Using the 9-BBN group as a transient protective group for the functionalization of reactive chains of α-amino acids

Article abstract of DOI:10.1055/s-0032-1316848

Achieving chemoselectivity is a longstanding challenge in chemical synthesis. This problem has been addressed using different approaches, but a definitive solution is still pending. For instance, in peptide chemistry, particularly with amino acids containing side chains functionalities with reactivity patterns similar to the main functional groups, such as aspartic and glutamic acids, and lysine and ornithine, specific semi-permanent protecting groups have been employed. The use of 9-borabicyclo[3.3.1]nonane (9-BBN-H) as a transient protective group for the selective protection of α-amino acids, which allows the chemoselective manipulation of the functional groups embedded in the side chains of the molecule, is described.

Full text of DOI:10.1055/s-0032-1316848

1364▌
PAPER
paper
Using the 9-BBN Group as a Transient Protective Group for the
Functionalization of Reactive Chains of α-Amino Acids
9-BBN as a Transient Protective Group
Adrián Sánchez,*a Ernesto Calderón,b Alfredo Vazquez*a
a
Departamento de Química Orgánica, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510,
México D.F., México
Fax +52(56)223722; E-mail: ausbir@yahoo.com.mx; E-mail: joseavm@unam.mx
b
Laboratorio de Inmunoquímica Hospital Infantil de México Federico Gómez, Dr. Márquez 162, Col Doctores, Cuauhtémoc, 06720,
México D.F., Mexico
Received: 11.12.2012; Accepted after revision: 01.01.2013
lation and cleavage. This protocol was employed to per-
form selective transformations on some amino acids.
Abstract: Achieving chemoselectivity is a longstanding challenge
in chemical synthesis. This problem has been addressed using dif-
ferent approaches, but a definitive solution is still pending. For in-
stance, in peptide chemistry, particularly with amino acids
containing side chains functionalities with reactivity patterns simi-
lar to the main functional groups, such as aspartic and glutamic
acids, and lysine and ornithine, specific semi-permanent protecting
groups have been employed. The use of 9-borabicyclo[3.3.1]non-
ane (9-BBN-H) as a transient protective group for the selective pro-
tection of α-amino acids, which allows the chemoselective
manipulation of the functional groups embedded in the side chains
of the molecule, is described.
Results and Discussion
α-Amino acids are bifunctional molecules, and certain
amino acids contain side chains with extra reactive groups
raising a selectivity concern, particularly with groups with
very close reactivity such as α- and ε-amino groups of ly-
sine, or the carboxy groups in aspartic acid. Thus, per-
forming chemical reactions, such as protections, on the
side chains might result in the formation of side products
(Scheme 1).5
Key words: α-amino acids, selective protection, 9-BBN-H, pro-
tecting groups, oxazaborolidinones
O
O
Introduction
R
Y–X
R
Y
Y
OH
or
Y
O
NHY
The presence of functional groups with similar reactivity
in the same molecule is an obvious concern during the
planning of a synthesis, since both groups will react alike
under the same conditions.1 The control over the individ-
ual reactivity of the groups within a molecule (chemose-
lectivity) still remains a largely unanswered challenge.2
This problem can be found frequently during the chemical
synthesis of peptides, particularly with amino acid resi-
dues containing side chains with carboxy or amino func-
tional groups such as aspartic and glutamic acids, or lysine
and ornithine.3 One partial solution to this problem is the
protection of the side chain functionalities with a variety
of specific semi-permanent protecting groups; although
this operation is not always simple to perform. For in-
stance, 9-borabicyclo[3.3.1]nonane (9-BBN-H)4 has been
utilized to protect functionalized amino acids for potential
chemoselective side chain manipulation.
NH2
O
2
3
R
OH
NH2
O
O
Y–X
ML2
R
R
1
Y
O
O
M
H2N
H2N
M
5
4
Scheme 1 Side chain functionalization of α-amino acids
In order to control the reactivity of the functional groups
present in the amino acids, metal complex formation has
been used. Among the manifold of possibilities, copper6
forms stable complexes with α-amino acids allowing the
functionalization of the side chain. However, H2S is re-
quired to cleave the copper complex,7 which imposes
safety concerns and makes this approach unattractive. The
use of oxazaborolidinones as semi-permanent protective
groups for amino acids has been documented in the liter-
ature.8 However, examples of its use for chemoselective
manipulation are not abundant. The general strategy used
in the present work is depicted in Scheme 2.
Herein, we present a synthetic procedure allowing the
chemoselective manipulation of α-amino acids containing
reactive side chains, based on the complex formation be-
tween 9-borabicyclo[3.3.1]nonane (9-BBN-H) and the
corresponding amino acid, followed by selective manipu-
SYNTHESIS 2013, 45, 1364–1372
Advanced online publication: 25.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316848; Art ID: SS-2012-M0583-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
9-BBN as a Transient Protective Group
1365
O
O
O
side-chain
functionalization
R
R
O
O
O
Y
deprotection
9-BBN-H
MeOH
R
R
OH
H2N
B
H2N
B
Y
OH
NH2
NH2
1
8
6
7
Scheme 2 Use of oxazaborolidinones for chemoselective transformations of α-amino acids
The corresponding amino acid 1 was complexed with ly, O-benzyltyrosine is formed by direct alkylation of the
9-BBN-H, followed by functionalization of the side chain; tyrosine-copper complex with benzyl bromide.7 Interest-
6 → to 7. Cleavage of the oxazaborolidinone 7 would af- ingly, removal of the O-benzyl group in Cbz-Tyr(Bn), can
ford the functionalized amino acid 8.
be performed efficiently through hydrogenolysis in the
presence of 2,2′-dipyridyl.9
Oxazaborolidinones 6 were prepared by refluxing the cor-
responding amino acid 1 with 9-BBN-H in methanol in Among the groups that have been employed to protect the
good yields. Two different sources of 9-BBN were tested, side chain of tyrosine, the benzyl group (Bn) has been
namely, the dimeric 9-BBN and a 0.5 M 9-BBN-H THF widely used, mainly because it can be removed under mild
solution. In general, better results were obtained using conditions (e.g., H2, Pd/C).10 In our case, Tyr-9-BBN
crystalline dimeric 9-BBN, including higher yields and complex 6a, was treated with BnBr in the presence of
short reaction times (Table 1). It is worth to mention that K2CO3 and KI in acetone at ambient temperature to pro-
in the case of serine (Ser) and threonine (Thr), compounds duce the benzyl ether in 78% (Scheme 3).
