Serial radical cyclisation on sugar-furanose templates to create angularly fused oxa- and dioxa-triquinane skeletons has been described, the salient feature of this approach being to incipiently generate a tertiary radical from cyclopropylmethyl bromide with simultaneous release of allyl group and to subsequently incorporate it in the triquinane system

Gurjar, Mukund K.

Kumar, Punit

Ravindranadh, S. V.

English

Publications of the IAS Fellows

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5-Exo-dig, 5-exo-trig cascade radical cyclisation on sugar-furanose
templates: entry to angularly fused oxa- and dioxa-triquinane
skeletons
Mukund K. Gurjar,* S. V. Ravindranadh and Punit Kumar 
National Chemical Laboratory, Pune 411 008, India. E-mail: gurjar@dalton.ncl.res.in
Received (in Cambridge, UK) 20th February 2001, Accepted 10th April 2001
First published as an Advance Article on the web 1st May 2001
Serial radical cyclisation on sugar-furanose templates to
create angularly fused oxa- and dioxa-triquinane skeletons
has been described, the salient feature of this approach being
to incipiently generate a tertiary radical from cyclopro-
pylmethyl bromide with simultaneous release of allyl group
and to subsequently incorporate it in the triquinane sys-
tem.
Ever since their isolation, the angularly fused triquinanes have
attracted intense attention of synthetic organic chemists as
challenging targets.1 Structural complexity associated with
significant biological activity has necessitated development of
very many approaches for their synthesis.2 Among them, the
radical cascade reactions are by far the most elegant and
efficient approaches as significantly demonstrated by the work
of Curran and others.3 Bis-annulated sugars are also useful
synthons for triquinane synthesis. For example, Fraser-Reid and
coworkers4 have performed some novel transformations medi-
ated by serial radical cyclization of pyranose based sugar
synthons5 to create pyranosin diquinanes, elaborated to natu-
rally occurring triquinanes.
We feel that radical cascade reactions on furanose ring
systems of sugar derivatives would be interesting to explore
primarily to understand the stereo-chemical behavior but more
importantly to obtain synthons potentially useful for angularly
fused, unknown and structurally novel oxa-triquinanes. The
direct approach for oxa-triquinane would be to trigger a cascade
of radical reactions by generating tertiary radicals on synthons
with prefabricated radical acceptors (Scheme 1). Realistically,
formation of a tertiary radical is a difficult proposition because
its precursor, namely tertiary halide or tertiary thiocarbamate, is
not easily accessible by conventional methods. However, the
indirect formation of a tertiary radical with concomitant
installation of an allylic side chain as radical acceptor, by our
recently developed approach6 of radical ring opening of spiro-
cyclopropyl methyl bromide, could constitute an elegant and
ideal proposition for this endeavor. This study forms the basic
premise of this communication.
1,2:5,6-Di-O-isopropylidene-a-D-glucofuranose (1) was
converted into the 3,3-spiro cyclopropylmethanol derivative (2)
in five steps (Scheme 2).7 It was then exposed to 0.8% sulfuric
acid in methanol at rt to give the triol derivative whose oxidative
cleavage with NaIO4 absorbed on silica gel8 in CH2Cl2 yielded
the aldehyde (3). Compound 3 was immediately treated with
Zn, allyl bromide under aqueous Barbier conditions9 to give a
predominantly (90%) and chromatographically separable allyl
addition product (4) whose stereochemical assignment was
