Stereocontrolled substitution

BROMOAMIDES. STEREOCONTROLLED SUBSTITUTION AND APPLICATION TO THE SYNTHESIS OF COMPOUNDS OF BIOLOGICAL INTEREST... 

The importance of the high regiospecificity of the photoinduced [3 + 2]cycloaddition reaction using silylmethylphthalimide should be emphasized. This reaction has opened the way to the synthesis of regio- and stereocontrolled substituted polycyclic compounds.323 350 460... 

Cycloheptodienyl-iron complexes.3 Cycloheptadienyl-Fe(CO)3 reacts with nucleophiles to give mixtures of products, usually in low yield. However, complexes 1, in which one CO ligand is replaced by triphenylphosphine or triphenyl phosphite, react with most nucleophiles at the dienyl terminus and in high yield. Hydride abstraction followed by reaction with a second nucleophile results in a regio- and stereocontrolled substitution at the opposite terminus and again anti to the metal. Decomplexation affords cw-5,7-disub-stituted cycloheptadienes. 

Lavilla et al. have reported several stereocontrolled oxidative electrophilic additions to A-alkyl-l,4-dihydropyridines 34 leading to the synthesis of 3-halo-2-substituted-l,2,3,4-tetrahydropyridines 67 (98JOC2728). Adding a stoichiometric amount of iodine or NIS (A-iodosuccinimide) to a methanolic solution of 1 -methy 1-... 

A salient structural feature of intermediate 18 (Scheme 2b), the retrosynthetic precursor of aldehyde 13, is its y,r5-unsaturated ester moiety. As it turns out, the Johnson ortho ester variant of the Clai-sen rearrangement is an excellent method for the synthesis of y,<5-unsaturated esters.11 In fact, the Claisen rearrangement, its many variants included, is particularly valuable in organic synthesis as a method for the stereocontrolled construction of trans di- and tri-substituted carbon-carbon double bonds.12,13 Thus, it is conceivable that intermediate 18 could be fashioned in one step from allylic alcohol 20 through a Johnson ortho ester Claisen rearrangement. In... 

The completion of the synthesis of the polyol glycoside subunit 7 requires construction of the fully substituted stereocenter at C-10 and a stereocontrolled dihydroxylation of the C3-C4 geminally-disub-stituted olefin (see Scheme 10). The action of methyllithium on Af-methoxy-Af-methylamide 50) furnishes a methyl ketone which is subsequently converted into intermediate 10 through oxidative removal of the /j-methoxybenzyl protecting group with DDQ. Intermediate 10 is produced in an overall yield of 83 % from 50) , and is a suitable substrate for an a-chelation-controlled carbonyl addition reaction.18 When intermediate 10 is exposed to three equivalents of... 

The E. coli enzyme accepts substitution on either cosubstrate propanal, acetone or 1-fluoro-2-propanone can replace the donor and a variety of aldehydes can replace the acceptor moiety 3. Shortcomings are the relatively low conversion rates obtained for any substrate analog and the as yet unidentified level of relative stereocontrol induced upon substitution at the nucleophilic carbon. 

A short and efficient synthetic approach to hydroxy-substituted ( )-stil-benoids, as exemplified by the natural compound resveratrol (371b) via solid-phase CM, was reported by a Korean group (Scheme 71) [154]. When two different stilbenes were allowed to couple by catalyst C, all three kinds of possible stilbenes were obtained as an inseparable mixture. Anchoring 4-vinylphenol to Merrifield resin, followed by exposing the supported styrenyl ether 368 and diacetoxy styrene 369 (10 equiv) to the catalyst, inhibited self-metathesis of the supported substrate. Sequential separation of the homodimer formed from 369 by washing and subsequent cleavage of the resin 370 with acid provided (E)-stilbene 371a with complete stereocontrol in 61% yield. 

Cyclization of an organolithium tethered to a suitably positioned carbon-carbon jt-bond is a thermodynamically favorable process that proceeds in a totally regioselective exo-fashion with a high degree of stereocontrol via a transition state in which the lithium atom is intramolecularly coordinated with the remote rc-bond.9 The stereochemical outcome of the cyclization of a substituted 5-hexenyllithium follows from the preference of the substituent to occupy a pseudoequatorial position in the chair-like transition state depicted below.7... 

