(L)-(Trimethylsilyl)alanine synthesis exploiting hydroxypinanone-induced diastereoselective alkylation

Article abstract of DOI:10.1007/s00726-013-1492-2

A new and efficient synthesis of (L)-(trimethylsilyl)alanine (TMSAla) with suitable protection for use in Solid Phase Peptide Synthesis (SPPS) has been accomplished starting from glycine tert-butyl ester and using hydroxypinanone as chiral inductor. The silylated side chain was introduced by alkylation of the Schiff base intermediate with iodomethyl(trimethylsilane) at -78 C. Among the different synthetic routes that were tested including several chiral inductors and different Schiff bases, this strategy was selected and afforded (L)-TMSAla in good chemical overall yield with 98 % ee.

Full text of DOI:10.1007/s00726-013-1492-2

Amino Acids (2013) 45:301–307
DOI 10.1007/s00726-013-1492-2
ORIGINAL ARTICLE
(L)-(Trimethylsilyl)alanine synthesis exploiting hydroxypinanone-
induced diastereoselective alkylation
•
A. Rene N. Vanthuyne J. Martinez
•
•
´
F. Cavelier
Received: 31 January 2013 / Accepted: 2 April 2013 / Published online: 26 April 2013
Ó Springer-Verlag Wien 2013
Abstract A new and efficient synthesis of (L)-(trimeth-
ylsilyl)alanine (TMSAla) with suitable protection for use in
Solid Phase Peptide Synthesis (SPPS) has been accom-
plished starting from glycine tert-butyl ester and using
hydroxypinanone as chiral inductor. The silylated side
chain was introduced by alkylation of the Schiff base
intermediate with iodomethyl(trimethylsilane) at -78 °C.
Among the different synthetic routes that were tested
including several chiral inductors and different Schiff
bases, this strategy was selected and afforded (L)-TMSAla
in good chemical overall yield with 98 % ee.
volume (Si 117 pm; C 77 pm) than carbon (Meanwell
2011). Despite these differences, silicon proved its
behavior as a carbon isostere in bioactive compounds. This
property has been recently exploited in drug design
(Meanwell 2011; Gately and West 2007; Franz and Wilson
2012).
In this domain, unnatural amino acids are of great
importance, and silylated amino acids have attracted syn-
thetic efforts. Their incorporation into bioactive peptides
can modulate conformational flexibility and structure
(Tacke et al. 2000; Vivet et al. 2000b; Cavelier et al. 2006),
modify biological properties (Cavelier et al. 2002, 2004),
induce enzymatic resistance and facilitate membrane
crossing (Pujals et al. 2006).
Keywords (Trimethylsilyl)alanine ꢀ Diastereoselectivity ꢀ
Schiff base ꢀ Sulfinamide ꢀ (1R,2R,5R)Hydroxy-3-
pinanone ꢀ Chiral HPLC
Despite interest in silicon-containing amino acids, they
are still limited in number and diversity, as shown in a recent
review (Mortensen et al. 2009). Since then, other synthetic
approaches have been reported to obtain chiral silylated
a-amino acids and a,a0-dialkylated a-amino acids, through a
hydrosilylation reaction on unsaturated substrates (Marc-
hand et al. 2008; Cavelier et al. 2008), or from diethylmal-
onate (Falgner et al. 2009a, b, 2010). A new silylated amino
acid carrying a 1-(4-dihydroxymethylsilyl)butyl side chain
was also prepared and showed efficiency as an inhibitor of a
specific enzyme (Kim and Sieburth 2012). Recently, the
silylated proline surrogate 4,4-dimethylsilaproline (Vivet
et al. 2000a; Handmann et al. 2000) has been produced on a
gram scale (Martin et al. 2012).
Introduction
For several decades, silicon was known to confer physical
and chemical properties to the compounds in which it was
incorporated, offering non-polar and hydrophobic proper-
ties. Physical studies showed that silicon has a smaller
electronegativity (Si 1.74; C 2.5) along with a larger steric
Electronic supplementary material The online version of this
article (doi:10.1007/s00726-013-1492-2) contains supplementary
material, which is available to authorized users.
