was prepared by the similar protocol used for the model
compound 7 and was treated with sodium hypochlorite.
Unfortunately, the undesired nine-membered ring compound
1514 was obtained as a mixture of diastereomers via the
conformation depicted in 14.
Scheme 5a
At this stage, we examined various substrates to achieve
the desired regiochemistry in the cycloaddition. After numer-
ous attempts, we have found that introduction of the
carboethoxy group on the terminus of the olefin completely
controlled both regio- and stereochemistry to furnish the
desired eight-membered ring 20 (Scheme 4). The structure
Scheme 4a
a (a) NaBH4, EtOH/THF (1:1), rt, 4 h, 99%; (b) TFAA, Et3N,
CH2Cl2, aq NaHCO3, rt, 82%; (c) Raney-Ni, H2, 5% aq H3BO3/
EtOH (1:5), rt, 62%; (d) NaBH(OAc)3, AcOH/THF (1:10), 0 °C,
30 min; (e) aq NaOH, MeOH, rt, 5 min, 85% (2 steps); (f) NaIO4,
MeCN/H2O (3:2), 0 °C, 10 min; (g) NaBH4, MeOH, rt, 10 min,
75% (2 steps); (h) TBSCl, Et3N, DMAP, CH2Cl2, rt, 2 h, 70%; (i)
MCPBA, CH2Cl2, 0 °C, 5 min; (j) Ac2O, rt, 1 h, 65% (2 steps); (k)
Dess-Martin periodinane, CH2Cl2, rt, 5 min, 95%.
sis. The resultant triol was treated with NaIO4, and the
aldehyde formed was immediately reduced to give diol 23.
Scheme 6a
a (a) EtO2CCHdPPh3, EtOH, rt, 20 min, 96%; (b) Zn, AcOH,
CH2Cl2, rt, 30 min, 93%; (c) p-NsCl, Py, CH2Cl2, rt, 15 h, 87%;
(d) 5, DEAD, PPh3, benzene, 50 °C, 30 min, 93%; (e) TBAF, THF,
rt, 45 min, 95%; (f) (COCl)2, DMSO, CH2Cl2, -78 °C; Et3N; (g)
NH2OH‚HCl, NaOAc, EtOH, rt, 30 min; (h) aq NaOCl, CH2Cl2, 0
°C, 4 h, 57% (3 steps); (i) PhSH, Cs2CO3, MeCN, 50 °C, 30 min,
74%.
of the cycloadduct 20 was unequivocally established by
X-ray crystallography. Although the stereochemistry at C(7)
was found to be opposite to that required for FR-900482,
switching the starting L-tartrate to D-tartrate could allow us
to set up the correct stereochemistry.
Having successfully constructed the eight-membered ring,
we then converted the cycloadduct 21 to the benzazocinone
key intermediate 24 (Scheme 5). After reduction of the ethyl
ester and protection of the amine as trifluoroacetamide,
isoxazoline was reductively cleaved to give â,γ-dihydroxy-
ketone 22. Ketone 22 was reduced stereoselectively with
NaBH(OAc)3, and the TFA group was removed by hydroly-
a (a) NH2NH2‚H2O, CH2Cl2-MeOH (1:1), rt, 10 min, 78%; (b)
TBAF, AcOH, THF, rt, 2 h, 98%; (c) Amberlist 15E, MeOH, rt, 5
min; (d) Me2C(OMe)2, CH2dC(OMe)Me, PPTS, DMF, 0 °C, 30
min, 78% (2 steps); (e) TESCl, Et3N, DMAP, CH2Cl2, rt, 1 h, 75%;
(f) MsCl, Et3N, CH2Cl2, 0 °C, 20 min, 92%; (g) TBAF, THF, rt, 5
min, 95%; (h) NaH, DMF/THF (1:3), 60 °C, 5 min, 80%; (i) LiN3,
DMF, 100 °C, 82%; (j) MsCl, Et3N, CH2Cl2, rt, 15 min, 79%; (k)
TFA, CH2Cl2, 91%; (l) CO(OCCl3)2, Py, CH2Cl2, 0 °C, 75%; (m)
PPh3, i-Pr2NEt, H2O-THF (1:10), 70%; (n) NH3, CH2Cl2, 75%.
(13) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831.
(14) The structure of the nine-membered ring product was confirmed
by extensive NMR studies.
Org. Lett., Vol. 3, No. 16, 2001
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