.
Finally, removal of the carbamate function under acidic
conditions gave a quantitative yield of the hydrochloride
salt of (2S,3S)-â-hydroxyleucine (2), whose physical data
were identical in all respects with the literature values.10
In summary, reaction of N,N-dibenzylserine (TBDMS)
aldehyde (7) with organometallic reagents shows an
excellent diastereoselectivity. The anti selectivity ob-
served is more predictable than with Garner’s aldehyde
and is complementary to that observed with Lajoie’s
synthon. The utility of this chiral building block has been
demonstrated by a short synthesis of (2S,3S)-â-hydroxy-
leucine (2).
(CI) m/z 386 (M + 1). Anal. Calcd for C23
H
35NO
2
Si: C, 71.64;
H, 9.15; N, 3.63. Found: C, 71.21; H, 8.78; N, 3.54.
2R)-3-[(ter t-Bu tyld im eth ylsila n yl)oxy]-2-(d iben zyla m i-
n o)p r op ion a ld eh yd e (7). To a cooled solution (-78 °C) of
oxalyl chloride (140.4 µL, 1.62 mmol) in CH Cl (3 mL) was
added DMSO (252.8 µL, 3.56 mmol) dropwise. After 10 min, a
solution of alcohol 13 (312 mg, 0.81 mmol) in CH Cl was added
(
2
2
2
2
in ca. 2 min. The reaction mixture was stirred for another 15
min, and TEA (1 mL, 7.3 mmol) was then added. After being
stirred for 10 min at -78 °C, the cooling bath was removed and
water was added at room temperature. The aqueous phase was
extracted with CH
washed with brine, dried over Na
reduced pressure. Flash chromatography on silica gel (eluent:
heptane/EtOAc ) 10/1) afforded aldehyde 7 (138 mg, 45%): [R]
+7° (c 1.2, EtOAc); IR (CHCl ) 2952, 2938, 2860, 1722, 1616,
510, 1447, 1257 cm ; H NMR (CDCl , 250 MHz) δ 0.04 (s,
2
Cl
2
, and the combined organic extracts were
2
SO , and concentrated under
4
D
)
3
-
1
1
1
3
4
3
Exp er im en ta l Section
H), 0.05 (s, 3H), 0.85 (s, 9H), 3.32 (t, J ) 5.7 Hz, 1H), 3.82 (s,
H), 3.98 (d, J ) 5.7 Hz, 2H), 7.1-7.4 (m, 10H), 9.65 (s, 1H);
General procedures and methods for characterization have
1
3
C NMR (CDCl ) δ -5.5, 18.2, 26.0, 55.9, 60.1, 67.9, 127.3, 128.5,
3
3
9
been described previously. Melting points are uncorrected.
2R)-3-Hyd r oxy-2-(d iben zyla m in o)p r op ion ic Acid Meth -
yl Ester (11). To a solution of D-serine methyl ester 10 (10.0 g,
4.3 mmol) in a mixture of THF (160 mL) and DMSO (40 mL)
were added benzyl bromide (23.0 mL, 192.9 mmol) and NaHCO
21.3 g, 253.6 mmol). The reaction mixture was heated to reflux
+
1
28.9, 139.6, 203.5; MS (CI) m/z 384 (M + 1) . Compound 7 is
(
unstable in CHCl
tor.
