in moderate yield (53-85%) with good selectivity (76-87%
de) using 2.5 equiv of PtO2 (8 bar H2, AcOH, 26 °C, 41 h).
In the case of dimethylsubstituted cyclohexa-2,5-diene
17a, olefin 19a was obtained in 93% yield using 1.2 equiv
of PtO2 (4 bar H2, AcOH, 26 °C, 28 h). More forcing
conditions (3.5 equiv PtO2, 10 bar H2, AcOH, 26 °C, 4
days) afforded dimethylcyclohexane 19b as an inseparable
mixture of diastereomers for which the de was determined
upon subsequent cyclization to the spirolactam (60% de).
In comparison to amide-directed hydrogenations using
homogeneous iridium catalysts, heterogeneous catalysts
(PtO2) deliver the opposite sense of facial selectivity with
respect to the cyclohexa-1,4-diene ring system.19 Hydrogena-
tion of the cyclohexadienes took place anti to the amide
functionality, and this was confirmed by X-ray analysis of
7,6-spirolactam 21a obtained via hydrolysis and cyclization
of amide 18a (Figure 3).20
H(OMe)3,22 MeLi, or alkynyl boranes23 all failed to affect
conversion to an aldehyde or ketone. Only acidolysis under
harsh conditions proved effective to convert the tertiary
amide to a carboxylic acid in moderate yield (∼50%).
Amides 18a-c, 19a,b were therefore hydrolyzed using 5.8
M HCl under reflux then dried on a freeze-drier to afford
the corresponding crude amino acid hydrochloride salts 20.
The final intramolecular cyclization of the amino acids to
form the bicyclic spirolactams was then attempted using
several coupling reagents (Table 2). Use of PyBOP, DMAP,
and i-Pr2EtN in CH2Cl2/DMF24 (conditions B) proved
optimum to effect cyclization of the crude amino acids
18a-c to spirolactam 21a-c (entries 2, 6, and 8, Table 2).
Spirolactam 22a, however, was only obtained in poor yield
(entry 9, Table 2) due to the sensitivity of the olefin to
aqueous HCl.
In summary, a new method for construction of a range of
enantiopure bicyclic R,R-disubstituted spirolactams has been
developed using a diastereoselective Birch reductive alky-
lation to instal the quaternary center. Importantly, the
synthesis of (1R,6R)-1-methyl-8-azaspiro[5.6]dodecan-7-one
21a provides the core 7,6-ring system of the spiroimine unit
of the spirolides and the introduction of an additional methyl
group in (1R,6R,10R)-1,10-dimethyl-8-azaspiro[5.6]dodecan-
7-one 21c provides momentum for the synthesis of the
challenging spiroimine unit of spirolide A.
Supporting Information Available: Experimental pro-
cedures, copies of NMR spectra for all compounds, and CIF
file for the X-ray structure of compound 21a. This material
Figure 3. X-ray crystal structure of 21a. Note the presence of two
conformers differing in the conformation adopted by the six-
membered ring. Ellipsoids are drawn at the 50% probability level.
OL8029017
(21) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am.
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Finally, removal of the sterically hindered chiral auxiliary
needed to be addressed. Use of Schwartz reagent,21 LiAl-
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5620.
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(23) Yamaguchi, M.; Waseda, T.; Hirao, I. Chem. Lett. 1983, 35–36.
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(25) Qian, L.; Sun, Z.; Deffo, T.; Mertes, K. B. Tetrahedron Lett. 1990,
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(20) Gue´ret, S. M.; Choi, K. W.; O’Connor, P. D.; Boyd, P. D. W.;
Brimble, M. A. Acta Crystallogr. Sect. E: Struct. Rep. Online 2008, 64, 1151.
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