Chemoenzymatic synthesis of (4S,5R)-5-hydroxy-γ-decalactone

Reduction of ethyl 2-hydroxy-3-oxooctanoate with immobilised baker's yeast at pH 4.0 yields anti-2R,3R-dihydroxy ester with high diastereoselectivity and enantioselectivity (de 70%, ee 80%) which is conveniently converted to (4S,5R)-5-hydroxy-γ-decalactone.     

Chiral alpha-branched benzylic carbocations: diastereoselective intermolecular reactions with arene nucleophiles and NMR spectroscopic studies

The chiral benzylic alcohols 1-6 were prepared and subjected to S(N)1-type displacement reactions with various arene nucleophiles in acidic medium. Under optimized conditions (HBF(4).OEt(2), CH(2)Cl(2), -78 degrees C --> r.t.) the corresponding 1,1-diarylalkanes 11-18 and 20 were obtained in good chemical yields (48-99%). The facial diastereoselectivity of the reaction is high (d.r. = 91/9-97/3) when the substrate bears a stereogenic carbon center -CHtBuMe in the alpha-position to the electrophilic carbon atom. If the starting material was enantiomerically pure, no significant racemization was observed (94% ee --> 92% ee). The reactions proceed stereoconvergently as demonstrated by the conversion of the separated diastereoisomers syn-1a and anti-1a in separate reactions to the same product syn-11 (d.r. = 97/3). Further evidence for long-lived chiral benzylic carbocations as reaction intermediates was obtained from NMR studies in superacidic medium. The chiral cation 24 was generated in SO(2)ClF as the solvent at -70 degrees C employing SbF(5) as the Lewis acid and characterized by its (1)H and (13)C NMR spectra. NOE measurements suggest a preferred conformation in which the diastereotopic faces of the cation are differentiated by the two carbon substituents R and Me at the stereogenic carbon center in the alpha-position. The hypothesis is further supported by the observation that the diastereoselectivity of the substitution reaction decreases if the bulky tert-butyl (R = tBu) substituent in the substrate 1a is replaced by a smaller ethyl group (2a, R = Et).     

Diastereo- and enantio-selective crotylation of α-ketoesters using crotyl boronic acid ester complexes

A diastereo- and enantio-selective crotylation of ethyl pyruvate has been achieved using a chiral boronic acid auxiliary-based approach. This reaction creates two contiguous stereogenic centers, one of which is a quaternary carbon with complete diastereoselectivity and with enantioselectivities up to 7:1 (73% ee).     

Intermolecular C-H functionalization versus cyclopropanation of electron rich 1,1-disubstituted and trisubstituted alkenes

Rhodium(II)-catalyzed reactions of aryldiazoacetates with electron rich 1,1-disubstituted and trisubstituted alkenes were systematically studied. The regio-, diastereo- and enantioselectivity of the chemistry was profoundly influenced by the nature of the substrates and the catalyst. Conditions were developed for either selective cyclopropanation or C-H insertion. Both reactions can be achieved with high diastereo- and enantioselectivity (for C-H insertion: >90% de, up to 96% ee, for cyclopropanation: >94% de, up to 95% ee). For the 1,1-disubstituted vinyl ethers, cyclopropanation occurs with variable diastereoselectivity but in optimized systems the cyclopropane is formed in >94% de and up to 98% ee.     

Enantioselective synthesis of cyclopropylphosphonates containing quaternary stereocenters using a D2-symmetric chiral catalyst Rh2(S-biTISP)2

[reaction: see text] Rh(2)(S-biTISP)(2)-catalyzed reactions of dimethyl aryldiazomethylphosphonates generate donor/acceptor-substituted rhodium carbenoid intermediates capable of cyclopropanation of styrenes in high yields (85-96%), diastereoselectivity (> or =98% de), and enantioselectivity (76-92% ee).     

SuperQuat N-acyl-5,5-dimethyloxazolidin-2-ones for the asymmetric synthesis of alpha-alkyl and beta-alkyl aldehydes

