LETTER
Convergent Synthesis of the C31–C46 Fragment of Phorboxazoles
1539
(8) (a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am.
Chem. Soc. 1998, 120, 5597. (b) Smith, A. B. III; Verhoest,
P. R.; Minbiole, K. P.; Schelhaas, M. J. Am. Chem. Soc.
2001, 123, 4834. (c) Smith, A. B. III; Minbiole, K. P.;
Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123,
10942. (d) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V.
J. J. Am. Chem. Soc. 2000, 122, 10033. (e) Evans, D. A.;
Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S. Angew.
Chem. Int. Ed. 2000, 39, 2533. (f) Evans, D. A.; Fitch, D.
M. Angew. Chem. Int. Ed. 2000, 39, 2536. (g) Gonzalez, M.
A.; Pattenden, G. Angew. Chem. Int. Ed. 2003, 42, 1255.
(h) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M.
P.; Berliner, M. A.; Reeves, J. T. Angew. Chem. Int. Ed.
2003, 42, 1258; and references cited therein.
CH3COOEt (LiHMDS, THF; –78 °C; 15 min) to give 18
in 79% yield. The epimeric mixture 18 was oxidised with
PDC in CH2Cl2 to b-keto ester 19 in 80% yield.
The substrate 19 was sonicated for 36 hours using PPTS
as catalyst in MeOH, during which deprotection of the
isopropylidene group as well as the cyclisation occurred
to yield a single diastereomer of the cyclic acetal methyl
ether 20 in 50%. The free alcohol was protected with
methoxymethyl chloride and DIPEA in CH2Cl2 (in 94%
yield), and the chloro functionality was converted to for-
mate 21 with sodium formate in DMF at 80 °C for 3 days
in 70% yield.
(9) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc.
Chim. Fr. 1993, 130, 336. (b) Baudin, J. B.; Hareau, G.;
Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993,
130, 856. (c) Review on modified Julia olefination:
Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1. 2002, 2563.
(10) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(11) Mitsunobu, O. Synthesis 1981, 1.
Deformylation with NaBH4 in MeOH furnished primary
alcohol 23 in 96% yield. The Dess–Martin periodinane
oxidation afforded the aldehyde 5 in quantitative yield.
Coupling of the secondary sulphone 4 and the aldehyde 5
under the modified Julia olefination conditions gave an in-
separable mixture of E:Z geometrical isomers in 70%
yield in a ratio of 1:1 (Scheme 4).
(12) Vanhessche, K. P. M.; Wang, Z. M.; Sharpless, K. B.
Tetrahedron Lett. 1994, 35, 3469.
(13) i) Epichlorohydrin, MPMOH, NaH; ii) Jacobsen
resolution.15
(14) i) Homoallyl alcohol, MPMBr, NaH; ii) m-CPBA; iii)
Jacobsen resolution15 and related work reported by our
group: Yadav, J. S.; Bandyopadhyay, A.; Kunwar, A. C.
Tetrahedron Lett. 2001, 42, 4907.
(15) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936.
(16) Spectral data for the key fragments: Compound 3 (E:Z
mixture): 1H NMR (200 MHz, CDCl3): d = 6.61 (d, J = 17.3
Hz, 1 H), 6.27–6.02 (m, 5 H), 5.61–5.42 (m, 2 H), 5.37–5.24
(m, 2 H), 4.58–4.36 (m, 6 H), 4.14 (q, J = 14.1 Hz, 4 H),
3.72–3.45 (m, 6 H), 3.34 (s, 6 H), 3.31 (s, 6 H), 3.24 (s, 6 H),
3.23 (s, 6 H), 2.66 (dd, J = 14.1, 4.6 Hz, 4 H), 2.44–2.22 (m,
6 H), 1.90 (s, 3 H), 1.83 (s, 3 H), 1.69–1.55 (m, 2 H), 1.41–
1.19 (m, 10 H). IR (neat): 2926, 1736, 1619, 1418, 1376,
1207, 1146, 1089, 1033 cm–1. MS-FAB: m/z = 536 [M + 1].
[a]D –19.8 (c 0.5, CHCl3).
