Radical-mediated stereoselective synthesis of (+)-dihydrocanadensolide and (-)-3-epi-dihydrocanadensolide from D-xylose

Article abstract of DOI:10.1016/S0040-4039(01)01168-6

An intramolecular radical cyclisation protocol on 5-hexenyl systems was utilised for the first time in a synthesis of (+)-dihydrocanadensolide and its C-3 epimer. This study also revealed the effect of the additional stereocentre at the 2′-position of the

Full text of DOI:10.1016/S0040-4039(01)01168-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6183–6186
Radical-mediated stereoselective synthesis of
(
+)-dihydrocanadensolide and (−)-3-epi-dihydrocanadensolide
†
from
D-xylose
G. V. M. Sharma* and T. Gopinath
D-211, Discovery Laboratory, Organic Chemistry Division III, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
Received 9 May 2001; revised 19 June 2001; accepted 28 June 2001
Abstract—An intramolecular radical cyclisation protocol on 5-hexenyl systems was utilised for the first time in a synthesis of
(
+)-dihydrocanadensolide and its C-3 epimer. This study also revealed the effect of the additional stereocentre at the 2%-position
of the radical systems. © 2001 Elsevier Science Ltd. All rights reserved.
1
Regio- and stereoselective radical cyclisation reactions
play a crucial role for CꢀC bond formation, in particu-
lar for the synthesis of cis-fused bicyclic systems via
efficient intramolecular routes. Such a protocol on tem-
plates derived from monosaccharides has attracted a lot
of attention resulting in the synthesis of several bio-
active compounds especially those containing bis-buty-
rolactone moieties. Earlier, by the adoption of an
intramolecular route on 5-hexynyl systems, we reported
The regio- and stereochemical outcome of radical cycli-
12
sations on systems with 2, 3, 4 and 5 stereocentres has
been well studied and many reactions are well defined
13,14
theoretically.
It is well known in the literature that
the presence of a stereocentre at C-2 in a radical system
generates a 1,2- and 1,5-cis fused bicyclic system as the
only, or major, product. In this context, our interest
was to see the impact of an additional stereocentre at
the 2%-position, which would alter the ratios of the
products (1,5-cis/trans) and could be exploited in syn-
thetic studies on 1 and 2. Unlike our earlier studies
using 5-hexynyl systems, in the present study we were
interested in observing the effect of the 2%-stereocentre
(at the anomeric position) in addition to the stereocen-
tre at the C-2 position of the radical carbon on the
2
3,4
the synthesis of avenaciolide and canadensolide, and
the first synthesis and structure determination of
5
5
6
sporothriolide, 4-epi-ethisolide and discosiolide. In
continuation of our studies on radical routes on sugar
templates, herein, we describe the synthesis of (+)-dihy-
drocanadensolide and its C-3 epimer from
D-xylose.
5
-hexenyl systems. The requisite, 2- and 2%-substituted
Dihydrocanadensolide 1 was isolated as a mold
metabolite with biological activity from Penicillium
radical systems were thus generated from D-xylose.
7
,8
15
canadense. Its first total synthesis was reported by
Accordingly, known diol 3 (Scheme 1) was subjected
to tosylation (TsCl, pyridine, CH Cl ) to give 4, which
on subsequent reaction with n-propylmagnesium bro-
mide afforded 5. Reaction of 5 with allyl bromide
(NaH, THF) gave 6, [h] =−15.4 [c 1.0, CHCl ]. Fur-
ther, hydrolysis of 6 (H resin, MeOH) and treatment
of the resultant alcohols 7, (l 4.94, d, J=7.0 Hz, H-1)
and 7a (l 4.68, d, J=2.3 Hz, H-1) with NaH, CS and
9
10
11
Mulzer, while 1 and its epimer 2 were also synthe-
sised. The main strategy of the present synthesis
involves the utilisation of radical cyclisation of 5-hex-
2
2
enyl systems derived from
D-xylose.
D
+
3
H
H
O
O
O
O
O
H
H
CH3
H
2
H
H
CH3
H
O
MeI in THF furnished the xanthates 8 and 8a, respec-
tively, thus providing the radical precursors with 2- and
2%-stereocentres.
O
1
O
2
The xanthate
cyclisation with n-Bu SnH (AIBN, benzene, reflux) to
8
(Scheme 2) was subjected to
3
16
*
Corresponding author. E-mail: esmvee@iict.ap.nic.in
IICT Communication No: 4797.
