New fast and practical method for the enantioselective synthesis of α-vinyl, α-alkyl quaternary α-amino acids

Article abstract of DOI:10.1016/j.tetasy.2007.12.012

We describe a fast and practical enantioselective synthesis of (S)-N-Cbz-α-vinyl, phenylalanine, suitable for the preparation of different N-Cbz-α-vinyl aminoacids of both configurations. The new protocol exploits a Wittig reaction on highly enantiomeric enriched N-Cbz-α-formyl-α-alkyl amino esters, readily accessible from (l)-serine through a stereoselective alkylation of Seebach's oxazolidine, carried out with a significant improvement of the previously reported method. The synthetic scheme is suitable for gram scale preparation of the desired product with a 94% ee.

Full text of DOI:10.1016/j.tetasy.2007.12.012

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 247–257
New fast and practical method for the enantioselective synthesis of
a-vinyl, a-alkyl quaternary a-amino acids
Marcello Di Giacomo,* Valerio Vinci, Massimo Serra and Lino Colombo*
`
Dipartimento di Chimica Farmaceutica, Universita di Pavia, Via Taramelli 12, I-27100 Pavia, Italy
Received 27 November 2007; accepted 19 December 2007
Available online 24 January 2008
Abstract—We describe a fast and practical enantioselective synthesis of (S)-N-Cbz-a-vinyl, phenylalanine, suitable for the preparation of
different N-Cbz-a-vinyl aminoacids of both configurations. The new protocol exploits a Wittig reaction on highly enantiomeric enriched
N-Cbz-a-formyl-a-alkyl amino esters, readily accessible from (L)-serine through a stereoselective alkylation of Seebach’s oxazolidine,
carried out with a significant improvement of the previously reported method. The synthetic scheme is suitable for gram scale prepara-
tion of the desired product with a 94% ee.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
lent capture of self-assembled peptides.7 However, almost
all reported examples make use of allyl or homoallyl gly-
cine derivatives, probably due to the ease of synthesis
and the reduced steric hindrance near the reactive olefinic
centers when the double C–C bond is used for further func-
tionalizations. Therefore, a practical method for the enan-
tioselective synthesis of a-vinyl-a-aminoacids would
expand the scope and applications of the olefin metathesis
reaction of peptides.
In recent years, the importance of a,a-disubstituted
a-amino acids has grown exponentially, in parallel with
the quest for valuable tools to design and prepare short
peptidic chains endowed with particular conformational
properties.1
A particularly interesting class is represented by quaternary
a-amino acids bearing b-c unsaturation. Natural amino
acids modified by the introduction of a vinyl moiety at
the a position cannot only induce remarkable conforma-
tional changes if introduced in peptides,2,3 but also possess
important biological features. As a consequence of the con-
current presence of a natural side-chain and a vinyl moiety,
they can act as enzymatic inhibitors4 and, when incorpo-
rated in a peptide, increase the resistance to proteolysis,
eventually enhancing the bioavailability of the molecule.3,5
Our particular interest in quaternary vinyl-glycines was
dictated by the need for a practical and scaleable method
for the enantioselective preparation of N-Cbz vinyl Phe
that we exploited as a building block for the construction
of proline-based bicyclic lactams through a peptide cou-
pling and an RCM reaction sequence.8
Although a fairly good number of enantioselective synthe-
ses of b,c-unsaturated amino acids without an additional
substituent at the a-position have been reported, less liter-
ature precedents are found for the asymmetric synthesis of
quaternary vinyl-glycines.
Furthermore, the impressive application range of olefin
metathesis and ring closing metathesis reactions has
aroused new interest in the synthesis of olefinic a-amino
acids as functional building blocks for the synthesis of con-
formationally constrained peptidomimetics6 and the cova-
Approaches to this class of compounds can be classified
according to the following general strategies: (a) alkylation
of amino acid derivatives by two-carbon alkyl halides func-
tionalized with a group susceptible to an elimination reac-
tion;9 (b) deconjugative a-alkylation of dehydro amino
acid derivatives or 3-vinyl-4-imidazolidinones;10 (c) phenyl-
selenylation of vinylglycine derivatives followed by alkyl-
ation and elimination;11 (d) Wittig methylenation of
*
Corresponding authors. Tel.: +39 382 987366; fax: +39 38242275
(M.D.G.); e-mail addresses: marcello.digiacomo@unipv.it; lino.
colombo@unipv.it
Present address: Centro Ricerche Chimiche Boehringer Inghelheim Italia
spa, via Lorenzini 8, 20139 Milano, Italy.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.12.012

248
M. Di Giacomo et al. / Tetrahedron: Asymmetry 19 (2008) 247–257
protected a-alkyl serinal derivatives or masked a-formyl
glycine equivalents;12 (e) aldol reactions of a quaternary
lithiated bis-lactim ether with aldehydes followed by dehy-
dration;13 (f) Pd(II)-mediated sigmatropic rearrangement
of allylic N-p-methoxyphenyl trifluoroacetimidates.14
The results were disappointing, as yields not higher than
20% were attained. Modification of the experimental
conditions such as an increase in the amount of benzyl
bromide and/or base (LDA), variation of the final concen-
tration of 5, THF/hexane ratio, and reaction time and tem-
perature were of no avail, the best yield being only 39%
versus 52% in the original procedure. As already noticed
by Seebach, the low yields of alkylated product are mainly
due to a concurrent elimination reaction of the enolate
leading to the deprotected a,b-unsaturated ester 7.
Each of the previous methods suffers from one or more lim-
itations due to a lengthy or laborious synthetic scheme, use
of toxic reagents, lack of generality, or overall low yields.
We reasoned that the only way to reduce the relative
amount of elimination product was to enhance the rate
of the alkylation step. The use of Na+ or K+ counterions
of the enolate should promote the formation of less tight
ion-pairs, making the enolate more reactive toward electro-
philes. Moreover, we observed that at ꢀ78 °C the forma-
tion of the enolate requires only seconds to be complete
while the elimination reaction is much slower. We also ver-
ified that at ꢀ78 °C sodium hexamethyldisilazide is com-
patible with the presence of benzyl bromide. Taken
together, these observations led to the idea of forming
the enolate at ꢀ78 °C in the presence of excess benzyl bro-
mide. A similar procedure has been already adopted for the
preparation of enolsilane derivatives under kinetic con-
trol.17 Much to our delight, such a modified procedure,
involving a slow, dropwise addition at ꢀ78 °C of NaH-
MDS (1.5 equiv) to a mixture of the oxazolidine 5 in
6:1:1 THF/hexane/DMPU and 4 equiv of benzyl bromide,
led to a dramatic increase in the yield (83%). To test the
generality of this new protocol, the same alkylation reac-
tion was carried out with different alkyl halides (methyl
iodide, ethyl iodide, allyl bromide). The yields were always
higher than 75% (see Scheme 3) exceeding by 10–30% those
previously reported for the same substrates.
2. Results and discussion
Although our primary aim was the synthesis of vinyl phen-
ylalanine, we set up a synthetic scheme that could allow the
preparation of homologated b,c-unsaturated derivatives
and the introduction of various alkyl groups on the a-car-
bon starting from a common intermediate. The most
straightforward solution to the former issue could be a
Wittig olefination of a formyl group whereas a stereoselec-
tive alkylation reaction could serve for the installation of
the quaternary stereocenter.
A retrosynthetic scheme was then devised whereby the final
quaternary vinyl amino acids could be derived by methyl-
enation of enantioenriched N-Cbz-a-alkyl serinal deriva-
tives, easily obtainable by oxidation of the primary alcohol
of the corresponding serine derivatives (Scheme 1).
One of the most reliable methods for the preparation of
such compounds through a highly stereoselective alkyl-
ation reaction relies on the use of an enolate derived
from N-formyl-2-t-butyl-4-carbomethoxy oxazolidine 5
(Scheme 2), pioneered by Seebach two decades ago.15,16
The major advantages of this protocol lie in the high stereo-
induction values and the commercial availability of chiral
precursors in both enantiomeric forms. On the other hand,
the use of carcinogenic HMPA as an additive and alkyl-
ation yields not higher than 68% are strong limitations.
