Silylcupration of (R)-2,2-dimethyl-3-(tert-butoxycarbonyl)-4- ethynyloxazolidine: A stereoselective approach to the synthesis of γ- silylated saturated and unsaturated α-amino acids

Article abstract of DOI:10.1021/jo991272r

Enantioselective synthesis of γ-silylated amino acids is reported, using a four-step procedure based on the silylcupration of ethynyloxazolidine 2. Silylcuprates 6a-c are highlighted as useful reagents to be employed with enantiomerically enriched substrates. Vinylsilanes 5 are easily prepared and highlighted as useful intermediates to yield the final compounds after reduction, opening of the oxazolidine ring, and oxidation. Moreover, β,γ- unsaturated amino acids are obtained as very interesting vinylglycine derivatives. The capability of silicon-containing amino acids to be incorporated into dipeptides is also shown.

Full text of DOI:10.1021/jo991272r

J . Org. Chem. 1999, 64, 9211-9216
9211
Silylcu p r a tion of
(R)-2,2-Dim eth yl-3-(ter t-bu toxyca r bon yl)-4-eth yn yloxa zolid in e: A
Ster eoselective Ap p r oa ch to th e Syn th esis of γ-Silyla ted Sa tu r a ted
a n d Un sa tu r a ted r-Am in o Acid s
Gianna Reginato,* Alessandro Mordini, Michela Valacchi, and Elena Grandini
Centro CNR Composti Eterociclici, Dipartimento di Chimica Organica “U. Schiff”, via G. Capponi 9,
I-50121 Firenze, Italy
Received August 10, 1999
Enantioselective synthesis of γ-silylated amino acids is reported, using a four-step procedure based
on the silylcupration of ethynyloxazolidine 2. Silylcuprates 6a -c are highlighted as useful reagents
to be employed with enantiomerically enriched substrates. Vinylsilanes 5 are easily prepared and
highlighted as useful intermediates to yield the final compounds after reduction, opening of the
oxazolidine ring, and oxidation. Moreover, â,γ-unsaturated amino acids are obtained as very
interesting vinylglycine derivatives. The capability of silicon-containing amino acids to be
incorporated into dipeptides is also shown.
In tr od u ction
knowledge, the only examples of silicon-containing amino
acids which have been synthesized so far.
The biological importance of natural and unnatural
R-amino acids has increasingly attracted the attention
for the search of new enantioselective synthetic routes
to these compounds.1-4 An interesting class of unnatural
amino acids are those which contain silicon, trialkylsilyl
chains being known to have hydrophobic properties which
might be relevant for biological activity.5,6 For this reason
they can be used as suitable substitutes of natural
lipophilic amino acids, or as replacements in naturally
occurring peptides. This fact can be responsible for
enhancing the biological activity and proteolytic stability
of the modified peptide, as has already been observed
when â-trimethysilylalanine was employed as a bio-
isostere for phenylalanine in the search for stable renin
inhibitors.7 Moreover, because of the rich reactivity
known for organosilanes,8 coupled with the growing
importance of amino acids as chiral synthons,9 silylated
amino acids can be considered as useful optically active
starting materials for a variety of synthetic applications.
Despite this interest only a few reports on the synthesis
of these compounds are known: some trialkylsilylalanine
derivatives have been prepared, in both racemic and
enantiomerically enriched form,10-13 but these are, to our
We have recently reported that the addition of (tribu-
tylstannyl)cuprate 1 to (R)-2,2-dimethyl-3-(tert-butoxy-
carbonyl)-4-ethynyloxazolidine (2) is a very efficient and
mild procedure to obtain γ-substituted amino acid pre-
cursors. Substrate 2 can be readily prepared,14-16 with
high enantiomeric purity, from naturally occurring L-
serine, and used as an ethynylglycine synthon. The
oxazolidine moiety is widely employed as a synthetic
equivalent1 of R-amino acids, and the presence of an
unsaturated lateral chain14,15,17,18 has been exploited to
obtain precursors to ethynyl- and vinylglycine deriva-
tives. For example, addition of 1 to 219,20 afforded, regio-
and stereoselectively, the corresponding γ-stannylated
(E)-ethenyloxazolidine 3, a useful intermediate which
was subsequently coupled with electrophiles under Pd
catalysis21 to give the corresponding γ-substituted amino
acids precursors 4 (Scheme 1). One of the most remark-
able features of this protocol is that the resulting
compounds showed no loss of stereochemical information,
confirming metallocuprates as suitable reagents to be
used on enantiomerically enriched compounds.22,10
In view of these results we envisaged ethynylglycine
2 as a useful substrate for the synthesis of vinylsilanes
* To whom correspondence should be addressed. Phone: +39 055
2757609. Fax: +39 055 2476964. E-mail: reginato@cesce.fi.cnr.it.
(1) Williams, R. M. Synthesis of optically active R-amino acids;
Pergamon Press: New York, 1989; Vol. 7.
(13) Smith, R. J .; Bratovanov, S.; Bienz, S. Tetrahedron 1997, 53,
13695.
(14) Meffre, P.; Gauzy, L.; Perdigues, C.; Desanges-Leveque, F.;
Branquet, E.; Durand, P.; Le Goffic, F. Tetrahedron Lett. 1995, 36,
877.
(15) Meffre, P.; Gauzy, L.; Branquet, E.; Durand, P.; Goffic, F. L.
Tetrahedron 1996, 52, 11215.
(16) Reginato, G.; Mordini, A.; Degl’Innocenti, A.; Caracciolo, M.
Tetrahedron Lett. 1995, 36, 8275.
(2) Ohfune, Y. Acc. Chem. Res. 1992, 25, 360.
(3) Duthaler, R. O. Tetrahedron 1994, 50, 12789.
(4) Sardina, F. J .; Rapoport, H. Chem. Rev. 1996, 96, 1825.
(5) Tacke, R.; Linoh, H. The Chemistry of Organosilicon Compounds;
J ohn Wiley & Sons: New York, 1989.
