A new method for the enantioselective synthesis of N-Boc-α,α-disubstituted α-amino acids

Article abstract of DOI:10.1016/S0040-4020(01)00503-8

A new method for the enantioselective synthesis of N-Boc-α,α-disubstituted α-amino acids has been developed. The starting materials are diastereomerically pure 3,3-disubstituted allyl alcohols, prepared by DIBAL-H reduction of the corresponding unsaturate

Full text of DOI:10.1016/S0040-4020(01)00503-8

TETRAHEDRON
Pergamon
Tetrahedron 57 <2001) 6367±6374
A new method for the enantioselective synthesis
of N-Boc-a,a-disubstituted a-amino acids
p
Ruben Martõn, Gabriela Islas, Albert Moyano, Miquel A. Pericas and Antoni Riera
p
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 Á  Á  Á
Unitat de Recerca en Sõntesi Asimetrica, Departament de Quõmica Organica, Universitat de Barcelona, c/ Martõ i Franques, 1-11,
08028 Barcelona, Spain
Received 24 January 2001; revised 15 February 2001; accepted 6 March 2001
AbstractÐA new method for the enantioselective synthesis of N-Boc-a,a-disubstituted a-amino acids has been developed. The starting
materials are diastereomerically pure 3,3-disubstituted allyl alcohols, prepared by DIBAL-H reduction of the corresponding unsaturated
esters derived from carbocupration of an acetylenic ester or from Wadsworth±Emmons ole®nation of a ketone. Sharpless epoxidation of the
allylic alcohols provided enantiomerically enriched epoxy alcohols that were submitted to nucleophilic ring-opening under Crotti's con-
ditions <N3Na/LiClO4) to give 3-azido-1,2-diols. Hydrogenation and in situ protection provided the N-Boc-3-amino-1,2-diols that were
oxidatively cleaved to the a,a-disubstituted N-Boc-a-amino acids. Protected a-methyl-a-phenylglycine and a-methylisoleucine have been
prepared by this methodology. q 2001Elsevier Science Ltd. All rights reserved.
1. Introduction
etc.) and reduction. The catalytic Sharpless epoxidation15 of
II reliably provides enantiomerically enriched epoxy
alcohols III which are then submitted to a regio- and stereo-
speci®c ring-opening using a synthetic equivalent of ammo-
nia.16 We have used several reagents as a nucleophiles in
this crucial step: benzhydrylamine,7a,b,11 p-methoxybenzyl-
amine,7c NaN3,7b,8,9 Ti<N3)2<OiPr)2.11,13b The reaction
products have been converted into N-Boc-3-amino-1,2-
diols IV. Oxidation of diol IV affords directly the corre-
sponding a-amino acids without any epimerization at the
chiral center. This sequence has proven to be particularly
useful for a-alkyl or a-aryl glycines7 such as homophenyl-
alanine7a and naphtylglycine7b and has been effective for the
preparation of highly lipophilic amino acids such as mesityl
glycine8 <Scheme 1).