TMSAla is probably the most reviewed silylated amino
acid in the literature. It has been first synthesized as a
racemate in 1968 (Porter and Shive 1968). Twenty years
later, the first synthesis of the (L)-enantiomer was descri-
bed using imidazolinone glycine derivatives (Fitzi and
Seebach 1988), and other auxiliaries have been later tested
as chiral inductors (Weidmann 1989, 1992; Walkup et al.
´
A. Rene ꢀ J. Martinez ꢀ F. Cavelier (&)
´
IBMM, UMR-CNRS-5247, Universites Montpellier I and II,
Place Eugene Bataillon, 34095 Montpellier, France
e-mail: florine@univ-montp2.fr
`
N. Vanthuyne
Chirosciences, ISm2,UMR-7313, Aix-Marseille Universite,
´
Avenue Escadrille Normandie Niemen, 13397 Marseille, France
´
123

´
A. Rene et al.
302
˚
1995). Enzymatic syntheses were also employed (Yama-
naka et al. 1996; Pietzsch et al. 2000; Smith et al. 2001), as
well as kinetic resolution (Chen et al. 2002). Synthetic
routes starting from (l)-serine derivatives proved also to be
efficient (Sibi et al. 1998; Kenworthy et al. 2004). Sur-
prisingly, the most recent synthesis of TMSAla resulted in
a racemic mixture, and the structure of the racemate was
characterized by single-crystal X-ray diffraction (Falgner
et al. 2009b).
6.45 mmol) and then 4 A molecular sieves (activated
overnight at 100 °C). After 24 h, the reaction mixture was
filtered through CeliteÒ and the residue washed with
CH2Cl2 (3 9 50 mL). Organic layers were combined, dried
over MgSO4, filtered and concentrated to give colorless oil.
Flash chromatography through a short frit (SiO2, CH2Cl2)
afforded (?)-(para-toluenesulfinyl)-iminoacetate 2 (1.11 g;
72 %) as a colorless oil, which solidified on storage at 5 °C.
NMR 1H (CDCl3, 300 MHz): d (ppm) 1.33 (t, 2H,
3J = 6 Hz, CH2CH3); 2.39 (s, 3H, CH3Ph); 4.3–4.32 (q,
3H, 3J = 6 Hz, CH2CH3); 7.3 (d, 2H, 3J = 9 Hz, CHoSO);
3
Materials and methods
7.57 (d, 2H, J = 9 Hz, CHmSO); 8.13 (s, 1H, CHCO2Et).
NMR 13C (CDCl3, 75 MHz): d (ppm) 13.8 (CH2CH3);
21.2 (CH3Ph); 62.4 (CH2CH3); 124.5 (CSO); 129.9
(CmSO); 138.9 (CoSO); 142.3 (CpSO); 152.9 (CHCO2Et);
161.0 (CO2Et).
All reactions involving air-sensitive reagents were per-
formed under nitrogen or argon. Purifications were per-
formed with column chromatographies using silica gel
(Merck 60, 230–400 mesh) or with a Biotage instrument
Isolera 4 using SNAP KP-SIL flash cartridges. Proton
Alkylation procedure to obtain (3)
1
nuclear magnetic resonance H-NMR and carbon nuclear
magnetic resonance 13C-NMR spectra were recorded on a
Bruker spectrometer avance 300 at 300 and 75 MHz, a
Bruker spectrometer avance 400 at 400 and 100 MHz or a
Bruker spectrometer 600 at 600 and 150 MHz, respec-
tively. All chemical shifts were recorded as values (ppm)
relative to internal tetramethylsilane when CDCl3 was used
as solvent. Low-resolution electrospray ionization (ESI)
mass spectra were recorded on a micromass platform
electrospray mass spectrometer. Spectra were recorded in
the positive mode (ESI?). Optical rotation values were
measured on a Perkin-Elmer 341 (20 °C, sodium ray). The
analytical chiral HPLC experiments were performed on a
unit composed of a Merck D-7000 system manager,
Merck-Lachrom L-7100 pump, Merck-Lachrom L-7360
oven, Merck-Lachrom L-7400 UV-detector, and on-line
Jasco OR-1590 polarimeter. Hexane, ethanol and isopro-
panol, HPLC grade, were degassed and filtered on a 0.45-
lm membrane before use. Chiral columns (250 9 4.6 mm)
tested are Chiralcel OD-H, OJ, OC, OB-H, Chiralpak
AS-H, IC and AD-H from Chiral Technologies Europe
(Illkirch, France), Whelk O1 (S,S) and Ulmo (S,S) from
Regis Technologies (Morton Grove, USA), Sumichiral
OA-2500 from Sumika (Japan) and Lux-Cellulose-2 from
Phenomenex.