(6) Tacke, R. Organosilicon and Bioorganosilicon Chemistry; Struc-
ture, Bonding, Reactivity and Synthetic Application; J ohn Wiley &
Sons: New York, 1985.
(17) Crisp, G. T.; J iang, Y. L.; Pullman, P. P.; Savi, C. D.
Tetrahedron 1997, 53, 17489.
(7) Weidman, B. Chimia 1992, 46, 312.
(18) Cameron, S.; Khambay, B. P. S. Tetrahedron Lett. 1998, 39,
1987.
(19) Reginato, G.; Mordini, A.; Caracciolo, M. J . Org. Chem. 1997,
62, 6187-6192.
(20) Reginato, G.; Mordini, A.; Degl’Innocenti, A.; Manganiello, S.;
Capperucci, A.; Poli, G. Tetrahedron 1998, 54, 10227.
(21) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(22) Reginato, G.; Mordini, A.; Messina, F.; Degl’Innocenti, A.; Poli,
G. Tetrahedron 1996, 52, 10985.
(8) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97, 2063.
(9) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis: Construc-
tion of Chiral Molecules Using Amino Acids; J ohn Wiley & Sons: New
York, 1987.
(10) Sibi, M. P.; Harris, B. J .; Shay, J . J .; Hajra, S. Tetrahedron
1998, 54, 7221.
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(12) Fitzi, R.; Seebach, D. Tetrahedron 1988, 44, 5277.
10.1021/jo991272r CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/19/1999

9212 J . Org. Chem., Vol. 64, No. 25, 1999
Reginato et al.
Sch em e 1
Sch em e 3
Resu lts a n d Discu ssion
Syn th esis of Vin ylsila n es 5. Trimethylsilylcyanocu-
prate 6a was found to add efficiently to ethynyloxazoli-
dine 2 at low temperature, affording, after hydrolytic
workup, the corresponding γ-silylated (E)-ethenyloxazo-
lidine 5a in a regio- and syn stereoselective manner
(Scheme 3). Remarkably, only one isomer was detected,
as determined by 1H NMR analysis of the crude mixture,
the double-bond configuration being easily confirmed
from the 18.3 Hz coupling for the vinyl protons, in good
agreement with the assigned E geometry of 5a .
Sch em e 2
Two other silylcuprates (6b,c) have also been exam-
ined. Dimethylphenylcyanocuprate 6b was chosen for
introducing a dimethylphenylsilyl group which, although
endowing vinylsilanes with a similar reactivity, has the
advantage that it can be converted, if required, into a
hydroxyl group.28 A new procedure for copper-catalyzed
silylcupration of terminal alkynes has been recently
reported;29 in this case a mixed species, (PhMe2Si)(Me)-
Cu(CN)Li2 (6b), is generated from a mixed zincate,
PhMe2SiZnMe2Li, and 3 mol % Me2Cu(CN)Li2. Most
notably, the process minimizes the amount of silyl ligand
involved and requires only small percentages of CuCN
and is therefore particularly appealing for large scale
reactions. We have successfully applied this procedure
to the synthesis of vinylsilane 5b, which was obtained
selectively on a multigram scale. (tert-Bu)Ph2SiCu(CN)-
Li2 (6c) was then chosen to introduce a hindered silyl
group which could impart useful differences30 to the
chemical behavior of our target compound; once again, a
clean addition leading to 5c was observed.
5 through silylcupration (Scheme 2). These intermedi-
ates, after reduction of the double bond, hydrolytic
removal of the acetonide protecting group and oxidation,
led to a new class of silylated amino acids 9, bearing
different trialkylsilyl substituents at the γ-position of the
lateral chain.
The current approach would also offer the opportunity
of obtaining â,γ-unsaturated amino acids 7. Unsaturated
amino acids display interesting biological properties,23-25
and some methods have been described for the prepara-
tion of these products,26 but most suffer from either poor
control of double bond geometry or variable enantiomeric
purity. Wittig condensation of phosphorus ylides with the
Garner aldehyde, followed by deprotection and oxidation
of the corresponding unsaturated amino alcohol, has been
shown to be a practical way for preparing chiral â,γ-
unsaturated amino acids with the defined double-bond
geometry. The most challenging step in this procedure
is the oxidation of the unsaturated amino alcohol, and
we reasoned that a trialkylsilyl group could be a suitable
substituent, promoting a successful oxidation of the
amino alcohol derived from 5.
In all the examined cases, no starting material was
recovered in the final crude mixture, and vinylsilanes
5a -c were isolated after chromatographic purification
in good yields.
Syn th esis of Silyla ted Am in o Alcoh ols 10 a n d 11b.
Pure 5a -c were hydrogenated with Pd catalysis to
quantitatively yield the corresponding saturated oxazo-
lidines 8a -c, which were deprotected to the correspond-
ing amino alcohols 10a -c (Scheme 4). Optimal reaction
conditions were found to involve carefully monitored
treatment of each starting material with an excess of CF3-
COOH in MeOH at 0 °C. Unexpectedly the t-Boc-
protective group was not removed despite the acidic
conditions, and workup afforded essentially pure amino
alcohols 10a -c, which were employed without further
purification in the subsequent oxidative step. To check
the possibility of using vinylsilanes 5 as intermediates
to unsaturated amino acids, compound 5b was depro-
Here we report the full experimental details to obtain
saturated and unsaturated silicon-containing amino acids
9 and 7, respectively. Vinylsilanes 5, easily obtainable
through addition of different silylcuprates 6 to 2, are
highlighted as useful intermediates. We also report some
preliminary results which demonstrate the capability of
our silylated amino acids to be incorporated into dipep-
tides, following the typical coupling and deprotection
steps associated with peptide synthesis.
Some of the results described herein have been the
subject of a preliminary communication.27
(27) Reginato, G.; Mordini, A.; Valacchi, M. Tetrahedron Lett. 1998,
39, 9545.