based on literature precedents.10 Compound 4 upon treatment
with CBr4–PPh3 in CH2Cl2 in the presence of pyridine at rt gave
the corresponding bromo derivative (5). Treatment of 5 with tri-
n-butyl tin hydride (TBTH), AIBN in toluene (0.05 M) at
100 °C gave a single product whose fused bicyclic structure (6)
was assigned on the basis of NMR and MS studies. Presence of
compound 7 was not noticed. The formation of 6 indicated
premature termination of serial radical cyclisation after the first
exo-trig addition. This abrupt termination could be attributed to
the poor reactivity of the methyl radical.11 In order to
circumvent this problem, we sought to explore the vinyl radical
primarily for its pronounced reactivity coupled with the ease
with which it could be generated.12
Accordingly, 3 was subjected to Barbier reaction in aqueous
conditions with Zn and propargyl bromide to afford 8 as an
exclusive product. The transformation of 8 into 9 was carried
out as described earlier (Scheme 3).
The radical reaction of 9 with TBTH and AIBN (cat.) in dry
toluene (0.05 M) at 100 °C gave the angularly fused oxa-
triquinane derivatives 10a and 10b, whose formation was
attributed to 5-exo-dig, 5-exo-trig serial cyclisations. The
structure of the product was thoroughly investigated by high
resolution 1H NMR, 13C NMR, MS and elemental analysis. The
1H and 13C NMR spectra indicated that it was a 8.5+1.5 mixture
of diastereomers 10a and 10b. However, COSY and NOSY
Scheme 1
Scheme 2 Reagents and conditions: (a) (i) 0.8% H2SO4, MeOH, rt, 10 h; (ii)
silica gel adsorbed NaIO4, CH2Cl2, 15 min, 78% (two steps); (b) allyl
bromide, Zn, aq. NH4Cl, THF, 0 °C, 6 h, 72%; (c) PPh3, CBr4, pyridine,
CH2Cl2, rt, 1 h, 83%; (d) TBTH, AIBN (cat), C6H5CH3, 100 °C, 1 h,
70%.
Scheme 3 Reagents and conditions: (a) HC·C–CH2Br, Zn, aq. NH4Cl,
THF, 0 °C, 6 h, 74%; (b) PPh3, CBr4, pyridine, CH2Cl2, rt, 1 h, 80%; (c)
TBTH, AIBN (cat), C6H5CH3, 100 °C, 1 h, 74%.
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b101641p Chem. Commun., 2001, 917–918 917
studies (Fig. 1) on the major diastereomer 10a revealed the
absolute stereochemistry of the methyl group as indicated.12
We also synthesized starting from 1,2:5,6-di-O-cyclohex-
ylidene-a-D-glucofuranose (10) the 2,2-spirocyclopropyl
methyl bromide derivative 14 via intermediates 11–13 as shown
in Scheme 4. Subsequent radical cascade reaction of 14 with
TBTH and AIBN (cat.) in toluene at 100 °C gave the fused ring
derivatives 15a and 15b. The 1H and 13C NMR spectra of the
product showed to be a 8+2 mixture of diastereomers. The
COSY and NOSY studies (Fig. 1) predicted the stereochemistry
of the methyl group of the major product 15a as indicated.13
In conclusion, we have developed a one pot, stereoselective
5-exo-dig, 5-exo-trig cascade radical cyclization utilizing the
incipiently formed C-allyl radical leading to useful and
structurally novel oxa-triquinane system.
S. V. R. thanks CSIR, New Delhi for a research fellowship.
Notes and references
1 L. A. Paquette and A. M. Doharty, Polyquinane Chemistry, Verlag, New
York, 1987.
2 T. Hudlicky, G. Sinai-Zingde, M. G. Natchus, B. C. Ranu and P.
Papadopolous, Tetrahedron, 1987, 43, 5685; P. A. Wender and S. K.
Singh, Tetrahedron Lett., 1985, 26, 5987; E. J. Enholm and Z. J. Jia,
J. Org. Chem., 1997, 62, 174; J. Tormo, A. Moyano, M. A. Pericas and
A. Riera, J. Org. Chem., 1997, 62, 4851; C.-K. Sha, K. C. Santhosh and
S.-H. Lhi, J. Org. Chem., 1998, 63, 2699; J. Seo, H. Fain, J. B. Blanc and
J. Montgomery, J. Org. Chem., 1999, 64, 6060; J. M. MacDougall and
H. W. Moore, J. Org. Chem., 1999, 64, 7445; S. K. Verma, E. B.
Fleischer and H. W. Moore, J. Org. Chem., 2000, 65, 8564; J. M.
