Conjugate addition of radicals generated from diacyloxyiodobenzenes to dehydroamino acid derivatives; a synthesis of diaminopimelic acid analogues

Article abstract of DOI:10.1039/b109343f

Radical decomposition of bis((2S)-N-benzyloxycarbonyl-2-aminopentan-5-carboxy-1-methyl ester)iodobenzene followed by decarboxylation and subsequent conjugate addition with a series of selectively protected dehydroamino acids leads to new analogues of diam

Full text of DOI:10.1039/b109343f

Conjugate addition of radicals generated from diacyloxyiodobenzenes to
dehydroamino acid derivatives; a synthesis of diaminopimelic acid
analogues
Andrew Sutherlandab and John C. Vederas*a
a Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
E-mail: john.vederas@ualberta.ca
b School of Chemistry, Cantock’s Close, University of Bristol, Bristol, UK BS8 1TS
Received (in Cambridge, UK) 19th October 2001, Accepted 3rd December 2001
First published as an Advance Article on the web 24th January 2002
Radical decomposition of bis((2S)-N-benzyloxycarbonyl-
2-aminopentan-5-carboxy-1-methyl ester)iodobenzene fol-
lowed by decarboxylation and subsequent conjugate addi-
tion with a series of selectively protected dehydroamino
acids leads to new analogues of diaminopimelic acid.
yiodobenzene by distillation under reduced pressure of the
relatively volatile acetic acid formed during the reaction.
Two achiral dehydroamino acid substrates, 5 and 6 were then
prepared by base elimination of an analogous mesylate derived
from a suitably protected serine analogue (Table 1).10 For the
stereoselective synthesis of the DAP skeleton, it seemed
plausible that a dehydroamino acid analogue containing one or
more stereogenic centres would, after conjugate attack, exert
facial control over hydrogen atom transfer from the hydrogen
donor.6,7 Therefore, dehydroamino acid analogues, 7 and 8
were generated from a Williams oxazinone and a Seebach
oxazolidinone, respectively, using reported procedures.7,11
Finally, dehydroamino acid analogue, 9 (entry 3) was made by
alkylation of (2R)-1-benzoyl-2-(1,1-dimethylethyl)-3-methyl-
4-imidazolidinone with chloromethyl benzyl ether followed by
elimination of benzyl alcohol with LDA (61% for the two
steps).
Inhibition of the biosynthesis of the cell wall layer in bacteria
has become a major strategy in the development of new
antibiotics.1 In particular the inhibition of the biosynthetic
pathway leading to meso-diaminopimelic acid (DAP) 1, a key
constituent of the peptidoglycan cell wall layer in Gram
negative bacteria has attracted much attention.2 Several studies
have shown that inhibitors of the DAP pathway possess
antibiotic activity and this has led to many syntheses of 1 and its
analogues.2–4 Although elegant approaches to 1 have been
reported, the major synthetic problem generally consists of
facile stereocontrolled assembly of derivatives with orthogonal
protection on the two amino and the carboxy functions. This
permits manipulation of each of the four functionalities for
preparation of DAP containing peptides which have been shown
to exhibit diverse biological activities.2,4,5 We now report an
investigation into the synthesis of selectively protected DAP
derivatives using the conjugate addition of protected amino acid
radicals generated from diacyloxyiodobenzenes with a series of
dehydroamino acid derivatives.
The conjugate addition of radicals with dehydroamino acid
derivatives has been reported by the groups of both Beckwith
and Jones who use either mercury or tin compounds during the
reaction process.6–8 We were interested in using an approach
with less toxic reagents, such as the generation of an amino acid
radical by decomposition and decarboxylation of a diacylox-
yiodobenzene (Scheme 1). It seemed that capture of this radical
with a protected dehydroamino acid and reduction with a
hydrogen donor should give the DAP skeleton.
A series of reactions was then done using the diacyloxy-
iodobenzene 3 with these dehydroamino acid derivatives under
themolysis conditions with benzene as the solvent and 1,4-cy-
clohexadiene as the hydrogen donor (Table 1).12 Extended
reaction times of up to 12 hours were required for complete
consumption of the relatively stable trivalent iodobenzene 3.
Reaction of 3 with dehydroamino acids 5, 6, 7 and 9 (entries
1–4) gave in each case the unsaturated adduct in modest yields.
In certain cases, such compounds are formed by disproportiona-
tion of the radical intermediate after conjugate addition to give
a saturated and unsaturated version of the analogue.12 However,
in these examples none of the saturated compound could be
detected. The unsaturated adducts may be formed by abstraction
of a hydrogen atom from the carbon adjacent to the radical
centre (generated through conjugate addition) by the iodine
radical intermediate to give iodobenzene and N-Cbz- -glutamic
L
acid a-methyl ester as the other products. An alternative
possibility is electron transfer from the initial adduct followed
by proton loss (i.e. elimination). This suggests that the radical
formed after conjugate addition is sterically crowded and cannot
readily abstract a hydrogen atom from 1,4-cyclohexadiene.
Surprisingly, reaction of diacyloxyiodobenzene 3 with dehy-
droamino acid analogue 8 gives the dimerisation product in
