A Formal Synthesis of (+)-Cassiol Exploiting Meyers'''' Bicyclic Lactam Methodology

ＩｎｔｒｏｄｕｃｔｉｏｎＩｎ 1988,ｆｒｏｍａｎａｑｕｅｏｕｓｅｘｔｒａｃｔｉｏｎｏｆＣｈｉｎｅｓｅｃｉｎ ｎａｍｏｎ ,ｗｈｉｃｈｈａｓｌｏｎｇｂｅｅｎｕｓｅｄｉｎｔｈｅｔｒａｄｉｔｉｏｎａｌＣｈｉ ｎｅｓｅｍｅｄｉｃｉｎｅａｓａｄｉａｐｈｏｒｅｔｉｃ ,ａｎｔｉｐｙｒｅｔｉｃ ,ｏｒａｎａｌｇｅｓｉｃａｇｅｎｔ,Ｆｕｋａｙａａｎｄｃｏ ｗｏｒｋｅｒｓｉｓｏｌａｔｅｄｃａｓｓｉｏｓｉｄｅ (1)ａｎｄｆｏｕｎｄｔｈａｔｔｈｉｓｃｏｍｐｏｕｎｄｐｏｓｓｅｓｓｅｄｒｅｍａｒｋａｂｌｅａｎｔｉｕｌ ｃｅｒｏｇｅｎｉ…     

Design of chiral organocatalysts for practical asymmetric synthesis of amino acid derivatives

A series of structurally rigid, chiral quaternary ammonium salts and several chiral sec-amine catalysts derived from commercially available (R)- or (S)-binaphthol have been designed as new C(2)-symmetric chiral phase-transfer catalysts and chiral bifunctional amino-catalysts. These chiral organocatalysts have been successfully applied to the highly practical asymmetric synthesis of various amino acid derivatives.     

Enantioselective synthesis of "quaternary" 1,4-benzodiazepin-2-one scaffolds via memory of chirality

Glycine-derived 1,4-benzodiazepine-2-ones such as diazepam are chiral by virtue of the boat-shaped conformation of the diazepine ring and exist as a racemic mixture of conformational enantiomers. However, the presence of a chiral center at C-3 of the benzodiazepine perturbs this equilibrium and preferentially stabilizes one ring conformer. We report that N-i-Pr 1,4-benzodiazepine-2-ones derived from (S)-Ala and (S)-Phe can be deprotonated and alkylated in 86-99% ee, despite the fact that the original chiral center is destroyed in the deprotonation step. We attribute this highly enantioselective alkylation to the chiral memory of the benzodiazepine ring. This protocol provides easy access to the previously unexplored "quaternary" 1,4-benzodiazepine-2-ones.     

Asymmetric synthesis of alpha,alpha-disubstituted alpha-amino acids using (S,S)-cyclohexane-1,2-diol as a chiral auxiliary

Diastereoselective alkylation of ethyl 2-methyl- and/or 2-ethylacetoacetates using the (S,S)-cyclohexane-1,2-diol as an acetal chiral auxiliary afforded enol ethers (2a-f and 5a-f) of 92->95% de in 31-70% yields. Removal of the cyclohexane-1,2-diol with BF(3)-OEt(2) afforded beta-keto esters (3 and 6) bearing a chiral quaternary carbon. The beta-keto esters could be easily converted into optically active alpha-methylated and/or alpha-ethylated alpha,alpha-disubstituted amino acids (12 and 13) in 21-99% yields using Schmidt rearrangement.     

Asymmetric synthesis,stereochemistry, and absolute configuration of 1,2-5-trimethyl-5-(2-cyanoethyl)- and 1,2,5-trimethyl-4-piperidinones

The asymmetric Michael alkylation of (–)-1,2,5-trimethyl-4-(1S-phenylethylimino)piperidine by electrondeficient alkenes proceeds with the formation of(+)-cis-(2S,5S)- and (–)-trans-(2R,5S) diastereomers of 1,2,5-trimethyl-5-(2-cyanoethyl)- and 1,2,5-trimethyl-5-(2-methoxycarbonylethyl)-4-piperidinones containing a chiral quaternary center C(₅). The spatial structure of these new chiral 4-piperidinones has been established on the basis of ¹H and ¹³C NMR spectroscopic data. The absolute configuration of the C(₂) and c(₅) chiral centers in the diastereomers has been determined by stereochemical correlation on the basis of circular dichroism data.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1369–1378, October, 1992.     

