Preparation and synthetic applications of (S)- and (R)-N-boc-N, O- isopropylidene-α-methylserinals: Asymmetric synthesis of (S)- and (R)-2- amino-2-methylbutanoic acids (Iva)

Article abstract of DOI:10.1021/jo990957o

This report describes an efficient and convenient large-scale synthesis procedure for (S)- and (R)-N-Boc-α-methylserinal acetonides (3 and 4) starting from (R)-2-methylglycidol 5. The application of both of these compounds as valuable chiral building blocks in the asymmetric synthesis of α-methylamino acids is also demonstrated by the synthesis of (S)- and (R)- isovalines (Iva) (6 and 7).

Full text of DOI:10.1021/jo990957o

8220
J . Org. Chem. 1999, 64, 8220-8225
P r ep a r a tion a n d Syn th etic Ap p lica tion s of (S)- a n d
(R)-N-Boc-N,O-isop r op ylid en e-r-m eth ylser in a ls: Asym m etr ic
Syn th esis of (S)- a n d (R)-2-Am in o-2-m eth ylbu ta n oic Acid s (Iva )†
Alberto Avenoza,*,‡ Carlos Cativiela,*,§ Francisco Corzana,‡ J esu´s M. Peregrina,‡ and
Mar´ıa M. Zurbano‡
Departamento de Quı´mica (Quı´mica Orga´nica), Universidad de La Rioja, 26001 Logron˜o, Spain, and
Departamento de Quı´mica Orga´nica, Instituto de Ciencia de Materiales de Arago´n,
Universidad de Zaragoza-C.S.I.C., 50009 Zaragoza, Spain
Received J une 14, 1999
This report describes an efficient and convenient large-scale synthesis procedure for (S)- and (R)-
N-Boc-R-methylserinal acetonides (3 and 4) starting from (R)-2-methylglycidol 5. The application
of both of these compounds as valuable chiral building blocks in the asymmetric synthesis of
R-methylamino acids is also demonstrated by the synthesis of (S)- and (R)-isovalines (Iva) (6 and
7).
In tr od u ction
Recently, several studies on the synthesis of these
aldehydes have been reported4 since the development of
a convenient large-scale procedure is crucial to their
broad use in synthesis.
In recent years, there has been a growing interest in
chiral N-protected R-amino aldehydes because of their
wide utility in organic synthesis.1 In particular, (S)-N-
Boc-N,O-isopropylidene serinal (1), known as Garner’s
aldehyde,2 and its enantiomer 2 are of special interest,
owing to their ready availability from natural sources (L-
serine) and their pronounced versatility in stereocon-
trolled organic synthesis as chiral building blocks.3
As a part of our research project on the asymmetric
synthesis of R-amino acids, we have exploited the behav-
ior of L-serinal 1 as a chiral starting material to synthe-
size bis(R-amino acids),5 and we have also described two
straightforward synthetic routes for the preparation of
enantiomerically pure D-serinal 2 starting from naturally
occurring L-serine.6 In this context, and taking into
account the special role that R-alkylamino acids7 have
played in the design of peptides with enhanced proper-
ties,8 we have focused our attention on the stereoselective
synthesis of R-methylamino acids. Indeed, one of us has
recently published9 the synthesis of the homologue of
serinal 1, the (S)-R-methyl derivative 3, which can be
regarded as an ideal precursor for the synthesis of
R-methylamino acids. The synthesis of (S)-R-methylseri-
nal 3 was achieved on a milligram scale starting from
(S)-R-methylserine by using a procedure similar to that
described for the synthesis of Garner’s aldehyde.2,4
† Dedicated to Professor J ose´ Elguero on the occasion of his 65th
birthday.
‡ Universidad de La Rioja.
§ Universidad de Zaragoza.
(1) J urczak, J .; Golebiowski, A. Chem. Rev. 1989, 89, 149-164.
(2) (a) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361-2364.
(b) Garner, P.; Park, J . M. Org. Synth. 1992, 70, 18-27.
(3) For an extensive list on asymmetric reactions with L-serinal 1,
see: (a) Herold, P. Helv. Chim. Acta 1988, 71, 354-362. (b) Garner,
P.; Park, J . M.; Malecki, E. J . Org. Chem. 1988, 53, 4395-4398. (c)
Kahne, D.; Yang, D.; Lee, M. D. Tetrahedron Lett. 1990, 31, 21-22.
(d) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P. J . Org. Chem.
1990, 55, 1439-1446. (e) Ibuka, T.; Habashita, H.; Otaka, A.; Fujii,
N.; Oguchi, Y.; Uyehara, T.; Yamamoto, Y. J . Org. Chem. 1991, 56,
4370-4382. (f) Coleman, R. S.; Carpenter, A. J . Tetrahedron Lett. 1992,
33, 1697-1700. (g) Boyd, E. C.; Paton, R. M. Tetrahedron Lett. 1993,
34, 3169-3172. (h) Blake, A. J .; Boyd, E. C.; Gould, R. O.; Paton, R.
M. J . Chem. Soc., Perkin Trans. 1 1994, 2841-2847. (i) Soai, K.;
Takahashi, K. J . Chem. Soc., Perkin Trans. 1 1994, 1257-1258. (j)
Lee, C. S.; Forsyth, C. J . Tetrahedron Lett. 1996, 37, 6449-6452. (k)
Hanessian, S.; Wang, W.; Gai, Y. Tetrahedron Lett. 1996, 37, 7477-
7480. (l) Kauppinen, P. M.; Koskinen, A. M. P. Tetrahedron Lett. 1997,
38, 3103-3106. (m) Mordini, A.; Valacchi, M.; Nardi, C.; Bindi, S.; Poli,
G.; Reginato, G. J . Org. Chem. 1997, 62, 8557-8559. (n) Deng, L.;
Scha¨rer, O. D.; Verdine, G. L. J . Am. Chem. Soc. 1997, 119, 7865-
7866. (o) Hertweck, C.; Goerls, H.; Boland, W. Chem. Commun. 1998,
1955-1956. (p) Villard, R.; Fotiadu, F.; Buono, G. Tetrahedron:
Asymmetry 1998, 9, 607-611. (q) Imashiro, R.; Sakurai, O.; Yamashita,
T.; Horikawa, H. Tetrahedron 1998, 54, 10657-10670. For an extensive
list on asymmetric reactions with D-serinal 2, see: (a) Garner, P.
Tetrahedron Lett. 1984, 25, 5855-5858. (b) Garner, P.; Park, J . M. J .
Org. Chem. 1988, 53, 2979-2984. (c) J ako, I.; Uiber, P.; Mann, A.;
Wermuth, C.-G.; Boulanger, T.; Norberg, B.; Evrard, G.; Durant, F. J .