The biological activity of a given peptide is strongly linked
to its lowest energy conformation. Small peptides designed
to mimic a protein are conformationally more ¯exible and
consequently less active than the parent protein due to the
absence of the multiple long-range interactions present in
proteins.1 A usual strategy to increase both the stability,
biological activity and selectivity of peptides is to restrict
their available conformations by the introduction of peptide
cyclizations or by the use of unnatural amino acids with
conformational constraints.2,3 The increasing interest of
modi®ed peptides in biological studies and as therapeutic
agents4 has fostered the research of methodologies directed
to the synthesis of new unnatural amino acids in enantio-
merically pure form.5 a,a-Disubstituted a-amino acids
<quaternary amino acids) are among the most important
unnatural residues able to give conformational rigidity to
a peptide. Many of them have been speci®cally designed
and synthesized in the last decade, this subject having been
recently reviewed.6
N-Boc-3-Amino-1,2-diols IV, key intermediates for the
synthesis of alkyl and aryl glycines, are also versatile
precursors for many other types of amino acids <Scheme
2). b-Aryl alanines, for instance, were obtained through
the intermediacy of N-Boc-aziridines V, which can be
readily prepared by a sequence of regioselective protection
of the primary alcohol <to give VI), mesylation of the
secondary alcohol and base-induced cyclization.8,9 Regio-
selective hydrogenolysis of V, followed by deprotection and
oxidation afforded directly b-aryl alanines. Nucleophilic
ring-opening of V by a cuprate reagent followed by the
same reaction sequence provided b-substituted-b-aryl
alanines. Intermediates IV are also suited for the synthesis
of a-hydroxy-b-amino acids and b-hydroxy-g-amino acids
of both diastereomeric series. The former can be prepared
by simple protecting group manipulation followed by oxi-
dation of the primary alcohol,10 whereas the latter are
Over the last years, we have developed a general synthetic
methodology which allows the stereocontrolled preparation
of amino acids of different structural types in high enantio-
meric purity.7±14 The starting materials are allyl alcohols II
often prepared from carbaldehydes I by a two-step sequence
of ole®nation <Wittig, Wadsworth±Emmons, Knoevenagel
Keywords: a-amino acids; a,a-dialkylglycines; quaternary amino acids;
Sharpless epoxidation.
Corresponding authors. Tel.: 134-93-402-1245; fax: 134-933397878;
e-mail: mapericas@qo.ub.es; a.riera@qo.ub.es
p
0040±4020/01/$ - see front matter q 2001Elsevier Science Ltd. All rights reserved.
PII: S0040-4020<01)00503-8

Â
R. Martõn et al. / Tetrahedron 57 /2001) 6367±6374
6368
Scheme 1.
available through a sequence that involves cyanide ring-
opening11 of the 2-alkylamino epoxides VII and VIII.12
The syn- and anti-amino epoxides VII and VIII have been
respectively prepared by intramolecular Mitsunobu reaction
and a three step sequence featuring protection of the primary
alcohol, activation of the secondary alcohol and simul-
taneous deprotection with cyclization. In addition, pre-
cursors of dipeptide isosteres, such as g-aminoalkyl-g-
lactones,13 are also accessible from IV by homologation
of aldehydes IX following a protocol of Wittig ole®nation,
hydrogenation and acid treatment. Finally, b-alkyl b-amino
acids14 were prepared by deoxygenation of the diol fragment
to provide unsaturated amines X that were hydroborated and
oxidized.
The increasing importance of a,a-disubstituted a-amino
acids as components in biologically active peptides
prompted us to attempt their preparation by appropriate
modi®cation of our basic synthetic sequence. We describe
herein our methodology for the enantioselective synthesis of
Scheme 2.

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R. Martõn et al. / Tetrahedron 57 /2001) 6367±6374
6369
Scheme 3.
Scheme 4.
two targets: a-methyl-a-phenylglycine <1a) as an example
possesing an aromatic residue and a-methylisoleucine <1b)
as a representative of a,a-dialkyl glycine residue. a-Methyl-
a-phenylglycine <1a) has been synthesized in enantio-
merically pure form17 and used for a variety of biological
purposes.18 a-Methylisoleucine <1b) has been previously
synthesized by routes featuring alkylation of chiral glycine
equivalent19 and by microbial resolution.20
Peterson ole®nation23 gave excellent yields but low dia-
stereoselectivities, the Wadsworth±Emmons reaction24
gave the best combination of yield and selectivity. On the
contrary, in order to obtain diastereomerically pure <E)-2b,
we found that carbocupration25 of ethyl butynoate was the
most convenient procedure. Following the protocol
described by Henrick,26 the conjugate addition of a poly-
meric organocopper complex prepared from n-butyl lithium
took place in a completely diastereoselective manner afford-
ing <E)-2b in quantitative yield. The reduction of both
unsaturated esters with DIBAL-H took place uneventfully
providing the corresponding allylic alcohols <E)-3a and
<E)-3b27 in excellent yield <Scheme 4).
