Synthesis of Boronocysteine

Article abstract of DOI:10.1055/s-0036-1591491

Herein we report the first synthesis of protected boronocysteine. The target compound was prepared via copper-catalysed diastereoselective nucleophilic borylation of a sulfinimine. After deprotection to give the amine as the hydrochloride salt, four boron

Full text of DOI:10.1055/s-0036-1591491

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
S. M. Gibson et al.
Letter
Synlett
Synthesis of Boronocysteine
Samantha M. Gibson
O
S
O
Derek Macmillan
Tom D. Sheppard*
0
0
0
0
0-
0
0
3
4-
4
1
2
0-
3
1
4
OEt
tBu
O
NH
R
NH
4 steps
0
0
0
0
0-
0
0
2
3-
4
5
5
1-
1
6
4
EtO
O
B
O
B
O
Br
Department of Chemistry, University College London,
20 Gordon St, London, WC1H 0AJ, UK
tom.sheppard@ucl.ac.uk
SPMB
SPMB
Boronocysteine
4 examples
Received: 22.08.2017
Accepted after revision: 16.09.2017
Published online: 20.10.2017
Ph
Cl
Cl
O
O
OH
B
H
N
N
N
N
OH
DOI: 10.1055/s-0036-1591491; Art ID: st-2017-d0637-l
H
HN
O
Abstract Herein we report the first synthesis of protected boronocys-
teine. The target compound was prepared via copper-catalysed diaste-
reoselective nucleophilic borylation of a sulfinimine. After deprotection
to give the amine as the hydrochloride salt, four boronocysteine amide
derivatives were prepared through reaction with a variety of different
active acylating agents.
Bortezomib
O
NH
B
OH
O
OH
H
Ph
N
N
B
O
N
OH
O
HO2C
O
H
O
Delanzomib
Key words amino acids, boron, copper, imines, peptides
CO2H
Ixazomib
α-Aminoboronic acids have attracted considerable at-
tention as analogues of amino acids with potential applica-
tions in medicinal chemistry.1 Bortezomib (Velcade®), a
peptide analogue incorporating an α-aminoboronic acid
used in cancer treatment, became the first drug on the mar-
ket containing a boron atom (Figure 1). Subsequently, other
α-aminoboronic acid derivatives have reached the market
including ixazomib and delanzomib. The synthesis of α-am-
inoboronic acids has proved to be especially challenging,
however, as free α-aminoboronate compounds readily un-
dergo rearrangement to N-boryl compounds leading to pro-
todeboronation.2
Figure 1 Medicinally useful α-aminoboronic acid derivatives
tives.8 Notably, whilst a wide range of α-aminoboronic acid
derivatives have been reported,4–9 there are relatively few
examples containing heteroatomic functional groups on the
side chain.10 For an ongoing project involving the study of
peptides containing C-terminal cysteine derivatives,11 we
required access to the boron analogue of cysteine. Interest-
ingly, no previous synthesis of this compound (or a protect-
ed derivative) has been reported in the literature. Herein,
O
Nevertheless, Matteson was able to carry out the first
synthesis of an α-aminoboronic acid derivative in 1966
starting from iodomethylmercuric iodide (Scheme 1).3 He
was subsequently able to access a wider range of α-aminob-
oronic acids via rearrangement reactions of boronate esters
using dichloromethyllithium.4 Alternative approaches to α-
aminoboronic acid derivatives have included copper-cata-
lysed nucleophilic borylation of imines,5 alkylation of α-
sulfenyl boronates followed by nucleophilic displacement of
the sulfur,6 Curtius rearrangement of α-borylcarboxylic ac-
ids,7 and lithiation/borylation of protected amine deriva-
ref 3
ref 8
IHg
I
tBuO
N
Cl
CO2H
R
NH2
ref 7
ref 4
HO
HO
HO
HO
B
R
B
B
R
OH
SPh
OH
OH
EWG
N
ref 6
ref 5
B
R
R
OH
Scheme 1 Synthetic approaches to α-aminoboronic acid derivatives
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
S. M. Gibson et al.
Letter
Synlett
we report a concise synthesis of protected boronocysteine,
and its use in the synthesis of N-acyl derivatives including
dipeptide analogues.
