Stereoselective intramolecular oxime olefin cycloadditions involving carbohydrate derived precursors

Article abstract of DOI:10.1055/s-1998-1969

Intramolecular oxime olefin cycloaddition reactions of carbohydrate derived precursors can be used to prepare highly functionalised 3-oxa-2-azabicyclo[3.3.0]hexanes with good to excellent levels of stereocontrol.

Full text of DOI:10.1055/s-1998-1969

December 1998
SYNLETT
1333
Stereoselective Intramolecular Oxime Olefin Cycloadditions Involving Carbohydrate Derived
Precursors
Stéphane Moutel and Michael Shipman*
Department of Chemistry, University of Exeter, Stocker Rd., Exeter, EX4 4QD, U.K.
Fax: +44 1392 263 434; E-mail: m.shipman@exeter.ac.uk
Received 6 October 1998
Abstract: Intramolecular oxime olefin cycloaddition reactions of
carbohydrate derived precursors can be used to prepare highly
functionalised 3-oxa-2-azabicyclo[3.3.0]hexanes with good to excellent
levels of stereocontrol.
stereochemical outcome of this reaction, we suggest that after initial
1,2-prototropic shift, the cycloaddition proceeds with the oxime and
olefin components in exo orientations and the benzyl ethers orientated in
pseudo equatorial positions about the forming 5-membered ring.
In 1970, the first example of an intramolecular oxime olefin
1
cycloaddition (IOOC) reaction was reported by Oppolzer and Keller.
Further examples of IOOC reactions have been reported by the groups
2
3
4
5
6
of Wildman, Grigg, Heathcock, Hassner, among others. As part of
a programme directed towards the synthesis of novel glycosidase
inhibitors, we wished to determine whether IOOC reactions of
carbohydrate derived precursors could be used to construct highly
7
functionalised 3-oxa-2-azabicyclo[3.3.0]hexanes. Furthermore, while
some of the previous work indicated that good levels of stereocontrol
can be accomplished in relatively simple IOOC reactions, it was unclear
at the outset of our studies whether good, predictable levels of
stereocontrol could be accomplished in more complex systems. In this
letter, we describe a series of stereoselective IOOC reactions using
carbohydrate derived precursors and provide some insight into the
factors which control the stereochemical outcome of these reactions.
Scheme 1
To test the generality of this reaction, and to probe the remarkable
stereospecificity of this cycloaddition, we have undertaken several other
related reactions using other oxime precursors (see Table 1). Oximes 3-
6, derived from D-glucose, D-glucal, D-mannose and D-galactose
respectively, all undergo intramolecular oxime olefin cycloadditions in
good yields. Benzoate protected oxime 3 yielded cycloadduct 7 as the
sole product (Table 1, Entry 1). In the other cases, two stereoisomeric
cycloadducts were produced in varying proportions depending on the
precise structure of the oxime substrate (Table 1, Entries 2-4). With the
exception of 2-deoxyglucose series (Table 1, Entry 2), the
stereochemistry of the products was elucidated using nOe difference
measurements.
Our initial studies were conducted with oxime 1, which was prepared in
6 steps from methyl α-D-glucopyranoside using a Vasella fragmentation
7a,b
as the key step.
To our delight, thermolysis of this oxime in refluxing
toluene for 15 hours produced bicycle 2 in quantitative yield as
essentially a single stereoisomer as judged by NMR spectroscopy
8,9
(Scheme 1). Similar results were obtained using either pure (E)-1 or a
mixture of (E)-1 and (Z)-1. The cis ring junction and relative
stereochemical relationships within bicycle 2 were established using
9
selective nOe difference measurements. To account for the observed