Alcohols 3a and 3b were subsequently submitted to the
Sharpless catalytic epoxidation procedure15 using l-<1)-
DIPT to generate the catalyst <Scheme 5). Epoxy alcohols
4a and 4b were obtained in good yields and the enantio-
meric excesses of 83±84%28 as determined by 19F NMR of
their corresponding Mosher's esters.29 The enantiomeric
excesses of 4a and 4b were increased up to 91±92% ee by
using l-<1)-DET in the preparation of the catalyst.
2. Results and discussion
Experience from our previous work indicated several dif®-
culties that needed to be overcome to reach our target
<Scheme 3). First of all, stereochemically pure allyl alcohol
XI had to be prepared because each diastereomer would
lead to the opposite enantiomeric product. Two additional
issues to be addressed were the enantioselectivity of the
Sharpless epoxidation and the regioselectivity of the nucleo-
philic ring-opening of the epoxy alcohol XII, both of which
may diminish with the increased steric bulk at carbon 3 and
the tertiary nature of the carbocationic intermediate. Finally,
the oxidative cleavage of the N-Boc-aminodiol XIII was
expected to provide the desired amino acid.
Nucleophilic ring-opening of epoxy alcohol 4a proved to be
dif®cult due to the steric hindrance at C-3 and to the stability
of the putative carbocationic-like intermediate. We ®rst
used the complex Ti<N3)2<OiPr)2 in benzene,16a conditions
that usually give excellent results with sterically hindered
substrates,11,13b however, a complex mixture of products
was observed by TLC and the desired azidodiol could not
be isolated. The Caron±Sharpless conditions30 for the
nucleophilic ring opening with azide ion <TMS-N3,
Ti<OiPr)4, benzene) gave the unexpected allyl alcohol 5a
The ®rst step in the planned syntheses was the preparation of
the unsaturated esters <E)-2a and <E)-2b for reduction to the
starting allylic alcohols <Scheme 4). The preparation of
ethyl 3-phenylbutenoate <E)-2a had already been described
by the Reformatsky reaction on benzophenone21 as well as
by conjugate addition of lithium diphenylcuprate to ethyl-
butynoate.22 In our hands, however, the carbocupration
reaction was dif®cult to reproduce and the Reformatsky
reaction gave only moderate yields. Consequently, we
decided to explore other reaction condition. Whereas the
Scheme 5.

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R. Martõn et al. / Tetrahedron 57 /2001) 6367±6374
6370
Scheme 6.
in good yield <Scheme 6). Other conditions using Ti<OiPr)4
as a Lewis acid <NaN3, Ti<OiPr)4, CH2Cl2) also afforded the
undesired alcohol 5a which is presumed to have arisen from
a terminal epoxide formed on rearrangement and dehydra-
tion of 4a <Scheme 6). An analogous allylic alcohol was
obtained using benzhydrylamine as ammonia synthetic
equivalent <Ph2CHNH2, Ti<OiPr)4, CH2Cl2).31 These results
prompted us to explore milder Lewis acids. We were
pleased to ®nd that under Crotti's conditions32 the reaction
took place cleanly providing a single isomer of azidodiol
that was immediately submitted to catalytic hydrogenation
in the presence of <Boc)2O to give N-Boc-3-phenyl-3-
aminobutane-1,2-diol 6a. When the same reaction sequence
was applied to epoxy alcohol 4b, after hydrogenation and
N-Boc-protection of the crude, N-Boc-aminodiol 6b was
isolated in good yield.
alcohols. As representative examples of this interesting
class of compounds we have described the preparation of
two enantiomerically enriched N-Boc-protected a-disubsti-
tuted glycines from the corresponding allyl alcohols.
