Photochemical alkylation of glycine leading to phenylalanines

Article abstract of DOI:10.1016/S0040-4039(00)01175-8

UV photolysis of protected glycines in the presence of di-tert-butyl peroxide, benzophenone and substituted toluenes is shown to lead to selective alkylation at the α-position. Phenylalanines are isolated in yields of generally > 50% (based on recovered s

Full text of DOI:10.1016/S0040-4039(00)01175-8

Tetrahedron Letters 41# (2000) 7121±7124
Photochemical alkylation of glycine leading to phenylalanines
Haydn S. Knowles,a Keith Huntb and Andrew F. Parsonsa,*
aDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
bA. H. Marks and Co. Ltd, Wyke, Bradford, West Yorkshire BD12 9EJ, UK
Received 5 June 2000; accepted 12 July 2000
Abstract
UV photolysis of protected glycines in the presence of di-tert-butyl peroxide, benzophenone and
substituted toluenes is shown to lead to selective alkylation at the a-position. Phenylalanines are isolated in
yields of generally >50% (based on recovered starting material). # 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: radicals and radical reactions; amino acids and derivatives; photochemistry; alkylation.
The considerable diversity and biological importance of a-amino acids has attracted the
attention of organic chemists for many years.1 Of particular interest are phenylalanine derivatives
because of the medicinal importance of compounds such as dopa, melphalan and levothyroxin,
which are used in the treatment of Parkinson's disease, cancer and myxoedema, respectively.
These types of compounds are generally prepared using ionic reactions.1 In comparison, the
preparation of a-amino acids using radical carbon±carbon bond-forming reactions has received
considerably less attention.2 This is surprising bearing in mind the mild (neutral) reaction
conditions employed and the compatibility of radicals with a wide range of common functional
groups (including amides and esters).
The formation of glycine derivatives by an intermolecular radical coupling reaction was ®rst
reported by Elad and co-workers (Scheme 1).3 They showed that UV irradiation of N-acetyl-
glycine ethyl ester 1 in the presence of acetone and (excess) toluene led to the selective formation
Scheme 1.
* Corresponding author. Tel: +44-1904-432608; fax: +44-1904-432516; e-mail: afp2@york.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01175-8

7122
of phenylalanine 4, although the yield was only 3±5%. The proposed mechanism for this reaction
involved coupling of captodative radical 2 with a benzyl radical 3, these radicals being derived
from abstraction of a hydrogen atom from 1 and toluene, respectively, by an excited acetone
molecule. This method was extended to alkylation of glycine residues within peptides and
proteins, and this could be accomplished using visible light, when an a-diketone and di-tert-butyl
peroxide were used in place of acetone.4
More recently, these radical coupling reactions have been carried out in the absence of an
alkylating agent, to form amino acid dimers.5 Easton and co-workers6 have reported the formation
of butanedioate 6 in 37% yield on UV irradiation of a mixture of glycine 5 and di-tert-butyl
peroxide (Scheme 2). In this reaction it is tert-butoxyl radical, or methyl radical (produced on
t
.
b-scission of BuO ), that abstracts the a-hydrogen atom from 5. Although the use of di-tert-butyl
peroxide, in place of acetone, leads to more ecient hydrogen-atom abstraction, as methyl radicals
are produced, a competitive coupling to form alanine 7 (in 34% yield) was also observed. With a
view to developing an ecient photochemical approach to phenylalanines, this paper reports the
alkylation of various glycine derivatives using di-tert-butyl peroxide (as the initiator) in the
presence of substituted toluenes for the ®rst time.
Scheme 2.
Initial investigations centred on UV irradiation of 8a in the presence of toluene and di-tert-
butyl peroxide (Table 1). The mixture was irradiated using a 125 W lamp in degassed benzene and
a variety of reactions were carried out using di€erent concentrations of the reagents. In all cases,
1,2-diphenylethane (derived from dimerisation of 3) and small amounts of butanedioate 9a and
alanine 10a were isolated, but the major product was the desired phenylalanine 11a. The reaction
was most selective for 11a when a 1:2:5 ratio of 8a:peroxide:toluene was used; under these
conditions 11a was formed in 27% yield, or 59% yield based on recovered 8a (entry 1).7 Similar
results were obtained using N-Boc and N-Cbz protected glycines 8b and 8c, to form 11b and 11c,
respectively (entries 2 and 3). The selective alkylation of 8c is of particular note because (competitive)
hydrogen-atom abstraction at the benzylic position of the Cbz-protecting group is also possible
although no products derived from this reaction were isolated.8 With a view to decreasing the
reaction time, the alkylation of 8a was also carried out using a 400 W UV lamp (entry 4) and
although the total yield of products increased (from 70 to 91%), an additional product, namely
a-tert-butoxy-glycine 12, was isolated in 13% yield. The formation of 12 presumably re¯ects a
t
.
higher concentration of the BuO radical (which couples with the captodative radical) when using
the more powerful lamp, but the yield of 12 could be minimised by increasing the concentration
of 8a (entry 5). Further experiments investigated the addition of photosensitisers and when
benzophenone9 was used in combination with 10 equivalents of toluene an optimum yield of 37%
(or 57% based on recovered 8a) was isolated for 11a (entries 6 and 7). The use of benzophenone
also produced minor amounts of the serine derivative 13, derived from coupling of the captodative
.
radical with Ph2(HO)C . Indeed, when the same photolysis was carried out in the absence of
toluene, 13 was isolated in 23% yield (or 50% based on recovered 8a).10

