Scalemic α-cyanohydrin triflates undergo Pd-catalyzed cross-coupling with aryl, heteroaryl, and vinyl boronic acids under mild conditions. Coupling proceeds with complete inversion of configuration at the stereogenic carbon. The resultant nitrile can be easily converted into a variety of alternative functional groups of value in organic synthesis and thus achieves a higher level of molecular complexity than traditional Suzuki reactions.

A stereocontrolled synthesis of α-amino-α′-alkoxy ketones is described. This pH-neutral copper(I) thiophene-2-carboxylate (CuTC)-catalyzed cross-coupling of amino acid thiol esters and chiral nonracemic α-alkoxyalkylstannanes gives α-amino-α′-alkoxy ketones in good to excellent yields with complete retention of configuration at the α-amino- and α-alkoxy-substituted stereocenters.

Racemic and scalemic α-(acyloxy)-tri-N-butylstannanes undergo Pd-catalyzed cross-couplings with alkenyl/aryl/heteroaryl iodides, bromides, and triflates in moderate to good yields in THF at 45 °C. Simple aryl iodides and unprotected aza-arenes, two classes of electrophiles that typically react sluggishly, are also good substrates. Cross-couplings proceed with retention of configuration at the alkenyl and stannyl-substituted stereocenters.The Stille reaction, 1 i. e., the transition metal-mediated cross-coupling of organostannanes with organic electrophiles, has achieved wide acceptance 2 as an exceptionally mild and efficient method for the creation of C-C bonds, especially between sp-and/or sp 2 -hybridized centers. 3 Not surprisingly, the apparent advantages that would accrue from expanding the traditional scope and structural confines of the Stille reaction have attracted much interest. 4 In the early 1990's, this laboratory 5 and others 6 explored the utility of tri-n-butylstannanes for the transfer of stereogenic carbons bearing heteroatoms and reported the stereospecific palladium/copper co-catalyzed cross-coupling of scalemic α-alkoxy-and α-aminoalkylstannanes with acid chlorides. 7,8 Subsequent studies led to copper mediated cross-couplings with reactive electrophiles such as allylic and propargylic halides. 9 The utility of this methodology for the construction of chiral ethers and alcohols was cogently demonstrated during asymmetric total syntheses of the anticancer agent (+)-goniofufurone 10 and the potent endothelium-derived vasodilator 11,12, On the other hand, comparable unions between α-heteroatom-substituted triorganostannanes and alkenyl/aryl electrophiles were conspicuously absent 12 and suitable methodology has been elusive. 13 To address this methodological gap, we conducted an extensive survey of alternative reaction parameters including oxygen substituents 14 and herein describe a practical, stereospecific cross-coupling capable of using a broad range of sp 2 -hybridized iodides/triflates/bromides (Scheme 1). j.falck@UTSouthwestern.edu. Supporting Information Available: Synthetic procedures, analytical data, chiral HPLC chromatograms, and 1 H/ 13 C spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. Since esters and alkenyl iodides were identified as the most promising pairing in our initial evaluations, α-(acetyloxy)stannane 1a and (E)-β-iodostyrene (2) were selected as the test system. Screening an extensive collection of transition metals salts and complexes, tested individually or in combination, revealed palladium complexes were especially efficacious, and in particular freshly recrystallized Pd(dppe)Cl 2 . 15 The yield of adduct 3a increased proportionately with the amount of Pd(dppe)Cl 2 up to 10 mol % (62%; Replacement of the acetate of 3a with a benzoate, i.e., 3b, resulted in a modest improvement in yield. Electron donating substituents (3c-d) had little influence above that of the parent aromatic 3b and neither...