新型双膦配体及钯催化的烯丙基烷基化反应用于构筑季碳手 性中心

从二茂铁恶唑啉膦化合物(Sp)-1出发,合成了严平面手性二茂铁修饰的口袋型双膦配体(R,R,Sp,Sp)-4和(S,S,Sp,Sp)-4。这类配体在前手性亲核试剂的不对称烯丙基化构筑手性季碳中心的反应中,显示了较好的反应活性及对映选择性。当利用亚胺的氨基酸酯衍生物时,可以得到一些非天然的季碳氨基酸衍生物,ee值最高可以达到75.3%。一些简单的酮的烯醇负离子也可用作亲核试剂,产物为α-位双取代的具有季碳中心的酮,ee值可高达95%。     

C(2) symmetric chiral NHC ligand for asymmetric quaternary carbon constructing copper-catalyzed conjugate addition of grignard reagents to 3-substituted cyclohexenones

The asymmetric construction of quaternary carbon centers by conjugate addition of Grignard reagents to 3-methyl- and 3-ethylcyclohexenones was realized in a maximum enantioselectivity of 80% by using a C 2 symmetric chiral N-heterocyclic carbene (NHC)-copper catalyst, generated from (4 S,5 S)-1,3-bis(2-methoxyphenyl)-4,5-diphenyl-4,5-dihydro-1 H-imidazol-3-ium tetrafluoroborate and copper(II) triflate. The stereostructures of the NHC-Au complexes were analyzed by X-ray crystallography, which rationalized the good stereocontrolling ability of N-aryl NHCs.     

Highly enantioselective Michael reactions catalyzed by a chiral quaternary ammonium salt. Illustration by asymmetric syntheses of (S)-ornithine and chiral 2-cyclohexenones

[formula: see text] The use of the chiral quaternary ammonium salts 1a and 1b makes possible enantioselective Michael reactions which have been applied to the asymmetric syntheses of (S)-ornithine (2) and the chiral 2-cyclohexenone 6.     

Diastereoselective aziridination of chiral electron-deficient olefins with N-chloro-N-sodiocarbamates catalyzed by chiral quaternary ammonium salts

Chiral quaternary ammonium salt-catalyzed diastereoselective aziridination of electron-deficient olefins that possess a chiral auxiliary with N-chloro-N-sodiocarbamates was developed. The key to high stereoselectivity was found to be the employment of the "matching" stereochemical combination of chiral auxiliary/ammonium salt. For example, when 3-phenyl-(4R,7S)-4-methyl-7-isopropyl-4,5,6,7-tetrahydroindazole (L-menthopyrazole) as a chiral auxiliary and a cinchonidine-derived chiral ammonium salt as a catalyst were applied to the reaction system, perfect diastereoselectivity was realized. Furthermore, the preparation of enantiomerically pure aziridines by removal of the chiral auxiliary was demonstrated.     

Site- and enantioselective formation of allene-bearing tertiary or quaternary carbon stereogenic centers through NHC-Cu-catalyzed allylic substitution

Catalytic enantioselective allylic substitutions that result in addition of an allenyl group (<2% propargyl addition) and formation of tertiary or quaternary C-C bonds are described. Commercially available allenylboronic acid pinacol ester is used. Reactions are promoted by a 5.0-10 mol % loading of sulfonate-bearing chiral bidentate N-heterocyclic carbene (NHC) complexes of copper, which exhibit the unique ability to furnish chiral products arising from the S(N)2' mode of addition. Allenyl-containing products are generated in up to 95% yield, >98% S(N)2' selectivity, and 99:1 enantiomeric ratio (er). Site-selective NHC-Cu-catalyzed hydroboration of enantiomerically enriched allenes and conversion to the corresponding β-vinyl ketones demonstrates the method's utility.     