Org. Chem. 1991, 56, 5729-5733. (d) Raghavan, S.; Ishida, M.;
Shinozaki, H.; Nakanishi, K.; Ohfune, Y. Tetrahedron Lett. 1993, 34,
5765-5768. (e) Kan, T.; Ohfune, Y. Tetrahedron Lett. 1995, 36, 943-
946. (f) Han, B. H.; Kim, Y. C.; Park, M. K.; Park, J . H.; Go, H. J .;
Yang, H. O.; Suh, D.-Y.; Kang, Y.-H. Heterocycles 1995, 41, 1909-
1914. (g) Ageno, G.; Banfi, L.; Cascio, G.; Guanti, G.; Manghisi, E.;
Riva, R.; Rocca, V. Tetrahedron 1995, 51, 8121-8134. (h) D′Aniello,
F.; Falorni, M.; Mann, A.; Taddei, M. Tetrahedron: Asymmetry 1996,
7, 1217-1226. (i) Garner, P.; Yoo, J . U.; Sarabu, R.; Kennedy, V. O.;
Youngs, W. J . Tetrahedron 1998, 54, 9303-9316.
In this paper, we now describe a new and more
convenient synthesis procedure for (S)-R-methylserinal
3 on a gram scale, starting from commercially available
(4) (a) McKillop, A.; Taylor, R. J . K.; Watson, R. J .; Lewis, N.
Synthesis 1994, 31-32. (b) Meffre, P.; Durand, P.; Branquet, E.; le
Goffic, F. Synth. Commun. 1994, 24, 2147-2152. (c) Williams, L.;
Zhang, Z.; Shao, F.; Carroll, P. J .; J oullie´, M. M. Tetrahedron 1996,
52, 11673-11694. (d) Dondoni, A.; Perrone, D. Synthesis 1997, 527-
529. (e) Ravi Kumar, J . S.; Datta, A. Tetrahedron Lett. 1997, 38, 6779-
6782.
(5) (a) Avenoza, A.; Cativiela, C.; Peregrina, J . M.; Zurbano, M. M.
Tetrahedron: Asymmetry 1996, 7, 1555-1558. (b) Avenoza, A.; Cat-
iviela, C.; Peregrina, J . M.; Zurbano, M. M. Tetrahedron: Asymmetry
1997, 8, 863-871.
(6) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J . M.; Zurbano,
M. M. Synthesis 1997, 1146-1150.
10.1021/jo990957o CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/08/1999

(S)-, (R)-N-Boc-N,O-isopropylidene-R-methylserinals
J . Org. Chem., Vol. 64, No. 22, 1999 8221
Sch em e 1
Sch em e 2
(R)-2-methylglycidol (5). Moreover, we report the syn-
thesis, also starting from the same compound 5, of the
enantiomer of (S)-R-methylserinal 3, (R)-N-Boc-N,O-
isopropylidene-R-methylserinal (4). Furthermore, we dem-
onstrate the synthetic utility of both compounds (3 and
4) as chiral building blocks by carrying out the synthesis
of both (S)- and (R)-2-amino-2-methylbutanoic acids (6
and 7) (Iva) (Scheme 1).
We selected (S)- and (R)-isovaline to prove the ap-
plicability of this method for the synthesis of the R-me-
thylamino acids because of the significance that L- and
D-Iva have attained in the past few years.10 For example,
a large number of studies have focused on these amino
acids, particularly on D-Iva (also denoted by the letter
code J ), which is an important nonstandard constituent
of a family of polypeptides known as peptaibols.11 Pep-
taibols generally exhibit antimicrobial activity and are
referred to as antibiotic peptides. The antimicrobial
activity of the peptaibols is thought to arise from their
ability to form helical ion channels in lipid membranes.
The channels so formed are able to conduct ionic species,
leading to the loss of osmotic balance and cell death. After
searching in The Peptaibol Database12 for query J , we
found 67 peptides that incorporate the Iva residue.13
clearly needed if it were to be the starting material for a
practical synthesis of R-methylamino acids.
As shown in Scheme 2, the new synthesis starts with
commercially available (R)-2-methylglycidol (5) of 94%
ee,14 which was transformed into the corresponding
compound 8 according to the protocol described in the
literature.15 Et2AlCl-catalyzed cyclization of the trichlo-
roacetimidate derivative of 5, followed by pivaloylation,
acid hydrolysis of the oxazoline ring, and further tert-
butoxycarbonylation, gave alcohol 8 and an overall yield
of 75% from 5. After recrystallization from hexane,
compound 8 was converted into oxazolidine 9 by the use
of 2,2-dimethoxypropane (DMP) in acetone at room
temperature with boron trifluoride etherate as cata-
lyst.4a,6,16 The cleavage of the pivaloate ester in compound
9 was achieved in good yield by reduction with DIBAL-
H17 to give alcohol 10. This product was pure enough for
use in the next step (94% ee14); it was therefore oxidized
under Swern conditions6,18 to obtain the required (S)-R-
methylserinal 3. In this way, building block 3 was
prepared on a gram scale and in three steps with an
overall yield of 82% from alcohol 8 (or in seven steps with
a 61% yield from commercially available glycidol 5)
(Scheme 2).
(R)-N-Boc-N,O-isopr opyliden e-r-m eth ylser in al (4).
With the aim of obtaining large amounts of 4, the
building block enantiomer of 3, to produce the opposite
configuration of the reaction products derived from its
synthetic application (R-methylamino acids, for example),
we developed a straightforward and stereodivergent
synthetic route from compound 5. The same glycidol 5
was used as the source of chirality, because its enanti-
omer is not commercially available. Glycidol 5 was again
transformed into compound 8, but the hydroxyl group of
this compound was now protected with tert-butyldiphe-
nylsilyl chloride (TBDPSCl) (1.3 equiv) using dichlorome-
tane as solvent, to give compound 11 in a 60% yield, as
shown in Scheme 3. To improve the synthetic method by
attempting to increase the yield, DMF was used instead
of dichloromethane and an excess of 2 equiv of silylating
agent was added; an 85% yield was achieved.
Resu lts a n d Discu ssion
(S)-N-Boc-N,O-isopr opyliden e-r-m eth ylser in al (3).
Because the reported preparation9 of 3 uses five steps
and gives only 33% yield from (S)-R-methylserine, which
is not commercially available, and because 3 was ob-
tained only on a milligram scale, a better synthesis was
(7) (a) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2708-2748. (b) Wirth, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 225-227. (c) Cativiela, C.; D´ıaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 1998, 9, 3517-3599.
(8) (a) Mossel, E.; Formaggio, F.; Toniolo, C.; Crisma, M.; Boesten,
W. H. J .; Broxterman, Q. B.; Kamphuis, J .; Quaedflieg, P. J .; Temussi,
P. Tetrahedron: Asymmetry 1997, 8, 1305-1314 and references
therein. (b) Bellier, B.; McCort-Tranchenpain, I.; Ducos, B.; Danasci-
mento, S.; Meudal, H.; Noble, F.; Garbay, C.; Roques, B. P. J . Med.
Chem. 1997, 40, 3947-3956.
(9) Al´ıas, M.; Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J . A.;
Lapen˜a, Y. Tetrahedron 1998, 54, 14963-14974.