6g and 6h were the only isolated products and the OH
groups in the side chain did not form complexes with 9-
O
O
BBN-H.
BnBr
O
O
H2N
Table 1 Reaction of Amino Acids 1 with 9-BBN-Ha
B
H2N
K2CO3, NaI
acetone
B
HO
BnO
O
78%
6a
9
O
R
O
9-BBN-H
MeOH
R
OH
H2N
B
NH2
Scheme 3 Benzyl protection of tyrosine side chain
1
6
Methyl Ester Formation of the Side Chain of
Aspartic Acid
Amino acid
Time (h)
A
Yield (%) of 6
Orthogonal protection is required in most cases for the
amino dicarboxylic acids such as aspartic and glutamic
acids. Formation of isoaspartyl peptides via the corre-
sponding succinimide active esters11 is the most promi-
nent side reaction of aspartic side chain where an ester is
present. Regioselective acid-catalyzed esterification at the
α-carbonyl group with benzyl alcohol can be achieved us-
ing H2SO4 in yields over 75%. The oxazaborolidinone 6e
derived from aspartic acid was converted into the methyl
ester 10 upon treatment with MeI (K2CO3, acetone) in
88% yield (Scheme 4).
B
A
B
Tyrosine (Tyr) (1a)
Arginine (Arg) (1b)
Lysine (Lys) (1c)
3
24
24
24
24
36
36
24
24
90
89
91
63
90
95
–
84
83
82
38
70
95
94
98
1
2.5
2
Cysteine (Cys) (1d)
Aspartic acid (Asp) (1e)
Glycine (Gly) (1f)
Serine (Ser) (1g)
3
3
–
O
O
Threonine (Thr) (1h)
–
–
HO
MeO
a A: 9-BBN dimer; B: 0.5 M THF 9-BBN-H.
MeI
O
O
O
H2N
O
H2N
B
B
K2CO3
acetone
88%
Benzyl Protection of Tyrosine Side Chain
Blocking the hydroxyl groups with benzoyl or tert-butyl
type groups is of eminent practical importance. Common-
Scheme 4 Methyl ester formation of the side chain of aspartic acid
Synthesis 2013, 45, 1364–1372
© Georg Thieme Verlag Stuttgart · New York

1366
A. Sánchez et al.
PAPER
EtOAc).14 When this compound was coupled with phenyl-
alnine methyl ester (PheOMe), the corresponding dipep-
tide 13 was obtained in 88% yield (Scheme 6). This result
exemplifies the possibility to obtain two divergent peptid-
ic chains from aspartic acid in an easy manner.
Protection of the Guanidine Group of Arginine
Even though the guanidine group of arginine is usually
protected by protonation under normal conditions, due to
its strongly basic character, the low solubility of the cor-
responding derivative in organic solvents hampers the
manipulation of this compound. The arenesulfonyl group
offers complete protection for the guanidine group.12 For
instance, the toluensulfonyl group (Ts) is the most used
group for this purpose, and it can only be removed by ac-
idolysis, or by reduction with sodium in liquid ammonia.10
On the other hand, the reaction between 12 and BnNH2
produced the corresponding benzylic amide 14 in 92%
yield. Additionally, treatment of 12 with BnOH, in the
presence of DMAP15 produced the benzyl ester 15 in 74%
yield. Notably, in the absence of DMAP, no product was
obtained whatsoever (Scheme 6). The use of Swern reac-
tion conditions resulted in a complex mixture of products,
which were not isolated.
Typically, the side chain of arginine is protected using a
sulfonyl derivative in the presence of a base such as
NaOH. This procedure proved to give poor results in the
case of the Arg-9-BBN complex 6b. However, when 6b
was reacted with p-TsCl in the presence of neutral alumi-
na, and using microwaves13 as the source of heating, 11
was cleanly obtained in 68% yield (Scheme 5).
Compound 12 was reacted with N,O-dimethylhydroxyl-
amine hydrochloride (Et3N–DMAP), to obtain the corre-
sponding Weinreb amide16 16 in 84% yield (Scheme 6).
Although no further transformations were attempted with
this compound, we strongly believe that this intermediate
might be useful to introduce other functionalities on the
side chain, allowing the preparation of derivatives of as-
partic acid after removal of the oxazaborolidinone moiety.
NH
O
NH
O
N
TsHN
O
H
H2N
B
TsCl, THF
N
H2N
O
H
H2N
neutral alumina
MW, 3 min
68%
B
Reduction of the Side Chain of Asp-9-BBN and
Oxidation of Thr-9-BBN
To further investigate the usefulness of 9-BBN-H as a
protective group during redox reactions, the carboxylic
acid present in the side chain of the complex 6e, formed
between 9-BBN-H and aspartic acid, was smoothly re-
duced (Me2S·BH3, THF, r.t., Scheme 7) to alcohol 17 in
good yield (85%), along with some unreacted starting ma-
terial.
Scheme 5 Side chain protection of arginine
Further Transformations of the Complex
Asp-9-BBN (6e)
In order to functionalize the side chain of aspartic acid,
Asp-9-BBN (6e) was transformed into its pentafluorophe-
nol active ester 12 in practically quantitative yield (DCC,
Alternatively, experiments to investigate the viability to
oxidize the side chain of Thr-9-BBN (6h) were conduct-
Me
O
O
O
O
H
N
MeO
O
N
MeO
O
O
H2N
H2N
B
B
13
16
MeHNOMe·HCl
DMAP, Et3N, THF
PheOMe·HCl
Et3N, THF
74%
88%
RO
O
O
O
H2N
B
BnOH
DMAP, THF
O
O
BnNH2, THF
BnHN
BnO
78%
O
O
O
H2N
92%
B
O
H2N
B
6e R = H
C6F5OH
15
14
DCC, EtOAc
quant.