Moreover, the yield of the benzylation reaction, which
was of particular interest for our purposes, was reported
to be at the lowest end of the range. Initial benzylation
experiments were performed following the experimental
procedure reported by Seebach with the only modification
being the use of DMPU in place of HMPA (Scheme 2).
A further modification of the original protocol involved the
following simultaneous deprotection of the formamido,
methyl ester, and hemiaminal groups. To retain the ester
functionality, which is required for the next step, we found
that treatment of the oxazolidine 6 with a saturated HCl
methanol solution selectively removed the formamido
group. Evaporation of the solvent followed by treatment
with aqueous 3 M HCl in THF led to benzyl serine methyl
ester 3 in almost quantitative yield.18 It is interesting to
note that the deformylated oxazolidine intermediate 11
was shown to be a mixture of two diastereoisomers, epi-
meric at the hemiaminal center. This can be explained by
the equilibration of the free oxazolidine with the acyclic
iminium and/or oxocarbenium ions (12 and 13), as de-
picted in Scheme 4.
Methylenation
Oxidation
NHCbz
COOH
NHCbz
COOMe
O
R
R
1
2
The protection of the amine group in compound 3 as a Cbz
derivative turned out to be less trivial than expected. Stan-
dard reaction conditions led to poor yields of the desired
compound, and to variable amounts of the N,O-diprotect-
ed derivative as well as the ozazolidinone derived by intra-
molecular attack of the hydroxyl group onto the carbonyl
carbon of the benzyl carbamate. The formation of an
oxazolidinone may be favored by the Thorpe–Ingold effect
exerted by the geminal benzyl and carboxymethyl groups.
After many trials we found that an almost quantitative
Stereoselective
alkylation
NH2
NH2
COOMe
HO
COOMe
HO
R
H
3
4
Scheme 1.

M. Di Giacomo et al. / Tetrahedron: Asymmetry 19 (2008) 247–257
249
O
H
H
N
O
COOMe
H
COOMe
Ph
N
+
H
H
O
a
b
O
7
.
6
H
NH2 HCl
Ref.15
<20%
(52%)
COOMe
HO
N
COOMe
H
O
O
H
4
5
COOMe
Ph
N
O
6
83%
Scheme 2. Reagents and conditions: (a) LDA, BnBr, DMPU, THF/hexane 10:1, ꢀ78 °C to rt in 12 h; (b) NaHMDS, BnBr, DMPU, THF/hexane 6:1,
ꢀ78 °C, 900.
O
O
in the presence of molecular sieves, thus avoiding the use
of low temperature regimes. Crude 2 was routinely used
in the ensuing methylenation reaction. We were aware that
any methylenation procedure involving as a first step the
addition of a carbon nucleophile onto the aldehyde would
have inevitably produced a b-alkoxy ester, prone to under-
go a facile retro-Claisen reaction to give the ester enolate of
N-Cbz phenylalanine 18. Standard Wittig conditions using
THF as a solvent led to the formation of the retro-Claisen
compound 19 (Scheme 6) as the major or unique reaction
product, in spite of a large variation of experimental condi-
tions involving the base, temperature, and addition order
of reagents. These negative results prompted us to screen
other olefination conditions.
H
H
COOMe
R
COOMe
N
N
a
O
O
8 R= Me 95% (68%)
9 R= Et 75% (62%)
10 R= Ally 89% (57%)
5
Scheme 3. Reagents and conditions: (a) NaHMDS, DMPU, THF/hexane
6:1, ꢀ78 °C. For 8: CH3I; for 9: EtI; for 10: AllylBr. The yields in brackets
were previously reported.15
yield of 14 could be obtained by inverse addition of the
amino alcohol 3 to a THF solution of 1.4 equiv of di-
benzyldicarbonate with no added base at 0 °C. Under these
conditions the reaction is complete in less than a minute
(Scheme 5).
We first considered the Takai–Nozaki olefination,21 treating
2 with the organo zinc reagent CH2I2–Zn–Me3Al in anhy-
drous THF, but the results obtained were minimal and
unsatisfactory, even performing the addition of the aldehyde
at lower temperature (ꢀ78 °C instead of 0 °C). Switching to
The following oxidation of the primary alcohol was ini-
tially performed under Swern conditions,19 furnishing the
desired benzyl serinal derivative 2 in very good yields
(92%). Comparable results (93%) were also obtained by
the use of a more practical oxidizing agent such as PCC20
22
CH2Br2–Zn–TiCl4 did not lead to any improvement. We
23
also tried samarium iodide–CH2I2 and dimethyl-1-diazo-
oxopropylphosphonate24 as methylenation agents, but,
once again, we obtained only the side product 18.
H
H
COOMe
N
COOMe
N
+
O
O
O
Ph
Ph
H
NH2
cis-11
trans-11
COOMe
Ph
N
b
a
HO
COOMe
95%
O
Ph
6
3
H H
N
H
COOMe
Ph
N
COOMe
Ph
O
O
H
12
13
Scheme 4. Reagents: (a) HCl–MeOH; (b) 3 M aq HCl/THF.

250
M. Di Giacomo et al. / Tetrahedron: Asymmetry 19 (2008) 247–257
Switching from THF to a less polar solvent such as toluene,
NH2
COOMe
NHCbz
COOMe
b
a
salt free conditions were shown to be really effective,
affording the desired vinyl derivative 15 in a satisfactory
68% yield over two steps under carefully controlled temper-
ature conditions (see Section 4). Methyl ester saponifica-
tion with LiOH afforded the desired N-Cbz-a-vinyl
phenyl alanine in almost quantitative yield. The synthesis
of the target compound was thus accomplished in an over-
all 35% yield from serine methyl ester (corresponding to a
86% average yield for each of the seven steps), significantly
higher than the ones provided by all the other previously
reported methods.
HO
O
HO
87%
95%
Ph
Ph
3
14
NHCbz
COOMe
NHCbz
COOMe
d
c
96%
68%
Ph
Ph
15
2
NHCbz
COOH
The whole synthetic scheme was then repeated using the
methyl and allyl derivatives 8 and 9, leading, respectively,
to N-Cbz-a-vinyl alanine 24a and N-Cbz-a-vinyl a-allyl
glycine 24b in comparable yields (Scheme 7).
Ph
1
The enantiomeric excess of the final N-Cbz-a-vinyl phenyl
˚
Scheme 5. Reagents and conditions: (a) Cbz2O, THF, 0 °C; (b) PCC, 4 A
MS, CH2Cl2; (c) Ph3PCH3Br, KHMDS, toluene, ꢀ78 °C to rt; (d)
LiOHꢁH2O, H2O/THF/MeOH.
1
alanine was measured by H NMR analysis of the corre-
sponding Mosher’s esters (Scheme 8).26
Reduction of the carboxylic acid methyl ester of (S)-1 with
LiAlH4 gave the expected primary alcohol (S)-25, that was
eventually converted into the corresponding ester (S,R)-27
by reaction with the Mosher acid (R)-(+)-26 in the presence
of DCC. The same sequence was previously performed on
rac-1,8 obtaining an equimolar mixture of the two
Mosher’s esters (referred to as rac-27 in Section 4) to test
After establishing the ineffectiveness of alternative routes,
we re-examined the Wittig reaction. We reasoned that the
preponderant formation of the retro-Claisen product
would be reduced if the stability of the intermediate phos-
phorane would be reduced by avoiding complexation with
Li ions acting as Lewis acids (Scheme 6).25
NHCbz
NHCbz
O
O
COOMe
COOMe
Ph3 P CH2
Ph
Ph
Ph3P
16
2
ylide
B
A
NHCbz
NHCbz
COOMe
O
O
COOMe
Ph
Ph
Ph3P
Ph3P
O
H
Ph3P
NHCbz
NHCbz
O
COOMe
COOMe
Ph3P
Ph
Ph
17
18
aqueous
work-up
Ph3PO
NHCbz
COOMe
NHCbz
H
COOMe
Ph
Ph
15
19
Scheme 6. Proposed mechanistic explanation for the formation of compound 19 during the Wittig reaction.