†
afford a separable mixture of isomers 9 and 10 in a 3:1
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01168-6

6
184
G. V. M. Sharma, T. Gopinath / Tetrahedron Letters 42 (2001) 6183–6186
H C
9
H9C4
OCH3
4
O
O
O
R
HO
O
OCH3
O
a, b , c
O
d, e
+
OR
OR
O
O
O
O
HO
R’O
7
8
R = H
R = CSSMe
7a R = H
8a R = CSSMe
3
4 R = CH2OTs; R’ = H
5
6
R = n-C H ; R’ = H
4 9
R = n-C H ; R’ =
4
9
Scheme 1. Reagents and conditions: (a) TsCl, pyridine, CH Cl , rt, 6 h, 82%; (b) C H MgBr, dry THF, reflux, 10 h, 75%; (c) NaH,
2
2
3
7
allyl bromide, dry THF, rt, 4 h, 83%; (d) MeOH, conc. HCl, reflux, 45 min, 91%; (e) NaH, CS , CH I, dry THF, 0°C to rt, 4
2
3
h, 78% (a), 81% (b).
H
H
O
O
OCH3
O
1
OH
4
d
3
2
5
c
2
H
H
CH3
H
H
H
72%
O
CH3
H
H
X
O
1
3 (84%)
9
X = H, H
a
b
8
11 X = O (46%)
H
O
H
O
O
OH
OCH3
d
c
1
H
H
H
CH3
6
8%
CH3
O
H
H
X
O
14 (86%)
1
1
0 X = H, H
2 X = O (45%)
Scheme 2. Reagents and conditions: (a) n-Bu SnH, dry benzene, AIBN, reflux, 12 h, 82%; (b) CH Cl :CH CN:H O (2:2:3), NaIO ,
3
2
2
3
2
4
cat. RuCl ·H O, rt, 18 h; (c) 60% CH COOH, 60°C, 30 min; (d) PDC, dry CH Cl , reflux, 2 h.
3
2
3
2
2
17
ratio, which on further oxidation with RuCl –NaIO4
The study was next extended to see the effect of the
3
afforded the lactones 11 and 12, respectively. The struc-
tures of these lactones were unambiguously assigned
based on spectral analysis. Compound 11 was found to
be 2,3- and 2,5-cis, while, 12 was 2,3-cis and 2,5-trans.
On further hydrolysis (aq. AcOH-conc. HCl-cat.) lac-
tones 11 and 12 furnished the lactols 13 and 14, respec-
b-anomeric stereocentre in 8a. Accordingly, 8a (Scheme
3) on cyclisation with n-Bu SnH, as described for 8,
3
gave 9a and 10a in a 1.5:1 ratio. This result amply
indicated the effect of the 2%-stereocentre in 8 (a-OMe)
and 8a (b-OMe) on the cyclisation.
tively. Finally, PDC oxidation of 13 and 14 in CH Cl2
In a further study, 9a and 10a were converted into
lactones 11a and 12a, respectively, with RuCl –NaIO
and subsequently transformed into the lactols 13 and
14. Finally, oxidation of 13 and 14 resulted in the
2
independently afforded 2 and 1, respectively, whose
3
4
optical rotation values and spectroscopic data were
10
comparable with reported values.
Scheme 3. Reagents and conditions: (a) n-Bu SnH, dry benzene, AIBN, reflux, 12 h, 84%; (b) CH Cl :CH CN:H O (2:2:3), NaIO ,
3
2
2
3
2
4
cat. RuCl ·H O, rt, 18 h; (c) 60% CH COOH, 60°C, 30 min; (d) PDC, dry CH Cl , reflux, 2 h.
3
2
3
2
2

G. V. M. Sharma, T. Gopinath / Tetrahedron Letters 42 (2001) 6183–6186
6185
1
formation of 2 and 1, which were identical in all
respects with the products prepared from the a-anomer
8.
CHCl ); H NMR (200 MHz, CDCl ): l 0.92 (t, 3H,
3
3
J=7.4 Hz, CH ), 1.18–1.50 (m, 7H, 2CH , CH ), 1.58–
1.76 (m, 2H, CH ), 2.50 (dq, 1H, J=8.2, 7.7 Hz, H-5),
.65 (dd, 1H, J=8.2, 4.5 Hz, H-2), 3.30 (s, 3H, OMe),
3
2
3
2
2
During the radical cyclisation of 8 and 8a, the effect of
the 2%-stereocentre in the xanthate in altering the ratios
of the products 9 and 10 (3:1) 9a and 10a (1.5:1), may
be explained as depicted in Fig. 1.
