Synthesis of chiral trans-fused pyrano[3,2-c][2]benzoxocines from D-mannose by regioselective 8-endo-aryl radical cyclization

Article abstract of DOI:10.1016/S0040-4039(02)01252-2

A simple chiral synthesis of trans-pyrano[3,2-c][2]benzoxocines 8a-d in good yields (60-75%) through regioselective 8-endo-trig aryl radical cyclization of the D-mannose derived enopyranosides 7a-d with Bu₃SnH is described.

Full text of DOI:10.1016/S0040-4039(02)01252-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5977–5980
Synthesis of chiral trans-fused pyrano[3,2-c][2]benzoxocines from
D-mannose by regioselective 8-endo-aryl radical cyclization
Aniruddha Nandi and Partha Chattopadhyay*
Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Calcutta 700 032, India
Received 15 May 2002; revised 13 June 2002; accepted 27 June 2002
Abstract—A simple chiral synthesis of trans-pyrano[3,2-c][2]benzoxocines 8a–d in good yields (60–75%) through regioselective
8-endo-trig aryl radical cyclization of the
Science Ltd. All rights reserved.
D-mannose derived enopyranosides 7a–d with Bu3SnH is described. © 2002 Elsevier
The synthesis of conformationally flexible medium ring
ethers, the structural core of a large number of linearly
condensed cyclic polyether marine neurotoxins,1 has
received considerable attention.1,2 Interest in the use of
easily accessible carbohydrates from the chiral pool,
first recorded in the synthesis of 8- and 9-membered
ethers from sugar derivatives. We have reported11
a
convenient synthesis of chiral cis and trans-furo[3,2-
c][2]benzoxocines II through endo-trig aryl radical
cyclization via a Bu3SnH (TBTH) induced reaction of
the respective olefins Ia,b easily derived from D-glucose
(Eq. (1)).
ring ethers from D-glucose involving regioselective radi-
cal cyclization3 and Oxy–Cope rearrangement,4 respec-
tively, has been growing rapidly. In 1998, Nicolaou and
his group5 reported the total synthesis of brevetoxin-A,
which includes condensed 8- and 9-membered cyclic
In this communication, we record a simple and conve-
nient conversion of -mannose to the linearly benzan-
nulated tricyclic analogues (Scheme 2) of the
synthetically challenging trans 6,8-ring fused cyclic
ethers, a common structural feature present in many
bioactive marine neurotoxins,1 by 8-endo-trig aryl radi-
cal cyclization.12
D
ethers, from
D
-glucose and
D-mannose using
Yamaguchi lactonization and phosphate cross-coupling
reactions.6 Very recently, Hirama et al.7 have achieved
the total synthesis of the highly complex ciguatoxin
CTX3C from a series of sugar derivatives by chemose-
lective ring closing metathesis.
The key olefinic substrates 7a–d, for radical reaction,
were prepared from
D-mannose. Thus, the O-methyl
ether of mannopyranoside was transformed into diol
113 and then into alcohol 2, using conventional protec-
tion and deprotection protocols.16 O-Arylation of 2
These,8a,b,9 as well as a few other reactions,10 have also
been extended for the construction of medium ring
(1)
Keywords: pyranobenzoxocines; radical cyclization; Bu3SnH; carbohydrate.
* Corresponding author. Fax: +91-33-4730284; e-mail: partha@iicb.res.in, partha chatto@yahoo.co.in
–
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01252-2

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A. Nandi, P. Chattopadhyay / Tetrahedron Letters 43 (2002) 5977–5980
Scheme 1. (i) MeOH, H+ resin, reflux, 2 h, 70%; (ii) DMP, DMF, PTSA, rt,12 h, 70%; (iii) AcOH/H2O (1:3), 6 h, rt, stirring, 56%;
(iv) TBDMSCl, imidazole, CH2Cl2, 0°C, 1 h, stirring, 78%; (v) TBAB, 50% NaOH, CH2Cl2, 25°C, 8 h, 75–80%; (vi) TBAF, THF,
reflux, 4 h, 67–73%; (vii) DMSO, (COCl)2, CH2Cl2, −40°C, 1 h and then Et3N, −40°C to rt; (viii) Ph3PꢀCH2, THF, −78°C to rt,
overall yield 50–60% two steps from 5.
with each of the bromides 3a–d using TBAB/aq. NaOH
under phase transfer conditions afforded the respective
O-2-bromobenzylated mannopyranosides 4a–d. Depro-
tection of silyl ethers 4a–d to 5a–d was realized smoothly
in the presence of TBAF/THF. Swern oxidation of 5a–d,
according to the procedure described by Sinay¨,17
afforded the corresponding hydrates of aldehydes 6a–d.
