Stereoselectivity carbamic esters

Intramolecular conjugate addition of carbamates to a,fi-unsaturated esters.3 In the presence of potassium f-butoxide or NaH, allylic carbamate esters 1 cyclize stereoselectively to traws-oxazolidones (2). 

This same chemical logic was extended to methacholine and led to synthesis of its carbamate ester, bethanechol, an orally effective potent muscarinic agonist with almost no nicotinic activity at therapeutic doses. Muscarinic receptors exhibit stereoselectivity tor the two optical isomers of bethanechol, and similar to methacholine, the S-(+)-enantiomer exhibits greater binding affinity at muscarinic receptors than the R-(-)-enantiomer in isolated receptor preparations. 

The mechanism of the stereoselective syntheses of (K)-3-aryl-5-(hydroxy-methyl)oxazolidinones via the Mannenin reaction of aryl carbamic acid esters with (Jt)-glycidyl butyrate has been explored in detail by Brickner et al. [60]. Namely, N-lithiated carbamate derivatives of anilines are allowed to react with the commercially available (K)-glycidyl butyrate (96-98% enantiomeric excess ee) under appropriate conditions to obtain enantiomerically pure (Jt)-3-aryl-5-(hydroxymethyl)oxazolidinones in 85-99% yields, according the pathways depicted in Scheme 19. 

Common achiral reducing agents such as borohydrides produce the anri-isomer 18 as the major product of the reduction of the carbamate protected y-amino-p-oxo esters 31 (Table 4, entries a-e)J36 38 41 50l The syn-isomer is accessible with high diastereoselectivity by reduction of the corresponding AA-dibenzyl p-oxo esters using sodium borohydride stereoselective reduction under nonchelation control (Table 4, entry f).t45 52l... 

Enantiomerically pure, unprotected tetramic acids are accessible by hydrogenolytic deprotection of 4-(benzyloxycarbonyl)amino-3-oxocarboxylic esters 31 (X= Z Y = H) followed by ring closure (Scheme 11)J55 In the absence of TV-carbamate protection, the next reduction step is not totally stereoselective/54 ... 

P,y-Diamino analogues 49 of statine are prepared stereoselectively starting from the O-methyl hydroxamate derivative of N-protected statine. The reaction sequence involves the formation of a p-lactam intermediate obtained by internal cyclization under Mitsunobu conditions.184 Alternatively, direct amination of either a p-oxo ester 31 followed by reduction of the resulting enamine 50, 85 or by reduction of the corresponding ,p-unsaturated ester, 88 gives an enantiomeric mixture of the corresponding unprotected p-amine, which is protected by a carbamate prior to chromatographic separation (Scheme 20). 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

Various functionalized alkynes can be submitted to carbocupration reactions, such as alkoxyalkynes,150 alkynyl carbamates,151 acetylenic orthoesters,152 and thioalkynes.153 The carbocupration of orthoesters, for example, 204, has been used to prepare a-substituted esters of the type 206 by acidic hydrolysis of the adduct 205 (Scheme 51).152 This allows the formation of regioisomers that are not accessible by copper-mediated addition to acetylenic esters. A stereoselective synthesis of trisubstituted alkenes has been described by Normant et al.lSd> starting from phenylthio-acetylene 207. Carbocupration with lithium di- -butylcuprate affords the intermediate 208 which, upon addition of /z-butyllithium, undergoes a 1,2-metalate rearrangement to the vinylcuprate 209. The latter can be trapped with various electrophiles, for example, ethyl propiolate, providing product 210 with complete regio- and stereocontrol. 

Iodocyclization of carbamates involving electron-deficient alkenes such as a,/l-unsaturated esters is greatly facilitated by the use of silver triflate and proceeds with excellent trans ring stereoselectivity. It is worth mentioning, however, that the resultant iodides can undergo epimerization, whose rate depends on the solvent used in the process21. 

Lewis acids such as silyl triflates7 or boron trifluoride8 initiate the rearrangement of allyl acetates, usually with low stereoselectivity. But soft electrophilic metal ions such as Hg2+ or Pd2 + catalyze the rearrangement of allylic esters and carbamates (Table l)9. 

Dialkyl azodicarboxylates. 15, lll-l Allyl carbamates. By catalysis reaction of alkenes and diethyl azodica ducts are converted to allylic carbamai a-Amino P-kydroxy esters. Enc carboxylate stereoselectively, giving tli N-N bond the reaction sequence accoi... 

Camphorsulfonyl chlorides 45 readily form amides by reaction with amines. On reduction of the carbonyl group, alcohols, e.g., 46 and 47, are obtained which are extremely useful auxiliaries for many purposes. Thus, esters are formed with carboxylic acids which may then undergo enolate reactions (SectionsD.1.1.1.3.2., D.l.5.2.1., D.3. and D.7.1.) or act as dienophiles and dipolar-ophiles (Sections D.l.6.1.1.1.2.2.1. and D.l.6.1.2.1.). Enol ethers of these auxiliaries give [2 + 2] cycloadditions with dichloroketene (Section D.l.6.1.3.), while carbamate derivatives have been used in acyliminium reactions (Section D.l.4.5.). Generally, steric hindrance in the sulfonamide group improves the stereoselectivity of the reactions and, therefore, the amides with diisopropylamine and dicyclohexylamine are used as auxiliaries both enantiomers of the dicyclohexyl derivative are commercially available. 

