Stereoselective, nonracemic synthesis of ω-borono-α-amino acids

Article abstract of DOI:10.1016/S0957-4166(98)00186-4

ω-Unsaturated α-amino acids are synthesized through condensation of allyl and propargyl bromides or of 9-bromoundecene with a Ni(II) complex of the Schiff base derived from glycine and BPB. Hydroboration with Ipc₂BH followed by oxidation with acetaldehyde affords enantiomerically pure ω- borono-α-aminocarboxylic acids.

Full text of DOI:10.1016/S0957-4166(98)00186-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2121–2131
Stereoselective, nonracemic synthesis of ω-borono-α-amino
acids
∗
Sylvain Collet, Patrick Bauchat, Renée Danion-Bougot and Daniel Danion
Synthèse et électrosynthèse organiques, UMR 6510, Université de Rennes I, 35042 Rennes Cedex, France
Received 22 April 1998; accepted 12 May 1998
Abstract
ω-Unsaturated α-amino acids are synthesized through condensation of allyl and propargyl bromides or of 9-
bromoundecene with a Ni(II) complex of the Schiff base derived from glycine and BPB. Hydroboration with
Ipc2BH followed by oxidation with acetaldehyde affords enantiomerically pure ω-borono-α-aminocarboxylic
acids. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The increasing interest in the biological applications of boron containing biomolecules stems from
1
the medicinal applications of borononeutrotherapy (BNCT). Boron analogues of amino acids and
peptides constitute a second topic of major importance. α-Aminoboronic acids and related peptides have
1,2
been extensively investigated. Among them are found the most potent inhibitors of serine proteases
3
achieving subnanomolar affinity. They function by forming stable tetrahedral complexes with serine in
the active site of the enzymes.
The present work deals with the synthesis of nonracemic ω-borono-α-aminocarboxylic acids. Amino
acids with a carboxylic group in the side chain, such as aspartic, glutamic or 2-aminoadipic acids,
play a central role in a number of biological processes and it could be of interest to synthesize some
4
boronic analogues. Potential applications are in the field of neuromediators or enzyme inhibition. ω-
5
6
Boronic analogues of aspartate or of carbamylaspartate have been investigated as antineoplastic agents,
inhibitors of dihydroorotase in the pyrimidine biosynthetic pathway. 2-Amino-6-boronohexanoic acid has
7
also been demonstrated to be an efficient inhibitor of arginase (IC ≈0.5 µM) . In the present work, a
50
long chain ω-borono-α-aminocarboxylic acid was also investigated as an amphiphile.
∗
Corresponding author.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00186-4

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S. Collet et al. / Tetrahedron: Asymmetry 9 (1998) 2121–2131
A common retrosynthetic pathway cannot be considered for all the ω-borono-α-amino acids and we
report herein the approach based on hydroboration of ω-unsaturated, nonracemic, α-amino acids. Two
examples of racemic derivatives were previously reported in a preliminary work.8
2. Synthesis of ω-unsaturated, nonracemic, α-amino acids
9
The methodology developed by Y. N. Belokon was used. The Ni(II) complex 2 of the Schiff base
0
derived from glycine and (S)-2-[N -(N-benzylprolyl)amino]benzophenone (BPB, 1) was reacted with
alkenyl or alkynyl bromides under thermodynamic equilibrating conditions (Scheme 1).
Scheme 1.
1
Diastereoisomeric ratios were close to 95/5 ( H NMR determination on benzylic hydrogens) and the
major diastereoisomer was purified by column chromatography or recrystallization prior to decomplex-
ation in 2 M HCl. One of the major advantages of this approach is that the chiral auxiliary, BPB 1, is
recovered in ≈90% yield and can be re-used. Results are summarized in Table 1. (S)-Configurations
were attributed according to specific rotations reported in the literature for the known amino acids 4a
and 4c. We have postulated the same configuration for the long chain derivative 4b. As a general rule,
(
S)-configurations result in these alkylations, the Si-face of the glycine enolate being largely favored.9
Table 1
Enantioselective synthesis of ω-unsaturated-α-amino acids

S. Collet et al. / Tetrahedron: Asymmetry 9 (1998) 2121–2131
2123
3. Hydroboration of ω-unsaturated α-amino acids 4a, 4b and 4c
Protection of amino and carboxylic acid functions were first performed, under standard procedures,
as the NHBoc and methyl carboxylic ester derivatives 5 (Scheme 2). To avoid these protection steps,
one attempt to hydroborate directly complex 3a was done, but without success. However, the following
reactions were performed in a one-pot procedure.
Scheme 2.
readily available diisopinocampheylborane (Ipc BH) proved to be the most regioselective hydro-
2
borating reagent, affording exclusively boranes 6. It should be noted that a slight excess (2.0 equivalents
for 5a and 5b and 1.2 equivalents for 5c) of Ipc BH was necessary to ensure a complete reaction. This
2
fact is probably related to the relative acidity of the NHBoc hydrogen.
Boranes 6 were converted, in situ, into the boronic esters 7 according to the procedure reported by H.
12
C. Brown. Oxidation by an excess of acetaldehyde afforded α-pinene and diethylboronates that were
then converted to isolable and thoroughly characterized pinanediol boronates 7. These boronic esters can
be chromatographed without decomposition.
Total deprotection of the 2-aminoadipic analogue 7a was performed in an almost quantitative manner
+
by refluxing with 6 M HCl, followed by Dowex (H ) column chromatography, affording 5-borono-2-
aminopentanoic acid 8a. It was isolated as an amorphous, hygroscopic powder and characterized by
1
11
NMR and mass spectroscopy. It should be noted that H and B NMR spectra are strongly dependent on
11
pH. In an acidic medium (8a, HCl), one open-chain structure is likely with δ B near 33 ppm, indicative
of a three coordinated boron atom, and methylenic protons in the 4 or 5 position appearing equivalent.
11
At biological pH (7.4), δ B shifts to 14 ppm and all the methylenic protons are nonequivalent, giving
rise to a complex pattern. As previously reported,3 intramolecular complexation must be considered.
