Rapid access to N-Boc phenylglycine derivatives via benzylic lithiation reactions

Article abstract of DOI:10.1016/S0040-4020(01)00159-4

We report a novel and efficient method for the enantioselective synthesis of N-Boc protected phenylglycines. Yields and enantiomeric ratios vary widely depending on the nature of the solvent, the substrate and on the method of forming the chiral complex. Results show that the major reaction pathway is an enantioselective deprotonation/substitution process. The enantioselectivity appears to be limited by the chiral discrimination ability of the s-BuLi-(-)-sparteine complex. The synthetic method described is one of the shortest route to useful enantioenriched N-Boc phenylglycine derivatives.

Full text of DOI:10.1016/S0040-4020(01)00159-4

TETRAHEDRON
Pergamon
Tetrahedron 57 42001) 2965±2972
Rapid access to N-Boc phenylglycine derivatives via benzylic
lithiation reactions
p
Claude Barberis, Normand Voyer, Johanne Roby, Sylvain Chenard, Martin Tremblay and
Philippe Labrie
Â
   Â
Departement de chimie and CREFSIP, Faculte des sciences et de genie, Universite Laval, Ste Foy, Quebec, Canada G1K 7P4
Received 25 September 2000; accepted 6 February 2001
AbstractÐWe report a novel and ef®cient method for the enantioselective synthesis of N-Boc protected phenylglycines. Yields and
enantiomeric ratios vary widely depending on the nature of the solvent, the substrate and on the method of forming the chiral complex.
Results show that the major reaction pathway is an enantioselective deprotonation/substitution process. The enantioselectivity appears to be
limited by the chiral discrimination ability of the s-BuLi±42)-sparteine complex. The synthetic method described is one of the shortest route
to useful enantioenriched N-Boc phenylglycine derivatives. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
enriched amino acids 3. Therefore, the key steps involve
an asymmetric deprotonation and a selective carboxylation.
We used 42)-sparteine 4±s-BuLi complex as a chiral base.6
This versatile chiral complex has been used successfully in
several processes, especially by Hoppe7 and Beak.8 The
latter reported asymmetric syntheses of a-, b-, and g-aryl
aminoacids8a,b from N-Boc N-protected benzylamine
derivatives using n-BuLi±42)-sparteine complex as chiral base.
Due to the widespread occurrence of a-amino acids in
biologically active compounds, the development of ef®cient
methods for their enantioselective synthesis has been a
challenge of considerable practical importance.1 More
speci®cally, arylglycines constitute an important class of
non-proteogenic amino acids. They are present in many
biologically active compounds2 and are also important as
chiral building blocks or as precursors of chiral ligands for
asymmetric synthesis.3 Elegant synthetic methods have
been developed for the preparation of phenylglycine
derivatives, but there is still a need for ef®cient, rapid pro-
cedures toward these compounds. Notably, the formation
and reactions of dipole-stabilized anions adjacent to nitro-
gen have been studied extensively and were shown to be a
useful approach for the synthesis of amino acid derivatives.4
Herein, we demonstrate that N-Boc-protected phenyl-
glycines 3 can be prepared ef®ciently and enantioselectively
through path B.
As part of our research program on the development of
peptide based supramolecular devices,5 we required the
preparation of N-t-Boc protected phenylglycine derivatives.
Therefore, we sought to develop a rapid and ef®cient
method to synthesize these compounds, generalized by 3,
using the strategy shown in Scheme 1. We envisioned at ®rst
that the protected phenylglycines could be made by the two
strategies shown in Scheme 1. Path A involves the forma-
tion of a chiral dianionic species 1, whereas path B implies
the generation of a dipole stabilized chiral anion 2. The
intermediates 1 and 2 could in turn react stereoselectively
with an electrophilic source of CO2 to generate enantio-
Keywords: enantioselective deprotonation; 42)-sparteine; organolithium;
carboxylation; phenylglycine.
p
Corresponding author: Tel.: 1418-656-3613; fax: 1418-656-7916;
e-mail: normand.voyer@chm.ulaval.ca
Scheme 1. Strategies for the synthesis of N-protected arylglycines.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020401)00159-4

2966
C. Barberis et al. / Tetrahedron 57 -2001) 2965±2972
Scheme 2.
2. Results and discussion
on compound 8 13 leading to enantioenriched N-Boc phenyl-
sarcosine 9.14
2.1. Synthesis via dianionic species
Two different strategies were investigated for the deproto-
nation procedure of 8. In the ®rst one, the chiral complex
was formed in situ, and in the second, it was preformed
separately, then cannulated at 2788C onto the substrate.
The results obtained are summarized in Table 1.
Pathway A 4Scheme 1) which involves a dianionic inter-
mediate 1 was ®rst investigated. As precedent, Tischler,9
Greene,10 and Schlosser11 have reported results on dianionic
species. Schlosser's group demonstrated the importance of
having a carbamate moiety as stabilizing factor. Using
s-BuLi±42)-sparteine, we prepared 7 by the route shown
in Scheme 2. In Et2O or THF, we have been able to obtain 7
in 50±54% yields similar to the reported yields. However,
the maximum enantioselectivity observed topped at an
enantiomeric ratio 4er) of 56/44 using a warm±cool
protocol.12 We attributed the lack of enantioselectivity to
the presence of a negative charge on the carbamate, which
decreases the con®gurational stability of the benzylic
organolithium 6. These results brought us to focus our
efforts on pathway B, in which the carbamate proton is
replaced by a protecting group.
