C O M M U N I C A T I O N S
Scheme 2 a
the 1,2-disubstituted olefin in the presence of three trisubstituted
olefins that are typically more susceptible toward oxidation. We
hypothesized that the endocyclic trisubstituted olefins would have
a facial bias owing to their restricted rotation, whereas the
disubstituted olefin is more conformationally flexible. By using an
asymmetric oxidation that is mismatched for the trisubstituted
alkenes, oxidation of the disubstituted olefin should be kinetically
favored. Indeed, Sharpless asymmetric dihydroxylation (AD-mix
R/CH3SO2NH2) was ultimately found to provide a satisfactory
chemoselectivity,11 giving the desired diol 15 in 65% (brsm ∼80%)
yield. Subsequent periodate cleavage of the diol and chemoselective
reduction of the aldehyde in the presence of the ketone with NaBH4
at -78 °C in DCM/MeOH completed the construction of the side
chain. The final deprotections (hydrolysis and PMB-ether cleavage)
afforded (-)-terpestacin (1), which is spectroscopically identical
to those previously reported.3,4
In summary, we have designed a novel and concise strategy for
the total synthesis of terpestacin by multiple usage of the R-diketone
functionality, first in the Pd AAA-Claisen protocol, and second
by the employment of its oxidized form, the ene-1,2-dione, as an
excellent Michael acceptor, which is quite distinct from other
previous syntheses. Many interesting chemoselectivity issues have
been addressed in this synthesis, including a highly selective RCM
and a dihydroxylation, which may have implications beyond this
work.
a Reaction conditions: (a) isoprene monoepoxide, Pd2dba3‚CHCl3 (1 mol
%), (R,R)-L (2.6 mol %), Bu4NCl (50 mol %), DCM; TIPSOTf, 2,6-lutidine,
95%, 88-96% ee; (b) CHCl3, microwave, 100 °C, 15 min; 120 °C, 15
min; (c) Pd(OAc)2, Cs2CO3, CH3CN, rt, 78% over two steps, E/Z 4:1; (d)
MgBr2‚Et2O, allyltrimethylsilane, DCM, -78 °C to rt, 86%, dr 5.7:1; (e)
PMBCl, Cs2CO3, cat. Bu4NI, DMF, 79%; (f) TBAF, THF, 86%; (g) CBr4,
PPh3, CH3CN, 88%.
Scheme 3 a
Acknowledgment. We thank the National Institutes of Health
(GM33049) for their generous support of our programs. Mass
spectra were provided by the Mass Spectrometry Regional Center
of the University of CaliforniasSan Francisco, supported by the
NIH Division of Research Resources. G.D. is a Stanford Graduate
Fellow. Pd salts were generally supplied by Johnson-Matthey.
Note Added after ASAP Publication. Scheme 3 was
replaced March 13, 2007, and Scheme 2 was replaced and
Supporting Information updated March 23, 2007.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF). This material is
References
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a Reaction conditions: (a) Ti(OiPr)4, TBHP, L-DET, DCM, -20 °C, 80%,
98% ee; (b) Py, I2, PPh3, CH3CN/ether (3:5), 0 °C; H2O, 38 °C, 74%; (c)
17, LiHMDS (2 equiv), THF/HMPA (3:1), -40 °C, 74-85%; (d) Pd(OAc)2
(20 mol %), DPPP (25 mol %), NaBH4, DMSO, 77%; (e) Grubbs second
generation catalyst (10 mol %), benzene, rt, c ) 0.001 M, 35%-44% E
isomer; (f) MgBr2‚Et2O, DMS, DCM, -78 to 0 °C, 93%; (g) 17 (2.0 equiv),
Pd2(dba)3‚CHCl3 (2.5 mol %), (S,S)-L (7.5 mol %), DCM, rt, 89%, dr >15:
1; (h) microwave, DME, 150 °C; (i) PMBCl, Cs2CO3, cat. Bu4NI, DMF;
(j) Ac2O, Py, 69% over three steps; (k) K2OsO2(OH)4 (1 mol %),
(DHQ)2PHAL (5 mol %), K3Fe(CN)6, K2CO3, t-BuOH/H2O (1:1), 0 °C,
65% (∼80% brsm); (l) NaIO4, THF/H2O (4:1); (m) NaBH4, DCM/MeOH,
-78 °C, 78% over two steps; (n) LiOH, THF/MeOH/H2O (3:1:1), 89%;
(o) MgBr2‚Et2O, DMS, DCM, -78 to 0 °C, 74%.
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(6) To our knowledge, there is only one other report of cyclopenten-1,2-
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into 4-substituted cyclopenten-1,2-dione in the total synthesis of batra-
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(9) Higher temperature or the substrate with the hydroxyl protected did not
provide any 15-membered macrocyclization. Six-membered ring formation
dominated when employing the substrate with the side chain already
installed. For a recent example of constructing a polyunsaturated macro-
cycle via RCM, see: Fu¨rstner, A.; Nevado, C.; Tremblay, M.; Chevrier,
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The resulting enol in 12 could chemoselectively serve as a
nucleophile (vs the secondary alcohol) in the second Pd AAA
reaction to give 13 in high yield and high diastereoselectivity.
Subsequently, Claisen rearrangement of 13 resulted in the C-
alkylated product and established the requisite chirality of the side
chain. At this stage, all of the stereocenters and the carbon skeleton
were constructed. The remaining challenge was to oxidatively cleave
(10) Onoda, T.; Shirai, R.; Iwasaki, S. Tetrahedron Lett. 1997, 38, 1443.
(11) AD-mix â resulted in lower yields and slower reactions. For a related
example, see: Andrus, M. B.; Lepore, S. D.; Sclafani, J. A. Tetrahedron
Lett. 1997, 38, 4034.
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