Chiral discrimination of cryptochiral saturated quaternary and tertiary hydrocarbons by asymmetric autocatalysis

Chiral discrimination of saturated hydrocarbons has been very difficult to establish, or has not been possible at all. The first chiral discrimination of cryptochiral 5-ethyl-5-propylundecane 1, that is, (n-butyl)ethyl(n-hexyl)(n-propyl)methane, a chiral saturated quaternary hydrocarbon, which is known to exhibit practically no detectable value of optical rotation between 280 and 580 nm, has been accomplished by asymmetric autocatalysis of pyrimidyl alkanol. The absolute configuration of 1 has been determined. In the presence of (R)- or (S)-1, the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc affords (S)- and (R)-pyrimidyl alkanol with 91-97% ee, respectively. Thus, asymmetric autocatalysis serves as a powerful tool for the chiral discrimination of saturated hydrocarbons.     

Asymmetric total synthesis of fredericamycin A: an intramolecular cycloaddition pathway

The asymmetric total synthesis of the potent antitumor antibiotic fredericamycin A ((S)-1) was achieved by the intramolecular [4+2] cycloaddition of the silylene-protected styrene derivative (S)-7 followed by the aromatic Pummerer-type reaction of the sulfoxide (S)-5. Although we had already succeeded in the total synthesis of racemic 1 by the same approach, synthesis of its asymmetric version was more complicated than we had expected due to the difficulties involved in constructing the quaternary carbon center and the tendency of this center to undergo facile racemization. Racemization of this center during the installation of the acetylene moiety on the dione (R)-8 was the most serious aspect. Systematic studies of its DE-ring analogue (R)-25 revealed that racemization of the quaternary carbon center proceeded by a retro-aldol-aldol reaction of the initial adduct, (1R)-39 a-Li, and that the degree of racemization was dependent on the reaction temperature. The racemization process could be completely depressed by keeping the reaction temperature at -78 degrees C. The construction of the stereogenic quaternary carbon center was achieved by the lipase-catalyzed desymmetrization of the prochiral 1,3-diol 9 a bearing the DEF-ring moiety. These studies enabled us to attain the asymmetric total synthesis of (S)-1 while completely retaining the chiral integrity created by the enzymatic reactions.     

Syntheses of chiral β- and γ-amino ethers, morpholines, and their homologues via nucleophilic ring-opening of chiral activated aziridines and azetidines

Lewis acid catalyzed quaternary ammonium salt mediated highly regioselective ring-opening of chiral activated aziridines and azetidines with alcohols to nonracemic β- and γ-amino ethers has been developed. The reaction mainly proceeds via an S(N)2 pathway, and the partial racemization of the starting substrate was effectively controlled by using quaternary ammonium salts. β- and γ-amino ethers are obtained with high enantio- and diastereospecificity (ee up to >99%, de up to 99%). The methodology was further extended to synthesize morpholines and their homologues with high enantiospecificity (ee up to 90%) when halo alcohols were employed as the nucleophiles.     

New,improved procedure for the synthesis of structurally diverse N-spiro C2-symmetric chiral quaternary ammonium bromides

Selective, direct ortho magnesiation of (S)-2,2'-bis(isopropoxycarbonyl)-1,1'-binaphthyl (6) has been achieved under mild conditions, using magnesium bis(2,2,6,6-tetramethylpiperamide) [Mg(TMP)(2)]. In combination with the subsequent reaction with the appropriate electrophiles, bromine and iodine, this method constitutes a key step in establishing a new and concise synthetic route to a wide variety of N-spiro C(2)-symmetric chiral quaternary ammonium bromides of type 1.     

Chiral tetraaminophosphonium carboxylate-catalyzed direct Mannich-type reaction

The cooperative asymmetric catalysis of chiral tetraaminophosphonium carboxylate (P,S)-1.OCOR has been established, and its synthetic utility has been successfully demonstrated by application to the highly enantioselective direct Mannich-type reaction of azlactones with N-sulfonyl imines. The present study stimulates the cultivation of the potential of the chiral quaternary onium salt catalysis by the structural modification of organic anion.     

Palladium-catalyzed asymmetric synthesis of axially chiral allenylsilanes and their application to SE2' chirality transfer reactions

Stepwise application of the Pd-catalyzed S(N)2' reaction and the desilylative S(E)2' reaction to the ambivalent 2-bromo-1-silyl-1,3-dienes provides a novel route to the highly enantioselective construction of tertiary and quaternary propargylic stereogenic centers via axially chiral allenylsilanes.     