Epoxidation of Acyclic Alkenes. Stereoselective epoxidation of a series of allylic carbamate methyl esters (eq 34), homoallylic alcohols (eq 35), and acetates (eq 36) could be performed with good to excellent stereocontrol. It is believed that the directing effect of the carbamate protecting group plays an important role in dictating the level of stereocontrol. 

The process from the FMC company involves as the pivotal step an intramolecular stereoselective [2 + 1 [-cycloaddition. In a Prins reaction [94] of chloral and isobutene, followed by an isomerisation, a racemic, trichloromethyl-substituted aUyl alcohol is obtained. Reaction with the isocyanate from (R)-naphthylethyl-amine enables separation ofthe diastereomers by crystallisation. The carbamate is cleaved by trichlorosilane/triethylamine, thus permitting the recycling of the chiral auxiliary. The optically pure (R)-aUyl alcohol is reacted with diketene, to produce the / -keto-ester. After diazo transfer and basic cleavage, the diazoacetate is obtained catalysed by a copper salt, this is converted in a [2 + 1 ]-cyclo-addition into a bicyclic lactone. The Boord reaction (discovered by Cecil E. Boord in 1930) [95] finally gives (IR)-cis-permethric acid. [96]... 

It was shown that vinyl deprotonation of unsymmetrical cis-stilbene 2-styryl-phenyl-carbamic acid tert-butyl ester can be achieved using s-BuLi in TH F at —25 °C. The generated l-lithio-l,2-diphenylethene undergoes an insituZ-to-Eisomerization, and subsequent reaction with electrophiles results in stereoselective synthesis of trisubstituted alkenes. 

Davies and co-workers also applied a ring-closing metathesis strategy in their preparation of constrained p-amino acid derivatives. Their work employed a chiral auxiliary, S -(l-phenyl-ethyl)-carbamic acid benzyl ester, to achieve the desired P-amino acid derivatives in a stereoselective fashion. Treatment of diene precursors 46 and 48 with 4 mol % of 3 in refluxing dichloromethane provided the corresponding carbocyclic P-amino acid derivatives 47 and 49 in 85 and 35% yield, respectively, with greater than 95% diastereoselectivity in both cases. The diminished yield in the case of 49 is presumably due to sterics effects. 

Various functional alkenes were similarly synthesized with high regio and E-stereoselective manner via [RuCl2(p-cymene)]2/AgSbF6 catalysed hydroarylation of phenyl or ester substituted alkynes with aromatic carbamates. The addition of 5 equiv. of pivalic acid improves the reaction in 1,4-dioxane. The alkenyl ester is converted into carboxylic acid by using 2 equiv. of LiOH, whereas phenol derivatives were deprotected by addition of 10 equiv. of LiOH [(Eq. 82)] [166]. 

Lhommet and coworkers prepared the chiral bicyclic carbamate 1189 from L-lysine by a method that involved an electrochemical methoxylation (Scheme 150). ° This precursor, in effect a disguised acyliminium ion, reacted with the sdylated enol 1190 and trimethylsilyl triflate to give a diaste-reomeric mixture of p-keto esters (+)-1191, hydrolysis and decarboxylation of which produced ketone (—)-1192 as the only discernible product. It was essential to reduce this ketone stereoselectively in order to set up the configuration of the target alkaloid s side chain correctly. Fortunately, this was achieved with either K-Selectride or with lithium triethylborohydride. 

The reaction between ethyl Hthiopropiolate and the N-acylpyridinium salt formed by reaction of 4-methoxy-3-methyl-5-(triisopropylsilyl)pyridine 2363 with (+)-frafis-2-(a-cumyl)-cyclohexyl chloroformate (TCC chloro-formate) was the starting point in the synthesis of (-l-)-aUopumihotoxin 267A (1718) by Comins et al. (Scheme 301). The dihydropyridone product (—)- 2364 was obtained diastereoselectively (>96%) before hydrogenation to the saturated ester (+)-2365. However, some epimerization of the methyl substituent was apparent after cleavage of the TCC carbamate with lithium methoxide and cyclization to the indolizidinone (—)-2366 (dr 8 1). Acetoxylation at C-8 with lead tetraacetate was stereoselective, and introduced the acetate from the axial direction, possibly by stereoelec-tronicaUy-controUed intramolecular transfer of acetate from a lead—enol intermediate. The acetoxy product (—)-2367 was protodesilylated with formic acid, after which a one-pot tandem reduction with K-Selectride followed by hthium aluminum hydride gave diol (- -)-2368 with complete... 

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