(23) Posner, B. L.; Flavin, M. J . Biol. Chem. 1972, 56, 4196.
(24) Rando, R. R. Acc. Chem. Res. 1975, 8, 281.
(25) Castelhano, A. L.; Plivra, D. H.; Taylor, G. J .; Hsieh, K. C.;
Krantz, A. J . Am. Chem. Soc. 1984, 106, 2734.
(26) Beaulieau, P. L.; Duceppe, J . S.; J ohnson, C. J . Org. Chem.
1991, 56, 4196.
(28) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson,
P. E. J . J . Chem. Soc., Perkin Trans. 1 1995, 317.
(29) Lipshutz, B. H.; Sclafani, J . A.; Takanami, T. J . Am. Chem.
Soc. 1998, 120, 4021-4022.
(30) Barbero, A.; Cuadrado, P.; Fleming, I.; Gonzales, A. M.; Pulido,
F. J .; Sanchez, A. J . Chem. Soc., Perkin Trans. 1 1995, 1525.

Synthesis of γ-Silylated R-Amino Acids
J . Org. Chem., Vol. 64, No. 25, 1999 9213
Sch em e 4
Sch em e 6
Sch em e 5
For characterization purposes, crude amino acids were
treated with excess MeI in the presence of KHCO3, and
the corresponding methyl esters 13a -c and 15b were
isolated in pure form after chromatography. The crude
amino acids showed, however, sufficient purity for further
uses.
Syn th esis of Dip ep tid es. To demonstrate that si-
lylated amino acids are capable of undergoing typical
reactions associated with peptides synthesis, different
dipeptides bearing one or two silylated residues were
synthesized as shown in Scheme 6. The t-Boc-protected
amino acids 12a ,b were coupled with L-leucine methyl
ester using DEPC/DIEA (diethylcyanophosphonate/di-
isopropylethylamine) procedure to produce peptides 16a,b,
respectively, in 48% and 54% yields after purification.
Conversely, amino ester 13b was deprotected and the
obtained trifluoroacetate 17b coupled with Boc-protected
amino acid 12b to afford disilylated peptide 18 in good
yield.
1H and 13C NMR analysis of the three peptides 16a ,b
and 18 indicated the absence (within limits of detection,
5%) of peaks due to epimerization at any of the R carbons
in the amino acids formed. This confirmed that during
our synthetic sequence no racemization occurred and
pointed out that γ-silylated amino acids are not affected
by coupling and deprotection conditions usually associ-
ated with peptide synthesis.
Finally, we decided to check whether the conversion
of the phenyldimethyl group into the hydroxyl group was
feasible on 13b. Among the different methods reported
in the literature, bromodesilylation28 was chosen, as the
mild reaction conditions are compatible with the presence
of the t-Boc-protective group. Addition of an excess of
peracetic acid to a solution of 13b in buffered acetic acid
and potassium bromide, provided, after purification, a
1:1 mixture of Boc-protected homoserine ester 19 and
lactone 20 in 64% combined yield (Scheme 7). Slow
cyclization of 19 into lactone 20 occurred spontaneously
in solution and was accelerated in an acidic medium.
tected under the same conditions, and the corresponding
unsaturated amino alcohol 11b was obtained in good
yield.
Oxid a tion of Am in o Alcoh ols. Although numerous
methods are reported in the literature for the direct
conversion of primary alcohols to the corresponding
carboxylic acids, this transformation is still a challenge
especially in the presence of other functional groups. In
the oxidation of our substrates we previously observed
satisfactory results27 when J ones’ reagent was used
applying the reverse addition procedure.15 Recently, a
new oxidative method has been reported by Zhao31 in
which the oxidation of primary alcohols to carboxylic
acids is performed using periodic acid (H5IO6) as the
stoichiometric oxidant in the presence of a catalytic
amount of CrO3. Nonracemic alcohols are oxidized with-
out any evidence of racemization, and Cbz-protected
amino alcohols are also oxidized to the corresponding
Cbz-protected amino acids. This procedure worked ef-
ficiently also when applied on our silylated amino alco-
hols. The t-Boc-protective group was in fact capable of
withstanding the acidic conditions required, and a rapid,
clean, and high-yielding oxidation to the corresponding
t-Boc-protected amino acids occurred as shown in Scheme
5.
It is also remarkable how the presence of a reactive
double bond in 11b did not affect the yield of oxidation,
since unsaturated amino acid 14b was recovered in
satisfactory yield. The efficiency of the oxidative step in
this case, which was also observed27 when J ones’ condi-
tions were used, confirms trialkylsilyl groups as suitable
substituents for obtaining vinylglycine derivatives. This
is in agreement with the observation that a successful
oxidation of unsaturated amino alcohols is dependent on
the substituent of the terminal vinylic position, the best
results being obtained in the presence of electron donor
groups.26
Con clu sion s
A general and mild synthetic route to a novel class of
silicon-containing amino acids has been developed. Vi-
nylsilanes 5 have been highlighted as intermediates
(31) Zhao, M.; Li, J .; Song, Z.; Desmond, R.; Tschaen, D. M.;
Grabowski, E. J . J .; Reider, P. Tetrahedron Lett. 1998, 39, 5323.