12 R = C6F5
Scheme 6 Further transformations of the side chain of Asp-9-BBN
Synthesis 2013, 45, 1364–1372
© Georg Thieme Verlag Stuttgart · New York

PAPER
9-BBN as a Transient Protective Group
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O
O
O
O
OH
O
HO
HO
O
O
O
oxidation
O
Me2S·BH3, THF
r.t., 8 h
H2N
B
H2N
B
H2N B
H2N
B
O
85%
6e
17
6h
18
Scheme 7 Reduction of the side chain of Asp-BBN complex and oxidation of the side chain of Thr-BBN
ed. Thus, Thr-9-BBN (6h) was treated with IBX (DMSO, When alcohol 17, obtained upon reduction of Asp-9-BBN
80 °C, 8 h) and only unreacted starting material was ob- (vide supra), was deprotected under acidic conditions
1
served by TLC and H NMR analyses of the crude reac- (Method A), followed by N-Boc protection, compound 19
tion mixture. When PCC was used as the oxidizing agent, was obtained in 82% isolated yield, although with some
cleavage of the Thr-9-BBN complex was observed, along reproducibility problems. However, when a solution of 1
with some unreacted starting material and two unidenti- M hydrochloric acid in methanol was used instead of con-
fied products.
centrated hydrochloric acid in methanol, the correspond-
ing lactone of 19 was cleanly obtained in 85% yield after
columm chromatography (SiO2, 30% EtOAc–hexanes)
The possibility to perform selective reductions on α-ami-
no acids with two carboxy functionalities, represents an
interesting result, because it might be an entry to prepare
a wide variety of non-proteinogenic amino acids from
readily available starting materials.
1
showing H and 13C NMR data in accordance with the
data reported in the literature for this compound.17 When
the previously isolated lactone was treated with potassium
hydroxide in methanol, compound 19 was obtained in
83% isolated yield.18
Cleavage of Amino Acid-9-BBN Complexes
O
This transformation can be achieved either under acidic
(Method A: concd HCl) or basic conditions (Method B:
ethylenediamine, or Method C: ethanolamine, Table 2).
1. HCl, MeOH, r.t.
2. (Boc)2O, Et3N, CH2Cl2, r.t.
3. KOH, MeOH, r.t.
O
HO
O
HO
H2N
B
OH
83%
NHBoc
Table 2 Deprotection of Oxazaborolidinonesa
17
19
O
deprotection
R
6
OH
Scheme 8 Cleavage and N-Boc protection of 17
NH2
1
It was observed that in some cases, the isolation of the
functionalized complex is rather complicated, and there-
fore the products were identified after cleavage of the 9-
BBN complexes. Depending on the transformations to be
performed after breaking the complex, a selective N- or C-
protection can be carried out on the resulting amino acid.
Oxazaborolidinone
Yield (%) of 1
A
B
C
Tyr-9-BBN (6a)
Arg-9-BBN (6b)
Lys-9-BBN(6c)
Cys-9-BBN (6d)
Asp-9-BBN (6e)
Gly-9-BBN (6f)
Ser-9-BBN (6g)
Thr-9-BBN (6h)
80
74
91
66
81
93
85
78
29
45
50
45
60
47
47
56
30
50
33
50
72
62
62
67
For instance, when the oxazaborolidinone approach was
used, the ε-amino group of lysine was Cbz-protected in
very good yield. However, since Cbz-6c was obtained as
a light yellow gum, the oxazaborolidinone was cleaved
with ethanolamine (MW, 3 min) to afford 20 in 82% yield
(Scheme 9). Clearly, this procedure offers some advantag-
es over the typical protocol commonly used for the same
purpose.
To establish the scope of the complex formation between
α-amino acids and 9-BBN-H as a tool to control the selec-
tivity during chemical manipulations of these compounds,
the arylation of the side chain of Lys-9-BBN complex 6c
was carried out with iodobenzene in the presence of CuI
and K3PO4, using a mixture of ethylene glycol–i-PrOH.19
Without purification, the resulting product was subjected
a Method A: concd HCl. Method B: NH2CH2CH2NH2. Method C:
NH2CH2CH2OH.
© Georg Thieme Verlag Stuttgart · New York
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A. Sánchez et al.
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1. CbzCl, 2 M NaOH
EtOH–H2O (2:1)
O
CbzHN
OH
2. NH2CH2CH2OH, MW
3 min
O
B
NH2
H2N
20
82%
O
H2N
O
6c
H
N
1. PhI, CuI, K3PO4
OH
NHBoc
HOCH2CH2OH, i-PrOH
21
2. HCl, MeOH
3. (Boc)2O
43%
Scheme 9 Protection of the side chain of lysine
completely dissolved. The reaction mixture was concentrated and
the residue was redissolved in hot THF (100 mL). The solid was fil-
tered and the filtrate was concentrated under vacuum. The residue
was triturated with hexanes to obtain the corresponding oxazaboro-
lidinone.
to acidic hydrolysis and Boc-protection of the α-amino
group to isolate 21 in an overall yield of 43% (Scheme 9).
This interesting result demonstrates the possibility to per-
form chemical transformation on the side chain of lysine
other than simple protections, and opens the possibility to
prepare modified amino acids that can be employed in dif-
ferent fields.
Using 0.5 M THF 9-BBN-H; General Procedure B
A mixture of the corresponding amino acid 1 (3.12 mmol) in MeOH
(20 mL) was heated under reflux until the mixture became clear,
then 0.5 M 9-BBN-H in THF (6.7 mL, 3.2 mmol) was added drop-
wise and the heating was continued until the solution became clear.
The mixture was cooled to r.t. and concentrated in vacuo. The resi-
due was suspended in hot THF (15 mL) and filtered; the filtrate was
concentrated, and the residue triturated with hot hexanes to obtain
the corresponding oxazaborolidinone after filtration.
Conclusions
The reaction between amino acids and 9-BBN-H to form
the corresponding oxazaborolidinones was used as a tool
to control the selectivity during transformations per-
formed on amino acids containing reactive side chains.
The transient group thus introduced allowed the function-
alization of the side chains under different conditions il-
lustrating the scope of oxazaborolidinones as protective
groups. We believe that the results reported here represent
an important contribution to peptide chemistry and can be
used elsewhere.
(S)-4-(4-Hydroxybenzyl)-2,2-borabicyclo[3.3.1]nonane-1,3,2-
oxazaborilidin-5-one (6a)
Prepared from 1a (0.56 g) following the General Procedure B to af-
ford 0.78 g (84%) of the desired product as a white solid; mp 210 °C
(dec.).
