Asymmetric copper-catalyzed synthesis of α-amino boronate esters from N-tert-butanesulfinyl aldimines

Article abstract of DOI:10.1021/ja800829y

A general and efficient new method for the asymmetric synthesis of α-amino boronate esters has been developed. The key step is the Cu(I)-catalyzed addition of bis(pinacolato)diboron to N-tert-butanesulfinyl aldimines, which proceeds in good yields (52-88%) and with very high diastereoselectivities (>96:2) for a variety of aldimine substrates. This method was applied to an efficient synthesis of bortezomib, a potent α-amino boronic acid inhibitor of the proteasome that is in clinical use for the treatment of multiple myeloma and mantle cell lymphoma. Copyright

Full text of DOI:10.1021/ja800829y

Published on Web 05/08/2008
Asymmetric Copper-Catalyzed Synthesis of r-Amino Boronate Esters from
N-tert-Butanesulfinyl Aldimines
Melissa A. Beenen, Chihui An, and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received February 1, 2008; E-mail: jellman@berkeley.edu
Table 1. Catalyst Screen for R-Amino Boronate Ester Synthesis
R-Amino boronic acids have emerged as key mechanism-based
pharmacophores for serine protease inhibition and have been
incorporated into inhibitors of numerous therapeutically important
proteases, including thrombin,1a elastase,1b and dipeptidyl peptidase
IV.1c Indeed, bortezomib (Velcade), was the first FDA approved
proteasome inhibitor drug and is in clinical use for the treatment
of multiple myeloma and mantle cell lymphoma.2
entry
B2R2
catalysta
temp (°C)
solvent
yield (%)b
drc
Despite the clear biological importance of R-amino boronic acids,
few methods are currently available for their asymmetric synthesis.
In fact, the only reported syntheses of enantioenriched R-amino
boronic acids have relied on Matteson’s protocol.3 This method
utilizes chiral pinanediol boronate esters in a homologation reaction
to prepare R-chloroboronate esters that are further transformed to
R-amino boronic acids. While Matteson’s chemistry has been
extensively used in both academia and industry,1–3 the R-amino
boronic acid side chain is derived from an alkyl boronic acid input,
few of which are commercially available. Herein, we report a new
and more direct approach for the asymmetric synthesis of diverse
R-amino boronic acids by the highly diastereoselective copper-
catalyzed addition of bis(pinacolato)diboron to N-tert-butanesulfinyl
aldimines4 at ambient temperature. We further report on the
synthetic utility of the N-sulfinyl R-amino boronate ester addition
products by the efficient asymmetric synthesis of bortezomib.
Few reports have appeared in the literature on the addition of
boron to a carbon heteroatom double bond.5,6 However, Baker and
co-workers demonstrated diborylation of a very limited number of
N-aryl aromatic aldimines with bis(catecholato)diboron (B2cat2) in
the presence of a platinum catalyst to afford racemic R-amino
boronate esters.6 We therefore began by examining the platinum-
catalyzed diborylation of N-tert-butanesulfinyl aldimines. Unfor-
tunately, no reaction was observed using this catalyst system (Table
1, entry 1). Recently, Sadighi and co-workers reported the addition
of bis(pinacolato)diboron (B2pin2) across aldehydes using a catalytic
amount of (1,3-dicyclohexylimidazol-2-ylidene)copper(I) tert-bu-
toxide ((ICy)CuOtBu).7 Gratifyingly, the addition of B2pin2 to tert-
butanesulfinyl aldimines with Sadighi’s catalyst proceeded in 78%
yield (Table 1, entry 2). A very high diastereomeric ratio of >98:2
was achieved as determined by 19F NMR analysis of the corre-
sponding (+)- and (-)-MTPA amides prepared by acidic depro-
tection of the N-sulfinyl group followed by treatment with either
(+)- or (-)-MTPACl.8 A control reaction was performed to
demonstrate that in the absence of catalyst no reaction was observed
(Table 1, entry 3). Performing the reaction at lower temperatures
required extended times for reaction completion (entry 4), and at
higher temperatures, a lower yield was observed (entry 5). Using
toluene, dioxane, or THF as the solvent (entries 6-8) gave lower
yields but diastereoselectivity comparable to that obtained with
benzene (entry 2).
1
2
3
4d
5
6
7
8
B2cat2 Pt(cod)Cl2
B2pin2 (ICy)CuOtBu
B2pin2 none
B2pin2 (ICy)CuOtBu
B2pin2 (ICy)CuOtBu
B2pin2 (ICy)CuOtBu
B2pin2 (ICy)CuOtBu
B2pin2 (ICy)CuOtBu
rt
rt
rt
10
50
rt
rt
rt
C6H6
C6H6
C6H6
C6H6
NR
78
NR
71
54
69
62
50
>98:2
>98:2
97:3
>98:2
98:2
C6H6
toluene
dioxane
THF
99:1
a With 5 mol % of catalyst used. b Yields were determined by 1H
NMR of the crude material relative to 1,3,5-trimethoxybenzene as an
internal standard. c Diastereomeric ratio was determined by 19F NMR of
the corresponding (R)- and (S)-MTPA amides. d The reaction time was
30 h.
Table 2. Synthesis of Functionalized R-Amino Boronate Esters
entry
R
product
yield (%)b
dr
1
2
3
4
5
6
7
8
9
(CH3)2CHCH2-
PhCH2-
2a
2b
2c
2d
2e
2f
2g
2h
2i
74
59
70
88
81
75
>98:2c
>98:2c
99:1c
PhCH2CH2-
(CH3)2CH-a
cyclohexyl-
>98:2d
97:3d
(CH3)3C-
96:4d
Ph-e
(66f) 54
(74f) 57
(77f) 61
(79f) 52
(66f)
75
99:1c
4-methoxyphenyl-e
4-chlorophenyl-e
2-chlorophenyl-e
4-(CF3)-phenyl-e
TBDPSOCH2-
>98:2c,g
99:1c
10
11
12
2j
2k
2l
>97:3g
>95:5g
>99:1c
a Absolute configuration was determined by X-ray crystallography.
b Isolated yields after silica gel chromatography. c See footnote c, Table
1. d Determined by 1H and 13C NMR after preparation of an authentic
mixture of diastereomers. e Reaction was run in toluene at 0 °C for 48 h
with 2.0 equiv of B2pin2 and 10 mol % of catalyst. f See footnote b,
Table 1. g No minor diastereomer detected by 1H and 13C NMR.
aliphatic aldimines proceeded in good yields and with high
diastereoselectivities to provide the N-sulfinyl-R-amino boronate
esters corresponding to leucine, phenylalanine, and homophenyla-
lanine, respectively (entries 1-3). The addition reaction is not
sensitive to sterics as demonstrated by the syntheses of the analogues
of valine, R-cyclohexylglycine (entries 4 and 5), and, most
dramatically, tert-leucine (entry 6). Addition of B2pin2 to N-tert-
With optimal reaction conditions identified, the scope of the
methodology was investigated by the borylation of various N-tert-
butanesulfinyl aldimines (Table 2). Additions to unbranched
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2008 American Chemical Society