9214 J . Org. Chem., Vol. 64, No. 25, 1999
Reginato et al.
ter t-Bu tyl 4-((1E)-3-Meth yl-3-p h en yl-3-sila bu t-1-en yl)-
(4R)-2,2-d im eth yl-1,3-oxa zolid in e-3-ca r boxyla te (5b). Di-
methylphenylsilyllithium was prepared according to the lit-
erature.34 Mixed dimethylphenylsilylzincate 6b was prepared,
Sch em e 7
and used in the presence of CuCN (0.03 equiv, 3% CuCN).29
A
precooled solution of 2 (1.66 g, 7.4 mmol) in THF (4 mL) was
added, and the reaction mixture was stirred at -78 °C for 2
h. The reaction was hydrolyzed with saturated aqueous NH4-
Cl and then extracted with ether. The organic layer was
washed twice with brine and dried. Evaporation of the solvent
afforded 2.75 g of crude 5b, which was purified by flash
chromatography (petroleum ether/ethyl acetate, 6/1). Pure 5
(1.81 g, 67%) was obtained as a colorless oil. 1H NMR: δ 7.56-
7.46 (m, 2 H), 7.36-7.30 (m, 3 H), 6.11-5.76 (AB, J ) 18.8,
6.6 Hz, 2 H), 4.35-4.25 (br m, 1 H), 4.09-3.73 (AB, J ) 8.8,
6.2, 2.2 Hz, 2 H), 1.60 (br s, 3 H), 1.51 (br s, 3 H), 1.38 (br s,
9 H), 0.34 (s, 6 H). 13C NMR: δ 151.94, 146.18, 133.78, 128.98,
128.65, 127.94, 127.74, 94.06, 79.51, 67.99, 61.54, 28.28, 26.48,
23.67, -2.71. MS: m/z 346 (1), 290 (18), 135 (53), 57 (100).
which can favorably be applied to the synthesis of
silylated vinylglycine derivatives. Noteworthy, the yields
of the overall process are satisfactory, since all steps can
be carried out without purification of intermediates.
The ability of γ-silylated amino acids to be incorporated
into peptides by solution-phase methodology has also
been demonstrated, and silylated dipeptides have been
synthesized.
[R]26 ) -36.8 (c ) 0.9, CHCl3). Anal. Calcd for C20H31NO3Si:
D
Exp er im en ta l Section
C, 66.44; H, 8.64; N, 3.87. Found: C, 66.32; H, 8.67; N, 3.58.
Gen er a l P r oced u r es. Ethereal extracts were dried with
Na2SO4. The temperature of dry ice/ethanol baths is indicated
as -78 °C. Reactions were monitored by TLC on SiO2;
detection was made using a KMnO4 basic solution. Flash
column chromatography32 was performed using glass columns
(10-50 mm wide) and SiO2 (230-400 mesh). 1H NMR were
recorded at 200 or 300 MHz. 13C NMR spectra were recorded
at 50.3 MHz. Chemical shifts were determined relative to the
ter t-Bu tyl 4-((1E)-4,4-Dim eth yl-3,3-d iph en yl-3-sila p en t-
1-en yl)(4R)-2,2-d im et h yl-1,3-oxa zolid in e-3-ca r b oxyla t e
(5c). tert-Butyldiphenylsilylcuprate 6c (2 equiv) was prepared
according to the literature.30 A solution of 2 (168 mg, 0.75
mmol) in THF (1 mL) was added, and the reaction mixture
was stirred at -78 °C for 2 h. The reaction was hydrolyzed
with ammonium buffer at low temperature, allowed to warm
to room temperature, and extracted with ether. The organic
layer was washed twice with brine and then dried. Evaporation
of the solvent afforded 510 mg of a crude mixture, which was
purified by flash chromatography (petroleum ether/ethyl ac-
etate, 6/1). Pure 5c (283 mg, 80%) was obtained as a low
melting white solid. 1H NMR: δ 7.75-7.58 (m, 4 H), 7.42-
7.30 (m, 6 H), 6.28-5.98 (AB, J ) 18.6, 4.8 Hz, 2 H), 4.48-
4.39 (m, 1 H), 4.11-3.75 (AB, J ) 8.8 Hz, 6.2, 1.4 Hz, 2 H),
1.62 (br s, 3 H), 1.55 (br s, 3 H), 1.45 (br s, 9 H), 1.10 (s, 9 H).
13C NMR: δ 151.94, 148.71, 137.48, 136.17, 129.12, 127.56,
123.50, 94.18, 79.66, 68.08, 61.29, 28.33, 27.62, 26.44, 24.87,
23.53. MS: m/z 408 (3), 352 (34), 276 (20), 199 (62), 164 (70),
1
residual solvent peak (CHCl3, δ 7.26 ppm for H NMR; CHCl3,
δ 77.0 ppm for 13C NMR). Coupling constants (J ) are reported
in hertz. Multiplicities are indicated as s (singlet), d (doublet),
t (triplet), q (quartet), dd (doublet of doublets), m (multiplet),
br s (broad singlet), br t (broad triplet), and br q (broad
quartet). For those compounds which are present as slowly
interconverting rotamers, NMR experiments were performed
at 50 °C, and signals of the averaged spectrum are reported
when possible. Mass spectra were obtained at
a 70 eV
ionization potential and are reported in the form m/z (intensity
relative to base, 100). Polarimetric measurements were per-
formed in CHCl3 solution at λ ) 589 nm, and the temperature
is specified case by case.
Ma ter ia ls. Oxazolidine 2 was prepared according to the
literature.19 Starting materials are commercially available
unless otherwise stated. All commercial reagents were used
without further purification. THF was dried by distillation over
sodium benzophenone ketyl. CH2Cl2 was purified by the
standard procedure, dried over CaCl2, and stored over 4 Å
molecular sieves. DMF was distilled over CaCl2, and stored
over 4 Å molecular sieves. Petroleum ether, unless specified,
is the 40-70 °C boiling fraction.
135 (17), 83 (46), 57 (100). [R]23 ) -52.0 (c ) 1.3, CHCl3).
D
Anal. Calcd for C28H39NO3Si: C, 72,21; H, 8,44; N, 3,01.
Found: C, 72.39; H, 8.47; N, 3.07.