Magnesium turnings (250 mg, 10.3 mmol) were placed in
a high-dry three-neck round-bottom flask equipped with an
addition funnel and a cooling system. Ether was added
(10 mL) through the addition funnel. Then, the chloro-
methyl(trimethylsilane) (1.436 mL, 10.3 mmol) was dilu-
ted in ether (10 mL) in the addition funnel. Few drops were
added and the mixture was heated to weak reflux. Di-bro-
moethane (a few drops) was added as an Mg activator. The
reaction mixture trouble shows that the reaction started.
Then, the rest of chloride derivative diluted in ether was
added dropwise and heating was maintained. After addi-
tion, reaction mixture was diluted with ether (20 mL).
Heating was continued for 10 min.
In a second three-necked round-bottom flask under
argon atmosphere was placed imino-ester 2 (350 mg,
1.255 mmol) in CH2Cl2 (10 mL) and a few drops of boron
trifluoride diethyl ether were added. After cooling to -
78 °C, the Grignard derivative (5 equiv.) was transferred
and the reaction mixture was stirred at -78 °C for 1 h and
a half. The reaction was quenched with a saturated solution
of ammonium chloride. Aqueous layer was separated and
extracted with CH2Cl2 (3 9 20 mL). Organic layers were
combined, dried over MgSO4, filtered and concentrated.
The diastereoisomers were separated with a chromatogra-
phy separation on silica flash (cyclohexane/ethyl acetate;
from 0 to 30 %). The desired diastereoisomer 3 was
obtained in 17 % yield (70.7 mg, 0.216 mmol).
Para-tolylsulfiniminoacetate (2)
In a 500-mL round-bottom flask under argon atmosphere
was placed ethyl glyoxalate (50 % solution in toluene,
1.279 mL; 6.45 mmol). The flask was heated with a heat
gun to about 50 °C for 1 min to depolymerize the reagent
and then, allowed to cool to room temperature and CH2Cl2
(160 mL) was introduced. To this rapidly stirred solution
was added (S)-(?)-N-para-toluenesulfinamide 1 (1 g;
m.p. 56 °C; NMR 1H (CDCl3, 600 MHz): d (ppm) -0.12
(s, 9H, Si(CH3)3); 0.83–0.92 (m, 2H, 3J = 54 Hz, CH2
3
Si(CH3)3); 1.30 (t, 2H, J = 6 Hz, CH2CH3); 2.41 (s, 3H,
3
CH3Ph); 3.72–3.77 (m, 1H, J = 30 Hz, CH2CH3); 4.13–
3
4.18 (m, 1H, J = 30 Hz, CH2CH3); 4.21–4.26 (m, 1H,
3J = 30 Hz, SiCH2CHa); 4.75–4.76 (d, 1H, NH); 7.3 (d,
2H, 3J = 9 Hz, CHoSO); 7.59 (d, 2H, 3J = 9 Hz, CHmSO).
123

(L)-TMSAla synthesis exploiting alkylation
303
NMR 13C (CDCl3, 150 MHz): d (ppm) 1.10 (Si(CH3)3);
14.1 (CH2CH3); 21.5 (CH3Ph); 22.9 (CH2Si); 50.8
(CHCH2Si); 61.5 (CH2CH3); 126.1 (CmSO); 129.6 (CoSO);
141.0 (CpSO); 141.6 (CSO); 174.8 (CO2Et).
Rf = 0.4 (cyclohexane 8/ethyl acetate 2); MS-ESI
[MH?] = 368; NMR 1H (CDCl3, 400 MHz): d (ppm)
0.008 (s, 9H, Si(CH3)3); 0.83 (s, 3H, CH3 bridge); 1.19–1.21
(m, 2H, CH2Si); 1.30 (s, 3H, CH3 bridge); 1.41 (s, 9H,
OtBu); 1.45 (s, 3H, C(OH)CH3); 1.99–2.05 (m, 1H,
CHC(CH3)2; 2.48–2.49 (m, 2H, CH2CHC(OH)CH3); 2.54–
2.57 (m, 2H, CH2CN); 4.14 (m, 1H, SiCH2CHa).