M. Di Giacomo et al. / Tetrahedron: Asymmetry 19 (2008) 247–257
251
O
NHCbz
OH
NHCbz
H
a
b
COOMe
COOMe
R
NH2
COOMe
N
b
d
a
c
85%
90%
HO
Ph
Ph
(S)-1
O
R
(S)-25
8 R= Me
20a R= Me (90%)
20b R= Allyl (91%)
10 R= Allyl
CbzHN
Ph
OMe
O
Ph
O
O
NHCbz
NHCbz
F3C
HO
OMe
F3C
(R)-26
Ph
O
HO
COOMe
COOMe
R
R
(S,R)-27
21a (98%)
21b (88%)
22a (87%)
22b (88%)
NHCbz
NHCbz
a
b
COOMe
OH
72%
81%
NHCbz
NHCbz
Ph
rac-1
Ph
rac-25
e
COOH
COOMe
R
R
23a (63%)
23b (70%)
24a (99%)
24b (98%)
CbzHN
CbzHN
Ph
OMe
Ph
O
O
+
Scheme 7. Reagents and conditions: (a) (i) HCl–MeOH; (ii) 3 N aq HCl/
THF; (b) Cbz2O, THF, 0 °C; (c) PCC, 4 A MS, CH2Cl2; (d) Ph3PCH3Br,
KHMDS, toluene, ꢀ78 °C to rt; (e) LiOHꢁH2O, H2O/THF/MeOH.
O
O
OMe
F3C
F3C
(S,R)-27
˚
Ph
(R,R)-27
Ph
Scheme 8. Reagents and conditions: (a) LiAH4, THF, 0 °C to rt; (b) (R)-
26, DCC, CH2Cl2.
the viability of the method. Baseline separation of signals
was observed only in spectra of Mosher esters in DMSO-
d6 solution. Relative integration of the doublets at 4.41.
and 4.49 [for (S,R)-27] and 4.31 and 4.61 [for (R,R)-27],
assigned to the diastereotopic methylene protons linked
to the ester oxygen, gave an enantiomeric excess >94%
(Fig. 1).
3. Conclusions
In conclusion, we have described a fast and practical enan-
tioselective synthesis of (S)-N-Cbz-a-vinyl phenylalanine,
suitable for the preparation of different (S)-N-Cbz-a-vinyl
Figure 1. In blue: DMSO-d6 1H NMR of the equimolar mixture of Mosher’s esters 27; in red: DMSO-d6 1H NMR of the enantioenriched Mosher’s ester
(S,R)-27.

252
M. Di Giacomo et al. / Tetrahedron: Asymmetry 19 (2008) 247–257
a-alkyl amino acids and their enantiomers as well. The new
protocol exploits a Wittig reaction on highly enantio-
enriched N-Cbz, a-formyl, and a-alkyl amino esters,
readily accessible from L-serine through a stereoselective
alkylation of Seebach’s oxazolidine 5, performed with a
significant improvement of the previously reported meth-
od. The new protocol (1) affords final products with good
overall yields (>43% from Seebach’s oxazolidine 5); (2)
can provide easy access to both enantiomers of the target
electrophile, and quenched after 70 min. The crude was
then purified by flash chromatography on silica gel (elution
with hexanes/AcOEt 7:3), affording 9.4 g of the title com-
pound (83%) as colorless crystals, mp = 129–130 °C
(Et2O/pentane) [a]D = +32.6 (c 1.2, CHCl3, 23 °C). IR
(Nujol) 2960, 1740, 1670, 1434, 1400, 1376, 1364, 1347,
1
1129, 1062, 1032, 980, 964, 885 cmꢀ1. H NMR (DMSO-
d6, 120 °C): d 0.90 (s, 9H), 3.40 (d, J = 13.7 Hz, 1H), 3.47
(d, J = 13.7 Hz, 1H), 3.73 (s, 3H), 4.08 (d, J = 9.1 Hz,
1H), 4.25 (d, J = 9.1 Hz, 1H), 4.63–4.93 (br s, 1H), 7.14–
7.21 (m, 2H), 7.23–7.33 (m, 3H), 8.53 (s, 1H). 13C NMR
(CDCl3, DMSO-d6, 120 °C): d 26.6, 38.0 (s), 53.1, 69.3
(s), 73.4 (t), 97.7, 127.9, 129.1, 130.9, 135.8 (s), 162.0,
171.7 (s). The benzylic methylene signal is obscured by
the solvent. DEPT spectrum recorded in CDCl3 revealed
methylene carbon at 44.6 ppm; MS (ESI) m/z: 306.2
[M+H]+, 328.1 [M+Na]+. Anal. Calcd for C17H23NO4:
C, 66.86; H, 7.59; N, 4.59. Found: C, 66.93; H, 7.53; N,
4.54.
compounds with
a very good enantiomeric excess
(>94%); (3) is very practical, with a limited number of steps
and simple experimental procedures; (4) can be easily
applied also to a multi-gram scale synthesis: in our labora-
tory we routinely processed 8–10 g batches.
4. Experimental
4.1. General
THF and toluene were distilled from sodium/benzo-
phenone ketyl and CH2Cl2 from CaH2. TLC was per-
formed on Kieselgel 60 F254 (Merck) glass Plate with
detection by UV light, iodine, or a solution of 4,4-methyl-
enebis-N,N-dimethylaniline, ninidrine, KI in an aqueous
ethanolic solution of AcOH. Flash chromatography was
performed on Merck Kieselgel 60 (230–400 mesh). Melting
points were determined on a Kofler apparatus and are
uncorrected. Optical rotations were measured with a
Perkin–Elmer 343 polarimeter. The 1H (400 MHz) and
13C NMR (100 MHz) spectra were recorded with Bruker
Avance 400 instruments. In the peak listing of 13C spectra
abbreviations s and t refer to zero and two protons
attached to the carbons, as determined by DEPT experi-
ments. Infrared spectra were recorded on a Perkin–Elmer
FTIR 1600 series spectrometer. Mass spectra were
recorded on a Finnigan LCQ-DECA mass spectrometer.
Elemental analyses were performed on a Carlo Erba
Elemental Analyzer Mod. 1106.
4.4. (2R,4S)-Methyl 2-tert-butyl-3-formyl-4-methyloxazol-
idine-4-carboxylate 8
The reaction was performed on 1 g (4.65 mmol) of 5, using
methyl iodide (4.34 mL, 69.75 mmol) as electrophile and
quenched after 40 min. The crude was then purified by
flash chromatography on silica gel (elution with hexanes/
AcOEt = 6:4), affording 1.1 g of the title compound
(95%) as a colorless oil. [a]D = ꢀ32.6 (c 0.9, CDCl3,
23 °C). IR (neat) 2975, 2920, 2880, 1745, 1676, 1405,
1
1385, 1370, 1350, 1303, 1146, 1121, 1080, 968 cmꢀ1. H
NMR (DMSO-d6, 120 °C): d 0.95 (s, 9H), 1.65 (s, 3H),
3.72 (s, 3H), 3.75 (d, J = 8.8 Hz, 1H), 4.40 (d, J = 8.7 Hz,
1H), 5.10 (s, 1H), 8.40 (s, 1H). 13C NMR (DMSO-d6,
120 °C): d 22.6, 26.5, 37.8 (s), 53.1, 65.6 (s), 76.1 (t), 97.1,
161.9, 172.6 (s). MS (ESI) m/z: 230.2 [M+H]+, 252.1
[M+Na] Anal. Calcd for C11H19NO4: C, 57.62; H, 8.35;
N, 6.11. Found: C, 57.52; H, 8.22; N, 6.01.
