Synthesis of chiral oxepinopyran and oxepinooxepane systems from 1,2-isopropylidene furanoside ring-fused cyclic ether derivatives through 4-O-allyl nitrone and nitrile oxide cycloadditions

Article abstract of DOI:10.1016/S0040-4039(00)01802-5

A novel strategy was developed by which chiral oxepinopyran and oxepinooxepane derivatives were synthesised from 1,2-isopropylidene furanoside fused pyran and oxepane derivatives by the cycloaddition of 4-O-allyl nitrone or nitrile oxide species generated from the furanoside ring. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01802-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10135–10139
Synthesis of chiral oxepinopyran and oxepinooxepane
systems from 1,2-isopropylidene furanoside ring-fused cyclic
ether derivatives through 4-O-allyl nitrone and nitrile oxide
cycloadditions
Arani Pal, Anup Bhattacharjya* and Ranjan Mukhopadhyay
Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Calcutta 700 032, India
Received 2 August 2000; revised 2 October 2000; accepted 11 October 2000
Abstract
A novel strategy was developed by which chiral oxepinopyran and oxepinooxepane derivatives were
synthesised from 1,2-isopropylidene furanoside fused pyran and oxepane derivatives by the cycloaddition
of 4-O-allyl nitrone or nitrile oxide species generated from the furanoside ring © 2000 Elsevier Science
Ltd. All rights reserved.
The application of intramolecular cycloaddition of nitrones and nitrile oxides prepared from
O-alkenyl and O-alkynyl carbohydrate derivatives has led to an easy access to chiral cyclic ether
skeletons of varying ring sizes.1,2 A number of such cyclic ether derivatives are found to be fused
to 1,2-isopropylidene furanoside moieties, which constitute the carbohydrate scaffold bearing
the O-alkenyl and -alkynyl residues as well as the 1,3-dipolar moieties. One of the notable
advantages of using this particular carbohydrate scaffold is its convertibility to other useful
systems, such as a tetrahydrofuran ring through 2-O-allyl nitrone cycloaddition.2,3 Herein we
report a novel strategy for the construction of a dioxaheterobicyclic system 4 or 5 involving a
facile transformation of the isopropylidene furanoside ring of a cyclic ether derivative 1 to
another cyclic ether skeleton (Scheme 1).
The strategy essentially involves the transformation of the furanoside ring to a 4-O-alkenyl
nitrone 2 or nitrile oxide 3, cycloaddition of which leads to the formation of 4 or 5 incorporating
the dioxaheterobicyclic skeleton. The importance of the strategy stems from the frequent
occurrence of similarly fused cyclic ether skeletons in a number of marine toxins, e.g. brevetox-
ins and ciguatoxin. Recent synthetic exercises in this regard involved the construction of such
* Corresponding author. Tel: (91-33) 4735197/4733493; fax (91-33) 4735197/4730284; e-mail: anupbhattacharjya@iicb.
res.in, anupbh@hotmail.com
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01802-5

10136
Scheme 1.
bicyclic systems through different methodologies.4,5 We demonstrate our strategy by the synthesis
of oxepinopyran and oxepinooxepane ring systems by the cycloaddition of 4-O-allyl nitrone and
nitrile oxide species generated from the 1,2-isopropylidene furanoside fused cyclic ether derivatives
7a and 7b (Scheme 2).
Following the procedures reported in the literature, the isoxazole 7a and the isoxazolidine 7b
were prepared from the aldehyde 6 by the application of 3-O-allyl nitrile oxide and 3-O-allyl
nitrone cycloaddition.6,7
Although the more versatile N-Bn derivative 7c was available,8 the N-CH3 derivative was used
in this study for easier characterisation. A sequence of known2,3 reactions on 7a and 7b involving
(a) removal of the isopropylidene group and simultaneous methylglycosylation by treatment with
p-TsOH and methanol, (b) benzylation of ꢀOH with benzyl bromide in the presence of tetrabutyl-
ammonium bromide in CH2Cl2–50% aqueous NaOH, (c) deglycosylation with 50% aqueous
trifluoroacetic acid and (d) dithioacetalisation with ethanethiol in conc. HCl gave the dithioacetal
derivatives 8a (91%) and 8b (90%) (Scheme 2). Allylation of 8a and 8b with allyl bromide in the
presence of tetrabutylammonium bromide in CH2Cl2–50% aqueous NaOH or NaH in THF
afforded the O-allyl derivatives 9a (89%) and 9b (68%), dethioacetalisation of which furnished
the aldehydes 10a and 10b (Scheme 2). All the intermediates involved in the above sequence of
reactions were found to be liquids and could be characterised by 1H and 13C NMR spectroscopy
and mass spectral analysis, but purification to a level suitable for microanalytical analysis was
not possible because of the adherence of traces of unidentifiable contaminants. However, the
aldehydes 10a and 10b were used immediately without any purification for the next step.