We were unable to isolate any crystal of this boronic α-amino acid for X-ray structural determination.
Tentatively, a cyclic borate complex may be considered.
b,5
The long chain boronic α-amino acid 8b was isolated and characterized as the hydrochloride. It was
slightly soluble only in trifluoroacetic acid.
The vinyl boronic derivative 8c (Scheme 3) was obtained according to the same scheme but, during
the deprotection step, a partial protonolysis of the carbon–boron bond occurred (10%, NMR determina-
tion). The 5-borono-2-aminopentenoic acid 8c was isolated after column chromatography on silica gel
(
ethanol:14 M NH , 2:1). NMR data are strongly indicative that intramolecular complexation does not
3

2124
S. Collet et al. / Tetrahedron: Asymmetry 9 (1998) 2121–2131
1
1
1
occur. At pH 7.4, δ B=27 ppm and, in H NMR, the coupling constants are in good agreement with a
trans configuration of the double bond.
Scheme 3.
Enantiomeric purities were measured by HPLC, using a chiral column, on the protected boronates 7,
after derivatization as the benzamides 9 for UV detection (Scheme 4). Samples of racemic derivatives
were obtained through a subsequent deprotection of the carboxylic group with sodium hydroxide,
13
oxazolone formation with DCC and opening of the heterocycle with methanol. Enantiomeric excesses
were found superior to 98% for the three derivatives.
Scheme 4.
To ensure that no racemisation occurred during the hydrolysis step with 6 M HCl, a sample of the
free 5-boronic-2-aminopentanoic acid 8a was converted to 9a and submitted to a new chromatographic
determination without appreciable change.
4. Conclusion
Hydroboration of nonracemic ω-unsaturated α-amino acids opens a convenient access to enantiomeri-
cally pure ω-borono-α-amino acids. The Ni(II) complex of the Schiff base derived from BPB and glycine
allows the synthesis of the enantiomerically pure unsaturated α-amino acids on a preparative scale and
the protected ω-borono-α-amino acids are then obtained in a simple one-pot procedure.
The synthesis of the boronic analogues of aspartic and glutamic acids, through a different approach,
will be described later.

S. Collet et al. / Tetrahedron: Asymmetry 9 (1998) 2121–2131
2125
5. Experimental
Melting points were determined with a Köfler apparatus and are uncorrected. NMR spectra were
1
13
11
recorded on Brucker AM WB 300 (300 MHz, 75 MHz and 96 MHz for H, C and B, respectively)
1
13
and ARX 200 (200 MHz and 50 MHz for H and C, respectively) spectrometers, using CDCl as
a solvent, unless otherwise stated. Chemical shifts are reported in ppm [relative to internal TMS ( H,
C) or external BF /OEt ( B)] and coupling constants in hertz. When necessary, assignments were
determined after selective decoupling and two-dimensional experiments. Multiplicities of the C NMR
were assigned using DEPT sequence. Rotations were measured on a Perkin–Elmer 341 polarimeter.
The enantiomeric excesses were determined by HPLC on a Perkin–Elmer chromatograph 250 equipped
with a PIRKLE covalent (S,S) Whelk-01 column (UV detection, λ=225 nm, flow rate=1 ml/mn). Mass
spectra were recorded on Varian MAT 311 (electron impact, EI) or Micromass ZABSpec TOF [LSIMS
or electrospray (CH CN/H O), as stated] spectrometers by the ‘Centre Régional de Mesures Physiques
3
1
13
11
3
2
13
3
2
de l’Ouest’ (Rennes). Elemental analyses were performed by the ‘Laboratoire Central de microanalyse
du CNRS’ (Lyon). Column chromatography was carried out using Merck silica gel 60 (40–63 µm).
0
Ni(II) complex 2 of the Schiff base derived from glycine and (S)-2-[N -(N-benzylprolyl)amino]benzo-
phenone (BPB) was prepared according to the literature method.14
5.1. Alkylation of complex 2 with allylbromide: Ni(II) complex of the Schiff base derived from BPB and
allylglycine, 3a
To a stirred mixture of 2 (5 g, 10 mmol) in dry CH CN (45 ml) were added, under N , finely
3
2
powdered NaOH (1 g, 25 mmol) and allylbromide (1.3 ml, 1.5 equiv.). After 3 hours, the reaction
mixture was treated with 150 ml of 0.1 M HCl. The red product was then extracted with CH Cl2
2
(
4×100 ml), dried over MgSO and the solvent removed in vacuo. The two diastereoisomers (98:2)
4
were separated by chromatography on silica gel (CH Cl :Me CO, 2:1) and 3a was obtained as a red
2
2
2
15
amorphous solid that was recrystallized in AcOEt. Yield: 4.3 g (80%); m.p. 217°C (lit. 210–212°C).
1
H NMR δ=2.00–2.20 (m, 2H); 2.50–2.60 (m, 1H); 2.73–2.83 (m, 1H) (β-Hpro and γ-Hpro); 3.45 (dd,
J=10.7 and 6.1, 1H, α-Hpro); 3.45–3.59 (m, 2H, δ-Hpro); 3.60 and 4.45 (AB system, J =12.7, 2H,
CH Ph); _C H–C H –C H_C H part: 2.39 (m, J
AB
2
3
4
5
3a
H3a
3b =14.0, JH3aH
2
=6.5, JH3aH
4
=7.6, 1H, H ), 2.45
2
2
2
3
H
2
b
5a
(m, JH
3bH2
=4.2, JH
3bH4
=7.3, 1H, H ), 4.03 (dd, 1H, H ), 5.19 (dd, J
H5aH5b
=1.7, JH
5aH4
=17.0, 1H, H ),
5
b
4
13
5
.40 (dd, J 5b 4=10.0, 1H, H ), 6.44 (ddt, 1H, H ); 6.55–8.20 (m, 14H, Ar–H). C NMR δ=22.3 (γ-
H
H
3
2
5
Cpro); 29.8 (β-Cpro); 37.5 (C ); 55.9 (δ-Cpro); 62.2 (CH Ph); 69.3, 69.4 (α-Cpro and C ); 118.8 (C );
1
2
4
1
19.7–141.5 (C and 18 Ar–C); 169.8 (C_N); 177.8 (NC_O); 179.4 (C ). HRMS (LSIMS): m/z=538
+
[M+H] , calcd for C H N O Ni: 538.1641. Found: 538.164.