35% yield as a single diastereomer (entry 5). A similar result
was obtained using the Boc-protected glutamate derived
iodobenzene 4 (entry 6). Efforts to prove the absolute
Two diacyloxyiodobenzenes were prepared in good yield
using a procedure involving reaction of two equivalents of a
commercially available glutamate with (diacetoxyiodo)benzene
2 in the presence of a high boiling solvent (Scheme 2).9 This
reaction is reversible. However, the equilibrium can be shifted
towards the synthesis of the glutamate-derived diacylox-
Scheme 1
Scheme 2 Reagents and conditions: i, chlorobenzene, 50 °C.
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Table 1 Conjugate addition of radicals derived from diacyloxyiodo-
benzenes with dehydroamino acids
Dehydro-
amino acid
Diacyloxy-
iodobenzene
Entrya
1
Product (yield)
3
3
5
6
10 (44 %)
2
3
Scheme 3 Reagents and conditions: i, [(COD)Rh((R,R)-Et-DuPHOS)]BF4,
MeOH, 100 psi, H2, 59%; ii, Boc2O, NEt3, DMAP, CH2Cl2, 95%; iii, LiOH,
MeOH, H2O, 59%.
(54 %)
3
3
This procedure, as well as removing the trityl protecting group,
gives the meso-DAP derivative 11 in a 9+1 mixture of
diastereomers (by 1H NMR spectroscopy). This fortuitous result
obviously allows selective manipulation at this stage of one of
the amino groups. To show orthogonality of the carboxy
functions, the amino group was re-protected with Boc2O and
then treated with one equivalent of lithium hydroxide. This led
to the hydrolysis of predominantly the methyl ester to give the
mono-acid 12 in 59% yield.
9
7
(44 %)
(32 %)
4
5
In summary, thermolysis of glutamate-derived iodobenzenes
leads to primary radicals which can be captured by dehy-
droamino acids by conjugate addition. In contrast to related
systems,12 the newly formed secondary radical, is not reduced
by 1,4-cyclohexadiene or other hydrogen atom donors, resulting
in production of unsaturated adducts and dimerisation products.
Chiral hydrogenation of an unsaturated derivative gives se-
lectively-protected DAP. Orthogonality of protection has also
been demonstrated.
3
4
8
(35 %)
Financial support from the Alberta Heritage Foundation for
Medical Research (Fellowship to A. S.), the Natural Sciences
and Engineering Research Council of Canada and the Canada
Research Chair in Bioorganic and Medicinal Chemistry (to
J. C. V.) is gratefully acknowledged.
6
8
(35 %)
a All reactions were carried out using 1,4-cyclohexadiene (5.0 equiv.) in
benzene under reflux for 12 h.
Notes and references
1 T. D. H. Bugg and C. T. Walsh, Nat. Prod. Rep., 1992, 9, 199; J. Van
Heijenoort, Nat. Prod. Rep., 2001, 18, 503.
stereochemistry of these dimerisation products either by NMR
spectroscopy or X-ray crystallography were unsuccessful.
However, it is likely that after conjugate addition, dimerisation
takes place from the least hindered face of the oxazolidinone
ring to give the dimerisation products with absolute ster-
eochemistry as shown in Table 1. These intriguing results
suggest that the conjugate adduct radical while not accessible
enough to abstract a hydrogen atom from 1,4-cyclohexadiene
can still undergo dimerisation. It should be noted that none of
the unsaturated adducts were isolated from either of these two
reactions. Entry 5 was also repeated under photolytic conditions
using a high pressure mercury lamp as the source of irradiation.
However, as with the thermolysis conditions, only the dimerisa-
tion product was isolated (25% yield). In a further series of
experiments other sources of hydrogen donors were studied.
Entry 5 was repeated using tributyltin hydride, trimethyl
orthoformate or triethylsilane under thermolysis conditions.12
These reactions gave very complex mixtures of products, with
neither the dimers nor the unsaturated derivatives being
produced in isolable amounts.
Due to the inability of this approach to directly produce the
saturated skeleton of DAP, we examined reduction of an
unsaturated derivative to give the desired selectively-protected
skeleton. Stereoselective hydrogenation of unsaturated pro-
tected DAP skeletons to make DAP isomers is well pre-
cedented.4,13 Therefore, the unsaturated derivative 10 was
hydrogenated with [(COD)Rh((R,R)-Et-DuPHOS)]BF4 using
the conditions described by Burk and co-workers (Scheme 3).14
2 R. J. Cox, Nat. Prod. Rep., 1996, 13, 29; G. Scapin and J. S. Blanchard,
Adv. Enzymol. Relat. Areas Mol. Biol., 1998, 72, 279; R. J. Cox, A.
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3 For some recent syntheses of DAP and its analogues see: F. A. Davis
and V. Srirajan, J. Org. Chem., 2000, 65, 3248; B. T. Shireman and M.
J. Miller, J. Org. Chem., 2001, 66, 4809; J. F. Caplan, A. Sutherland and
J. C. Vederas, J. Chem. Soc., Perkin Trans. 1, 2001, 2217.
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8 For a review of intramolecular radical conjugate addition see: W.
Zhang, Tetrahedron, 2001, 57, 7237.
9 E. B. Merkushev, A. N. Novikov, S. S. Makarchenko, A. S.
Moskalchuk, V. V. Glushkova, T. I. Kogai and L. G. Polyakova, J. Org.
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12 H. Togo, M. Aoki and M. Yokoyama, Tetrahedron, 1993, 49, 8241.
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Tetrahedron Lett., 1994, 35, 7005.
14 M. J. Burk, J. E. Feaster, W. A. Nugent and R. L. Harlow, J. Am. Chem.
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