Synthesis of aryl glycines by the α arylation of weinreb amides

Article abstract of DOI:10.1002/anie.200704689

(Chemical Equation Presented) A rare example of the umpolung of an enolate forms the basis of the title reaction. In this procedure, a Grignard reagent is added to the iminium ion formed from the Weinreb amide upon treatment with a base (see scheme). When a chiral amide was used as the starting material, the nucleophilic addition proceeded with high diastereoselectivity. LDA = lithium diisopropylamide.

Full text of DOI:10.1002/anie.200704689

Angewandte
Chemie
DOI: 10.1002/anie.200704689
Synthetic Methods
Synthesis of Aryl Glycines by the a Arylation of Weinreb Amides
Sebastian Hirner, Olaf Panknin, Magnus Edefuhr, and Peter Somfai*
Aryl glycines are an important class of nonproteinogenic
a-amino acids that are present in many drugs and natural
products, such as glycopeptide antibiotics (e.g. vancomycin)[1]
and many b-lactam antibiotics (e.g. penicillins, cephalospor-
ins,[2] and nocardicins[3]). Despite their deceptively simple
structure, the enantioselective synthesis of aryl glycines is
Scheme 2. Synthesis of amide 6: a) bromoacetyl bromide, K2CO3,
complicated by the ease of base-catalyzed racemization of the
a stereocenter. As a result, many aryl glycines are synthesized
in racemic form, and the enantiomers are then separated by
resolution.[4a] During the last few decades, a wide range of
racemic and asymmetric syntheses of aryl glycines have been
developed.[4,5] However, owing to the lack of generality and
functional diversity of most of these methods, the generation
of aryl glycines remains a challenge in organic chemistry.
A straightforward approach to aryl glycines is the
a arylation of electrophilic glycine equivalents with aryl
nucleophiles.[5e,6] We envisaged that a-lactams 2, derived
from hydroxamic esters 1a, could serve as electrophilic
glycine equivalents in reactions with various nucleophiles
(Scheme 1). A related intramolecular version of this reaction
H2O/Et2O, 5a: 80%, 5b: 83%; b) N-allyl-N-benzylamine, K2CO3,
MeCN, 6a: 74%, 6b: 80%.
Table 1: Optimization of the addition of PhMgCl to amides 6.
Entry
R
Base (equiv)
Yield [%][a]
1
2
3
4
5
Me
Me
Me
tBu
tBu
LiHMDS (1.5)
nBuLi (1.5)
LDA (1.5)
LDA (1.5)
LDA (1.0)
trace
trace
12
77
86
[a] Yield of the isolated product. HMDS = hexamethyldisilazide, LDA =
lithium diisopropylamide.
found that the deprotonation of 6a with LDA (1.5 equiv) at
ꢀ788C and subsequent addition of PhMgCl (2.0 equiv)
afforded the desired a-arylated product 8a, albeit in low
yield (Scheme 3, Table 1, entry 3). The main product isolated
from the reaction mixture was the secondary amide 7, which
results from the demethoxylation of 6a by an E2 elimination
reaction.[11]
Scheme 1. Proposed generation of electrophilic glycine equivalents.
Ms = methanesulfonyl.
was reported recently by Mislin et al.,[7] and a similar strategy
has also been used for the synthesis of a-heteroatom-
substituted amides from N-mesyloxy amides 1b.[8]
We commenced our investigation of this method with the
Weinreb amide 6a, which was synthesized in two steps from
N,O-dimethylhydroxylamine hydrochloride (4a; Scheme 2).[9]
We circumvented the direct formation of an aryl ketone from
6a by generating the corresponding a-lactam at low temper-
ature prior to the addition of the Grignard reagent.[10] After
several attempts with different strong bases (Table 1), we
Scheme 3. Addition of PhMgCl to amide 6a.
[*] S. Hirner, O. Panknin, M. Edefuhr, Prof. P. Somfai
Organic Chemistry, KTH Chemical Science and Engineering
Royal Institute of Technology
It has been shown previously that this type of elimination
can be suppressed by using an N-tert-butoxy substituent.[11a]
Thus, compound 6b was selected as a suitable substrate and
prepared in the same manner as amide 6a, in this case from
N-methyl-O-tert-butylhydroxylamine hydrochloride (4b;
Scheme 2). When 6b was treated with LDA and PhMgCl,
the desired arylation product 8a was isolated in good yield
(Table 1, entry 4). The yield of 8a was increased further to
86% simply by decreasing the amount of base used (Table 1,
entry 5).