(10) (a) Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J . A. Tetra-
hedron: Asymmetry 1993, 4, 1445-1448. (b) Formaggio, F.; Crisma,
M.; Bonora, G. M.; Pantano, M.; Valle, G.; Toniolo, C.; Aubry, A.;
Bayeul, D.; Kampuis, J . Pept. Res. 1995, 8, 6-15. (c) J aun, B.; Tanaka,
M.; Seiler, P.; Ku¨hnle, F. N. M.; Braun, C.; Seebach, D. Liebigs Ann.
1997, 1697-1710.
In this case, the cleavage of the pivaloate ester in
compound 11 was achieved only in 71% yield by reduction
(14) Determined by 1H or 19F NMR (300 MHz) analysis of the
corresponding (R)- or (S)-R-methoxy-R-(trifluoromethyl)phenylacetates.
(15) Hatekayama, S.; Matsumoto, H.; Fukuyama, H.; Makugi, Y.;
Irie, H. J . Org. Chem. 1997, 62, 2275-2279.
(16) Moriwake, T.; Hamano, S. I.; Saito, S.; Torii, S. Chem. Lett.
1987, 2085-2088.
(17) (a) Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453-461.
(b) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: New York, 1991. (c) Kocienski, P. J . Protecting
Groups; George Thieme Verlag: Stuttgart, 1994.
(11) J ung, G.; Bru¨ckner, H.; Schmitt, H. In Structure and Activity
of Natural Peptides; Voelter, W., Weitzel de Gruyter, G., Eds.; Berlin,
1981; p 75.
(12) The Peptaibol Database. A World Wide Web resource currently
found at http://www.cryst.bbk.ac.uk/peptaibol/welcome.html; Whitmore
L., Snook C. F., Wallace B. A., 1997
(13) (a) Rebuffat, S.; Goulard, C.; Bodo, B. J . Chem. Soc., Perkin
Trans. 1 1995, 1849-1855 and references therein. (b) Chikanishi, T.;
Hasumi, K.; Harada, T.; Kawasaki, N.; Endo, A. J . Antibiot. 1997, 50,
105-110.
(18) (a) Tidwell, T. T. Synthesis 1990, 857-870. (b) Roush, W. R.;
Hunt, J . A. J . Org. Chem. 1995, 60, 798-806.

8222 J . Org. Chem., Vol. 64, No. 22, 1999
Avenoza et al.
Sch em e 3
olefin 15 in 93% yield. Hydrogenation of this compound
was completed in 12 h using palladium on carbon as a
catalyst and ethyl acetate as a solvent at room temper-
ature to give oxazolidine 16.
Starting from this compound, our initial plan was to
obtain the corresponding R-methylamino acid 6 in one
step by trying J ones oxidation20 because we thought that
under the acid conditions of this reaction (sulfuric acid)
cleavage of the acetonide moiety and hydrolysis of the
N-Boc would take place. Unfortunately, after 6 h at room
temperature no reaction was observed. As an alternative,
we chose first to cleave the acetonide of 16 by Lewis acid
hydrolysis, employing TsOH, but once again the reaction
did not progress. When boron trifluoride-acetic acid
complex was used under the standard conditions de-
scribed in the literature4c,21 (BF3‚AcOH, MeOH, 0 °C) once
again no reaction occurred after 12 h, so we had to carry
out the reaction at room temperature to give compound
17 in 60% yield after 12 h. All attempts to improve the
yield by increasing the temperature were unsuccessful,
because at 40 °C we observed deprotection of the N-Boc
group. Taking into account that the cleavage of the
acetonide moiety of 16 would not provide an acceptable
yield, we decided to try using Sc(OTf)3 (10 mol %) as a
Lewis acid catalyst,19 and we then obtained compound
17 in an almost quantitative yield after 24 h at 25 °C.
The reaction temperature is critical to the success of the
reaction, because at 40 °C we observed deprotection of
the N-Boc group.
with DIBAL-H17 to give alcohol 12. Once again, to
increase this yield we examined the basic hydrolysis of
the ester group. However, because the cleavage of this
function requires strong basic reagents (0.25 N NaOH,
12 h, rt or K2CO3/MeOH, 12 h, rt), which were incompat-
ible with the other protecting group (TBDPS), we ob-
tained the corresponding symmetric diol as the sole
product.
Starting from compound 12, the acetonide formation
in compound 13 occurred without hydrolysis of the O-Si
bond in the same conditions as described above for
compound 9 but now only in a 63% yield. However, when
the acetonide formation was carried out using DMP in
toluene as a solvent with p-toluenesulfonic acid (TsOH)
as a catalyst, at reflux, we obtained 13 in a 94% yield.
This compound was desilylated by treatment with tet-
rabutylammonium fluoride (TBAF‚3H2O) to give alcohol
14 in 88% yield, because the use of other recent proce-
dures to cleave silyl ethers was unsuccessful. In this
sense, attempts to desilylate 13 under acidic conditions
(Sc(OTf)3; H2O, MeCN)19 failed.
Alcohol 17 was converted into (R)-Iva (6) as follows. It
was oxidized by treatment with J ones reagent to give the
corresponding protected amino acid, which was then
subjected to hydrolysis using a mixture of concentrated
HCl and THF at room temperature. Liberation of the
amino acid from its hydrochloride salt was then achieved
by treating with propylene oxide in ethanol at reflux to
furnish (R)-Iva (6) in high yield. The spectral data and
optical activity of this compound proved to be identical
to that previously reported.10
Finally, the oxidation of alcohol 14 under Swern
conditions6,18 was completed to give the required building
block (R)-R-methylserinal acetonide 4 in 96% yield (48%
overall yield from alcohol 8, using five steps).
The enantiomer of (R)-Iva, (S)-Iva (7), was obtained
using the same strategy but starting from (R)-R-meth-
ylserinal 4, which was transformed into olefin 18, as
shown in Scheme 4. Hydrogenation of 18 gave oxazolidine
19, and the subsequent cleavage of its acetonide moiety
allowed the synthesis of alcohol 20, the direct precursor
of the desired amino acid 7, whose spectral data were
identical to that previously obtained for amino acid 6 but
with an optical rotation of opposite sign.
Syn th esis of (R)- a n d (S)-Isova lin e. Starting from
(S)-R-methylserinal 3 and (R)-R-methylserinal 4 and
using five steps, we obtained both enantiomers of Iva
with an excellent overall yield (61%) (Scheme 4).
Although Wittig methylenation of R-amino aldehydes
has been reported to be problematic because racemization
occurs during the reaction,4a,16,20 in our case, this fact did
not represent a problem because 3 and 4 are quaternary
amino aldehydes. We therefore investigated two olefina-
tion methods. The first of these was based on the use of
the zinc/methylene iodide/trimethylaluminum reagent,
which gave optically pure material 15 in 80% yield. The
second method proved to be more effective; the olefination
was carried out under salt-free Wittig conditions using
methyltriphenylphosphonium bromide and potassium
bis(trimethylsilyl)amide (KHMDS) as base, providing
Deter m in a tion of En a n tiom er ic P u r ity. The opti-
cal purity of starting material 5, purchased from Lan-
caster, was determined by preparation of its Mosher
esters (Scheme 5). According to the protocol described in
the literature,2a,22 glycidol 5 was coupled with (R)-(+)-
methoxytrifluorophenylacetic acid [(R)-(+)-MTPA] in the
presence of DCC and DMAP to give the Mosher ester 21.
