Preparation of 3-alkylpyridines. Formal total synthesis of haliclamines A and B

Article abstract of DOI:10.1016/S0040-4039(99)02120-6

The formal total synthesis of two sponge alkaloids Haliclamines A and B is achieved through the preparation of 3-alkylpyridines 3, 4 and 5 via an advanced common intermediate 6. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02120-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 733–736
Preparation of 3-alkylpyridines. Formal total synthesis of
Haliclamines A and B
Jack E. Baldwin,∗ Delyth A. James and Victor Lee
The Dyson Perrins Laboratory, South Parks Road, Oxford, OX1 3QY, UK
Received 5 October 1999; accepted 10 November 1999
Abstract
The formal total synthesis of two sponge alkaloids Haliclamines A and B is achieved through the preparation
of 3-alkylpyridines 3, 4 and 5 via an advanced common intermediate 6. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: sponge; pyridines; alkaloids; Haliclamines.
3-Alkylpyridine is a motif commonly found in sponge derived natural products.1 It has been su-
ggested that 3-alkylpyridines are plausible biosynthetic precursors for the complex manzamine and
related alkaloids.2 Recently this principle has been demonstrated by the biomimetic synthesis of sponge
alkaloid keramaphidin B.3,4 One subclass of these 3-alkylpyridine containing natural products is the bis-
pyridine macrocycles, exemplified by the cyclostellettamines5 (in pyridinium form) and Haliclamines6
(in tetrahydropyridine form).
Haliclamines A 1 and B 2 are two macrocyclic alkaloids isolated from the sponge of the genus
Haliclona by Fusetani et al.6 These compounds inhibit cell division of fertilized sea urchin and the
growth L1210 and P338 leukaemia cells. The total synthesis of Haliclamines A 1 and B 2 was reported
by Morimoto et al.7,8 In Morimoto’s synthesis, Haliclamine A 1 was obtained from precursors 3 and 4.
Similarly, union of precursors 3 and 5 gave Haliclamine B 2. Our continued interest in 3-alkylpyridine
derived sponge natural products9,10 prompted us to investigate an alternative synthesis of compounds 3,
4 and 5. We envisaged the use of an advanced intermediate 6 for the preparation of all three compounds
and kept the use of protecting groups to a minimum (Scheme 1).
Our synthesis began with the esterification11 of trans-β-hydromuconic acid 7 to give diester 8 in
90% yield. Reduction of diester 8 to diol 9 was effected in 78% yield with lithium aluminium hydride.
Selective monoprotection of diol 9 with tert-butyldiphenylsilyl chloride using McDougal’s protocol12
delivered alcohol 10 in 55% yield. Iodination of 10 by Corey’s method13,14 furnished iodide 6, the
common advanced intermediate, in 97% yield (Scheme 2).
∗
Corresponding author. E-mail: jack.baldwin@chem.ox.ac.uk (J. E. Baldwin)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02120-6
tetl 16048

734
Scheme 1.
Scheme 2. (1) MeOH/H2SO4; (2) LiAlH4/THF; (3) (a) NaH/THF, (b) TBDPSCl; (4) PPh3/I2/imidazole/Et2O/CH3CN
Iodide 6 was coupled with allyl magnesium chloride catalysed by lithium tetrachlorocuprate(II)15
to give diene 11 in 92% yield. Selective hydroboration16 of diene 11 with 9-BBN under ultrasound
irradiation17,18 followed by Suzuki coupling of the resultant alkylborane with 3-bromopyridine19,20
furnished compound 12 in 65% yield. Deprotection of 12 with ammonium fluoride in methanol21 gave
compound 3 in 40% yield (Scheme 3).
Scheme 3. (5) Allylmagnesium chloride/Li2CuCl4/THF; (6) (a) 9-BBN/THF/ultrasound, (b) 3-bromopyridine/Pd(PPh3)4/K3-
PO4(aq.)/THF; (7) NH4F/MeOH
To synthesise compound 4, intermediate 6 was coupled with 6-chlorohexylmagnesium iodide22 me-
diated by lithium tetrachlorocuprate(II) to give chloride 13 in 36% yield. Finkelstein reaction of 13 with
sodium iodide provided iodide 14 in 95% yield. Transmetallation of iodide 14 with tert-butyllithium fol-
lowed by the addition of 9-methoxy-9-borabicyclo[3.3.1]nonane generated the corresponding boronate
in situ.23 Suzuki coupling of this boronate with 3-bromopyridine delivered 15 in 72% yield. Deprotection
of 15 gave 4 in 77% yield (Scheme 4).
The synthesis of compound 5 commenced with the reaction of 6 with lithiated acetaldehyde
dimethylhydrazone24 to give dimethylhydrazone 16 in 79% yield. Deprotection of 16 with buffered
periodic acid25 at pH 4 provided aldehyde 17 in 63% yield. Wittig reaction of aldehyde 17 with ylide
generated from (4-chlorobutyl)triphenylphosphonium iodide26–30 furnished chloride 18 in 83% yield.
Iodide 19 was obtained in 63% yield from 18 via a Finkelstein reaction. Suzuki coupling of 19 with 3-
bromopyridine delivered 20 in 60% yield. Compound 20 was deprotected to give 5 in 40% yield (Scheme
5).
We have completed the synthesis of compounds 3, 4 and 5 using a series of σ-bond forming reactions