7123
Table 1
Photoalkylation of glycines 8a±c leading to phenylalanines 11a±c
The reaction of toluene with alternative glycine derivatives, namely 14 and 16, was also
explored using the optimum alkylation conditions developed for the formation of 11a. Hence,
reaction of 14 resulted in the formation of 15 in 28% yield (or 62% yield based on recovered 14)
as a 1:1 mixture of diastereomers, while reaction of diketopiperazine 16 gave 17 in 29% yield. The
reaction of 16 also produced a small amount of dialkylation (8%) to give 18 as a 1:1 mixture of
diastereomers.
Having established the alkylation of glycine derivatives using toluene, a variety of substituted
toluenes were then reacted with 8a under the same conditions. This allowed the formation of
phenylalanines 19±25 in 12±36% isolated yield or 35±87% yield based on recovered 8a.
Although a variety of substituents could be introduced on the benzene ring, the reaction
proved to be very sensitive to variation of the (toluene) methyl group. When substituents were
introduced at this site the yields of alkylation decreased and, for example, reaction of 8a with

7124
diphenylmethane or ¯uorene, produced 26 or 27 in 10 and 8% yield, respectively. This could be a
t
.
consequence of BuO preferentially reacting with the weaker (benzylic) C±H bonds in diphenyl-
methane and ¯uorene (compared to toluene) resulting in a low concentration of the captodative
radical (derived from 8a).
In all reactions, no products derived from dialkylation of glycine 8a were observed. Indeed,
attempts to alkylate alanine 10a or phenylalanine 11a by photolysis with toluene/peroxide resul-
ted in typically ꢀ1% yield of dialkylated product 28. Similarly, the presence of a second ester
served to hinder the alkylation of malonate 29 and photolysis in the presence of di-tert-butyl
peroxide (2 equiv.) and toluene (5 equiv.) produced 30 in 13% yield (or 58% yield based on
recovered 29). The reaction also produced a small amount (3%) of phenylalanine 11a,
presumably derived from photo-decarboxylation of 30.
This work has demonstrated that a variety of glycine derivatives can be alkylated to form
phenylalanines, on photolysis in the presence of substituted toluenes. Whereas related anionic
alkylations are often complicated by polyalkylation, this mild free radical method of alkylation
allows the selective formation of monoalkylated products.
Acknowledgements
We thank A. H. Marks and Co. Ltd and the EPSRC for funding (research grant, GR/L58538).
References
1. Tetrahedron Symposia-in-Print No. 33; Ed. O'Donnell, M. J. 1988, 44, 5253±5614.
2. (a) Easton, C. J. Chem. Rev. 1997, 97, 53±82. (b) Easton, C. J.; Hutton, C. A. Synlett 1998, 457±466.
3. (a) Elad, D.; Sperling, J. J. Chem. Soc. (C) 1969, 1579±1585. (b) Sperling, J.; Elad, D. J. Am. Chem. Soc. 1971, 93,
967±971.
4. Schwarzberg, M.; Sperling, J.; Elad, D. J. Am. Chem. Soc. 1973, 95, 6418±6426.
5. (a) Obata, N.; Niimura, K. J. Chem. Soc., Chem. Commun. 1977, 238±239. (b) Viehe, H. G.; Merenyi, R.; Stella,
L.; Janousek, Z. Angew. Chem., Int. Ed. Engl. 1979, 18, 917±932. (c) Benson, O.; Demirdji, S. H.; Haltiwanger,
R. C.; Koch, T. H. J. Am. Chem. Soc. 1991, 113, 8879±8886.
6. Burgess, V. A.; Easton, C. J.; Hay, M. P.; Steel, P. J. Aust. J. Chem. 1988, 41, 701±710.
7. All new compounds exhibited satisfactory spectral and analytical (high resolution mass) data.
8. There was no evidence for benzylic radical formation on photolysis of related amines, e.g. PhNHCbz or
tBuNHCbz (under similar conditions).
9. Alternative photosensitisers, such as 4,40-dimethoxybenzophenone, were less e€ective.
10. Photolysis of N-acetylglycine methyl ester with benzophenone or 4,40-dimethoxybenzophenone gave the tertiary
alcohol in much lower yield (i.e. 7.7 and 6.4% yield, respectively). Deseke, E.; Nakatani, Y.; Ourisson, G. Eur. J.
Org. Chem. 1998, 243±251.