Methoxycarbonylation, stereoselective

Alkyl-1,4-dihydropyridines on reaction with peracids undergo either extensive decomposition or biomimetic oxidation to A-alkylpyridinum salts (98JOC10001). However, A-methoxycarbonyl derivatives of 1,4- and 1,2-dihydro-pyridines (74) and (8a) react with m-CPBA to give the methyl tmns-2- 2>-chlorobenzoyloxy)-3-hydroxy-1,2,3,4-tetrahydropyridine-l-carboxylate (75) and methyl rran.s-2-(3-chlorobenzoyloxy)-3-hydroxy-l,2,3,6-tetrahydropyridine-l-carboxylate (76) in 65% and 66% yield, respectively (nonbiomimetic oxidation). The reaction is related to the interaction of peracids with enol ethers and involves the initial formation of an aminoepoxide, which is opened in situ by m-chlorobenzoic acid regio- and stereoselectively (57JA3234, 93JA7593). 

The stereoselectivity is not significantly improved if boron enolates are used instead of lithium enolates. For example, the enantiomerically pure aldehyde (—)-(2S,4/ )-4-methoxycarbonyl-2-methylpentanal delivers the diastereomeric thioeslers in a ratio of 3 2 when treated with the indicated boron enolate29. 

Entry 4 shows the reaction of 9-(E-2-butenyl)-9BBN with methyl pyruvate. This reaction is not very stereoselective, which is presumably due to a modest preference for the orientation of the methyl and methoxycarbonyl groups in the TS. Only use of an extremely sterically demanding pyruvic ester achieved high diastereoselectivity. 

Cycloalkene Derivatives Cyclopropenes readily interact with nitrile oxides. Reactions of a broad series of 3,3-disubstituted cyclopropenes with 4-substituted benzonitrile, methoxycarbonyl- and cyanoformonitrile oxides (229) as well as with di(isopropoxy)phosphorylformonitrile oxide (230) give 2-oxa-3-azabicyclo[3.1.0]hexene derivatives 62. Stereoselectivity of the cycloaddition is governed by both steric and polar factors. In particular, steric factors are supposed to prevail for 3-methyl-3-phenylcyclopropene affording 62 [R1 =... 

Heterocycles Both non-aromatic unsaturated heterocycles and heteroaromatic compounds are able to play the role of ethene dipolarophiles in reactions with nitrile oxides. 1,3-Dipolar cycloadditions of various unsaturated oxygen heterocycles are well documented. Thus, 2-furonitrile oxide and its 5-substituted derivatives give isoxazoline adducts, for example, 90, with 2,3- and 2,5-dihydro-furan, 2,3-dihydropyran, l,3-dioxep-5-ene, its 2-methyl- and 2-phenyl-substituted derivatives, 5,6-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene, and 1,4-epoxy-l,4-dihydronaphthalene. Regio- and endo-exo stereoselectivities have also been determined (259). 

Further studies demonstrated the influence of the double-bond substitution on both the reactivity and the stereoselectivity of the reaction [78-81]. Tamaru and co-workers reported then that using the same PdCl2/CuCl2/MeOH system on butenol derivatives, with the double bond in either the terminal or an internal position, furnished selectively y-butyrol-actones. This dicarbonylation process most probably includes (i) a lactoniza-tion step and (ii) a methoxycarbonylation step, as displayed in Scheme 11 in which we clarify some intermediate steps on a representative example [82, 83]. The use of propylene oxide as an additive promotes this Pd-catalyzed dicarbonylation by playing the role of an HC1 quencher to maintain neutral conditions. 

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

The racemic stereoisomer (16b) of monomorine I has been stereoselectively synthesized (416). Thus, successive bis-alkylations of l-methoxycarbonyl-3-pyrroline (379) gave tranj-2,5-diaIkylpyrroIine (381) as a 1 1 mixture of 4 -bromopentane isomers. N-Decarbomethoxylation gave the bicyclic compound... 

More recently, Hoppe et all63 also reported a stereoselective synthesis of a P -amino-u -hydroxy enone and its transformation to a 1,2-dihydroxyethylene isostere (Scheme 29). The addition of dilithium dimethylcyanocuprate to the conjugated C=C bond proceeds smoothly to produce a Z-enolate. The C-methoxycarbonylation with methyl cyanoformate forms the epimeric mixture of the 3-oxo ester. The product is then reduced with sodium cyanobo-rohyde to provide a protected form of the 1,2-dihydroxyethylene isostere. 

Cyclization of a variety of y-allenic alcohols with silver nitrate proceeds by 5-exo cyclization to form 2-alkenyltetrahydrofurans (equation 87).205c 206 Little stereoselectivity is seen in cyclizations of secondary alcohols. Cyclization by intramolecular oxypalladation/methoxycarbonylation or oxymercuration followed by transmetallation and methoxycarbonylation also showed no stereoselectivity (equation 88 and Table 24, entries 1 and 2).50 207 However, cyclization of the corresponding r-butyldimethylsilyl ether derivatives with mercury(II) trifluoroacetate followed by transmetallation/methoxycarbonylation pro-... 

Cyclization of 8-allenylamines is successful also. Synthesis of 2-alkenylpiperidines can be effected with mercury(II) or silver salts, with silver salts giving higher yields (equation 141 and Table 35).268a The significant asymmetric induction found in the cyclization of a chiral allene (78% ee, entry 2) suggests that the low stereoselectivity observed in the synthesis of the 2,6-disubstituted system (entry 3)269 may be a result of starting with a diastereomeric mixture. Aminopalladation/methoxycarbonylation has been effected in moderate yield also (entry 4). 