Treatment of 10a with MeNHOH·HCl in 80% aqueous MeOH in the presence of NaHCO3 under
reflux led to the formation of the nitrone 11a, cycloaddition of which did not occur under the
1
aforementioned conditions, as was evident from the H NMR spectrum of the crude product.
Heating the crude nitrone in toluene led to cycloaddition resulting in the formation of the
oxepinopyran derivatives 14 and 15 in yields of 18 and 31% respectively (Scheme 2). The structures
of 14 and 15 (and the products described later) were established by high-resolution mass spectral
data and DEPT, HMQC/C,H-COSY, DQFCOSY/H,H-COSY and ROESY/NOESY experi-
ments.9 The cis relationship between 6a-H and 9a-H in 14 was indicated by J6a,9a=8.2 Hz, while
the observation of cross peaks between 9a-H and 11a-H in the ROESY spectrum established the
assigned stereochemistry of 6a-C and 9a-C in 14 (Scheme 2). On the other hand, the observation
of J6a,9a=9.3 Hz was consistent with the trans relationship between 6a-H and 9a-H in 15, and
the occurrence of cross peaks between 9a-H and 11a-H in the ROESY spectrum indicated the
assigned stereochemistry in 15 (Scheme 2).

10137
Scheme 2. Reagents: (a) For 7a: MeOH, TsOH (catalyst), reflux, 5 h; for 7b: MeOH, HCl gas, 25°C, 15 h. (b) BnCl,
Bu4NBr, 50% aq. NaOH–CH2Cl2, 25°C, 15 h. (c) 50% aq. TFA, 25°C, 24 h. (d) EtSH, conc. HCl, 0°C, 18 h, 91%
(8a), 90% (8b). (e) For 8a: allyl bromide, Bu4NBr, 50% aq. NaOH–CH2Cl2, 25°C, 15 h, 89%; for 8b: allyl bromide,
NaH, THF, 25°C, 20 h, 68%. (f) HgCl2, CaCO3, CH3CN–H2O (4:1), 25°C. (g) i. MeNHOH·HCl, NaHCO3, 80% aq.
EtOH, reflux, 20 h; ii. toluene, reflux, 8 h, 18% (14), 31% (15), 23% (16). (h) NH2OH·HCl, MeOH, py, reflux, 8 h,
91%. (i) 4% aq. NaOCl, Et3N, CH2Cl2, 25°C, 25 h, 23% (17), 14% (18)
The nitrone 11b, obtained from the aldehyde 10b, underwent cycloaddition under the
conditions mentioned for 11a leading to the formation of the oxepinooxepane derivative 16 as
the exclusive product in 23% yield. The high diastereoselectivity of the cycloaddition of 11b
compared to that of 11a is worth mentioning, although the reason for this is not known at
present. The cis relationship between 6a-H and 9a-H in 16 was assigned on the basis of
J
6a,9a=7.9 Hz, and the observation of cross peaks between 9a-H and 11a-H as well as 5a-H and
6a-H in the ROESY spectrum established the stereochemistry at 6a-C and 9a-C.
In a separate route 10a was converted to the oxime 12a (91%) by treatment with NH2OH·HCl
in methanol–pyridine (Scheme 2), and oxidation of 12a with NaOCl in CH2Cl2 led to the
1
formation of 17 (23%) and 18 (14%) via the nitrile oxide 13a. The H and 13C NMR spectra of
the compounds clearly indicated that they were 9a-C epimers by their spectral similarity. The
occurrence of cross peaks between 9a-H and 5a-H in 17 established the stereochemistry at 9a-C
in 17, and consequently the corresponding stereochemistry in 18 was also known.

10138
A striking feature of the above work is that the conversion of the aldehyde 6 to the bicyclic
compounds above made use of the difference in regioselectivity of 3-O-allyl carbohydrate nitrile
oxide and nitrone cycloaddition (in the synthesis of 7a and 7b) as well as the regioselectivity of
4-O-allyl nitrone and nitrile oxide cycloaddition (in the formation of the oxepane skeleton from
the furanoside ring). Another notable aspect is that all the five carbon atoms and three chiral
centres of the carbohydrate backbone of 6 are retained in the dioxaheterobicyclic skeletons in
14–18.