3.96 (ddd, 1H, J=6.9, 5.9, 4.1 Hz, H-4), 4.77 (s, 1H,
H-1), 4.89 (dd, 1H, J=6.9, 4.5 Hz, H-3); FABMS: 228
+
−1
(M ); IR (neat); 1770 cm ; Compound 11a: [h] =
D
1
+37.73 (c 0.50, CHCl
); H NMR (200 MHz, CDCl
): l
3
3
0
.92 (t, 3H, J=7.2 Hz, CH ), 1.22–1.54 (m, 7H, 2CH ,
3
2
Compound 8 (R=OMe) undergoes cyclisation through
CH ), 1.64–1.80 (m, 2H, CH ), 2.84 (dq, 1H, J=8.9, 7.3
Hz, H-5), 2.98 (dd, 1H, J=9.1, 6.9 Hz, H-2), 3.32 (s,
3
2
‘
chair-like’ transition state ‘A’ to give the 2,5-cis
3
H, OMe), 3.98 (ddd, 1H, J=7.7, 7.4, 3.2 Hz, H-4),
.80 (dd, 1H, J=6.9, 3.2 Hz, H-3), 4.94 (s, 1H, H-1);
product 9 (major) while the minor product 10 results
through the transition state ‘B’. Similarly, 8a (R%=
OMe) gave 9a through transition state ‘A’ while 10a is
formed through transition state ‘B’. In the case of
cyclisation of 8, the 2,5-cis product 9 is the major
product, where the a-OMe (C-1) and Me (C-5) are
placed apart from each other. However, due to the
presence of the b-OMe in 8a, the cyclisation resulted in
the prodcuts 9a and 10a in almost equal quantities
4
+
−1
FABMS: 228 (M ); IR (neat); 1770 cm ; Compound 1:
10
mp 92°C; lit. mp 94°C; [h] =+30.9 (c 0.50, CHCl );
D
3
10
1
lit. [h] =+29.8 (c 0.35, CHCl ); H NMR (400 MHz,
D
3
CDCl ): l 0.92 (t, 3H, J=7.6 Hz, CH ), 1.38–1.55 (m,
3
3
7
H, 2CH , CH ), 1.76–1.98 (m, 2H, CH ), 3.02 (dq, 1H,
2 3 2
J=8.0, 1.2 Hz, H-5), 3.08 (dd, 1H, J=6.4, 1.2 Hz,
H-2), 4.50 (ddd, 1H, J=7.2, 6.8, 4.4 Hz, H-4), 5.05 (dd,
1
13
H, J=6.4, 4.4 Hz, H-3); C NMR (125 MHz,
(
1.5:1). This change in the ratios of 2,5-cis to 2,5-trans
CDCl ): l 13.8, 17.1, 22.4, 27.5, 28.5, 38.3, 49.0, 78.3,
products for the cyclisation of 8a, may be attributed to
the steric interaction between the b-OMe and the C-5
methyl group in 9a, which is less pronounced in 10a.
3
+
8
1
2.4, 174.6, 176.7; FABMS: 213 (M +1); IR (CHCl ):
3
−1
770 cm ; Compound 2: mp 53°C; [h] =−18.02 (c 0.75,
D
10
1
CHCl ); lit. [h] =−20.2 (c 0.50, CHCl ); H NMR
3
D
3
(
500 MHz, CDCl ): l 0.92 (t, J=7.2 Hz, 3H, CH ),
3
3
Thus, in the present study the first radical mediated
route was developed for the synthesis of 1 and its
C-3-epimer 2. The formation of the 2,5-trans product
and the change in the ratios of the products formed
from the b-anomer, clearly indicate the effect of the
1
.30−1.54 (m, 7H, 2CH , CH ), 1.74–1.94 (m, 2H,
2 3
CH ), 3.08 (dq, 1H, J=10.0, 7.3 Hz, H-5), 3.45 (dd,
2
1
4
H, J=10.0, 6.0 Hz, H-2), 4.50 (ddd, 1H, J=7.2, 6.8,
13
.5 Hz, H-4), 5.02 (dd, 1H, J=6.0, 4.5 Hz, H-3);
C
NMR (125 MHz, CDCl ): l 10.9, 13.8, 22.4, 27.4, 28.4,
3
2%-stereocentre, which was well exploited for the suc-
+
3
1
6.6, 44.6, 77.9, 81.6, 172.0, 176.2; FABMS: 213 (M +
); IR (CHCl ): 1770 cm .
cessful synthesis of 1.