4.5. (2R,4S)-Methyl 2-tert-butyl-4-ethyl-3-formyloxazol-
idine-4-carboxylate 9
4.2. General procedure for the alkylation of oxazolidine 5
To a 0.2 M solution of 515 (1 equiv) in freshly distilled THF
stirred in a nitrogen atmosphere were added in sequence
DMPU (1:6 of the THF volume), the alkyl halide (4 equiv),
and hexane (1:6 of the THF volume). The resulting solu-
tion was then cooled to ꢀ78 °C and NaHMDS (1.2 equiv
of a 1.0 M solution in THF) was added dropwise (very
slowly); the reaction mixture turned to pale yellow. The
reaction was quenched by addition of a saturated aqueous
solution of NH4Cl; the reaction mixture was then allowed
to warm to rt, diluted with water, and extracted three times
with AcOEt; the combined organic phases were dried over
Na2SO4, and the solvent evaporated under reduced pres-
sure. The resulting crude was purified by flash
chromatography.
The reaction was performed on 1 g (4.65 mmol) of 5, using
ethyl iodide (5.6 mL, 69.7 mmol) as electrophile and
quenched after 60 min. The crude was then purified by
flash chromatography on silica gel (elution with hexanes/
AcOEt = 6:4), affording 848 mg of the title compound
(75%) as a colorless oil. [a]D = ꢀ29.1 (c 0.7, CHCl3,
23 °C). IR (neat): 2980, 2920, 2890, 1745, 1676, 1482,
1462, 1440, 1404, 1358, 1335, 1268, 1230, 1216, 1090,
1
1072, 1039, 970, 890 cmꢀ1. H NMR (CDCl3, 7:3 mixture
of rotamers): d 0.88 (t, J = 7.4 Hz, 0.9 H), 0.90 (s, 6 H),
0.94 (t, J = 7.4 Hz, 2.1H), 1.01 (s, 3H), 1.90 (dq,
J1 = 7.4 Hz, J2 = 14.7 Hz, 0.7H), 2.07 (dq, J1 = 7.4 Hz,
J2 = 14.7 Hz, 0.3H), 2.19 (dq, J1 = 7.4 Hz, J2 = 14.7 Hz,
0.7 H), 2.51 (dq, J1 = 7.4 Hz, J2 = 14.7 Hz, 0.3H), 3.75
(s, 0.9H), 3.78 (d, J = 8.9 Hz, 0.9H), 3.94 (d, J = 8.9 Hz,
2.1H), 4.29 (d, J = 8.9 Hz, 0.9H), 4.62 (d, J = 8.9 Hz,
2.1H), 4.90 (s, 0.3H), 5.32 (s, 0.7H), 8.42 (s, 0.3H), 8.46
(s, 0.7H) 13C NMR (CDCl3, mixture of rotamers): d 8.0,
8.5, 25.6 (t), 25.9, 26.3, 31.5 (t), 37.9 (s), 38.8 (s), 53.0,
53.3, 68.8 (s), 69.2 (s), 73.5 (t), 74.8 (t), 97.4, 98.5, 160.0,
4.3. (2R,4S)-Methyl 4-benzyl-2-tert-butyl-3-formyloxazol-
idine-4-carboxylate 6
The reaction was performed on 8 g (37.2 mmol) of 5, using
freshly distilled benzyl bromide (22 mL, 148.8 mmol) as

M. Di Giacomo et al. / Tetrahedron: Asymmetry 19 (2008) 247–257
253
163.0, 172.5 (s). MS (ESI) m/z: 244.2 [M+H]+, 266.1
4.9. (2S)-Methyl 2-amino-3-hydroxy-2-methylpropanoate
20a
[M+Na]+. Anal. Calcd for C12H21NO4: C, 59.24; H,
8.70; N, 5.76. Found: C, 59.30; H, 8.81; N, 5.79.
The reaction was performed on 800 mg (3.49 mmol) of 8 as
described in the general procedures, affording 418 mg of
the title compound (90%) as a colorless oil. TLC Rf 0.32
AcOEt/MeOH 95:5. [a]D = ꢀ17.2 (c 1.2, CHCl3, 23 °C).
IR (neat) 3369.7, 2924.6, 2854.4, 1732.3, 1261.8,
4.6. (2R,4S)-Methyl 4-allyl-2-tert-butyl-3-formyloxazol-
idine-4-carboxylate 10
The reaction was performed on 1g (4.65 mmol) of 5, using
freshly distilled allyl bromide (6.0 mL, 69.7 mmol) as elec-
trophile, and quenched after 65 min. The crude was then
purified by flash chromatography on silica gel (elution with
hexanes/AcOEt = 7:3), affording 1.059 g of the title com-
pound (89%) as a colorless oil. [a]D = ꢀ8.6 (c 0.8, CHCl3,
23 °C). IR (neat) 2960, 2910, 2875, 1740, 1670, 1434,
1477, 1436, 1399, 1376, 1365, 1350, 1319, 1296, 1126,
1
1156.2 cmꢀ1. H NMR (DMSO-d6): d 1.15 (s, 3H); 3.20–
3.96 (b, exchanges with D2O, 2H); 3.32 (d, J = 10.5 Hz,
1H); 3.53 (d, J = 10.5 Hz, 1H); 3.63 (s, 3H); 4.96–5.28 (b,
exchanges with D2O, 1H). 13C NMR (CDCl3): d 21.3,
54.1, 60.8 (s), 70.1 (t), 178.5 (s). MS (ESI) m/z: 134.0
[M+H]+, 156.1 [M+Na]+. Anal. Calcd for C5H11NO3: C,
45.10; H, 8.33; N, 10.52. Found: C, 45.23; H, 8.25; N,
10.57.
1
1097, 990, 930, 886 cmꢀ1. H NMR (DMSO-d6, 120 °C):
d 0.94 (s, 9H), 2.83–2.95 (m, 2H), 3.73 (s, 3H), 3.99 (d,
J = 9.0 Hz, 1H), 4.37 (d, J = 9.0 Hz, 0.5H), 5.07 (s, 1H),
5.13–5.23 (m, 2H), 5.73 (tdd, J = 7.1, 10.2, 17.3 Hz, 1H),
8.44 (s, 1H). 13C NMR (CDCl3, mixture of rotamers): d
25.9, 26.4, 36.8 (t), 37.9 (s), 38.8 (s), 42.9 (t), 53.2, 53.4,
67.7 (s), 68.5 (s), 73.5 (t), 74.5 (t), 97.4, 98.7, 120.7 (t),
121.9 (t), 129.8, 131.9, 160.1, 162.9, 171.4 (s), 172.0 (s).
MS (ESI) m/z: 256.1 [M+H]+, 278.2 [M+Na]+. Anal.
Calcd for C13H21NO4: C, 61.16; H, 8.29; N, 5.49. Found:
C, 61.32; H, 8.35; N, 5.69.
4.10. (2S)-Methyl 2-amino-2-(hydroxymethyl)pent-4-enoate
20b
The reaction was performed on 510 mg (2 mmol) of 10 as
described in the general procedures, affording 289 mg
(91%) of the title compound as yellow oil. TLC Rf 0.38
AcOEt/MeOH 98:2. [a]D = +2.3 (c 1.7, CHCl3, 23 °C).
IR (neat) 3418.6, 2363.5, 1728.8, 1643.7, 1441.0, 1228.6,
1
1060.3 cmꢀ1. H NMR (CDCl3): d 2.24 (dd, J1 = 8.4 Hz,
J2 = 13.6 Hz, 1H), 2.47 ( dd, J1 = 13.6 Hz, J2 = 6.5 Hz,
1H), 2.63 (br s, 3H, exchange with D2O), 3.50 (d,
J = 10.8 Hz, 1H), 3.64 (s, 3H), 3.79 (d, J = 10.8 Hz, 1H),
5.08–5.20 (m, 2H), 5.57–5.71 (m, 1H). 13C NMR (CDCl3):
d 40.7(t), 52.9, 62.8 (s), 68.2 (t), 120.4 (t), 132.0, 176.1 (s).
MS (ESI) m/z 160.0 [M+H]+, 182.1 [M+Na]+. Anal. Calcd
for C7H13NO3: C, 52.82; H, 8.23; N, 8.80. Found: C, 52.89;
H, 8.37; N, 8.80.
