O. Andrey et al. / Tetrahedron Letters 44 (2003) 7901–7904
7903
Scheme 4. Reagents and conditions: (a) EtNO2, 1,1,3,3-tetramethylguanidine 15 mol%, THF, 0°C, 3 h, quant.; (b) TFAA, Et3N,
−10°C, 1 h, 72%; (c) propionaldehyde 10 equiv., (S,S)-iPBP 15%, CHCl3, −10°C, 7 d, 92%; (d) ethylene glycol, PPTS 10 mol%,
C6H6, Dean–Stark, 3 h, 74%; (e) NaNO2, isoamyl nitrite, DMSO, rt, 4 d, 73%; (f) Pd(OH)2/C 15%, H2 1 atm, MeOH, rt, 3 h,
91%; (g) HCl 10−2 M, ether, rt, 3 d, 62%.
Acknowledgements
to provide the crude free alcohol in 91% yield.
Attempts to purify the alcohol led only to a complex
mixture of the desired product, a partially hydrolyzed
product and a new compound resulting from an
intramolecular transacetalization. For this reason the
crude was used without further purification for the
next step. The second deprotection was carried out in
a biphasic mixture of dilute aqueous hydrochloric acid
(10−2 M solution) and ether, and vigorously stirred for
three days at room temperature to give (−)-
botryodiplodin in 62% yield after filtration through
silica gel. Use of a more acidic solution increased the
reaction rate but damaged a large part of product via
b-elimination to the corresponding a,b-unsaturated
ketone.
We thank the Swiss National Science Foundation
(grant no. 20-61891-00) for financial support.
References
1. (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J.
Am. Chem. Soc. 2001, 123, 5260; (b) Betancort, J. M.;
Sakthivel, K.; Thayumanavan, R.; Barbas, C. F., III
Tetrahedron Lett. 2001, 42, 4441; (c) Betancort, J. M.;
Barbas, C. F., III Org. Lett. 2001, 3, 3737.
2. List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3,
2423.
3. Enders, D.; Seki, A. Synlett 2002, 26.
The purity of (−)-botryodiplodin was determined by
chiral GC;21 the enantiomeric excess was 92.5%, and
only 4% of the anti product (epi-botryodiplodin epi-1)
was detected. Optical rotation measurements con-
firmed the negative sign of the isolated product:
[h]2D5=−62.5 (c 2.5, 92.5% ee, CHCl3); lit.15 [h]2D5=−69
(c 1, CHCl3).
4. (a) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611; (b)
Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett.
2003, 5, 2559.
5. New experiments have revealed a problem with the opti-
cal purity of some crops of our chiral diamine, which was
only 89% ee. With an optically pure diamine iPBP, under
the same conditions, we have now obtained the adduct
with 93% ee and 95:5 dr instead of 83% ee and 95:5 dr
(Ref. 4a).
6. For other syntheses of racemic botryodiplodin see: (a)
McMurry, P. M. J.; Abe, K. J. Am. Chem. Soc. 1973, 95,
5824; (b) McMurry, P. M. J.; Abe, K. Tetrahedron Lett.
1973, 14, 4103; (c) Mukaiyama, T.; Wada, M.; Hanna, J.
Chem. Lett. 1974, 94, 1181; (d) Wilson, S. R.; Myers, R.
S. J. Org. Chem. 1975, 40, 3309; (e) Kurth, M. J.; Yu,
C.-M. J. Org. Chem. 1985, 50, 1840. (f) Dulcere, J. P.;
Mihoubi, M. N.; Rodriguez, J. J. Org. Chem. 1993, 58,
5709; (g) Daub, G. W.; Edwards, J. P.; Okada, C. R.;
Allen, J. W.; Maxey, C. T.; Wells, M. S.; Goldstein, A.
S.; Dibley, M. J.; Wang, C. J.; Ostercamp, D. P.; Chung,
S.; Cunningham, P. S.; Berliner, M. A. J. Org. Chem.
1997, 62, 1976; (h) Nouguier, R.; Gastaldi, S.; Stien, D.;
Bertrand, M.; Renaud, P. Tetrahedron Lett. 1999, 40,
3371; (i) Villar, F.; Andrey, O.; Renaud, P. Tetrahedron
Lett. 1999, 40, 3375.
The structure of (−)-botryodiplodin was unambigu-
ously assigned after acetylation and comparison of the
1H and 13C NMR spectra of acetate 11 with literature
data.6g Chiral GC was used to separate the mixture of
eight acetylated products.22 The enantiomeric excess of
11a was still 91% but the diastereomeric ratio between
11 and 12 had slightly decreased due to the basic
media employed during the formation of the acetyl-
ated derivative.
In conclusion, we have described a short and highly
enantioselective synthesis of (−)-botryodiplodin 1 and
have demonstrated the potential of organocatalysis in
asymmetric total synthesis. Moreover, our synthesis
could be applied to the synthesis of a large variety of
analogues by simply changing the starting nitroalkane
or aldehyde.