Efficient method for selective introduction of substituents as C(5) of isoleucine and other α-amino acids

Article abstract of DOI:10.1021/ol060952v

A useful process for the position-selective remote bromination of N-trifluoroacetyl-α-amino esters is illustrated for the isoleucine case. The 5-bromoisoleucine derivative shown above can be used for the synthesis of many modified amino acids, as described herein.

Full text of DOI:10.1021/ol060952v

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2819-2821
Efficient Method for Selective
Introduction of Substituents as C(5) of
Isoleucine and Other
Leleti Rajender Reddy, B. V. Subba Reddy, and E. J. Corey*
r-Amino Acids
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford
Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received April 20, 2006
ABSTRACT
A useful process for the position-selective remote bromination of N-trifluoroacetyl-r-amino esters is illustrated for the isoleucine case. The
5-bromoisoleucine derivative shown above can be used for the synthesis of many modified amino acids, as described herein.
This paper describes an efficient methodology for the
synthesis of useful chiral substances from the readily
available R-amino acids isoleucine, norleucine, and leucine.
Although isoleucine is unique among the 20 genetically
coded amino acids in having both a branched carbon chain
and two stereocenters, it has not been used as a platform for
generating more complex R-amino acids by the selective
introduction of new substituents. We envisaged that such
R-amino acids with enhanced molecular complexity could
be of value in a variety of research applications, including
the discovery of new bioactive substances.
Freytag type2,3 occurred rapidly (1 h) to give the 5-bromo
derivative 3 in 90% isolated yield. The structure of 3
followed unambiguously from 1H NMR, 13C NMR, infrared,
and mass spectral data. No products isomeric with 3 could
be detected by careful chromatographic and spectral analysis.
The high yield and positional selectivity of the conversion
of 1 f 3 stand in contrast to an early study in which the
reaction of various R-amino acids in 90% sulfuric acid with
chlorine was found to yield mixtures of â- and γ-chlorinated
products.4 We believe that the electron-withdrawing ability
The approach that we have taken is based on the use of
the R-amino function to effect hydrogen atom abstraction
selectively from C(5) of isoleucine to allow subsequent
attachment of a reactive group. Specifically, N-trifluoro-
acetylisoleucine methyl ester (1) was converted to the
N-bromo derivative 2 (>97%) using acetyl hypobromite1 in
CCl4 at 23 °C for 1 h (flask protected from light). When
of the CF3CO group renders the intermediate amide radical
4 especially reactive in H atom abstraction to form δ-carbon
(1) Duhamel, L.; Ple´, G.; Angibaud, P.; Desmurs, J. R. Synth. Commun.
1993, 23, 2423-2433.
(2) (a) Corey, E. J.; Hertler, W. R. J. Am. Chem. Soc. 1960, 82, 1657-
1668. (b) Hofmann, A. W. Chem. Ber. 1883, 16, 558-560 and 586-591.
(c) Lo¨ffler, K.; Freytag, C. Chem. Ber. 1909, 42, 3421-3426 and 3427-
3434. (d) Coleman, G. H.; Goheen, G. E. J. Am. Chem. Soc. 1938, 60,
730-730. (e) Coleman, G. H.; Nichols, G.; Martens, T. F. Organic
Syntheses; John Wiley: New York, 1955; Coll. Vol. 3, pp 159-162.
(3) For reviews, see: (a) Cekovic, Z. J. Serb. Chem. Soc. 2005, 70, 287-
318. (b) Neale, R. S. Synthesis 1971, 1-15. (c) Minisci, F. Synthesis 1973,
1-24. (d) Wolff, M. E. Chem. ReV. 1963, 63, 55-64.
this solution was exposed to light from a sunlamp at 23 °C,
a free radical chain reaction of the Hofmann-Lo¨ffler-
10.1021/ol060952v CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/26/2006