4.7. General procedure for the hydrolysis of 4-alkyl-
oxazolidines
A solution of the suitable 4-alkyl oxazolidine (1.0 mmol) in
saturated HCl methanol was stirred at 0 °C for 5 min and
then at rt for 6 h (or until complete consumption of the
starting material, as seen by TLC). The solvent was evapo-
rated under reduced pressure and the residue taken up in
THF (2.7 mL) and 3 M HCl aqueous solution (1 mL),
and the whole stirred overnight at rt. Then the reaction
mixture was basified with solid Na2CO3, diluted with
AcOEt, and extracted three times. The combined organic
layers were dried over Na2SO4 and evaporated to dryness
under reduced pressure, affording the desired alkyl serine
derivative.
4.11. General procedure for the selective N-protection of the
a-alkyl-serines
The suitable alkyl serine derivative (1 mmol) was added to
an ice-chilled solution of dibenzyldicarbonate (1.4 mmol)
in anhydrous THF (3.8 mL). The reaction was quenched
by the addition of a saturated aqueous solution of NaH-
CO3 and the reaction mixture extracted with AcOEt three
times. The combined organic layers were dried on Na2SO4
and evaporated to dryness under reduced pressure at rt.
4.8. (2S)-Methyl 2-amino-2-(hydroxymethyl)-3-phenyl-
propanoate 3
4.12. (S)-Methyl 2-benzyl-2-(benzyloxycarbonylamino)-3-
hydroxypropanoate 14
The reaction was performed on 4 g (13.11 mmol) of 6 as de-
scribed in the general procedures, affording 2.6 g of the title
compound (95%), as a white solid, which can be crystal-
lized from AcOEt/Et2O, affording white needles,
mp = 91–93 °C (AcOEt/Et2O). TLC Rf 0.28 (AcOEt/
MeOH 98:2). [a]D = +5.4 (c 1.2, CDCl3, 23 °C). IR (Nu-
The reaction was performed by adding 1.0 g (5 mol) of so-
lid 3 to the ice-chilled solution of dibenzyldicarbonate and
quenched after 15 min. The aqueous work-up and purifica-
tion by flash chromatography (elution with hexanes/
AcOEt 4:3), afforded 1.63 g of the title compound (95%)
jol): 2923.1, 2360.4, 2340.6, 1734.2, 1558.4 cmꢀ1 1H
.
NMR (CDCl3): d 2.46 (br s, 3H, exchanges with D2O);
2.83 (d, J = 13.4 Hz, 1H); 3.12 (d, J = 13.4 Hz, 1H); 3.63
(d, J = 10.8 Hz, 1H); 3.75 (s, 3H); 3.89 (d, J = 10.8 Hz,
1H); 7.12–7.15 (m, 2H); 7.25–7.34 (m, 3H). 13C NMR
(CDCl3): d 42.2 (t), 52.8, 64.1 (s), 68.2 (t), 127.6, 129.0,
130.2, 135.6 (s), 175.5 (s). MS (ESI) m/z: 210.1 [M+H]+,
232.1 [M+Na]+. Anal. Calcd for C11H15NO3: C, 63.14;
H, 7.23; N, 6.69. Found: C, 63.15; H, 7.35; N, 6.55.
as a colorless oil. TLC Rf 0.37 (Ex/AcOEt 6:4).
[a]D = ꢀ70.0 (c 1.9, CHCl3, 23 °C). IR (neat): 3419.9;
1
3031.8; 2953.2; 1733.6; 1699.6 cmꢀ1. H NMR (CDCl3): d
2.90–3.16 (b, 1H exchanges with D2O); 3.10 (d,
J = 13.6 Hz, 1H); 3.39 (d, J = 13.6 Hz, 1H); 3.80 (s, 3H);
3.97 (d, J = 11.0 Hz, 1H), 4.33 (d, J = 11.1 Hz, 1H), 5.07
(d, J = 12.2 Hz, 1H); 5.22 (d, J = 12.2 Hz, 1H); 5.64 (s,
1H); 6.94–7.04 (m, 2H); 7.17–7.27 (m, 3H); 7.33–7.46 (m,

254
M. Di Giacomo et al. / Tetrahedron: Asymmetry 19 (2008) 247–257
5H). 13C NMR (CDCl3): d 52.9 (t), 68.0, 82.0, 80.6 (t), 82.0
(t), 142.4, 143.4, 143.5, 143.7 (2 peaks), 144.9, 150.0 (s),
151.4 (s), 170.5 (s), 187.3 (s). MS (ESI): 344.3 [M+H]+,
366.2 [M+Na]+. Anal. Calcd for C19H21NO5: C, 66.46;
H, 6.16; N, 4.08. Found: C, 66.59; H, 6.21; N, 4.22.
then more PCC (0.5 mmol) and MS (1:6 of the initial
amount used) were added. After 1 h and 30 min, the reac-
tion mixture was filtered through a pad of CeliteÒ and sil-
ica, washing carefully first with anhydrous Et2O (4 ꢂ
5 mL) and then with CH2Cl2, until a clear and colorless
filtrate was obtained. Evaporation of the solvent under
reduced pressure at rt afforded a crude that was used in
the next step without any further purification.
4.13. (S)-Methyl 2-(benzyloxycarbonylamino)-3-hydroxy-2-
methylpropanoate 21a
The reaction was performed by adding 418 mg (3.14 mmol)
of 20a dissolved in 3.5 mL of distilled THF to the ice-
chilled solution of dibenzyldicarbonate and quenched after
15 min. The aqueous work-up and purification by flash
chromatography (gradient elution hexanes/AcOEt, from
8:2 to 6:4) afforded 822 mg of the title compound (98%)
as a white solid, mp 61–62 °C (AcOEt). TLC Rf 0.33 (Ex/
AcOEt 6:4). [a]D = +3.9 (c 1.7, CDCl3, 23 °C) {lit.27
[a]D = +5.4 (c 0.50, CHCl3, 27 °C)}. IR (Nujol) 3378.1,
4.16. (S)-Methyl 2-benzyl-2-(benzyloxycarbonylamino)-3-
oxopropanoate 2
The reaction was performed on 1 g of 14 (2.91 mmol), fol-
lowing the general procedure for the oxidation, and affor-
ded a pale yellow oil that was used in the next step
without any further purification. A sample from the reac-
tion mixture (300 mg) was purified by flash chromatogra-
phy (elution with hexanes/AcOEt 77:23) for sake of
characterization, affording 261 mg of the title compound
(87%) as a colorless oil. TLC Rf 0.37 (hexanes/AcOEt
77:23). [a]D = ꢀ16.1 (c 0.9, CDCl3, 23 °C). IR (neat)
3408.4, 2954.6, 1726.3, 1687.2, 1496.4, 1272.7, 1213.4,
1075.7, 1042.4 cm1. 1H NMR (CDCl3): d 3,53 (d,
J = 14.0 Hz, 1H); 3.61 (d, J = 14.0 Hz, 1H); 3.81 (s, 3H);
5.16 (d, J = 12.2 Hz, 1H); 5.21 (d, J = 12.2 Hz, 1H); 5.84
(s, 1H), 6.93–7.00 (m, 2H); 7.20–7.27 (m, 3H); 7.33–7.45
(m, 5H); 9.63 (s, 1H). 13C NMR (CDCl3): d 37.2 (t),
53.5, 67.2 (t), 71.8 (s), 126.3, 127.4, 128.2, 128.5 (2 peaks),
129.7, 133.7 (s), 135.8 (s), 154.9 (s), 167.0 (s), 192.6. MS
(ESI) m/z: 342.2 [M+H]+, 364.1 [M+Na]+. Anal Calcd
for C19H19NO5 C, 66.85; H, 5.61; N, 4.10. Found: C,
66.99; H, 5.64; N, 4.05.
1744.8, 1686.4, 1545.0, 1280.3, 1228.1, 1073.3 cmꢀ1 1H
.