O
S
O
S
tBu
O
NH
tBu
N
a
SPMB
B
SPMB
Matteson has previously noted that rearrangement of a
thioether-functionalised alkylboronate using dichloro-
methyllithium was unsuccessful, probably due to loss of a
sulfur-stabilised carbanion from the ‘ate’ complex.12 We
therefore envisaged that boronocysteine 1 could readily be
constructed by Cu-catalysed borylation of a suitably pro-
tected sulfinimine 2 (Scheme 2).5 The required imine 2
should be readily available from commercially available
bromoacetaldehyde diethyl acetal.
H
5
O
6
NH3Cl
SPMB
b
NH3Cl
O
B
SPMB
8
O
7
Scheme 4 Copper-catalysed borylation of imine 5 and sulfinamide
deprotection. Reagents and conditions: a. CuCl, (±)-BINAP, KOtBu, B2pin2,
THF, 60%;17 b. HCl, dioxane, MeOH, 82%.18
O
OH
S
9b. Dipeptide analogues 10 were obtained through reaction
with either an in situ generated mixed anhydride 10a, or a
pre-formed acyl fluoride 10b. These reactions demonstrate
that boronocysteine can readily be converted into amide
derivatives through reaction with a range of different active
acylating agents.
B
NH2
SH
N
O
O
HO
B
[Cu]
1
2
PgS
Scheme 2 Proposed synthetic strategy for preparing boronocysteine
O
O
Bromoacetaldehyde dimethyl acetal 3a was converted
into the corresponding sulfide 3b by reaction with p-me-
thoxybenzyl thiol (PMBSH) and sodium hydroxide (Scheme
3).13 After deprotection of the acetal, the aldehyde 414 was
then converted into sulfinimine 5 through condensation
with the sulfinimide.
Cl
NH
NH
a or b
O
O
B
B
O
SPMB
O
SPMB
NH3Cl
SPMB
O
9b
9a
B
O
7
O
O
O
FMocHN
BocHN
OEt
O
NH
NH
S
c
b
tBu
N
X
c or d
SPMB
O
O
EtO
3a X = Br
3b X = SPMB
H
B
B
SPMB
4
a
5
H
O
SPMB
10b
O
SPMB
10a
Scheme 3 Synthesis of imine 5. Reagents and conditions: a. NaOH,
PMBSH, EtOH, 52%; b. HCl, acetone, 99%. c. tBuSONH2, CuSO4, CH2Cl2,
80%.16
Scheme 5 Synthesis of boronocysteine amides. Reagents and condi-
tions: a. MeCOCl, pyridine, MeCN, 22% (9a); b. ClCH2COCl, N-methyl-
morpholine, CH2Cl2, 85% (9b); c. Boc-Gly-OH, N-methylmorpholine,
iBuOCOCl, CH2Cl2, then 7, 89% (10a);19 d. FMoc-Gly-F, iPr2NEt, CH2Cl2,
60% (10b).
With the required sulfinimide in hand, the Cu-catalysed
borylation reaction was investigated. Pleasingly, by using
CuCl in the presence of KOtBu and rac-BINAP as a ligand,5a
the desired boronate 6 was obtained in 60% isolated yield as
a single diastereoisomer (Scheme 4). As reported previous-
ly, the sulfinimide could be removed using HCl to give the
corresponding α-aminoboronate as the hydrochloride salt
7.5a This compound required careful handling as it readily
underwent protodeboronation to give the corresponding 2-
aminoethylthio ether 8.15 For example, deboronated com-
pound 8 was obtained when 6 was exposed to HCl for 24 h
instead of the 3 h reaction time required to produce 7.
We were, however, able to prepare boronocysteine am-
ides derived from 7 through reaction with appropriate acy-
lating reagents (Scheme 5). Thus, reaction of 7 with acid
chlorides provided the acetamide 9a and chloroacetamide
In summary, we have described the first synthesis of
protected boronocysteine, and demonstrated its applica-
tion in the formation of amide derivatives.