The proclivity of alpha-branched N-2'-benzyl-3'-phenylpropionyl derivatives of (S)-4-benzyl-5,5-dimethyl-, (S)-4-phenyl-5,5-dimethyl-, (S)-4-isopropyl-5,5-dimethyl-, (S)-4-benzyl- and (S)-4-benzyl-5,5-diphenyl-oxazolidin-2-ones to generate directly 2-benzyl-3-phenylpropionaldehyde upon hydride reduction with DIBAL is investigated. The (S)-4-benzyl-5,5-dimethyl-derivative proved optimal for inhibition of endocyclic nucleophilic attack, giving 2-benzyl-3-phenylpropionaldehyde in good yield upon reduction. Application of this methodology for the asymmetric synthesis of chiral aldehydes via diastereoselective enolate alkylation of a range of (S)-N-acyl-4-benzyl-5,5-dimethyloxazolidin-2-ones to afford and array of alpha-substituted-N-acyl-5,5-dimethyloxazolidin- 2-ones (85-94% de) and subsequent reduction with DIBAL afforded directly non-racemic alpha-substituted aldehydes without loss of stereochemical integrity (87-94% ee). The extension of this protocol for the asymmetric synthesis of beta-substituted aldehydes is demonstrated, via the diastereoselective conjugate addition of a range of organocuprates to (S)-N-acyl-4-phenyl-5,5-dimethyloxazolidin-2-ones which proceeds with high diastereoselectivity (generally > 95% de). Reduction of the conjugate addition products with DIBAL gives non-racemic beta-substituted aldehydes in high yields and in high ee (generally > 95% ee). This methodology is exemplified by the asymmetric synthesis of (R)-3-isopropenylhept-6-enal, which has previously been used in the synthesis of (3Z,6R)-3-methyl-6-isopropenyl-3,9-decadien-1-yl acetate, a component of the sex pheromones of the California red scale.     

Asymmetric sulfonium ylide mediated cyclopropanation: stereocontrolled synthesis of (+)-LY354740

The reaction of ester-stabilized sulfonium ylides with cyclopentenone to give (+)-5 ((1S,5R,6S)-ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate), an important precursor to the pharmacologically important compound (+)-LY354740, has been studied using chiral sulfides operating in both catalytic (sulfide, Cu(acac)2, ethyl diazoacetate, 60 degrees C) and stoichiometric modes (sulfonium salt, base, room temperature). It was found that the reaction conditions employed had a major influence over both diastereo- and enantioselectivity. Under catalytic conditions, good enantioselectivity with low diastereoselectivity was observed, but under stoichiometric conditions low enantioselectivity with high diastereoselectivity was observed. When the stoichiometric reactions were conducted at high dilution, diastereoselectivity was reduced. This indicated that base-mediated betaine equilibration was occurring (which is slow relative to ring closure at high dilution). Based on this model, conditions for achieving high enantioselectivity were established as follows: use of a preformed ylide, absence of base, hindered ester (to reduce ylide-mediated betaine equilibration), and low concentration. Under these conditions high enantioselectivity (95 % ee) was achieved, albeit with low diastereocontrol. Our model for selectivity has been applied to other sulfonium ylide mediated cyclopropanation reactions and successfully accounts for the diastereoselectivity observed in all such reported reactions to date.     

Diastereoselective synthesis of 3,4-disubstituted 5-(p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones: chirality transfer in the enantioselective synthesis of ethyl (+)-(3S,4aS,7aS)-1-oxo-octahydro-1H-cyclopenta[c]pyridine-3-carboxylate

The base-mediated reaction of enantiomerically pure -sulfinylketimine (+)-1 with (E)-,β-disubstituted propenoate esters afforded 3,4-disubstituted-5-(p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones 9-13 and 14 with high or complete diastereoselectivity. A sole diastereomer of the four possible ones, with regard to the nature of ester, was isolated, which revealed the stereocontrol of the chiral sulfinyl group in the Michael reaction and transenolization steps. In addition, the enantioselective synthesis of ethyl (+)-(3S,4aS,7aS)-1-oxo-octahydro-1H-cyclopenta[c]pyridine-3-carboxylates (+)-17 is described (five steps; 47% yield; ee 97%). The absolute configuration of stereocentres introduced in (+)-17 was assigned on the basis of ¹H NMR data.     

Diastereoselective synthesis of quaternary alpha-amino acids from diketopiperazine templates

Sequential enolate alkylations of (S)-N(1)-methyl-5-methoxy-6-isopropyl-3,6-dihydropyrazin-2-one and (S)-N(1)-p-methoxybenzyl-5-methoxy-6-isopropyl-3,6-dihydropyrazin-2-one proceed with excellent levels of diastereoselectivity (>90% de) affording quaternary alpha-amino acids in high enantiomeric excess (>98% ee) after deprotection and hydrolysis.     

Stereoselectivity of methyl aryldiazoacetate cyclopropanations of 1,1-diarylethylene. Asymmetric synthesis of a cyclopropyl analogue of tamoxifen

[formula: see text] Dirhodium tetrakis(S-(N-dodecylbenzenesulfonyl)prolinate) (Rh2(S-DOSP)4)-catalyzed decomposition of methyl phenyldiazoacetate in the presence of 1,1-diarylethylenes results in intermolecular cyclopropanation with high enantioselectivity (up to 99% ee) and moderate diastereoselectivity (up to 80% de). The reaction was applied to the asymmetric synthesis of a cyclopropyl analogue of tamoxifen.     