Because our methodology relies on the Sharpless catalytic
epoxidation for enantioselective introduction of chirality, it
may be applicable to amino acids of both enantiomeric
series possessing a variety of side chains. Moreover, taking
into account the synthetic versatility of N-Boc-3-amino-1,2-
diols, which have been converted into many types of bio-
logically active compounds, the new 3,3-disubstituted-3-
amino-1,2-diols may exhibit a similarly broad synthetic
potential. In addition, a serendipitous discovery has
provided an ef®cient synthesis of enantiomerically enriched
vinyl azido alcohols 5 has been developed. The synthetic
potential of these intermediates is currently being studied in
our laboratory.
The N-Boc-3-amino-1,2-diols 6a and 6b were somewhat
unstable, probably due to the easy hydrolysis of the carba-
mate. To convert them into the target amino acids, they were
each submitted to oxidation with KMnO4/NaIO4/Na2CO3 in
dioxane/water33 <Scheme 7). Puri®cation and characteri-
zation of the N-Boc-amino acids, was facilitated by con-
version to the respective methyl esters. The enantiomeric
purity of 8a was ascertained by HPLC analysis on a chiral
stationary phase <Chiracel OD) which indicated the same
enantiomeric excess as the starting epoxy alcohol 4a. The
absence of a chromophore in 8b forced us to prepare the
amino acid protected as a benzyloxycarbamate methyl
ester34 which also exhibited the same enantiomeric excess
as the starting epoxy alcohol 4b.
3. Experimental
3.1. General
Speci®c rotations were recorded at room temperature <238C,
Concentration in g/100 mL). 1H NMR spectra were
obtained at 200 and 300 MHz <sˆsinglet, dˆdoublet, tˆ
triplet, qˆquartet, dtˆdouble triplet, mˆmultiplet, brsˆ
broad signal). 13C NMR spectra were obtained at 50.3 or
75.4 MHz. Carbon multiplicities have been assigned by
distortionless enhancement by polarization transfer
<DEPT) experiments. Low-resolution mass spectra were
recorded in CI mode using ammonia. High-resolution
mass spectra <CI) were performed by the `Unidade de
Espectrometria de Masas, Universidade de Santiago de
In summary, we have developed a new methodology for the
synthesis of a,a-disubstituted a-amino acids from epoxy
Scheme 7.

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R. Martõn et al. / Tetrahedron 57 /2001) 6367±6374
6371
Compostela'. Dichloromethane was distilled from CaH2
under nitrogen prior to use. Chromatographic separations
were carried out using NEt3 pre-treated <2.5% v/v) SiO2
<70±230 mesh). <E)-3-Methyl-2-heptenoic acid ethyl ester
was prepared according to the described procedure26 and
used without puri®cation in the next step.
108C, and anhydrous MgSO4 <0.9 g) and Celitee <0.12 g)
were added. After stirring for 15 min at room temperature,
the mixture was ®ltered through a short pad of Celitee. The
solvents were evaporated in vacuo and the excess of tert-
butyl hydroperoxide was removed by azeotropic distillation
with toluene. The crude product was puri®ed by column
chromatography eluting with hexanes/ethyl acetate
mixtures to yield 1.63 g of 4a <88% yield) as a colorless
3.1.1. *E)-3-Phenyl-2-butenoic acid ethyl ester *2a). To a
solution of sodium hydride <0.2 g, 8.33 mmol) in anhydrous