Funding Information
This work was supported by an Engineering and Physical Sciences Re-
search Council Studentship.
)(
Acknowledgment
We would like to thank the Department of Chemistry, University Col-
lege London for providing a studentship to support this work.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
S. M. Gibson et al.
Letter
Synlett
Supporting Information
vacuo and the residue obtained was purified by column chro-
matography to give an orange oil (865 mg, 2.89 mmol, 80%). 1H
NMR (600 MHz, CDCl3): δ = 7.98 (1 H, t, J = 5.6 Hz, NCH), 7.23 (2
H, d, J = 6.5 Hz, ArH), 6.85 (2 H, d, J = 6.5 Hz, ArH), 3.79 (3 H, s,
OCH3), 3.66 (2 H, s, ArCH2), 3.35 (1 H, dd, J = 14.3, 6.0 Hz, 1 ×
SCH2CH), 3.31 (1 H, dd, J = 14.3, 5.3, 1 × SCH2CH), 1.22 (9 H, s,
tBu). 13C NMR (150 MHz, CDCl3): δ = 164.2, 158.9, 130.3, 129.2,
114.1, 57.0, 55.4, 35.02, 34.3, 22.5. LRMS (CI): m/z (%) = 420
(100), 300 (37) [M + H+], 240 (30), 195 (32) [M – SOtBu]+), 121
(88) [PMB+]. HRMS: m/z calcd for C14H22NO2S2: 300.10865;
found: 300.10877. IR (film): νmax = 2958 (C–H), 1609 (C=C),
1510 (C=N), 1458 (C=C), 1083 (S=O) cm-1.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591491.
S
u
p
p
ortiInfogrmoaitn
S
u
p
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References and Notes
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(17) N-{2-[(4-Methoxybenzyl)thio]-1-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)ethyl}-2-methylpropane-2-sulfinamide (6)
Using flame-dried glassware under an argon atmosphere, CuCl
(38.4 mg, 0.388 mmol), (±)-BINAP (111.1 mg, 0.1784 mmol),
and B2pin2(1.331 g, 5.242 mmol) were dissolved in anhydrous
THF (4 mL). KOtBu (1 M in THF, 1.4 mL, 1.4 mmol) was added
whilst stirring at r.t. After 10 min, the reaction was cooled to
–20 °C, and aldehyde 5 (1.0338 g, 3.4522 mmol) was added fol-
lowed by MeOH (300 μL, 7.41 mmol) and the reaction stirred
overnight. The solvent was removed in vacuo and the resultant
oil purified by flash column chromatography using EtOAc in
CH2Cl2 (20 → 35%) to give 6 as an orange oil (878 mg, 2.056
mmol, 60%); Rf = 0.08 (EtOAc/CH2Cl2 = 1:4). 1H NMR (600 MHz,
CDCl3): δ = 7.24 (2 H, d, J = 8.6 Hz, ArH), 6.82 (2 H, d, J = 8.6 Hz,
ArH), 3.78 (3 H, s, OCH3), 3.71 (1 H, d, J = 5.6 Hz, NH), 3.69 (s, 2
H, ArCH2S), 3.22 (1 H, m, CHB), 2.77 (1 H, dd, J = 13.4, 6.3 Hz, 1 ×
SCH2CH), 2.72 (1 H, dd, J = 13.4, 7.9 Hz, 1 × SCH2CH), 1.25 (s, 6 H,
2 × pinacol-CH3), 1.23 (s, 9 H, tBu), 1.20 (s, 6 H, 2 × pinacol-CH3).
13C NMR (150 MHz, CDCl3): δ = 158.7, 130.1, 130.0, 114.0, 84.3,
(7) He, Z.; Zajdlik, A.; St Denis, J. D.; Assem, N.; Yudin, A. K. J. Am.
Chem. Soc. 2012, 134, 9926.
(8) Batsanov, A. S.; Grosjean, C.; Schütz, T.; Whiting, A. J. Org. Chem.