1
Analysis of the H NMR spectra of ester 21 showed that
the enantiomeric purity of compound 5 was 94%. In any
case, to be sure that compound 5 was almost enantio-
merically pure, we determined the cross-contamination
by conversion of this compound to its Mosher ester
derivative 22, coupling 5 in the same conditions with (S)-
(-)-methoxytrifluorophenylacetic acid [(S)-(-)-MTPA].
(19) Sc(OTf)3 was discovered by Kobayashi et al. to be a new type
of water-soluble Lewis acid (Kobayashi, S.; Hachiya, I.; Araki, M.;
Ishitani, H. Tetrahedron Lett. 1993, 34, 3755-3758), and convenient
procedures for deprotection of silyl ethers using a catalytic amount of
Sc(OTf)3 have been developed (Kobayashi, S.; Oriyama, T,; Noda, K.
Synlett. 1998, 1047-1048).
(21) Williams, L.; East, S. P.; Shao, F.; J oullie´, M. M. Tetrahedron
1998, 54, 13371-13390.
(22) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
(20) Beaulieu, P. L.; Duceppe, J .-S.; J ohnson, C. J . Org. Chem. 1991,
56, 4196-4204.

(S)-, (R)-N-Boc-N,O-isopropylidene-R-methylserinals
J . Org. Chem., Vol. 64, No. 22, 1999 8223
Sch em e 4
Sch em e 5
Con clu sion
We report a large scale and stereodivergent synthesis
of both enantiomers of (S)- and (R)-Garner’s aldehyde
homologues, the R-methyl derivatives 3 and 4, starting
from commercially available (R)-2-methylglycidol (5).
These compounds have proved to be valuable starting
materials in a new approach to the synthesis of both (S)-
and (R)-Iva.
Other applications of R-methylserinals 3 and 4 are
currently under investigation to explore the scope of their
behavior as building blocks in asymmetric synthesis of
R-methylamino acids.
The enantiomeric purity of the intermediates in the
synthesis of building blocks 3 and 4 was examined by
derivatization of alcohol intermediates 10 and 14. Be-
cause 10 and 14 are enantiomers, we only needed to use
(R)-(+)-MTPA to obtain diastereomers 23 and 24. In this
case, the analysis of their 19F NMR spectra showed that
the enantiomeric purity was 94% for both compounds.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected. All
manipulations with air-sensitive reagents were carried out
under a dry argon atmosphere using standard Schlenk tech-
niques. Solvents were purified according to standard proce-
dures. Lewis acids and other chemical reagents were pur-
chased from the Aldrich Chemical Co. or Acros Organics.
Analytical TLC was performed by using Polychrom SI F254
plates. Column chromatography was performed by using
Kieselgel 60 (230-400 mesh). Organic solutions were dried
over anhydrous Na2SO4 and, when necessary, were concen-
trated under reduced pressure using a rotary evaporator.
Optical rotations were measured in 1 and 0.5 dm cells of 1
and 3.4 mL capacity, respectively. Values for υmax (cm-1) of IR
spectra are given for the main absorption bands. Compound
8 was prepared according to procedures in the literature.15
NMR spectra were recorded at 300 (1H) and at 75 (13C) MHz
and are reported in ppm downfield from TMS. Mass spectra
were obtained by electron impact (EI) or electrospray ioniza-
tion (ESI) techniques. Nitrogen inversion in the oxazolidine
ring or slow interconversion of both amide or carbamate
conformers of compounds 3, 4, 9, 10, 13-16, 18, 19, 23, and
24 causes considerable line broadening and duplication of
signals in the 1H and 13C NMR spectra.
(S)-N-(ter t-Bu toxycar bon yl)-4-(pivaloyloxy)m eth yl-2,2,4-
tr im eth yl-3-oxa zolid in e (9). Alcohol 8 (3.61 g, 12.5 mmoL)
was dissolved in a mixture of acetone (50 mL) and DMP (15
mL), and then BF3‚OEt2 (0.1 mL) was added. The resulting
solution was stirred at room temperature for 2 h. The solvent
was removed, and the residual oil was taken up in CH2Cl2 (50
mL). The resulting solution was washed with a mixture of
saturated NaHCO3 and H2O (1:1 v/v, 30 mL) and then brine
(30 mL) and dried, and the solvent was evaporated to give a
yellow oil, which was purified by column chromatography
The enantiomeric purity of methylserinals 3 and 4 was
1
checked by means of H NMR, using an europium(III)
chelate as a chiral shift reagent (94% and >95% ee,
respectively). Different chemical shifts for the aldehyde
proton were observed when a 0.09 molar ratio of Eu(hfc)3/
substrate and a concentration of substrate of 0.2 mmol/
ml in deuterated chloroform at 20 °C were used.23 Thus,
1
no racemization could be detected by H NMR.
The optical rotation found for methylserinal 3 was near
to that previously described,9 and the optical rotation of
methylserinal 4 was identical to that found for 3 but
opposite in sign. Because the optical rotation value of
methylserinal 4 had not been previously reported, the
absolute configuration of this compound was confirmed
by converting serinal 3 and 4 to known Iva 6 and 7,
respectively. The absolute configurations of building
blocks 3 and 4 were thus confirmed as the (S)- and (R)-
forms, respectively.
The [R]25D values of Iva 6, [R]25D ) -10.8 (c 1.00, H2O),
and Iva 7, [R]25 ) +10.9 (c 1.00, H2O), confirmed their
D
chiral purity as well as the absolute configuration as-
signed to all compounds.
We were unable to use HPLC on the chiral phase24 to
determine the enantiomeric ratio of 6 and 7, as no
separation of both enantiomers could be achieved.
(hexane/ethyl acetate, 9:1) to give 9 (3.71 g, 90%) as a white
1
solid. Mp 44-45 °C. [R]25 ) -14.9 (c 1.54, CHCl3). H NMR
D
(CDCl3) δ 1.20, 1.21 (2s, 9H), 1.36, 1.44 (2s, 3H), 1.47 (s, 9H),
1.54, 1.58, 1.59 (3s, 6H), 3.66 (“t”, 1H, J ) 8.7 Hz), 3.93, 3.99
(2d, 1H, J ) 8.7, 9.0 Hz), 4.14, 4.18 (2d, 1H, J ) 8.1, 10.8 Hz),
4.22, 4.30 (2d, 1H, J ) 8.4, 10.5 Hz). 13C NMR (CDCl3) δ 20.2,
21.3, 25.0, 25.5, 26.2, 26.6, 27.1, 28.4, 38.8, 60.8, 61.7, 65.0,
65.5, 71.6, 72.0, 80.0, 80.2, 94.8, 95.8, 151.2, 151.4, 177.9, 178.0.