1334
LETTERS
SYNLETT
From these results, it would appear that the stereogenic centre adjacent
to the oxime carbon atom on the linking tether exerts the greatest
influence on the stereochemical outcome of these reactions. In major
cycloadducts 2, 7, 10 and 12, this ether substituent is positioned in an
exo orientation relative to the bicyclic ring. Further evidence in support
of the importance of this substituent is provided by the observation that
low stereoselectivity is observed in the reaction of oxime 4 which only
possesses a methylene group next to the oxime carbon atom. These
findings parallel observations made concerning intramolecular nitrone
(4) Norman, M.H.; Heathcock, C.H. J. Org. Chem., 1987, 52, 226.
(5) (a) Padwa, A.; Chiacchio, U.; Dean, D.C.; Schoffstall, A.M.;
Hassner, A.; Murthy, K.S.K. Tetrahedron Lett., 1988, 29, 4169;
(b) Hassner, A.; Maurya, R.; Mesko, E. Tetrahedron Lett., 1988,
29, 5313; (c) Hassner, A.; Maurya, R. Tetrahedron Lett., 1989, 30,
2289; (d) Hassner, A.; Maurya, R. Tetrahedron Lett., 1989, 30,
5803; (e) Hassner, A.; Maurya, R.; Padwa, A.; Bullock, W.H. J.
Org. Chem., 1991, 56, 2775; (f) Hassner, A.; Maurya, R.; Padwa,
A.; Bullock, W.H. J. Org. Chem., 1991, 56, 2775; (g) Hassner, A.;
Maurya, R.; Friedman, O.; Gottlieb, H.E.; Padwa, A.; Austin, D. ;
J. Org. Chem., 1993, 58, 4539.
10
olefin cycloadditions.
Preliminary attempts to use this chemistry for the construction of
functionalised cyclobutanes has proven unsuccessful. Thermolysis of
oxime 14 (prepared in 5 steps from D-ribose) in refluxing toluene, failed
to produce cyclobutane 15 and only unreacted oxime was returned in
high yield. Attempts to facilitate the cycloaddition by the use of higher
boiling solvents (xylene or 1,2-dichlorobenzene) were unsuccessful.
(6) (a) Arnone, A.; Cavicchioli, M.; Donadelli, A.; Resnati, G.
Tetrahedron: Asymmetry, 1994, 5, 1019; (b) Baskaran, S.; Aurich,
H.G., Synlett, 1998, 277.
(7) Intramolecular nitrone cycloadditions of carbohydrate derived
precursors have been described, see (a) Bernet, B.; Vasella, A.;
Helv. Chim. Acta, 1979, 62, 1990; (b) Bernet, B.; Vasella, A.;
Helv. Chim. Acta, 1979, 62, 2400; (c) Ferrier, R.J.; Furneaux,
R.H.; Prasit, P.; Tyler, P.C.; Brown, K.L.; Gainsford, G.J.; Diehl,
J.W. ; J. Chem. Soc., Perkin Trans. 1, 1983, 1621.
(8) All new compounds have been fully characterised using standard
spectroscopic and analytical techniques.
Scheme 2
(9) Typical procedure: A stirred solution of oxime 1 (87 mg, 0.20
mmol) in dry toluene (3 ml) under nitrogen was heated at reflux
overnight. On cooling, the solvent was removed in vacuo to give 2
as a white solid (87 mg, 100%); m.p. 108°C (recrystallised from
In summary, we have demonstrated that intramolecular oxime olefin
cycloaddition reactions of carbohydrate derived precursors can be used
to prepare highly functionalised 3-oxa-2-azabicyclo[3.3.0]hexanes with
good to excellent levels of stereocontrol. We believe that this chemistry
will provide an expedient entry into a variety of highly functionalised
ether/hexane); [α] -3° (c 0.93, CHCl ); Found: C 75.16; H 6.72;
D
3
N 3.22% Calc. for C
Observed (M ): 431.2103; C
H NO : C 75.15; H 6.77; N 3.24%;
27 29 4
+
H NO requires 431.2097; ν
27 29 4 max
7a
cyclopentanoids, and work to exploit these findings are ongoing.
(KBr) 3206, 3028, 2874, 1497, 1453, 1360, 1117, 1094, 1069,
-1
1029 cm ; δ (400 MHz, C D ) 2.49 (1H, m, H-5), 2.87 (1H, m,
H
6 6
H-4), 3.35 (1H, dd, 10.0, 6.5 Hz, H-1), 3.65 (1H, d, 8.5 Hz, H-4),
3.70 (1H, t, 8.0 Hz, H-6), 4.00 (1H, dd, 8.0, 6.5 Hz, H-8), 4.07
(1H, t, 8.0 Hz, H-7), 4.47 (1H, d, 12.0 Hz, PhCH), 4.52 (1H, bs,
NH), 4.59 (1H, d, 12.0 Hz, PhCH), 4.76 (1H, d, 12.0 Hz, PhCH),
4.88 (1H, d, 12.0 Hz, PhCH), 4.90 (1H, d, 12.0 Hz, PhCH), 4.99
Acknowledgements. We are grateful to the Leverhulme Trust for their
generous financial support. We are indebted to Dr J.A. Ballantine and
his staff at the EPSRC Mass Spectrometry Service for high resolution
mass spectra.
(1H, d, 12.0 Hz, PhCH), 7.12-7.46 (15H, m, Ph); δ (100 MHz,
C
References and Notes
C D ) 49.8 (C-5), 66.5 (C-1), 71.9 (CH ), 72.1 (CH ), 72.4 (CH ),
6
6
2
2
2
(1) Oppolzer, W.; Keller, K. Tetrahedron Lett., 1970, 1117.
(2) Slabaugh, M.R.; Wildman, W.C. J. Org. Chem., 1971, 36, 3202.
75.4 (C-4), 85.3 (C-6), 86.1 (C-7 & C-8), 127.3 (CH), 127.4 (CH),
127.55 (CH), 127.63 (CH), 127.68 (CH), 127.74 (CH), 128.24
(CH), 128.27 (CH), 128.33 (CH), 138.9 (C), 139.1 (C), 139.3 (C).
Selected nOe data: irradiation of H-1 enhances H-5 (9.6%), H-7
(2.8%), H-8 (2.0%) and NH (5.0%); irradiation of H-5 enhances
H-1 (9.4%) and H-4 (3.1%).
(3) (a) Grigg, R.; Thianpantangul, S. J. Chem. Soc., Perkin Trans. 1,
1984, 653; (b) Grigg, R.; Markandu, J.; Perrior, T.;
Surendrakumar, S.; Warnock, W.J. Tetrahedron Lett., 1990, 31,
559; (c) Grigg, R.; Heaney, F.; Markandu, J.; Surendrakumar, S.;
Thornton-Pett, M.; Warnock, W.J. Tetrahedron, 1991, 47, 4007.
(10) For a discussion and leading reference, see reference 6a.