2007, 72, 6276.
(9) For other approaches, see: (a) Zheng, B.; Deloux, L.; Pereira, S.;
Skrzypczak-Jankun, E.; Cheesman, B. V.; Sabat, M.; Morris, S.
Appl. Organomet. Chem. 1996, 10, 267. (b) Touchet, S.; Carreaux,
F.; Molander, G. A.; Carboni, B.; Bouillon, A. Adv. Synth. Catal.
2011, 353, 3391. (c) Kawamorita, S.; Miyazaki, T.; Iwai, T.;
Ohimiya, H.; Sawamura, M. J. Am. Chem. Soc. 2012, 134, 12924.
(d) Hu, N.; Zhao, G.; Zhang, Y.; Liu, X.; Li, G.; Tang, W. J. Am.
Chem. Soc. 2015, 137, 6746. (e) Li, C.; Wang, J.; Barton, L. M.; Yu,
S.; Tian, M.; Peters, D. S.; Kumar, M.; Yu, A. W.; Johnson, K. A.;
Chatterjee, A. K.; Yan, M.; Baran, P. S. Science 2017, 357, in press;
DOI: 10.1126/science.aam7355.
(10) (a) Kettner, C.; Mersinger, L.; Knabb, R. J. Biol. Chem. 1990, 265,
18289. (b) Lebarbier, C.; Carreaux, F.; Carboni, B.; Boucher, J. L.
Bioorg. Med. Chem. Lett. 1998, 8, 2573. (c) Watanabe, T.;
Momose, I.; Abe, M.; Abe, H.; Sawa, R.; Umezawa, Y.; Ikeda, D.;
Takahashi, Y.; Akamatsu, Y. Bioorg. Med. Chem. Lett. 2009, 19,
2343. (d) Lebarbier, C.; Carreaux, F.; Carboni, B. Synthesis 1996,
1371. (e) Matteson, D. S.; Michnick, T. J.; Willett, R. D.;
Patterson, C. D. Organometallics 1989, 8, 726.
56.2, 55.3, 41.3 (br), 35.2, 34.6, 25.0 (2 C), 22.6. LRMS (CI): m/z
t
(%) = 428 (41), [M + H]+, 371 (18) [M+ – Bu)], 322 (38) [M+
–
SOtBu), 121 (100) [PMB+]. IR: νmax = 2977 (C–H), 2930 (C–H),
1609 (Ar), 1511 (Ar), 1544 (Ar), 1369 (B–O), 1246, 1140 (B–C),
1033 (S=O). HRMS: m/z calcd for C20H34BNO4S2: 428.2095;
found: 428.2095.
(18) 2-[(4-Methoxybenzyl)thio]-1-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)ethanamine hydrochloride (7)
A solution of HCl in dioxane (4 M, 585 μL, 2.34 mmol) was
added to 6 (99.7 mg, 0.233 mmol) dissolved in anhydrous
MeOH (3 mL) to give a pale yellow solution. The reaction was
stirred for 3 h. The solvent was removed in vacuo to give an
orange residue (75.3 mg). The residue was washed with Et2O,
sonicated, and centrifuged to give 7 as a light brown solid (68
1
mg, 0.190 mmol, 82%). H NMR (400 MHz, MeOD-d4): δ = 7.29
(2 H, d, J = 8.7 Hz, ArH), 6.89 (2 H, d, J = 8.7 Hz, ArH) 3.80 (3 H, s,
OCH3), 3.79 (2 H, s, ArCH2), 3.01 (1 H, dd, J = 8.7, 4.7 Hz, CHB),
2.85 (1 H, dd, J = 14.3,4.8 Hz, 1 × CΗ2CH), 2.73 (1 H, dd, J = 14.3,
8.8 Hz, 1 × CH2CH), 1.33 (12 H, s, 4 × CH3). 13C NMR (100 MHz,
MeOD-d4): δ = 159.1, 129.9, 129.5, 113.7, 85.5, 74.4, 54.5, 35.1,
30.4, 23.8, 23.7. LRMS (CI): m/z (%) = 323 (100) [M + H]+, 198
(18) [M – Bpin]+. HRMS: m/z calcd for C16H27BNO3S: 323.1836;
found: 323.18359. IR (solid): νmax = 2975 (C–H), 2958 (C–H),
(11) (a) Cowper, B.; Shariff, L.; Chen, W.; Gibson, S. M.; Di, W.-L.;