3
solution and should be kept in the refrigera-
6
(
2R,3S)-1-[(ter t-Bu tyld im eth ylsila n yl)oxy]-2-(d iben zyl-
a m in o)-4-m eth ylp en ta n -3-ol (14a ). Oxidation of alcohol 13
6.32 g, 16.4 mmol) was carried out under standard conditions
as described above. Following the conventional workup proce-
dure, the aqueous phase was extracted with CH Cl , and the
combined organic extracts were washed with brine, dried over
Na SO , and evaporated to dryness. The crude aldehyde was
3
(
(
for 15 h, cooled to room temperature, and diluted by addition of
water. The aqueous phase was extracted with EtOAc. The
combined organic phases were washed with brine, dried over
2
2
Na
2 4
SO , and concentrated under reduced pressure. Flash
2
4
chromatography on silica gel (eluent: heptane/EtOAc ) 5/1 then
dried in vacuo and was redissolved in diethyl ether (50 mL) and
cooled to -78 °C. To this solution was added isopropylmagne-
sium chloride (2 M in THF, 16.4 mL, 32.8 mmol) dropwise. The
reaction course was monitored by TLC, and once all the starting
material (aldehyde) was consumed (1 h), the reaction was
quenched by addition of saturated aqueous NH
aqueous solution was extracted with EtOAc, and the combined
organic extracts were washed with brine, dried over Na SO ,
4
4
/1) afforded compound 11 (19.2 g, quantitative): [R] ) +138°
D
3 3
(c 1.2, CHCl ); IR (CHCl ) 3627, 3001, 2973, 2896, 1754, 1511,
1
3
7
1
441, 1251, 1180, 1047 cm-1; 1H NMR (CDCl3, 200 MHz) δ 3.60-
.80 (m, 3H), 3.68, 3.92 (AB q, J ) 13.4 Hz, 4H), 3.80 (s, 3H),
.1-7.4 (m, 10H); 13C NMR (CDCl
) δ 51.6, 54.9, 59.4, 61.8,
27.5, 128.6, 129.1, 138.7, 171.8; MS (EI) m/z 299, 268. Anal.
: C, 72.21; H, 7.07; N, 4.68. Found: C,
2.02; H, 7.28; N, 4.44.
2R)-3-[(ter t-Bu tyld im eth ylsila n yl)oxy]-2-(d iben zyl)a m i-
3
4
Cl solution. The
Calcd for C18H21NO
3
7
2
and concentrated under reduced pressure. Flash chromatogra-
phy on silica gel (eluent: heptane/EtOAc ) 15/1 then 10/1)
afforded the amino diol 14a (6.12 g, 88%): [R] ) -40° (c 0.4,
(
n op r op ion ic Acid Meth yl Ester (12). To a solution of 11 (7.0
g, 23.4 mmol) in DMF (30 mL) were added imidazole (2.39 g,
D
CHCl
3
); IR (CHCl
3
) 3693, 3062, 2412, 1600, 1462, 1118, 937
cm ; H NMR (CDCl , 200 MHz) δ 0.09 (s, 3H), 0.11 (s, 3H),
0.80 (s, 9H), 0.81 (d, J ) 6.6 Hz, 3H),
3
5.1 mmol) and TBDMSCl (4.58 g, 30.4 mmol). After being
-1
1
3
stirred at room temperature under argon for 15 h, the reaction
mixture was diluted with water and extracted with EtOAc. The
combined organic phases were washed with brine, dried over
0
1
1
.40 (d, J ) 6.6 Hz, 3H)
,
.95 (d of septet, J ) 3.4, 6.6 Hz, 1H), 2.61 (dt, J ) 5.0, 7.7 Hz,
H), 2.70 (br s, 1H, OH), 3.45 (d, J ) 13.7 Hz, 2H), 3.60 (dd, J
Na
chromatography on silica gel (eluent: heptane/EtOAc ) 5/1)
afforded TBDMS ether 12 (8.7 g, 90%): [R] ) +42° (c 0.9,
CHCl ); IR (CHCl ) 3002, 2952, 2931, 2861, 1736, 1497, 1454,
356, 1258, 1110, 843 cm-1; H NMR (CDCl3, 200 MHz) δ 0.09
2 4
SO , and concentrated under reduced pressure. Flash
)
3.4, 7.7 Hz, 1H), 3.75 (d, J ) 13.7 Hz, 2H), 3.9-4.0 (m, 2H),
13
7
2
1
.0-7.2 (m, 10H); C NMR (CDCl
3
) δ -4.8, -4.7, 15.6, 18.8,
D
1.1, 26.6, 30.5, 56.0, 59.5, 62.0, 78.1, 127.6, 129.0, 129.7, 130.0,
3
3
+
2
40.8; MS (CI) m/z 428 (M + 1) . Anal. Calcd for C26H41NO -
1
1
Si: C, 73.02; H, 9.66; N, 3.28. Found: C, 72.85; H, 9.77; N, 3.12.