30 30 3 3
5.2. Alkylation of complex 2 with 11-undecenylbromide: Ni(II) complex of the Schiff base derived from
BPB and 11-undecenylglycine, 3b
The reaction was carried out as above but in dry DMF (12 ml) with 3 equivalents of NaOH and
1.1 equivalents of the bromide derivative. After 10 minutes, the mixture was neutralized with AcOH
(
2 ml) and poured into water (200 ml). Compound 3b was extracted with CH Cl and purified by
2
2
1
chromatography on silica gel (CH Cl :Me CO, 95:5). Yield 4.9 g (76%); red amorphous solid. H NMR
2
2
2
δ=1.00–1.45 (m, 12H), 1.50–1.75 (m, 2H), 1.85–2.25 (m, 6H), 2.40–2.60 (m, 1H), 2.65–2.85 (m, 1H)
(
9CH , β-Hpro and γ-Hpro); 3.47 (dd, J=10.8 and 5.9, 1H, α-Hpro); 3.46–3.60 (m, 2H, δ-Hpro); 3.58
2
2
and 4.44 (AB system, JAB=12.6, 2H, CH Ph); 3.92 (dd, J=3.1 and 7.8, 1H, H ); 4.93 (dd, J=10.3 and 1.5,
2

2126
S. Collet et al. / Tetrahedron: Asymmetry 9 (1998) 2121–2131
1
H) and 4.99 (dd, J=16.8 and 1.5, 1H) (H C_); 5.81 (ddt, J=16.8, 10.3 and 6.6, 1H, HC_); 6.63–8.15 (m,
2
13
1
4H, Ar–H). C NMR δ=23.6 (γ-Cpro); 25.4, 28.9, 29.1, 29.3, 29.4, 29.5, 29.7, 30.7, 33.8, 35.3 (9CH2
2
and β-Cpro); 57.0 (δ-Cpro); 63.1 (CH Ph); 70.3, 70.4 (α-Cpro and C ); 114.1 (_CH ); 120.7–142.2
2
2
1
+
(_CH and 18 Ar–C); 170.2 (C_N); 179.5 (NC_O); 180.3 (C ). HRMS (LSIMS): m/z=650 [M+H] ,
calcd for C H N O Ni: 650.2892. Found 650.289. Anal. calcd for C H N O Ni (650.51): C, 70.16;
38
46
3
3
38 45
3
3
H, 6.97; N, 6.46. Found: C, 69.94; H, 6.98; N, 6.33.
5.3. Alkylation of complex 2 with propargylbromide: Ni(II) complex of the Schiff base derived from BPB
and propargylglycine, 3c
The reaction was carried out as with allylbromide (propargylbromide, 1.5 equiv.=1.1 ml). The
two diastereoisomers (97:3) were separated by chromatography on silica gel (CH Cl :Me CO, 2:1)
2
2
2
and 3c was obtained as a red amorphous solid (lit.16 207–209°C). Yield 4.1 g (76%). H NMR
1
δ=2.05–2.15 (m, 2H, γ-Hpro); 2.49–2.62 (m, 1H), 2.80–2.90 (m, 1H) (β-Hpro); 3.50 (dd, J=10.6 and
6
.5, 1H, α-Hpro); 3.60–3.72 (m, 2H, δ-Hpro); 3.71 and 4.50 (AB system, J =12.7, 2H, CH Ph);
AB
2
2
3
4
5
3a
5
_
C H–C H –C ^C H part: 2.31 (ddd, J
H3aH3b
=17.2, J 3a
2
=6.9, JH3aH
=2.8, 1H, H ), 2.59 (t, 1H, H ),
5
2
H
H
3b
2
13
2.69 (dt, 1H, JH
3bH2
=J
H3bH5
=2.8, H ), 4.07 (dd, 1H, H ); 6.65–8.30 (m, 14H, Ar–H). C NMR δ=23.2,
3
2
2
3.3 (γ-Cpro and C ); 30.7 (β-Cpro); 56.9 (δ-Cpro); 63.3 (CH Ph); 67.6 (C ); 70.4 (α-Cpro); 73.8
2
1
(C^); 79.0 (HC^); 120.6–142.8 (18 Ar–C); 171.9 (C_N); 178.5 (NC_O); 180.4 (C ). HRMS (LSIMS):
+
m/z=536 [M+H] , calcd for C H N O Ni: 536.1484. Found: 536.148.
30
28
3
3
5.4. Hydrolysis of 3a, 3b and 3c and recovery of 1
A solution of 3 (6 mmol) in MeOH (100 ml) was added to a warm 2 M HCl solution (70 ml). The
mixture was refluxed for 1 hour. After cooling to room temperature, conc. NH was added until the
3
pH reached between 9 and 10. For 3a and 3c, ligand 1 was quantitatively recovered by extraction with
CH Cl . The aqueous layer was concentrated to dryness and the residue was chromatographed with a
2
2
+
cation exchange resin (Dowex 50X8 H ) to obtain 4a or 4c in 90% yield. For 4b, insoluble at pH 9–10,
the solution was concentrated to dryness, then ligand 1 dissolved in acetone, and the insoluble 4b was
washed with water, and purified by crystallization from 1 M HCl.
5
.4.1. (S)-2-Amino-4-pentenoic acid 4a
White powder; yield: 90%; m.p. 208°C (dec). [α]2 (c=2.1 g/100 ml, HCl 6 M)=−6.4 (lit. −6.4).