After azeotropic removal of the water of hydration, each
of these crude intermediates 6a–d was submitted to
Wittig olefination18 to afford a single epimer of enopy-
ranosides 7a–d in good yields (50–60%) in each case
(Scheme 1). The assigned stereochemistry is based upon
the comparison of the reported J values for comparable
products by Aurrecoechea et al.18 Unlike the low yields
(15–20%) of the trans-furobenzoxocines (IIb)11 due to the
unfavorable steric disposition from the parent enofura-
nosides (Ib) compared to those in cis-olefins (Ia) (Eq. (1)),
radical cyclization of each of the enopyranosides 7a–d
with TBTH and a catalytic amount of AIBN in refluxing
benzene furnished the respective crystalline tricyclic
ethers 8a–d (Scheme 2) in good yields (60–75%) as the
only isolable product after separation of tin compounds19
followed by chromatography. The assigned structures† of
the products 8a–b resulting from 8-endo-aryl radical
cyclization‡ were based upon spectroscopic data.22
Scheme 2. (i) TBTH (3 equiv.), AIBN, benzene, reflux (300 W
lamp), 4 h, 60–75%.
1
In the H spectra of 8a–d,22,23 the furthest downfield
signal due to a sugar proton could be assigned to H-2;
it appears around l 4.7 as a singlet, indicating that the
dihedral angle between H-2 and H-3 is ca. 90°. The signal
due to H-3 exhibits a doublet around l 4.0 (J=5.7–6 Hz),
being coupled to both H-3 and H-4a and the signal due
to H-4 appears as a triplet at l 4.2 (J=6 Hz). The H-4a
signal exhibits a double doublet pattern around l 3.4–3.5
(J4,4a=6.3–6.6, J4a,12a=9.6–9.9 Hz). A double triplet
could be assigned to H-12a near l 3.5–3.7 (Jb12a,12H=9.6–
9.9, J4a,12a=9.6–9.9, Ja12a,12H=6.3 Hz) being split by
H-4a, Hb of H2-12 and Ha of H2-12.
† Assignment of the trans geometry of the pyranoxocine ring in 8a–d
is supported by 1H–1H COSY results and decoupling studies (J4a,12a
9.9 Hz suggesting a trans assignment).
In conclusion we have demonstrated the usefulness of the
present methodology for the convergent syntheses of
benzannulated analogues of the trans-6,8-fused ring
ether systems common to marine neurotoxins, starting
from sugar derivatives.
‡ As predicted by MO calculations and experimentally corroborated
by Beckwith (Ref. 20) and others (Refs. 8a,12,21), 8-endo cycliza-
tion is preferred over the 7-exo process.

A. Nandi, P. Chattopadhyay / Tetrahedron Letters 43 (2002) 5977–5980
5979
Acknowledgements
11. Nandi, A.; Mukhopadhyay, R.; Chattopadhyay, P. J.
Chem. Soc., Perkin Trans. 1 2001, 3346–3351.
12. Ghosh, K.; Ghosh, A. K.; Ghatak, U. R. J. Chem. Soc.,
Chem. Commun. 1994, 629–630.
We are grateful to DST (Government of India) for
financial support, CSIR for a JRF to A.N., and Profes-
sor U. R. Ghatak for his suggestions and advice. The
authors thank Dr B. Achari of our Institute for his
valuable advice regarding NMR analyses and Dr R.
Mukhopadhyay for providing 1H–1H COSY and
decoupling spectra. We are indebted to Dr A. Bhat-
tacharjya of our Department for his interest in this
work.
13. Diisopropylidination of methyl
D-mannopyranoside and
its selective hydrolysis to diol 1 was realized according to
the reported procedures.14,15
14. Evans, M. E. Methods Carbohydrate Chem. 1980, 8,
169–171.
15. Gelas, J.; Horton, D. Carbohydrate Res. 1978, 67, 371–
387.
16. The conversion of primary alcohol 1 to the respective
silyl derivative 2 was achieved by stirring with TBDM-
SCl, imidazole in anhydrous CH2Cl2 for 1 h at 0°C (cf.
Malmstro¨m, J.; Gupta, V.; Engman, L. J. Org. Chem.
1998, 63, 3318–3323).