10044 Stockholm (Sweden)
Fax : (+46)8-791-2333
Prof. P. Somfai
Institute of Technology, University of Tartu
Nooruse 1, 50411 Tartu (Estonia)
E-mail: somfai@kth.se
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
We investigated the reaction of 6b with various aryl
Grignard reagents under the optimized conditions (Table 2).
The adduct 8 was formed in good to excellent yield when
10 from enolate 9, or the conversion of 9 into the correspond-
ing a-lactam (see structure 2 in Scheme 1) followed by ring
opening to give 10 (compounds 2 and 10 are valence
tautomers). Although the exact course of events can not be
deduced from the data present, the formation of compound
8a as the sole regioisomer strongly suggests the involvement
of iminium ion 10.
Table 2: a Arylation of amide 6b.[a]
With an operationally simple and high yielding procedure
for the synthesis of racemic aryl glycines at hand, we next set
out to develop an asymmetric protocol. Amide 11, derived
from (ꢀ)-a-methylbenzylamine, was selected for an initial
study (Scheme 5). The treatment of 11 with LDA (1.05 equiv)
Entry
ArMgX
Product
Yield [%][b]
1
PhMgCl
4-FC6H4MgBr
4-MeOC6H4MgBr
3-PhC6H4MgBr
(2-thienyl)MgBr
8a
8b
8c
8d
8e
8 f
86
77
92
81
91
77
76
2[c]
3
4[d]
5[c]
6[d]
7[d]
(3-pyridinyl)MgCl·LiCl
(5-bromo-3-pyridinyl)MgCl·LiCl
8g
[a] Molar ratio: 6b/LDA/RMgX 1:1:2. [b] Yield of the isolated product.
[c] 1.5 equivalents LDA. [d] LDA was added at 08C.
Scheme 5. Diastereoselective nucleophilic addition to amide 11:
a) LDA, THF, 08C; then PhMgCl, ZnCl2, ꢀ78!258C, 74%, d.r. 7:1;
b) 1. NaNO2, CH2Cl2, Ac2O, AcOH; 2. MeOH, NaHCO3, reflux, 84%
(2 steps); c) 1. [Pd(PPh3)4], N,N’-dimethylbarbituric acid, CH2Cl2,
reflux, 92%; 2. Pd(OH)2, MeOH, HCl, 100%.
electron-donating or electron-withdrawing substituents were
present on the aryl ring. Functionalized aryl Grignard
reagents were synthesized in situ from the corresponding
bromides by Br–Mg exchange with iPrMgCl·LiCl (Table 2,
entries 6 and 7).[12] With most of the Grignard reagents
screened, full conversion was only observed when the LDA
was added at 08C (Table 2, entries 4, 6, 7) or 1.5 equivalents of
followed by PhZnCl (1.2 equiv), which was used instead of
the more basic Grignard reagent to minimize potential
epimerization, yielded the desired adduct 12 in high yield
with high selectivity (d.r. 7:1). The configuration of the newly
formed stereocenter was determined to be S by the trans-
formation of 12 into the known methyl ester 14.[14,15] After
separation of the diastereomers by flash chromatography,
amide 12 was converted into ester 13 without epimeriza-
tion.[16,17] Subsequent deallylation[18] and hydrogenolysis gave
enantiomerically pure 14 in good overall yield. As noted
previously for related compounds, the N-methylamide func-
tionality in 12 constitutes an advantageous protecting group
for the carboxy terminus of aryl glycines.[16] By straightfor-
ward derivatization to the corresponding N-nitrosoamide, the
amide can be hydrolyzed to the free amino acid[16b] or
converted into the methyl ester.[19]
[13]
LDA were used (entries 2 and 5).
We propose the following mechanism for the formation of
compound 8a from 6b (Scheme 4): The deprotonation of 6b
generates enolate 9. Subsequent elimination of tBuOꢀ from
In summary, an efficient and diastereoselective synthesis
of aryl glycines from readily available starting materials has
been developed. We are presently exploring the scope and
limitations of this reaction.
Received: October 10, 2007
Revised: December 12, 2007
Published online: January 25, 2008
Scheme 4. Proposed mechanism for the formation of 8a from 6b.
this intermediate constitutes the key step and generates
iminium ion 10 with the overall result that the dipole of the a
carbon center is reversed (umpolung). The addition of the
Grignard reagent to 10 then gives amide 8a. For the base-
promoted addition of amines and halides to O-sulfonylated
hydroxamic acid derivatives, it has been shown that both
Keywords: amino acids · aryl glycines · arylation ·
Grignard reaction · Weinreb amides
.
[1] F. Wolter, S. Schoof, R. D. Süssmuth, Top. Curr. Chem. 2007, 267,
143 – 185.