NMR 13C (CDCl3, 75 MHz): d (ppm) 0.66 (Si(CH3)3);
21.3 (CH2CN); 22.9 (CH2Si); 27.4 (CO2tBu); 33.5
(CH3 bridge); 38.3 (C(OH)CH3); 38.4 (CH2C(OH)CH3);
50.2 (CHCH2Si); 60.5 (CC(OH)CH3); 81.1 (C(OH)CH3);
172.2 (CN); 177.6 (CO2tBu).
1
Compound 5: NMR H (CDCl3, 300 MHz): d (ppm)
0.01 (s, 9H, Si(CH3)3); 2.39 (s, 3H, CH3Ph); 3.30 (dd, 2H,
AB, 2J = 12 Hz; 3J = 304 Hz, CH2Si(CH3)3); 7.29 (d,
2H, J = 12 Hz, CH3CHo); 7.52 (d, 2H, J = 12 Hz,
CH3CHm)NMR 13C (CDCl3, 150 MHz): d (ppm) 3.13
(Si(CH3)3); 21.6 (CH2Si); 53.7 (CSO); 125.7 (CHoCSO);
129.7 (CHmCSO); 141.3 (CHoCSO); 142.6 (CH3C).
(?)-(1R,2R,5R)-2-hydroxy-3-pinanone Schiff base (10)
Synthesis of Fmoc-(L)-(trimethylsilyl)alanine-OH (12)
from (11)
A suspension of glycine tert-butyl ester hydrochloride 9
(1.68 g, 10 mmol, 1.5 equiv.) in dry toluene (30 mL) was
stirred in the presence of triethylamine (1.4 mL, 1.5 equiv.)
for 1 h. After triethylammonium chloride filtration,
(1R,2R,5R)hydroxy-3-pinanone (1.12 g, 6.67 mmol) was
added to the free amine. The mixture was heated to reflux
for 4 h in the presence of boron trifluoride diethyl ether
(100 lL). Water, formed during the reaction, was removed
with a Dean-Stark trap. After cooling, the mixture was
concentrated. The crude product was purified by chroma-
tography separation on silica flash (cyclohexane 7/ethyl
acetate 3; 1 % TEA). The Schiff base 10 (1.76 g,
6.24 mmol) was obtained in 94 % yield.
To a solution of the alkylated Schiff base 11 (0.63 g,
1.72 mmol) in THF (3.5 mL) was added a solution of citric
acid 15 % (10 mL). The mixture was stirred at room
temperature for 3 days. After removing THF in vacuo, the
aqueous layer was extracted with diethyl ether (15 mL) in
order to remove the chiral inductor. Then, the pH was
increased to 8–9 with potassium carbonate addition. The
free amine was then extracted with ethyl acetate
(3 9 30 mL). The organic layer was concentrated at room
temperature due to the amine volatility. The (trimethyl-
silyl)alanine tert-butylester was then dissolved in ethyl
acetate (10 mL) and Fmoc-OSu (753 mg, 1.3 equiv.) was
added. The pH was adjusted to 8–9 with triethylamine
addition. The mixture was stirred for 6 h. After TLC
monitoring, the solvent was removed. The organic layer
was washed with a solution of potassium hydrogenosulfate
(3 9 20 mL) and saturated solution of sodium hydro-
genocarbonate (3 9 20 mL). Then, organic layer was dried
over MgSO4 and concentrated. The crude product was
purified on silica flash (cyclohexane 9/ethyl acetate 1). The
Fmoc-trimethyl(silylalanine) tert-butyl ester (646 mg,
1.47 mmol) was obtained in 86 % yield.
Rf = 0.3 (cyclohexane 7/ethyl acetate 3); MS-ESI
[MH?] = 282; NMR 1H (CDCl3, 300 MHz): d (ppm) 0.85
(s, 3H, CH3 bridge); 1.30 (s, 3H, CH3 bridge); 1.46 (s, 9H,
OtBu); 1.5 (s, 3H, C(OH)CH3); 2.02–2.06 (m, 3H,
CH2CHC(OH)CH3); 2.25–2.35 (m, 1H, CHCH2CN); 2.45
(m, 2H, CH2CN); 4.07 (s, 2H, CNCH2).