0
10
D
1
3
2
H NMR (D O; δ =4.80) δ=2.45–2.71 (m, 2H, 2H ); 3.75 (dd, J=6.8 and 5.0, 1H, H ); 5.21 and 5.23
2
2
H O
5
4
13
3
2
(2dm, 2H, 2H ); 5.74 (ddt, J=17.1, 10.1, 7.3, 1H, H ). C NMR (D O) δ=35.4 (C ); 54.4 (C ); 120.7
2
5
4
1
(C ); 131.8 (C ); 174.8 (C ).
5
.4.2. (S)-2-Amino-12-tridecenoic acid hydrochloride 4b, nHCl
1
White powder; yield: 70%; m.p. 260°C (dec). H NMR (D O/CF CO H; δ 2O=4.80) δ=0.30–0.60 (m,
2
3
2
H
2
14H), 0.90–1.20 (m, 4H) (9CH ); 3.12 (t, J=6.3, 1H, H ); 4.00 (b.dd, J=10.0 and 1.5, 1H) and 4.07 (b.dd
2
13
J=16.9 and 1.5, 1H) (H C_); 4.86 (ddt, J=16.9, 10.0 and 6.6, 1H, HC_). C NMR (D O/CF CO H)
2
2
3
2
2
δ=24.6, 28.5, 28.7, 28.8, 28.9, 29.0, 29.2, 29.9, 33.4 (9CH ); 52.9 (C ); 113.6 (_CH ); 138.4 (_CH);
2
2
1
+
171.7 (C ). HRMS (LSIMS): m/z=228 [M+H] , calcd for C H NO : 228.1964. Found: 228.196. Anal.
13 26 2
calcd for C H NO , 0.37HCl (240.84): C, 64.83; H, 10.62; N, 5.82. Found: C, 64.75; H, 10.61; N,
13
25
2
5.82.

S. Collet et al. / Tetrahedron: Asymmetry 9 (1998) 2121–2131
2127
1
5
.4.3. (S)-2-Amino-4-pentynoic acid 4c
2
0
11
White powder; yield: 90%; m.p. 228°C (dec). [α] (c=1 g/100 ml, H O)=−32.9 (lit. −35). H
D
2
5
3
NMR (D O; δ =4.80) δ=2.47 (t, J=2.6, 1H, H ); 2.80 (dd; J=2.5 and 5.5, 2H, 2H ); 3.84 (t, J=5.5, 1H,
2
2
H O
2
13
3
2
5
4
1
H ). C NMR (D O) δ=23.4 (C ); 55.6 (C ); 76.0 (C ); 80.0 (C ); 175.9 (C ).
2
5.5. Protected amino acids 5
To a suspension of amino acid 4 (5 mmol) in methanol (10 ml) was added, dropwise at 0°C, freshly
distilled thionyl chloride (0.41 ml, 5.5 mmol) via syringe. The resulting solution was kept at reflux for
h. After removal of the solvent and excess of thionyl chloride in vacuo, the residue was dissolved in
dry acetonitrile (5 ml), then triethylamine (0.77 ml, 5.5 mmol) and di-tert-butyl dicarbonate (Boc O)
3
2
(1.20 g, 5.5 mmol) were added. The mixture was stirred for 1.5 h at room temperature. The solvent was
removed in vacuo, 1 M KHSO (10 ml) was added, and compound 5 was extracted with dichloromethane
4
(
3×10 ml). The organic layer was washed with 1 M NaHCO (10 ml) and the solvent was removed under
3
reduced pressure. The residue was chromatographed on silica gel (heptane:ethyl acetate, 9:1) to give pure
protected amino acids 5.
5
.5.1. (S)-2-tert-Butoxycarbonylamino-4-pentenoic acid methyl ester 5a
18
17
1
Oil; yield: 0.91 g (80%). [α]D (c=1.5 g/100 ml, CHCl )=19.27 (lit. [α] =19.3). H NMR δ=1.44
3
D
3a
(s, 9H, (CH ) ); 2.48 (m, J
H3aH3b
=14.0, JH
3aH2
≈J
H3aH4
=6.7, 1H, H ); 2.55 (m, J =5.2, JH
H3bH2
=8.2, 1H, H ); 5.07 (d, 1H, NH); 5.13 (m, J
H5bH4
=10.1, 1H, H ); 5.70 (ddt, 1H, H ). C NMR δ=28.3 [(CH ) ];
3bH4
=7.6,
=1.8,
3
3
3
b
2
1H, H ); 3.74 (s, 3H, OCH ); 4.38 (m, J
2
H5aH5b
3
H ,NH
5a
5b
4
13
JH
5aH4
=16.7, 1H, H ); 5.14 (m, J
3 3
1
3
2
5
4
36.8 (C ); 52.2 (OCH ); 52.9 (C ); 79.8 [C(CH ) ]; 119.1 (C ); 132.4 (C ); 155.2 (NC_O); 172.6 (C ).
3 3 3
+
HRMS (EI): m/z=170 [M−·CO CH ] , calcd for C H NO : 170.1181. Found: 170.118. Anal. calcd
2
3
9
16
2
for C H NO (229.28): C, 57.63; H, 8.35; N, 6.11. Found: C, 57.92; H, 8.39; N, 6.21.
11
19
4
5
.5.2. (S)-2-tert-Butoxycarbonylamino-12-tridecenoic acid methyl ester 5b
20
1
Oil; yield: 1.59 g (93%). [α]D (c=3 g/100 ml, CHCl )=9.63. H NMR δ=1.23–1.40 (m, 14H, 7
3
3
3
4
CH ); 1.44 (s, 9H, (CH ) ); 1.54–1.67 (m, 1H) and 1.70–1.83 (m, 1H) (2H ); 2.04 (qt, J=6.7, J≈1.3,
2
3 3
2
2
3
4
2H, CH C_); 3.74 (s, 3H, OCH ); 4.29 (m, 1H, H ); 4.93 (ddt, J=2.1, J=10.2, J=1.2, 1H) and
2 3
3
4
13
4.99 (ddt, J=17.1, J=1.5, 1H) (H C_); 4.99 (d, J
2
=8.3, 1H, NH); 5.81 (ddt, 1H, HC_).