dimethoxyethane <16 mL) at room temperature, triethyl
phosphonoacetate <1.64 mL, 8.33 mmol) and a solution
of acetophenone <970 mL, 8.33 mmol) in anhydrous
dimethoxyethane <5 mL) were sequentially added, dropwise
and with stirring. After 3±4 h, the reaction mixture was
partitioned between water <5 mL) and diethyl ether
<15 mL). The aqueous layer was extracted with diethyl
ether. The combined organic phases were washed with
brine and dried <MgSO4). Solvent was removed in vacuo
and the residual oil <7:1diastereomeric ratio) was puri®ed
by column chromatography eluting with hexanes/ethyl
acetate mixtures yielding 1.35 g of pure trans isomer
<85% yield) as a colorless oil. The spectral data were
identical to those from the literature.21c
23
oil. [a]D ˆ219.2 <c 1.0, CHCl3). IR <NaCl) n: 3422, 1725,
1
1653, 1603, 1447, 1259, 1068 cm21. H NMR <300 MHz,
CDCl3) d 7.42±7.34 <m, 5H), 4.01<dd, Jˆ8.9, 4.4 Hz, 1H),
3.88 <dd, Jˆ8.9, 6.6 Hz, 1H), 3.61 <brs, 1H), 3.18 <dd,
Jˆ6.6, 4.4 Hz, 1H), 1.75 <s, 3H) ppm. 13C NMR <75 MHz,
CDCl3) d 141.85 <C), 128.18 <CH), 127,31 <CH), 124.89
<CH), 66.03 <CH), 60.96 <CH2), 60.71<C), 71.59
<CH3) ppm. MS <CI±NH3). m/z <%): 165 <100) [M11]1,
182 <12) [M118]1. The enantiomeric excess was deter-
1
mined to be 91% by 19F NMR and H NMR of the corre-
sponding MTPA ester. When the reaction was performed
using l-<1)-diisopropyl tartrate, the enantiomeric excess
was determined to be 83% by the same method.
3.1.5. *2S,3S)-2,3-Epoxy-3-methyl-heptan-1-ol *4b).
Employing 3b <0.6 g, 4.69 mmol) in the procedure
described for the preparation of 4a, 4b <0.65 g, 96% yield)
was obtained as an oil. IR <NaCl) n: 3855, 3426, 2959,
3.1.2. *E)-3-Phenyl-2-buten-1-ol *3a). To a solution of 2a
<335 mg, 1.76 mmol) in diethyl ether <4 mL) at 08C,
DIBALH <3.52 mL, 1M in hexanes) was added slowly.
The reaction mixture was allowed to warm to room
temperature, and stirred for 1.5 h, diluted with diethyl
ether <13 mL), cooled to 08C and quenched with careful
addition of brine <10 mL). Then, 4 M HCl was added
dropwise under stirring until two clear phases were formed
<ca. 10 mL). The aqueous layer was extracted with diethyl
ether and the combined organic phases were washed with
brine, dried <sodium sulfate) and evaporated. The residue
was puri®ed by column chromatography eluting with
hexanes/ethyl acetate mixtures yielding 243 mg of 3a
<93% yield) as an colorless oil. The spectral data was
identical to those from the literature.21c
2936, 2863 cm21. [a]D ˆ27.0 <c 1.0, CHCl3). H NMR
<300 MHz, CDCl3) d 3.82 <dd, Jˆ4.2, 12 Hz, 1H), 3.65
<dd, Jˆ6.6, 12 Hz, 1H), 2.95 <dd, Jˆ4.5, 6.6 Hz, 1H),
2.62 <brs, 1H), 1.62 <m, 1H), 1.31 <m, 8H), 0.90 <t, Jˆ
7 Hz, 3H) ppm. 13C NMR <75 MHz, CDCl3) d 63.0 <CH),
23
1
61.4 <C), 61.3 <CH2), 38.2 <CH2), 27.1<CH ), 22.6 <CH2),
2
16.6 <CH3), 13.9 <CH3) ppm. MS <CI±NH3). m/z <%): 145
<26.5) [M11]1, 127 <55.7) [M218]1, 108 <100) [M236]1.
HRMS calcd for MH1, C8H17O2: 145.1228, found
145.1230. The enantiomeric excess was determined to be
92% by 19F NMR and 1H NMR of the corresponding MTPA
ester. When the reaction was performed using l-<1)-diiso-
propyl tartrate, the enantiomeric excess was determined to
be 83% by the same method.
