Stereoselective cycloadditions of chiral acyl-nitroso compounds; selective reactions of ring-cleaved cycloadducts leading to a new approach to polyoxamic acid

Article abstract of DOI:10.1039/b201645c

Diesters obtained from diacids produced by oxidative ring cleavage of cycloadducts derived from acyl-nitroso compounds and cyclic 1,3-dienes undergo highly regioselective hydrolysis on reaction with lithium hydroperoxide, which allows for easy differentia

Full text of DOI:10.1039/b201645c

Stereoselective cycloadditions of chiral acyl-nitroso compounds; selective
reactions of ring-cleaved cycloadducts leading to a new approach to
polyoxamic acid
Adrian G. Pepper,a† Garry Proctera and Martyn Voyleb
a Department of Chemistry and Applied Chemistry, University of Salford, Salford, UK M5 4WT
b SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK
CM19 5AW
Received (in Cambridge, UK) 13th February 2002, Accepted 3rd April 2002
First published as an Advance Article on the web 15th April 2002
Diesters obtained from diacids produced by oxidative ring
cleavage of cycloadducts derived from acyl-nitroso com-
pounds and cyclic 1,3-dienes undergo highly regioselective
hydrolysis on reaction with lithium hydroperoxide, which
allows for easy differentiation of the carboxyl groups leading
to a new approach to polyoxamic acid.
The stereoselective cycloaddition of acyl-nitroso compounds to
cyclic dienes can provide a powerful approach to the synthesis
of a range of natural products.1 We are interested in extending
our previous studies2 in this area to their application in natural
product synthesis. A strategy common to several of these
synthetic endeavours involves oxidative cleavage of the double
bond of the cycloadduct 1, followed by differentiation of the
resulting diacid 2, to give an intermediate 3 in which the groups
R1 and R2 can be selectively modified in the subsequent
synthetic scheme (Scheme 1).
Scheme 3
tetrahydrofurans 7 and 8 (Scheme 3). The physical data (MS,
IR, H NMR and 13C NMR spectra) are consistent with the
1
proposed structures, and it is possible that these products arise
via an elimination process (Scheme 3).3
The chemoselectivity might then be a consequence of the
conformation of diester 6. The 1H NMR spectrum of 6 shows a
low-field proton with a large trans-diaxial coupling constant (12
Hz) assigned to H-6, implying that the C-6 ester group is
equatorial. Consequently H-3 should be equatorial, and well
aligned for a trans elimination. Molecular modelling4 using the
MM2 force field predicts that the lowest energy conformation
of the diester corresponds to that suggested from analysis of the
1H NMR spectrum (Scheme 3).
Scheme 1
Selective hydrolysis could however be achieved using
lithium hydroxide and hydrogen peroxide5 to produce the
mono-ester 9 in high yield. The structure of this mono-ester was
provisionally assigned as 9, confirmed by its subsequent
reactions. This difference in reactivity towards nucleophilic
attack was also evident in the reaction of diester 6 with sodium
borohydride. Reaction of 6 with sodium borohydride supported
on alumina6 (NaBH4–Al2O3) gave selectively the alcohol, 10.
Although the reduction of diester 6 into 10 is direct and
experimentally simple, the yield is moderate (45%), and in our
hands the reaction did not scale up well. Reduction of acid 9
with borane–methyl sulfide (Scheme 4) is both clean and high
yielding, and this two step process represents a better route to
alcohol 10.
The highly regioselective hydrolysis of 6 is also consistent
with the above conformation (Scheme 3), as it corresponds to
preferential attack on the equatorial, rather than the axial ester
group, known to be the case in cyclohexane systems.7
As might be expected for nucleophilic attack on the more
reactive ester group, both hydrolysis and reduction of diester 6
One of the most convenient methods for the oxidative
cleavage (1 to 2) uses potassium permanganate under phase
transfer conditions. The resulting diacids are often rather
insoluble solids and so for convenience in subsequent reactions
they are converted to the corresponding diesters (Scheme 2).
One of the simplest approaches to the differentiation of
diesters derived from diacids such as 2 would be by selective
hydrolysis. To investigate this, the racemic tert-butoxycarbonyl
(Boc) cycloadduct 4 was converted into the diester 6 in high
yield (Scheme 2) and its reaction with aqueous base investi-
gated. Initial attempts to carry out such selective hydrolysis of
6 led to either decomposition, or to a rearrangement. For
example, exposure of the diester 6 to barium hydroxide
octahydrate in methanol resulted in the isolation of an
inseparable mixture of two compounds, isomeric with starting
material, which have been tentatively assigned as the epimeric
Scheme 2
† Correspondence to School of Chemistry, University of Exeter, EX4 4QD,
UK (E-mail; a.g.pepper@exeter.ac.uk)
Scheme 4
1066
CHEM. COMMUN., 2002, 1066–1067
This journal is © The Royal Society of Chemistry 2002