735
Scheme 4. (8) Cl(CH2)6MgI/Li2CuCl4/THF; (9) NaI/acetone/reflux; (10) (a) tBuLi, Et2O, (b) 9-BBN-OMe, (c)
3-bromopyridine/PdCl2(dppf)/K3PO4(aq.)/THF; (7) NH4F/MeOH
Scheme 5. (11) LDA/CH3CHNNMe2/THF; (12) H5IO6/HOAc/NaOAc/H2O/THF; (13) [Cl(CH2)4PPh3]+I−/KHMDS/THF; (9)
NaI/acetone/reflux; (10) (a) tBuLi/Et2O; (b) 9-BBN-OMe, (c) PdCl2(dppf)/3-bromopyridine/K3PO4(aq.)/THF; (7) NH4F/MeOH
and a minimal protection strategy. As compounds 3–5 were previously converted into Haliclamines, our
work constitutes a formal total synthesis of Haliclamines A 1 and B 2.
References
1. Andersen, R. J.; Van Soest, R. W. M.; Kong, F. In Alkaloids: Chemical and Biological Perspectives; Pelliter, S. W., Ed.;
Pergamon: London, 1996; Vol. 10, pp. 302–352.
2. Baldwin, J. E.; Whitehead, R. C. Tetrahedron Lett. 1992, 33, 2059–2062.
3. Baldwin, J. E.; Claridge, T. D. W.; Culshaw, A. J.; Heupel, F. A.; Lee, V.; Spring, D. R.; Whitehead, R. C.; Boughtflower, R.
J.; Mutton, I. M.; Upton, R. J. Angew. Chem., Int. Ed. 1998, 37, 2661–2663.
4. Baldwin, J. E.; Claridge, T. D. W.; Culshaw, A. J.; Heupel, F. A.; Lee, V.; Spring, D. R.; Whitehead, R. C. Chem. Eur. J.
1999, 5, 3154–3161.
5. Fusetani, N.; Asani, N.; Matsunaga, S.; Honda, K.; Yasumuro, K. Tetrahedron Lett. 1994, 35, 3967–3970.
6. Fusetani, N.; Yasumuro, K.; Matsunaga, S.; Hirota, H. Tetrahedron Lett. 1989, 30, 6891–6894.
7. Morimoto, Y.; Yokoe, C. Tetrahedron Lett. 1997, 38, 8981–8984.
8. Morimoto, Y.; Yokoe, C.; Kurihara, H.; Kinoshita, T. Tetrahedron 1998, 54, 12197–12214.
9. Baldwin, J. E.; Melman, A.; Lee, V.; Firkin, C. R.; Whitehead, R. C. J. Am. Chem. Soc. 1998, 120, 8559–8560.
10. Baldwin, J. E.; Spring, D. R.; Atkinson, C. E.; Lee, V. Tetrahedron 1998, 54, 13655–13680.
11. Gassman, P. G.; Bonser, S. M.; Mlinaric-Majerski, K. J. Am. Chem. Soc. 1989, 111, 2652–2662.
12. McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. D. J. Org. Chem. 1986, 51, 3388–3390.
13. Corey, E. J.; Pyne, S. G.; Su, W. Tetrahedron Lett. 1983, 24, 4883–4886.
14. Marshall, J. A.; Cleary, D. G. J. Org. Chem. 1986, 51, 858–863.
15. Scholsser, M.; Bossert, H. Tetrahedron 1991, 47, 6287–6292.
16. Liotta, R.; Brown, H. C. J. Org. Chem. 1977, 42, 2836–2839.
17. Brown, H. C.; Racherla, U. S. Tetrahedron Lett. 1985, 26, 2187–2190.
18. Crimmins, M. T.; Bankaitis-Davies, D. M.; Hollis, W. G. J. Org. Chem. 1988, 53, 652–657.
19. Alvarez, R.; Herrero, H.; López, S.; de Lera, A. R. Tetrahedron 1998, 54, 6793–6810.

736
20. Ishiyama, T.; Miyaura, N.; Suzuki, A. Org. Synth. 1993, 71, 89–95.
21. Zhang, W.; Robins, M. J. Tetrahedron Lett. 1992, 33, 1177–1180.
22. Bernady, K. F.; Poletto, J. F.; Nocera, J.; Mirando, P.; Schaub, R. E.; Weiss, M. J. J. Org. Chem. 1980, 45, 4702–4715.
23. Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885–7892.
24. Corey, E. J.; Enders, D. Chem. Ber. 1978, 111, 1337–1361.
25. Corlay, H.; Motherwell, W. B.; Pennell, A. M. K.; Shipman, M.; Slawin, A. M. Z.; Williams, D. J.; Binger, P.; Stepp, M.
Tetrahedron 1996, 52, 4883–4902.
26. Abouabdellah, A.; Bonnet-Delpon, D. Tetrahedron 1994, 50, 11921–11932.
27. Pearson, W. J.; Lin, K.-C. Tetrahedron Lett. 1990, 31, 7571–7574.
28. Pearson, W. J.; Hembre, E. J. Tetrahedron Lett. 1993, 34, 8221–8224.
29. Pearson, W. J.; Hembre, E. J. J. Org. Chem. 1996, 61, 5537–5545.
30. Pearson, W. J.; Suga, H. J. Org. Chem. 1998, 63, 9910–9918.