FT-IR (ATR): 3272, 2923, 2803, 1709, 1231 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 0.36 (br s, 1 H), 0.72 (br s, 1
H), 1.34–1.72 (m, 14 H), 2.81–2.88 (dd, J = 6, 15 Hz, 1 H), 3.01–
3.07 (dd, J = 6, 15 Hz, 1 H), 3.70–3.76 (m, 1 H), 5.56 (dd, J = 9, 12
Hz, 1 H), 6.45 (dd, J = 6, 12 Hz, 1 H), 6.68 (d, J = 9 Hz, 2 H), 7.11
(d, J = 9 Hz, 2 H), 9.25 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 24.4, 24.7, 31.0, 31.2, 31.8,
35.7, 49.1, 56.6, 115.6, 127.6, 130.7, 156.6, 173.7.
1H NMR measurements were performed on a Varian Inova (300
MHz) spectrometer. Chemical shifts (δ) of 1H NMR are expressed
in parts per million downfield from TMS as internal standard
(δ = 0). IR spectra were recorded on a PerkinElmer Spectrum 400
FT-IR/FIR spectrometer with ATR. Mass spectra were carried out
on a Jeol SMX-102a spectrometer. The progress of all the reactions
was monitored by TLC using glass plates precoated with silica gel
60 F254 (0.5 mm, Merck). Column chromatography was performed
using 230–400 mesh silica gel. Commercially available α-amino
acids, 9-BBN-H, solvents, and other reagents were used (Aldrich
Chemical Co.). All reactions were performed under N2 atmosphere.
THF was distilled from sodium benzophenone ketyl under N2 prior
to use. Et3N was dried over CaH2.
LRMS (TOF): m/z = 302 [M + 1]+, 138, 136.
(S)-4-(3-Guanidinopropyl)-2,2-borabyciclo[3.3.1]nonane-1,3,2-
oxazaborolidin-5-one (6b)
Prepared from 1b (0.54 g) following the General Procedure B to af-
ford 0.76 g (83%) of the desired product as a white solid; mp 196–
198 °C.
FT-IR (ATR): 3334, 3162, 2920, 2845, 1673, 1632, 1216 cm–1.
1H NMR (300 MHz, MeOD): δ = 0.64 (m, 2 H), 1.44–2.08 (m, 16
H), 3.26–3.35 (m, 4 H), 3.75–3.79 (m, 4 H).
13C NMR (75 MHz, DMSO-d6): δ = 23.7, 25.3, 26.1, 26.5, 27.8,
30.7, 31.8, 32.1, 40.5, 41.4, 54.4, 70.9, 157.4, 175.6.
LRMS (TOF): m/z = 295 [M + 1]+, 69, 67, 56.
All the products were characterized using a combination of spectro-
scopic and spectrometric techniques.
Complex Formation Between α-Amino Acids and 9-BBN-H
Using 9-BBN Dimer; General Procedure A
(S)-4-(4-Aminobutyl)-2,2-borabicyclo[3.3.1]nonane-1,3,2-
oxazaborolidin-5-one (6c)
Prepared from 1c (0.45 g) following the General Procedure B to af-
ford 0.67 g (82%) of the desired product as a white solid; mp 250 °C
(dec.).
In a flask under N2 atmosphere was dissolved 9-BBN dimer (1.1
equiv) in anhyd MeOH (150 mL) under reflux conditions. After 30
min, the corresponding amino acid 1 was added (25 mmol) and the
refluxing was continued until gas evolution ceased and the solid had
Synthesis 2013, 45, 1364–1372
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PAPER
9-BBN as a Transient Protective Group
1369
FT-IR (ATR): 3260, 2915, 2842, 1709, 1252 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 0.50 (m, 2 H), 1.26 (d, J = 6
Hz, 3 H), 1.45–1.79 (m, 13 H), 3.51–3.57 (td, J = 3, 9 Hz, 1 H),
4.15–4.20 (m, 1 H), 5.04 (dd, J = 9, 12 Hz, 1 H), 5.31 (t, J = 3 Hz,
1 H), 6.45 (dd, J = 9, 12 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 20.9, 23.9, 24.3, 30.6, 30.7,
31.2, 31.3, 60.3, 64.1, 172.3.
1H NMR (300 MHz, DMSO-d6): δ = 0.66 (br s, 1 H), 0.72 (br s, 1
H), 1.60–1.96 (m, 16 H), 2.95 (m, 2 H), 3.67–3.82 (m, 2 H), 6.11
(dd, J = 9, 12 Hz, 1 H), 6.73 (dd, J = 9, 12 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 22.7, 24.4, 24.7, 26.8, 30.0,
31.2, 31.8, 54.6, 174.2.
LRMS (FAB+): m/z = 240 [M + 1]+, 185, 102, 93, 75, 57.
LRMS (TOF): m/z = 267 [M + 1]+, 195.
Functionalization of the Side Chain
(S)-4-(Mercaptomethyl)-2,2-borabicyclo[3.3.1]nonane-1,3,2-
oxazaborolidin-5-one (6d)
Prepared from 1d (0.37 g) following the General Procedure A to af-
ford 0.47 g (63%) of desired product as a white solid; mp 194–
196 °C (dec.).
(S)-4-[4-(Benzyloxy)benzyl]2,2-borabicyclo[3.3.1]nonane-1,2,3-
oxazaboralidin-5-one (9)
A mixture of 6a (1 g, 33 mmol), K2CO3 (0.165 g, 1.5 mmol), benzyl
bromide (0.4 mL, 3.5 mmol) and NaI (0.52 g, 3.3 mmol) in anhyd
acetone (20 mL) was refluxed for 3 h, cooled to r.t., and the solvent
removed. The residue was taken up in EtOAc (30 mL), washed with
10% citric acid (2 × 15 mL) and brine (2 × 15 mL), and dried
(Na2SO4). The solvent was evaporated and the residue was purified
by chromatography (silica gel, EtOAc–hexanes, 30:70) to afford
0.38 g (78%) of 9 as a white solid; mp 170–171 °C
FT-IR (ATR): 3215, 2981, 2837, 1701, 1294 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 0.47 (br s, 1 H), 0.59 (br s, 1
H), 1.41–1.77 (m, 12 H), 2.87 (d, J = 3 Hz, 2 H), 3.84 (t, J = 6 Hz,
1 H), 5.76 (dd, J = 9, 12 Hz, 1 H), 6.61 (dd, J = 9, 12 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 22.7, 21.2, 22.7, 24.4, 24.7,
31.1, 31.2, 31.7, 37.9, 54.15, 60.2, 172.7.