METHOXYCARBONYL-1,1,6-TRIMETHYL-1,4,4a,5,6,7,8,8a-OCTAHYDRO-2,3-BENZOPYRONE, an intramolecular Diels-Alder reaction is responsible for the diastereoselectivity. The stereoselective 1,4-functionalization of 1,3-dienes is exemplified by a two-step process leading to cis- and trans-1-ACETOXY-4-(DICARBOMETHOXYMETHYL)-2-CYCLOHEXENE. The effectiveness of a silyl hydride in providing a means for erythro-directed reduction of a p-keto amide is applied in a route to ERYTHRO-1 -(3-HYDROXY-2-METHYL-3-PHENYL-PROPANOYLJPIPERIDINE. This is followed by an asymmetric synthesis based on a chiral bicyclic lactam leading to (R)-4-ETHYL-4-ALLYL-2-CYCLOHEXEN-1-ONE. The stereoselectivity with which acetoxy migration can operate to an adjacent radical center is reflected in the one-step reaction that gives rise to 1,3,4,6-TETRA-O-ACETYL-2-DEOXY-a-D-GLUCOPYRANOSE. 

The oxidation of iV-methoxycarbonyl-l,2-dihydropyridine 56 with K 2-chloroperbenzoic acid results in /ra j-dioxygenation of the 5,6-alkene to give the allylic alcohol 57<1998JOC10001> (Scheme 16). The reaction is thought to proceed via an unstable aminoepoxide which is regio- and stereoselectively trapped by m-chloiobenzoic acid. 

The stereoselectivity of the second and key Michael-type conjugate addition reaction can be rationalized as follows. The conformation of 63 will be restricted to 63-A due to A(l 3) strain between the N-methoxycarbonyl and w-propyl groups in 63-B. Attack of the vinyl anion from the stereoelectronically favored a-axial direction provides the adduct 64 exclusively. It is noteworthy that the stereochemical course of the above reaction is controlled by the stereoelectronic effect in spite of severe 1,3-diaxial steric repulsion between the axial ethyl group at the 5-position and the incoming vinyl anion. This remarkable stereoselectivity can be also explained by Cieplak s hypothesis[31]. On the preferred conformation 63-A, the developing a of the transition state is stabilized by the antiperiplanar donor Gc-h at the C-4 position. 

When the two faces of the double bond are diastereotopic, hydroboration proceeds from the less hindered side of the double bond (see Section D.2.5.2.). A high degree of stereoselectivity is consistently observed for compounds with one side of the double bond significantly more hindered than the other. There are many examples of such additions in cyclic systems1 , for example, bicyclo[2.2.1]hept-2-ene and c/.v-4,5-bis(methoxycarbonyl)cyclohexene17-19/... 

Unsaturated benzylidene and alkylidene acetals, under methoxycarbonylation conditions, give tetrahydro-2//-pyran-2-acetates in low to good yield. Moderate stereoselectivity is observed in the cyclization and the ra-2,6-disubstituted isomer is predominant in the reaction mixture. The preferred 2,6-cis relationship can be ascribed to the 2,6-diequatorial orientation of the substituents on the tetrahydro-2//-pyran ring83. 

Furthermore, Tiecco and co-workers have reported the conversion of j9,y-un-saturated alcohols into 2,5-dihydrofurans with a catalytic amount of diphenyl diselenide and an excess amount of ammonium persulfate in acetonitrile (Scheme 20) [22]. In all cases, excellent yields of 3-methoxycarbonyl-2,5-di-hydrofurans were obtained (90-96%) without any by-products. The cycliza-tion-elimination process of those j3,y-unsaturated alcohols capable of giving rise to stereoisomeric 2,5-dihydrofurans proceeds with high stereoselectivity. Thus, the eryfhro-unsaturated alcohols gave the frau5-2,5-dihydrofurans, whereas the f/ireo-unsaturated alcohols gave the cis derivatives. 

It follows that a cis stereoselective nickel-ene process yields (279) and that (279) forms a C-acylnickel intermediate which inserts into either methanol (-> 280) or the internal alkenic bond affording, after final methoxycarbonylation, keto ester (281). It is interesting to note that the bidentate ligand dppb favored the latter process and that no -elimination of (279) was observed. Thus a catalyst, prepared in situ from Ni(COD)2/dppb (1 1) under CO, effected complete bicyclization of (278) to give only (281 80%, 10 1 epimer mixture). ... 

Ruthenium(ll)-catalyzed cycloaddition reactions of Y-sulfonylimines 1308 with methyl isocyanoacetate 1309 gave /ra r-2-imidazolines 1310 stereoselectively in 75-90% yields under neutral, mild conditions [R = phenyl, substituted phenyl, 2-furyl, lrans-PhCH=CH, tert-Bu R = tosyl, PI1SO2] (Scheme 333) < 1997JOG1799>. In contrast, the same reaction catalyzed by 1 mol% AuCl(( -HexNG) provides 4-methoxycarbonyl-5-alkyl-2-imidazolines 1321 with over 98% -selectivity (Scheme 333) <1996TL4969>. 

Interestingly, 2-phenylmethylenecyclopropane behaves differently. In the presence of phosphane-modified Ni(0) catalysts both types of cycloaddition products (A and B) are formed 27) (Eq. 88). Moreover the regioselectivity of Pathway b changes, as considerable amounts of frans-3-phenyl-4-methoxycarbonyl-methylenecyclopentanes are formed. On the other hand, the stereoselectivity of cycloaddition Products B is much better than in the same reactions with 2-methylmethylenecyclopropane. 

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