Azetidines chiral—

The intramolecular cyclization route to p-lactams still provides interest. P-Amino esters (obtained by a Reformatsky-type reaction of an imine and bromoacetates derived from chiral alcohols) are cyclized by the action Grignard reagents to 4-substituted P-lactams with impressive e.e. <96TL4095>. A similar approach through a Reformatsky-type reaction uses tricarbonyl(Ti -benzaldimine)chromium complexes and ultrasound <96T4849>. 3-Methyl-azetidin-2-ones (obtained from 3-amino-2-methylpropionates) have been resolved and their... 

On the other hand, other chiral dirhodium(II) tetracarboxylate catalysts based on azetidine- and aziridine-2-carboxylic acids have been prepared by Zwanenburg et al. and submitted to the cyclopropanation of styrene with... 

Metal-mediated carbonyl allylation, allenylation, and propargylation of optically pure azetidine-2,3-diones were investigated in aqueous environments.208 Different metal promoters showed varied regioselec-tivities on the product formation during allenylation/propargylation reactions of the kcto-fi-lactams. The stereochemistry of the new C3-substituted C3-hydroxy quaternary center was controlled by placing a chiral substituent at C4. The process led to a convenient entry to densely functionalized hydroxy-ji-lactams (Eq. 8.82). 

Scheme 2.92. Three-component asymmetric synthesis of 3-alkyl-4-methoxycarbonyl-azetidin-2-ones 2-386 from chiral crotonyl derivatives.

The ORD curves and ECD spectra of a number of chiral methyl-substituted cyclic amines, aziridine, azetidine, pyrrolidine and piperidine, and their A-mcthyl, A-halo and A-cyano derivatives, and of (5 )-l-azabicyclo[3.1.0]hexane [(5 )-115] were measured96. 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

For example (+)-43a was obtained after two purifications at 55 % ee and 10 % yield. Treatment of (+)-43a with hydrazine and KOH gave (+)-45a at 55 % ee and 40 % yield. The chiral host (S)-(—)-40 has been found to be extremely effective as a chiral selector towards comparatively bulky molecules of the phthalimide formed from of l- < r -butyl-3-chloro-azetidin-2-one, 47. A crystalline inclusion complex of 1 1 stoichiometry was formed between one mole of (S)-(—)-40 and two moles of rac-47 dissolved in benzene/hexane 1 1 solution. After one recrystallization, the complex was chromatographed on silica gel, and the crystalline product was treated with hydrazine. Optically pure (—)-3-amino-l-ieri-butyl-azetidin-2-one (—)-47, was obtained at 100% ee and 44% yield [51]. Primary diamines, like 1,3-dibromobutane (49), can undergo a similar reaction with potassium phthalimide, yielding diphthalimide, 50. The complexation process between rac-diphthalimide 50 and host (S,S)-(—)-6 gave a 1 1 complex containing (—)-50... 

Sakamoto et al. provided an example of absolute asymmetric synthesis involving hydrogen abstraction by thiocarbonyl sulfur (Scheme 6). [24] Achiral A -diphenylacetyl-iV-isopropylthiobenzamide 33 and Y-diphenylacetyl-A-isopropyl(p-chloro)thio-benzamide 33 crystallize in chiral space group P2 2 2. Photolysis of the chiral crystals in the solid state gave optically active azetidin-2-ones whereas achiral thioketones were obtained as main products. When 33a was irradiated in the solid state at -45°C followed by acetylation (at -78°C), 2-acetylthio-3,3-dimethyl-l-diphenylacetyl-2-phenylaziridine (34a 39% yield, 84% ee), 4-acetylthio-5,5-dimethyl-2-diphenylmetyl-4-phenyloxazoline (35a 10% yield, 50% ee), 3,3-diphenyl-1-isopropy 1-4-... 