Compounds 14b and 14c were prepared according to the same
synthetic procedure described for the synthesis of 14a .
(
s, 6 H), 1.00 (s, 9H), 3.58 (t, J ) 6.1 Hz, 1H), 3.70 (d, J ) 14.1
13
Hz, 2H), 3.76 (s, 3H), 3.8-4.1 (m, 4H), 7.0-7.4 (m, 10H),
C
NMR (CDCl ) δ -5.6, -5.5 18.2, 25.9, 26.1, 51.2, 55.5, 62.8, 63.0,
3
(
2R,3S)-1-[(ter t-Bu tyld im eth ylsila n yl)oxy]-2-(d iben zyl-
) -62° (c 0.9, CHCl ); IR (CHCl
456, 2973, 2937, 2854, 1609, 1510, 1469, 1456, 1357 cm ; H
1
27.0, 128.3, 128.8, 140.0, 172.0; MS (CI) m/z 414 (M + 1). Anal.
Calcd for C24 Si: C, 69.69; H, 8.52; N, 3.38. Found: C,
9.22; H, 8.36; N, 3.32.
2S)-3-[(ter t-Bu tyld im eth ylsila n yl)oxy]-2-(d iben zyla m i-
n o)p r op a n - 1-ol (13). To a solution of ester 12 (13.0 g, 31.5
mmol) in Et O (300 mL) were added LiBH (2.8 g, 125.9 mmol)
a m in o)bu ta n -3-ol (14b): [R]
D
3
3
)
H
35NO
3
-1 1
3
6
3
NMR (CDCl , 300 MHz) δ 0.10 (s, 3H), 0.12 (s, 3H), 0.95 (s, 9H),
(
1
.28 (d, J ) 6.8 Hz, 3H), 2.62 (td, J ) 5.4, 7.0 Hz, 1H), 3.15 (br
s, 1H, OH), 3.60, 3.90 (AB q, J ) 13.7 Hz, 4H), 3.9-4.1 (m, 3H),
2
4
7
6
3
.1-7.3 (m, 10H); C NMR (CDCl
1.3, 62.7, 68.7, 126.9, 128.3, 128.8, 139.8; MS (EI) m/z 399, 384,
54. Anal. Calcd for C24 Si: C, 72.13; H, 9.27; N, 3.51.
13
) δ -4.9, 18.1, 21.5, 25.8, 55.2,
3
and MeOH (5 mL) at 0 °C. The reaction mixture was then
heated to reflux for 3 h and quenched by addition of saturated
H
37NO
2
NH
and the combined organic phases were washed with brine, dried
over Na SO , and concentrated under reduced pressure. The
4
Cl solution. The aqueous phase was extracted with EtOAc,
Found: C, 72.22; H, 9.09; N, 3.25.