[2] H. Schutt, G. Schmidt-Kastner, A. Arens, M. Preiss, Biotechnol.
Bioeng. 1985, 27, 420 – 433.
[3] G. M. Salituro, C. A. Townsend, J. Am. Chem. Soc. 1990, 112,
760 – 770.
ꢀ
deprotonation of the a carbon atom and loss of the N OR
moiety are occurring at the transition state of the rate-
determining step.[7,8] The application of this scenario to the
present reaction suggests the direct formation of iminium ion
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Chemie
[4] For reviews on the asymmetric synthesis of aryl glycines, see:
a) R. M. Williams, J. A. Hendrix, Chem. Rev. 1992, 92, 889 – 917;
b) C. Nµjera, J. M. Sansano, Chem. Rev. 2007, 107, 4584 – 4671.
[5] For leading references on aryl glycine syntheses, see: a) E. L.
Lee, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 12066 – 12067;
b) M. A. Beenen, D. J. Weix, J. A. Ellman, J. Am. Chem. Soc.
2006, 128, 6304 – 6305; c) G. Shang, Q. Yang, X. Zhang, Angew.
Chem. 2006, 118, 6508 – 6510; Angew. Chem. Int. Ed. 2006, 45,
6360 – 6362; d) R. Cannella, A. Clerici, W. Panzeri, N. Pastori, C.
Punta, O. Porta, J. Am. Chem. Soc. 2006, 128, 5358 – 5359; e) P.
Calí, M. Begtrup, Synthesis 2002, 63 – 66; f) K. L. Reddy, K. B.
Sharpless, J. Am. Chem. Soc. 1998, 120, 1207 – 1217.
[6] P. D. Bailey, A. N. Boa, J. Clayson, Contemp. Org. Synth. 1995, 2,
173 – 187.
[12] A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396 – 3399;
Angew. Chem. Int. Ed. 2004, 43, 3333 – 3336.
[13] Use of the standard reaction conditions resulted in recovery of
the starting material.
[14] [a]D20 = + 125.6 (c = 0.43, MeOH); lit:[15] [a]2D4:1 = + 136.0 (c =
2.17, MeOH). For the determination of the ee value, the
hydrochloride was converted into the free amine by treatment
with NaHCO3 in H2O. The ee value was shown to be greater than
96% by HPLC on a chiral phase (chiralcel OD-RH, KPF6
(50 mm)/MeCN, 85:15!70:30, 0.4 mLminꢀ1).
[15] G.-I. Li, G. Zhao, Org. Lett. 2006, 8, 633 – 636.
[16] a) D. A. Evans, J. C. Barrow, P. S. Watson, A. M. Ratz, C. J.
Dinsmore, D. A. Evrard, K. M. DeVries, J. A. Ellman, S. D.
Rychnovsky, J. Lacour, J. Am. Chem. Soc. 1997, 119, 3419 – 3420;
b) D. A. Evans, P. H. Carter, C. J. Dinsmore, J. C. Barrow, J. L.
Katz, D. W. Kung, Tetrahedron Lett. 1997, 38, 4535 – 4538.
[17] No epimerization of the a stereocenter was observed for the
ester-formation and deallylation steps (Scheme 5, steps b and c)
by 1H NMR spectroscopic analysis of the crude products.
[18] F. Garro-Helion, A. Merzouk, F. Guibꢀ, J. Org. Chem. 1993, 58,
6109 – 6113.
[7] G. L. Mislin, A. Burger, M. A. Abdallah, Tetrahedron 2004, 60,
12139 – 12145.
[8] a) R. V. Hoffman, N. K. Nayyar, W. Chen, J. Am. Chem. Soc.
1993, 115, 5031 – 5034; b) R. V. Hoffman, N. K. Nayyar, W.
Chen, J. Org. Chem. 1995, 60, 4121 – 4125; c) R. V. Hoffman, Z.
Zhao, A. Costales, D. Clarke,J. Org. Chem. 2002, 67, 5284 – 5294.
[9] R. Tillyer, L. F. Frey, D. M. Tschaen, U.-H. Dolling,Synlett 1996,
225 – 226.
[10] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815.
[11] a) O. Labeeuw, P. Phansavath, J.-P. GenÞt, Tetrahedron Lett.
2004, 45, 7107 – 7110; b) S. L. Graham, T. H. Scholz, Tetrahedron
Lett. 1990, 31, 6269 – 6272.
[19] D. M. Shendage, R. Frꢁhlich, G. Haufe, Org. Lett. 2004, 6, 3675 –
3678.
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