A total synthesis of toddaquinoline exposes a dual role for cobalt in radical additions to pyridines

Article abstract of DOI:10.1016/S0040-4039(00)01119-9

This paper describes the first total synthesis of toddaquinoline, an alkaloid from the root bark of Formosan Toddalia asiatica. Importantly, the synthesis has exposed a dichotomy in radical reactions mediated by tin and cobalt(I) that involve additions to pyridines. Our observations suggest that cobalt plays a dual role in such reactions: Firstly initiating homolysis of the carbon to halogen bond, then acting as a Lewis acid to promote radical additions to the carbon centre adjacent to nitrogen. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01119-9

Tetrahedron Letters 41 (2000) 6681±6683
A total synthesis of toddaquinoline exposes a dual role for
cobalt in radical additions to pyridines
David C. Harrowven,a,* Michael I. T. Nunn,a Nigel J. Blumirea
and David R. Fenwickb
aDepartment of Chemistry, The University, Southampton S017 1BJ, UK
bDiscovery Chemistry, P®zer Central Research, Sandwich, Kent CT13 9NJ, UK
Received 5 June 2000; accepted 29 June 2000
Abstract
This paper describes the ®rst total synthesis of toddaquinoline, an alkaloid from the root bark of
Formosan Toddalia asiatica. Importantly, the synthesis has exposed a dichotomy in radical reactions
mediated by tin and cobalt(I) that involve additions to pyridines. Our observations suggest that cobalt
plays a dual role in such reactions: ®rstly initiating homolysis of the carbon to halogen bond, then acting as
a Lewis acid to promote radical additions to the carbon centre adjacent to nitrogen. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: radicals and radical reactions; natural products; polycyclic heterocyclic compounds; cobalt and its
compounds; photochemistry; pyridines.
We recently reported a synthesis of toddaquinoline methyl ether 4 in which the intramolecular
addition of an aryl radical to a pyridine featured as the key step.1 3 One disappointing aspect of
that reaction was its lack of regiochemical control. Indeed, under standard tin-mediated radical
forming conditions addition of the aryl radical derived from 1 occurred with equal propensity to
C-4 and C-6 of the pyridine moiety leading to a 1:1 mixture of benzo[f]isoquinoline 3 and the
desired benzo[h]quinoline 4 (Scheme 1).1 In this letter we report two extensions that allow greater
control of the regiochemical course of cyclisation and report a synthesis of toddaquinoline which
required a change of protecting group.
Ring closure was readily biased in favour of benzo[f]isoquinoline 3 through recourse to a
photocyclisation of azastilbene 2. Thus, irradiation of a cyclohexane solution of 2 with a medium
pressure mercury lamp led to a readily separable 5:2 mixture of 3 and 4 after 16 hours. That
fusion of the rings preferentially occurred between C-6 of the benzodioxole and C-4 of the
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01119-9

6682
Scheme 1.
pyridine moiety was expected from literature precedent and has been rationalised in terms of
favourable molecular orbital interactions.4
More interesting was our ®nding that azastilbene 1, when exposed to sodium cobalt(I)
salophen,5 underwent radical cyclisation to give toddaquinoline methyl ether 4, exclusively. The
dichotomy between the regiochemical course of the tin and cobalt(I) mediated radical cyclisations
was quite unexpected and may be due to the Lewis acidic nature of cobalt(II) salophen (Scheme 2).
Thus, formation of complex 8 would enhance electrophilicity at C-6 in the pyridine thereby
accelerating addition of the nucleophilic aryl radical to that centre relative to C-4.
Finally, it is worth noting that our attempts to remove the methyl ether in 4 using a host of
deprotection methods either failed or provided toddaquinoline 11 in low yield. By switching to a
benzyl protecting group, toddaquinoline could be accessed in good yield (Scheme 3).6
In conclusion, we have developed a short total synthesis of toddaquinoline that has exposed a
dual role for cobalt in radical cyclisations to pyridines. We are presently examining further the
dichotomy between tin and cobalt(I)-mediated radical reactions in intramolecular additions to
heteroaromatic substrates.
Scheme 2.

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Scheme 3. Reagents and conditions: (a) 2 equiv. NaOBn, DMF, 65ꢀC, 90 min, 57%; (b) BuLi, THF, ^90ꢀC, 1 h;
DMF, ^90 to ^60ꢀC over 30 min; brine, 81%; (c) Br2, AcOH, 0ꢀC, 2 h, 70%; (d) PPh3, xylene, 80ꢀC, 5 h, 88%; (e)
NaH, THF, 0ꢀC, 10 min; rt, 2 h; add aldehyde over 10 min; rt, 2 h, 81% (E:Z, 2:5); (f) as Scheme 2; (g) H2, Pd±C, rt,
AcOH, 5 h, 86%
References
1. Harrowven, D. C.; Nunn, M. I. T. Tetrahedron Lett. 1998, 39, 5875.
2. Toddaquinoline was isolated from the root bark of Toddalia asiatica., see: (a) Chen, I. S.; Tsai, I. L.; Wu, S. J.;
Sheen, W. S.; Ishikawa, T.; Ishii, H. Phytochem. 1993, 34, 1449; (b) Chen, I. S.; Wu, S. J.; Tsai, I. L. J. Nat. Prod.
1994, 57, 1206.
3. For recent examples of intramolecular radical additions to pyridines, see: (a) de Mata, M. L. E. N.; Motherwell,
W. B.; Ujjainwalla, F. Tetrahedron Lett. 1997, 38, 141; (b) de Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla,
F. Tetrahedron Lett. 1997, 38, 137; (c) Murphy, J. A.; Sherburn, M. S. Tetrahedron 1991, 47, 4077.
4. For a review of photocyclisation reactions including azastilbenes, see: Mallory, F. B.; Mallory, C. W. Org. React.
1984, 30, 1.
5. (a) Pattenden, G. Chem. Soc. Rev. 1988, 17, 361; (b) Schrauzer, G. N. Angew. Chem., Int. Ed. Engl. 1976, 15, 417.
6. Our synthetic toddaquinoline exhibited spectral and physical characteristics identical to those reported in the
isolation papers.2