Hyd r ogen a tion of Vin ylsila n es. Compounds 5a -c were
dissolved in 95% ethanol, and hydrogenated (H2, 1 atm) over
a catalytic amount of Pd on carbon. The reaction was moni-
tored by GC; after completion, the solution was filtered over
Celite. Evaporation of the solvent afforded pure compounds
8, which were employed in the following step without further
purification.
ter t-Bu tyl (4R)-4-(3,3-Dim eth yl-3-silabu tyl)-2,2-dim eth yl-
1,3-oxa zolid in e-3-ca r boxyla te (8a ). Compound 5a (644 mg,
2.2 mmol) was hydrogenated for 3 h, affording 625 mg (96%)
of 8a . 1H NMR (300 MHz, 55 °C): δ 3.96-3.86 (m, 1 H), 3.76-
3.62 (m, 1 H + 1 H), 1.79-1.62 (m, 2 H), 1.57 (br s, 3 H), 1.48-
1.46 (m, 9 H + 3 H), 0.48-0.35 (m, 2 H), 0.01 (s, 9 H). 13C
NMR (75.45 MHz): δ 156.60, 93.65, 79.46, 66.52, 55.54, 28.43,
27.61, 25.75, 23.28, 12.90, -1.83. MS: m/z 286 (2), 230 (9), 73
ter t-Bu tyl 4-((1E)-3,3-Dim eth yl-3-sila bu t-1-en yl)(4R)-
2,2-d im eth yl-1,3-oxa zolid in e-3-ca r boxyla te (5a ). Trimeth-
ylsilylcuprate 6a was prepared according to the literature.33
A solution of 2 (1.112 g, 4.9 mmol) in THF (2 mL) was added,
and the reaction mixture was stirred at -78 °C for 30 min.
The reaction was diluted with ether, and hydrolyzed with
ammonium buffer. The organic layer was washed twice with
brine and then dried. Evaporation of the solvent afforded 1.536
g of crude 5a , which was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate, 15/1). Pure 5a (1.162
mg, 79%) was obtained as a low melting colorless solid. 1H
NMR (300 MHz, 55 °C): δ 6.01-5.72 (AB, J ) 18.3, 6.3 Hz, 2
H), 4.36-4.22 (br m, 1 H), 4.08-3.70 (AB, J ) 8.8, 6.4, 2.7
Hz, 2 H), 1.61 (s, 3 H), 1.52 (s, 3 H), 1.44 (s, 9 H), 0.08 (s, 9 H).
13C NMR: δ 151.96, 144.36, 130.86, 93.95, 79.46, 68.02, 61.63,
28.30, 26.40, 23.67, -1.42. MS: m/z 299 (0.2), 284 (11), 73 (78),
(33), 57 (100). [R]20 ) -36.1 (c ) 1.05, CHCl3).
D
ter t-Bu tyl (4R)-2,2-Dim eth yl-4-(3-m eth yl-3-p h en yl-3-si-
la bu tyl)-1,3-oxa zolid in e-3-ca r boxyla te (8b). Compound 5b
(1.48 g, 4.1 mmol) was hydrogenated for 6 h, affording 1.48 g
1
(99%) of 8b. H NMR: δ 7.52-7.46 (m, 2 H), 7.36-7.32 (m, 3
H), 3.90 (dd, J ) 8.4, 5.4 Hz, 1 H), 3.76-3.45 (m, 1 H + 1 H),
1.60-1.20 (m, 2 H + 3 H + 3 H), 1.44 (br s, 9 H), 0.90-0.60
(m, 2 H), 0.27 (s, 6 H). 13C NMR (75.45 MHz): δ 156.64, 138.70,
133.48, 128.98, 127.82, 87.00, 79.58, 65.49, 55.35, 28.33, 27.39,
26.64, 25.64, 11.86, -3.27. MS: m/z 348 (2), 292 (10), 135 (100),
57 (100). [R]25 ) -30.7 (c ) 0.9, CHCl3). Anal. Calcd for
D
C
15H29NO3Si: C, 60.16; H, 9.76; N, 4.68. Found: C, 60.39; H,
57 (100). [R]22 ) -13.2 (c ) 0.7, CHCl3).
D
9.72; N, 4.53.
ter t-Bu tyl (4R)-4-(4,4-Dim eth yl-3,3-d ip h en yl-3-sila p en -
tyl)-2,2-d im eth yl-1,3-oxa zolid in e-3-ca r boxyla te (8c). Com-
(32) Still, W. C.; Ahn, M. K.; Mitra, A. J . Org. Chem. 1978, 43,
2923.
(33) Capella, L.; Degl’Innocenti, A.; Reginato, G.; Ricci, A.; Taddei,
M. J . Org. Chem. 1989, 54, 1473.
(34) Fleming, I. In Organocopper Reagents; Taylor, R. J . K., Ed.;
Oxford University Press: Oxford, 1994; p 260.

Synthesis of γ-Silylated R-Amino Acids
J . Org. Chem., Vol. 64, No. 25, 1999 9215
pound 5c (281 mg, 0.6 mmol) was dissolved in a mixture of
0.51-0.39 (m, 2 H), -0.03 (s, 9 H). 13C NMR: δ 173.31, 154.69,
79.77, 55.52, 52.13, 28.26, 27.20, 11.44, -2.02. MS: m/z 233
95% ethanol/petroleum ether (70/30) and hydrogenated for 7
1
h, affording 248 mg (88%) of 8c. H NMR: δ 7.77-7.58 (m, 4
(1), 73 (100), 57 (100). [R]25 ) -21.7 (c ) 1.05, CHCl3). Anal.
D
H), 7.41-7.32 (m, 6 H), 3.99-3.69 (m, 2 H + 1 H), 1.65-1.30
(m, 2 H + 6 H), 1.47 (br s, 9 H), 1.25-0.90 (m, 2 H), 1.05 (s, 9
H). 13C NMR: δ 152.13, 137.50, 135.86, 129.11, 127.70, 93.81,
79.62, 65.80, 55.71, 28.33, 27.78, 26.51, 24.65, 23.18, 20.30,
Calcd for C13H27NO4Si: C, 53,94; H, 9,40; N, 4,84. Found: C,
53.47; H, 9.47; N, 4.92.