C
2
H ,NH
NMR δ=28.3 [(CH ) ]; 25.3, 28.9, 29.1, 29.2, 29.4, 29.45, 29.5, 32.8, 33.8 (9CH ); 52.2 (OCH );
3
3
2
3
2
1
5
3.5 (C ); 79.8 [C(CH ) ]; 114.2 (_CH ); 139.2 (_CH); 155.4 (NC_O); 173.6 (C ). HRMS (EI):
3 3 2
+
m/z=282 [M−·CO CH ] , calcd for C H NO : 282.2433. Found: 282.244. Anal. calcd for C H NO
2
3
17 32
2
19 35
4
(
341.49): C, 66.83; H, 10.33; N, 4.10. Found: C, 66.99; H, 10.25; N, 4.23.
5
.5.3. (S)-2-tert-Butoxycarbonylamino-4-pentynoic acid methyl ester 5c
18
18
20
1
Oil; yield: 0.93 g (82%). [α] (c=3 g/100 ml, MeOH)=−4.7 (lit. [α] =−5.2). H NMR δ=1.46
D
D
4
5
3
(s, 9H, (CH ) ); 2.05 (t, J
5
3
=2.5, 1H, H ); 2.74 (dd, J
3
2
=4.8, 2H, 2H ); 3.79 (s, 3H, OCH );
3
3
H H
H H
3
2
2
13
3
4.48 (dt, J
2
=8.1, 1H, H ); 5.39 (d, 1H, NH). C NMR δ=22.8 (C ); 28.3 [(CH ) ]; 52.0 (C );
H ,NH
3 3
5
4
1
52.6 (OCH ); 71.6 (C ); 78.5 (C ); 80.2 [C(CH ) ]; 155.1 (NC_O); 171.1 (C ). HRMS (EI): m/z=168
3
3 3
+
[
M−·CO CH ] , calcd for C H NO : 168.1024. Found: 168.102. Anal. calcd for C H NO (227.26):
2
3
9
14
2
11 17
4
C, 58.14; H, 7.54; N, 6.16. Found: C, 57.89; H, 7.65; N, 6.13.

2128
S. Collet et al. / Tetrahedron: Asymmetry 9 (1998) 2121–2131
5.6. Hydroboration of compounds 5: boronic esters 7
A suspension of diisopinocampheylborane (3 mmol) in freshly distilled THF (1 ml) was prepared
according to H. C. Brown19 and cooled to −20°C under dry nitrogen. A solution of the ω-unsaturated
amino ester 5 (1.5 mmol for 5a, 5b and 2.5 mmol for 5c) in THF (2.5 ml) was then transferred via
cannula. After warming to room temperature the mixture was stirred for 24 h (5a, 5b) or 5 h (5c). Then
an excess of acetaldehyde (30 mmol for 5a, 5b and 25 mmol for 5c) was added at 0°C and the resulting
mixture was kept at room temperature for 24 h. After hydrolysis with water (2 ml), the solvent and excess
acetaldehyde were removed under reduced pressure. Boronic acids were extracted with dichloromethane
(
3×20 ml). The organic layer was dried over MgSO , and the solvent removed in vacuo. The residue was
4
dissolved in Et O (10 ml), and (+)-pinanediol (1 equiv./5) and a small amount of MgSO were added.
2
4
After stirring overnight at room temperature, the solvent was removed under reduced pressure and the
resulting residue was chromatographed on silica gel (heptane:ethyl acetate, 8:2) to afford boronic esters
7.
5.6.1. (S)-2-(tert-Butoxycarbonylamino)-5-[(1S,2S,3R,5S)-(+)-pinanedioxaboranyl]-pentanoic acid
methyl ester 7a
Oil; yield: 0.40 g (65%). [α]2 (c=3 g/100 ml, CHCl )=18.3. H NMR δ=0.83 (t, J=7.6, 2H, 2H );
2
1
5
D
3
0
7
0
1
1
.84 (s, 3H), 1.29 (s, 3H) and 1.38 (s, 3H) (3CH ); 1.08 (d, J=10.8, 1H, 1H ); 1.44 (s, 9H, (CH ) );
.41–1.55 (m, 2H, 2H ); 1.59–1.72 (m, 1H) and 1.75–1.87 (m, 1H) (2H ); 1.83 (ddd, 1H) (1H );
.88–1.91 (m, 1H, H ); 2.04 (t, J=5.5, 1H, H ); 2.17–2.26 (m, 1H, 1H ); 2.33 (ddt, 1H) (1H ); 3.73
3
3 3
0
4
3
4
0
0
0
0
4
5
1
7
0
2
3
(
s, 3H, OCH ); 4.21–4.31 (m, 1H, H ); 4.25 (dd, J=8.7 and J=1.9, 1H, H ); 5.07 (d, J=8.1, 1H, NH).
3
0
13
5
4
7
3
C NMR δ=10.1 (C ); 19.9 (C ); 24.0, 27.1 and 28.7 (3CH ); 26.5 (C ); 28.3 [(CH ) ]; 34.9 (C );
3
3 3
0
0
0
0
0
3
4
6
5
1
2
3
5.5 (C ); 38.1 (C ); 39.5 (C ); 51.2 (C ); 52.1 (OCH ); 53.5 (C ); 77.6 (C ); 79.7 [C(CH ) ]; 85.5
3 3 3
0
2
1
11
+
(
C ); 155.4 (NC_O); 173.5 (C ). B NMR δ=33.1. HRMS (EI): m/z=350 [M−·CO CH ] , calcd for
2
3
C H NO B: 350.2502. Found: 350.249. Anal. calcd for C H NO B (409.34): C, 61.62; H, 8.86; N,