3.1.3. *E)-3-Methyl-2-heptenen-1-ol *3b). Following the
procedure described for the preparation of 3a, alcohol 3b
<1.04 g, 89% overall yield from ethyl butynoate) was
synthesized from 2b <1.5 g, 8.8 mmol) and obtained as an
oil. The spectral data were identical to those from the litera-
ture.27
3.1.6.
butan-1,2-diol *6a). To
*2R,3R)-3-tert-Butoxycarbonylamino-3-phenyl-
solution of 4a <0.5 g,
a
3.05 mmol) in acetonitrile <15 mL), LiClO4 <8 g,
75.2 mmol) and sodium azide <0.99 g, 15.2 mmol) were
added under nitrogen. The reaction mixture was then heated
at 658C with stirring for 24 h, allowed to cool to room
temperature and quenched by addition of water and diethyl
ether. The aqueous layer was extracted with diethyl ether
and the combined organic phases were dried <MgSO4) and
evaporated. The crude product was directly used in the next
step.
3.1.4. *2S,3S)-2,3-Epoxy-3-phenyl-butan-1-ol *4a). In a
Ê
250 mL round-bottomed ¯ask, anhydrous powdered 4 A
molecular sieves <0.636 g) and anhydrous CH2Cl2
<102 mL) were placed under nitrogen. After cooling the
¯ask to 2208C, the following reagents were introduced
sequentially via cannula with stirring: l-<1)-diethyl tartrate
<173 mg, 0.84 mmol) in dichloromethane <1 mL), titanium
In a 50 mL round-bottomed ¯ask, palladium on activated
charcoal <109 mg, 10% mol) was added to ethyl acetate
<5 mL). Air was removed in vacuo from the ¯ask which
was purged with nitrogen, evacuated and re®lled with
nitrogen three times. The mixture was brie¯y stirred for
15 min and treated with a solution of the previously
obtained reaction crude with Boc2O <0.76 g, 3.48 mmol)
in 4 mL ethyl acetate. After purging with hydrogen, the
reaction mixture was stirred at room temperature under
dry hydrogen. After 5 h, the mixture was ®ltered through
tetraisopropoxide <170 mL, 0.55 mmol) and
a 2.5 M
solution of tert-butyl hydroperoxide in isooctane <8.9 mL,
22.25 mmol). The mixture was stirred for 1h at 2208C and
treated dropwise with a solution of 3a <1.67 g, 11.3 mmolÐ
Ê
previously distilled and stored for 24 h over 4 A molecular
sieves) in dichloromethane <7 mL). After stirring for 4 h at
2208C, the reaction was quenched by addition of 10%
NaOH solution saturated with NaCl <0.9 mL) and diethyl
ether <6 mL). The mixture was then allowed to warm to

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R. Martõn et al. / Tetrahedron 57 /2001) 6367±6374
6372
a short pad of Celitee. The solvent was evaporated in vacuo
and the resulting oil was puri®ed by column chroma-
tography eluting with hexanes/ethyl acetate mixtures to
afford 6a <0.6 g, 70% overall yield from 3) as an oil.
crude product which was used without further puri®cation in
the next step.
A solution of the crude acid <0.059 g, 0.192 mmol) in 1 mL
of anhydrous DMF was treated with KHCO3 <0.036 g,
0.39 mmol) and methyl iodide <0.03 mL, 0.49 mmol) at
room temperature and stirred overnight. After the addition
of 1mL of NH 4Cl, the aqueous phase was extracted with
ethyl acetate. The combined organics layers were washed
with brine and then dried with MgSO4. The solvent was
removed in vacuo to give 0.055 g of crude ester that was
puri®ed by chromatography <SiO2/Et3N, 5% EtOAc in
hexanes as the eluant) to afford pure 8a <0.05 g, 68% overall
23
[a]D ˆ224.3 <c 0.9, CHCl3) IR <NaCl) n: 3415, 1694,
1
1497, 1252, 1169 cm21. H NMR <300 MHz, CDCl3) d
7.29±7.36 <m, 5H), 5.78 <brs, 1H), 3.88 <brs, 1H), 3.62
<dd, Jˆ7.6, 3.4 Hz, 1H), 3.43 <dd, Jˆ11.4, 3.4 Hz, 1H),
3.27 <dd, Jˆ11.4, 7.6 Hz, 1H) 2.82 <brs, 1H), 1.78 <s, 3H),
1.26 brs, 9H) ppm. 13C NMR <75 MHz, CDCl3) d 156.1 <C),
142.8 <C), 128.5 <CH), 127.9 <CH), 126.5 <CH), 79.9 <C),
69.6 <C), 62.3 <CH3) 60.6 <CH2), 28.2 <CH3), 23.3
<CH3) ppm. MS <CI±NH3). m/z <%): 282 <100) [M11]1,
299 <40) [M118]1.
