S. Chandrasekhar et al. / Tetrahedron Letters 48 (2007) 7339–7342
7341
O
NBoc
N
O
b, c, B
OH
Ph
Ph
a, C
76%
MPMO
O
O
O
90%
A
MPMO
MPMO
22
23
O
O
N
O
N
O
ref 4
Ph
d, e
Ph
O
O
80%
HO
1
24
Scheme 4. Reagents and conditions: (a) Cl3C6H2COCl (1.2 equiv), DIPEA (3 equiv), N-Me-N-Boc-Phe (1.1 equiv), THF; DMAP, toluene, 89%; (b)
TBSOTf, 2,6-lutidine, TBAF, THF, rt; (c) EDCI, HOBt, CH2Cl2, then B; (d) Grubbs’ II catalyst, CH2Cl2, reflux, 12 h; (e) Pd–C, H2, EtOAc, 8 h.
6. (a) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 3696; (b) Varseev, G. N.; Maier, M. E.
Org. Lett. 2007, 9, 1461.
7. (a) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2003, 125, 10808; For other
reports on proline-catalyzed oxidation of aldehydes see: (i)
(b) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247; (ii)
Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M.
Tetrahedron Lett. 2003, 44, 8293.
8. Hatakeyama, S.; Shintani, T.; Noguchi, Y.; Yamada, H.;
Nishizawa, M. Tetrahedron 1994, 50, 13369.
9. Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933.
10. The dr was determined from the crude reaction mixture by
1H NMR spectroscopy.
with N-methyl-N-Boc-L-phenyl alanine C under Yamag-
uchi conditions to realize ester 22 in 90% yield.11 This,
on stepwise deprotection of the N-Boc group using
TBSOTf, 2,6-lutidine and TBAF12 and treatment with
B in the presence of EDCI, HOBt provided the RCM
precursor 23. The ring closing metathesis of diene 23
was achieved using Grubbs’ second generation catalyst13
followed by palladium-catalyzed hydrogenation (Pd–C,
EtOAc, H2, 8 h) to give macrolactone 24 in 80% yield
(two steps).4 This late stage intermediate has been al-
ready converted to the target compound in two steps
by Cossy and co-workers.4 All the intermediate com-
pounds including macrolactone 24 were fully character-
ized by IR, 1HNMR, 13C NMR, and mass spectral
data.14
11. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamag-
uchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
12. Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
13. (a) Scholl, M.; Ding, S.; Lee, C.; Grubbs, R. H. Org. Lett.
1999, 1, 953; (b) Chatterjee, A. K.; Morgan, J. P.; Scholl,
M.; Grubbs, R. J. Am. Chem. Soc. 2000, 122, 3783, and
references cited therein.
In summary, a formal total synthesis of (ꢀ)-spongidep-
sin has been achieved in a highly divergent and high
yielding manner combining the ‘chiron approach’ and
‘asymmetric synthesis’ strategies. The key steps were
organocatalyzed a-hydroxylation, a-methylation of an
Enders intermediate, and Grubbs RCM.
14. The spectral and physical data of macrolactone 24
matched in all respects with reported data (Ref. 4).
Spectral and physical data for selected compounds,
23
Compound 24: colorless oil. ½aꢁD ꢀ186 (c 0.4, CHCl3);
1H NMR (600 MHz, CDCl3): d 7.32–7.22 (m, 3H), 7.21–
7.15 (m, 2H), 5.16 (m, 1H), 3.67 (t, J = 6.4 Hz, 2H), 3.58–
3.48 (m, 2H), 3.32–3.25 (m, 1H), 3.00–2.90 (m, 1H), 2.86
(s, 3H), 1.95–1.78 (m, 1H), 1.66–1.18 (m, 13H), 1.16–0.99
(m, 3H), 0.94 (d, J = 7.1 Hz, 3H), 0.91–0.78 (m, 6H); 13C
NMR (75 MHz, CDCl3): 178.6, 170.2, 138.8, 129.5, 128.4,
126.5, 74.2, 65.2, 62.1, 41.3, 40.8, 37.4, 35.5, 34.3, 33.4,
32.6, 32.2, 32.4, 29.6, 28.3, 23.6, 23,4, 22.5, 21.7, 21.4, 18.8;
IR (neat): mmax 3434, 3027, 2925, 2854, 1735, 1632, 1452,
1275, 1213, 1076 cmꢀ1; HRMS (ESI): m/z 454.2941 (calcd
for C26H41NO4Na 454.2933). Compound A: colorless oil.
Acknowledgments
Y.S. and L.S. thank CSIR, New Delhi, for financial
assistance. We also thank Professor Janine Cossy, ESP-
CI, Laboratoire de Chimie Organique, 10 Rue Vauqu-
elin, Paris, France, for providing the spectral data of
compound 24.
23
1
References and notes
½aꢁD +4.0 (c 1.1, CHCl3); H NMR (400 MHz, CDCl3): d
7.26 (d, J = 9.2 Hz, 2H), 6.87 (d, J = 9.2 Hz, 2H), 5.90–
5.60 (m, 1H), 5.12–5.84 (m, 2H), 4.43 (s, 2H), 3.80 (s, 3H),
3.75–3.59 (m, 1H), 3.45 (t, J = 5.8 Hz, 2H), 2.43–2.22 (m,
1H), 1.80–1.2 (m, 8H), 1.00 (d, J = 6.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3): 159.3, 145.3, 130.9, 129.4, 114.0, 113.1,
72.8, 70.4, 70.1, 55.4, 44.7, 37.7, 35.7, 29.9, 26.2, 22.5, 20.5,
18.4; IR (neat): mmax 3425, 2929, 2860, 1612, 1512, 1246,
1096 cmꢀ1; LC–MS: m/z 293 (M+H+). Compound 15:
1. Grassia, A.; Bruno, L.; Debitus, C.; Marzocco, S.; Pino,
A.; Gomez-Paloma, L.; Riccio, R. Tetrahedron 2001, 57,
6257.
2. Chen, J.; Forsyth, C. Angew. Chem., Int. Ed. 2004, 43,
2148.
3. Ghosh, A. K.; Xu, X. Org. Lett. 2004, 6, 2055.
4. Ferrie, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Org.
Lett. 2006, 8, 3441.
5. Against HEK-293 and WEHI-164 cells, spongidepsin has
shown IC50 values of 0.60 and 0.42 lM, respectively.
23
colorless oil. ½aꢁD ꢀ62.9 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.63 (m, 4H), 7.42–7.30 (m, 6H),
6.38 (d, J = 6.0 Hz, 1H), 3.56–3.42 (m, 3H), 3.38 –3.20 (m,