Scheme 4
In conclusion, the practical synthesis of the highly func-
tionalised C31–C46 fragment achieved in 17 steps (in the
longest linear sequence) from MPM protected (S)-ho-
moallyl alcohol epoxide 1216 is described. Modified Julia
olefination between secondary benzothiazole sulphone 4
and the aldehyde 5 was achieved. Efforts towards the syn-
thesis of the other fragments 1 and 2 and the total synthe-
sis of phorboxazoles are under progress.
Compound 4 (mixture of diastereomers): 1H NMR (200
MHz, CDCl3): d = 8.22–8.18 (m, 2 H), 8.02–7.96 (m, 2 H),
7.67–7.53 (m, 4 H), 6.02–5.44 (m, 8 H), 4.36–4.23 (m, 2 H),
3.56–3.46 (m, 2 H), 3.16 (s, 3 H), 3.02 (s, 3 H), 2.14–1.95
(m, 4 H), 1.64–1.56 (m, 6 H). IR (neat): 2926, 1701, 1469,
1325, 1145, 1093 cm–1. MS-FAB: m/z = 418 [M + 2].
[a]D –8.20 (c 0.8, CHCl3).
Acknowledgment
G. R thanks CSIR, New Delhi for financial assistance.
Compound 6: 1H NMR (200 MHz, CDCl3): d = 7.25 (d,
J = 8.8 Hz, 2 H), 6.81 (d, J = 8.8 Hz, 2 H), 4.45 (Ab q,
J = 12.3 Hz, 2 H), 3.81 (s, 3 H), 3.69–3.63 (dd, J = 12.5, 6.0
Hz, 1 H), 3.45–3.34 (dd, J = 12.5, 6.0 Hz, 1 H), 3.23–3.18
(m, 1 H), 2.76–2.69 (dd, J = 12.3, 5.9 Hz, 1 H), 2.57–2.54
(dd, J = 12.3, 5.9 Hz, 1 H). IR (neat): 2922, 1512, 1245
cm–1. MS (EI): m/z = 194 [M+].
References
(1) IICT Commn No. 030704.
(2) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117,
8126.
(3) (a) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J.
W. J. Am. Chem. Soc. 1996, 118, 9422. (b) Molinski, T. F.
Tetrahedron Lett. 1996, 37, 7879.
(4) Hayward, M. M.; Roth, R. M.; Duffy, K. J.; Dalko, P. I.;
Stevens, K. L.; Guo, J.; Kishi, Y. Angew. Chem. Int. Ed.
1998, 37, 192; and references cited therein.
(5) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.;
Charette, A. B.; Lautens, M. Angew. Chem. Int. Ed. 1998,
37, 2354; and references cited therein.
(6) Nicolaou, K. C.; Dai, W. M.; Guy, R. K. Angew. Chem., Int.
Ed. Engl. 1994, 33, 15.
[a]D +3.1 (c 1.5, CHCl3).
Compound 10: 1H NMR (200 MHz, CDCl3): d = 6.64–6.49
(m, 1 H), 6.32–6.08 (m, 3 H), 3.93–3.70 (m, 1 H), 3.29 (s, 3
H), 2.58–2.46 (m, 1 H), 2.38–2.26 (m, 1 H), 2.22 (s, 3 H). IR
(neat): 2932, 1735, 1612, 1310 cm–1. MS (EI): m/z = 233
[M+].
[a]D +2.9 (c 0.6, CHCl3).
Compound 12: 1H NMR (200 MHz, CDCl3): d = 7.18 (d,
J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 4.40 (s, 2 H), 3.81
(s, 3 H), 3.58–3.53 (m, 2 H), 3.06–2.96 (m, 1 H), 2.76–2.72
(m, 1 H), 2.50–2.43 (m, 1 H), 1.89–1.78 (m, 1 H), 1.72–1.60
(m, 1 H). IR (neat): 2845, 1612, 1513 cm–1. MS (EI):
(7) Nicolaou, K. C.; Roschanger, F.; Vourloumis, D. Angew.
Chem. Int. Ed. 1998, 37, 2014; and references cited therein.
Synlett 2004, No. 9, 1537–1540 © Thieme Stuttgart · New York