FT-IR (ATR): 3203, 2914, 2848, 1713, 1514, 1246, 1174 cm–1.
LRMS (FAB): m/z = 242 [M + 1]+, 195, 112, 109, 91, 76, 55.
1H NMR (300 MHz, DMSO-d6): δ = 0.40 (br s, 1 H), 0.46 (br s, 1
H), 1.34–1.73 (m, 15 H), 2.84–2.92 (dd, J = 9, 12 Hz, 1 H), 3.08–
3.17 (dd, J = 9, 15 Hz, 1 H), 3.76–3.80 (m, 1 H), 5.08 (s, 2 H), 5.68
(dd, J = 6, 12 Hz, 1 H), 6,45 (dd, J = 6, 12 Hz, 1 H), 6.96 (d, J = 9
Hz, 2 H), 7.26 (d, J = 9 Hz, 2 H), 7.34–7.48 (m, 5 H).
13C NMR (75 MHz, DMSO-d6): δ = 22.0, 23.0, 23.7, 24.0, 30.3,
30.5, 31.0, 31.3, 35.0, 55, 8, 68.9, 114.4, 127.4, 127.6, 128.3, 129.2,
130.2, 137.0, 156.9, 172.9.
(S)-4-(Carboxymethyl)-2,2-borabicyclo[3.3.1]nonane -1,3,2-
oxaborolidin-5-one (6e)
Prepared from 1e (0.42 g) following the General Procedure B to af-
ford 0.56 g (70%) of the desired product as a white solid; mp 220 °C
(dec.).
FT-IR (ATR): 3346, 3221, 2920, 2847, 1717, 1681, 1203, 1115
cm–1.
LRMS (FAB): m/z = 392 [M + 1]+, 296, 197, 107, 91, 77.
1H NMR (300 MHz, DMSO-d6): δ = 0.47 (br s, 1 H), 0.59 (br s, 1
H), 1.39–1.78 (m, 13 H), 2.72 (d, J = 6 Hz, 2 H), 3.79 (s, 1 H), 5.98
(dd, J = 9, 12 Hz, 1 H), 6.45 (dd, J = 9, 12 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 23.9, 24.3, 25.2, 30.7, 30.9,
31.1, 31.2, 34.2, 51.1, 67.0, 171.6, 172.8.
(S)-4-(2-Methoxy-2-oxoethyl)-2,2-borabicyclo[3.3.1]nonane-
1,3,2-oxazoborolidin-5-one (10)
A mixture of 6e (0.3 g, 1.2 mmol), anhyd K2CO3 (0.165 g, 1.5
mmol), and MeI (2 mL) in anhyd acetone (15 mL) was refluxed for
2 h under N2 atmosphere. The solvent was removed and the residue
was taken up in EtOAc (30 mL), washed with 10% citric acid
(2 × 15 mL) and brine (2 × 15 mL), and dried (Na2SO4). The solvent
was evaporated and the residue was purified by chromatography
(silica gel, EtOAc–hexanes, 30:70) to afford 0.15 g (85%) of the de-
sired product 10 as a white solid; mp 188–190 °C.
LRMS (FAB): m/z = 254 [M + 1]+, 162, 102, 88, 55.
2,2-Borabicyclo[3.3.1]nonane-1,3,2-oxazaborolidin-5-one (6f)
Prepared from 1f (0.61 g) following the General Procedure B to af-
ford 1.5 g (95%) of the desired product as a white solid; mp 200 °C
(dec.).
FT-IR (ATR): 3224, 2920, 2842, 1703, 1614, 1515, 1217 cm–1.
FT-IR (ATR): 3247, 2951, 2839, 1752, 1703, 1224, 1182 cm–1.
1H NMR (300 MHz, CD3OD): δ = 0.5 (m, 2 H), 1.41 (s, 4 H), 1.57–
1.75 (m, 8 H), 3.36 (t, J = 6 Hz, 2 H), 6.23 (s, 2 H).
13C NMR (75 MHz, CD3OD): δ = 24.3, 24.7, 31.3, 31.6, 43.1, 172.4.
LRMS (FAB): m/z = 196 [M + 1]+, 162, 102, 88, 55.
1H NMR (300 MHz, CDCl3): δ = 0.67 (m, 2 H), 1.53–1.95 (m, 14
H), 2.98 (d, J = 6 Hz, 2 H), 3.78 (s, 3 H), 4.07–4.10 (m, 1 H), 5.93
(dd, J = 9, 12 Hz, 1 H), 5.42 (dd, J = 9, 12 Hz, 1 H).
13C NMR (75 MHz, CD3OD): δ = 23.9, 24.3, 30.8, 31.1, 31.2, 33.4,
51.2, 51.5, 171.0, 174.6.
LRMS (FAB): m/z = 268 [M + 1]+, 148, 128, 102, 91, 70.
(S)-4-(Hydroxymethyl)-2,2-borabicyclo[3.3.1]nonane-1,3,2-
oxaborolidin-5-one (6g)
Prepared from 1g (0.5 g) following the General Procedure B to af-
ford 1.0 g of product (94%) as a white solid; mp 215 °C (dec.).
(S)-4-[3-(3-Tosylguanidino)propyl]-2,2-borabicyclo[3.3.1]non-
ane-1,3,2-oxazaborolidin-5-one (11)
A mixture of the corresponding oxazaborolidinone 6c (0.56 g, 2
mmol), p-TsCl (0.347 g, 1.8 mmol), and basic activated alumina (1
g, 150 mesh) in THF (2 mL) was irradiated in a microwave oven
(CEM Discover, 100 W, 60 °C) for 5 min. The mixture was cooled
to r.t., the THF was evaporated in vacuo, and the residue was tritu-
rated with CH2Cl2 (15 mL). The solid thus formed was filtered and
dried under vacuum to afford 0.55 g (62%) of 11 as a pale yellow
solid; mp 194–196 °C.
FT-IR (ATR): 3528, 3214, 1713, 1674, 1242 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 0.51 (d, J = 6 Hz, 2 H), 1.41–
1.78 (m, 13 H), 3.68–372 (m, 2 H), 3.78–3.86 (m, 1 H), 5.16 (t, J = 6
Hz, 1 H), 5.48 (dd, J = 9, 12 Hz, 1 H), 6.53 (dd, J = 9, 12 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 23.8, 24.3, 31.0, 31.1, 32.0,
53.6, 58.9, 176.9.
