Asymmetric synthesis of protected arylglycines by rhodium-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl imino esters

Article abstract of DOI:10.1021/ja060529h

A new method for the Rh(I)-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl imino esters has been developed for the asymmetric synthesis of arylglycine derivatives. This method provides high yields (61-90%) and diastereoselectivities (>98:2) for a variety of functionalized arylboronic acids. The N-sulfinyl arylglycine ester products are versatile intermediates for further transformations, including selective protecting group removal, conversion to β-amino alcohols, and direct incorporation into peptides. Copyright

Full text of DOI:10.1021/ja060529h

Published on Web 04/25/2006
Asymmetric Synthesis of Protected Arylglycines by Rhodium-Catalyzed
Addition of Arylboronic Acids to N-tert-Butanesulfinyl Imino Esters
Melissa A. Beenen, Daniel J. Weix, and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received January 23, 2006; E-mail: jellman@berkeley.edu
Table 1. Reaction Optimization
Arylglycines are components of a number of significant drugs,
including glycopeptide antibiotics, such as vancomycin,1 many
â-lactam antibiotics, such as cefprozil,2 and the cardiovascular agent
plavix.3 The synthesis of arylglycines is therefore an important goal
in organic chemistry.4 The addition of arylboronic acids to imino
acids via the Petasis reaction is a powerful method for arylglycine
synthesis5 because it capitalizes on the commercial availability of
a large number of diverse arylboronic acids displaying a wide array
of functionality. However, electron-deficient arylboronic acids are
not effective coupling partners, and, to our knowledge, an asym-
metric variant of this methodology has not been developed.6 Herein
we report an efficient asymmetric synthesis of arylglycines based
on the rhodium-catalyzed addition of arylboronic acids to N-sulfinyl
iminoacetates, which proceeds in high yields and with very high
diastereoselectivity for both electron-rich and -poor arylboronic acid
derivatives. We further report on the synthetic versatility of the
N-sulfinyl arylglycine products in subsequent transformations,
including peptide coupling reactions.
temp
C)
yield
(%)a
entry
catalyst/base
(
°
drb
1
Rh(acac)(coe)2, dppbenzc
[Rh(cod)(CH3CN)2]BF4, Et3N
Rh(acac)(coe)2, dppbenz, Et3N
none
70
rt
70
70
89
6
92
0
97:3
91:9
82:18
2d
3
4
a Isolated yields after column chromatography. b See Supporting Informa-
tion for diastereoselectivity determination. c dppbenz ) 1,2-bis(diphe-
nylphosphinyl)benzene. d Reaction conducted in 1:2 dioxane:H2O as de-
scribed in ref 9.
Table 2. Evaluation of Ester Protecting Groups
The asymmetric rhodium-catalyzed addition of arylboronic acids
to N-sulfonyl,7 N-diphenylphosphinoyl,8 and N-sulfinyl imines8,9
has recently been developed. However, the addition of arylboronic
acids to imino esters has yet to be described, presumably because
the presence of metal hydroxides, and, under some reaction
conditions, water, is not compatible with highly electrophilic imino
esters.10 N-Sulfinyl imino esters stand out as stable, isolable
compounds that can even be chromatographed on SiO2 making them
excellent starting materials for arylglycine synthesis.11
The reported reaction conditions for rhodium-catalyzed arylbo-
ronic acid additions to N-tert-butanesulfinyl imines were first
examined using ethyl imino ester 1 (Table 1). A high yield and
diastereomeric ratio were observed using dioxane as solvent and a
rhodium 1,2-bis(diphenylphosphinyl)benzene complex as the cata-
lyst (entry 1).8 In contrast, a poor yield occurred under ligand-free
conditions with water as a cosolvent due to competitive imine
hydrolysis (entry 2).9 Because Et3N has been reported to accelerate
the rhodium-catalyzed additions to imines in water,9 this base was
also added to the reaction conducted in dioxane (entry 3). Although
the reaction proceeded to high conversion, a loss of diastereose-
lectivity was observed due to base-mediated epimerization of the
product. A control reaction was also performed to demonstrate that
without the rhodium catalyst no reaction occurred (entry 4).
With optimal reaction conditions identified, a survey of different
esters11 was next carried out (Table 2). Additions to the methyl,
benzyl, and tert-butyl esters 2-4 all proceeded in high yields and
with excellent diastereoselectivity, providing a high degree of
flexibility in the choice of ester protecting groups. Methyl ester 2
was selected for further investigation of the scope of the reaction
with respect to the arylboronic acid.
imino
ester
yield
(%)a
entry
R1
drb
1
2
3
4
1
2
3
4
Et
Me
Bn
89
89
85
78
98:2
99:1
98:2
98:2
t-Bu
a Isolated yields after column chromatography. b See Supporting Informa-
tion for diastereoselectivity determination.
was present on the aryl ring of the boronic acid (Table 3, entries
1-3). While sterically hindered ortho-substituted aryl rings proved
problematic for this same catalyst in our previously reported
arylboronic acid addition to aldimines,8 o-tolylboronic acid was
