W. Tian, L. R. Chennamaneni, T. Suzuki, D. Y.-K. Chen
SHORT COMMUNICATION
droxy group in 21 employed
a two-step procedure oxidative coupling. This revised strategy should enable this
[(i) PhNTf2; (ii) Pd(OAc)2, HCO2H, Et3SiH], via intermedi- challenging target to be more accessible by synthetic means,
ate triflate 22, to give aniline 23 in 48% yield from β-carb- and further application of the 1,4-addition/formal [3+2] cy-
oline 5. Installation of the indoline moiety in 3 took advan- cloaddition reaction in the synthesis of related natural
tage of the Gassman synthesis[12] engaging aniline 23, to products is currently underway in our laboratory.
afford oxindole 24 in 73% yield. Reduction of oxindole 24
with concomitant removal of the methyl sulfide substituent
(BH3·THF), followed by methyl carbamate protection of in-
termediate indoline 25 (ClCO2Me, Et3N), completed the
synthesis of key intermediate 3 (46% yield over the two
steps).
Supporting Information (see footnote on the first page of this arti-
1
cle): Experimental procedures, physical data, and copies of the H
and 13C NMR spectra.
Acknowledgments
We thank Ms. Doris Tan (ICES) for high-resolution mass spec-
trometry assistance and Dr. Aitipamula Srinivasulu (ICES) and
Ms. Chia Sze Chen (ICES) for X-ray crystallographic analysis. Fin-
ancial support for this work was provided by the Agency for Sci-
ence, Technology and Research (A*STAR), Singapore.
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Scheme 3. Conversion of phenol 21 into hexacyclic aminal 3. Rea-
gents and conditions: (a) PhNTf2 (1.3 equiv.), Et3N (2.0 equiv.),
CH2Cl2, 23 °C, 1 h, 56% over the two steps from 5; (b) Pd(OAc)2
(0.1 equiv.), dppf (0.06 equiv.), Et3N (2.0 equiv.), HCO2H
(2.0 equiv.), Et3SiH (2.0 equiv.), DMF, 50 °C, 86%; (c) ethyl 2-
(methylthio)acetate (1.8 equiv.), SO2Cl2 (1.8 equiv.), CH2Cl2,
–78 °C, 15 min; then proton sponge (1.8 equiv.), 1 h, Et3N
(1.8 equiv.), –78
Ǟ 23 °C; then AcOH, 23 °C, 2 h, 73%;
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(d) BH3·THF (10.0 equiv.), THF, 0 °C, 15 h; e) ClCO2Me
(2.0 equiv.), Et3N (3.0 equiv.), DMAP (0.1 equiv.), CH2Cl2, 0 °C,
1 h, 41% over the two steps. Tf = trifluoromethanesulfonyl, dppf
= 1,1Ј-bis(diphenylphosphanyl)ferrocene.
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Conclusions
In summary, a second-generation, formal synthesis of
(+)-haplophytine (1) has been accomplished. The revised
strategy features a 1,4-addition/formal [3+2] cycloaddition
reaction to forge the challenging C-9Ј–C-15 quaternary cen-
ter linkage, with a much improved efficiency in comparison
with our previously reported hypervalent iodine-mediated
[8] CCDC-794821 (for 9) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
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Eur. J. Org. Chem. 2011, 1027–1031