Meth yl (2R)-2-[(ter t-Bu toxy)ca r bon yla m in o]-5-m eth yl-
5-p h en yl-5-sila h exa n oa te (13b). Compound 10b (386 mg,
1.2 mmol) was oxidized to afford 326 mg (81% yield) of crude
amino acid 12b. Esterification and purification (petroleum
ether/ethyl acetate, 5/1) afforded 196 mg of 13b (58% overall
yield) as a colorless oil. 1H NMR: δ 7.50-7.44 (m, 2 H), 7.36-
7.33 (m, 3 H), 5.01 (br d, J ) 7.2 Hz, 1 H), 4.34-4.24 (m, 1 H),
3.71 (s, 3 H), 1.84-1.53 (m, 2 H), 1.43 (s, 9 H), 0.91-0.65 (m,
2 H), 0.26 (s, 6 H). 13C NMR: δ 173.20, 156.59, 138.23, 133.53,
129.09, 127.87, 79.86, 55.48, 52.15, 28.28, 27.15, 10.65, -3.34.
18.05. MS: m/z 354 (21), 135 (17), 57 (100). [R]19 ) -30.2
D
(c ) 1.0, CHCl3).
Dep r otection to Am in o Alcoh ols. A solution of 8 in
MeOH was cooled to 0 °C and then treated with an excess of
CF3COOH. The reaction was monitored by TLC every 30 min;
after completion, solvent was evaporated and the residue
redissolved with ethyl acetate. The organic layer was washed
with saturated NaHCO3 aqueous solution and brine, then
dried, and evaporated to afford pure amino alcohols 10a -c
and 11b, which were oxidized without further purification.
N-[(1R)-1-(3,3-Dim et h yl-3-sila b u t yl)-2-h yd r oxyet h yl]-
(ter t-bu toxy)ca r boxa m id e (10a ). Compound 8a (551 mg, 1.8
mmol) was reacted for 4 h to afford, after workup, 469 mg
(98%) of 10a . 1H NMR: δ 4.70-4.44 (br m, 1 H), 3.74-3.46
(m, 2 H + 1 H), 1.90 (br s, 1 H), 1.58-1.32 (m, 2H), 1.45 (s, 9
H), 0.64-0.38 (m, 2 H), 0.01 (s, 9 H). 13C NMR: δ 156.69, 79.57,
65.27, 55.48, 28.33, 25.69, 12.60, -1.93. MS: m/z 230 (2), 73
MS: m/z 352 (1.6), 135 (100), 57 (90). [R]25 ) -20.2 (c ) 2,
D
CHCl3). Anal. Calcd for C18H29NO4Si: C, 61,50; H, 8,32; N,
3,98. Found: C, 61.47; H, 8.38; N, 3.92.
Met h yl (2R)-2-[(ter t-Bu t oxy)ca r b on yla m in o]-6,6-d i-
m eth yl-5,5-d ip h en yl-5-sila h ep ta n oa te (13c). Compound
10c (166 mg, 0.4 mmol) was oxidized to afford 118 mg (70%
yield) of crude amino acid 12c. Esterification and purification
(petroleum ether/ethyl acetate, 5/1) afforded 23 mg of 13c (13%
overall yield) as a colorless oil. 1H NMR: δ 7.58-7.52 (m, 4
H), 7.41-7.34 (m, 6 H), 5.02 (br d, J ) 7.8, 1 H), 4.34-4.22
(m, 1 H), 3.70 (s, 3 H), 1.66-1.54 (m, 2 H), 1.45 (s, 9 H), 1.21-
1.07 (m, 2 H), 1.02 (s, 9 H). 13C NMR: δ 173.01, 155.38, 135.80,
133.96, 129.17, 127.70, 79.90, 55.53, 52.12, 28.30, 27.79, 27.49,
18.10, 5.40. MS: m/z 342 (54), 239 (9), 57 (100). [R]21D ) -28.7
(c ) 1.1, CHCl3). Anal. Calcd for C26H37NO4Si: C, 68.53; H,
8.18; N, 3.07. Found: C, 68.44; H, 8.12; N, 2.89.
(46), 57 (100). [R]25 ) +9.12 (c ) 1.02, CHCl3).
D
N-[(1R)-2-H yd r oxy-1-(3-m et h yl-3-p h en yl-3-sila b u t yl)-
eth yl](ter t-bu toxy)ca r boxa m id e (10b). Compound 8b (1.48
g, 4.1 mmol) was reacted for 4 h to afford, after workup, 1.31
g (99%) of 10b. 1H NMR: δ 7.56-7.44 (m, 2 H), 7.38-7.31 (m,
3 H), 4.75-4.62 (br m, 1 H), 3.65-3.49 (m, 2 H + 1 H), 2.68
(br s, 1 H), 1.55-1.35 (m, 2 H), 1.44 (s, 9 H), 0.83-0.70 (m, 2
H), 0.27 (s, 6 H). 13C NMR: δ 156.60, 138.70, 133.49, 128.94,
127.80, 79.55, 65.26, 55.35, 28.30, 25.60, 11.78, -3.31. MS: m/z
Meth yl
(3E)(2R)-2-[(ter t-Bu toxy)ca r bon yla m in o]-5-
m eth yl-5-p h en yl-5-sila h ex-3-en oa te (15b). Compound 11b
(177 mg, 0.55 mmol) was oxidized to afford 126 mg (69% yield)
of crude amino acid 14b. Esterification and purification
(petroleum ether/ethyl acetate, 4/1) afforded 96 mg (51%
324 (8), 135 (100), 57 (100). [R]22 ) -1.06 (c ) 1.3, CHCl3).
D
N-[(1R)-1-(4,4-Dim et h yl-3,3-d ip h en yl-3-sila p en t yl)-2-
h yd r oxyeth yl](ter t-bu toxy)ca r boxa m id e (10c). Compound
8c (248 mg, 0.5 mmol) was reacted for 5 h to afford, after
workup, 217 mg (96%) of 10c. 1H NMR: δ 7.65-7.56 (m, 4
H), 7.39-7.31 (m, 6 H), 3.81-3.64 (br m, 1 H), 3.63-3.42 (m,
2 H + 1 H), 2.83 (br s, 1 H), 1.48-1.04 (m, 2 H + 2 H), 1.44 (s,
9 H), 1.03 (s, 9 H). 13C NMR: δ 156.62, 137.43, 135.81, 129.05,
127.54, 79.53, 64.91, 55.55, 28.28, 27.75, 26.25, 20.25, 6.38.
