Asymmetric synthesis of α-aryl amino acids; Aryne-mediated diastereoselective arylation

Article abstract of DOI:10.1021/ol1030469

An aryne-mediated α-arylation reaction of Schoellkopf's bis-lactim ether is described. Arynes were generated via an ortho-lithiation approach, affording syn-arylated products in up to 94:6 dr with moderate to good yields and excellent regioselectivities. Hydrolysis provided a variety of substituted arylglycines containing a range of functional groups without racemization.(Figure Presented)

Full text of DOI:10.1021/ol1030469

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1012–1015
Asymmetric Synthesis of r-Aryl Amino
Acids; Aryne-Mediated Diastereoselective
Arylation
Elizabeth P. Jones,† Peter Jones,‡ and Anthony G. M. Barrett*,†
Department of Chemistry, Imperial College London, London SW7 2AZ, U.K., and
Worldwide Medicinal Chemistry, Pfizer Limited, Ramsgate Road, Sandwich, Kent,
CT13 9NJ, U.K.
agm.barrett@imperial.ac.uk
Received December 16, 2010
ABSTRACT
€
An aryne-mediated R-arylation reaction of Schollkopf’s bis-lactim ether is described. Arynes were generated via an ortho-lithiation approach,
affording syn-arylated products in up to 94:6 dr with moderate to good yields and excellent regioselectivities. Hydrolysis provided a variety of
substituted arylglycines containing a range of functional groups without racemization.
The ability to synthesize unnatural aryl amino acids has
facilitated their application in multiple areas of organic
chemistry, not only as fragments in the preparation
of natural products but also in their incorporation into
glycopeptide antibiotics and as building blocks in medic-
inal chemistry.1 Replacement of a natural amino acid side
chain with a more hydrophobic aryl analogue has been
shown to have wide implications on the biological struc-
ture and activity of the corresponding molecules.2
Methods to generate chiral arylglycines have previously
involved starting materials already containing the crucial
carbon-aryl bond3 and/or late stage resolution ap-
proaches due to the high acidity of the R-aryl proton.4
An alternative strategy employing metal-catalyzed C-H
activation of protected amino acids has recently been
developed by Hartwig and Buchwald,5,6 but the asym-
metric variant has yet to be reported.
† Imperial College London.
‡ Pfizer Ltd.
(1) (a) Gao, Y. Nat. Prod. Rep. 2002, 19, 100. (b) Conway, S. J.;
Miller, J. C.; Howson, P. A.; Clark, B. P.; Jane, D. E. Bioorg. Med.
Chem. Lett. 2001, 11, 777. (c) Townsend, C. A.; Brown, A. M. J. Am.
Chem. Soc. 1983, 105, 913. (d) Harris, C. M.; Kibby, J. J.; Fehiner, J. R.;
Raabe, A. B.; Barber, T. A.; Harris, T. M. J. Am. Chem. Soc. 1979, 101,
437. (e) Hunt, A. A.; Molloy, R. M.; Occolowitz, J. L.; Marconi, G. G.;
Debono, M. J. Am. Chem. Soc. 1984, 106, 4891. (f) McGahren, W. J.;
Martin, J. H.; Morton, G. O.; Hargreaves, R. T.; Leese, R. A.; Lovell,
F. M.; Ellestad, G. A. J. Am. Chem. Soc. 1979, 101, 2237. (g) Hunt, A. A.;
Merkel, K. E.; Barnhart, M. J. Org. Chem. 1984, 49, 635.
(2) (a) Wang, L.; Schultz, P. G. Chem. Commun. 2002, 1. (b) Crisma,
M.; Valle, G.; Bonora, G. M.; Toniolo, C.; Lelj, F.; Barone, V.;
Fraternali, F.; Hardy, P. M.; Maia, H. L. S. Biopolymers 1991, 31,
637. (c) Gante, J. Angew. Chem., Int. Ed. 1994, 33, 1699.
(3) For a review on the asymmetric synthesis of arylglcines, see:
Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889 and references
within. For a recent review on asymmetric Streker reactions, see: (b) Yet,
L. Angew. Chem., Int. Ed. 2001, 40, 875.
(4) Hang, J.; Li, H.; Deng, L. Org. Lett. 2002, 19, 3321.
(5) For a review, see: Johansson, C. C. C.; Colacot, T. J. Angew.
Chem., Int. Ed. 2010, 49, 676.
(6) (a) Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001,
123, 8410. (b) Liu, X.; Hartwig, J. F. Org. Lett. 2003, 5, 1915. (c) Moradi,
W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996.
r
10.1021/ol1030469
Published on Web 02/08/2011
2011 American Chemical Society

