Total Synthesis of Clavepictines A and B. Diastereoselective Cyclization of δ-Aminoallenes

Abstract

The stereocontrolled total synthesis of (−)-clavepictine A (1A) and (+)-clavepictine B (1B) has been accomplished in an enantioselective fashion, which has unequivocally established the absolute configuration of 1A and 1B. The pivotal step in the synthesis is diastereoselective silver(I)-promoted cyclization of δ-amino allenes. Another key method includes cross-coupling of enol triflates of N-acyl lactams, which allows stereocontrolled functionalization of otherwise unreactive lactams under mild conditions. The utility of Beak's α-lithiation-substitution chemistry of N-BOC piperidines involving a functionalized aldehyde as the electrophile is demonstrated in the preparation of highly substituted nitrogen heterocycles. These new synthetic strategies should be of general synthetic utility in the stereoselective syntheses of quinolizidines, indolizidines, and related aza-heterocylces. Also included is the unique conformational preference of the highly substituted cis-quinolizidine core of clavepictines; the (superfluous) m-(trifluoromethyl)benzoate substituent has a surprisingly significant influence on the relative energies of the two possible chair−chair conformations.

4.07 Electrophilic Cyclization

“…198 The total synthesis of clavepictines was skillfully designed and realized with Ag þ -catalyzed cyclization of a piperidinoallene as the key step affording the desired cis-quinolizidine derivative in 48% yield (7% of vinyl isomer is obtained) (Scheme 185). 199 When the substrate is modified, the cyclization yield is significantly improved as well as the diastereoselectivity, and no other isomer could be detected.…”

Synthesis of Saturated Heterocycles via Metal-Catalyzed Alkene Hydroamination or Hydroalkoxylation Reactions

“…The zinc(II) center is ligated with an anionic troponiminato group that renders the complex stable toward Scheme 34 Proposed mechanism for Cu(I)-catalyzed hydroamination Scheme 35 Cationic copper-catalyzed hydroamination air and moisture. In a subsequent report the following year, a modified catalyst (84) was found to cyclize secondary aminoalkenes containing various Lewis basic functionalities with improved efficiency (Scheme 36) [66]. Although the catalyst was tolerant of several functional groups, reaction times were often slow and the catalyst showed little reactivity toward substrates lacking backbone substituents.…”

“…Gold and palladium catalysts are the most studied. However, reports of other late transition metal catalysts for intramolecular allene hydroamination have also been published [84]. Recent advances in the hydroamination of allenes will be highlighted in the following sections.…”

Development of Useful Reactions Involving Tandem Cyclizations Based on the Novel Reactivities of Allenic Compounds

“…35,36) Particularly, cyclization of amino allenes using such metals as Pd(0 or II), [37][38][39][40][41][42][43][44][45] Ag(I), [46][47][48][49][50] and organolanthanides 51) has become quite useful methodology for the synthesis of fiveor six-membered azacycles, and several groups have applied such cyclization to the total synthesis of natural products. [52][53][54] It is well documented that cyclization of amino allene 30 with a one-or two-carbon tether between the allene and the nitrogen atom (nϭ1 or 2) yields five-or six-membered azacycles 31 (nϭ1 or 2) selectively by path A (Chart 5), while an amino allene bearing a longer carbon tether (nϭ3 or 4) also affords five-or six-membered rings 32 (nϭ3 a) Reactions were carried out in THF at room temperature under argon using Pd(PPh 3 ) 4 (10 mol%) and Et 2 Zn (2 eq), unless otherwise stated. b) 4mol% of Pd(PPh 3 ) 4 was used.…”