successfully incorporated into the arylglycine product (entry 3).
Electron-neutral substituents were also tolerated (entry 4). Given
the lack of success achieved with electron-deficient arylboronic
acids in the Petasis reaction,5,6 we were most interested in evaluating
the preparation of electron-deficient arylglycine derivatives. Both
weakly and strongly electron-withdrawing substituents on the aryl
rings gave good yields of desired product (entries 5-8). However,
no reaction was observed when a 3-pyridylboronic acid was
subjected to our optimized reaction conditions (entry 9). Throughout
this series of experiments, we were very pleased to find that the
addition of all types of arylboronic acids proceeded with high levels
of diastereoselectivity (g98:2).
We were pleased to discover that the methodology is tolerant of
many functional groups (Table 3). Similar to the Petasis reaction,
high yields were achieved when an electron-donating substituent
A key feature of this arylglycine synthesis method is the
versatility of the N-sulfinyl-R-amino ester products 5 in subsequent
transformations. Selective cleavage of the sulfinyl group or ester
9
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J. AM. CHEM. SOC. 2006, 128, 6304-6305
10.1021/ja060529h CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Synthesis of Functionalized Arylglycines
Scheme 2. Peptide Coupling of N-Sulfinyl-Protected Arylglycines
yield
(%)a
entry
R1
product
drb
1
2
3
4
5
6
7
8
9
4-methoxyphenylc
para-tolyl
5a
5b
5c
5d
5e
5f
5g
5h
5i
89
90
61
79
87
82
74
69
0
99:1
98:2
99:1
99:1
99:1
99:1
98.5:1.5
99:1
ortho-tolyl
Phc
3-acetylphenyl
4-chlorophenylc
4-trifluoromethylphenyl
3-(NO2)-phenyl
3-pyridinyl
arylglycine products are also versatile synthetic intermediates for
further transformations, including selective protecting group re-
moval, conversion to â-amino alcohols and direct incorporation into
peptides, with each transformation proceeding in good yields with
minimal to no racemization.
a Isolated yields after column chromatography. b See Supporting Informa-
tion for diastereoselectivity determination. c Absolute configuration was
determined by comparing the optical rotation of the corresponding free
amino ester to those reported in the literature (see Supporting Information).
Acknowledgment. This work was supported by the NSF (CHE-
0446173).
Scheme 1. Selective Functional Group Transformationsa
Supporting Information Available: Experimental procedures and
characterization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
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N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463. (b)
N-sulfinyl imines: Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E.
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a See Supporting Information for determination of enantiomeric and
diastereomeric purity.
(7) (a) Ueda, M.; Saito, A.; Miyaura, N. Synlett 2000, 1637. (b) Kuriyama,
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can be accomplished in high yields with no loss in stereochemical
purity (Scheme 1). In addition, straightforward conversion of amino
esters 5 to â-amino alcohols can be achieved using NaBH4.
The applicability of the N-sulfinyl-R-amino acids as protected
amino acid derivatives in peptide synthesis was also demonstrated
for the first time.12 Using coupling conditions developed by
Carpino,13 N-sulfinyl amino acid 7 was successfully coupled to both
the R- and S-leucine methyl ester in good yields (Scheme 2).
Moreover, despite the acidity of the R-proton in arylglycines, little
to no epimerization was observed for either coupling reaction as
determined by HPLC analysis of the diastereomeric products 11
and 12 prepared by oxidation of the sulfinyl group in coupling
products 9 and 10.14
(8) Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092.
(9) Bolshan, Y.; Batey, R. A. Org. Lett. 2005, 7, 1481.
(10) For leading references on nice applications of N-sulfonyl imino esters,
see: (a) France, S.; Shah, M. H.; Weatherwax, A.; Wack, H.; Roth, J. P.;
Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206. (b) Kjaersgaard, A.;
Jorgensen, K. A. Org. Biomol. Chem. 2005, 3, 804. (c) Kobayashi, S.;
Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem.
Soc. 2003, 125, 2507.
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Org. Chem. 1999, 64, 1278. (b) Davis, F. A.; McCoull, W. J. Org. Chem.
1999, 64, 3396. (c) Jayathilaka, L. P.; Deb, M.; Standaert, R. F. Org.
Lett. 2004, 6, 3659.
(12) N-Sulfinyl â-amino acids have been employed in peptide coupling
reactions, but racemization is not possible for these systems. Tang, T. P.;
Ellman, J. A. J. Org. Chem. 2002, 67, 7819.
(13) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398.
(14) Deprotection of the sulfinyl group from 9 with methanolic HCl proceeded
in 93% yield (see Supporting Information).
In summary, an efficient and highly diastereoselective synthesis
of arylglycines has been developed that allows incorporation of
electronically and sterically diverse arylboronic acids. The N-sulfinyl
JA060529H
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