(entry 1, Table 1). Interestingly, the major diastereoi-
somer was determined to be the syn-adduct by observa-
tion of a larger H1-H4 coupling constant (J = 6.3 Hz)
than that for the anti-adduct (J = 3.1 Hz) as reported
for similar compounds, as well as by NOE analyses
(Figure 1).13 Increasing the number of equivalents of
chloride 2a to 1.75 and base to 3.0 (entries 2 and 3) resulted
in improved yields of adduct 3a to 63%.
Table 1. R-Arylation Optimization
equiv
proton
sourceb
yielde
(%)
entry
2
base
equiv 2
drc
1
a
a
a
a
a
a
b
2.1
2.5
3.0
3.0
3.0
3.0
3.0
1
H2O
88:12
91:9
45
38
63
69
60
75
56
2
1.25
1.75
1.75
1.75
1.75
1.75
H2O
3
H2O
89:11
89:11
92:8
4
citric acid
t-BuOH
BHTd
BHT
5
6
7a
94:6
94:6
a n-BuLi was added at -78 °C for precursor 2b. b Reactions were
quenched at room temperature by water, citric acid, tert-butanol, or
BHT. c As determined by integration of 1H NMR spectra. d BHT = 2,6-
di-tert-butyl-4-methylphenol. e Isolated yield.
Figure 1. J values and nOes for syn- and anti- diastereomers.
To rationalize the stereochemical outcome, a mecha-
nism was proposed in which initial attack of lithiated 1
onto the aryne occurs as expected, on the opposite face to
the iso-propyl group. Subsequent inter- or intramolecular
proton transfer to the R-aryl position with the newly
formed carbanion 4 gave the planar species 5. Subsequent
diastereoselective protonation occurred on the less hin-
dered face to give syn-adduct 3a (Scheme 1).
We have previously demonstrated multiple component
coupling reactions of arynes in order to synthesize the
natural products clavilactoneB7 and dehydroaltenuene B.8
Arynes are extremely attractive candidates for the R-aryla-
tion reaction of ketones, esters, and other enolizable starting
materials. Their intrinsic electrophilicity should allow for
nucleophilic addition by a suitably protected glycine enolate
to provide diverse derivatives of phenylglycine. Attracted
by the simplicity of approach, we began our studies.
Since additions of enolates to arynes have been re-
ported to result in the formation of adducts derived by
the intramolecular cyclization of the resultant aryl anion
Scheme 1. Proposed Mechanism
9
€
onto the carbonyl group, we chose Scholkopf’s bis-
lactim ether 110 as the protected glycine equivalent, due
to the reduced nucleophilicity of the ring nitrogen
atoms11 and the lack of electrophilic carbonyl groups.
Deprotonation of bis-lactim 1 and aryne precursor 2a12
at low temperature using sec-butyllithium, followed by
warming to room temperature and quenching with
water, afforded adduct 3a as an inseparable (88:12)
mixture of diastereoisomers in a combined 45% yield
ꢀ
(7) Larrosa, I.; Da Silva, M. I.; Gomez, P. M.; Hannen, P.; Ko, E.;
Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barrett, A. G. M.
J. Am. Chem. Soc. 2006, 128, 14042.
(8) Soorukram, D.; Qu, T.; Barrett, A. G. M. Org. Lett. 2008, 10, 3833.
(9) (a) Liu, Y.; Liang, Y.; Pi, S.; Li, J. J. Org. Chem. 2009, 74, 5691. (b)
Huang, X.; Xue, J. J. Org. Chem. 2007, 72, 3965. (c) Tambar, U. K.;
Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340. (d) Bhawal, B. M.;
Khanapure, S. P.; Zhang, H.; Biehl, E. R. J. Org. Chem. 1991, 56, 2846.
(e) Carre, M.; Gregoire, B.; Caubere, P. J. Org. Chem. 1984, 49, 2050. (f)
Carre, M.; Jarmet-Gregoire, B.; Geoffroy, P.; Caubere, P. Tetrahedron
1988, 44, 127.
Based on this model, we examined bulkier weak acids,
with the aim of improving the dr (entries 4-6). To our
delight the use of 2,6-di-tert-butyl-4-methylphenol (BHT)14
gave an excellent dr of 94:6. Benzyne generation from
€
(10) (a) Schollkopf, U. Tetrahedron 1983, 39, 2085 and references
€
€
therein. (b) Schollkopf, U.; Gruttner, S.; Anderskewitz, R.; Egert, E.;
Dyrbusch, M. Angew. Chem. 1987, 99, 717.
(11) Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673.
(12) Kaelin, D. E., Jr.; Lopez, O. D.; Martin, S. F. J. Am. Chem. Soc.
2001, 123, 6937.
(13) Pearson, A. J.; Bruhn, P. R. J. Org. Chem. 1991, 56, 7092.
ꢀ ~
n, I.; Gonzalez, J. F.; de la Cuesta, E.; Avendano, C.
(14) Ortı
´
Tetrahedron 2009, 65, 9944.
Org. Lett., Vol. 13, No. 5, 2011
1013