Sakamoto et al. found that. S -phenyl Y-benzoylfomiyl-A-tp-tolyljthiocarbamatc 54 crystallized in chiral space group P2i.[33] Photolysis of the chiral crystals in the solid-state gave optically active l-benzyl-4-phenyl-4-phenylthiooxazolidine-2,4-dione (55, 16% chemical yield, 21% ee) and cw-3,4-diphenyl-3-hydroxy-l-(thiophenylcarbonyl)-azetidin-2-one (56, 18% chemical yield, 23% ee) in 62 % conversion yield. Better optical purities were observed at low conversion (in 17% cov.), 46% ee for 55, and 32% ee for 56, respectively. 

The CD spectra of optically active l-nitroso-2-substituted azetidines are analysed by non-empirical quantum chemical calculations. The sign of the Cotton effect for the n-n transition at 380 nm is determined by the chirality of the chromophore (95JA928). 

Chiral azetidines have been synthesized by lipase-catalyzed selective acylation of the hydroxyl group in 2,4-bis(hydroxymethyl)azetidine 112 (Scheme 24) <2001TA605>. The resulting alcohol 113 was then transformed into an amino alcohol 114 (Equation 29), which represents an interesting precursor for the chiral catalyst 115. 

Reduction of A,(V-di bcnzy lam i noalkyl chloromethyl ketones 133, followed by spontaneous intramolecular ring closure of the resulting 7-chloroamines 134, afforded azetidinium salts 135, which were subsequently deprotected toward chiral 3-hydroxyazetidines 136 and 137 (Scheme 29) <1997JOC1815>. In a similar approach, ct-amino aldehydes 138 were converted into 3-hydroxyazetidinium salts 139 upon treatment with diiodomethane and samarium iodide, followed by stabilization using AgBF4. Ar-Dealkylation with Pd afforded enantiopure azetidines 140 (Scheme 30) <2000TL1231>. 

The electroreductive cyclization of chiral aromatic a-iminoesters 175, prepared from ( )-a-amino acids such as (6)-valine, (A)-leucine, and ( -phenylalanine, in the presence of chlorotrimethylsilane and triethylamine afforded mixed ketals of ar-2,4-disubstituted azetidin-3-ones 176 stereospecifically (>99% de and 85-99% ee) (Equation 46) <2003JA11591>. The best result was obtained using tetrabutylammonium chlorate as a supporting electrolyte and a platinum cathode. 

When K2C03 or CsC03 was used as base in acetonitrile, the desired azetidine was isolated in 85-92% yield. The use of 8equiv of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base in dichloromethane at room temperature gave excellent results (90-96%, yield), whereas TEA or diisopropyl ethyl amine (DIEA) gave poor yields (5-25%). Several substituted diazetidines were synthesized (Equation 28). Use of the corresponding optically pure hydrazines 219 afforded chiral diazetidines <2006TL6835>. 

The ease of racemization of chiral a-amino aldehydes under MBH conditions is undoubtedly a major difficulty in studying diastereoselective reactions [53]. Epi-merization can be essentially avoided by conducting the reaction at low temperature [54, 67], or it can be minimized at room temperature when a conformation-ally restricted amino aldehyde, such or N-trityl-azetidine 2-(S)-carboxyaldehyde is used [54]. The use of ultrasound also increases the rate of the MBH reaction, avoiding racemization almost completely, even at room temperature [55]. When adding various a-amino acid-derived aldehydes to methyl acrylate using DABCO... 

Indium-promoted reaction of l,4-dibromo-2-butyne with carbonyl compounds gives 1,3-butadiene derivatives via the allenic indium intermediates (Scheme 56).220 Similar indium-mediated l,3-butadien-2-ylation reactions of optically pure azetidine-2,3-diones have been investigated in aqueous media, offering a convenient asymmetric entry to the 3-substituted 3-hydroxy-/ -lactam moiety (Equation (40)). The diastereoselectivity of the addition reaction is controlled by the bulky chiral auxiliary at Q4 221 222... 

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