In conclusion, the above work demonstrates a useful and novel transformation of the
1,2-isopropylidene furanoside ring according to Scheme 1, and the inherent potential of the
strategy for the construction of polyether frameworks of marine toxins becomes visible through
a variation in the structure and stereochemistry of the O-alkene residue. The tetracyclic
compounds 14, 15, 17 and 18 incorporate cis-fused oxepinopyran skeletons and 16 incorporates
a cis-fused oxepinooxepane skeleton unlike the naturally occurring marine toxins. The stereo-
chemistry of this ring fusion is determined by that of 3-C and 4-C of the starting aldehyde 6. So,
the application of this strategy to toxin synthesis requires the use of stereochemically different
starting materials as well as different alkene moieties in order to allow for the correct
substitution pattern present in toxins. Work in this field is currently in progress.
Acknowledgements
A.B. is grateful to DST, India, for financial assistance, and thankfully acknowledges a joint
grant from Ranbaxy Research Laboratories and DST, India. A.P. thanks DST, India, for a
Senior Research Fellowship. The experimental assistance of Mr Sandip Chowdhury is gratefully
acknowledged. Thanks are due to IICT, India, for the mass spectroscopy including HRMS
analysis and the Bose Institute, Calcutta, for the 500 MHz NMR analysis.
References
1. Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863.
2. Pal, A.; Bhattacharjee, A.; Bhattacharjya, A. Synthesis 1999, 1427.
3. Pal, A.; Bhattacharjee, A.; Bhattacharjya, A.; Patra, A. Tetrahedron 1999, 55, 4123–4132.
4. Delgado, M.; Martin, J. D. J. Org. Chem. 1999, 64, 4798.
5. Nicolau, K. C.; Duggan, M. E.; Hwang, C. K. J. Am. Chem. Soc. 1989, 111, 6676.
6. Mukhopadhyay, R.; Datta, S.; Chattopadhyay, P.; Bhattacharjya, A. Indian J. Chem. 1996, 35B, 1190.
7. Shing, T. K. M.; Fung, W. C.; Wong, C. H. J. Chem. Soc., Chem. Commun. 1994, 449.
8. Datta, S.; Chattopadhyay, P.; Mukhopadhyay, R.; Bhattacharjya, A. Tetrahedron Lett. 1993, 34, 3585.
9. Spectroscopic and other physical data: 14: sticky material; [h]D −13.2 (CHCl3, c 0.15); HRMS: calcd for
1
C19H24N2O5, 360.16852; found, 360.16958; H NMR (500 MHz, CDCl3): l 2.70 (s, 3H), 2.96 (br d, J=8.2 Hz,
1H), 3.33 (d, J=2.6 Hz, 1H), 3.34 (t, J=10.6 Hz, 1H), 3.57 (m, 1H), 3.60–3.64 (m, 2H), 3.76–3.80 (m, 2H), 3.82
(dt, J=7.5, 9.1 Hz, 1H), 3.99 (t, J=7.5 Hz, 1H), 4.02 (dd, J=7.5, 10.5 Hz, 1H), 4.32 (dd, J=6.8, 10.5 Hz, 1H),
4.43 (dd, J=7.6, 10.1 Hz, 1H), 4.64 (d, J=11.8 Hz, 1H), 4.66 (s, 1H), 4.86 (d, J=11.6 Hz, 1H), 7.31 (m, 5H); 13C
NMR (75 MHz): l 41.6 (CH), 44.0 (CH3), 45.0 (CH), 68.5 (CH2), 68.7 (CH), 69.2 (CH2), 70.0 (CH2), 72.1 (CH),
72.6 (CH2), 73.5 (CH2), 75.1 (CH), 81.9 (CH), 127.7 (CH), 127.8 (CH), 128.4 (CH), 138.0 (q), 156.4 (q). 15: sticky