Generally, better yields and enantioselectivities were
observed in hexane as compared with Et2O. It has been
reported that the selectivity of the deprotonation and
carboxylation steps is solvent-dependent.7 In addition, the
methodology involved in the deprotonation process was also
shown to in¯uence the degree of enantioselectivity, which
was higher when the chiral complex was formed in situ. It is
legitimate to presume that different organolithium
complexes are produced by the two methodologies, hence
leading to different levels of enantioselectivity.
On the other hand, Beak and co-workers16 observed the
introduction of the chirality proceeded either by an enantio-
selective deprotonation or by an enantioselective substitu-
tion in related benzylic organolithiums. Hence, to de®ne our
mechanism, the racemic intermediate 10 4Scheme 4) was
generated with s-BuLi, then 42)-sparteine was added at
2788C before CO2 was bubbled through the reaction
mixture. The acid 9 was obtained in 39% yield in a racemic
form. This result suggests that the reaction proceeds most
likely via an enantioselective deprotonation step, although
it is possible that the ligand exchange reaction with 42)-
sparteine is very slow at 2788C.
2.2. Synthesis via monoanionic species
Pathway B 4Scheme 1) requires a double `protection' of the
amino group. In this approach, the s-BuLi±42)-sparteine
complex would stereoselectively deprotonate the benzylic
center to generate chiral intermediate 2, and stereoselective
electrophilic substitution with CO2 was expected to lead to
enantioenriched N-protected a-amino acid 3. We initiated
the study with the N-methyl N-Boc derivative 8 4Scheme 3),
thereby, replacing the carbamate proton by a methyl group.
The deprotonation±carboxylation sequence was performed
Studies on the mechanism of deprotonation±substitution
sequence with benzylic organolithiums have been reported.
Carboxylation with retention17 or inversion18 have been
discussed extensively and reported. Therefore, it is dif®cult
to assess unambigously which prostereogenic proton is
abstracted by the chiral complex at this point.
The stereoselectivity of the addition of CO2 was demon-
strated by quenching the intermediate 11 with TMSCl
4Scheme 5). On the basis of earlier work, we assumed that
the reaction of TMSCl with organolithiums proceeds with
retention.18,19 The silyl-substituted benzylamine 12 was
Scheme 3.
Table 1. Yields and enantiomeric ratios of 4R)-42)/4S)-41)-9 using 42)-4±
s-BuLi, pre-formed or formed in situ as chiral base
Entry
Complex
In situ
Hexane
In situ
Preformed
Solvent
Yield 4%)
era
1
2Preformed
3
Hexane
85
Et2O
Et2O
55
89/11
69/31
54
36
79/21
65/35
4
a
Enantiomeric ratios were determined by polarimetry 4see Section 4).
Scheme 4.

C. Barberis et al. / Tetrahedron 57 -2001) 2965±2972
2967
and the best chemical yields were observed with substrates
having a TMS group. As the presence of the silyl protecting
group in¯uences the yield and the stereoselectivity, we
reveri®ed the reaction mechanism, as described previously,
by generating the racemic intermediates of 5a, then adding
sparteine. We obtained an er of 55/45 for 7 as compared
with 81/19 and 70/30 4Entry 4) when using hexane as
Scheme 5.
Scheme 6.
obtained in an er of 84/16, a level of enantioselectivity
sligthly higher than the one obtained in Et2O with CO2
4Scheme 5). Therefore, it can be concluded that the
carboxylation of the benzylic organolithium derived from
8 is stereoselective. Thus, the enantioselectivity of the over-
all process is limited by the selectivity of the deprotonation
step.
solvent. This result indicates that the mechanism proceeds
mainly through an enantioselective deprotonation, but a
kinetic resolution appears to compete partially. Results in
Table 2demonstrate again that the carboxylation and the
deprotonation steps are solvent-dependent as described
above for 8. Comparing results with 5a 4TMS group), the
best yields were obtained in Et2O when the chiral complex
was preformed 4Entry 1) and in toluene when the complex
was formed in situ 4Entry 7). As for the enantiomeric ratios,
the highest one was observed when using the preformed
complex in hexane, although the yield was low 410%;
Entry 4). The best combination of yield and enantio-
selectivity was obtained in toluene with the chiral complex
formed in situ 4Entry 7). In addition, reactions in THF lead
to low yields and enantioselectivity 4Entry 8), in agreement
with results from Schlosser.11
Based on this groundwork, we decided to approach the
synthesis of phenylglycines by `protecting' temporarily
the carbamate proton by a silyl group. Our approach to
the asymmetric synthesis of aryl glycine derivatives 7
requires only three chemical steps from commercially
available benzylic amines and is shown in Scheme 6. The
silylation of the Boc-nitrogen atom was done ef®ciently
using a versatile procedure we have described recently.20
To evaluate the in¯uence of steric hindrance of the silyl
protecting group on the reactivity and the stereoselectivity
of the monoanionic species generated by the deprotonation
step, different silyl groups were used. The importance of the
silyl group variation was demonstrated earlier using N-Boc
benzylic substrates.6d The results are reported in Table 2.