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22. Satisfactory elemental analyses and spectroscopic data
were obtained for all new compounds. Selected data for
8a: mp: 94–95°C; [h]2D9 +52.7 (c 1.1, CHCl3); 1H NMR
(300 MHz, CDCl3): l=1.33 (3H, s, CH3), 1.38 (3H, s,
CH3), 1.60–1.71 (1H, m, Ha of H2-12), 2.29–2.38 (1H, m,
Hb of H2-12), 2.73–2.80 (1H, brt, Ha of H2-11), 3.22–3.34
(1H, t-like, overlapped by OCH3 signal, Hb of H2-11),
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Commun. 1997, 2139–2140.
4. Sudha, A. V. R. L.; Nagarajan, M. Chem. Commun.
3.34 (3H s, OCH3), 3.47–3.52 (1H, dd, J4,4a=6.6, J4a,12a
=
=
1996, 1359–1360.
9.9 Hz, H-4a), 3.59–3.68 (1H, dt, Jb12a,12H=9.9, J4a,12a
5. Nicolaou, K. C.; Yang, Z.; Shi, G.-Q.; Gunzner, J. L.;
Agrios, K. A.; Ga¨rtner, P. Nature 1998, 392, 264–269.
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Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–
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7. Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.;
Maruyama, M.; Oguri, H.; Satake, M. Science 2001, 294,
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8. (a) For functionalized medium sized carbocyclic rings,
from carbohydrates, through radical cyclization, see
Marco-Contelles, J.; de Opazo, E. Tetrahedron Lett.
2000, 41, 5341–5345 and References cited therein; (b)
Medium sized cyclic ethers, from carbohydrates, through
radical cyclization, see Leeuwenburgh, M. A.; Litzens, R.
E. J. N.; Codee, J. D. C.; Overkleeft, H. S.; Van der
Marel, G. A.; Van Boom, J. H. Org. Lett. 2000, 2,
1275–1277 and References cited therein.
9. For medium sized rings through RCM from carbohy-
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Tetrahedron Lett. 1998, 39, 8321–8324; (b) Dirat, O.;
Vidal, T.; Langlois, Y. Tetrahedron Lett. 1999, 40, 4801–
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Panda, J.; Ghosh, S. J. Org. Chem. 2000, 65, 482–493 and
References cited therein; (d) Oishi, T.; Kosaka, M.;
Hirama, M. Chem. Commun. 2001, 381–382.
9.9, Ja12a,12H=6.3 Hz, H-12a), 4.06 (1H, d, J=5.7 Hz,
H-3), 4.21–4.25 (1H, t, J=6 Hz, H-4), 4.73 (1H, s, H-2),
4.87 (1H, d, J=14 Hz, Ha of ArCH2), 5.14 (1H, d, J=14
Hz, Hb of ArCH2), 7.01–7.26 (4H, m, Ar-H); 13C NMR
(75 MHz, CDCl3): l 26.60 (CH3), 28.12 (CH3), 29.66
(CH2), 35.20 (CH2), 55.34 (OCH3), 67.50 (CH), 73.81
(CH2), 75.83 (CH), 77.69 (CH), 78.47 (CH), 98.19 (CH),
109.60(C), 126.79 (CH), 128.34 (CH), 128.55 (CH),
131.74 (CH), 136.23 (C), 142.35 (C). MS (EI) m/z 320
(M+, 10%); 8b: mp: 90–91°C; [h]D29 +22.9 (c 0.8, CHCl3);
1H NMR (300 MHz, CDCl3): l=1.33 (3H, s, CH3), 1.40
(3H, s, CH3), 1.60–1.67 (1H, m, Ha of H2-12), 2.28–2.32
(1H, m, Hb of H2-12), 2.71–2.75 (1H, brt, Ha of H2-11),
3.14–3.21 (1H, t, J=12 Hz, Hb of H2-11), 3.34 (3H, s,
OCH3), 3.46–3.52 (1H, dd, J4,4a=6.6, J4a,12a=9.9 Hz,
H-4a), 3.56–3.67 (1H, dt, Jb12a,12H=9.9,
J4a,12a=9.9,
Ja12a,12H=6.3 Hz, H-12a), 3.77 (3H, s, OCH3), 4.06 (1H,
d, J=5.7 Hz, H-3), 4.21–4.25 (1H, t, J=6 Hz, H-4), 4.73
(1H, s, H-2), 4.81 (1H, d, J=14.5 Hz, Ha of Ar-CH2),
5.10 (1H, d, J=14.5 Hz, Hb of Ar-CH2), 6.56 (1H, s,
Ar-H), 6.77 (1H, dd, J=8.4, 2.4 Hz Ar-H), 7.05 (1H, d,
J=8.3 Hz, Ar-H); 13C NMR (75 MHz, CDCl3): l 26.57
(CH3), 28.16 (CH3), 28.86 (CH2), 35.51 (CH2), 55.34
(OCH3), 55.66 (OCH3), 67.51 (CH), 73.79 (CH2), 75.84
(CH), 77.95 (CH), 78.45 (CH), 98.21 (CH), 109.60 (C),
113.61 (CH), 113.68 (CH), 132.81 (CH), 134.36 (C),
137.49 (C), 158.45 (C) ppm. MS (EI) m/z 350 (M+, 73%);
8c: mp: 56–58°C; [h]2D9 +15.2 (c 1.6, CHCl3); 1H NMR
(300 MHz, CDCl3), l=1.33 (3H, s, CH3), 1.39 (3H, s,
10. (a) Inoue, M.; Sasaki, M.; Tachibana, K. J. Org. Chem.