1
material; [h]D +97.8 (CHCl3, c 0.22); HRMS: calcd for C19H24N2O5, 360.16852; found, 360.16900; H NMR (500
MHz, CDCl3): l 2.75 (s, 3H), 3.27 (dd, J=10.7, 10.9 Hz, 1H), 3.35–3.44 (m, 1H), 3.40 (d, J=5.9 Hz, 1H), 3.47
(d, J=9.3 Hz, 1H), 3.57 (t, J=7.7 Hz, 1H), 3.72 (m, 1H), 3.85 (t, J=8.5 Hz, 1H), 4.03 (dd, J=6.6, 12.1 Hz, 1H),

10139
4.07–4.13 (m, 3H), 4.28 (dd, J=6.8, 10.5 Hz, 1H), 4.44 (dd, J=8.5, 10.5 Hz, 1H), 4.64 (d, J=11.5 Hz, 1H), 4.77
(s, 1H), 5.01 (d, J=11.5 Hz, 1H), 7.26–7.47 (m, 5H); 13C NMR (75 MHz): l 45.1 (CH), 45.6 (CH3), 46.9 (CH),
68.6 (CH), 68.7 (CH2), 69.7 (CH2), 69.9 (CH2), 72.1 (CH2), 73.0 (CH), 74.8 (CH2), 80.5 (CH), 81.1 (CH), 127.7
(CH), 128.4 (CH), 138.5 (q), 156.1 (q). 16: sticky material; [h]D −16.4 (CHCl3, c 0.80); HRMS: calcd for
C20H28N2O5, 376.19982; found, 376.19900; 1H NMR (500 MHz, CDCl3): l 2.39 (m, 1H), 2.55 (d, J=12.5 Hz, 1H),
2.65 (s, 3H), 2.66 (s, 3H), 2.87 (d, J=7.9 Hz, 1H), 3.34 (dd, J=5.3, 6.7 Hz, 1H), 3.52 (m, 1H), 3.55–3.62 (m, 4H),
3.57 (d, J=3.0 Hz, 1H), 3.79 (d, J=5.0 Hz, 1H), 3.91–4.00 (m, 2H), 3.92 (d, J=3.0 Hz, 1H), 4.53 (dd, J=2.5, 8.5
Hz, 1H), 4.71 (d, J=11.7 Hz, 1H), 4.78 (d, J=11.7 Hz, 1H), 7.26–7.40 (m, 5H); 13C NMR (100 MHz): l 27.1
(CH2), 41.7 (CH), 43.9 (CH2), 46.8 (CH3), 67.5 (CH), 68.6 (CH2), 68.8 (CH2), 71.8 (CH), 72.6 (CH2), 72.7 (CH2),
73.5 (CH), 75.1 (CH), 75.4 (CH), 78.9 (CH), 127.5 (CH), 127.9 (CH), 128.2 (CH), 138.4 (q). 17: mp 164–165°C;
1
[h]D +26.7 (CHCl3, c 0.01); HRMS: calcd for C18H20N2O5, 344.13722; found, 344.137124; H NMR (300 MHz,
CDCl3): l 3.31 (t, J=10.7 Hz, 1H), 3.55 (d, J=0.9, 4.7 Hz, 1H), 3.64–3.75 ((m, 2H), 3.85 (t, J=8.6 Hz, 1H), 3.99
(d, J=13.0 Hz, 1H), 4.06 (dd, J=4.5, 13.1 Hz, 1H), 4.09 (dd, J=8.0, 14.1 Hz, 1H), 4.34 (dd, J=6.8, 10.6 Hz, 1H),
4.42 (dd, J=8.4, 10.6 Hz, 1H), 4.52 (d, J=11.8 Hz, 1H), 4.63 (dd, J=7.9, 10.8 Hz, 1H), 4.64 (d, J=11.8 Hz, 1H),
4.72 (br s, 1H), 4.75 (d, J=4.6 Hz, 1H), 7.27–7.40 (m, 5H); 13C NMR (75 MHz): l 45.0 (CH), 51.1 (CH), 68.8
(CH2), 70.0 (CH2), 72.0 (CH2), 72.3 (CH2), 73.3 (CH2), 74.3 (CH), 74.7 (CH), 79.7 (CH), 127.8 (CH), 128.3 (CH),
128.7 (CH), 136.6 (q), 155.8 (q), 157.2 (q). 18: mp 113–114°C; [h]D +264.9 (CHCl3, c 0.01); HRMS: calcd for
1
C18H20N2O5, 344.13722; found, 344.138039; H NMR (300 MHz, CDCl3): l 3.36 (t, J=10.6 Hz, 1H), 3.61 (dd,
J=1.1, 5.5 Hz, 1H), 3.73–3.83 (m, 4H), 3.86 (dd, J=7.9, 9.1 Hz, 1H), 4.01 (m, 1H), 4.32 (dd, J=6.7, 10.7 Hz, 1H),
4.45 (dd, J=8.0, 10.6 Hz, 1H), 4.50 (m, 1H), 4.56 (d, J=5.5 Hz, 1H), 4.57 (d, J=11.7 Hz, 1H), 4.80 (br s, 1H),
4.81 (d, J=11.7 Hz, 1H), 7.33 (m, 5H); 13C NMR (75 MHz): l 44.8 (CH), 52.6 (CH), 68.2 (CH2), 70.1 (CH2), 70.9
(CH2), 71.2 (CH2), 72.1 (CH), 72.6 (CH2), 73.2 (CH), 82.2 (CH), 128.1 (CH), 128.2 (CH), 137.0 (q), 155.9 (q),
157.9 (q).
.
.