Designer chiral quaternary ammonium bifluorides as an efficient catalyst for asymmetric nitroaldol reaction of silyl nitronates with aromatic aldehydes

Designer chiral quaternary ammonium bifluoride 1 has been prepared, and both its catalytic and its chiral efficiency have been clearly demonstrated by achieving the first catalytic asymmetric nitroaldol reaction of silyl nitronate with aldehydes. For instance, the reaction of trimethylsilyl nitronate 2 (R(1) = Me) with benzaldehyde (R(2) = Ph) in THF in the presence of (S,S)-1 (2 mol %) proceeded smoothly at -78 degrees C, giving the corresponding nitroaldol adduct 3 (R(1) = Me, R(2) = Ph) in 92% isolated yield (anti/syn = 92:8) with 95% ee (anti isomer). The method was found to be successfully applicable to other aromatic aldehydes and silyl nitronates, and a high level of anti selectivity and enantiomeric excess was constantly observed. This finding should lead to the further development of fluoride ion-catalyzed asymmetric carbon-carbon bond-forming reactions.     

Catalytic asymmetric synthesis of allylsilanes through rhodium/chiral diene-catalyzed 1,4-addition of alkenyl[2-(hydroxymethyl)phenyl]dimethylsilanes

A new synthetic method of chiral allylsilanes has been developed through a rhodium-catalyzed asymmetric 1,4-addition of alkenyl[2-(hydroxymethyl)phenyl]dimethylsilanes to beta-silyl alpha,beta-unsaturated ketones. By employing (S,S)-Ph-bod* as a ligand, a range of alkenyl nucleophiles have been installed to these substrates in high yield and enantiomeric excess. The resulting allylsilanes can be used for stereoselective intramolecular allylation reactions to control two contiguous tertiary and quaternary stereocenters.     

The rearrangement of 2,3-epoxysulfonates and its application to natural products syntheses: formal synthesis of (-)-aphanorphine and total syntheses of (-)-alpha-herbertenol and (-)-herbertenediol

The Lewis acid treatment of 2,3-epoxysulfonates with 2,3-dialkyl substituents or 2-alkyl-3-aryl substituents produced the rearrangement products via C3-cleavage of the oxirane ring in high yields. On the other hand, 2-aryl-3-alkyl-2,3-epoxysulfonates produced the products via C2-cleavage of the oxirane ring. The sulfonyloxy groups of the alpha-sulfonyloxy ketones, having a chiral benzylic quaternary carbon center obtained by the rearrangement of 2-alkyl-3-aryl-2,3-epoxysulfonates, were reductively eliminated to give the ketones with a chiral benzylic quaternary carbon center. The method was applied to the formal synthesis of (-)-aphanorphine and total syntheses of (-)-alpha-herbertenol and (-)-herbertenediol.     

Nitrile biotransformations for highly enantioselective synthesis of oxiranecarboxamides with tertiary and quaternary stereocenters; efficient chemoenzymatic approaches to enantiopure alpha-methylated serine and isoserine derivatives

[reaction: see text] Biotransformations of a number of differently substituted and configured oxiranecarbonitriles using Rhodococcus sp. AJ270, a microbial whole-cell catalyst that contains nitrile hydratase/amidase, were studied. While almost all trans-configured 3-aryl-2-methyloxiranecarbonitriles and 2,3-dimethyl-3-phenyloxiranecarbonitrile were efficiently hydrated by the action of the less enantioselective nitrile hydratase, the amidase exhibited excellent 2S,3R-enantioselectivity against 2-methyl-3-(para-substituted-phenyl)oxiranecarboxamides. Under very mild conditions, biotransformations of nitriles provided an efficient and practical synthesis of 2R,3S-(-)-3-aryl-2-methyloxiranecarboxamides, electrophilic epoxides with tertiary and quaternary stereocenters, in excellent yield with enantiomeric excess greater than 99.5%. The synthetic applications of the resulting enantiomerically pure epoxides were demonstrated by convenient and straightforward syntheses of polyfunctionalized chiral molecules possessing a quaternary stereocenter such as R-(+)-2-hydroxy-2-methyl-3-phenylpropionic acid, 2R,3R-(-)-3-amino-2-hydroxy-2-methyl-3-phenylpropionic acid, and 2S,3S-(+)-2-amino-3-hydroxy-2-methyl-3-phenylpropionic acid, employing the regio- and stereospecific epoxide ring opening reactions of 2R,3S-(-)-2-methyl-3-phenyloxiranecarboxamide as the key steps.