Macmillan, D. Org. Biomol. Chem. 2015, 13, 7469. (b) Macmillan,
D. Synlett 2017, 28, 1517.
(12) Matteson, D. S. J. Organomet. Chem. 1999, 581, 51.
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19, 1375.
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876.
2831 (C–H), 1607, 1583, 1411 cm–1
(19) tert-Butyl [2-({2-[(4-Methoxybenzyl)thio]-1-(4,4,5,5-tetra-
.
(15) Ghosh, S.; Tochtrop, G. P. Tetrahedron Lett. 2009, 50, 1723.
(16) (E)-N-{2-[(4-Methoxybenzyl)thio]ethylidene}-2-methylpro-
pane-2-sulfinamide (5) Copper(II) sulfate (1.27 g, 7.94 mmol)
and aldehyde 4 (779 mg, 3.97 mmol, 1.1 equiv) were added to a
solution of (±)-tert-butyl sulfinamide (438 mg, 3.61 mmol) in
anhydrous CH2Cl2 (7.2 mL). The reaction was stirred at r.t. for 18
h, before filtering through Celite. The solvents were removed in
methyl-1,3,2-dioxaborolan-2-yl)ethyl}amino)-2-oxoethyl]car-
bamate (10a)
Using flame-dried glassware under an argon atmosphere, Boc-
Gly-OH (87.5 mg, 0.50 mmol) was dissolved in anhydrous
CH2Cl2 (1.5 mL) and cooled to –20 °C. To this was added NMM
(66 μL, 0.60 mmol) followed by IBCF (58 μL, 0.45 mmol), and the
mixture stirred for 5 h at –20 °C. HCl salt 7 (23.4 mg, 65.1 μmol)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
S. M. Gibson et al.
Letter
Synlett
was added, followed by NMM (7 μL, 65 μmol), and the reaction
stirred overnight. The reaction mixture was concentrated in
vacuo and the resultant oil purified by flash column chromatog-
raphy using deactivated silica (35% water w/w) eluting with
MeOH in EtOAc (0 → 10%) to give 10a as a pale yellow oil (28
mg, 58.0 μmol, 89%). 1H NMR (600 MHz, CDCl3): δ = 7.51 (1 H, br
s, CHNH), 7.21 (2 H, d, J = 8.7 Hz, ArH), 6.82 (2 H, d, J = 8.7 Hz,
ArH), 5.29 (1 H, br s, CH2NH), 3.93 (2 H, d, J = 5.7, NHCH2), 3.78
(3 H, s, OCH3), 3.65 (2 H, s, ArCH2), 2.81 (1 H, br d, J = 11.5 Hz,
CHB), 2.75 (1 H, dd, J = 14.1, 3.2 Hz, 1 × SCH2CH), 2.46 (1 H, dd,
J = 14.1, 11.5 Hz, 1 × SCH2CH), 1.44 (9 H, s, Bu), 1.18 (6 H, s, 2 ×
pinacol-CH3), 1.16 (6 H, s, 2 × pinacol-CH3). 13C NMR (150 MHz,
CDCl3): δ = 174.9, 158.7, 130.3, 130.1, 114.1, 81.6, 55.4, 54.0,
41.4, 35.2, 33.6, 29.8, 28.4, 25.0, 24.9, 14.3. LRMS (CI): m/z (%) =
481 (100) [M
480.2574; found: 480.2575. IR (film): νmax = 2970 (C–H), 2926
(C–H), 1697 (br, C=O), 1609 (C=O), 1511, 1456 cm–1
+
H]+. HRMS: m/z calcd for C23H37BN2O6S:
.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D