NMR (DMSO-d6, 120 °C): d 1.43 (s, 3H); 3.60 (d,
J = 10.8 Hz, 1H); 3.62 (s, 3H); 3.65 (d, J = 10.8 Hz, 1H);
4.37–4.70 (b, exchanges with D2O, 1H); 5.05 (s, 2H);
6.57–6.71 (b, exchanges with D2O, 1H); 7.28–7.40 (m,
5H).13C NMR (CDCl3): d 21.5, 53.3, 61.8 (s), 66.9 (t),
67.3 (t), 128.5, 128.7, 129.0, 136.5 (s), 156.0 (s), 174.0 (s).
MS (ESI) m/z: 268.2 [M+H]+, 290.1 [M+Na]+. Anal.
Calcd for C13H17NO5: C, 58.42; H, 6.41; N, 5.24. Found:
C, 58.49; H, 6.37; N, 5.44.
4.14. (S)-Methyl 2-(benzyloxycarbonylamino)-2-(hydroxy-
methyl)pent-4-enoate 21b
The reaction was performed by adding 300 mg (1.88 mol)
of 20b dissolved in 3 mL of distilled THF to the ice-chilled
solution of dibenzyldicarbonate and quenched after
15 min. The aqueous work-up and purification by flash
chromatography (gradient elution hexanes/AcOEt, from
7:3 to 1:1) afforded 486 mg of the title compound (88%)
as a colorless oil. TLC Rf 0.32 Ex/AcOEt 55:45.
[a]D = ꢀ2.1 (c 0.5, CHCl3, 23 °C). IR (neat) 3414.0,
3070.4, 2954.0, 2363.8, 1721.0, 1690.2, 1643.2, 1506.6,
1445.4, 1329.1, 1234.2, 1056.6, 923.7, 827.7, 741.8,
4.17. (S)-Methyl 2-(benzyloxycarbonylamino)-2-methyl-3-
oxopropanoate 22a
The reaction was performed on 712 mg of 21a (2.66 mmol),
following the general procedures for the oxidation and
afforded a pale yellow oil that was used in the next step
without any further purification. A sample from the reac-
tion mixture (200 mg) was purified by flash chromato-
graphy (elution with hexanes/AcOEt 7:3) for sake of
characterization, affording 174 mg of the title compound
(87%) as a colorless oil. TLC Rf 0.27 (Ex/AcOEt 7:3).
[a]D = ꢀ19.2 (c 1.0, CDCl3, 23 °C). IR (neat) 3405.1,
3067.3, 3024.7, 2925.0, 1746.8, 1689.2, 1545.7, 1279.8,
1
698.7 cmꢀ1. H NMR (DMSO-d6): d 2.59–2.74 (m, 2H),
3.64 (s, 3H), 3.72 (AB system, J = 12.1 Hz, 2H; after
D2O exchange: d 3.69 (d, J = 11.0 Hz, 1H); 3.73 (d,
J = 11.0, 1H)); 4.42–4.59 (br s, 1H, exchanges with D2O),
5.00–5.10 (m, 4H) 5.66–5.79 (m, 1H); 6.49 (s, 1H, ex-
changes with D2O); 7.26–7.41 (m, 5H). 13C NMR (CDCl3):
d 37.4 (t), 53.31, 65.4 (s), 65.7 (t), 67.3 (t), 120.5 (t), 128.4,
128.6, 128.9, 131.5, 136.5 (s), 155.7 (s), 172.8 (s). MS (ESI)
m/z: 294.2 [M+H]+, 317.3 [M+Na]+. Anal. Calcd for
C15H19NO5: C, 61,42; H, 6,53; N, 4,78. Found: C, 61.45;
H, 6.56; N, 4.79.
1229.3, 1071.3 cmꢀ1 1H NMR (CDCl3) d 1.70 (s, 3H);
.
3.81 (s, 3H); 5.13 (s, 2H); 6.00 (br s, 1H); 7.37 (br s, 5H);
9.54 (s, 1H). 13C NMR (CDCl3): d 19.5, 54.0, 67.4 (s),
67.7 (t), 128.6, 128.8, 129.0, 136.3 (s), 155.5 (s), 169.3 (s),
193.8. MS (ESI) m/z: 266.1 [M+H]+, 288.0 [M+Na]+.
Anal. Calcd for C13H15NO5: C, 58.86; H, 5.70; N, 5.28.
Found: C, 58.89; H, 5.61; N, 5.36.
4.15. General procedure for the oxidation of the a-alkyl-
serines
4.18. (S)-Methyl 2-(benzyloxycarbonylamino)-2-formylpent-
4-enoate 22b
˚
Activated 4 A molecular sieves (threefolds the weight of the
The reaction was performed on 440 mg of 21b (1.5 mmol),
following the general procedures for the oxidation, and
afforded a pale yellow oil that was used in the next step
without any further purification. A sample from the reac-
tion mixture (150 mg) was purified by flash chromatogra-
starting material) and PCC (1.5 mmol) were added in se-
quence to a solution of the suitable N-Cbz-a-alkyl serine
derivative (1 mmol) in dry CH2Cl2 (5 mL). The resulting
brownish suspension was vigorously stirred for 2 h, and

M. Di Giacomo et al. / Tetrahedron: Asymmetry 19 (2008) 247–257
255
phy (elution with hexanes/AcOEt 65:35) for sake of charac-
terization, affording 132 mg of the title compound (88%) as
a colorless oil. TLC Rf 0.32 Ex/AcOEt 65:35. [a]D = ꢀ17.8
(c 0.5, CHCl3, 23 °C). IR (neat) 3401.4, 3070.2, 3032.6,
2955.4, 1727.8, 1688.6, 1505.3, 1444.3, 1376.7, 1230.3,
H, 6.24; N, 4.13; O, 18.86. Found: C, 70.89; H, 6.17; N,
4.20.
4.21. (S)-Methyl 2-(benzyloxycarbonylamino)-2-methylbut-
3-enoate 23a
1041.6, 928.6, 841.1, 744.5, 698.9 cmꢀ1
.
1H NMR
(DMSO-d6): d 2.65–2.79 (m, 2H); 3.71 (s, 3H); 5.08 (s,
2H); 5.09–5.16 (m, 2H); 5.72 (tdd, J = 7.2, 10.2, 17.4 Hz,
1H); 7.29–7.40 (m, 5H); 7.39–7.47 (br s, exchanges with
D2O); 9.68 (s, 1H). 13C NMR (CDCl3): d 36.7 (t), 53.9,
67.7 (t), 70.5 (s), 121.5 (t), 128.5, 128.8, 129.0, 130.3,
136.0 (s), 168.0 (s), 173.8 (s), 193.6. MS (ESI) m/z: 292.2
[M+H]+, 314.1 [M+Na]+. Anal. Calcd for C15H17NO5:
C, 61.85; H, 5.88; N, 4.81. Found: C, 61.93; H, 5.94; N,
4.75.
The reaction was performed on 180 mg of 22a (0.67 mmol),
following the general procedures for the methylenation.
The crude was purified by flash chromatography (eluting
with hexanes/AcOEt 8:2), affording 112 mg of the title
compound (63%), as a colorless oil. TLC Rf 0.30 Ex/
AcOEt 8:2. [a]D = +3.5 (c 1.7, CDCl3, 23 °C). IR (neat)
3347.3; 2951.9; 1735.3; 1719.0; 1518.1; 1454.8; 1275.0;
1
1123.9 cmꢀ1. H NMR (DMSO-d6): d 1.52 (s, 3H); 3.63
(s, 3H); 5.05 (s, 2H); 5.15 (d, J = 10.7 Hz, 1H); 5.23 (d,
J = 17.3 Hz, 1H); 6.16 (dd, J1 = 10.7 Hz, J2 = 17.4 Hz,
1H); 7.10–7.25 (br s, 1H, exchanges with D2O); 7.27–7.43
(m, 5H). 13C NMR (CDCl3): d 23.5, 53.9, 61.0 (s), 67. 1
(t), 116.0 (t), 128.5, 128.6, 128.9, 136.7 (s), 138.1, 155.1
(s), 173.4 (s). MS (ESI) m/z: 264.1 [M+H]+, 286.0
[M+Na]+. Anal. Calcd for C14H17NO4: C, 63.87; H,
6.51; N, 5.32. Found: C, 63.78; H, 6.62; N, 5.35.