IR (CH2Cl2) 1725, 1691, 1390, 1376, 1368. MS(EI) (m/z) ) 41,
57, 114, 158, 214, 314. ESI+ (m/z) ) 330. Anal. Calcd for
(23) (3 + 4) without Eu(hfc)3 δ (HCdO): two singlets centered at
9.39 and 9.46 ppm, respectively, corresponding to duplication of signals.
(3 + 4) with Eu(hfc)3 δ (HCdO): two singlets centered at 9.78 and
9.95 ppm of (S)-isomer and two singlets at 9.79 and 9.89 ppm
corresponding to the splitting in the other isomer by the action of Eu-
(hfc)3.
(24) The HPLC analysis used columns with the chiral phases
Crownpak-CR(+) and Chiralcel-OD-H, purchased from Daicel Chemi-
cal.

8224 J . Org. Chem., Vol. 64, No. 22, 1999
Avenoza et al.
C17H31NO5: C, 61.98; H, 9.48; N, 4.25. Found: C, 62.57; H,
9.60; N, 4.16.
41, 56, 100, 181, 191, 211, 234, 312. ESI+ (m/z) ) 444. Anal.
Calcd for C25H37NO4Si: C, 67.68; H, 8.41; N, 3.16. Found: C,
67.49; H, 8.33; N, 3.23.
(R)-N-(ter t-Bu t oxyca r b on yl)-4-h yd r oxym et h yl-2,2,4-
tr im eth yl-3-oxa zolid in e (10). Compound 9 (3.57 g, 10.8
mmol) was dissolved in CH2Cl2 (50 mL), and the solution was
cooled to -78 °C before addition of DIBAL-H (1.0 M in CH2-
Cl2, 22.7 mL, 22.7 mmol). Stirring was continued for 12 h
before addition of MeOH (5 mL) and warming to room
temperature. The mixture was then poured into a solution of
potassium sodium tartrate (25.0 g) in H2O (75 mL), and the
biphasic mixture was stirred vigorously for 2 h. The phases
were separated, and the aqueous layer was extracted with
Et2O (2 × 50 mL). The combined organic extracts were dried
and evaporated to give 10 (2.52 g, 95%) as a white solid, which
(R)-N-(ter t-Bu toxyca r bon yl)-4-((ter t-bu tyld ip h en ylsi-
lyloxy)m eth yl)-2,2,4-tr im eth yl-3-oxa zolid in e (13). A solu-
tion of 12 (2.54 g, 5.70 mmol), DMP (1.19 g, 11.4 mmol), and
TsOH (11 mg, 0.06 mmol) in toluene (60 mL) was heated under
reflux for 2 h and then slowly distilled during 15 min to
eliminate the MeOH formed. After that, DMP (1.19 g, 11.4
mmol) was added, and the procedure was repeated twice. After
this time, the TLC showed no remaining starting material and
clean formation of a single product. The solvent was removed
to give a yellow oil, which was purified by column chromatog-
raphy (hexane/ethyl acetate, 19:1) to give 13 (2.59 g, 94%) as
1
was used without further purification. Mp 59-60 °C. [R]25
)
a white solid. Mp 71-73 °C. [R]25 ) +5.2 (c 1.02, CHCl3). H
D
D
1
+1.3 (c 1.99, CHCl3). H NMR (CDCl3) δ 1.43, 1.49, 1.56 (3s,
18H), 3.52-3.75 (m, 4H), 4.55, 4.57 (2brs, 1H). 13C NMR
(CDCl3) δ 19.5, 20.8, 25.2, 25.6, 27.1, 28.4, 64.6, 65.6, 67.7,
72.1, 80.9, 95.3, 153.4. IR (CH2Cl2) 3381, 1687, 1663, 1397,
1378, 1368. MS(EI) (m/z) ) 41, 57, 114, 130, 158, 214, 246.
ESI+ (m/z) ) 246. Anal. Calcd for C12H23NO4: C, 58.75; H,
9.45; N, 5.71. Found: C, 58.74, H, 9.53; N, 5.68.
NMR (CDCl3) δ 1.05, 1.06 (2s, 9H), 1.28, 1.51, 1.52 (3s, 9H),
1.37 (s, 3H), 1.48, 1.56 (2s, 6H), 3.55-3.75 (m, 2.6H), 4.05 (d,
0.4H, J ) 9.6 Hz), 4.20, 4.26 (2d, 1H, J ) 8.7 Hz), 7.30-7.45
(m, 6H), 7.58-7.73 (m, 4H). 13C NMR (CDCl3) δ 19.3, 20.1,
21.0, 25.1, 25.5, 26.0, 26.8, 27.1, 28.3, 28.5, 62.9, 63.9, 64.4,
66.1, 71.6, 72.2, 79.6, 94.8, 95.6, 127.6, 127.7, 129.6, 129.7,
133.2, 133.4, 135.6, 151.3, 151.7. IR (CH2Cl2) 1688, 1392, 1376,
1367. MS(EI) (m/z)) 42, 57, 97, 114, 368. ESI+ (m/z)) 484.
Anal. Calcd for C28H41NO4Si: C, 69.52; H, 8.54; N, 2.90.
Found: C, 69.62; H, 8.65; N, 2.87.
(S)-N-(ter t-Bu toxyca r bon yl)-4-for m yl-2,2,4-tr im eth yl-
3-oxa zolid in e (3). DMSO (2.23 g, 28.6 mmol) was added, at
-78 °C, to a solution of oxalyl chloride (2.18 g, 17.2 mmol) in
CH2Cl2 (30 mL). The resulting solution was stirred for 5 min
at -78 °C, and then a solution of 10 (3.52 g, 14.3 mmol) in
CH2Cl2 (30 mL) was added. The resulting mixture was stirred
for 15 min at -78 °C, and then Et3N (5.79 g, 57.2 mmol) was
added. The solution was allowed to warm to room temperature.
The reaction was quenched by addition of saturated NaHCO3
(70 mL) and then diluted with Et2O (70 mL). The phases were
separated, and the organic phase was washed with 1 M KHSO4
(30 mL), saturated NaHCO3 (30 mL), and brine (30 mL), dried,
filtered, and concentrated. The crude product was purified by
column chromatography (hexane/ethyl acetate, 9:1) to give 3
(S)-N-(ter t-Bu t oxyca r b on yl)-4-h yd r oxym et h yl-2,2,4-
tr im eth yl-3-oxa zolid in e (14). A solution of Bu4N+F-‚3H2O
(2.73 g, 8.68 mmol) in THF (20 mL) was added to a solution of
compound 13 (2.80 g, 5.83 mmol) in THF (30 mL) at room
temperature. The mixture was stirred for 24 h at room
temperature. After this time, the TLC showed no remaining
starting material. The solvent was removed to give a brown
solid, which was purified by column chromatography (hexane/
ethyl acetate, 4:1) to give 14 (1.23 g, 88%) as a white solid.
[R]25 ) -1.6 (c 1.99, CHCl3). Anal. Calcd for C12H23NO4: C,
D
58.75; H, 9.45; N, 5.71. Found: C, 58.68; H, 9.46; N, 5.71.