LRMS (FAB+): m/z = 226 [M + 1]+, 180, 102, 91, 88, 60.
FT-IR (ATR): 3334, 3162, 2920, 2845, 1673, 1632, 1216 cm–1.
(S)-4-(1-Hydroxyethyl)-2,2-borabicyclo[3.3.1]nonane-1,3,2-
oxaborolidin-5-one (6h)
Prepared from 1h (0.5 g) following the General Procedure B to af-
ford 0.98 g of product (98%) as a white solid; mp 220 °C (dec.).
1H NMR (300 MHz, CD3OD): δ = 0.56 (m, 2 H), 1.48–2.01 (m, 16
H), 2.34 (s, 3 H), 3.22–3.24 (m, 2 H), 3.71 (m, 2 H), 5.8 (dd, J = 9,
12 Hz, 1 H), 6.44 (dd, J = 9, 12 Hz, 1 H), 7.25 (d, J = 9 Hz, 2H),
7.34 (d, J = 9 Hz, 1 H), 7.70 (d, J = 9 Hz, 2 H).
FT-IR (ATR): 3559, 3146, 1686, 1659, 953 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1364–1372

1370
A. Sánchez et al.
PAPER
13C NMR (75 MHz, CD3OD): δ = 19.9, 23.5, 24.1, 24.2, 27.9, 30.6,
31.4, 40.6, 54.6, 60.1, 125.5, 128.5, 140.5, 141.9, 157.2, 175.7.
LRMS (EI): m/z = 453 [M]+, 421, 257, 155, 121, 95, 81, 55.
mL), washed with 10% NaHCO3 (2 × 15 mL) and 10% citric acid
(2 × 15 mL), and dried (Na2SO4). The solvent was evaporated and
the residue was purified by chromatography (silica gel, EtOAc–
hexanes, 30:70) to afford 0.32 g (78%) of the desired product 15 as
a white solid; mp 177–80 °C.
(S)-4-(2-Acetamido-3-phenyl-2-oxopropyl)-2,2-borabicy-
clo[3.3.1]nonane-1,3,2-oxazoborolidin-5-one (13)
FT-IR (ATR): 3324, 1711, 1625, 1573, 1214 cm–1.
The protected amino acid 6e (0.3 g, 0.118 mmol), pentafluorophe-
nol (0.218 g, 1.18 mmol), and DCC (0.165 g, 1.18 mmol) in EtOAc
(10 mL) was stirred for 1 h at r.t. followed by removal of the DCU
formed by filtration. The filtrate was evaporated in vacuo and the
product 12 obtained was redissolved in anhyd THF (10 mL), fol-
lowed by the addition of PheOMe·HCl (0.255 g, 1.18 mmol) and
Et3N (0.17 mL, 1.18 mmol). The resultant mixture was stirred for 7
h at r.t., concentrated, and the residue was redissolved in EtOAc (30
mL), washed with 10% NaHCO3 (2 × 15 mL) and 10% citric acid
(2 × 15 mL), and dried (Na2SO4). The solvent was evaporated and
the residue was purified by chromatography (silica gel, EtOAc–
hexanes, 30:70) to afford 0.41 g (84%) of the desired product 13 as
a white solid; mp 142–144 °C.
1H NMR (300 MHz, CDCl3): δ = 0.60 (br s, 2 H), 0.88–1.82 (m, 12
H), 3.04 (d, J = 3 Hz, 2 H), 3.91–3.94 (m, 1 H), 5.12 (d, J = 3 Hz, 2
H), 5.16 (dd, J = 9, 12 Hz, 1 H), 6.03 (dd, J = 9, 12 Hz, 1 H), 7.32–
7.34 (m, 5 H).
13C NMR (300 MHz, CDCl3): δ = 24.0, 24.6, 25.7, 26.3, 31.6, 31.8,
32.9, 49.4, 51.9, 67.5, 128.4, 128.8, 129.8, 134.9, 171.7, 173.4.
LMRS (FAB): m/z = 344 [M + 1]+, 225, 178, 143, 91, 70.
(S)-4-(2-N,O-Dimethoxy-2-acetamido)-2,2-borabicy-
clo[3.3.1]nonane-1,3,2-oxazoborolidin-5-one (16)
A mixture of the protected amino acid 6e (0.3 g, 0.118 mmol), pen-
tafluorophenol (0.218 g, 1.18mmol), and DCC (0.165 g, 1.18
mmol) in EtOAc (10 mL) was stirred for 1 h at r.t. The mixture was
filtered to remove the DCU and the filter cake rinsed with EtOAc
(25 mL). After removing the solvent in vacuo, the product 12 ob-
tained was redissolved in anhyd THF (10 mL), followed by the ad-
dition of N,O-dimethylhydroxylamine hydrochloride (0.12 g, 1.18
mmol), Et3N (0.16 mL, 1.18 mmol), and DMAP (0.014 g, 10%).
The resultant mixture was stirred at r.t. for 7 h, the THF was evap-
orated in vacuo, and the residue taken up in EtOAc (30 mL), washed
successively with 10% NaHCO3 (2 × 15 mL) and 10% citric acid
(2 × 15 mL), and dried (Na2SO4). The solvent was evaporated and
the residue was purified by chromatography (silica gel, EtOAc–
hexanes, 30:70) to afford 0.29 g (84%) of the desired product 16 as
a white solid; mp 95–97 °C.
FT-IR (ATR): 3324,2926, 1771, 1657, 1627, 1573, 1216 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.42 (br s, 1 H), 0.46 (br s, 1 H),
0.67–1.74 (m, 12 H), 2.54–2.62 (dd, J = 6, 15 Hz, 1 H), 2.64–2.71
(dd, J = 6, 15 Hz, 1 H), 2.88–2.95 (dd, J = 6, 15 Hz, 1 H), 2.95–3.01
(dd, J = 6, 15 Hz, 1 H), 3.58 (s, 3 H), 3.77–3.81 (m, 1 H), 4.33 (dd,
J = 9, 12 Hz, 1 H), 4.61–4.67 (q, J = 6 Hz, 1 H), 5.84 (dd, J = 9, 12
Hz, 1 H), 6.39 (d, J = 9 Hz, 1 H), 6.98 (d, 2 H), 7.12 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 22.7, 23.9, 24.5, 25.7, 31.4, 32.4,
36.1, 37.6, 41.2, 52.6, 53.8, 55.7, 127.2, 128.7, 129.2, 135.8, 170.6,
172.0, 173.7.