Asymmetric intermolecular C-H functionalization of benzyl silyl ethers mediated by chiral auxiliary-based aryldiazoacetates and chiral dirhodium catalysts

[reaction: see text] C-H functionalization of benzyl silyl ethers by means of rhodium-catalyzed insertions of aryldiazoacetates can be achieved in a highly diastereoselective and enantioselective manner by judicious choice of chiral catalyst or auxiliary. The dirhodium tetraprolinates such as Rh2((S)-DOSP)4 have been widely successful as chiral catalysts in the C-H functionalization chemistry of aryldiazoacetates, but give poor enantioselectivity in the reactions of aryldiazoacetates with benzyl silyl ether derivatives. The use of (S)-lactate as a chiral auxiliary resulted in C-H functionalization with moderately high diastereoselectivity (79-88% de) and enantioselectivity (68-85% ee). The best results (91-95% de, 95-98% ee), however, were achieved using Hashimoto's Rh2((S)-PTTL)4 catalyst.     

Pd-catalyzed asymmetric allylic alkylation of glycine imino ester using a chiral phase-transfer catalyst

Pd-catalyzed asymmetric allylic alkylation of the glycine imino ester 1a has been developed using a chiral quaternary ammonium salt 3d without chiral phosphine ligands. The proper choice of the achiral Pd ligand, P(OPh)3, is important to achieve high enantioselectivity. By this method with the dual catalysts, numerous enantiomerically enriched alpha-allylic amino acids 4a-h could be prepared with comparable to higher enantioselectivity than that of the conventional asymmetric alkylation of 1a. In addition, the Pd-catalyzed reaction of 1a with 1-phenyl-2-propenyl acetate 2i afforded the branch product 6 with high enantio- and diastereoselectivity (>95% de, 85% ee).     

Synthesis of new chiral 2,2'-bipyridine ligands and their application in copper-catalyzed asymmetric allylic oxidation and cyclopropanation

A series of modular bipyridine-type ligands 1 and 3-9 has been synthesized via a de novo construction of the pyridine nucleus. The chiral moieties of these ligands originate from the isoprenoid chiral pool, namely, beta-pinene (10 --> 1), 3-carene (14 --> 3 and 5), 2-carene (28 --> 4), alpha-pinene (43 --> 6-8), and dehydropregnenolone acetate (48 --> 9), respectively. Copper(I) complexes, derived from these ligands and (TfO)(2)Cu (1 mol %) upon an in situ reduction with phenylhydrazine, exhibit good enantioselectivity (up to 82% ee) and unusually high reaction rate (typicaly 30 min at room temperature) in allylic oxidation of cyclic olefins (52 --> 53). Copper-catalyzed cyclopropanation proceeded with < or =76% enantioselectivity and approximately 3:1 to 99:1 trans/cis-diastereoselectivity (54 --> 55 + 56). The level of the asymmetric induction is discussed in terms of the ligand architecture that controls the stereochemical environment of the coordinated metal.     

Synthesis of 2,3-dihydropyrroles by photo rearrangement of Hantzsch 1,4-dihydropyridines with high diastereoselectivity

The Hantzsch 1,4-dihydropyridines were found to be transforming to the 2,3-dihydropyrroles by photo rearrangement with air under irradiation of LED light (410 nm) with high diastereoselectivity (dr > 20:1). This reaction includes tandem photo oxidation/rearrangement. The 2,3-dihydropyrroles were obtained in moderate yields with successfully one-pot process starting from aldehydes, ammonium acetate and ethyl acetoacetate.     

Asymmetric glyoxylate-ene reaction catalyzed by C2-symmetric chiral bis(oxazoline)–lanthanide complexes

Efficient C₂-symmetric chiral bis(oxazoline)-lanthanide catalysts are developed for the glyoxylate-ene reaction to afford the α-hydroxy esters in 85% yield and up to 54% ee. An enhanced level of diastereoselectivity (81% de) was obtained in the reaction between menthyl glyoxylate and alkenes catalyzed by bis(oxazoline)–Ln(OTf)₃ complex.     