2R,3S)-1-[(ter t-Bu tyld im eth ylsila n yl)oxy]-2-(d iben zyl-
am in o)-3-ph en ylpr opan -3-ol (14c): [R] ) -15° (c 0.9, CHCl );
IR (CHCl ) 3459, 3022, 2964, 2924, 2868, 1609, 1504, 1499, 1447
cm ; H NMR (CDCl , 250 MHz) δ 0.10 (s, 3H), 0.12 (s, 3H),
.01 (s, 9H), 1.60 (brs, 1H, OH), 2.98 (td, J ) 5.0, 7.1 Hz, 1H),
.61, 3.72 (AB q, J ) 13.7 Hz, 4H), 4.00 (d, J ) 5.0 Hz, 2H),
(
2
4
D
3
crude product was purified by filtration through a short pad of
3
silica gel (eluent: heptane/EtOAc ) 10/1) to give compound 13
-1
1
3
(
2
12.0 g, 99%): [R]
D
) -64° (c 0.4, CHCl
3
-
); IR (CHCl
3
) 3465, 2959,
1
3
4
-
1
1 1
931, 2868, 1497, 1455, 1258, 1103 cm ; H NMR (CDCl , 300
3
MHz) δ 0.10 (s, 3H), 0.11 (s, 3H), 0.90 (s, 9H); 2.80 (brs, 1H,
OH), 2.95 (m, 1H), 3.4-3.5 (m, 2H), 3.56 (d, J ) 13.4, 2H), 3.65
13
.98 (d, J ) 7.1 Hz, 1H), 7.0-7.3 (m, 15H); C NMR (CDCl
5.0, 18.2, 26.0, 55.3, 62.0, 62.5, 74.7, 126.9, 127.2, 127.4, 128.1,
28.3, 128.7, 128.8, 139.9, 143.4; MS (EI) m/z 461, 446, 404, 354.
Anal. Calcd for C29 Si: C, 75.44; H, 8.51; N, 3.03.
Found: C, 75.24; H, 8.40; N, 2.80.
2R,3S)-1-[(ter t-Bu tyld im eth ylsila n yl)oxy]-2-(d iben zyl-
a m in o)h ep ta n -3-ol (14d ). Cerium chloride (CeCl ‚7H O) (480
mg, 1.3 mmol) was placed in a two-necked flask and was heated
3
) δ
(
dd, J ) 5.7, 10.6 Hz, 1H), 3.75 (dd, J ) 6.1, 10.6 Hz, 1H), 3.81
13
(d, J ) 13.4 Hz, 2H), 7.1-7.3 (m, 10H); C NMR (CDCl
3
) δ -5.5,
H
39NO
2
1
8.2, 26.0, 54.1, 59.5, 59.7, 61.0, 127.1, 128.4, 129.0, 139.6; MS
(
(39) Beugelmans, R.; Singh, G. P.; Bois-Choussy, M.; Chastanet, J .;
3
2
Zhu, J . J . Org. Chem. 1994, 59, 5535-5542.

Notes
J . Org. Chem., Vol. 63, No. 5, 1998 1713
in vacuo at 140 °C for 3 h until the weight became consistent to
Hz, 3H), 0.82 (s, 9H), 0.89 (d, J ) 6.6 Hz, 3H), 1.85 (d of septet,
J ) 6.6, 10.4 Hz, 1H), 3.01 (m, 1H), 3.21 (dd, J ) 5.9, 10.4 Hz,
formula CeCl
3
. After being cooled to room temperature, dry THF
(5 mL) was added and cooled to -78 °C. To this suspension was
1H), 3.22 (dd, J ) 4.9, 10.4 Hz, 1H), 3.58 (dd, J ) 6.5, 10.4 Hz,
1
added butyllithium (1.6 M in heptane, 812 µL) with stirring.
Stirring was continued for another 1 h, and crude aldehyde
obtained by standard Swern oxidation of alcohol 13 (231 mg,
1H), 5.35 (brs, 1H, NH); H NMR (CDCl
3
, 250 MHz) δ -0.05 (s,
6H), 0.88 (s, 9H), 0.99 (d, J ) 6.6 Hz, 3H), 1.06 (d, J ) 6.6 Hz,
3H), 1.9-2.0 (m, 1H), 3.51 (dd, J ) 8.7, 10.5 Hz, 1H), 3.6-3.8
1
3
0
.6 mmol) in Et
2
O (2 mL) was added. The reaction course was
(m, 2H), 4.08 (dd, J ) 6.2, 10.5 Hz, 1H), 5.4 (br s, 1H, NH);
NMR (CDCl
161.0; MS (CI) m/z 274 [M + 1] , 259. Anal. Calcd for C13
NO Si: C, 57.10; H, 9.95; N, 5.12. Found: C, 56.87; H, 9.62; N,
5.36.