These results indicate that the size of the silyl group
impedes the approach of the large chiral complex and the
deprotonation step. Indeed, the use of bulkier silyl groups
leads to lower yields of 7.
It is important to note that the enantiomeric ratios reported
in Tables 1 and 2are the ones measured on crude Boc-
protected acids 7 and 9 obtained after one simple acid-
base extraction work-up. In the case of 7 though, the
enantiomeric purity could be increased to over 90%
4erˆ96/4) by crystallizing out the mismatched dimer in an
ether/hexane mixture 4see Section 4 for details).
From Table 2, it is clear that the yields decreased dramati-
cally with the size of the protecting group. This phenomena
is mainly due to a competitive [1,2] silyl rearrangement of
the organolithium intermediates as shown in Scheme 7.21,22
The enantiomeric ratios observed varied from 55/45 to 99/1,
Table 2. Yields and enantiomeric ratios of 4R)-41)/4S)-42)-7 obtained
using s-BuLi±42)-4, preformed or formed in situ as chiral base
Further studies on that rearrangement22 showed that it
proceeds faster with the larger silyl group. Indeed, the
TIPS substituted benzylamine 13c was formed in an 80%
yield by this process from 5c. Notably, the rearrangement is
stereoselective and leads to enantioenriched products like
13a and 13c.22 Therefore, there is a competition between the
intermolecular carboxylation and the intramolecular [1,2]
silicon rearrangement even at 2788C with substrates bear-
ing large silyl groups.
Entry Solvent Substrate
Preformed
Yield 4%)
In situ
Yield 4%)
era
era
1
2Et
3
4
5
6
7
8
Et2O
2O
Et2O
Hexane
Hexane
Hexane
Toluene 5a
THF 5a
5a
5b
5c
5a
5b
5c
86
25
11
10
±
±
11
71/39
75/25
59/41
81/19
±
49
19
7
37
13
±
76/24
69/31
99/1
70/30
55/45
±
±
79/21
In light of these results, the remaining of the carboxylation
studies were conducted with the monoanion of N-Boc
N-trimethylsilylbenzylamine derivatives. To better under-
stand the reactivity of this speci®c anion, we investigated
52
57/43
80/20
1250/50
18
a
Enantiomeric ratios were determined by polarimetry 4see Section 4).

2968
C. Barberis et al. / Tetrahedron 57 -2001) 2965±2972
Scheme 7.
meta isomers 17 and 18. The enantiomeric ratios however
are not in¯uenced by the ¯uorine position. These observa-
tions could also be explained, in that speci®c case, by the
propensity of the carbanionic center to become planar more
easily in the presence of a ¯uorine substituent. So the enan-
tioselectivity could therefore originate from a restoration of
the chirality after a rapid racemization 4kinetic resolution).
Results with ¯uorine substituted substrates 4Entries 1±9,
Table 3) suggested that the mechanism of the reaction
could go through a rapid racemization followed by restora-
tion of chirality. But results with 4-methyl substituted
benzylamine 4Entries 10±12, Table 3) are in contradiction
with that hypothesis. If there was a speci®c substituent
effect, a simple methyl substituent on the phenyl moiety
should have the same reactivity as the unsubstituted phenyl
group. However, the yield increased to 92% in toluene
4Entry 12) and decreased to 14% yield in Et2O 4Entry 10)
as compared with the unsubstituted substrate 5a 4Table 2;
Entries 1 and 7). In addition, if the electron delocalization
on the aromatic system was responsible for the increased
yields in 17±19, the 4-biphenyl substrate 21 would con®rm
that hypothesis. But we only got a 41% yield in hexane
4Entry 14) minimizing the importance of charge delocaliza-
tion in the chemical yields. It is noteworthy, however, that a
very high enantioselectivity 4erˆ98/2) was observed in the
case of 21 in hexane 4Entry 14). This unusually high selec-
tivity can be rationalized by a more selective approach of
the chiral base complex favored by some p-cation inter-
action between the large aromatic surface and Li1.23
However, this phenomena was not observed with the
naphthyl substrate 22. Indeed, the enantiomeric ratio tops
at 81/12with 22 just like with the other substrates 4Entries
17 and 18). It is likely that the solubility of the chiral inter-
mediates formed during the process plays an important role
in the outcome. We proposed that, in general, the enantio-
selectivity is limited by the discrimination ability of the
chiral complex. Nevertheless, a simple crystallization
could be used to generate easily 4R)-Boc-protected phenyl-
glycine derivatives with high enantiomeric purity making
them suitable for a direct use as chiral building blocks. In
addition, yields strongly depend on the solubility of the
intermediates and the prevalence of the [1,2] silicon
rearrangement described. Furthermore, it is possible that a
kinetic resolution pathway competes in some cases with the
enantioselective deprotonation±substitution sequence. In
summary, the best conditions to yield rapidly enantio-
enriched arylglycine derivatives is to use toluene as solvent
and to form the chiral complex s-BuLi±42)-sparteine in
situ. Although in certain cases other conditions give better
results due to the complex interplay of solubility, substituent
effects, and aggregation states.
