Allenamides and ynamides, subgroups of heteroatom-substituted allenes and alkynes, have become highly versatile organic synthons applicable to a diverse array of transformations that can be useful for natural product syntheses. In the last ten years, the chemistry of allenamides and ynamides has become an emerging field with contributions from many groups around the world including our own. We have succeeded in identifying allenamides and ynamides as useful equivalents of allenamines and ynamines that possess the right balance between reactivity and stability. We have developed their practical and efficient synthetic access, and implemented these novel functional groups in highly stereoselective inter- and intramolecular reactions that were otherwise difficult, if not impossible, to achieve using allenamines and ynamines. The goals of this NIH renewal are to explore novel tandem methods involving the allenamide chemistry, and to accomplish total syntheses of complex alkaloids featuring stereoselective methods using both allenamides and ynamides. Specifically, we intend to focus on three Aims in this renewal with two in the area of allenamides and one in the area of ynamides:
In Aim -1, we intend to develop N-tethered IMDA reactions in tandem with ?-isomerization of allenamides.
In Aim -2, we intend to design a series of de novo tandem reaction sequences initiated from allenamide ?-isomerizations.
In Aim -3, we intend to pursue a total synthesis of (+)-davisine featuring one of these novel tandem reactions.
In Aim -4, we intend to accomplish a total synthesis of (+)-thalbadenzine featuring a Bronsted acid catalyzed tandem keteniminium Pictet-Spengler cyclization involving a macrocyclic bis-ynamide. Having led the efforts in revitalizing interest in a research area that has been largely overlooked, we have a tremendous amount of momentum and are poised not only to continue demonstrating with these new Aims the synthetic utility of chiral allenamides and ynamides as novel functional groups, but more significantly, to take their chemistry to the next level of visibility.

Public Health Relevance

This renewal intends to explore novel methods involving the allenamide chemistry and accomplish the total synthesis of a complex alkaloid featuring stereoselective methods using ynamides. In the last ten years, the chemistry of allenamides and ynamides has become an emerging field with contributions from many groups around the world including our own. Having led the efforts in revitalizing interest in a research area that has been largely overlooked, we have a tremendous amount of momentum and are poised in this renewal, not only to continue demonstrating the synthetic utility of chiral allenamides and ynamides as novel functional groups, but also more significantly, to take their chemistry to the next level of visibility

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066055-08
Application #
8536311
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2005-03-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2013
Total Cost
$291,700
Indirect Cost
$91,076
Name
University of Wisconsin Madison
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Wang, Xiao-Na; Krenske, Elizabeth H; Johnston, Ryne C et al. (2014) Torquoselective ring opening of fused cyclobutenamides: evidence for a cis,trans-cyclooctadienone intermediate. J Am Chem Soc 136:9802-5
He, Shuzhong; Hsung, Richard P; Presser, William R et al. (2014) An approach to cyclohepta[b]indoles through an allenamide (4 + 3) cycloaddition-Grignard cyclization-Chugaev elimination sequence. Org Lett 16:2180-3
Fang, Li-Chao; Hsung, Richard P (2014) Stereoselective synthesis of isoquinuclidines through an aza-[4 + 2] cycloaddition of chiral cyclic 2-amidodienes. Org Lett 16:1826-9
Wang, Xiao-Na; Yeom, Hyun-Suk; Fang, Li-Chao et al. (2014) Ynamides in ring forming transformations. Acc Chem Res 47:560-78
Wang, Xiao-Na; Hsung, Richard P; Fox, Sierra K et al. (2014) SYNTHESIS OF DE NOVO CHIRAL ?-AMINO-YNAMIDES USING LITHIATED YNAMIDES. OBSERVATION OF A UNIQUE 5-ENDO-DIG CYCLIZATION WITH AN INVERSION OF S-CENTER. Heterocycles 88:1233-1254
Wang, Xiao-Na; Winston-McPherson, Gabrielle N; Walton, Mary C et al. (2013) Synthesis of cyclopentenimines from N-allyl ynamides via a tandem aza-Claisen rearrangement-carbocyclization sequence. J Org Chem 78:6233-44
Wang, Xiao-Na; Hsung, Richard P; Qi, Rui et al. (2013) A highly stereoselective addition of lithiated ynamides to Ellman-Davis chiral N-tert-butanesulfinyl imines. Org Lett 15:2514-7
Krenske, Elizabeth H; He, Shuzhong; Huang, Jian et al. (2013) Intramolecular oxyallyl-carbonyl (3 + 2) cycloadditions. J Am Chem Soc 135:5242-5
Qi, Rui; Wang, Xiao-Na; Dekorver, Kyle A et al. (2013) A Convenient Synthesis of ýý-Amino-Ynamides via Additions of Lithiated Ynamides to Aryl Imines. Observation of an Aza-Meyer-Schuster Rearrangement. Synthesis (Stuttg) 45:1749-1758
Du, Yunfei; Krenske, Elizabeth H; Antoline, Jennifer E et al. (2013) Control of regioselectivity and stereoselectivity in (4 + 3) cycloadditions of chiral oxyallyls with unsymmetrically disubstituted furans. J Org Chem 78:1753-9

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