19
33
4
21 36
6
3.42. Found: C, 61.56; H, 8.45; N, 3.32.
5.6.2. (S)-2-(tert-Butoxycarbonylamino)-13-[(1S,2S,3R,5S)-(+)-pinanedioxaboranyl]-tridecanoic acid
methyl ester 7b
Oil; yield: 0.55 g (69%). [α]2 (c=3 g/100 ml, CHCl )=14.6. H NMR δ=0.81 (t, J=7.6, 2H, CH B);
0
1
D
3
2
0
7
0
9
1
.84 (s, 3H), 1.29 (s, 3H) and 1.38 (s, 3H) (3CH ); 1.12 (d, J=10.7, 1H, 1H ); 1.21–1.34 (m, 18H,
3
0
3
4
CH ); 1.44 (s, 9H, (CH ) ); 1.51–1.69 (m, 1H) and 1.73–1.88 (m, 1H) (2H ); 1.86 (ddd, 1H) (1H );
2
3 3
0
0
0
0
4
5
1
7
.86–1.95 (m, 1H, H ); 2.05 (t, J=5.5, 1H, H ); 2.15–2.29 (m, 1H, 1H ); 2.34 (ddt, 1H) (1H ); 3.73
0
2
3
(
s, 3H, OCH ); 4.20–4.35 (m, 1H, H ); 4.25 (dd, J=8.6 and J=1.8, 1H, H ); 5.02 (d, J=8.3, 1H, NH).
3
0
7
13
C NMR δ=10.9 (BCH ); 24.0, 27.1 and 28.7 (3CH ); 26.5 (C ); 28.3 [(CH ) ]; 24.1, 25.3, 29.2, 29.4,
2
3
4
3 3
0
0
0
0
1
6
5
2
5
9.45, 29.5, 29.55, 29.6, 32.5, 32.8 (10CH ); 35.6 (C ); 38.1 (C ); 39.6 (C ); 51.3 (C ); 52.1 (OCH );
2
3
0
0
2
3
2
1
11
3.5 (C ); 77.5 (C ); 79.8 [C(CH ) ]; 85.3 (C ); 155.4 (NC_O); 173.5 (C ). B NMR δ=33.5. HRMS
3
3
+
(
EI): m/z=462 [M−·CO CH ] , calcd for C H NO B: 462.3754. Found: 462.377. Anal. calcd for
2
3
27 49
4
C H NO B (521.55): C, 66.79; H, 10.05; N, 2.69. Found: C, 66.37; H, 9.92; N, 2.68.
29
52
6
5
.6.3. (S)-2-(tert-Butoxycarbonylamino)-5-[(1S,2S,3R,5S)-(+)-pinanedioxaboranyl]-4-pentenoic acid
methyl ester 7c
Oil; yield: 0.66 g (65%). [α]2 (c=1.5 g/100 ml, CHCl )=34.3. H NMR δ=0.85 (s, 3H), 1.29 (s,
0
1
D
3
0
0
4
7
3H), and 1.40 (s, 3H) (3CH ); 1.12 (d, J=10.9, 1H, 1H ); 1.44 (s, 9H, (CH ) ); 1.86 (ddd, 1H) (1H );
3
3
3
0
0
0
0
4
5
1
7
1.87–1.95 (m, 1H, H ); 2.06 (t, J=5.5, 1H, H ); 2.16–2.26 (m, 1H, 1H ); 2.34 (ddt, 1H) (1H ); 2.56

S. Collet et al. / Tetrahedron: Asymmetry 9 (1998) 2121–2131
2129
3
a
3b
(
3
m, JH
3aH3b
=14.5, JH
3aH2
=6.7, JH
3aH4
=6.9, 1H, H ); 2.66 (m, J
H3bH2
=4.6, JH3bH4 =6.9, 1H, H ); 3.74 (s,
0
3
2
H, OCH ); 4.30 (dd, J=8.7 and J=1.9, 1H, H ); 4.43 (m, J
=1.3, 1H, H ); 6.45 (dt, 1H, H ). C NMR δ=24.0, 27.1 and 28.6 (3 CH ); 26.4
C ); 28.3 [(CH ) ]; 35.4 (C ); 38.2 (C ); 38.7 (C ); 39.5 (C ); 51.3 (C ); 52.3 (OCH ); 52.7 (C );
2
=8.2, 1H, H ); 5.03 (d, 1H, NH); 5.56
3
H ,NH
5
4
13
(dt, J
5
4
=17.9, J
5
3
H H
H H
3
0
0
0
0
0
1
7
4
6
3
5
2
(
7
3
3
3
1
0
0
3
2
5
4
11
7.8 (C ); 79.9 [C(CH ) ]; 85.8 (C ); 122.5 (C ); 146.9 (C ); 155.1 (NC_O); 172.4 (C ). B NMR
3
3
δ=29.4. HRMS (EI): m/z=351 [M−C H ], calcd for C H NO B: 351.1853. Found: 351.186. Anal.
4
8
17 26
6
calcd for C H NO B, H O: C, 59.30; H, 8.53; N, 3.29. Found: C, 59.08; H, 8.08; N, 3.21.
21
34
6
2
5.7. ω-Borono-α-amino acids 8
A mixture of boronic esters 7a or 7c (0.5 mmol) in 6 M HCl (2 ml) was kept at 70°C for 2 h. The
resulting brown solution was evaporated to dryness and the residue was dissolved in water. The aqueous
phase was washed with ethyl acetate and water removed in vacuo to give 8a and 8c as the hydrochlorides.
+
Compound 8a was isolated after ion exchange chromatography (Dowex 50X8 H ; 2 M ammonia as
eluent). Compound 8c was purified by chromatography on silica gel (EtOH:14 M NH ; 2:1).
3
Hydrolysis of 7b (0.5 mmol) was performed in 12 M HCl (10 ml) at 70°C over 5 h. After evaporation
to dryness, the residue was chromatographed on silica gel (AcOEt/MeOH of increasing polarity) to afford
8b as the hydrochloride.