Table 2. Scope of R-Arylation Reaction with Different Benzyne Precursors
a General Procedure: To a solution of 1 (1 equiv, 1 mmol) and halide 2 (1.75 equiv) in THF (0.2 M) at either -78 °C (for n-BuLi) or -95 °C (for s-
BuLi) was added a base (3.0 equiv). After stirring for 1 h, the reaction was allowed to warm to room termperature over 18 h and then BHT (4 equiv) was
added. b Isolated yield. c Determined by 1H NMR integration. d HPLC analysis of a representative number of compounds 3 determined that they
undergo negligible racemization upon hydrolysis to the corresponsing amine; this indicates that the er’s of 8 are the same as the dr’s of 3. See Supporting
Information. e Isolated as a 1:1 mixture of regioisomers. f Separable by chromatography. g After separation by chromatography.
1014
Org. Lett., Vol. 13, No. 5, 2011

fluoride 2b15 also gave 3a with a comparable diastereo-
selectivity.
rationalized by competing lithiation at the 5-position.
Changing the nature of the directing groups to ethyl,
benzyl, or MOM ethers (entries 5-7) gave adducts 3g-i,
again in good diastereoselectivities and yields except for in
the case of the sterically demanding benzyl precursor 2h. It
is worth noting that, under these mild hydrolysis condi-
tions, no deprotection of the MOM ether in adduct 3i was
observed. Altering the position of the para-methoxy
groups in 2a to the ortho-2j and meta-2k dimethoxy
percursors17 provided adducts 3j and 3k in good yields
(entries 8-9), again with complete arene regioselectivity.18
The diastereoselectivity for formation of these adducts was
dramatically reduced to around 75:25. 3-Chloroanisole 2l
reacted without a problem to give adduct 3l (entry 10).
The nature of this single directing group was varied from
an ether to oxazoline precursor19 2m and 1-chloro-
2-(trifluoromethyl)benzene20 2n, affording their respective
adducts 3m and 3n in respectable yields (entries 11 and 12).
Although there was no diastereoselectivity in the forma-
tion of adduct 2n, the two diastereoisomers were easily
separable, and hence the methyl ester 8n was obtained in
high enantiopurity. A fluorine on the anisole ring was also
tolerated, giving adduct 3o (entry 13). It is clear that, for all
aryne precursors without a chelating substituent in the
To support the mechanistic hypothesis, a deuterium
labeling experiment was undertaken. Quenching the reac-
tion with D2O as opposed to water gave deuterium in-
corporation only in the C1 position to give 6, indicating
that that the second deprotonation had occurred as ex-
pected (Scheme 2).
Scheme 2. Deuterium Labelling Experiment
Hydrolysis of adduct 3a under mild acidic conditions10
provided the desired amine 7in 89% yield (Scheme 3). Chiral
HPLC analysis confirmed that negligible prior epimeriza-
tion of adduct 3a occurred under the reaction conditions.16
€
ortho-position to the Schollkopf glycine (entries 8-13), the
diastereoselectivity of the reaction noticeably decreased. It
is possible that without this substituent, there is twisting of
the linked6-memberedringsout of plane, hencedecreasing
facial selectivity.
Scheme 3. Hydrolysis of 3a
Hydrolysis and N-Boc protection were high yielding in
all cases, except for oxazoline 3m, which is most likely due
to the acid-sensitive nature of this directing group.
In conclusion, a general approach has been developed
for the synthesis of enantiomerically enriched R-arylgly-
cines, using arynes as electrophilic arylation reagents.
Further extension of this research, involving the formation
of quaternary arylglycine derivatives, is in progress and
will be reported in due course.
The scope of the reaction was investigated to ascertain
which substitution patterns and functionality were toler-
ated on the aryl unit. Benzyne precursors 2 containing
ortho-directing groups (ODG) and either a chloride or
fluoride leaving group were employed (Table 2). Following
hydrolysis, the amines were protected immediately as the
corresponding tert-butyl carbamates 8 for ease of han-
dling. Dimethylamino, methoxy, and fluoride analogues
gave adducts 3c-d (entries 2-4) with excellent diastereo-
selectivity and as single regioisomers except for 2e which
exhibited no regioselectivy and gave fluoride adduct 3e as a
1:1 mixture of arene regioisomers. Fortunately upon hy-
drolysis and N-Boc protection, the two isomeric carba-
mates 8e and 8f were separable. The low yield for 3c can be
Acknowledgment. We thank P. R. Haycock and R. N.
Sheppard (Imperial College London) for high-resolution
NMR spectroscopy and the EPSRC and Pfizer for provid-
ing funding through the collaborative EPSRC-Pharma
Synthesis Programme (to E.P.J.) and GlaxoSmithKline
for providing the Glaxo endowment (to A.G.M.B.)
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Biehl, E. R.; Nieh, E.; Hsu, K. C. J. Org. Chem. 1969, 34, 3595.
(18) Gschwend, H. W.; Rodriguez, H. R. Org. React. (N.Y.) 1979,
26, 1.
(19) Meyers, A. I.; Pansegrau, P. D. J. Chem. Soc., Chem. Commun.
1985, 11, 690.
(20) Bailly, F.; Cottet, F.; Schlosser, M. Synthesis 2005, 791.
(15) Shoji, Y.; Hari, Y.; Aoyama, T. Tetrahedron Lett. 2004, 45, 1769.
(16) See Supporting Information.
Org. Lett., Vol. 13, No. 5, 2011
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