Total syntheses of justicidin B and retrojusticidin B using a tandem Horner-Emmons-Claisen condensation sequence

Article abstract of DOI:10.1016/S0040-4039(01)01436-8

Short syntheses of justicidin B 1 and retrojusticidin B 4 are reported. The key feature is a new annulation reaction, involving a base induced union of ketoaldehyde 2 and phosphonate 3, that is used to construct the highly substituted naphthalene core.

Full text of DOI:10.1016/S0040-4039(01)01436-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6973–6975
Total syntheses of justicidin B and retrojusticidin B using a
tandem Horner–Emmons–Claisen condensation sequence
David C. Harrowven,a,* Mark Bradley,a J. Lois Castrob and Stuart R. Flanagana
aDepartment of Chemistry, The University, Southampton S017 1BJ, UK
bThe Neuroscience Research Centre, Merck Sharp & Dohme, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
Received 27 June 2001; accepted 3 August 2001
Abstract—Short syntheses of justicidin B 1 and retrojusticidin B 4 are reported. The key feature is a new annulation reaction,
involving a base induced union of ketoaldehyde 2 and phosphonate 3, that is used to construct the highly substituted naphthalene
core. © 2001 Elsevier Science Ltd. All rights reserved.
The arylnaphthalene lignans have attracted consider-
able attention in recent years with biological studies
uncovering a host of potentially exploitable activities.1
These include the inhibition of leukotriene biosynthesis
by human leukocytes,2 as well as antitumour,3 antifun-
gal,4 hypolipidemic,5 antiviral and anti-PAF activity.6,7
Unsurprisingly, many synthetic entries to this family
of natural products have been developed.1 In this Let-
ter we report a new approach that has culminated in
short syntheses of justicidin B 1 and retrojusticidin B
4, a recently identified natural product and inhibitor
of HIV-1 reverse transcriptase.8,9 A key feature is the
base induced union of ketoaldehyde 2 and phospho-
nate 3 by sequential Horner–Emmons and Claisen
condensations, used to construct the highly substituted
naphthalene core (Scheme 1).10
Sequential treatment of 7 with sodium hydride
and butyllithium next facilitated union with piperonal
to give diol 8 which was oxidized with PCC on
alumina to give ketoaldehyde 2.12 Simultaneous addi-
tion of this material 2 and phosphonate 3 to a cooled
(0°C) solution of sodium ethoxide in THF–
ethanol then effected the desired annulation, giving a
14:1 ratio of diester 9 and acid 10 in 73% yield
(Scheme 2).
To complete the total syntheses of justicidin B and
retrojusticidin B was straightforward from this junc-
ture.6,13 Thus, diester 9 was first hydrolyzed to acid 10
with potassium trimethylsilanolate.13 Reduction of 10
with borane dimethylsulfide complex then gave justi-
cidin B 1 after an acidic work-up while reduction of
the sodium salt of 10 with lithium borohydride gave
retrojusticidin B 4 as the major product, together with
some justicidin B 1 (Scheme 3).
Each synthesis began with the known conversion of
veratraldehyde 5 into 6-bromoveratryl alcohol 7.11
Scheme 1.
Keywords: natural products; annulation; lignans; Horner–Emmons; Claisen condensation.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01436-8

6974
D. C. Harrow6en et al. / Tetrahedron Letters 42 (2001) 6973–6975
Scheme 2.
Scheme 3.
In conclusion, we have developed a new annulation
reaction based on the union of a ketoaldehyde and
phosphonate 3 by sequential Horner–Emmons and
Claisen condensation reactions.14 The utility of the
method has been demonstrated through the total syn-
thesis of two arylnaphthalene lignans, justicidin B 1 and
retrojusticidin B 4. We are presently seeking to extend
the scope of this method to other ring systems and to
exploit it in combinatorial library synthesis.
2. (a) Hutchinson, J. H.; Charleson, S.; Evans, J. F.; Fal-
gueyret, J.-P.; Hoogsteen, K.; Jones, T. R.; Kargman, S.;
Macdonald, D.; Mcfarlane, C. S.; Nicholson, D. W.;
Piechuta, H.; Riendeau, D.; Scheigetz, J.; Therien,
M.; Girard, Y. J. Med. Chem. 1995, 38, 4538;
(b) Delorme, D.; Ducharme, Y.; Brideau, C.; Chan, C.
C.; Chauret, N.; Desmarais, S.; Dube, D.; Falgueyret, J.
P.; Fortin, R.; Guay, J.; Hamel, P.; Jones, T. R.; Lepine,
C.; Li, C.; McAuliffe, M.; McFarlane, C. S.;
NicollGriffith, D. A.; Riendeau, D.; Yergey, J. A.;
Girard, Y. J. Med. Chem. 1996, 39, 3951 and references
cited therein.
Acknowledgements
3. (a) Pradheepkumar, C. P.; Panneerselvam, N.; Shan-
mugam, G. Mutat. Res. 2000, 464, 185; (b) Prabhakaran,
C.; Kumar, P.; Panneerselvam, N.; Rajesh, S.; Shan-
mugam, G. Mutagenesis 1996, 11, 553 and references
cited therein.
The authors thank Merck Sharp and Dohme for their
financial support.
4. Atta-ur-Rahman; Ashraf, M.; Choudhary, M. I.; Habib-
ur-Rehman; Kazmi, M. H. Phytochemistry 1995, 40, 427
and references cited therein.
References
5. Iwasaki, T.; Kondo, K.; Nishitani, T.; Kuroda, T.;
Hirakoso, K.; Ohtani, A.; Takashima, K. Chem. Pharm.
Bull. 1995, 43, 1701 and references cited therein.
6. Cow, C.; Leung, C.; Charlton, J. L. Can. J. Chem. 2000,
78, 553 and references cited therein.
1. For recent overviews of lignan natural products, see: (a)
Ward, R. S. Nat. Prod. Rep., 1990, 7, 349; (b) Ward, R.
S. Nat. Prod. Rep. 1993, 10, 1; (c) Ward, R. S. Nat. Prod.
Rep. 1995, 12, 183; (e) Ward, R. S. Nat. Prod. Rep. 1997,
14, 43; (f) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75.