Obtention of (11)
To a solution of diisopropylamine (1.38 mL, 2.5 equiv.) in
dry THF (24 mL) was added very slowly a solution of
n-butyllithium 2.5 M in hexane (3.78 mL, 2.4 equiv.) at
-10 °C. After 30 min, the mixture was cooled to -78 °C
and the Schiff base 10 (1.11 g, 3.94 mmol) dissolved in
THF (2.5 mL) was added. After 40 min, the iodo-
methyl(trimethylsilane) (1.05 mL, 1.8 equiv.) was added.
The mixture was stirred at -78 °C for 8 h. Then, the
mixture was allowed to cool to -10 °C overnight. The
reaction was quenched with a saturated solution of
ammonium chloride (40 mL). Then, THF was concen-
trated. The aqueous phase was extracted three times with
ethyl acetate (3 9 20 mL). The organic phase was dried
over MgSO4. After concentration, the crude product was
purified on silica flash (cyclohexane 8/ethyl acetate 2; 1 %
TEA). The alkylated Schiff base 11 (1.58 g, 2.83 mmol)
was obtained in 72 % yield.
Rf = 0.4 (cyclohexane 9/ethyl acetate 1); MS-ESI
[MH?] = 440; [M ? Na] = 462.
The Fmoc-(trimethylsilyl)alanine tert-butyl ester
(646 mg; 1.47 mmol) was dissolved in trifluoroacetic acid
(6 mL). The mixture was stirred for 1 h at room tempera-
ture. The reaction solvent is concentrated and the acid
excess is removed by coevaporation with cyclohexane. The
Fmoc silylated amino acid 12 is obtained as foam.
MS-ESI?: [M ? H] = 384; [M ? Na] = 406; [M ?
1
K] = 422; [a]D20 -13° (c 1, CH2Cl2); NMR H (CDCl3,
300 MHz): d (ppm) 0.05 (s, 9H, Si(CH3)3); 0.94–1.24 (m,
2H, CH2Si); 4.21 (m, 1H, SiCH2CHa); 4.39–4.41 (m, 2H,
CH2CO2); 5.07–5.09 (m, 1H, CHCH2CO2); 7.28–7.38
(m, 4H, Hm and p); 7.55–7.57 (dd, 2H, Ho); 7.73–7.75 (dd,
0
2H, Hm ).
123

´
A. Rene et al.
304
NMR 13C (CDCl3, 150 MHz): d (ppm) 1.07 (Si(CH3)3);
21.05 (CH2Si); 47.3 (CO2CH2CH); 51.2 (CHCH2Si); 67.2
were separable by column chromatography affording 3 in
17 % yield (Scheme 1). In addition, we observed formation
of a side product 5 resulting from sulfoxide nucleophilic
attack (p-tolylSOCH2SiMe3) obtained in 30 % yield. In the
step from 2 to 3, the nucleophilic agent was issued from a
classic Grignard reaction using Mg turnings and chloro-
methyl(trimethylsilane). The halogen–metal exchange
between iPrMgBr and iodomethyl(trimethylsilane) leading
to the corresponding bromide Grignard intermediate did
not afford the desired compound.
0
(CO2CH2); 120.1 (CHo); 125.1 (CHm); 127.2 (CHm ); 127.9
0
(CHp); 141.5 (CHo ); 143.9 (CO2CH2CHC); 155.9
(CO2NH); 178.9 (CO2H).
Obtention of (13)
Using the same procedure as to obtain 11 but with iodo-
propyl(trimethylsilane) (1.93 g, 8 mmol, 1.5 equiv.), the
alkylated Schiff base was obtained in 65 % yield. Fol-
lowing the same cleavage/protection procedure, the amino
acid 13 was obtained in 88 % yield.
To prevent the side reaction leading to 5, we envisaged
to use a bulkier group, the tert-butyl sulfinamide auxiliary
6 (Liu et al. 1997; Ellman et al. 2002; Robak et al. 2010).