Scheme 8.
Table 3. Yields and enantiomeric ratios for 17, 18, 19, 23, 24, 25 using
s-BuLi±42)-4 formed in situ as chiral base
Entry
Ar
Solvent
Yield 4%)
era
1
2
3
4
5
6
7
8
2-Fluorophenyl
2-Fluorophenyl
2-Fluorophenyl
3-Fluorophenyl
3-Fluorophenyl
3-Fluorophenyl
4-Fluorophenyl
4-Fluorophenyl
4-Fluorophenyl
4-Methylphenyl
4-Methylphenyl
Et2O
87
79
95
95
84
80
5264/36
44
84
57/43
72/28
74/26
60/40
75/25
85/15
Hexane
Toluene
Et2O
Hexane
Toluene
Et2O
Hexane
Toluene
Et2O
Hexane
902
Et2O
Hexane
Toluene
Et2O
Hexane
Toluene
79/21
84/16
58/42
82/18
9
10
11
14
80
124-Methylphenyl
Toluene
80/2
13
14
15
16
17
18
p-Biphenyl
28
41
95
26
87
94
87/13
98/2
90/10
62/38
81/19
82/18
p-Biphenyl
p-Biphenyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
a
Enantiomeric ratios were determined by 1H NMR in CDCl3 and by polari-
metry 4see Section 4).
the in¯uence of different aromatic substituents as shown in
Scheme 8. Results are summarized in Table 3.
The yields are excellent in all solvents for ortho and meta
isomers 17 and 18 ranging from 79±95%. However for the
para isomer 19, yields are moderate in ether and hexane but
very good in toluene. The enantiomeric ratios still top at a
maximum around 85/15. The best enantioselectivity was
obtained in toluene, and the worst in ether. Thus, the
enantioselectivity and yields are generally higher in non-
coordinating solvents, which either enhance the selectivity
of the deprotonation or the electrophilic substitution. The
latter phenomena has been reported by Hoppe.7
The inductive effect of the ¯uorine seems to be responsible
for the increased chemical yields observed for the ortho and

C. Barberis et al. / Tetrahedron 57 -2001) 2965±2972
2969
3. Conclusions
4s, 9H), 4.29 4d, 2H, Jˆ5.85 Hz), 4.91 4s br, 1H), 6.89±
7.04 4m, 3H), 7.23±7.30 4m, 1H); 13C NMR 475.5 MHz,
CDCl3, d ppm) 164.5, 161.2, 155.7, 141.5, 129.9, 129.8,
122.6, 114.1, 113.8, 79.5, 44.0, 28.2; IR 4CHCl3, n)
3500±3200, 2982, 2920, 1710 cm21; MS 4m/e) 2 2 6
4MH1), 170 4M12C4H9), 124 4M12Boc).
We have described a new, enantioselective, and practical
method to synthesize N-Boc arylglycines. These useful
enantioenriched acids can be obtained at a low cost and
the chiral source is also recovered at the end of the synthe-
sis. The enantiomeric ratios obtained vary from 56/44 to 98/
2but could eventually be increased substantially by one
simple crystallization. We demonstrated that the inter-
molecular carboxylation was in competition with an intra-
molecular [1,2] silicon shift, favored with larger silyl
groups. The synthetic methodology reported gives access
rapidly and ef®ciently to N-Boc protected aryl glycine
analogs ready to use in medicinal or combinatorial
chemistry. Current efforts are devoted to elucidate in more
detail the mechanistic aspects of the process.
4.2.4. N-,tert-Butyloxycarbonyl)-4-¯uorobenzylamine.6c,11
Yield: 80%; white solid; Rfˆ0.37 4hexane/15%AcOEt); mp:
68±708C; 1H NMR 4300 MHz, CDCl3, d ppm) 1.50 4s, 9H),
4.24 4d, 2H, Jˆ5.7 Hz), 4.97 4s, 1H), 7.24±7.94 4m, 4H);
13C NMR 475.5 MHz, CDCl3, d ppm) 129.1, 115.5, 115.2,
44.0, 28.4, 27.9; IR 4CHCl3, n) 3452, 2982, 1710 cm21; MS
4m/e): 226 4MH1), 170 4M12C4H9), 124 4M12Boc).
4.2.5. N-,tert-Butyloxycarbonyl)-4-methylbenzylamine.
Yieldˆ70%; white solid; Rfˆ0.46 4hexane/15% AcOEt);
mp: 73±748C 4Lit. 72.5±738C).26
4. Experimental
4.1. General
4.2.6. N-,tert-Butyloxycarbonyl)-4-phenylbenzylamine.
Yieldˆ65%; white solid; mp: 101±1038C; 1H NMR
4300 MHz, CDCl3,
d ppm) 1.48 4s, 9H), 4.38 4d,
Jˆ5.9 Hz, 2H), 4.90 4s, 1H), 7.25±7.61 4m, 9H); 13C
NMR 475.5 MHz, CDCl3, d ppm) 156.8, 128.8, 127.9,
127.3, 127.1, 81.0, 44.4, 28.5; IR 4CHCl3, n): 3454, 3020,
2980, 1710 cm21; MS 4m/e) 284 4MH1), 227 4MH12C4H9),
1824M 12Boc); HRMS 4CI) calcd for C18H21NO2 4MH1)
284.1650 found 284.1648.