C
monitored by TLC, and once all the starting material (aldehyde)
was consumed (2 h), the reaction was quenched by addition of
3
) δ -5.4, 18.2, 19.0, 19.9, 25.9, 27.5, 56.7, 61.5, 84.4,
+
27
H -
saturated aqueous NH
extracted with EtOAc, and the combined organic extracts were
washed with brine, dried over Na SO , and concentrated under
4
Cl solution. The aqueous solution was
3
2
4
(4S,5S)-5-Isop r op yl-2-oxooxa zolid in e-4-ca r boxylic Acid
(17). To a solution of compound 16 (311 mg, 1.14 mmol) in
acetone (5 mL), cooled at 0 °C, was added potassium fluoride
(132 mg, 2.28 mmol) and J ones reagent (8 N, 853 mL). After
being stirred at 0 °C for 6 h, the reaction was quenched by
dropwise addition of 2-propanol at the same temperature, and
stirring was continued for another 30 min. The reaction mixture
reduced pressure. Flash chromatography on silica gel (eluent:
heptane/EtOAc ) 15/1 then 10/1) afforded the amino diol 14d
(
2
198.5 mg, 75%): [R]
D
3 3
) -43° (c 0.4, CHCl ); IR (CHCl ) 3456,
-
1 1
956, 2925, 2850, 1606, 1500, 1468, 1443, 1368, 1250 cm ; H
3
NMR (CDCl , 250 MHz) δ 0.10 (s, 3H), 0.11 (s, 3H), 0.91 (s, 9H),
0
.92 (t, J ) 6.5 Hz, 3H), 1.2-1.4 (m, 5H), 1.75 (m, 1H), 2.65 (td,
J ) 5.4, 7.1 Hz, 1H), 3.0 (br s, 1H, OH), 3.62, 3.88 (AB q, J )
3.7 Hz, 4H), 3.90 (m, 1H), 4.00 (m, 2H), 7.0-7.3 (m, 10H); 13
NMR (CDCl ) δ -4.9, 14.4, 18.4, 23.1, 26.2, 28.0, 35.0, 55.7, 61.5,
1.7, 72.6, 127.3, 128.6, 128.8, 140.4; MS (EI) m/z 441, 426, 384,
54. Anal. Calcd for C27 Si: C, 73.47; H, 9.81; N, 3.17.
was diluted with saturated NaHCO solution, the volatiles were
3
1
C
removed in vacuo, and the aqueous phase was extracted with
EtOAc to remove all the neutral species. The aqueous phase
was then acidified to pH ) 2 and extracted again with EtOAc.
The combined organic extracts were washed with brine, dried
over Na SO , and concentrated under reduced pressure to give
3
6
3
H
43NO
2
Found: C, 73.77; H, 9.73; N, 3.47.
4R,5S)-4-[(ter t-Bu tyld im eth ylsila n yl)oxy]m eth yl]-5-iso-
p r op yloxa zolid in -2-on e (16). A solution of compound 14a
1.03 g, 2.41 mmol) in methanol was hydrogenated in the
presence of 10% of Pearlman’s catalyst [Pd(OH) ] at 1 atm. After
2
4
(
analytically pure acid 17 (142 mg, 72%): mp 170 °C; [R] )
D
+16.1° (c 0.18, MeOH) [lit.10b ) +16.9 (c 1.95, MeOH)];
1
H NMR
(
(CD OD, 200 MHz) δ 1.02 (d, J ) 6.5 Hz, 3H), 1.05 (d, J ) 6.5
3
Hz, 3H), 1.95 (m, 1H), 4.40 (m, 2H); 13C NMR (CD OD, 250 MHz)
2
3
being stirred vigorously for 1 h, the reaction mixture was filtered
through a short pad of Celite and washed thoroughly with
MeOH. The filtrate was evaporated to give compound 15, which
19.4, 30.8, 59.6, 85.8, 162.5, 173.2; MS (CI) m/z 174 [M + 1]
Anal. Calcd for C H NO : C, 48.55; H, 6.40; N, 8.08. Found:
+
.