1
overall yield) of 15b as a colorless oil. H NMR: δ 7.52-7.46
(m, 2 H), 7.37-7.33 (m, 3 H), 6.12 (s, 2 H), 5.20 (br d, J ) 8.2,
1 H), 4.95 (br d, J ) 8 Hz, 1 H), 3.76 (s, 3 H), 1.45 (s, 9 H),
0.35 (s, 6 H). 13C NMR: δ 171.08, 154.97, 140.60, 137.78,
133.78, 130.28, 129.13, 127.79, 80.10, 57.35, 52.54, 28.24,
-2.77. MS: m/z 249 (0.5), 234 (27), 189 (33), 135 (34), 57 (100).
MS: m/z 354 (10), 135 (31), 57 (100). [R]20 ) -14.8 (c ) 1.6,
[R]21 ) -15.3 (c ) 1.06, CHCl3). Anal. Calcd for C18H27NO4-
D
D
CHCl3).
Si: C, 61.86; H, 7.79; N, 4.01. Found: C, 61.95; H, 7.76; N,
4.11.
N-[1-((1E)-3-Met h yl-3-p h en yl-3-sila b u t -1-en yl)(1R)-2-
h yd r oxyeth yl](ter t-bu toxy)ca r boxa m id e (11b). Compound
5b (560 mg, 1.5 mmol) was reacted for 8 h to afford, after
workup, 395 mg (79%) of 11b. 1H NMR: δ 6.03 (br s, 2 H),
4.27 (br s, 1H), 3.76-3.55 (AB, J ) 11.1, 5.8, 4.2 Hz, 2 H),
2.52 (br s, 1 H), 1.44 (s, 9 H), 0.35 (s, 6 H). 13C NMR: δ 156.12,
144.27, 138.15, 133.78, 129.38, 129.07, 127.80, 79.84, 65.09,
56.44, 28.26, -2.73. MS: m/z 250 (5), 234 (46), 135 (29), 57
Syn th esis of Dip ep tid es 16a ,b a n d 18. Amino alcohols
were oxidized, and the crude mixture obtained after workup
was dissolved in dry CH2Cl2 and reacted under N2 at 0 °C.
The desired hydrochloride or trifluoroacetate amino ester was
added followed by DIEA (3 equiv) and DEPC (1.3 equiv). The
mixture was allowed to reach rt and left to stir overnight. The
reaction was then diluted with ethyl acetate, washed with
saturated aqueous NH4Cl and brine, and then dried. Flash
chromatography yielded pure dipeptides as single diastereo-
isomers.
(100). [R]23 ) -5.5 (c ) 1.1, CHCl3).
D
Oxid a tion of Am in o Alcoh ols. A stock solution of H5IO6
(0.4 M, 2.5 equiv) and CrO3 (0.5% mol) in wet acetonitrile31
was added dropwise to a cooled solution of amino alcohols
10a -c and 11b in wet acetonitrile, over a period of 30-40 min.
After completion of the addition, the reaction mixture was
stirred for 30 min and monitored by TLC. The reaction was
quenched with phosphate buffer, toluene added, and the
organic layer separated, washed with brine/H2O, aqueous
NaHSO3 (0.4 M), and brine, and then dried. Crude amino acids
12a -c and 14b were dissolved in dry DMF at room temper-
ature, KHCO3 (2 equiv) and MeI (2 equiv) were added, and
the mixture was allowed to react for 24-48 h at room
temperature. After completion, ethyl acetate was added, and
the organic layer was washed with water and brine and then
dried. Purification afforded pure amino esters 13a -c and 15b.
Met h yl (2R)-2-[(ter t-Bu t oxy)ca r b on yla m in o]-5,5-d i-
m eth yl-5-sila h exa n oa te (13a ). Compound 10a (53 mg, 0.2
mmol) was oxidized to afford 38 mg (72% yield) of crude amino
acid 12. Esterification and purification (petroleum ether/ethyl
acetate, 5/1) afforded 23 mg (40% overall yield) of 13a as a
Met h yl 2-{(2R)-2-[(ter t-Bu t oxy)ca r b on yla m in o]-5,5-
d im et h yl-5-sila h exa n oyla m in o}(2S)-4-m et h ylp en t a n o-
a te (16a ). Compound 10a (341 mg, 1.3 mmol) was oxidized
and the crude mixture reacted with 118 mg (0.6 mmol) of
L-Leu-OMe‚HCl to give after purification (petroleum ether/
1
ethyl acetate, 3/1) 251 mg (48%) of 16a as a colorless oil. H
NMR: δ 6.53 (br d, J ) 8 Hz, 1 H), 5.10-4.94 (m, 1 H), 4.66-
4.53 (m, 1 H), 4.12-3.98 (m, 1 H), 3.70 (s, 3 H), 1.93-1.73 (m,
1 H), 1.68-1.48 (m, 2 H + 2 H), 1.43 (s, 9 H), 0.91 (d, J ) 4.8
Hz, 6 H), 0.47 (dd, J ) 10.1, 7.5 Hz, 2 H), -0.04 (s, 9 H). 13C
NMR: δ 173.24, 171.79, 155.59, 80.06, 56.66, 52.24, 50.54,
41.41, 28.25, 26.88, 24.76, 22.80, 21.72, 11.84, -1.94. MS: m/z
331 (6), 73 (66), 57 (100). [R]22D ) +3.44 (c ) 1.1, CHCl3). Anal.
Calcd for C19H38N2O5Si: C, 56.68; H, 9.51; N, 6.96. Found: C,
56.76; H, 9.50; N, 6.81.