In this route, we started from (S)-tert-butyl sulfinamide 6
as chiral inductor. After the tert-butylsulfiniminoacetate 7
synthesis, the methyl(trimethylsilyl)magnesium chloride
was first synthesized as previously described, but the
alkylation step failed. Then, the magnesium bromide
derivative was synthesized. Unfortunately, only the ester
function attack was observed in this case. Even using the
Zn intermediate instead of the Mg intermediate, this
alkylation key step experimented at lower temperature
(-78 °C) failed. We only observed a partial alkylation of
the tert-butylsulfiniminoacetate 7 by the Zn intermediate
(Scheme 2). We could hypothesize that the methyl(tri-
methylsilyl) group hindrance, combined with the low
temperature, hampered a good access to the imine function.
At -50 °C, the nucleophilic attack with the Zn reagent
occurred on the ester function.
MS-ESI?: [M ? H] = 468; [M ? Na] = 490; [2M ?
1
H?] = 935; NMR H (CDCl3, 300 MHz): d (ppm) 0.00
(s, 9H, Si(CH3)3); 0.50–0.65 (m, 2H, CH2Si); 1.30–1.40
(m, 2H, SiCH2CH2CH2); 1.45 (s, 9H, OtBu); 1.7–1.90
(m, 2H, SiCH2CH2CH2); 4.20–4.50 (m, 4H, CHa and
CHCH2 Fmoc); 5.35 (d, 1H, J = 9.49 Hz, NH); 7.20–7.80
(m, 8H, fluorenyle).
Obtention of (14)
Using the same procedure as to obtain 11 but with iodo-
methyl(dimethylmethylphenylsilane) (1.7 g, 8 mmol,
1.5 equiv.), the alkylated Schiff base was obtained in 68 %
yield. Following the same cleavage/protection procedure,
the amino acid 14 was obtained in 76 % yield.
MS-ESI?: [M ? H] = 502; [M ? Na] = 524; NMR
1H (CDCl3, 300 MHz): d (ppm) 0.35 (s, 6H, Si(CH3)2);
1.15–1.45 (m, 2H, Ph(CH3)2SiCH2);1.45(s, 9H, OtBu);4.15–
4.25 (m, 1H, SiCH2CHa); 4.25–4.40 (m, 3H, CHCH2 Fmoc);
5.00 (d, J = 9.2 Hz, 1H, NH); 7.25–7.80 (m, 13H, fluore-
nyle and SiPh).
Finally, we tested (?)-(1R,2R,5R)-2-hydroxy-3-pina-
none as the chiral part of the Schiff base. This commer-
cially available chiral inductor was first used (Yamada
et al. 1976) and further proved its efficiency (Tabcheh et al.
1991; Solladie-Cavallo and Nsenda 1998).
The starting glycinate tert-butyl ester hydrochloride 9
was neutralized with triethylamine in toluene and con-
densed with the hydroxypinanone. The synthesis of the
Schiff base 10 was performed in the presence of boron
trifluoride diethyl ether using a Dean-Stark trap. A 94 %
yield of product was obtained after purification of the
amine excess. The alkylation step was achieved using
LDA, followed by iodomethyl(trimethylsilane) addition.
The reaction was initiated at low temperature (-78 °C) to
control the diastereoselectivity, then allowed to reach
-10 °C overnight, thus affording 11 in 72 % yield after
purification by column chromatography. NMR spectra
displayed one diastereoisomer only, thus assuming that the
induction was beyond NMR precision. The chiral auxiliary
was disconnected by acid hydrolysis. The amine function
was then protected with a Fmoc group and the tert-butyl
ester was removed with trifluoroacetic acid (Scheme 3).
Compound 12 was obtained in 86 % yield over these three
steps. Afterwards, chirality was analyzed by chiral HPLC
Results and discussion
In this study, we present different new routes for the syn-
thesis of (L)-TMSAla, with a comparison of their efficiency
in term of chimio- and stereoselectivities.
Starting from several chiral Schiff bases, the key
alkylation reaction permitted to evaluate the chiral induc-
tion of each auxiliary.