Organolithiums were handled under dry nitrogen. All
reagents were obtained from commercial sources and were
used without further puri®cation unless otherwise noted.
42)-Sparteine was distilled under vacuum from KOH.
Toluene, hexane, and dichloromethane were distilled from
calcium hydride under a nitrogen atmosphere. Et2O was
distilled from sodium and benzophenone under nitrogen.
Solutions of s-BuLi in cyclohexane were titrated using the
method of Suffert.24 Melting points are uncorrected. Purity
of all synthetic intermediates was established by TLC and
1H- and 13C NMR. Purity of the ®nal amino acids was also
con®rmed by HRMS.
4.2.7. N-,tert-Butyloxycarbonyl)-1-naphthylmethylamine.
Yieldˆ79%; white solid; Rfˆ0.50 4hexane/15% AcOEt);
1
mp: 99±1008C; H NMR 4300 MHz, CDCl3, d ppm) 1.47
4s, 9H), 4.77 4s br, 2H), 7.38±7.57 4m, 4H), 7.76±7.88 4m,
2H), 8.03±8.06 4d br, 1H, Jˆ7.9 Hz); 13C NMR 475.5 MHz,
CDCl3, d ppm) 155.5, 134.0, 131.2, 128.6, 126.3, 125.7,
125.2, 123.3, 79.4, 76.9, 76.5, 42.7, 28.3; IR 4CHCl3, n)
3500±3000, 1775, 1600 cm21; HRMS 4EI) calcd for
C16H19NO2 4M1) 257.1416 found 257.1420.
4.2. General procedure for the preparation of Boc-
benzylamines
To a solution of primary amine 41.0 equiv., 0.5 M) in
anhydrous DCM was added NEt3 41.5 equiv.). After cooling
to 08C 4Boc)2O 41.2equiv.) was added dropwise and the
resulting mixture was stirred for about 3 h. After quenching
with HCl 0.5 N, the organic phase was washed twice with
20 mL of HCl 0.5 N and twice with brine. The organic phase
was then dried with anhydrous MgSO4. After ®ltration and
evaporation to dryness, the white solid was recrystallized in
hexane to give white crystals of the Boc-protected amines.
4.3. General procedure for the silylation of carbamates
To a solution of carbamate 414 mmol) in anhydrous DCM at
08C was added 1.1 equiv. of NEt3, then dropwise 1.1 equiv.
of R3SiOTf. The mixture was stirred for 5 min at 08C then
warmed to rt. After quenching with saturated sodium
bicarbonate, the organic phase was washed twice with
saturated NaHCO3, then dried with anhydrous MgSO4.
Filtration and evaporation lead to the crude compound 4oil),
which was puri®ed by ¯ash chromatography 4hexane/ethyl
acetate 95/511% NEt3) to give the pure compound. Spectro-
scopic data for N-Silyl N-Boc protected amines are following.
4.2.1. N-,tert-Butyloxycarbonyl)-N-methylbenzylamine
,8). See Refs. 14b, 25.
4.2.2. N-,tert-Butyloxycarbonyl)-2-¯uorobenzylamine.11
Yield: 98%, colorless oil; Rfˆ0.37 4hexane/15%AcOEt);
1H NMR 4300 MHz, CDCl3, d ppm) 1.34 4s, 9H), 4.23 4d,
2H, Jˆ5.9 Hz), 5.424s br, 1H), 6.84±7.24 4m, 4H); 13C
NMR 475.5 MHz, CDCl3, d ppm) 162.1, 158.9, 155.8,
129.3, 128.5, 126.0, 123.9, 115.0, 114.7, 79.0, 38.1, 28.1;
IR 4CHCl3, n) 3500±3200, 2982, 2920, 1710 cm21; MS
4m/z) 226 4MH1), 170 4M12C4H9), 124 4M12Boc).
4.3.1. N-,Trimethylsilyl)-N-,tert-butyloxycarbonyl)ben-
zylamine ,11).20 Yieldˆ92%; colorless oil; Rfˆ0.73
4hexane/15%AcOEt/1%Et3N).
4.3.2. N-,tert-Butyldimethylsilyl)-N-,tert-butyloxycarbo-
nyl)benzylamine ,12).20 Yieldˆ89%; colorless oil;
Rfˆ0.89 4hexane/15%AcOEt/1%Et3N).
4.2.3. N-,tert-Butyloxycarbonyl)-3-¯uorobenzylamine.11
Yield: 85%; white solid; Rfˆ0.37 4hexane/15%AcOEt);
4.3.3. N-,Triisopropylsilyl)-N-,tert-butyloxycarbonyl)-
benzylamine ,13).20 Yieldˆ98%; colorless oil; Rfˆ0.90
4hexane/15%AcOEt/1%Et3N).
