Rate constants for 1,n-hydrogen transfer reactions in some amino acid derived radicals

Article abstract of DOI:10.1016/j.tetlet.2006.09.010

Absolute rate constants for 1,n-hydrogen atom transfers in some substituted amino acid derived radicals have been determined in benzene through the use of competitive kinetic experiments. Radicals derived from methyl N-(2-iodobenzoyl)-N-(tert-butyloxycarbonyl)glycinate, -alaninate, -leucinate, -tert-leucinate and -phenylglycinate undergo intramolecular 1,5-hydrogen atom transfer to afford the corresponding α-amino acid ester radicals with rate constants in the range: 1.0-4.3 × 10⁷ s^-1 at 80 °C. Where abstractable hydrogen atoms exist in the amino acid side-chain, 1,6- and 1,7-translocations are competitive processes.

Full text of DOI:10.1016/j.tetlet.2006.09.010

Tetrahedron Letters 47 (2006) 7911–7914
Rate constants for 1,n-hydrogen transfer reactions
in some amino acid derived radicals
Le Zeng,a Talbi Kaoudia and Carl H. Schiessera,b,
*
aSchool of Chemistry, The University of Melbourne, Vic. 3010, Australia
bBio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Vic. 3010, Australia
Received 4 August 2006; revised 23 August 2006; accepted 1 September 2006
Available online 25 September 2006
Abstract—Absolute rate constants for 1,n-hydrogen atom transfers in some substituted amino acid derived radicals have been deter-
mined in benzene through the use of competitive kinetic experiments. Radicals derived from methyl N-(2-iodobenzoyl)-N-(tert-
butyloxycarbonyl)glycinate, -alaninate, -leucinate, -tert-leucinate and -phenylglycinate undergo intramolecular 1,5-hydrogen atom
transfer to afford the corresponding a-amino acid ester radicals with rate constants in the range: 1.0–4.3 · 107 sꢀ1 at 80 ꢀC. Where
abstractable hydrogen atoms exist in the amino acid side-chain, 1,6- and 1,7-translocations are competitive processes.
ꢁ 2006 Elsevier Ltd. All rights reserved.
There are arguably 21 essential amino acids of relevance
to man.1 In their natural ‘L’ form, these molecules are
mostly (S)-configured at the stereogenic centre, with cys-
teine and selenocysteine being obvious exceptions, but
only because of a change in substituent priorities.
Unnatural ‘D’ amino acids, while rare in nature, play a
significant role as key intermediates in the synthesis of
many pharmaceutical products.2 High-value drugs such
as: Cialis 1 (sexual dysfunction),3 Zoloft 2 (depression),4
Ceclor 3 (antibiotic)5 and Lumota 4 (prostate cancer),6
just to name a few, are prepared using one or more D-
configured amino acids as building blocks. It is interest-
ing to note that annual sales of Zoloft 2 exceeded US
$370 million in 1996.7
been important in the past,8 there are also many exam-
ples that utilize chiral templates, chiral auxiliaries and
catalytic hydrogenation methods for the preparation
of these important compounds.8 Recent literature sug-
gests that most efforts are currently directed toward
enzymatic methods for direct enantiomeric synthesis or
for the resolution of racemates.9
Recently, we reported the preparation of chiral, non-
racemic stannanes for use in enantioselective free-radical
reduction chemistry10–12 and demonstrated that in con-
junction with Lewis acids, these stannanes are capable
of providing single enantiomer outcomes for a variety
of transformations of synthetic and commercial
significance.13,14
The development of methods for the preparation of
unnatural amino acids is an important objective and
there are numerous research groups around the world
working in this area. While separation techniques have
Given these outcomes, it seemed reasonable to apply
this chemistry to the preparation of enantiomerically-
pure unnatural amino acids. While we reported some
Cl
O
CO2H
H
N
Cl
O
N
Cl
N
H
CO2H
O
N
O
N
N
H
H2N
S
O
N
H
O
H
N
S
Ph
N
N
H
3
H
4
O
Ph
OH
O
2
1
NHMe
O
*
Corresponding author. Tel.: +61 3 8344 2432; fax: +61 3 9347 8189; e-mail: carlhs@unimelb.edu.au
0040-4039/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.010