radical 5 (see above) which propagates the chain reaction
by intermolecular Br abstraction from 2 to form 3. The
positional selectivity derives from the exceptional favorable
stereoelectronics of the transition state for 1,5-H migration.2a,5,6
N-Trifluoroacetyl-5-bromoisoleucine methyl ester (3) is an
excellent starting material for the synthesis of a wide variety
of R-amino acid derivatives. For instance, treatment of 3 with
3 equiv of diisopropylethylamine in THF at 23 °C for 8 h
results in the formation of N-trifluoroacetyl (S,S)-3-methyl-
proline methyl ester 6 in 90% yield whereas sequential
treatment of 3 with CS2 and NaOMe in THF at 23 °C for 6
h and K2CO3 in MeOH at 0 °C for 12 h produces N-trifluoro-
5-mercaptoisoleucine methyl ester 7, an interesting homo-
logue of cysteine, in 90% overall yield. In addition, 3 could
Scheme 2. Synthesis of
5-Alkylated-N-trifluoroacetylisoleucine Methyl Esters
be converted efficiently into N-trifluoroacetyl-5-hydroxy-
isoleucine methyl ester 8 and then into N-trifluoroacetyl-
(S,S)-3-methyl glutamic acid methyl ester 9, as shown in
Scheme 1. Also shown in Scheme 1 is the transformation of
Very good yields of C-C coupling products were obtained
from the reaction of the 5-iodoisoleucine derivative 10 with
Me-, n-Bu-, and t-Bu-cuprate reagents. These carbon-
extended higher homologues of isoleucine have considerable
potential as probes for research in chemical biology.7
We have converted N-trifluoroacetylnorleucine methyl
ester (14) to the 5-bromo and 5-iodo derivatives (15 and 16)
in a manner completely analogous to that for the synthesis
of 3 from 1, as shown in Scheme 3. Using the iodo derivative
Scheme 1. Synthesis of 5-Functionalized Isoleucine
Derivatives
Scheme 3. Transformations of N-Trifluoroacetyl Norleucine
Methyl Ester
3 into N-trifluoroacetyl-5-aminoisoleucine methyl ester via
the iodide 10 in 81% overall yield.
The transformations shown in Scheme 2 illustrate the
application of iodide 10 to the synthesis of higher homo-
logues of isoleucine in which the carbon chain has been
extended from the C(5) position as the point of attachment.
(4) Kollonitsch, J.; Rosegay, A.; Doldouras, G. J. Am. Chem. Soc. 1964,
86, 1857-1858.
(5) Corey, E. J.; Hertler, W. R. J. Am. Chem. Soc. 1958, 80, 2903-
2904.
(6) The N‚‚‚H‚‚‚C angle for the six-membered transition state corre-
sponding to 4 f 5 of approximately 115° is intermediate between the
optimum for anionic N-‚‚‚H-C proton abstraction (ca. 180°) and nitrenium
N+‚‚‚H-C hydride abstraction (ca. 90°), in accord with expectations based
on orbital interactions.
16, we prepared the corresponding alcohol 17 by hydrolysis,
and the n-butyl (18) and tert-butyl (19) homologues were
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Org. Lett., Vol. 8, No. 13, 2006

synthesized by coupling with the appropriate dialkyl cuprate
reagents as outlined in Scheme 3.
lamine (27) in 91% isolated yield.
91%
When N-trifluoroacetylleucine methyl ester (22) was
N-brominated and exposed to light at 23 °C for 1 h, it was
transformed into a diastereomeric mixture of 5-bromo
derivatives 23 (diastereomeric ratio, 1.5:1). In contrast to this
intramolecular pathway, the reaction of 22 with N-bromo-
succinimide gave no 23 but instead a mixture of the 4-bromo
derivative 24 (80% yield) and the R,â-unsaturated ester
25 (10% yield), possibly formed via an initial bromina-
tion at C(2) (Scheme 4). Finally, the prototype reaction of
CF3CONH(CH2)3CH3
CF CONH(CH ) CH Br
8
3 2 3 2
26
27
We have also examined other modifications of the in-
tramolecular N-halogenation reaction described in this article.
First, with regard to the acyl group on nitrogen, as we had
anticipated, N-trifluoroacetyl is the most useful.8 For instance,
N-t-butoxycarbonyl (Boc) derivatives undergo slower and
less efficient N-bromination and intramolecular C-bromina-
tion reactions, resulting in significantly lower conversions
and yields of product. Thus, our experience leads us to the
view that N-trifluoroacetyl derivatives are optimum, in accord
with theoretical expectations.8
Scheme 4. Intermolecular and Intramolecular Bromination of
N-Trifluoroacetylleucine Methyl Ester
It has also been found that the use of N-chloroamides in
these intramolecular halogenations is problematic because
of the resistance of these compounds9 to photoinduced radical
chain reactions.
The position-selective intramolecular bromination process
described herein provides efficient and convenient synthetic
access to many interesting nonnatural R-amino acids. We
believe that this chemistry can be applied not only to the
synthesis of new bioactive compounds but also for bioorganic
research. For instance, the 5-bromoisoleucine derivative 3
provides a greatly shortened route to N-methyl (2S,3S)-5-
hydroxyisoleucine derivatives and simplifies the synthesis
of halipeptins A and B.10
Supporting Information Available: Experimental pro-
cedures and characterization data for the new compounds
described herein. This material is available free of charge
via the Internet at http://pubs.acs.org.
26 f 27 was studied. As expected, conversion of 26 to
the N-bromo derivative and the light-initiated radical
chain reaction produced N-trifluoroacetyl-4-bromo-buty-
(7) See, for example: Hartman, M. C. T.; Josephson, K.; Szostak, J. W.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 4356-4361.
OL060952V
(8) Recent theoretical analyses of C-H abstraction reactions by free
radicals indicate that the barrier heights for these processes are lowered in
proportion to the electron deficiency (or electron affinity) of the abstracting
radical. See: Donahue, N. M.; Clarke, J. S.; Anderson, J. G. J. Phys. Chem.
A 1998, 102, 3923-3933. As far as we are aware, this paper describes the
first synthetic application and support of this theoretical proposal.
(9) N-Chloroamides can be readily prepared by the trichloroisocyanuric
method. See: De Luca, L.; Giacomelli, G.; Nieddu, G. Synlett 2005, 223-
226.
(10) See: Hara, S.; Makino, K.; Hamada, Y. Tetrahedron 2004, 60,
8031-8035.
Org. Lett., Vol. 8, No. 13, 2006
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