7
11
4
C, 48.41; H, 6.26; N, 7.86.
2S,3S)-â-Hyd r oxyleu cin e (2). A solution of compound 17
500 mg, 2.89 mmol) in concentrated HCl (20 mL) was refluxed
for 40 h, and evaporation of the volatile gave pure product 2 as
was used without further purification: [R]
MeOH); IR (CHCl ) 3690, 3466, 2397, 1602, 1236, 843 cm ; H
NMR (CD OD, 200 MHz) δ 0.10 (s, 6H), 0.9-1.0 (m, 15H), 1.85
m, 1H), 2.80 (ddd, J ) 3.8, 6.7, 7.8 Hz, 1H), 3.19 (dd, J ) 5.3,
D
) +10° (c 0.5,
(
-
1 1
3
(
3
(
10c
hydrochloride salt (453 mg, 85%): [R]
D
) +39° (c 0.1 H
2
O), [lit.
6
.7 Hz, 1H), 3.52 (dd, J ) 7.8, 9.8, 1H), 3.85 (dd, J ) 3.8, 9.8
+37° (c 0.9, 1 N HCl)]; IR (KBr) 3130-3160, 1740, 1647 cm-1;
)
1
1
Hz, 1H); H NMR (CDCl
.90 (d, J ) 6.6 Hz, 3H), 0.98 (d, J ) 6.6 Hz, 3H), 1.75 (septet,
J ) 6.6 Hz, 1H), 2.98 (dt, J ) 4.4, 6.7 Hz, 1H), 3.1-3.2 (m, 4H,
3
, 300 MHz) δ 0.05 (s, 6H), 0.87 (s, 9H),
H NMR (CD OD, 300 MHz) δ 0.95 (d, J ) 6.5 Hz, 3H), 0.99 (d,
3
0
J ) 6.5 Hz, 3H), 2.04 (m, 1H), 3.42 (dd, J ) 8.5, 2.8 Hz, 1H),
13
4
5
3
.01 (d, J ) 2.8 Hz, 1H); C NMR (CD OD) δ 19.4, 20.0, 32.0,
1
4
3
CH + NH
.2, 10.1 Hz, 1H); 1 C NMR (CDCl
0.5, 53.5, 64.2, 79.0; MS (EI) m/z 232 [M - 15] , 204, 190. To
2
+ OH), 3.63 (dd, J ) 6.7, 10.1 Hz), 3.69 (dd, J )
+
6.8, 77.5, 169.5; MS (CI) m/z 149 [M + 1] .
3
3
) δ -5.4, 18.0, 18.6, 19.2, 25.9,
+
Ackn owledgm en t. Financial support from the CNRS
and a doctoral fellowship from “Ligue National Contre
le Cancer” to T.L. are gratefully acknowledged.
the solution of so obtained amino alcohol in THF were added
carbonyldiimidazole (CDI, 507.5 mg, 3.13 mmol) and a catalytic
amount of DMAP (0.24 mol, 29.4 mg). After being stirred at
room temperature for 15 h, the reaction mixture was diluted
with saturated aqueous NH
was extracted with EtOAc, and the combined organic extracts
were washed with brine, dried over Na SO , and concentrated
under reduced pressure. Flash chromatography on silica gel
eluent: heptane/EtOAc ) 3/1 then 2/1) afforded the oxazolidi-
none 16 (559.2 mg, 85%): [R] ) +65° (c 0.2, CHCl ); IR (CHCl
683, 2960, 2931, 1757, 1468, 1391, 1103, 836 cm ; H NMR
, 250 MHz) δ -0.05 (s, 3H), -0.04 (s, 3H), 0.48 (d, J ) 6.6
4
Cl solution. The aqueous solution
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 2, 7, 13, and 15 (4 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page of
ordering information.
2
4
(
D
3
3
)
-
1
1
3
(C
6
D
6
J O971468W