23
yield from 4a) as an oil. [a]D ˆ140.6 <c 1.3, CHCl3) IR
<NaCl) n: 2979, 1721.1, 1704, 1451, 1279, 1167,
1
3.1.7.
*2R,3R)-3-tert-Butoxycarbonylamino-3-methyl-
1057 cm21. H NMR <300 MHz, CDCl3) d 7.31±7.43 <m,
heptan-1,2-diol *6b). Employing 4b <0.20 g, 1.38 mmol)
in the procedure described for the preparation of 4a, 6b
5H), 5.82 <brs, 1H), 3.69 <s, 3H), 1.99 <s,3H), 1.36 <s,
9H) ppm. 13C NMR <75 MHz, CDCl3) d 173.5 <C), 154.0
<C), 140.3 <C), 128.5 <CH), 127.7 <CH), 126.5 <CH), 64.8
<C), 61.8 <C), 53.0 <CH3), 28.3 <CH3), 23.2 <CH3) ppm. MS
<CI±NH3). m/z <%): 280 <17) [M11]1, 297 <100) [M118]1.
HRMS calcd for C15H21NO4: 279.1471, found 279.1483.
The enantiomeric excess was determined to be 91% by
HPLC analysis on a Chiralcelw OD column <25 cm) at
308C with the detector centered at 254 nm using a ¯ow
rate of 0.5 mL min21 and an eluant of hexane/isopropyl
alcohol 95/5: tR <2R,2R)ˆ10.17 min; tR <2S,2S)ˆ11.12 min.
23
<0.11 g, 69% yield) was obtained as an oil. [a]D ˆ13.4
<c 0.5, CHCl3) IR <NaCl) n: 3361, 2960, 2937, 2875,
1690 cm21 1H NMR <300 MHz, CDCl3) d 5.10 <bs, 1H),
4.60 <s, 1H), 2.51±2.75 <m, 3H), 1.62 <m, 2H), 1.49 <s,
3H), 1.47 <s, 9H), 1.25±1.37 <m, 4H), 0.96 <t, Jˆ6.6 Hz,
3H) ppm. 13C NMR <75 MHz, CDCl3) d 156.2 <C), 79.7 <C),
73.5 <CH), 62.8 <CH2), 57.4 <C), 36.7 <CH2), 36.3p <CH2),
28.0 <CH3), 27.9p <CH3), 25.2 <CH2) 25.1p <CH2), 23.0
<CH2), 22.8p <CH2), 21.0 <CH3), 13.7 <CH3), 13.6p
<CH3) ppm. Signals marked with an asterisk correpond to
a rotamer.