At first, we tested a N-sulfinyl auxiliary resulting from
the (S)-(?)-p-tolylsulfinamide 1 and ethyl glyoxalate con-
densation. The chiral sulfonamide group is known to
activate the C=N bond for nucleophilic addition (Davis and
McCoull 1999) and to induce a good diastereoselectivity
(Davis et al. 1998). In the reaction with the appropriate
alkyl magnesium chloride, we obtained a moderate dia-
stereoselectivity (76:24 diastereomer ratio) of the desired
compound obtained in 30 % yield. These diastereomers
123

(L)-TMSAla synthesis exploiting alkylation
305
Scheme 1 p-
Tolylsulfiniminoacetate
induction
Scheme 2 Tert-
butylsulfiniminoacetate
induction
Scheme 3 (1R,2R,5R)-2-
hydroxy-3-pinanone induction
and showed an ee superior to 98 %. It is worth to note that
Fmoc-(L)-TMSAla-OH has a (R) configuration while all
natural (L) amino acids have a (S) configuration, the silicium
atom inverting the priority in Cahn–Ingold–Prelog rules.
Fmoc-(D/L)-TMSAla-OtBu and Fmoc-(L)-TMSAla-
OtBu resulting from the diastereoselective synthesis using
the (?)-(1R,2R,5R)-2-hydroxy-3-pinanone induction were
injected into a Chiralcel OD-3 column and elution were
performed with hexane/ethanol (80/20). Chromatogram b
showed that Fmoc-(L)-TMSAla-OtBu was almost the only
formed enantiomer with a positive sign on the circular
dichroism spectra at 220 nm. Thus for the racemic mixture
of Fmoc-TMSAla-OtBu (chromatogram a), the first eluted
enantiomer was Fmoc-(D)-TMSAla-OtBu with a negative
sign, the second eluted enantiomer was Fmoc-(L)-
TMSAla-OtBu with a positive sign (Fig. 1).
After acidic deprotection of the tert-butyl group with
trifluoroacetic acid, racemic and Fmoc-(L)-TMSAla-OH
were injected to evaluate the chiral purity of the final
product 12 ready for solid-phase peptide synthesis. More-
over, the value of its specific optical rotation was measured
[a]D20 = -13° (c = 1, CH2Cl2) and confirmed the forma-
tion of the (L) enantiomer (lit. [a]D20 = -8.7°, c 1 CH2Cl2)
(Weidmann 1992).
To explore the scope of this reaction, the Schiff base
10 was subjected to alkylation with 3-iodopropyl
123

´
A. Rene et al.
306
Chiralcel OD-3
Hexane/ethanol (8/2)
1 ml/min and 25°C
Chiralpak AD-H
Hexane/2-PrOH (8/2)
1 ml/min and 25°C
(b)
(c)
(d)
(a)
UV 254nm
UV 254nm
CD 220nm
UV 254nm
CD 220nm
UV 254nm
CD 220nm
CD 220nm
0
1
2
3
4
5
6
7
8
9
10
0
1
2
3
4
5
6
7
8
9
10
0
1
2
3
4
5
6
7
8
9
10
0
1
2
3
4
5
6
7
8
9
10
Minutes
Minutes
Minutes
Minutes
Fig. 1 Chiral HPLC analyses of TMS-alanine resulting from (?)-(1R,2R,5R)-2-hydroxy-3-pinanone induction: a Fmoc-(D/L)-TMSAla-OtBu, b
Fmoc-(L)-TMSAla-OtBu, c Fmoc-(D/L)-TMSAla-OH and d Fmoc-(L)-TMSAla-OH
Scheme 4 Extension of the
strategy
(trimethylsilane) and iodomethyl(dimethylphenylsilane),
TMSAla-OH in 58 % overall yield in 5 steps with 98 % ee.
Two other silylated amino acids were obtained applying
the same strategy. These silylated amino acids could be
incorporated into bioactive molecules to bring lipophily
and potentially enzymatic resistance.
leading to amino acids 13 and 14, respectively (Scheme 4).
Conclusion
Acknowledgments We thank ANRT and Medincell S.A for finan-
´
cial support (Cifre Grant of Adeline Rene).
In conclusion, we compared the diastereoselectivity
induced by chiral Schiff bases involving different mecha-
nisms. On the one hand, we used p-tolylsulfinamide Schiff
base as an electrophile, which was subjected to a nucleo-
philic attack. On the other hand, the Schiff base derived
from hydroxypinanone was used as equivalent nucleophile
of the glycine to stabilize an enolate. According to our
results, the use of (?)-(1R,2R,5R)-2-hydroxy-3-pinanone
as chiral inductor with electronegative properties permitted
to develop a new diastereoselective synthesis of Fmoc-(L)-
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