(R)-N-(ter t-Bu toxyca r bon yl)-4-for m yl-2,2,4-tr im eth yl-
3-oxa zolid in e (4). In a manner similar to that described for
its enantiomer 3, compound 4 (3.31 g, 96%) was obtained from
(3.34 g, 96%) as a white solid. Mp 54-55 °C. [R]25 ) -20.0 (c
D
2.13, CHCl3). 1H NMR (CDCl3) δ 1.30-1.70 (m, 18H), 3.65,
3.68 (2d, 1H, J ) 6.9 Hz), 3.92 (d, 1H, J ) 9.3 Hz), 9.39, 9.46
(2s, 1H). 13C NMR (CDCl3) δ 17.2, 18.1, 24.5, 25.5, 26.0, 26.9,
28.0, 28.2, 68.5, 68.9, 69.0, 69.2, 81.2, 81.3, 94.9, 96.0, 150.5,
151.7, 197.9, 198.4. IR (CH2Cl2) 1699, 1368, 1354. MS(EI) (m/
alcohol 14 (3.51 g, 14.3 mmol). [R]25 ) +19.2 (c 2.12, CHCl3).
D
Anal. Calcd for C12H21NO4: C, 59.24; H, 8.70; N, 5.76. Found:
C, 59.58; H, 8.68; N, 5.88.
z) ) 41, 57, 114, 214. ESI+ (m/z) ) 244. Anal. Calcd for C12H21
-
(R)-N-(ter t-Bu toxyca r bon yl)-2,2,4-tr im eth yl-4-vin yl-3-
oxa zolid in e (15). Methyltriphenylphosphonium bromide (4.98
g, 13.9 mmol) was suspended in THF (60 mL) at room
temperature, and KHMDS (0.5M in toluene, 27.9 mL, 13.9
mmol) was added. The resulting yellow suspension was stirred
at room temperature for 1 h and then cooled to -78 °C, and a
solution of aldehyde 3 (1.13 g, 4.6 mmol) in THF (20 mL) was
added dropwise. The cooling bath was removed, and the
mixture allowed to reach room temperature over 2 h and then
warmed to 35 °C for a further 12 h. The reaction was quenched
with MeOH (10 mL), and the resulting mixture was poured
into a solution of saturated potassium sodium tartrate and
H2O (1:1, v/v, 150 mL). Extraction with ethyl ether (2 × 75
mL), drying and evaporation of the solvent gave a pale yellow
syrup, which was purified by flash chromatography (hexane/
ethyl acetate, 4:1) to give 15 (1.03 g, 93%) as a colorless liquid.
NO4: C, 59.24; H, 8.70; N, 5.76. Found: C, 59.52; H, 8.76; N,
5.71.
(R)-2-((ter t-Bu toxycar bon yl)am in o)-3-((ter t-bu tyldiph e-
n ylsilyl)oxy)-2-m eth yl-1-(p iva loyloxy)p r op a n e (11). Al-
cohol 8 (2.05 g, 7.1 mmol) was dissolved in DMF (30 mL),and
TBDPSCl (3.90 g, 14.2 mmol) was added. The mixture was
cooled to 0 °C, and imidazole (0.97 g, 14.2 mmol) was added
portionwise over 5 min. The cooling bath was removed, and
the mixture was stirred for 48 h at 25 °C. The solvent was
removed, and the residual oil was taken up in ethyl acetate.
The resulting solution was washed with H2O (50 mL), dried,
filtered,and concentrated to give a colorless oil, which was
purified by column chromatography (hexane/ethyl acetate, 9:1)
to give 11 (3.18 g, 85%) as a colorless oil. [R]25D ) -1.9 (c 1.20,
1
CHCl3). H NMR (CDCl3) δ 1.07 (s, 9H), 1.14 (s, 9H), 1.34 (s,
3H), 1.42 (s, 9H), 3.60, 3.68 (2d, 2H, J ) 9.0 Hz), 4.22, 4.30
(2d, 2H, J ) 9.0 Hz), 4.78 (brs, 1H), 7.30-7.45 (m, 6H), 7.55-
7.70 (m, 4H). 13C NMR (CDCl3) δ 19.2, 19.3, 26.8, 27.1, 28.4,
38.8, 55.8, 65.2, 66.2, 79.1, 127.8, 129.8, 132.9, 135.5, 154.6,
177.9. IR (CH2Cl2) 1724. MS(EI) (m/z) ) 41, 57, 438. ESI+
(m/z) ) 528. Anal. Calcd for C30H45NO5Si: C, 68.27; H, 8.59;
N, 2.65. Found: C, 68.15; H, 8.51; N, 2.71.
[R]25 ) +5.0 (c 2.16, CHCl3). 1H NMR (CDCl3) δ 1.30-1.64
D
(m, 18H), 3.70 (d, 1H, J ) 8.7 Hz), 3.80 (d, 1H, J ) 8.7 Hz),
5.00-5.20 (m, 2H), 5.80-6.04 (m, 1H). 13C NMR (CDCl3) δ
21.0, 21.8, 24.9, 25.6, 26.1, 26.8, 28.3, 62.9, 63.5, 74.6, 75.0,
79.6, 79.8, 94.6, 95.4, 113.0, 113.4, 141.0, 141.8, 151.0, 151.8.
IR (CH2Cl2) 1687, 1385, 1366. MS(EI) (m/z) ) 41, 57, 126, 170,
242. ESI+ (m/z)) 242. Anal. Calcd for C13H23NO3: C, 64.70;
H, 9.61; N, 5.80. Found: C, 64.57; H, 9.58; N, 5.79.
