Lactams, preparation from Subject

Most traditional methods use hydrochloric acid solutions as the acid reagent for the hydrolysis or alcoholysis of fi-lactams. Methanolic solutions of trimethylchloro-silane are able to generate HCI in situ, and the trick has been employed successfully for the methanolysis of fi-lactams in a route to aspartic acid derivatives [60, 61] and 2-oxazolidinones[62], respectively. Recently the use of silica-supported acid reagent has been reported as a convenient alternative. The reagent (Si02-Cl) prepared from admixing silica gel and SOCl2 in dichloromethane and subjected to dryness, is able to run the methanolysis of (1-lactams at room temperature in 20 min [63]. 

The imine 188, derived from 3-(trimethylsilyl)-2-propynal and (S)-a-methyl-benzylamine, was treated at — 40 °C with the born enolate 187 prepared from S-phenyl butanethioate, 9-borabicyclo[3.3.1]nonyl triflate and DIPEA. After workup, a mixture of the anti p-amino acid 189 and the syn adducts 190 was formed in a 5.2 1 ratio. This mixture was then subjected to cyclization using tert-butylmagnesium chloride in diethylether to give the trans P-lactam 191 in... 

Jarrahpour et al. [135] have described the synthesis of novel mono- and bis-spiro-[S-lactams 231 and 233, respectively, from benzylisatin 229 (Scheme 52). The starting substrate, benzylisatin 229 was prepared by reaction of isatin 228 with benzyl bromide and calcium chloride in DMF. The benzylisatin substituted imines 230 and di-imines 232 were further subjected to Staudinger reaction with ketenes derived from methoxy, phenoxy, and phthaloglycyl chlorides to afford novel mono- and bis-spiro-p-lactams 231 and 233, respectively. The configuration of benzylisatin 229 and monocyclic spiro-p-lactams 231 was established by X-ray crystallographic studies. These spiro-p-lactams will be studied as precursors of modified p-amino acids, (3-peptides and monobactam analogues. 

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

As previously discussed, 2 -i- 2 photocycloaddition can be stereoselective when carried out with rigid starting materials. When unsaturated lactam 178, prepared in a few steps from levulinic acid and (S)-( -f )-valinol, was subjected to photocycloaddition with ethylene, a very diastereoselective addition (de = 85%) takes place [152] (Scheme 29). Acidic methanolysis produces the corresponding esters and recovered valinol. Preferential formation of 179 involves an attack of ethylene from the convex side of the molecule. 

As shown in Schane 10.35a, this distinct synthesis began with the scalable preparation of benzocyclobntenol silyl ether 178 from 6-bromopiperonal (177) throngh epoxida-tion, cyclization, and silylation procedure [69]. The subsequent thermal cycloaddition of 179, via an o-quinodi-methane intermediate 180, with fumarate-derived amide 181 afforded C—H functionalization precursor 182 albeit in moderate yield and diastereoselectivity. As expected, when this amide is subjected to stoichiometric Pd(OAc)j in hot CHjCN, the Pd" complex 183 was formed in 53% yield. However, upon the exposure of this intermediate with C7 —H activation to excess of 3,4,5-trimethoxyiodobenzene (163) under the usual arylation condition, p-lactam 184 was obtained exclusively in 75% yield, instead of the expected... 

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