7912
L. Zeng et al. / Tetrahedron Letters 47 (2006) 7911–7914
EtO2C
R
O
Cl
H3C
CH2Cl
H3C
CH3
H3C
CH3
SO2Cl2
N
+
CF3SO2NH
CO2Me
CF3SO2NH
CO2Me
CF3SO2NH
CO2Me
O
H
H
H
6
5
Scheme 1.
initial success utilizing a-bromoamino acids,14 this
chemistry suffered from serious drawbacks that included
the instability of the radical precursors, as well as diffi-
culties in their synthesis. Indeed, Easton reported that
some substituted amino acids (e.g., 5) undergo preferen-
tial free-radical halogenation in the alkyl side-chain
rather than at the a-position (Scheme 1).15 This has been
attributed to both steric repulsion between the amide
carbonyl and the side-chain in structures such as Naph-
thaloyl substituted (and other) amides 6, themselves
mimics of peptide residues, as well as the lower p-donat-
ing ability of amides and triflamides.15,16
O
O
X
O
R
Cl
OMe
R
OMe
NH
NH2
Et3N
48 - 80%
O
X
Boc2O
NaH
O
9a: R = H
b: R = Me
c: R = iBu
d: R = tBu
e: R = Ph
R
OMe
OtBu
N
O
O
X
1,5-Hydrogen transfer chemistry has been used on a
number of occasions to translocate a radical centre to
a desired, but inaccessible location, so that further
chemistry can be carried out. When used to generate
a-amidyl radicals, Curran and Snieckus demonstrated
the importance of influencing amide rotamer popula-
tions through the judicious choice a of nitrogen substit-
utent,17 since 1,5-hydrogen transfers are faster than the
rotation about the amide C–N bonds.18
50 - 83%
Scheme 3.
with 2-iodobenzoyl chloride (X = I) in the presence of
triethylamine to afford the N-(2-iodobenzoyl)amino acid
methyl esters in moderate yield. These amides were fur-
ther reacted with sodium hydride and bis(tert-butyloxy-
carbonyl) anhydride (Boc2O) to afford the precursors (9,
X = I). An analogous procedure, utilizing benzoyl chlo-
ride, was used to prepare the ‘reduced’ compounds (9,
X = H) as NMR standards.
With this in mind, together with an understanding that a
knowledge of rate constant data is crucial to the design
of free-radical reactions of synthetic significance, we set
about determining kinetic data for 1,5-hydrogen trans-
fer from the a-carbon in substituted Boc-protected ami-
no acid radicals 7 to afford the a-centred radicals 8. We
reasoned that the bulky protecting group would ensure
that the correct rotamer of 7 was available for reaction,
and that, unlike the intermolecular radical chemistry
described by Easton,15 entropy would work in our
favour (Scheme 2). During this work we discovered that
while radicals 8 were able to be generated for these
amino acids, competition with 1,6- and 1,7-abstractions
by the radical centre in 7 are significant competing
processes.
With iodides (9, X = I) in hand, we next turned our
attention to the determination of translocation rate
data. Absolute rate constants for the 1,5-hydrogen
transfer reactions in benzene were determined under
pseudo first-order conditions (5 equiv Bu3SnD) through
the use of competition kinetics as depicted in Scheme 4.
Initial experiments were conducted using the leucine
derivative. When 9c (X = I) was reacted with Bu3SnD
(0.1 M) as described above, 2H NMR spectroscopy
revealed three main signals. Two of these corresponded
to the directly reduced product (9c, X = D) and the
translocated product (10c) at 7.6 and 5.2 ppm, respec-
tively.19 The third peak (1.5 ppm) corresponded to the
product 11 of 1,7-hydrogen transfer, while the fourth
peak (0.9 ppm) was consistent with small amounts of
the product arising from 1,6-H transfer and too small
for a value of k1,6 to be determined in this system.
Aryl iodides 9 were prepared as precursors for 7 using
standard synthetic methodology (Scheme 3). Accord-
ingly, the required amino acid (glycine, alanine, leucine,
tert-leucine, phenylglycine) methyl ester was treated
Given a best estimate for kD of 6.7 · 108 Mꢀ1 sꢀ1 at
80 ꢀC,20,21 integration of these signals and application
of the appropriate integrated rate equation (Eq. 1) pro-
vided an estimate for the rate constant for 1,5-hydrogen
MeO2C
MeO2C
R
H
1,5-H
N
N
O
O
R
O
O
O
O
transfer and formation of the a-leucinyl radical 8c (k1,5
)
of 3.1 · 107 sꢀ1 at 80 ꢀC, while applying analogous prin-
ciples, k1,7 in this system is estimated to be 1.9 · 107 sꢀ1
at 80 ꢀC.
7
8
Scheme 2.