4.19. General procedure for the methylenation of N-carbo-
benzyloxy-a-formyl-a-alkyl-glycines
The phosphonium salt Ph3PCH3Br (2 mmol), dried over-
night at 110 °C, was quickly transferred to a flame-dried
flask and purged with nitrogen; anhydrous distilled toluene
(3.7 mL) was added. The resulting suspension was magnet-
ically stirred and treated with KHMDS (1.9 mmol, 3.8 mL
of a 0.5 M solution in toluene), affording a brilliant yellow
suspension. After 90 min, the reaction mixture was cooled
to ꢀ78 °C and a solution of the suitable crude aldehyde
(1 mmol) in anhydrous distilled toluene (2.5 mL) was
added dropwise. After 45 min the temperature was slowly
warmed to ꢀ60 °C; after 10 min, the reaction mixture
was slowly warmed to ꢀ40 °C, and finally, after 30 min,
stirred at rt. After 1 h at room temperature, the reaction
mixture was cooled to ꢀ20 °C and quenched with 3 N
HCl (5.5 mL) and saturated NH4Cl (5.5 mL) aqueous solu-
tions. The reaction mixture was diluted with AcOEt, the
organic layer separated, and the aqueous one extracted
twice with the same solvent. The combined organic sol-
vents were dried over Na2SO4 and evaporated to dryness
under reduced pressure, affording a crude, which was puri-
fied by flash chromatography, affording the desired vinyl
derivative.
4.22. (S)-Methyl 2-(benzyloxycarbonylamino)-2-vinylpent-4-
enoate 23b
The reaction was performed on 175 mg of 22b (0.60 mol),
following the general procedures for the methylenation.
The crude was purified by flash chromatography (eluting
with hexanes/AcOEt 8:2), affording 122 mg of the title
compound (70%), as a colorless oil. TLC Rf 0.33 hex-
anes/AcOEt 8:2. [a]D = ꢀ17.6 (c 0.8, CHCl3, 23 °C). IR
(neat) 3357.5, 3072.0, 3031.5, 3952.5, 2363.7, 1729.1,
1642.4, 1500.6, 1443.7, 1229.4, 1078.7, 926.1, 820.9,
1
778.1, 741.7, 698.2 cmꢀ1. H NMR (CDCl3): d 2.65–2.79
(m, 2H); 3.64 (s, 3H); 5.02–5.09 (m, 4H); 5.07 (tdd,
J1 = 7.9, J2 = 13.1, J3 = 17.5, 1H); 5.19 (d, J = 10.8 Hz,
1H); 5.23 (d, J = 17.6 Hz, 1H); 6.10 (dd, J1 = 10.8,
J2 = 17.5, 1H); 6.92–7.06 (br s, 1H, exchanges with D2O);
7.27–7.41 (m, 5H). 13C NMR (CDCl3): d 40.2 (t), 53.4,
64.2 (s), 67.0 (t), 116.1 (t), 120.3 (t), 128.5 (2), 128.9,
132.0, 136.6, 136.8 (s), 154.7 (s), 172.5 (s). MS (ESI) m/z:
290.1 [M+H]+, 312.0. Anal. Calcd for C16H19NO4: C,
66.42; H, 6.62; N, 4.84. Found: C, 66.59; H, 6.67; N, 4.97.
4.20. (S)-Methyl 2-benzyl-2-(benzyloxycarbonylamino)but-
3-enoate 15
The reaction was performed on 700 mg of 2 (2.0 mmol),
following the general procedures for the methylenation.
The crude was purified by flash chromatography (gradient
elution hexanes/AcOEt, from 95:5 to 8:2), affording 472 mg
of the title compound (68%) as a colorless oil. TLC Rf 0.43
(hexanes/AcOEt 82:18). [a]D = ꢀ37.6 (c 1.1, CDCl3,
23 °C). IR (neat): 3420.1; 3031.6; 2951.6; 1733.8; 1684.1;
4.23. General procedure for the saponification of N-Cbz-a-
vinyl-a-alkyl-glycine methyl esters
LiOHꢁH2O (2 mmol) in 2.5 mL of H2O and distilled THF
(5 mL) were added to a stirred solution of the suitable N-
Cbz-a-alkyl-a-vinyl-glycine derivative (1 mmol) in MeOH
(1 mL). After 8 h the solvents were evaporated under re-
duced pressure, the resulting residue taken up with H2O
and acidified with 12 N HCl, then extracted three times
with AcOEt.
1
1506.5 cmꢀ1. H NMR (CDCl3): d 3.33 (d, J = 13.4 Hz,
1H); 3.65 (d, J = 13.5 Hz, 1H); 3.79 (s, 3H); 5.09 (d,
J = 12.3 Hz, 1H); 5.22 (d, J = 12.3 Hz, 1H); 5.30 (d,
J = 17.5 Hz, 1H); 5.36 (d, J = 10.5 Hz, 1H); 5.70 (br s,
1H); 6.09 (dd, J = 10.6 Hz, J2 = 17.3 Hz, 1H); 6.95–7.03
(m, 2H); 7.15–7.26 (m, 3H); 7.32–7.46 (m, 5H). 13C
NMR (CDCl3): d 40.3 (t), 52.8, 65.1 (s), 66.5 (t), 116.1
(t), 126.9, 128.1, 128.2 (2 peaks), 128.4, 129.9, 135.4 (s),
136.5, 154.3 (s), 171.7 (s). MS (ESI) m/z: 340.0 [M+H]+,
362.1 [M+Na]+. Anal. Calcd for C20H21NO4: C, 70.78;
The combined organic solvents were dried over Na2SO4
and evaporated to dryness under reduced pressure, afford-
ing the desired free carboxylic acid.

256
M. Di Giacomo et al. / Tetrahedron: Asymmetry 19 (2008) 247–257
4.24. (S)-2-Benzyl-2-(benzyloxycarbonylamino)but-3-enoic
acid 1
4.27. (2S) and (2S and 2R)-benzyl 2-benzyl-1-hydroxybut-3-
en-2-ylcarbamate [(S)-25 and rac-25]
The reaction was performed on 295 mg of 15 (0.87 mmol)
according to the general procedure for the saponification,
and afforded 271 mg of the title compound (96%) as a col-
orless oil. TLC Rf 0.42 (EtOAc/MeOH 99:1). [a]D = ꢀ30.9
(c 1.0, CDCl3, 23 °C). IR (neat) 3400.2, 3033.7, 1709.8,
LiAlH4 (177 mg, 4.65 mmol) was transferred in a flame
dried flask, and was dissolved in anhydrous THF (3 mL),
in a nitrogen atmosphere. The resulting solution was ice-
chilled and (S)-1 (220 mg, 0.67 mmol) in 3 mL di THF
was added dropwise. When the addition was over, the reac-
tion mixture was stirred at rt for 2 h. The reaction was
quenched by the addition of Et2O, AcOEt, and H2O, the
two layers were separated and the organic one was filtered
on CeliteÒ. The solvent was evaporated under reduced
pressure and the resulting crude purified by flash chroma-
tography (elution with hexanes/AcOEt 7:3), affording
176 mg of (S)-25 (85%). The same procedure, applied on
rac-1 (120 mg, 0.37 mmol), afforded after chromatographic
purification 83 mg of rac-25 (72%).
1688.7, 1495.3, 1446.7 cmꢀ1 1H NMR (CDCl3): d 3.39
.