D. C. Harrow6en et al. / Tetrahedron Letters 42 (2001) 6973–6975
6975
7. Tanabe, Y.; Seko, S.; Nishii, Y.; Yoshida, T.; Utsumi,
N.; Suzukamo, G. J. Chem. Soc. Perkin Trans. 1 1996,
2157 and references cited therein.
Ward, R. S.; Satyanarayana, P.; Collins, P. Tetrahedron
Lett. 1982, 23, 571; (c) Satyanarayana, P.; Rao, P. K.
Indian J. Chem. Sect. B 1985, 151; (d) Charlton, J. L.;
Oleschuk, C. J.; Chee, G.-L. J. Org. Chem. 1996, 61,
3452; (e) Chang, C. W.; Lin, M. T.; Lee, S. S.; Liu, K. C.
S. C.; Hsu, F. L.; Lin, J. Y. Antiviral Res. 1995, 27, 367.
10. For other annulation reactions involving phosphonate 3,
see: (a) Linke, S.; Kurz, J.; Lipinski, D.; Gau, W. Liebigs
Ann. Chem. 1980, 542; (b) Dhokte, U. P.; Rao, A. S.
Indian J. Chem. Sect. B 1990, 29, 1089; (c) Kadin, S. B.;
Lamphere, C. H. J. Org. Chem. 1984, 49, 4999; (d)
Rozhkov, E.; Piskunova, I.; Gol’d, M.; Kalvin’sh, I.
Chem. Heterocycl. Compd. (Engl. Transl.) 1998, 34, 77.
11. (a) Crombie, L.; Josephs, J. L. J. Chem. Soc., Perkin
Trans. 1 1993, 2599; (b) Paleo, M. R.; Lamas, C.;
Castedo, L.; Dominguez, D. J. Org. Chem. 1992, 57,
2029; (c) Khanapure, S. P.; Biehl, E. R. J. Org. Chem.
1990, 55, 1471.
12. Harrowven, D. C.; Newman, N. A.; Knight, C. A. Tetra-
hedron Lett. 1998, 39, 6757.
13. Padwa, A.; Cochran, J. E.; Kappe, C. O. J. Org. Chem.
1996, 61, 3706.
14. For an alternative approach to the arylnaphthalene lig-
nans developed in our laboratories see (a) Harrowven, D.
C.; Dennison, S. T. Tetrahedron Lett. 1993, 34, 3323; (b)
Harrowven, D. C. Tetrahedron Lett. 1991, 32, 3735; (c)
Harrowven, D. C. Tetrahedron 1993, 49, 9039.
8. Justicidin B is found widely in nature. See: (a) Asano, J.;
Chiba, K.; Tada, M.; Yoshii, T. Phytochemistry 1996, 43,
713; (b) Sheriha, G. M.; Amer, K. M. A. Phytochemistry
1984, 23, 151; (c) Bachmann, T. L.; Ghia, F.; Torssell, K.
B. G. Phytochemistry 1993, 33, 189; (d) Goezler, B.; Arar,
G.; Goezler, T.; Hesse, M. Phytochemistry 1992, 31, 2473;
(e) Pettit, G. R.; Cragg, G. M.; Suffness, M. I.; Gust, D.;
Boettner, F. E.; Williams, M.; Saenz-Renauld, J. A.;
Brown, P.; Schmidt, J. M.; Ellis, P. D. J. Org. Chem.
1984, 49, 4258; (f) Okigawa, M.; Maeda, T.; Kawano, N.
Tetrahedron 1970, 26, 4301. For previous syntheses, see:
(g) Ogiku, T.; Seki, M.; Takahashi, M.; Ohmizu, H.;
Iwasaki, T. Tetrahedron Lett. 1990, 31, 5487; (h) Banerji,
J.; Das, B.; Chatterjee, A.; Shoolery, J. N. Phytochemistry
1984, 23, 2323; (i) de Silva, S. O.; St. Denis, C.; Rodrigo,
R. J. Chem. Soc., Chem. Commun. 1980, 995; (j) Kamal,
A.; Daneshtalab, M.; Micetich, R. G. Tetrahedron Lett.
1994, 35, 3879; (k) Ogiku, T.; Yoshida, S.-i.; Ohmizu, H.;
Iwasaki, T. J. Org. Chem. 1995, 60, 4585; (l) Kobayashi,
K.; Tokimatsu, J.; Maeda, K.; Morikawa, O.; Konishi,
H. J. Chem. Soc., Perkin Trans. 1 1995, 3013; (m) Charl-
ton, J. L.; Oleschuk, C. J.; Chee, G.-L. J. Org. Chem.
1996, 61, 3452.
9. (a) Pelter, A.; Ward, R. S.; Satyanarayana, P.; Collins, P.
J. Chem. Soc., Perkin Trans. 1 1983, 643; (b) Pelter, A.;