More functionalized 5,6-dihydro-2H-pyran-derivatives 71 and 72 have been prepared [26] by cycloaddition of 1 -methoxy-3-trialkylsilyloxy-1,3-butadienes 69 with t-butylglyoxylate (70) (Scheme 5.6). Whereas thermal reactions did not occur in good yields because of the decomposition of the cycloadducts, application of pressure (10 kbar) allowed milder conditions to be used, which markedly improved the reaction yields. The use of high pressure also gives preferentially en Jo-adduct allowing a stereocontrolled synthesis of a variety of substituted 5,6-dihydro-2H-pyran-derivatives, which are difficult to prepare by other procedures. 

This homoenolate methodology has been extended to the use of nitrones 170 as electrophiles [72]. Scheldt and co-workers have shown that enantiomerically enriched y-amino esters 172 can be prepared with excellent levels of stereocontrol from an enal 27 and a nitrone 170 using the NHC derived from triazolium salt 164 (Scheme 12.37). The oxazinone product 171, formally a result of a [3-1-3] cycloaddition, is cleaved to afford the y-amino ester product 172. The reaction shows broad substrate scope, as a range of substituted aryl nitrones containing electron donating and withdrawing substituents are tolerated, while the enal component is tolerant of both alkyl and aryl substituents. 

The synthesis in Scheme 13.21 starts with a lactone that is available in enantiomer-ically pure form. It was first subjected to an enolate alkylation that was stereocontrolled by the convex shape of the cis ring junction (Step A). A stereospecific Pd-mediated allylic substitution followed by LiAlH4 reduction generated the first key intermediate (Step B). This compound was oxidized with NaI04, converted to the methyl ester, and subjected to a base-catalyzed conjugation. After oxidation of the primary alcohol to an aldehyde, a Wittig-Horner olefination completed the side chain. 

Aubele et al. studied the aqueous Prins cyclization using cyclic unsaturated acetals as oxocarbenium ion progenitors and allylsilanes are used as nucleophiles. Cyclizations proceed efficiently inside Lewis acidic micelles (of cerium salt) in water. A variety of vinyl- and aryl-substituted tetrahydropyrans with excellent stereocontrol was obtained (Eq. 3.26).113... 

The use of silylketals derived from allylic alcohols and 1-substituted nitroethanols for the stereocontrolled synthesis of 3,4,5-trisubstituted 2-isoxazolines via intramolecular 1,3-dipolar cycloaddition has been demonstrated. Here again, the use of silyl nitronates (ISOC) increases the level of selectivity compared to INOC (Eq. 8.92).145... 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

CARBOETHOXY-2,3-DIMETHYL-1-OXA-8-AZASPIRO[4-5]DECANE, a procedure that exemplifies a new stereocontrolled method for constructing substituted tetrahydrofurans. 

Stereocontrolled nucleophilic opening at the C 1-position of epoxides to furnish substituted piperidine 182 was accomplished through the use of Lewis acids TMSOTf or Sc(OTf), <06CC2156>. 

Reggelin et al. reported the application of methylated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines 203 for the synthesis of highly substituted aza(poly)cyclic ring systems 204 under complete stereocontrol <06JA4023 06S2224>. 

The same authors also studied recently the preparation of substituted vinyl -lactams 14, with efficient stereocontrol [11], by use of limited amounts of solvent (chlorobenzene) (Scheme 8.7). Microwave oven-induced reaction enhancement (MORE) chemistry techniques have been used to reduce pollution at the source and to increase atom economy. 

The Baylis-Hillman reaction of TV-protected 3-substituted 4-formylazetidin-2-ones with methyl vinyl ketone has been used to prepare intermediates from which highly functionalised P-lactams fused to medium rings were obtained by radical, stereocontrolled methods <99CC1913>. 

Substituted 3-hydroxy-2-pyrrolidinones were synthesised via 1,3-DC reactions of furfuryl nitrones with acrylates and subsequent intramolecular cyclisation after N-0 bond reduction. Addition of iV-acryloyl-(2/()-bomane-10,2-sultam to Z-nitrone 83 gave the endo/exo cycloadducts in 85 15 ratio with complete stereoface discrimination <00JOC1590>. The 1,3-DC of pyrroline A-oxide to chiral pentenoates using (-)-/rans-2-phenylcyclohexanol and (-)-8-phenylmenthol as chiral auxiliaries occurred with moderate stereocontrol (39% de and 57% de, respectively) and opposite sense of diastereoselectivity <00EJO3595>. The... 

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