1999, 64, 9416–9429; (b) Takai, S.; Ploypradith, P.;
Hamazima, A.; Kira, K.; Isobe, M. Synlett 2002, 588–
592.

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A. Nandi, P. Chattopadhyay / Tetrahedron Letters 43 (2002) 5977–5980
CH3), 1.62–1.72 (1H, m, Ha of H2-12), 2.24–2.31 (1H, m,
1.58–1.67 (1H, m, Ha of H2-12), 2.23–2.32 (1H, m, Hb of
H2-12), 2.62–2.70 (1H, brt, Ha of H2-11), 3.11–3.19 (1H,
brt, Hb of H2-11), 3.34 (3H, s, OCH3), 3.48–3.53 (1H, dd,
Hb of H2-12), 2.66–2.74 (1H, brt, Ha of H2-11), 3.12–3.20
(1H, t, J=12 Hz, Hb of H2-11), 3.34 (3H, s, OCH3),
3.48–3.53 (1H, dd, J4,4a=6.3, J4a,12a=9.6 Hz, H-4a),
3.51–3.67 (1H, dt, Jb12a,12H=9.6, J4a,12a=9.6, J1a2a,12H=6.3
Hz, H-12a), 3.83 (3H, s, OCH3), 3.88 (3H, s, OCH3), 4.06
(1H, d, J=6 Hz, H-3), 4.21–4.26 (1H, t, J=6 Hz, H-4),
4.72 (1H, s, H-2), 4.76 (1H, d, J=14 Hz, Ha of ArCH2),
5.06 (1H, d, J=14 Hz, Hb of ArCH2), 6.55 (1H, s, ArH),
6.65 (1H, s, ArH); 13C NMR (75 MHz, CDCl3), l 26.10
(CH3), 27.67 (CH3), 28.80 (CH2), 34.82 (CH2), 55.00
(OCH3), 55.95 (OCH3), 56.02 (OCH3), 67.50 (CH), 72.74
(CH2), 75.29 (CH), 76.81 (CH), 77.98 (CH), 98.00 (CH),
109.13 (C), 111.47 (CH), 114.26 (CH), 127.52 (C), 134.18
(C), 147.28 (C). 148.57 (C), MS (EI) m/z 380 M+, 95%);
J
4,4a=6.6, J4a,12a=9.9 Hz, H-4a), 3.57–3.66 (1H, dt,
Jb12a,12H=9.9, J4a,12a=9.9, Ja12a,12H=6.3 Hz, H-12a), 4.05
(1H, d, J=6 Hz, H-3), 4.19–4.23 (1H, t, J=6 Hz, H-4),
4.71 (1H, s, H-2), 4.72 (1H, d, J=14 Hz, Ha of ArCH2),
5.00 (1H, d, J=14 Hz, Hb of ArCH2), 5.92 (2H, s,
O-CH2-O), 6.53 (1H, s, Ar-H), 6.63 (1H, s, Ar-H); 13C
NMR (75 MHz, CDCl3), l 26.47 (CH3), 28.12 (CH3),
29.38 (CH2), 35.15 (CH2), 55.40 (OCH3), 67.82 (CH),
73.15 (CH2), 75.72 (CH), 77.12 (CH), 78.37 (CH), 98.44
(CH), 101.37 (O-CH2-O), 108.73 (CH), 109.54 (C), 111.40
(CH), 129.06 (C), 135.98 (C), 146.43 (C), 147.77 (C); MS
(EI) m/z 364 (M+, 75%).
23. The 1H NMR assignments are based on 1H–1H COSY
results.
1
8d: mp: 77°C; [h]2D9 +30.8 (c 1.2, CHCl3); H NMR (300
MHz, CDCl3), l=1.33 (3H, s, CH3), 1.40 (3H, s, CH3),