Mukaiyama’s reagent, and

As an aside, an exhaustive screening of virtually every major lactonization protocol was attempted in this step, but none worked as well as the indicated conditions. Equally important, even with the given protocol the use of MeCN was critical for a high yield of 1 since both Mukaiyama s reagent and the triol carboxylic acid (65) are poorly soluble in neat CH2CI2. 

Treatment of amino acid 156, imine and 2-chloro-l-methylpyridinium iodide (Mukaiyama s reagent) in the presence of triethylamine in refluxing dichloro-methane afforded spiro-(3-lactams 157,158. These were obtained as a 1.8 1 mixture of diastereoisomers and separated by column chromatography. The reaction of 159 and imine under the usual experimental conditions resulted in the formation of a single diastereoisomer 160. The absolute (3 S, 4 S, 7 -configuration was assigned on the basis of mechanistic considerations and XH NMR spectra. The presence of the stereocenter affords complete diastereoselectivity (only trans diastereoisomers 157, 158) and enantioselectivity (160). 

Coupling of 69 with methyl 4-hydroxyphenoxyacetate 70 was carried out in the presence of imidazole and confirmed by gel-phase 13C NMR of PSDES resin 71. The hydrolysis of resin-bound ester was efficiently achieved using trimethyltin hydroxide (TMTOH) [110-114] to give the corresponding immobilized carboxylic acid 72. For the key Staudinger reaction, activation of the carboxylic acid 72 by Mukaiyama s reagent 74 was employed (Scheme 20) [115-117]. The m-p-lactam 16 was obtained in a 12-14% isolated yield. 

RCHiCOOH - RCH=C—0.i Mukaiyama s reagent has been used for macro-lactonization of -hydroxy carboxylic acids (14,117-118). However, reaction of the substrate 2 with 1 and N(C2H5)3 in refluxing CH3CN does not lead to the expected... 

Immunosuppressant (-)-FK-S06 (2). This 23-membered lactone-lactam resembles cyclosporin A, a macrocyclic polypeptide, in that they both inhibit immune responses to transplantation, but FK-506 seems to be more active. The total synthesis of (- )-FK-506 has been achieved by a process research group at Merck.1 The cyclization to a carboxamide was carried out with Mukaiyama s reagent (1) under high dilution in 81% yield. The most unusual feature of 2 is the presence of a three-keto sequence at C8, C9, and C,(l (hemiketal). 

Enantiomerically pure 1,3-thiazolidine-derived spiro /3-lactams 505 and 506 were stereoselectively synthesized by means of a Staudinger ketene-imine reaction in the presence of 2-chloro-l-methylpyridinium iodide (Mukaiyama s reagent) starting from optically active A -BOC-l,3-thiazolidine-2-carboxylic acid derivatives 504 and imines (Scheme 127). The reactions were stereoselective and afforded spiro-/3-lactams with a /ra r -configuration. The spiro-/3-lactams 505 and 506 were transformed into enantiomerically pure chiral monocyclic /3-lactams 507 and 508... 

Yong, Y. F Kowalski, J. A. Lipton, M. A. Facile and Efficient Guanylation of Amines Using Thioureas and Mukaiyama s Reagent, J. Org. Chem. 1997,... 

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]. 

The same group of workers has proceeded to develop an intramolecular version of the reaction. The aldehyde acids (35, n = 1 or 2) on treatment with Mukaiyama s reagent, 2-chloro-l-methylpyridinium iodide, and triethylamine afforded the cis substituted bicyclic lactones (36, n = 1 or 2). The authors have adduced evidence in support of a nucleophile-catalysed aldol lactonisation (NCAL) reaction mechanism rather than the alternative thermal [2+2] cycloaddition. They have also found that the intramolecular reaction, like the intermolecular process, is subject to asymmetric catalysis. When an optically active base such as 0-acetylquinidine was present in the reaction mixture, the bicyclic lactones were produced with high ee <01 JA7945>. 

Two new glucose-derived oxazolidinones have been prepared, and converted to iV-acyl derivatives of type 204 (R = Me or Piv). The dialkylboron enolates derived from 204 underwent aldol reactions to give syn-products 205, with diastereomeric ratios between 8 1 and 16 1. The same group has also made the oxazolidinone 206 from D-xylose. When this was treated with Mukaiyama s reagent (2-chloro-l-methylpyridinium iodide) in the presence of an imine, a Staudinger ketene-imine cyclization occurred to give a p-lactam such as 207, the structure of which was confirmed by X-ray crystallography, in >98% de. ... 

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