Communications
predictions are reinforcing for C13 condensation. Saturated
ketones are more electrophilic than unsaturated ketones. This
can be observed spectroscopically (e.g. IR shift approximately
Dn˜ = 40 cmÀ1) and experimentally, for example, by competitive
reductive amination. A saturated carbonyl group is preferen-
tially reduced in the presence of NaB(OAc)3H, as noted in the
following reference: A. F. Abdel-Magid, K. G. Carson, B. D.
Harris, C. A. Maryanoff, R. D. Shah, J. Org. Chem. 1996, 61,
3849. Macrocycle 11a demonstrates no enol content by 1H NMR
or IR spectroscopy. For this reason, the ketone at C13 should be
regarded as a saturated ketone.
not only the target structure but also a diverse array of
complex nitrogen-containing polycyclic structures that are
accessible from simple Michael–Mannich reaction cascades.
The illustrated strategy of cyclization-based multistep bond
constructions is currently being applied to other complex
natural products.
Received: June 30, 2005
Published online: August 24, 2005
[12] Macrocycle 11a was decarboxylated under Krapcho conditions.
This material also exclusively favors condensation at C5.
[13] Ketoester 28 exists as a mixture of keto and enol tautomers. For
this reason, an accurate diastereomeric ratio of the preceding
Michael addition could not be determined. A small amount of 28
was decarboxylated under Krapcho conditions. The derived
ketone was isomerically pure (d.r. ꢀ 10:1), and the stereochem-
istry at C7 was proven by 2D 1H NMR spectral analysis
(NOESY).
[14] a) G. Stork, J. D. Winkler, N. A. Saccomano, Tetrahedron Lett.
1983, 24, 465; b) G. Stork, C. S. Shiner, J. D. Winkler, J. Am.
Chem. Soc. 1982, 104, 310; c) E. M. Arnett, S. G. Maroldo, S. L.
Schilling, J. A. Harrelson, J. Am. Chem. Soc. 1984, 106, 6759;
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2737.
[15] L. N. Mander, S. G. Pyne, J. Am. Chem. Soc. 1979, 101, 3373.
[16] Product 30d was prepared independently by alkylation of 28
with 1-iodo-3-amino-tert-butylcarbamate and tBuOK provided
30d as a single isomer in less than 30% yield.
[17] The use of methanolic HCl to effect a Mannich addition finds
precedent in the Heathcock synthesis of lycopodine; see
reference [2a].
Keywords: alkaloids · Michael addition · natural products ·
polycycles · synthetic methods
.
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Hori, Y. Sato, M. Nishida, Angew. Chem. 1998, 110, 659; Angew.
Chem. Int. Ed. 1998, 37, 636. For reviews of lycopodium alkaloid
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[20] CCDC 280174–280177 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
a = 33.325(6), b = 7.0106(12), c = 10.5283(17), space group
P21212; 18 (280175) C16H25NO2: a = 7.0625(6), b = 9.9378(9),
c = 20.3461(18), space group P212121; 11a (280176) C31H45NO7:
a = 9.3342(17), b = 10.0515(17), c = 16.339(3), b = 93.755(4),
space group P21; 2 (280177) C16H25NO2: a = 13.5174(12), c =
7.7656(10), space group P41.
[7] Abbreviations: 9-BBN = 9-borabicyclo[3.3.1]nonane; Bn =
benzyl; Boc = tert-butyloxycarbonyl; DibalH = diisobutylalumi-
num hydride; DMAP = 4-dimethylaminopyridine; DMP =
Dess–Martin periodinane; DMF = N,N-dimethylformamide;
DMS = dimethyl sulfide; DMSO = dimethyl sulfoxide; imid =
imidazole; LDA = lithium diisopropylamide; PPTS = pyridi-
nium p-toluenesulfonate; py = pyridine; TBDPS = tert-butyldi-
phenylsilyl; TBSCl = tert-butyldimethylsilyl chloride; TESCl =
triethylsilyl chloride; TFA = trifluoroacetic acid; TMSOTf = tri-
methylsilyl trifluoromethanesulfonate; TsOH = p-toluenesul-
fonic acid.
[8] b-Ketophosphonate 7 was prepared in four steps from the
previously synthesized protected d-amino valeric acid 6: D. L.
Flynn, R. E. Zelle, P. A. Grieco, J. Org. Chem. 1983, 48, 2425.
[9] C. R. Holmquist, E. J. Roskamp, J. Org. Chem. 1989, 54, 3258.
[10] a) P. Deslongchamps, Pure Appl. Chem. 1996, 68, 1831; b) D. A.
Evans, J. T. Starr, Angew. Chem. 2002, 114, 1865; Angew. Chem.
Int. Ed. 2002, 41, 1787; c) D. A. Evans, J. T. Starr, J. Am. Chem.
Soc. 2003, 125, 13531.
[11] If carbinolamine dehydration is rate-limiting, formation of the
stabilized vinylogous urethane 12 is predicted to occur favorably.
If carbinolamine formation is rate-determining, condensation at
the more electrophilic (C13) ketone should be observed. These
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Angew. Chem. Int. Ed. 2005, 44, 6038 –6042