MacDougall and H. W. Moore, J. Org. Chem., 1997, 62, 4554; F. C.
Watson and J. D. Kilburn, Tetrahedron Lett., 2000, 10 341; N. M. H.
Frost and G. Pattenden, Tetrahedron Lett., 2000, 41, 403; Y. K. Rao and
M. Nagarajan, J. Org. Chem., 1989, 54, 5678.
3 D. P. Curran and S.-C. Kuo, J. Am. Chem. Soc., 1986, 108, 1106; D. P.
Curran and S.-C. Kuo, Tetrahedron, 1987, 43, 5653; A. I. Meyers and
B. A. Lefker, Tetrahedron, 1987, 43, 5663; H. M. R. Hoffmann, Angew.
Chem., Int. Ed. Engl., 1992, 31, 1332; C. P. Jasperse, D. P. Curran and
T. L. Fevig, Chem. Rev., 1991, 91, 1237.
4 R. Tsang and B. Fraser-Reid, J. Am. Chem. Soc., 1986, 108, 2116; J. K.
Dickson, Jr., R. Tsang, J. M. Llera and B. Fraser-Reid, J. Org. Chem.,
1989, 54, 5350; H. Pak, J. K. Dickson and B. Fraser-Reid, J. Org.
Chem., 1989, 54, 5357; B. Fraser-Reid and R. Tsang, Strategies and
Tactics in Organic Synthesis, T. Lindberg (ed.), Academic Press, New
York, 1989; Vol. 2, 123; J. K. Dickson, Jr. and B. Fraser-Reid, J. Chem.
Soc., Chem. Commun., 1990, 1440; H. Pak, I. I. Canalda and B. Fraser-
Reid, J. Org. Chem., 1990, 55, 3009.
5 R. Nouguier, C. Lesueur, E. De Reggi and M. P. Bertrand, Tetrahedron
Lett., 1990, 31, 3541; C. Lesueur, R. Nouguier, M. P. Bertrand, P.
Hoffmann and A. De Mesmaeker, Tetrahedron, 1994, 50, 5369.
6 M. K. Gurjar, S. V. Ravindranadh and S. Karmakar, Chem. Commun.,
2001, 241.
7 M. K. Gurjar, B. V. N. B. S. Sharma and B. V. Rao, J. Carbohydr.
Chem., 1998, 17, 1107.
8 Y.-L. Zhong and T. K. M. Shing, J. Org. Chem., 1997, 62, 2622.
9 S. Hanessian, H. Park and R. Y. Yang, Synlett, 1997, 351; S. Hanessian,
H. Park and R. Y. Yang, Synlett, 1997, 353.
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12 G. Stork and N. H. Baine, J. Am. Chem. Soc., 1982, 104, 2321; G. Stork
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13 NMR data for 10a: 1H (500 MHz): d 0.98 (d, 3 H, J = 7.2 Hz), 1.26 (t,
1 H, J = 10.8 Hz), 1.34, (s, 3 H), 1.47, (s, 3 H), 1.80 (m, 1 H) 2.50 (dd,
1 H, J = 5.4, 12.7 Hz), 2.67 (dd, 1 H, J = 3.6, 10.8 Hz), 2.95 (brs, 1 H),
3.72 (m, 1 H), 4.24 (d, 1 H, J = 4.0 Hz), 4.28 (d, 1 H, J = 3.0), 5.41 (s,
1 H), 5.74 (d, 1 H, J = 3.0 Hz); 13C (125 MHz): d 19.98, 27.27, 27.59,
33.99, 40.51, 42.70, 65.52, 74.79, 85.75, 87.75, 106.55, 112.59, 132.33,
144.66. NMR data for 15a: 1H (500 MHz): d 1.09 (d, 3 H, J = 7.5 Hz),
1.3–1.75 (m, 10 H), 1.49 (t, 1 H, J = 12.7 Hz), 2.72 (dd, 1 H, J = 5.0,
12.7 Hz), 3.41 (brs, 1 H), 3.37 (s, 3 H), 3.90 (dd, 1H, J = 2.6, 7.6 Hz),
3.98 (dd, 1 H, J = 4.5, 7.6 Hz), 4.06 (ddd, 1 H, J = 1.5, 3.0, 11.3 Hz),
4.11–4.17 (m, 2 H), 4.29 (brd, 1 H, J = 10.6 Hz), 4.39 (m, 1 H), 4.69
(s, 1 H), 5.46 (s, 1 H); 13C (125 MHz): d 20.11, 23.85, 24.04, 25.17,
34.83, 36.55, 40.93, 44.99, 54.88, 65.86, 66.73, 71.34, 73.23, 81.79,
85.14, 108.32, 109.59, 128.59, 148.36.
Fig. 1 NOSY studies.
Scheme 4 Reagents and conditions: (a) (i) NaH, HC·C–CH2Br, DMF, 0 °C,
90%; (ii) H2SO4, MeOH, D, chromatography, 65%; (b) (I) IBX, DMSO, rt,
10 h; (ii) PPh3NCHCO2Et, C6H6, 80 °C, 2 h, 74% (two steps); (c)
Me2SOCH3I, NaH, DMSO, rt, 3 h, 55%; (d) (i) DIBAL-H, CH2Cl2, 78 °C,
0.5 h, 87%; (ii) PPh3, CBr4, pyridine, rt, 82%; (e) TBTH, AIBN (cat),
C6H5CH3, 100 °C, 1 h, 80%.
918 Chem. Commun., 2001, 917–918


5-Exo-dig, 5-exo-trig cascade radical cyclisation on sugar-furanose templates: entry to angularly fused oxa-and dioxa-triquinane skeletons

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5-Exo-dig, 5-exo-trig cascade radical cyclisation on sugar-furanose templates: entry to angularly fused oxa-and dioxa-triquinane skeletons

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