1
mp: 53±548C; H NMR 4300 MHz, CDCl3, d ppm) 1.44

2970
C. Barberis et al. / Tetrahedron 57 -2001) 2965±2972
4.3.4. N-,Trimethylsilyl)-N-,tert-butyloxycarbonyl)-2-
¯uorobenzylamine ,14). Yieldˆ80%; colorless oil;
Rfˆ0.64 4hexane/15%AcOEt/1% NEt3); 1H NMR
4300 MHz, C6D6, d ppm) 0.18 4s, 9H), 1.38 4s, 9H), 4.55
4s br, 2H), 6.69±6.88 4m, 3H), 7.35 4m br, 1H); 13C NMR
475.5 MHz, C6D6, d ppm) 162.1, 158.9, 158.1, 128.8, 127.6,
124.1, 115.27, 79.8, 41.5, 28.3, 0.5; IR 4CHCl3, n) 2978,
1688, 1210 cm21; HRMS 4CI) calcd for C15H24NO2SiF
4MH1) 298.1639 found 298.1635.
4.4. General procedure for the asymmetric
deprotonation of N-silylcarbamates forming the chiral
complex in situ
To a 0.1 M solution of a silylcarbamate 41 equiv.) under a
N2 atmosphere, was added 42)-sparteine 41.1 equiv.) and
the solution was cooled to 2788C. After 15 min at that
temperature, 1.1 equiv of s-BuLi 41.3 M in cyclohexane)
was added, and the yellow solution was allowed to stir at
2788C for 3 h before CO2 was bubbled through 420 min).
The mixture was warmed to rt and then quenched with 2N
HCl. The organic layer was separated and extracted with
1 N NaOH. The alkaline layer was acidi®ed with 2N HCl
and extracted back with ether. The organic phase was sepa-
rated, dried over anhydrous MgSO4, ®ltrated and evaporated
to give the crude Boc-protected acid. Trituration with
hexane yielded pure compound as white powder, which
was characterized by 1H, 13C NMR, and mass spectrometry.
4.3.5. N-,Trimethylsilyl)-N-,tert-butyloxycarbonyl)-3-
¯uorobenzylamine ,15). Yieldˆ62%; colorless oil;
Rfˆ0.64 4hexane/15%AcOEt/1% NEt3); 1H NMR
4300 MHz, C6D6, d ppm) 0.10 4s, 9H), 1.24 4s, 9H), 4.14
4s br, 2H), 6.51±6.58 4m, 1H), 6.73±6.85 4m, 3H); 13C NMR
475.5 MHz, C6D6, d ppm) 165.1, 161.8, 158.1, 130.0, 122.1,
113.8, 113.4, 79.9, 47.4, 28.2, 0.7; IR 4CHCl3, n) 2978,
1688, 1230 cm21; HRMS 4CI) calcd for C15H24NO2SiF
4MH1) 298.1639 found 298.1635.
4.5. General procedure for the asymmetric
deprotonation of N-silylcarbamates using the preformed
chiral complex
4.3.6. N-,Trimethylsilyl)-N-,tert-butyloxycarbonyl)-4-
¯uorobenzylamine ,16). Yieldˆ80%, colorless oil;
Rfˆ0.64 4hexane/15%AcOEt/1% NEt3); 1H NMR
4300 MHz, C6D6, d ppm) 0.14 4s, 9H), 1.40 4s, 9H),
4.26 4s, 2H), 6.74±7.03 4m, 4H); 13C NMR
475.5 MHz, C6D6, d ppm) 163.8, 115.2, 114.9, 80.0,
At 2788C, 1.24 mmol of s-BuLi 41.3 M solution in cyclo-
hexane) was added to freshly distilled 42)-sparteine
41.1 equiv.) in 3 mL of solvent. The mixture was stirred
for 15 min then cannulated to a solution of substrate
41.13 mmol) in 1.5 mL of solvent. The resulting mixture
was stirred at 2788C for 3 h before CO2 was bubbled
through 420 min). After warming to 08C and quenching
with 2N HCl, the organic layer was separated and extracted
with 1N NaOH. The alkaline layer was acidi®ed with 2N
HCl and extracted back with ether. The organic phase was
separated, dried over MgSO4, ®ltered and evaporated to give
the crude Boc-protected acid. Trituration with hexane
yielded pure compound as a white powder, which was char-
acterized by 1H, 13C NMR, and mass spectrometry.
47.0, 28.1, 0.6; IR 4CHCl3, n) 2978, 1688, 1230 cm21
;
HRMS 4CI) calcd for C15H24NO2SiF 4MH1) 298.1639
found 298.1635.
4.3.7. N-,Trimethylsilyl)-N-,tert-Butyloxycarbonyl)-4-
methylbenzylamine ,20). Yieldˆ74%; white solid;
Rfˆ0.68 4hexane/15% AcOEt, 1% NEt3); mp: 41±428C;
1H NMR 4300 MHz, C6D6, d ppm) 0.17 4s, 9H), 1.41 4s,
9H), 2.09 4s, 3H), 4.37 4s br, 1H), 6.96±6.93 4dd, 2H, Jˆ
6.9 Hz), 7.08±7.11 4dd, 2H, Jˆ7.9 Hz); 13C NMR 475.5
MHz, C6D6, d ppm) 158.0, 138.2, 135.7, 129.0, 128.6,
128.1, 127.8, 127.5, 126.6, 79.4, 47.5, 28.2, 20.8, 0.7;
IR 4CHCl3, n) 3100±3000, 1775, 1600, 1270 cm21
;
4.5.1. N-,tert-Butyloxycarbonyl)phenylsarcosine ,9). Yieldˆ
36±85% 4see text for details), white solid; mp: 111±1148C
4Lit. 112±1138C).14b,15
HRMS 4CI) calcd for C16H27NO2Si 4MH1) 294.1889 found
294.1886.