5
.7.1. (S)-2-Amino-5-boronopentanoic acid, hydrochloride 8a, HCl
1
5
4
H NMR (D O; δH =4.80) δ=0.78 (t, J=7.8, 2H, 2H ); 1.35–1.55 (m, 2H, 2H ); 1.77–1.99 (m, 2H,
2
2
O
3
2
13
5
4
3
2
2
H ); 4.02 (t, J=6.1, 1H, H ). C NMR (D O) δ=16.3 (C ); 21.8 (C ); 34.8 (C ); 56.1 (C ); 174.6
2
1
11
+
(C ). B NMR (D O) δ=32.6. HRMS (LSIMS): m/z=203 [M+H+CH CN] , calcd for C H N O B:
2
3
7
16
2
4
203.1203. Found: 203.120.
5
.7.2. (S)-2-Amino-5-boronopentanoic acid 8a
White powder; yield 73%; m.p. 260°C (dec). H NMR (H O/ext DSS) (for clarity, the numbering of
1
2
atoms is the same as in open-chain derivatives) δ=0.39 (m, J
H5aH5e
=14.4, JH
=11.2, JH
5aH4a
=9.0, JH
5aH4e
=6.1, 1H,
5a
5e
H ); 0.59 (m, J 5e 4a =5.2, JH5eH4e =5.4, 1H, H ); 1.39 (m, J
H4aH4e
4aH3a
=8.5, JH4aH3e =3.7, 1H,
H
H
4
a
3a
4e
H ); 1.49 (m, J
JH
H3a
3e =14.3, JH
3aH4e
≈0, J
H3aH2a
=9.5; 1H, H ); 1.61 (m, JH
=3.9, 1H, H ); 3.51 (dd, 1H, H ). C NMR (H O/ext DSS) δ=18.6 (C ); 23.9 (C ); 34.5 (C );
4eH3e
=6.6, 1H, H ); 1.92 (m,
H
3
e
2a 13
5
4
3
3eH2a
2
2
1
11
5
9.1 (C ); 180.0 (C ). B NMR (H O) δ=14.4.
2
5
.7.3. (S)-2-Amino-13-boronotridecanoic acid hydrochloride 8b, HCl
1
White powder; yield 71%; m.p. 266°C (dec). H NMR (CF CO H/ext TMS) δ=1.04 (t, J=7.6, 2H,
3
2
3
2
CH B); 1.36–1.68 (m, 18H, 9CH ); 2.10–2.32 (m, 2H, 2H ); 4.43 (b.sext., J≈6.0, 1H, H ); 7.39 (s,
2
2
+
13
3
H, NH ). C NMR (CF CO H/ext TMS) δ=15.6 (BCH ); 25.2, 26.5, 30.5, 30.8, 30.9, 31.0, 31.1,
3
3
2
2
2
1
11
31.2, 32.1, 34.0 (10CH ); 56.9 (C ); 176.2 (C ). B NMR (CF CO H) δ=36.1. HRMS (LSIMS):
2
3
2
+
+
m/z=296 [M+Na] , calcd for C H NO BNa: 296.2009. Found: 296.201; m/z=274 [M+H] , calcd for
13
28
4
C H NO B: 274.2189. Found: 274.219.
13
29
4
5
.7.4. (S)-2-Amino-5-borono-4-pentenoic acid 8c
1
White powder; yield 70%; m.p. 230°C (dec). H NMR (H O/ext DSS) δ=2.66 (m, J
H3aH3b
=14.8,
2
3
a
3b
JH
3aH2
=J 3a
4
=7.0, JH3aH
5
=1.3, 1H, H ); 2.72 (m, J
H3bH2
=5.1, J =7.0, JH
H3bH4
3bH5
=1.3, 1H, H ); 3.82 (dd,
H
H
2
5
4
13
3
1H, H ); 5.63 (dt, J
4
5
=18.0, 1H, H ); 6.34 (dt, 1H, H ). C NMR (H O/ext DSS) δ=39.4 (C ); 56.7
H H
2

2
130
S. Collet et al. / Tetrahedron: Asymmetry 9 (1998) 2121–2131
11
2
5
4
1
+
(C ); 131.4 (C ); 146.1 (C ); 176.8 (C ). B NMR (H O) δ=27.4. HRMS (LSIMS): m/z=182 [M+Na] ,
2
calcd for C H NO BNa: 182.0602. Found: 182.060.
5
10
4
5
5
1
.8. Measurement of enantiomeric excess
.8.1. Preparation of enantiomerically pure boronates 9
A solution of boronate 7 (0.12 mmol) in dichloromethane (2.5 ml) was saturated with dry HCl. After
h at room temperature, the solvent was removed in vacuo and the residue dissolved in acetonitrile (1
ml). Triethylamine (0.13 mmol) and benzoyl chloride (0.13 mmol) were added and the mixture allowed
to stand at room temperature for 4 h, then the solvent was removed in vacuo. The residue was dissolved
in dichloromethane (2 ml), washed with 0.1 M HCl (2 ml) and saturated NaHCO (2 ml) solutions,
3
then dried over MgSO . Concentration of the mixture and purification by silica gel chromatography
4
1
(
heptane:ethyl acetate, 8:2) gave the N-benzoyl boronate 9 with ≈50% overall yield. H NMR spectra
are in good agreement with structures. 9a was also synthesized from the free boronic α-amino acid 7a
through successive esterification, N-benzoylation and pinanediol protection.
5.8.1.1. (S)-2-Benzoylamino-5-[(1S,2S,3R,5S)-(+)-pinanedioxaboranyl]-pentanoic acid methyl ester 9a.
HPLC (hexane:isopropanol, 90:10) t =32.6 min.
R
5.8.1.2. (S)-2-Benzoylamino-13-[(1S,2S,3R,5S)-(+)-pinanedioxaboranyl]-tridecanoic acid methyl ester
9
b. HPLC (hexane:isopropanol, 95:5) t =33.4 min.
R
5.8.1.3. (S)-2-Benzoylamino-5-[(1S,2S,3R,5S)-(+)-pinanedioxaboranyl]-4-pentenoic acid methyl ester
9
c. HPLC (hexane:isopropanol, 90:10) t =29.1 min.
R
5.8.2. Racemic boronates 9
Pinanediol boronate 7 (0.12 mmol) was reacted with HCl as above. Water (35 µl) and 10 M NaOH
0.36 mmol) were added to the resulting hydrochloride and the reaction mixture was kept at room
(
temperature for 1 h. Benzoyl chloride (0.12 mmol) was added and the mixture allowed to stand at
room temperature for an additional 1 h, before treatment with HCl and extraction with dichloromethane.
