Staudinger reaction, polymer-supported

To demonstrate the feasibility of organic synthesis using this support, the authors immobilized a N-Boc protected glycin (22) on the support (Scheme 7.5). After deprotection imine formation readily occurs with an excess of benzaldehyde. The product was then subjected to a Staudinger reaction with phenoxyacetylchlor-ide to yield the polymer supported / -lactam (26) which could be released to give the yS-lactam (27) with TEA in methanol. 

Polymer-bound P-lactams have been prepared via the ester enolate imine condensation route <02JOC8034>. On the other hand, an efficient asymmetric synthesis of 2-azetidinones was accomplished when chiral acid chlorides or chiral aldehydes were used in the polymer-supported Staudinger reaction <02TA905>. 

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

Solid-phase and combinatorial synthesis of 6-lactams using the Staudinger reaction has widely been studied. Carbohydrates as a chiral pool, however, were not employed except for one report [148]. The polymer supported-imines were employed to prepare several -lactams by enolate/imine condensation and ketene/imine cycloaddition (Scheme 46) [146]. The reactions carried out on the polymer-boimd imines showed a remarkable similarity to those in solution, both in terms of yield and stereoselectivity [54,55]. )S-Lactams were removed from the polymer by CAN oxidation [ 148]. 

The formation of flve-membered cyclic imines through a Staudinger/intramolecular aza-Wittig reaction can also be performed by solid-phase synthesis and has been applied for the first synthesis of lanopylin Bi (108). The total synthesis, which takes only four steps, starts with a phase-transfer alkylation of diethyl 2-oxopropylphosphonate 105 with a 2-iodoethyl azide, affording the azido phosphonate 106, which undergoes a phase-transfer Homer-Emmons Wittig reaction with heptadecanal to provide the azido enone 107. An intramolecular aza-Wittig reaction of the enone 107 with polymer-supported triphenylphosphine in toluene completed the first total synthesis of lanopylin Bi (108) in 76% yield (Scheme 15.22). 

The antitumor antibiotic phloeodictine A1 (171) has been synthesized by Snider s group (Scheme 15.37). The unstable azide derived from 167 was subjected to a polymer supported tandem Staudinger-aza-Wittig followed by a retro Diels-Alder reaction to afford intermediate 170. Addition of 11-dodecenyl magnesium bromide followed by alkylation reaction and deprotection completes an efficient synthesis of phloeodictine A1 (171). 

In addition, a solid-phase [2 + 2] cycloaddition reaction was employed in the synthesis of ezetimibe analogs (Scheme 16.31). Imine 205 was prepared by a condensa- overall yield. tion reaction of resin-bound />-aminophenol with p-anisal-dehyde. Then, a polymer-supported Staudinger reaction with crotonic acid effectively gave the 3-vinyl-j6-lactam 206. The Staudinger reaction proceeded with excellent tram selectivity with no cis isomer detected. This result is opposite to the prior observation that Af-alkyl-substituted... 

---