take place at the same carbonyl group. That this corresponded to
attack at the C-6 ester rather than C-3 was demonstrated by
carrying out the cleavage of the N–O bond of alcohol 10 by the
action of anhydrous SmI2 in THF, and careful analysis of the 1H
NMR spectra of the product. From these spectra, and other
NMR measurements, it was clear that the proton next to the
ester group was adjacent to the NH, and that a CH(OH)CH2OH
fragment was present, thereby confirming the structure of 10 as
illustrated (Scheme 4).
At this stage we realised this strategy could open up a new
approach towards the polyoxamic acid, 11. This amino acid is a
Scheme 6
polyoxamic acid, which to date has not been unmasked to
polyoxamic acid itself.
All the chemistry described above was carried out using
racemic cycloadducts. This chemistry is easily transferred to
either enantiomeric series by use of the acyl-nitroso inter-
mediate derived from either enantiomer of mandelic acid, as
outlined in Scheme 7 for S-mandelohydroxamic acid.12
fragment of a number of natural products known as the
polyoxins, which form a class of peptidyl nucleoside antibiotics,
isolated from cultures of Streptomyces cacaoi var. asoensis.8 A
number of polyoxins have been isolated, including polyoxin E,
13. These natural products are known to inhibit chitin synthesis
and are active against the phytopathogenic fungus Pellicularia
filamentosa f. sasakii, which causes sheath blight disease of rice
plants. The polyoxins were found to be excellent agricultural
fungicides and have been widely used as such in Japan since
1966.
Scheme 7
No synthesis of the amino acid portion 11 of polyoxin E has
been uncovered, although there are a number of syntheses that
have been reported for various polyoxins,9 as well as for the
other amino acid, 12,10 commonly found in the polyoxin
series.
Our initial studies involved the acyl-nitroso cycloaddition
with cyclopentadiene, producing the racemic cycloadduct 14.
This was converted to the diacid by oxidative double bond
cleavage under phase transfer conditions, followed by a simple
esterification procedure to produce the desired diester 15 in
satisfactory yield (Scheme 5).
In conclusion we have demonstrated a facile approach for the
differentiation of diesters derived from cycloadducts of acyl-
nitroso species with cyclic dienes and have a useful route to
functionalised oxazines and isoxazolines, as well as applying
this methodology to develop a new approach to the synthesis of
polyoxamic acid. We are currently extending these studies, and
investigating the application of this approach to the synthesis of
other nitrogen containing natural products.
We thank the EPSRC and SmithKline Beecham for a CASE
studentship (A. G. P.).
Regioselective transformation of the diester 15 to the desired
alcohol ester 16 was carried out by selective hydrolysis to the
acid ester, followed by chemoselective reduction of the
carboxylic acid moiety (Scheme 5).
Notes and references
A moderate drop in overall yield was observed on going from
the six-ring system to this five-ring system, however the
regioselectivity of the hydrolysis step was complete with only a
single isomer being isolated from the reaction mixture, albeit it
in a modest yield of 43%.
At this point the O-carbamoyl group was attached by
standard chemistry11 in good yield, as illustrated in Scheme 6 to
give compound 17 a fully protected analogue of the desired
1 For example, S. Aoyagi, R. Tanaka, M. Naruse and C. Kibayashi,
Tetrahedron Lett., 1998, 39, 4513; C. Kibayashi and S. Aoyagi, Synlett,
1995, 873; S. B. King and B. Ganem, J. Am. Chem. Soc., 1994, 116,
562.
2 J. P. Muxworthy, J. A. Wilkinson and G. Procter, Tetrahedron Lett.,
1995, 36, 7535; J. P. Muxworthy, J. A. Wilkinson and G. Procter,
Tetrahedron Lett., 1995, 36, 7539; J. P. Muxworthy, J. A. Wilkinson
and G. Procter, Tetrahedron Lett., 1995, 36, 7541.
3 A. Defoin, T. Sifferlen and J. Streith, Synlett, 1997, 1294.
4 N. L. Allinger, J. Am. Chem. Soc., 1977, 99, 8127.
5 J. R. Gage and D. A. Evans, Org. Synth., 1989, 68, 83.
6 E. Santaniello, F. Ponti and A. Manzocchi, Synthesis, 1978, 891.
7 D. H. Barton, Experientia, 1950, 6, 316.
8 K. Isono, K. Asahi and S. Suzuki, J. Am. Chem. Soc., 1969, 91, 7490; K.
Isono and S. Suzuki, Heterocycles, 1979, 13, 333.
9 N. Chida, K. Koizumi, Y. Kitada, C. Yokoyama and S. Ogawa, J. Chem.
Soc., Chem. Commun., 1994, 111; A. Dondoni, F. Junquera, F. L.
Merchan, P. Merino and T. Tejero, J. Chem. Soc., Chem. Commun.,
1995, 2127.
10 L. M. Harwood and S. M. Robertson, J. Chem. Soc., Chem. Commun.,
1998, 2641.
11 M. M. Paz and F. J. Sardina, J. Org. Chem., 1993, 58, 6990.
12 G. W. Kirby and M. Nazeer, Tetrahedron Lett., 1988, 29, 6173; A.
Miller, T. McC. Patterson and G. Procter, Synlett, 1989, 32; A. Miller
and G. Procter, Tetrahedron Lett., 1990, 31, 1041; G. W. Kirby and M.
Nazeer, J. Chem. Soc., Perkin Trans. 1, 1993, 1397.
Scheme 5
CHEM. COMMUN., 2002, 1066–1067
1067