L. Zeng et al. / Tetrahedron Letters 47 (2006) 7911–7914
7913
O
O
O
O
D
R
R
O
OMe
OtBu
OMe
OtBu
Bu3Sn
k1,5
Bu3SnD
N
N
7
8
I
O
kD
Bu3SnD
O
9 (X = I)
10
R
O
OMe
OtBu
d[10]
d[9 (X = D)]
k1,5
O
D
rate equation:
=
N
kD[Bu3SnD]
OMe
OtBu
O
D
N
9 (X = D)
O
O
D
O
O
O
O
D
O
11
OMe
OtBu
OMe
OtBu
N
N
O
12
13
Scheme 4.
with the bulkiest group (tBu) providing the largest rate
constant for 1,5-transfer. We suggest that this observa-
tion is the result of release of steric compression during
the formation of radicals 8. We also expect that entropy
plays an important role in these translocation reactions
and therefore factors such as the number of available
abstracting hydrogen atoms at each site will be impor-
tant. This suggestion is consistent with the observation;
1,6-abstraction in the alanine-derived radical 7b is faster
than the analogous process in the leucine system 7c,
while the same trend is observed for 1,7-abstractions
involving tert-leucine and leucine.
½10cꢁ=½9cðX ¼ DÞꢁ ¼ k1;5=ðkD½Bu3SnDꢁÞ
ð1Þ
Of interest is the observation that when hydrogen atoms
in the side-chain are available for abstraction, 1,n-
hydrogen transfer becomes competitive with formation
of the a-carbon centred radical 8. While this is not
surprising based on the observations of Easton,15 this
finding is somewhat disappointing given our initial
objectives.
When the remaining systems of interest were examined
in the manner described above, apart from glycine 9a
and phenylglycine 9e, signals in addition to those for 9
(X = D) and 10 were observed in the relevant 2H
NMR spectra. These proved to correspond to 12, the
product from 1,6-hydrogen transfer in the case of ala-
nine (9b), as well as 13, the product from 1,7-hydrogen
transfer in the tert-leucine system (9d), respectively.19
Acknowledgements
We thank the Australian Research Council through the
Centres of Excellence program for financial support.
The data in Table 1 indicate that the rate constant for
1,5-H transfer is dramatically increased in the case of
phenylglycine 7e, consistent with the increased ability
of the phenyl substituent to stabilize the forming a-cen-
tred radical 8e. What is not immediately clear is the
ordering amongst alkyl-substituted systems (7b–7d),
References and notes
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Table 1. Rate constant dataa for 1,n-hydrogen atom transfers in amino
acid radicals 7 in benzene at 80 ꢀC
Entry Radical k1,5 (·107 sꢀ1
)
k1,6 (·107 sꢀ1
)
k1,7 (·107 sꢀ1
)
1
2
3
4
5
7a
7b
7c
7d
7e
1.0
1.9
2.2
3.1
4.9
—
1.5
Traceb
—
—
—
0.9
1.9
—
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a Average of three experiments.
b Trace amount of product observed—see text.

7914
L. Zeng et al. / Tetrahedron Letters 47 (2006) 7911–7914
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