C O M M U N I C A T I O N S
cedure by Millenium Pharmaceuticals,12 and without purification,
treatment with HCl then provided the amine hydrochloride 7.
Coupling of 2-pyrazinecarboxylic acid to crude 7 provided the
penultimate intermediate, the pinacol boronate of bortezomib. This
unpurified material was subsequently hydrolyzed under biphasic
conditions utilizing iso-butylboronic acid as a pinacol sequestering
agent.12 Purification by reverse phase chromatography produced
analytically pure bortezomib, 8, in an overall yield of 41% from 6
for the four-step process.
Scheme 1. Rationale for the Observed Sense of Induction
In conclusion, we have achieved the first asymmetric addition
of boron to a carbon heteroatom double bond, enabling the practical
production of highly enantioriched R-amino boronic acid derivatives
form readily accessible N-sulfinyl imine inputs 1 using a very
inexpensive Cu/ligand catalyst system. This transformation proceeds
in good yields and with very high diastereoselectivities for both
hindered and unhindered N-sulfinyl imine substrates. Moreover, the
N-sulfinyl R-amino boronate pinacol ester products 2 are perfectly
packaged for direct incorporation into R-amino boronic acid-based
protease inhibitors as demonstrated by the efficient synthesis of
bortezomib, a potent proteasome inhibitor approved for the treat-
ment of cancer.
Scheme 2. Asymmetric Synthesis of Bortezomib
Acknowledgment. This work was supported by the NSF. M.A.B.
gratefully acknowledges a Novartis graduate fellowship.
Supporting Information Available: Full author lists and complete
experimental details and spectral data for all compounds described.
This material is available free of charge via the Internet at http://
pubs.acs.org.
butanesulfinyl aromatic aldimines could also be achieved to produce
the boronate ester analogues of arylglycines, but the best yields
were obtained when the temperature was lowered to 0 °C, reaction
times were increased, and the catalyst loading and equivalents of
B2pin2 were increased (entries 7-11). Both electron-donating (entry
8) and -deficient (entries 9-11) substituents were tolerated on the
aryl ring, but protodeborylation occurred readily during chroma-
tography, particularly for electron-deficient addition product 2k.
The success of the method for functionalized R-amino boronic acid
analogues was demonstrated by the preparation of the R-amino
boronate ester corresponding to O-TBDPS-protected serine (entry
12).
References
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The sense of induction can best be understood by considering
Sadighi’s preliminary investigations on the Cu-catalyzed dibory-
lation of aldehydes with B2pin2 where he demonstrated that 3 is
generated upon mixing a copper NHC complex with B2pin2
(Scheme 1). From 3, two pathways for the stereodetermining step
are possible.9 In pathway A, direct boron-carbon bond formation
occurs, while in pathway B, an organocopper intermediate is first
generated, which is expected to undergo transmetalation with
retention of configuration to give the boronate ester product.10 For
both pathways, the sense of induction is consistent with an open
transition state with the reagent delivered from the least hindered
face.11
Upon establishing broad substrate scope, we sought to demon-
strate the versatility of the N-sulfinyl R-amino boronate esters 2
by the efficient synthesis of bortezomib. Selective removal of the
N-sufinyl group under acidic conditions afforded the amine
hydrochloride 6 in 93% yield (Scheme 2). N-Boc-L-phenylalanine
was coupled with 6 using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tet-
ramethyluronium tetrafluoroborate (TBTU) according to the pro-
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(5) Recently a boryl anion has been added to an aldehyde: Segawa, Y.;
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(9) Sadighi was unable to conclusively rule out either pathway (see ref 7).
Recently published DFT studies support pathway A, see: Zhao, H.; Dang,
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(10) While copper-tin transmetalation is reported to occur with retention, to
the best of our knowledge, copper-boron transmetalation has not been
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Chem. Soc. 1995, 117, 5973–5982, and references therein.
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