C O M M U N I C A T I O N S
Scheme 3. Synthesis of Aromatic C8-C21 Fragmenta
16.22 Finally, deprotection of the MOM and benzyl ethers was
accomplished using BCl3 to reveal reblastatin (1) in 53% yield.
The synthetic reblastatin exhibited physical, spectroscopic and
spectrometric characteristics (1H, 13C NMR, IR, [R]D, and HRMS)
identical to those reported for the natural product.1
In summary, the first total synthesis of reblastatin has been
achieved in 25 steps (longest linear sequence). Notable features of
our synthetic approach include a highly regio- and diastereoselective
hydrometalation addition reaction to install the C7 stereocenter. This
effort also documents the first example of an intramolecular copper-
mediated amidation to close the 19-membered macrolactam, thereby
further expanding the scope of this useful reaction. This convergent
synthesis allows for construction of stereochemical analogues of
reblastatin for further biological testing, which will be reported at
the appropriate time.
a Reagents and conditions: (a) TMSOTf, 8, DCM, -50 °C, 64%, 20:1
dr; (b) Et3SiH, BF3‚OEt2, DCM, 60%; (c) (i) BH3‚Me2S, THF, 0 °C to
room temperature, (ii) NaOH, H2O2 62%; (d) TBSCl, imidazole, DMF,
Et2O; (e) Me3OBF4, DCM; (f) HCl, MeOH, 95%; (g) BCl3‚Me2S, DCM,
-78 to 0 °C, 90%; (h) NaIO4, NaHCO3, acetone/H2O, 99%; (i) 12, 4 Å
MS, toluene, -78 °C, 80%, 20:1 dr; (j) MOMCl, DMAP, DIPEA, DCM,
89%; (k) OsO4, NMO, acetone/H2O; (l) Pb(OAc)4, K2CO3, benzene; (m)
(MeO)2P(O)CHN2, t-BuOK, THF, -78 °C; (n) LiHMDS, MeI, -78 °C,
74%.
Acknowledgment. Financial support for this research is ob-
tained from NIH CA56304. J.S.P. is grateful to Amgen, Johnson
& Johnson, Merck Co., Novartis, Pfizer, and GSK for financial
support.
Supporting Information Available: Experimental details and
selected spectral data for all new compounds. This material is available
Scheme 4. Fragment Coupling, Intramolecular Amidation, and
Completion of the Synthesisa
References
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a Reagents and conditions: (a) (i) Cp2ZrHCl, toluene, 50 °C, (ii) ZnMe2,
toluene, -65 °C, (iii) 4, 0 °C, 55%, 20:1 dr; (b) TBSOTf, 2,6-lutidine,
DCM, 0 °C, 92%; (c) LiOH, THF:MeOH:H2O, 92%; (d) (i) (CH3)2CHCH2-
OCOCl, NEt3, DCM, -20 °C, (ii) NH3(g), 59% (92% based on recovered
starting material); (e) CuI, N,N′-dimethylethylenediamine, K2CO3, toluene,
100 °C, 83%; (f) HF‚Pyr, Pyr, THF, 88%; (g) Cl3CCONCO, MeOH, K2CO3,
80%; (h) BCl3, -78 °C, DCM, 52%.
(9) Gonza´lez, I. C.; Forsyth, C. J. J. Am. Chem. Soc. 2000, 122, 9099.
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(11) For experimental details, see Supporting Information.
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55% yield.19 Analysis of the crude reaction mixtures showed partial
epimerization at C10; fortunately, the two diastereomers could be
readily separated by chromatography.20,21
After coupling of fragments 3 and 4, several chemical manipula-
tions were necessary before macrocyclization. To that end, the
secondary alcohol 14 was protected as a TBS ether, the ethyl ester
was hydrolyzed, and the resulting acid was converted to the amide
2 via a mixed anhydride in good overall yield. Having the required
bromoamide 2 in hand, we proceeded to explore the crucial
macrocyclization step. Subjection of the acyclic skeleton 2 to
Buchwald’s amidation conditions smoothly provided the desired
macrolactam 15 in 83% yield. Deprotection of the TBS ether was
achieved using HF/pyridine in pyridine to obtain the secondary
alcohol in 88% yield. Subjection of the secondary alcohol to reaction
conditions reported by Kocovsky provided the desired carbamate
(17) Hu, T.; Panek, J. S. J. Am. Chem. Soc. 2002, 124, 11368.
(18) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912.
(19) The absolute configuration of C7 alcohol was confirmed by Mosher ester
analysis. See Supporting Information for details.
(20) Approximately 5-10% epimerized product was determined by crude 1H
NMR. Recovery of starting material as the 2Z-alkene showed a similar
ratio of C10 diastereomers.
(21) We rationalize that reversible addition of a second equivalent of Cp2-
ZrHCl, followed by elimination at C10-C11, may lead to partial
epimerization. For precedent of this mechanism, see: (a) Schwartz, J.;
Labinger, J. Angew. Chem., Int. Ed. Engl. 1976, 15, 333. (b) Wailes, P.
C.; Weigold, H.; Bell, A. P. J. Organomet. Chem. 1971, 27, 373.
(22) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
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