13
Oxazolone formation was then performed according to Höfle, with DCC (0.12 mmol) in THF (150 µl)
for 1 h at room temperature. After filtration of dicyclohexylurea, the solvent was removed in vacuo and
the residue was refluxed in methanol for 2 h. Racemic derivatives were isolated as above, after removal
of the solvent and silica gel chromatography.
5.8.2.1. (R,S)-2-Benzoylamino-5-[(1S,2S,3R,5S)-(+)-pinanedioxaboranyl]-pentanoic acid methyl ester
9
a. HPLC (hexane:isopropanol, 90:10) t =29.5 min; t =32.2 min.
R1
R2
5.8.2.2. (R,S)-2-Benzoylamino-13-[(1S,2S,3R,5S)-(+)-pinanedioxaboranyl]-tridecanoic acid methyl
ester 9b. HPLC (hexane:isopropanol, 95:5) t =33.6 min; t =35.0 min.
R1
R2
5.8.2.3. (R,S)-2-Benzoylamino-5-[(1S,2S,3R,5S)-(+)-pinanedioxaboranyl]-4-pentenoic acid methyl
ester 9c. HPLC (hexane:isopropanol, 90:10) t =26.2 min; t =29.6 min.
R1
R2
In the three experiments, the peak related to (S)-9 grew up after addition of pure (S)-9.

S. Collet et al. / Tetrahedron: Asymmetry 9 (1998) 2121–2131
2131
References
1
2
3
. Morin, C. Tetrahedron 1994, 50, 12521–12569.
. Matteson, D. S. In Stereodirected Synthesis with Organoboranes; Springer-Verlag: Berlin, Heidelberg, 1995; pp. 196–202.
. (a) Tian, Z.-Q.; Brown, B. B.; Mack, D. P.; Hutton, C. A.; Bartlett, P. A. J. Org. Chem. 1997, 62, 514–522 and references
therein. (b) Snow, R. J.; Bachovchin, W. W.; Barton, R. W.; Campbell, S. J.; Coutts, S. J.; Freeman, D. M.; Gutheil, W. G.;
Kelly, T. A.; Kennedy, C. A.; Krolikowski, D. A.; Leonard, S. F.; Pargellis, C. A.; Tong, L.; Adams, J. J. Amer. Chem. Soc.
1994, 116, 10860–10869. (c) Kettner, C. A.; Shenvi, A. B. J. Biol. Chem. 1984, 259, 15106–15114. (d) Wityak, J.; Earl,
R. A.; Abelman, M. M.; Bethel, Y. B.; Fisher, B. N.; Kauffman, G. S.; Kettner, C. A.; Ma, P.; McMillan, J. L.; Mersinger,
L. J.; Pesti, J.; Pierce, M. E.; Rankin, F. W.; Chorvat, R. J.; Confalone, P. N. J. Org. Chem. 1995, 60, 3717–3722.
. Excitatory Amino Acid Receptors, Design of Agonists and Antagonists; Krogsgaard-Larsen, P.; Hansen, J. J., Eds. Ellis
Horwood: New York, London, 1992.
4
5
6
7
. Kinder, D. H.; Ames, M. M. J. Org. Chem. 1987, 52, 2452–2454.
. Kinder, D. H.; Frank, S. K.; Ames, M. M. J. Med. Chem. 1990, 33, 819–823.
. Baggio, R.; Elbaum, D.; Kanyo, Z. F.; Carroll, P. J.; Cavalli, R. C.; Ash, D. E.; Christianson, D. W. J. Amer. Chem. Soc.
1997, 119, 8107–8108.
8
9
. Denniel, V.; Bauchat, P.; Danion, D.; Danion-Bougot, R. Tetrahedron Lett. 1996, 37, 5111–5114.
. Belokon, Y. N. Janssen Chimica Acta 1992, 10, 4–12.
1
1
1
1
1
0. Commercially available from ACROS Organics, catalog no. 27541–2500.
1. Leukart, O.; Caviezel, M.; Eberle, A.; Escher, E.; Tun-Kyi, A.; Schwyzer, R. Helv. Chim. Acta 1976, 59, 2181–2183.
2. Brown, H. C.; Jadhav, P. K.; Desai, M. C. J. Amer. Chem. Soc. 1982, 104, 4303–4304.
3. Höfle, G.; Steglish, W.; Daniel, H. Chem. Ber. 1976, 109, 2648–2650.
4. Belokon, Y. N.; Bulychev, A. G.; Vitt, S. V.; Struchkov, Y. T.; Batsanov, A. S.; Timofeeva, T. V.; Tsyryapkin, V. A.; Ryzhov,
M. G.; Lysova, L. A.; Bakhmutov, V. I.; Belikov, V. M. J. Amer. Chem. Soc. 1985, 107, 4252–4259.
5. Belokon, Y. N.; Chernoglazova, N. I.; Ivanova, E. V.; Popkov, A. N.; Saporovskaya, M. B.; Suvorov, N. N.; Belikov, V.
M. Bull. Acad. Sci. URSS, Div. Chem. Sci. (Engl. transl.) 1988, 37, 2541–2544; Izv. Akad. Nauk SSSR, Ser. Khim. 1988,
1
1
2
818–2821.
6. Losilkina, V. I.; Sokolov, V. I. Dokl. Chem. (Engl. transl.) 1991, 320, 243–245; Dokl. Akad. Nauk SSSR, Ser. Khim. 1991,
20, 339–342.
3
1
1
1
7. Ohfune, Y.; Nishio, H. Tetrahedron Lett. 1984, 25, 4133–4136.
8. Fauchère, J. L.; Leukart, O.; Eberle, A.; Schwyzer, R. Helv. Chim. Acta 1979, 62, 1385–1395.
9. Pelter, A; Smith, K.; Brown, H. C. Borane Reagents; Academic Press: London, 1988; Chapter 5, p. 426.