−1
3
Spectral analysis for selected compounds
1
Acknowledgements
Compound 11: [h] =+36.48 (c 0.50, CHCl ); H NMR
D
3
(
200 MHz, CDCl ): l 0.92 (t, 3H, J=7.3 Hz, CH ),
3
3
1
.20–1.50 (m, 7H, 2CH , CH ), 1.64–1.82 (m, 2H,
2 3
T. Gopinath is thankful to UGC, New Delhi, for
financial support.
CH ), 2.86 (dq, 1H, J=9.8, 7.0 Hz, H-5), 3.0 (dd, 1H,
J=9.8, 6.9 Hz, H-2), 3.32 (s, 3H, OMe), 4.02 (ddd, 1H,
J=7.9, 4.3, 3.6 Hz, H-4), 4.82 (dd, 1H, J=6.9, 3.6 Hz,
2
+
H-3), 4.96 (s, 1H, H-1); FABMS: 228 (M ); IR (neat);
References
−
1
1
770 cm ; Compound 12: [h] =+11.36 (c 0.50, CHCl );
D
3
1
H NMR (200 MHz, CDCl ): l 0.92 (t, 3H, J=7.35
3
1
. Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma,
G.; Kulicke, K. J.; Trach, F. In Radical Cylisation Reac-
tions in Organic Reactions; Paquet, L. A.; et al., Eds.;
John Wiley & Sons, 1996; Vol. 48, p. 301.
Hz, CH ), 1.16–1.50 (m, 7H, 2CH , CH ), 1.58–1.72 (m,
3
2
3
2
1
1
H, CH ), 2.50 (dq, 1H, J=9.1, 6.8 Hz, H-5), 2.64 (dd,
H, J=9.1, 4.5 Hz, H-2), 3.30 (s, 3H, OMe), 3.94 (ddd,
H, J=6.9, 6.8, 4.5 Hz, H-4), 4.76 (s, 1H, H-1), 4.86
2
2
3
. Sharma, G. V. M.; Vepachedu, S. R. Tetrahedron Lett.
+
(dd, 1H, J=6.8, 4.5 Hz, H-3); FABMS: 228 (M ); IR
1
990, 31, 4931–4932.
. Sharma, G. V. M.; Vepachedu, S. R. Tetrahedron 1991,
7, 519–524.
−
1
(
neat); 1770 cm ; Compound 12a: [h] =+13.96 (c 0.50,
D
4
C H
O
C H
4 9
O
4
9
4. Sharma, G. V. M.; Krishnudu, K.; Mahender Rao, S.
R’
R’
Tetrahedron: Asymmetry 1995, 6, 543–548.
H
H
5
6
7
. Sharma, G. V. M.; Krishnudu, K. Tetrahedron Lett.
1995, 36, 2661–2664.
R
R
. Sharma, G. V. M.; Krishnudu, K. Tetrahedron: Asymme-
try 1999, 10, 869–875.
. McCorkindale, N. J.; Wright, J. L.; Brian, P. W.; Clarke,
S. M.; Hutchinson, S. A. Tetrahedron Lett. 1968, 727–
O
O
H
(
H
TsA
Chair)
TsB
(Boat)
730.
8. Kato, M.; Kageyama, M.; Tanaka, R.; Kuwahara, K.;
Figure 1.
Yoshikoshi, A. J. Org. Chem. 1975, 40, 1932–1941.

6
186
G. V. M. Sharma, T. Gopinath / Tetrahedron Letters 42 (2001) 6183–6186
9. Mulzer, J.; Kattner, L. Angew. Chem., Int. Ed. Engl. 3925–3941.
1
990, 29, 679–680.
0. Chen, M.-J.; Narkunan, K.; Liu, R. S. J. Org. Chem.
999, 64, 8311–8318.
1. Nubbemeyer, U. J. Org. Chem. 1996, 61, 3677–
686.
14. Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52,
1
1
1
1
959–974.
1
15. Moravcova, J.; Capkova, J.; Stanek, J. Carbohyd. Res.
1994, 263, 61–66.
16. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc.,
Perkin Trans. 1 1975, 1574–1585.
17. Ashby, E. C.; Goel, A. B. J. Org. Chem. 1981, 46,
3936–3938.
3
2. Rajanbabu, T. V.; Fukunaga, T.; Reddy, G. S. J. Am.
Chem. Soc. 1989, 111, 1759–1769.
3. Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41,
.