(R)-N-(ter t-Bu toxyca r bon yl)-4-eth yl-2,2,4-tr im eth yl-3-
oxa zolid in e (16). Palladium on carbon (1:10 catalyst/sub-
strate by weight) was added to a solution of 15 (1.20 g, 5.0
mmol) in ethyl acetate (20 mL). The suspension was stirred
at room temperature for 12 h. The catalyst was removed by
filtration, and the solvent was evaporated to give 16 (1.17 g,
(R)-2-((ter t-Bu toxycar bon yl)am in o)-3-((ter t-bu tyldiph e-
n ylsilyl)oxy)-2-m eth ylp r op a n ol (12). Starting from com-
pound 11 (2.71 g, 5.2 mmol) and in a similar way to that
described for compound 10, alcohol 12 (1.64 g, 71%) was
obtained as a white solid. Mp 62-63 °C. [R]25 ) -0.2 (c 0.98,
D
1
MeOH). H NMR (CDCl3) δ 1.08 (s, 9H), 1.23 (s, 3H), 1.44 (s,
9H), 1.61 (brs, 1H), 3.53-3.77 (m, 4H), 5.12 (brs, 1H), 7.30-
7.45 (m, 6H), 7.55-7.65 (m, 4H). 13C NMR (CDCl3) δ 19.2, 19.8,
26.8, 28.3, 57.3, 67.5, 68.0, 79.5, 127.7, 129.8, 132.7, 132.8,
135.5, 156.0. IR (CH2Cl2) 3424, 1715, 1696. MS(EI) (m/z) )
96%) as a colorless liquid, which was used without further
1
purification. [R]25 ) -1.7 (c 1.83, CHCl3). H NMR (CDCl3) δ
D
0.80-0.90 (m, 3H), 1.33, 1.39 (2s, 3H), 1.48 (s, 9H), 1.50, 1.53,

(S)-, (R)-N-Boc-N,O-isopropylidene-R-methylserinals
J . Org. Chem., Vol. 64, No. 22, 1999 8225
1.54, 1.57 (4s, 6H), 1.58-1.78 (m, 1H), 1.79-2.00 (m, 1H), 3.58,
3.61 (2d, 1H, J ) 5.4 Hz), 3.82, 3.85 (2d, 1H, J ) 3.6 Hz). 13C
NMR (CDCl3) δ 8.8, 8.9, 22.9, 24.4, 24.9, 25.4, 26.0, 26.7, 28.4,
28.6, 29.7, 62.3, 63.2, 72.7, 73.0, 79.2, 79.3, 94.3, 95.3, 151.2,
151.8. IR (CH2Cl2) 1686, 1391, 1374, 1366. MS(EI) (m/z) ) 41,
57, 172, 228. ESI+ (m/z) ) 244. Anal. Calcd for C13H25NO3:
C, 64.16; H, 10.36; N, 5.76. Found: C, 64.02; H, 10.21; N, 5.60.
mmol). [R]25 ) +10.9 (c 1.00, H2O). Anal. Calcd for C5H11
-
D
NO2: C, 51.26; H, 9.46; N, 11.96. Found: C, 50.10; H, 9.34; N,
11.86.
P r ep a r a tion of MTP A Ester s. A solution of MTPA (71.8
mg, 0.31 mmol) in CH2Cl2 (1 mL) was added to a solution of
the alcohol (0.27 mmol), DCC (60.5 mg, 0.29 mmol), and DMAP
(3.2 mg, 0.03 mmol) in CH2Cl2 (1.0 mL). The mixture was
stirred at room temperature for 4.5 h. The resulting white
suspension was filtered to remove the N,N′-dicyclohexylurea.
The filtrate was concentrated to give a white slurry, to which
Et2O was added. The resulting suspension was filtered to
remove the N-acyl-N′-cyclohexylurea and then concentrated
to give the crude product, which was purified by column
chromatography on silica gel (hexane/ethyl acetate, 9:1).
(2S,2′R)-2-((2′-Meth oxy-2′-(tr iflu or om eth yl)ph en ylacetyl-
(R)-2-((ter t-Bu t oxyca r b on yl)a m in o)-2-m et h ylb u t a n ol
(17). Compound 16 (200 mg, 0.82 mmol) dissolved in aceto-
nitrile (15 mL) and water (74 µL, 0.4 mmol) were added to a
solution of Sc(OTf)3 (40 mg, 0.08 mmol) in acetonitrile (5 mL),
at 25 °C. This mixture was stirred for 24 h at 25 °C and
quenched with a phosphate buffer (pH 7). The organic materi-
als were extracted with ethyl acetate (3 × 20 mL), and the
combined extracts were washed with brine and dried. The
solvent was removed to obtain a yellow oil, which was purified
by column chromatography (hexane/ethyl acetate, 4:1) to give
oxy)m eth yl)-2-m eth yloxir a n e (21). [R]25 ) +46.6 (c 0.89,
D
1
CHCl3). H NMR (CDCl3) δ 1.35 (s, 3H), 2.64 (d, 1H, J ) 4.5
Hz), 2.76 (d, 1H, J ) 4.8 Hz), 3.55 (s, 3H), 4.22 (d, 1H, J )
12.0 Hz), 4.47 (d, 1H, J ) 12.0 Hz), 7.35-7.45 (m, 3H), 7.50-
7.60 (m, 2H). 13C NMR (CDCl3) δ 18.2, 51.5, 54.3, 55.4, 68.1,
121.2, 125.1, 127.3, 128.4, 129.7, 131.9, 166.2. 19F NMR (CDCl3)
δ -71.9. IR (CH2Cl2, cm-1) 1753. MS(EI) (m/z) ) 43, 77, 105,
189, 304. ESI+ (m/z) ) 305. Anal. Calcd for C14H15F3O4: C,
55.26; H, 4.97. Found: C, 54.92; H, 5.08.
17 (155 mg, 93%) as a white solid. Mp 57 °C. [R]25 ) +4.1 (c
D
1.00, MeOH). 1H NMR (CDCl3) δ 0.90 (t, 3H, J ) 7.5 Hz), 1.43
(s, 9H), 1.52 (s, 3H), 1.50-1.67 (m, 1H), 1.69-1.82 (m, 1H),
3.58, 3.64 (2d, 2H, J ) 11.4 Hz), 4.39 (brs, 1H), 4.70 (brs, 1H).
13C NMR (CDCl3) δ 7.8, 21.9, 28.3, 29.0, 57.0, 69.4, 79.7, 156.2.
IR (CH2Cl2) 3433, 1714, 1691. MS(EI) (m/z) ) 41, 57, 72, 116,
174. ESI+ (m/z) ) 204. Anal. Calcd for C10H21NO3: C, 59.08;
H, 10.41; N, 6.89. Found: C, 58.94; H, 10.41; N, 6.79.
(2S,2′S)-2-((2′-Meth oxy-2′-(tr iflu or om eth yl)ph en ylacetyl-
oxy)m eth yl)-2-m eth yloxir a n e (22). [R]25 ) -29.2 (c 0.33,
D
(R)-2-Am in o-2-m eth ylbu ta n oic Acid (6). A 1.5-fold excess
of J ones reagent was dropwise added to a solution of 17 (200
mg, 0.98 mmol) in acetone (10 mL) at 0 °C over 5 min. The
mixture was stirred at 0 °C for 3 h and then at room
temperature for a further 3 h. The excess of J ones reagent
was destroyed with 2-propanol. The mixture was then diluted
with water (10 mL) and extracted with ethyl acetate (4 × 20
mL). The combined organic extracts were dried and concen-
trated. The residual yellow oil (187 mg) was dissolved in THF
(15 mL) and treated with concentrated HCl (1 mL). The
mixture was stirred at room temperature for 6 h. The solvent
was removed, and the residual oil was partitioned between
water (10 mL) and ethyl acetate (10 mL). The aqueous phase
was concentrated to give 2-amino-2-methylbutanoic acid hy-
drochloride as a white solid (129 mg). This compound was
dissolved in EtOH/propylene oxide (3:1, 8 mL), and the mixture
was heated under reflux for 2 h. After this time, the amino
acid partially precipitated as a white solid (33 mg). The filtrate
was concentrated, and the residue was dissolved in distilled
water and eluted through a C18 reverse-phase Sep-pak car-
tridge to give, after removal of the water, 51 mg of 6 as a white
1
CHCl3). H NMR (CDCl3) δ 1.33 (s, 3H), 2.66, 2.75 (2d, 2H, J
) 4.5 Hz), 3.56 (s, 3H), 4.16, 4.50 (2d, 2H, J ) 12.0 Hz), 7.36-
7.45 (m, 3H), 7.48-7.60 (m, 2H). 13C NMR (CDCl3) δ 18.2, 51.9,
54.4, 55.5, 68.8, 121.3, 125.1, 127.3, 128.4, 129.7, 131.9, 166.2.