LRMS (FAB+): m/z = 415 [M + 1]+, 295, 225, 180, 91, 67.
FT-IR (ATR): 3228, 2849, 1714, 1549, 1186 cm–1.
(S)-4-(2-N-Benzyl-2-acetamido)-2,2-borabicyclo[3.3.1]nonane-
1,3,2-oxazoborolidin-5-one (14)
1H NMR (300 MHz, DMSO-d6): δ = 0.48 (br s, 1 H), 0.56 (br s, 1
H), 1.37–1.77 (m, 12 H), 2.89–3.00 (m, 2 H), 3.12 (s, 3 H), 3.69 (s,
3 H), 3.89 (m, 1 H), 4.69 (dd, J = 9, 12 Hz, 1 H), 5.71 (dd, J = 9, 12
Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 23.4, 23.8, 24.3, 24.7, 31.2,
31.4, 31.6, 31.7, 51.3, 61.5, 170.7, 173.5.
A mixture of the protected amino acid 6e (0.3 g, 0.118 mmol), pen-
tafluorophenol (0.3 g, 1.18 mmol), and DCC (0.165 g, 1.18 mmol)
in EtOAc (10 mL) was stirred for 1 h at r.t., followed by removal of
the DCU formed by filtration. The filtrate was evaporated in vacuo,
and the product 12 obtained was redissolved in anhyd THF (10 mL),
followed by the addition of BnNH2 (0.13 mL, 1.18 mmol). The re-
sultant mixture was stirred for 7 h at r.t., concentrated, and the resi-
due was redissolved in EtOAc (30 mL), washed with 10% NaHCO3
(2 × 15 mL) and 10% citric acid (2 × 15 mL), and dried (Na2SO4).
The solvent was evaporated and the residue was purified by chro-
matography (silica gel, EtOAc–hexanes, 30:70) to provide 0.37 g
(92%) of the desired product 14 as a white solid; mp 164–166 °C.
LMRS (FAB): m/z = 297 [M + 1]+, 251, 133, 131, 91, 70.
(S)-4-(2-Hydroxyethyl)-2,2-borabicyclo[3.3.1]nonane-1,3,2-
oxazoborolidin-5-one (17)
Me2S·BH3 (0.18 mL, 1.9 mmol) was added dropwise to a solution
of oxazaborolidinone 6e (0.5 g, 1.9 mmol) in anhyd THF (10 mL)
under N2 atmosphere (balloon). The resultant mixture was stirred at
r.t. for 3 h, concentrated in vacuo, and the residue purified by col-
umn chromatography to afford 0.4 g (85%) of the desired product
as a white solid; mp 113–115 °C.
FT-IR (ATR): 3324, 2926, 1771, 1657, 1627, 1573, 1216 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.60 (br s, 2 H), 1.44–1.89 (m, 12
H), 2.88 (dd, J = 6, 12 Hz, 1 H), 2.71 (dd, J = 3, 15 Hz, 1 H), 3.01
(dd, J = 6, 12 Hz, 1 H), 3.72 (s, 3 H), 3.96–3.98 (m, 1 H), 4.74–4.81
(m, 1 H), 4.89 (dd, J = 9, 12 Hz, 1 H), 5.89 (dd, J = 9, 12 Hz, 1 H),
6.95 (d, J = 9 Hz, 1 H), 7.13–7.16 (d, J = 9 Hz, 2 H), 7.27–7.29 (m,
3 H).
13C NMR (75 MHz, CDCl3): δ = 24.0, 25.1, 25.8, 31.4, 31.7, 34.1,
37.8, 49.5, 52.9, 53.8, 55.7, 127.5, 128.4, 129.4, 135.7, 170.6,
172.0, 172.9.
FT-IR (ATR): 3442, 3224, 2843, 1722, 1600, 1573, 1276 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 0.50 (m, 2 H), 1.41–1.77 (m,
14 H), 1.94–1.98 (m, 2 H), 3.59–3.65 (m, 2 H), 4.08–4.14 (m, 1 H),
4.80 (t, J = 6 Hz, 1 H), 5.89 (dd, J = 9, 12 Hz, 1 H), 6.43 (dd, J = 9,
12 Hz, 1 H).
13C NMR (300 MHz, DMSO-d6): δ = 23.8, 24.3, 31.0, 31.1, 32.0,
53.6, 58.8, 176.3.
LRMS (FAB): m/z = 415 [M + 1]+, 295, 225, 180, 91, 67.
LMRS (FAB): m/z = 240 [M + 1]+, 194, 167, 149, 113, 74, 57.
(S)-4-(2-Benzyloxy-2-oxoethyl)-2,2-borabicyclo[3.3.1]nonane-
1,3,2-oxazoborolidin-5-one (15)
Cleavage of 9-BBN-Amino Acid Complex
A mixture of the protected amino acid 6e (0.3 g, 0.118 mmol), pen-
tafluorophenol (0.218 g, 1.18 mmol), and DDC (0.165 g, 1.18
mmol) in EtOAc (10 mL) was stirred for 1 h at r.t., followed by the
removal of the DCU by filtration. The filtrate was evaporated in
vacuo and the product 12 obtained was redissolved in anhyd THF
(10 mL), followed by the addition of BnOH (0.13 mL, 1.18 mmol)
and DMAP (0.14 g, 10%). The resultant mixture was stirred for 7 h
at r.t., concentrated, and the residue was redissolved in EtOAc (30
Method A: The corresponding oxazaborolidinone (4 mmol) was dis-
solved in methanol (8 mL), followed by the addition of concd HCl
(4 mL). The reaction mixture was stirred at r.t. for 30 min, then the
solvent was evaporated and hot THF (20 mL) was added and this
mixture was stirred for 15 min. The precipitate thus obtained was
collected by filtration and washed with hot THF (20 mL).
Synthesis 2013, 45, 1364–1372
© Georg Thieme Verlag Stuttgart · New York

PAPER
9-BBN as a Transient Protective Group
1371
Method B: A homogeneous mixture of the corresponding oxaza-
borolidinone (1.5 mmol) and ethanolamine (1 mL) was irradiated in
a microwave oven (CEM Discover, 40 W, 100 °C). The mixture
was cooled to r.t. and diluted with acetone (10 mL) and THF (2 mL),
and stirred for 15 min. The solid was collected by filtration and
rinsed with acetone–THF (5:1, 25 mL).