3.1.10. *2R,2R)-2-tert-Butoxycarbonylamino-2-methyl-
hexanoic acid methyl ester *8b). Following the procedure
described for the preparation of 8a, starting from 6b <0.10 g,
3.1.8. *2R)-1-Azido-3-phenyl-but-3-en-2-ol *5a). To a
solution of 4a <50 mg, 0.30 mmol) in benzene <3 mL)
under nitrogen, titanium tetraisopropoxide <0.12 mL,
0.37 mmol) and TMS-N3 <85 mL, 0.61mmol) were added
dropwise. The reaction mixture was stirred for 2 h at room
temperature and quenched by addition of 10% NaOH solu-
tion saturated with NaCl <2 mL). The mixture was stirred for
5 h, ®ltered through a short pad of Celite and washed
thoroughly with diethyl ether. The aqueous layer was
extracted with diethyl ether and the combined organic
phases were dried <MgSO4) and evaporated. The crude
product was then puri®ed by column chromatography
eluting with hexanes/ethyl acetate mixtures to yield 53 mg
0.38 mmol), 8a <0.071g, 72% yield) was obtained as an oil.
IR <®lm) n: 3432, 3380, 2959, 2875, 1719 cm21. [a]D
ˆ
23
1
27.3 <c 1.0, CHCl3). H NMR <300 MHz, CDCl3) d 5.22
<br, 1H), 3.77 <s, 3H), 1.95±2.16 <m, 1H), 1.65±1.82 <m,
1H), 1.56 <s, 3H), 1.46 <s, 9H), 1.2±1.4 <m, 2H), 1.15 <m,
2H), 0.91<t, Jˆ6.6 Hz, 3H) ppm. 13C NMR <75 MHz,
CDCl3) d 175.1 <C), 154.3 <C), 79.4 <C), 59.6 <C), 52.4
<CH3), 37.0 <CH2), 28.3 <CH3), 26.1<CH ), 23.3 <CH3),
2
22.6 <CH2), 13.9 <CH3) ppm. MS <CI±NH3). m/z <%): 260
<100) [M11]1, 160 <74) [M2Boc]1. HRMS calcd for
C13H26NO4: 260.1862, found 260.1859. The enantiomeric
excess was determined to be 83% by HPLC analysis of
the corresponding benzyloxycarbamate methyl ester,
prepared by the same reaction sequence34 from a sample
of epoxide 4b of 83% ee. HPLC performed as described
for 8a: tR <2R,2R)ˆ22.4 min; tR <2S,2S)ˆ29.7 min.
23
of 5a <83% yield) as an oil. [a]D ˆ27.8 <c 1, CHCl3). IR
1
<NaCl) n: 3390, 2101, 1725, 1684, 1601, 1065 cm21. H
NMR <300 MHz, CDCl3) d 7.28±7.36 <m, 5H), 5.43 <d,
Jˆ8 Hz, 2H), 4.77 <dd, Jˆ4.8, 2 Hz, 1H), 3.65 <dd, Jˆ
7.6, 2 Hz, 1H), 3.48 <dd, Jˆ7.6, 4.8 Hz, 1H), 2.85 <bd,
1H) ppm. 13C NMR <75 MHz, CDCl3) d 148.1 <C), 139.3
<C), 128.5 <CH) 128.4 <CH), 127.9 <CH), 113.8 <CH2), 73.8
<CH), 65.9 <CH2) ppm. MS <CI±NH3): m/z <%): 147 <15%),
190 <M11, 100%), 197 <40%).
Acknowledgements
Financial support from CIRIT <2000SGR-00019) and from
DGICYT <PB98-1246) is gratefully acknowledged. R. M.
thanks CIRIT <Generalitat de Catalunya) for a fellowship.
3.1.9. 2-tert-Butoxycarbonylamino-2-phenyl-propionic
acid methyl ester *8a). A solution of 4a <75 mg,
0.27 mmol) in dioxane <0.57 mL) and water <0.25 mL)
was treated with Na2CO3 <14 mg, 0.13 mmol), NaIO4
References
<231mg, 1.35 mmol) and KMnO <9 mg, 10% mol) at
4
room temperature and stirred overnight. Then, the mixture
was made alkaline with a solution of NaOH 1N until pH 8.
The aqueous layer was extracted with EtOAc. The aqueous
layer was carefully acidi®ed35 with a solution of HCl 2N and
extracted with EtOAc. Evaporation of the solvent afforded a
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