4.3.8. N-,Trimethylsilyl)-N-,tert-Butyloxycarbonyl)-4-
phenylbenzylamine ,21). Yieldˆ60%; white solid; mp:
4.5.2. N-,tert-Butyloxycarbonyl)phenylglycine ,7). Yieldˆ
7±86% 4see text for details), white solid; mp: 90±948C 4lit.
88±918C).29
1
84±888C; H NMR 4300 MHz, C6D6, d ppm) 0.21 4s, 9H),
1.44 4s, 9H), 4.47 4s, 2H), 7.08±7.46 4m, 9H); 13C NMR
475.5 MHz, C6D6, d ppm) 159.0, 141.0, 126.5±129, 79.5,
4.5.3. N-,tert-Butyloxycarbonyl)-2-¯uorophenylglycine
,17). Yieldˆ79±95% 4see text for details), white solid;
47.7, 28.4, 0.9; IR 4CHCl3, n) 2980, 2922, 2850, 1688 cm21
;
MS 4m/e): 356 4MH1), 300 4M12C4H9), 256 4M12Boc);
HRMS 4CI) calcd for C21H29NO2Si 4MH1) 356.2046 found
356.2029.
7
1
mp: 90±918C 4Lit. 121±1248C);2 H NMR 4300 MHz,
CDCl3,
d
ppm) major conformer: 1.00±1.17 and
1.21±1.42 42s br, 9H), 5.12 and 5.35 42d, Jˆ4.6 and
6.5 Hz, 1H), 5.71 and 8.11 42d, Jˆ6.4 and 5.1 Hz, 1H),
6.97±7.34 4m, 4H), 11.40 4s, br, 1H); 13C NMR
475.5 MHz, CDCl3, d ppm) 172.8, 164.3, 161.0, 158.6,
156.6, 129.5, 129.4, 127.9, 126.0, 125.8, 124.1, 115.3,
115.0, 81.7, 51.5, 28.1, 27.7, 26.3; IR 4CHCl3, n) 3296,
2500±3100, 1724, 1660 cm21; HRMS 4CI) calcd for
C13H16NO4F 4MH1) 270.1142 found 270.1137.
4.3.9. N-,Trimethylsilyl)-N-,tert-butyloxycarbonyl)-1-
naphthylmethylamine ,22). Yieldˆ79%; colorless oil;
Rfˆ0.68 4hexane/15%AcOEt/1% NEt3); 1H NMR
4300 MHz, C6D6, d ppm) 0 4s, 9H), 1.24 4s, 9H), 4.68 4s
br, 2H), 7.04±7.09 4m, 3H), 7.24±7.26 4m, 1H), 7.31±7.34
4m, 1H), 7.44±7.47 4m, 1H), 7.55±7.58 4m, 1H); 13C
NMR 475.5 MHz, C6D6, d ppm) 158.1, 136.3, 134.1,
131.1, 129.0, 127.6, 127.2, 125.7, 122.4, 79.7, 45.4, 28.2,
4.5.4. N-,tert-Butyloxycarbonyl)-3-¯uorophenylglycine
,18). Yieldˆ80±95% 4see text for details); white solid;
0.6; IR 4CHCl3, n) 3100±3000, 1775, 1600, 1270 cm21
;
HRMS 4CI) calcd for C19H27NO2Si 4MH1) 330.1889
found 330.1878.
1
mp: 90±938C; H NMR 4300 MHz, CDCl3, d ppm) major
conformer: 1.00±1.21 and 1.39±1.51 42s br, 9H), 5.12 and

C. Barberis et al. / Tetrahedron 57 -2001) 2965±2972
2971
25
25
5.35 42d, Jˆ4.6 and 6.2Hz, 1H), 5.71 and 8.11 42d, Jˆ6.2
and 5.2Hz, 1H), 6.90±7.45 4m, 4H), 11.30 4s br, 1H); 13C
NMR 475.5 MHz, CDCl3, d ppm) 172.6, 164.3, 161.0,
156.7, 154.8, 140.5, 134.2, 128.9, 116.0, 115.5, 115.2,
82.0, 81.4, 58.1, 56.8, 28.2, 28.0; IR 4CHCl3, d) 3296,
2500±3100, 1724, 1660 cm21; HRMS 4CI) calcd for
C13H16NO4F 4MH1) 270.1142 found 270.1137.
[a]D ˆ21348 4cˆ1 in EtOH).15 23: [a]D ˆ21448
25
4cˆ0.25 in 1 N HCl).30 25: [a]D ˆ21478 4cˆ1 in
MeOH)28).