The resultant mixture was concentrated to dryness and the residue
dissolved in 2 M KOH (5 mL) followed by the addition of dioxane
(16 mL) and Boc2O (0.44 g, 2.1 mmol) at 0 °C. After removal of the
ice bath, the stirring was continued at ambient temperature for 30
min, the solvent was removed in vacuo, and the residue was purified
by column chromatography (silica gel, EtOAc–hexanes) to provide
0.227 g (59%) of 21 as a white solid; mp 167–170 °C.
2-[(tert-Butoxycarbonyl)amino]-4-hydroxybutanoic Acid (19)
Oxazaborolidinone 17 (100 mg, 0.415 mmol) was treated with a so-
lution of 1 M HCl in MeOH (10 mL) for 2 h. The solvent was then
removed in vacuo and the residue was redissolved in CH2Cl2 (5
mL), followed by the addition of (Boc)2O (0.108 g, 0.497 mmol)
and Et3N (0.115 mL, 0.826 mmol). After stirring the resultant mix-
ture at ambient temperature for 17 h, the solvent was evaporated and
the residue was purified by columm chromatography (SiO2, 30%
EtOAc–hexanes) to provide 71 mg (85%) of the corresponding lac-
tone as a light yellow solid; mp 139–141 °C.
FT-IR (ATR): 3342, 2976, 1168, 780 cm–1.
1HNMR (300 MHz, CDCl3): δ = 1.29 (m, 2 H), 1.42 (s, 9 H), 1.5–
1.7 (m, 4 H), 3.10 (m, 2 H), 4.37 (m, 1 H), 6.12 (m, 2 H), 6.5 (m, 1
H), 7.0 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 20.9, 28.4, 29.5, 32.2, 40.1, 56.5,
80.0, 113.4, 129.3, 146.8, 155.7, 173.5.
LRMS (TOF): m/z = 323 [M + 1]+, 101, 77.
1H NMR measurements were performed on a Varian Inova (300
MHz) spectrometer. Chemical shifts (δ) of 1H NMR are expressed
in parts per million downfield from TMS as internal standard
(δ = 0). IR spectra were recorded on a PerkinElmer Spectrum 400
FT-IR/FIR spectrometer with ATR. Mass spectra were carried out
on a Jeol SMX-102a spectrometer. The progress of all the reactions
was monitored by TLC using glass plates precoated with silica gel
60 F254 (0.5 mm, Merck). Column chromatography was performed
using 230–400 mesh silica gel. Commercially available α-amino ac-
ids, 9-BBN-H, solvents, and other reagents were used (Aldrich
Chemical Co.). All reactions were performed under N2 atmosphere.
THF was distilled from sodium benzophenone ketyl under N2 prior
to use. Et3N was dried over CaH2.
FT-IR (ATR): 3356, 1774, 1680, 1526, 1155 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.46 (s, 9 H), 2.22–2.32 (m, 1 H),
2.68–2.77 (m, 1 H), 4.21–4.30 (m, 1 H), 4.41–4.48 (m, 2 H), 5.41
(br s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 28.3, 30.6, 50.3, 65.9, 80.7, 155.6,
175.4.
LRMS (TOF): m/z = 202 [M + 1]+.
The lactone obtained above was dissolved in MeOH (2 mL) and
treated with KOH (0.025 g, 0.446 mmol) at ambient temperature for
12 h. After removal of the solvent, the residue was redissolved in
H2O (15 mL) and the solution was acidified to pH 3 with 10% citric
acid and the product was extracted with EtOAc (15 mL), washed
with H2O (3 × 5 mL), dried (Na2SO4) and concentrated in vacuo to
provide 52 mg (83%) of 19 as a yellow oil.
All the products were characterized using a combination of spectro-
scopic and spectrometric techniques.
FT-IR (ATR): 3354, 1778, 1687, 1568, 1416 cm–1.
Acknowledgment
1H NMR (300 MHz, CDCl3): δ = 1.46 (s, 9 H), 1.74–1.81 (m, 1 H),
2.17–2.20 (m, 1 H), 3.75–3.80 (m, 2 H), 4.45–4.49 (m, 1 H), 5.54
(d, J = 9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 28.3, 35.1, 51.5, 58.3, 80.1, 156.4,
176.8.
We would like to thank Ms. Norma Castillo and Dr. Oscar Perez for
the preparation of some of the compounds. We thank DGAPA-
UNAM for financial support (Grant No. IN221510). AS thanks
CONACYT for a scholarship.
LRMS (TOF): m/z = 221 [M + 1]+.
Supporting Information for this article is available online at
(S)-N2-(Carbobenzyloxy)-L-lysine (20)
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
A mixture of the protected amino acid 6c (0.8 g, 3 mmol) and benzyl
choloroformate (0.5 mL, 3.5 mmol), aq 2 M NaOH (5 mL) in EtOH
(20 mL) was stirred for 1 h at r.t. After removal of the solvent in vac-
uo, the residue was taken up in EtOAc (30 mL), washed with 10%
citric acid (pH 3) (2 × 15 mL), dried (Na2SO4), and the solvent re-
moved in vacuo. The 9-BBN-amino acid complex was cleaved ac-
cording to Method B to afford 4.6 g (82%) of the desired product 20
as a white solid; mp >200 °C.
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(S)-2-[(tert-Butoxycarbonyl)amino]-6-(phenylamino)hexanoic
Acid (21)
A mixture of KI (0.02 g, 0.1 mmol), K3PO4 (0.88 g, 4.1 mmol), io-
dobenzene (300 mL, 2.6 mmol) and oxazaborolidinone 6a (0.532 g,
2 mmol) in i-PrOH (4 mL) was stirred at 80 °C (oil bath) under an
argon atmosphere for 16 h. The mixture was cooled to ambient tem-
perature and concentrated in vacuo. The residue was extracted with
EtOAc (2 × 10 mL). After removing the solvent under reduced pres-
sure, the residual oil (0.664 g) was redissolved in MeOH (4 mL) and
treated with concd HCl (2 mL) for 20 min at ambient temperature.
© Georg Thieme Verlag Stuttgart · New York
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© Georg Thieme Verlag Stuttgart · New York