Meth yl 2-{(2R)-2-[(ter t-Bu toxy)car bon ylam in o]-5-m eth -
yl-5-p h en yl-5-sila h exa n oyla m in o}(2S)-4-m eth ylp en ta n -
oa te (16b). Compound 10b (315 mg, 1.0 mmol) was oxidized
and the crude mixture reacted with 182 mg (1.0 mmol) of
L-Leu-OMe‚HCl to give after purification (petroleum ether/
1
colorless oil. H NMR: δ 5.03 (br d, J ) 7.6 Hz, 1 H), 4.31-
4.24 (m, 1 H), 3.73 (s, 3 H), 1.79-1.62 (m, 2 H), 1.44 (s, 9 H),

9216 J . Org. Chem., Vol. 64, No. 25, 1999
Reginato et al.
ethyl acetate, 3/1) 232 mg (51%) of 16b as a colorless solid
(mp 60-62 °C). 1H NMR: δ 7.50-7.45 (m, 2 H), 7.38-7.31
(m, 3 H), 6.42 (br d, J ) 7.3 Hz, 1 H), 4.98 (br d, J ) 4.4 Hz,
1 H), 4.65-4.55 (m, 1 H), 4.15-3.95 (m, 1 H), 3.70 (s, 3 H),
1.95-1.72 (m, 1 H), 1.70-1.50 (m, 2 H + 2 H), 1.43 (s, 9 H),
0.91 (d, J ) 5.5 Hz, 6 H), 0.79-0.66 (m, 2 H) 0.26 (s, 6 H). 13C
NMR: δ 173.13, 171.61, 155.54, 138.40, 133.47, 129.01, 127.80,
80.08, 56.58, 52.21, 50.54, 41.41, 28.23, 26.81, 24.76, 22.77,
21.73, 11.13, -3.33. MS: m/z 449 (7), 393 (7), 135 (73), 57 (100).
Meth yl (2R)-2-[(ter t-Bu toxy)ca r bon yla m in o]-4-h yd r ox-
ybu ta n oa te (19) a n d N-[(3R)-2-oxo(3,4,5-tr ih yd r ofu r -3-
yl)](ter t-bu toxy)ca r boxa m id e (20). Potassium bromide (42
mg, 0.4 mmol) and anhydrous potassium acetate (90 mg) were
added to a stirred solution of 13b (103 mg, 0.3 mmol) in glacial
acetic acid (3 mL). Peracetic acid (0.8 mL) was then added
dropwise to the mixture with ice cooling. More potassium
acetate (260 mg) and peracetic acid (2.5 mL) were added to
the mixture, and the resulting solution was stirred at rt
overnight. After addition of ether and powdered sodium
thiosulfate, the solution was filtered through Celite and
evaporated. The residue was redissolved in ether, and the
solution was washed with aqueous NaHCO3 and brine, then
dried, and evaporated to afford 122 mg of crude mixture. After
purification (petroleum ether/ethyl acetate, 1/1) 18 mg of 19
[R]20 ) 0.0 (c ) 1.1, CHCl3). Anal. Calcd for C24H40N2O5Si:
D
C, 62.03; H, 8.68; N, 6.03. Found: C, 61.72; H, 8.57; N, 5.93.
Meth yl (2R)-2-{(2R)-2-[(ter t-Bu toxy)ca r bon yla m in o]-5-
m eth yl-5-p h en yl-5-sila h exa n oyla m in o}-5-m eth yl-5-p h en -
yl-5-sila h exa n oa te (18). Amino ester 13b (130 mg, 0.4 mmol)
was dissolved in CH2Cl2 (4 mL) and reacted at rt with TFA (1
mL). After 15 min the solvent was evaporated to afford
trifluoroacetate 17. Crude amino acid 12b (109 mg 0.3 mmol)
was reacted with 17 to give after purification (petroleum ether/
ethyl acetate, 4/1) 89 mg (49%) of 18 as an oil. 1H NMR: δ
7.52-7.43 (m, 5 H), 7.37-7.32 (m, 5 H), 6.44 (br d, J ) 7.6
Hz, 1 H), 4.96 (br d, J ) 7.2 Hz, 1 H), 4.61-4.50 (m, 1 H),
4.06-3.98 (m, 1 H), 3.69 (s, 3 H), 1.91-1.54 (m, 4 H), 1.42 (s,
9 H), 0.81-0.62 (m, 4 H), 0.27 (s, 6 H), 0.25 (s, 6 H). 13C NMR:
δ 172.26, 171.54, 155.50, 138.41, 138.18, 133.45, 129.01,
127.78, 79.93, 56.67, 54.10, 52.15, 28.23, 26.79, 11.09, 10.58,
-3.23, -3.28, -3.38, -3.46. MS: m/z 556 (5), 500 (4), 236 (39),
1
(26%) and 22 mg of 20 (38%) were obtained. (19) H NMR: δ
5.38 (br s, 1 H), 4.54-4.39 (m, 1 H), 3.81-3.60 (m, 2 H), 3.75
(s, 3 H), 2.73 (br s, 1 H), 2.25-1.98 (m, 2H), 1.43 (s, 9 H). 13C
NMR: δ 175.29, 155.44, 80.62, 65.72, 52.50, 50.21, 30.57,
1
28.22. MS: m/z 174 (26), 57 (55). (20) H NMR: δ 5.12 (br s,
1 H), 4.47-4.16 (m, 1H + 2H), 2.77-2.67 (m, 1 H), 2.26-2.11
(m, 1H), 1.44 (s, 9 H). 13C NMR: δ 175.33, 155.45, 80.64, 71.77,
65.73, 28.22, 19.10. MS: m/z 146 (22), 57 (100). [R]21 ) -9.9
D
(c ) 1.3, CHCl3).
135 (100), 114 (47), 57 (39). [R]24 ) -19.7 (c ) 1.7, CHCl3).
D
Anal. Calcd for C30H46N2O5Si2: C, 63.16; H, 8.12; N, 4.91.
Found: C, 63.37; H, 8.20; N, 5.06.
J O991272R