4.7. Determination of er's by NMR spectroscopy
In the cases of 17, 18, 19, 21, the enantiomeric ratios
were determined by H NMR in CDCl3 by forming dia-
1
4.5.5. N-,tert-Butyloxycarbonyl)-4-¯uorophenylglycine
,19). Yieldˆ44±84% 4see text for details); white solid;
stereomeric salts in situ with 4S)-41)-mandelic acid and
the methyl ester of phenylglycines obtained after treatment
of 17, 18, 19, 21 with CH2N2 and 4 N HCl/dioxane. A typi-
cal procedure is as follows: Compound 17 was esteri®ed by
an excess of diazomethane in Et2O. After evaporation, the
crude N-Boc methyl ester was treated at 08C with 5 equiv. of
4N HCl in dioxane. The resulting mixture was stirred at rt
for 1 h. Volatile compounds were removed under reduced
pressure. The crude material was diluted in CDCl3, washed
three times with a saturated NaHCO3 solution and dried
1
mp: 44±488C; H NMR 4300 MHz, CDCl3, d ppm) major
conformer 1.22 4s, 9H), 5.11 and 5.32 42d, Jˆ5.0 and
6.3 Hz, 1H), 5.63 and 8.15 42d, Jˆ5.0 and 6.3 Hz, 1H),
7.00±7.43 4m, 4H), 11.81 4s, 1H); 13C NMR 475.5 MHz,
CDCl3, d ppm) 173.2, 164.1, 160.8, 157.0, 134.2, 128.9,
116.0, 115.5, 115.2, 82.0, 81.4, 58.1, 56.8, 28.2, 28.0; IR
4CHCl3, n) 3296, 2500±3100, 1724, 1660 cm21; HRMS
4CI) calcd for C13H16NO4F 4MH1) 270.1142 found
270.1137.
1
over K2CO3. After ®ltration, H NMR measurement of the
diastereomeric ratio was performed by adding 1 equiv. of
4S)-41)-mandelic acid. The signals of the a-CH groups of
the two diastereomeric complexes formed in situ are easily
integrated at 4.96 4major) and 5.08 4minor) ppm.
4.5.6. N-,tert-Butyloxycarbonyl)-4-methylphenylglycine
,23). Yieldˆ14±92% 4see text for details); white solid;
mp: 111±1128C; 1H NMR 4300 MHz, CDCl3, d ppm)
major conformer 1.24 4s, 9H), 2.34 4s, 3H), 5.11 4d, 1H,
Jˆ7.01 Hz), 7.14±7.16 4m, 2H), 7.25±7.34 4m, 2H),
7.97±7.98 4m, 1H); 13C NMR 475.5 MHz, CDCl3, d ppm)
173.7, 156.6, 137.6, 135.0, 129.0, 126.0, 81.3, 77.3, 58.4,
27.8, 21.0; IR 4CHCl3, n) 3540±2900, 1750, 1600,
1170 cm21; HRMS 4CI) calcd for C14H19NO4 4MH1)
266.1392 found 266.1397.
4.8. Enantiomeric enrichment procedure for 7by
recrystallization
25
N-t-Boc phenylglycine 7 4erˆ84/16; 68% ee; [a]D
ˆ
297.98 4cˆ0.91, EtOH)) was dissolved in a minimum
amount of boiling Et2O. To the clear solution was added
dropwise boiling hexane until appearance of cloudiness.
The solution was allowed to cool to rt and then to 58C for
3 days 4crystallization begun after 12h). White crystals
were ®ltered off, dried and submitted to polarimetry
measurement. The er observed was 55/45. The mother
liquor was evaporated and dried under vacuum. The result-
ing white powder was then submitted to polarimetry
measurement, and was shown to contain pure 7 with an er
4.5.7. N-,tert-Butyloxycarbonyl)-4-biphenylglycine ,24).
Yieldˆ28±41% 4see text for details); white solid; mp:
1
71±758C; H NMR 4300 MHz, CDCl3, d ppm) 1.20 4s,
9H), 5.14 and 5.35 42s, 1H), 7.20±7.54 4m, 9H), 5.49 and
7.78 42s, 1H); 13C NMR 475.5 MHz, CDCl3, d ppm) 174.0,
138.0, 128.8, 127.6, 127.1, 81.0, 57.3, 28.1; IR 4CHCl3, n)
3200, 2500±3100, 1722, 1658 cm21; MS 4m/e): 328 4MH1),
3724M 12C4H9), 228 4M12Boc); HRMS 4CI) calcd for
C14H21NO4 4MH1) 328.1549 found 328.1541.
25
of 96/4 493% ee; [a]D ˆ2133.98 4cˆ1, EtOH)).
4.5.8. N-,tert-Butyloxycarbonyl)-1-naphthylglycine ,25).
Yieldˆ26±94% 4see text for details); white solid; mp: 153±
1558C 4Lit. 182±1838C).28
Acknowledgements
We are grateful to Merck Frosst Canada, NSERC of Canada,
4.5.9. a-Trimethylsilyl-N-methyl-N-,tert-butyloxycarbo-
nyl)benzylamine ,12). After deprotonation under the above
conditions, TMSCl 42equiv.) was introduced at 2788C and
the reaction mixture was stirred at this temperature for
30 min. After quenching at 08C with 2N HCl, the organic
layer was separated, dried over anhydrous MgSO4, and
evaporated to give a yellow oil. Pure 12 was obtained
after ¯ash chromatography with hexane/ethylacetate
Â
the Fonds FCAR du Quebec, and to the Universite Laval for
®nancial support of our work.
Â
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