19F NMR (CDCl3) δ -71.9. IR (CH2Cl2) 1753. MS(EI) (m/z) )
43, 77, 105, 189, 289. ESI+ (m/z) ) 305. Anal. Calcd for
C
14H15F3O4: C, 55.26; H, 4.97. Found: C, 55.32; H, 5.01.
(4S,2′R)-N-(ter t-Bu toxyca r bon yl)-4-((2′-m eth oxy-2′-(tr i-
flu or om eth yl)p h en yla cetyloxy)m eth yl)-2,2,4-tr im eth yl-
3-oxa zolid in e (23). Mp 54-55 °C. [R]25 ) +22.2 (c 1.50,
D
CHCl3). 1H NMR (CDCl3) δ 1.28-1.60 (m, 18H), 3.53, 3.54 (2s,
3H), 3.56-3.61 (m, 1H), 3.79, 3.86 (2d, 1H, J ) 9.0 Hz), 4.38,
4.43 (2d, 1H, J ) 11.1 Hz), 4.49, 4.55 (2d, 1H, J ) 10.8 Hz),
7.35-7.45 (m, 3H), 7.46-7.55 (m, 2H). 13C NMR (CDCl3) δ
19.9, 20.9, 25.0, 25.3, 25.7, 26.7, 28.4, 55.4, 60.5, 61.3, 66.4,
67.0, 71.3, 71.7, 80.3, 80.6, 95.0, 96.0, 121.3, 125.2, 127.2, 128.4,
128.5, 129.6, 129.8, 131.8, 132.3, 151.3, 166.1, 166.2. 19F NMR
(CDCl3) δ -71.9, -71.6. IR (CH2Cl2) 1751, 1692, 1391, 1376,
1368. MS(EI) (m/z) ) 41, 57, 346. ESI+ (m/z) ) 462. Anal.
Calcd for C22H30F3NO6: C, 57.26; H, 6.55; N, 3.04. Found: C,
57.02; H, 6.49; N, 2.98.
solid; total amount 84 mg (73%). Mp > 300 °C. [R]25 ) -10.8
(4R,2′R)-N-(ter t-Bu toxyca r bon yl)-4-((2′-m eth oxy-2′-(tr i-
flu or om eth yl)p h en yla cetyloxy)m eth yl)-2,2,4-tr im eth yl-
3-oxa zolid in e (24). Mp 49 °C. [R]25D ) +31.7 (c 1.28, CHCl3).
1H NMR (CDCl3) δ 1.35-1.55 (m, 18H), 3.52 (s, 3H), 3.57-
3.63 (m, 1H), 3.81, 3.88 (m, 1H), 4.38, 4.51 (2brs, 2H), 7.35-
7.45 (m, 3H), 7.46-7.55 (m, 2H). 13C NMR (CDCl3) δ 19.9, 21.1,
25.1, 26.2, 26.3, 28.3, 28.4, 55.4, 60.4, 61.2, 67.0, 67.4, 71.5,
71.8, 80.4, 80.5, 95.0, 96.0, 121.3, 125.1, 127.3, 128.5, 129.7,
132.0, 151.4, 166.2. 19F NMR (CDCl3) δ -71.7, -71.6. IR (CH2-
Cl2) 1751, 1693, 1389, 1376, 1368. MS(EI) (m/z) ) 41, 57, 346.
ESI+ (m/z) ) 462. Anal. Calcd for C22H30F3NO6: C, 57.26; H,
6.55; N, 3.04. Found: C, 57.20; H, 6.50; N, 3.09.
D
1
(c 1.00, H2O). H NMR (D2O) δ 0.87 (t, 3H, J ) 7.5 Hz), 1.42
(s, 3H), 1.65-1.78 (m, 1H), 1.80-1.92 (m, 1H). 13C NMR (D2O)
δ 7.6, 22.2, 30.4, 62.1, 177.1. IR (Nujol, cm-1) 3000-2250, 1600.
ESI+ (m/z) ) 118. Anal. Calcd for C5H11NO2: C, 51.26; H, 9.46;
N, 11.96. Found: C, 50.03; H, 9.39; N, 11.87.
(S)-N-(ter t-Bu toxyca r bon yl)-2,2,4-tr im eth yl-4-vin yl-3-
oxa zolid in e (18). In a manner similar to that described for
its enantiomer 15, compound 18 (1.02 g, 93%) was obtained
from aldehyde 4 (1.12 g, 4.6 mmol). [R]25 ) -5.1 (c 2.16,
D
CHCl3). Anal. Calcd for C13H23NO3: C, 64.70; H, 9.61; N, 5.80.
Found: C, 64.60; H, 9.54; N, 5.71.
(S)-N-(ter t-Bu toxyca r bon yl)-4-eth yl-2,2,4-tr im eth yl-3-
oxa zolid in e (19). In a manner similar to that described for
its enantiomer 16, compound 19 (1.18 g, 96%) was obtained
Ack n ow led gm en t. This work was supported by the
Direccio´n General de Ensen˜anza Superior (project PB97-
0998-C02-02) and the Universidad de La Rioja (project
API-99/B02). F. Corzana thanks the Ministerio de
Educacio´n y Ciencia for a doctoral fellowship.
from compound 18 (1.20 g, 5.0 mmol). [R]25 ) +1.4 (c 1.82,
D
CHCl3). Anal. Calcd for C13H25NO3: C, 64.16; H, 10.36; N, 5.76.
Found: C, 64.00; H, 10.30; N, 5.73.
(S)-2-((ter t-Bu t oxyca r b on yl)a m in o)-2-m et h ylb u t a n ol
(20). In a manner similar to that described for its enantiomer
17, compound 20 (153 mg, 93%) was obtained from compound
1
Su p p or tin g In for m a tion Ava ila ble: A full listing of H
and 13C NMR data of all new compounds, complete with peak
assignments. Copies of H and 13C NMR spectra, as well as
1
19 (201 mg, 0.82 mmol). [R]25 ) -4.0 (c 1.02, MeOH). Anal.
D
1H-1H and H-13C correlations for all new compounds. Zoom
1
Calcd for C10H21NO3: C, 59.08; H, 10.41; N, 6.89. Found: C,
59.10; H, 10.39; N, 6.84.
of the NMR signals in which the enantiomeric purity of 3, 4,
5, 10, and 14 was determined. This material is available free
of charge via the Internet at http://pubs.acs.org.
(S)-2-Am in o-2-m eth ylbu ta n oic Acid (7). In a manner
similar to that described for its enantiomer 6, amino acid 7
(83 mg, 72%) was obtained from compound 20 (153 mg, 0.75
J O990957O