High acceleration of the direct aldol reaction cocatalyzed by BINAM-prolinamides and benzoic acid in aqueous media

The enantioselective direct aldol reaction, organocatalyzed by recoverable BINAM-prolinamide derivatives can be highly accelerated by a catalytic amount of a carboxylic acid without a detrimental of the obtained enantioselectivities. From the study of suitable acids and reaction conditions, benzoic acid in aqueous DMF or in water was shown to give the best results with high yields and enantioselectivities. Thus, the reaction between p-nitrobenzaldehyde and acetone catalyzed by (S_a)-BINAM-l-Pro and benzoic acid can be carried out at −20 °C in only 8.5 h to give the expected product with 86% ee. In the case of butan-2-one, the iso- and the anti-isomers are obtained in a 1:1 isomer ratio up to 99% ee. Cyclohexanone gives the anti-aldol in up to 99% dr and 97% ee in only 2 h. The opposite diastereoselectivity is obtained in the case of cyclopentanone with lower ee up to 65% for the syn and 85% for the anti-isomer.     

Regio-, Diastereo-, and Enantioselective Synthesis of Vicinal Diols via α-Silyl Ketones

A new versatile and efficient regio-, diastereo-, and enantioselective synthesis of vicinal diols s-trans- 4 , s-trans- 5 , and s-cis- 4 is described. Symmetrical ketones are converted into their SAMP-or RAMP-hydrazones which are then silylated with (isopropyloxy)dimethylsilyl chloride, followed by ozonolysis to afford the α-silyl ketones (R)- 2 of high enantiomeric purity (ee 90– ≥ 98%). On the other hand, methyl ketones, after conversion into the corresponding (?)–(S)-1-amino-2-(methoxymethyl) pyrrolidine (SAMP) hydrazones, are silylated and then alkylated with RI to afford unsymmetrical α-silyl ketones (S)- 3 of high enantiomeric purity (ee 90- ≥ 98%). The reduction of the above obtained α-silyl ketones with L -Selectride, followed by oxidative cleavage of the C? Si bond gives rise to s-trans-4, s-trans- 5 , and s-cis- 4 with high diastereoselectivity (de 95- ≥ 98%) and without racemization (ee ≥ 90– ≥ 98%).     

Highly enantioselective Michael additions of α-cyanoacetate with chalcones catalyzed by bifunctional cinchona-derived thiourea organocatalyst

The conjugate addition of ethyl α-cyanoacetate with chalcones has been developed. In the presence of cinchona alkaloid-derived thiourea organocatalyst 1i (10 mol %), ethyl α-cyanoacetate could react with various chalcones to afford Michael adducts with high yields (80–92%) and enantioselectivities (83–95% ee).     

Palladium-catalyzed asymmetric diene cyclization/hydrosilylation employing functionalized silanes and disiloxanes.

Pentasubstituted disiloxanes and silanes of the form HSiMe(2)CH(x)Ph(3-x)(x = 1 or 2) reacted with dimethyl diallylmalonate (1) and other functionalized 1,6-dienes in the presence of a catalytic 1:1 mixture of (N-N)Pd(Me)Cl [N-N = (R)-(+)-4-isopropyl-2-(2-pyridinyl)-2-oxazoline] [(R)-2] and NaBAr(4) [Ar = 3,5-C(6)H(3)(CF(3))(2)] to form the corresponding silylated cyclopentanes in good yield with high diastereoselectivity. The enantioselectivity of cyclization/hydrosilylation of 1 with disiloxanes and functionalized silanes at -20 degrees C increased in the following order: HSiMe(2)OSiMe(3) (75% ee) < HSiMe(2)OSiMe(2)-t-Bu (80% ee) < HSi(i-Pr)(2)OSiMe(3) (86% ee) = HSiMe(2)Bn (86% ee) < HSiMe(2)OSi(i-Pr)(3) (89% ee) < HSiMe(2)OSiPh(2)-t-Bu (91% ee) < HSiMe(2)CHPh(2) (93% ee). Silylated cyclopentanes derived from HSiMe(2)OSiMe(3) were oxidized with excess KF and peracetic acid at room temperature for 48 h to form the corresponding hydroxymethylcyclopentanes in good yield (82-95%). Silylated cyclopentanes derived from HSiMe(2)OSiPh(2)t-Bu were oxidized with a mixture of tetrabutylammonium fluoride and either H(2)O(2) or peracetic acid to form the corresponding alcohols in 48-76% yield. Silylated carbocycles generated from benzhydryldimethylsilane were oxidized with a mixture of TBAF/KHCO(3)/H(2)O(2) in 71-98% yield. Asymmetric cyclization/hydrosilylation/oxidation employing benzhydryldimethylsilane tolerated allylic and terminal olefinic substitution and a range of functional groups.     

A highly enantioselective organocatalyst for the Michael addition of cyclic ketones to nitroolefins

Enantiomerically pure triamine 2, which catalyses the Michael addition of cyclic ketones to nitroolefins with high diastereoselectivity (up to 99:1) and enantioselectivity (up to 91% ee), was designed and prepared.