(d, J = 13.4 Hz, 1H), 3.60 (d, J = 13.4 Hz, 1H), 5.11 (d,
J = 12.2 Hz, 1H), 5.21 (d, J = 12.2 Hz, 1H), 5.34 (d,
J = 17.3 Hz, 1H), 5.37 (d, J = 10.6 Hz, 1H), 5.48–6.80 (br
s, 1H, exchanges with D2O), 5.63 (s, 1H), 6.11 (dd
J1 = 10.6 Hz, J2 = 17.3 Hz, 1H), 7.04–7.11 (m, 2H), 7.16–
7.26 (m, 3H), 7.35–7.45 (m, 5H). 13C NMR (CDCl3): d
40.8 (t), 65.4 (s), 67.3 (t), 116.8 (t), 127.5, 128.2, 128.7 (2
peaks), 129.0, 130.5, 135.6 (s), 136.6, 136.7 (s), 155.1 (s),
176.3 (s). MS (ESI) m/z: 326.2 [M+H]+, 348.1 [M+Na]+.
Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.31.
Found: C, 70.27; H, 5.92; N, 4.53.
(S)-25: colorless oil. [a]D = +27.3 (c 1.0, CDCl3, 23 °C). 1H
NMR (CDCl3): d 3.06 (AB system, J = 14.4 Hz, 2H), 3.74
(d, J = 12.1 Hz, 1H), 3.78 (d, J = 12.1 Hz, 1H) 4.72 (s, 1H,
exchanges with D2O), 4.93 (br s, 1H, exchanges with D2O),
5.06 (d, J = 17.4 Hz, 1H), 5.12 (d, J = 12.5 Hz, 1H), 5.15
(d, J = 12.5 Hz, 1H), 5.26 (d, J = 10.8 Hz, 1H), 5.88 (dd,
J1 = 10.8, J2 = 17.4 Hz, 1H) 7.08–7.18 (m, 2H), 7.20–7.29
(m, 3H), 7.31–7.47 (m, 5H). 13C NMR (CDCl3): d 41.6
(t), 65.8 (s), 67.3 (t), 67.8 (t), 115.9 (t), 127.3, 127.9,
128.7, 129.0, 131.1, 136.0 (s), 136.7 (s), 139.5, 156.6 (s).
MS (ESI) m/z: 312.2 [M+H]+, 334.1 [M+Na]+. Anal.
Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found:
C, 73.16; H, 6.64; N, 4.42.
4.25. (S)-2-(Benzyloxycarbonylamino)-2-methylbut-3-enoic
acid 24a
The reaction was performed on 190 mg of 22a (0.72 mmol)
according to the general procedure for the saponification,
and afforded 177 mg of the title compound (99%) as a col-
orless oil. TLC Rf 0.43 AcOEt/MeOH 98:2. [a]D = +7.2 (c
1.0, CDCl3, 23 °C). IR (neat): 3431.3, 3050.2, 2543.4,
1
1686.1, 1450.9, 1208.7 cmꢀ1. H NMR (CDCl3): d 1.71 (s,
3H), 5.14 (s, 2H), 5.31 (d, J = 10.5 Hz, 1H), 5.36 (d,
J = 17.5 Hz, 1H), 5.60 (s, 1H), 5.67–6.40 (br s, 1H, ex-
changes with D2O), 6.10 (dd, J1 = 10.5 Hz, J2 = 17.5 Hz,
1H), 7.37 (m, 5H) 13C NMR (CDCl3): d 23.6 (q), 60.7,
60.8 (s), 67.4 (t), 116.4 (t), 128.5 (d), 128.6 (d), 128,8 (s),
128.9 (d), 137.5 (d), 147.9 (s), 77.1 (s). MS (ESI) m/z:
250.1 [M+H]+, 272.0 [M+Na]+. Anal. Calcd for
C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C, 62.67;
H, 6.09; N, 5.63.
4.28. (3R)-[(20S) and (20S and 20R)-20-benzyl-20-(benzyloxy-
carbonylamino)but-30-enyl]3,3,3-trifluoro-2-methoxy-2-phen-
ylpropanoate [(S,R)-27 and (S and R)-(R)-27]
Mosher’s acid (R)-(+)-26, (49.45 mg, 0.211 mmol) and
DCC (43.53 mg, 0.211 mmol) were added to a solution of
(S)-25 (55 mg, 0.176 mmol) in 5ml of CH2Cl2. The whole
was stirred at rt in a nitrogen atmosphere until complete
disappearance of the starting material (monitored by
TLC, eluting with hexanes/AcOEt 9:1). Then the reaction
mixture was filtered, and the solvent evaporated under re-
duced pressure; the resulting crude was purified by flash
chromatography, eluting with hexanes/AcOEt 7:3, afford-
ing 81 mg of (S,R)-27 as a colorless oil (90%). The same
procedure, applied to rac-25 (55 mg, 0.176 mmol), afforded
after chromatographic purification 73 mg of rac-27 as a
colorless oil (81%).
4.26. (S)-2-(Benzyloxycarbonylamino)-2-vinylpent-4-enoic
acid 24b
The reaction was performed on 100 mg of 22b
(0.346 mmol) according to the general procedure for the
saponification, and afforded 93 mg of the title compound
(98%) as a colorless oil.
TLC Rf 0.38 AcOEt/MeOH 98:2. [a]D = ꢀ7.5 (c 0.4,
CHCl3, 23 °C). IR (neat) 3427.9, 3081.8, 2363.5, 1713.4,
1502.8, 1415.8, 1232.7, 1083.4, 992.8, 926.5, 743.5,
(S,R)-27: [a]D = +7.2 (c 1.0, CDCl3, 23 °C). 1H NMR
(DMSO-d6):
d 2.98 (d, J = 13.4 Hz, 1H), 3.04 (d,
J = 13.4 Hz, 1H), 3.45 (s, 3H), 4.42 (d, J = 10.9, 1H),
4.49 (d, J = 10.9 Hz, 1H), 4.98–5.18 (m, 4H), 5.75 (dd,
J1 = 11.2, J2 = 17.6 Hz, 1H), 6.95–7.05 (m, 2H), 7.18–
7.27 (m, 3H), 7.30–7.47 (m, 9H), 7.51–7.58 (m, 2H). MS
(ESI) m/z 528.2 [M+H]+. Anal. Calcd for C29H28F3NO5:
C, 66.03; H, 5.35; N, 2.66. Found: C, 66.22; H, 5.37; N,
2.43.
696.1 cmꢀ1 1H NMR (CDCl3): d 2.68–2.88 (m, 1H),
.
2.93–3.08 (m, 1H), 5.08–5.22 (m, 4H), 5.28–5.38 (app. d,
2H), 5.61–5.79 (m, 2H), 6.10 (dd, J1 = 10.5, J2 = 17.3 Hz,
1H), 7.29–7.43 (m, 5H), 11.30–12.50 (br s, 1H, exchanges
with D2O) 13C NMR (CDCl3): d 40.3(t), 60.9 (s), 67.4 (t),
116.6 (t), 120.7 (t), 128.5, 128.6, 128.9, 131.7, 136.3, 136.6
(s), 155.1(s), 176.4 (s). MS (ESI) m/z: 276.2 [M+H]+,
298.1 [M+Na]+. Anal. Calcd for C15H17NO4: C, 65.44;
H, 6.22; N, 5.09. Found: C, 65.64; H, 6.31; N, 4.99.
rac-27: 1H NMR (DMSO-d6): d 2.91–3.07 (m, 2H); 3.45 (s,
3H); 4.32 (d, J = 11.1 Hz, 0.5H); 4.42 (d, J = 10.9 Hz,

M. Di Giacomo et al. / Tetrahedron: Asymmetry 19 (2008) 247–257
257
10. (a) Jones, M. C.; Marsden, S. P.; Munoz Subtil, D. M. Org.
˜
0.5H); 4.49 (d, J = 10.8 Hz, 0.5H); 4.61 (d, J = 11.1 Hz,
0.5H); 4.98–5.18 (m, 4H); 5.71 (dd, J1 = 11.1 Hz,
J2 = 17.6 Hz, 0.5H); 5.75 (dd, J1 = 11.2 Hz, J2 = 17.6 Hz,
0.5H); 6.86–6.96 (m, 2H); 7.13–7.22 (m, 3H); 7.26 (br s,
0.5H); 7.29–7.41 (m, 5.5H); 7.44–7.53 (m, 5H).
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Acknowledgment
MUR is acknowledged for funding (PRIN2006 Prot.
2006030449 Research Program).
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