Prochiral ketones are reduced to enantioenriched, secondary alcohols using catecholborane and a family of air-stable, bifunctional thiourea-amine organocatalysts. Asymmetric induction is proposed to arise from the in situ complexation between the borane and chiral thiourea-amine organocatalyst resulting in a stereochemically biased boronate-amine complex. The hydride in the complex is endowed with enhanced nucleophilicity while the thiourea concomitantly embraces and activates the carbonyl.The enantioselective reduction of prochiral ketones is a mainstay in the production of enantioenriched, secondary alcohols. 1 As in other areas of chiral synthetic methodology, the trend has been away from stoichiometric reductants 2 towards more economic and environmentally friendly catalytic processes 3 and, in recent years, has embraced organocatalysis. 4,5 One of the most prominent and frequently applied members of this latter category is the Corey-Bakshi-Shibata (CBS) catalyst, a chiral oxazaborolidine pioneered by Itsuno 6 and further developed by Corey 7 and other investigators. 8 However, the sensitivity of oxazaborolidines to oxygen and moisture as well as the need in conjunction with a current project for a highly enantioselective reducing agent compatible with a challenging combination of highly sensitive functionality, prompted us to explore the utility of urea-/ thiourea-based organocatalysts as an alternative to CBS oxazaborolidines. 9,10 Whilst chiral ureas and thioureas have emerged as efficacious catalysts for a variety of nucleophilic conjugate additions 11 and 1,2-carbonyl additions, e.g., hydrocyanation, 12 Henry reaction, 13 15,16 However, the insights gained developing asymmetric oxy-Michael additions of boronic acids with α,β-unsaturated ketones 17 revealed several unique attributes that we felt could be harnessed for enantioselective carbonyl reductions. Specifically, we envisioned that the union between a borane and a chiral thiourea-amine organocatalyst would result in a stereochemically biased boronate-amine complex. 18 The hydride in the complex is endowed with enhanced nucleophilicity (the push) while the thiourea concomitantly embraces and activates the carbonyl (the pull) ( Figure 1). As proof-of-concept, we developed of a family of robust, bifunctional thiourea-amine catalysts and describe herein their exploitation for the stereodefined reduction of prochiral ketones to enantioenriched, secondary alcohols.Despite its outstanding performance catalyzing the aforementioned oxy-Michael additions, 17 thiourea catalyst A 19 furnished (S)-(−)-1-phenylethanol (2) in poor yield and low enantioselectivity at room temperature in THF (Table 1, entry 1) using acetophenone (1) and BH 3 ·THF as the model substrate and hydride source, respectively. Reasoning that the cinchona alkaloid moiety might be responsible, it was replaced with the simpler (R,R)-trans-N,N′-dimethylcyclohexane-1,2-diamine. The resultant monobasic catalyst B provided a modest improvement in yield and enantioselectivity, albeit d...

A catalytically asymmetric synthesis of α-(hydroxyalkyl)-tri-n-butylstannanes 1 in good-excellent yields and enantioselectivities (up to 98% e.e.) via addition of ethyl(tri-n-butylstannyl)zinc to aldehydes was achieved. In practice, 1 was isolated after protection as its more stable ester or thiocarbamate (PG). The reagent was prepared from equimolar amounts of tri-n-butylstannyl hydride and Et 2 Zn in DME so as to avoid contamination by lithium and magnesium ions which suppress enantioselectivity. Keywordsaldehydes; asymmetric synthesis; organometallic compounds; tin; zinc α-(Hydroxyalkyl)triorganostannanes are versatile synthetic intermediates that have found wide applicability in natural products total synthesis. [1] Most notably, they offer a higher level of structural and stereochemical complexity compared with their tetraorganotin congeners, yet still participate in a variety of stereospecific transformations including transition metal catalyzed cross-couplings, [2] generation of configurationally stable anions, [3] Wittig rearrangements, [4] S E '-additions to carbonyls, [5] nucleophilic displacements, [6] and other reactions. [7] Numerous synthetic strategies to enantioenriched α-(hydroxyalkyl)triorganostannanes have been devised, inter alia, (i) asymmetric reduction of acyl stannanes, [8] (ii) classical resolution, [9] (iii) enzymatic resolution, [10] (iv) cleavage of C 2 -symmetric stannyl acetals, [11] (v) electrophilic stannylation, [12] and (vi) nucleophilic stannylation, [13] however, the goal of a widely applicable, economic and operationally simple synthesis from readily available starting materials remains elusive. Herein, we report the catalytically asymmetric synthesis of α-(hydroxyalkyl)-tri-n-butylstannanes 1 i n g o o d-excellent yields and enantioselectivities via addition of ethyl(tri-n-butylstannyl)zinc to aldehydes (eq 1). In practice, 1 was isolated after protection as its more stable ester or thiocarbamate (PG).[**] We thank the NIH (GM31278, DK38226) and the Robert A. Welch Foundation for financial support. Bolstered by the precedent of catalytic, asymmetric organozinc additions to carbonyls [14] and the equally well documented preparation of racemic α-(hydroxyalkyl)triorganostannanes from aldehydes and ketones using triorganostannyl nucleophiles, [15] we were attracted to the possibility of comparable asymmetric additions of tri-n-butylstannylzinc reagents to aldehydes. Yet, this proved not to be straightforward. Despite extensive attempts using tri-n-butylstannyllithium or Grignard [16] in combination with various ratios with zinc halides and chiral ligands, 1 (PG = Ac) was generated with little, if any, useful enantioselectivity, albeit in good yield. Reasoning the Li or Mg-ions might have detrimental effects, alternative approaches to stannylzinc generation were systematically investigated. Finally, we were gratified to discover that addition of ethyl(trin-butylstannyl)zinc, [17] generated in situ via transmetalation of tri-n-butyltin hydride with diethylzinc, [...

No abstract

Cross metathesis of the acrolein derived phosphono allylic carbonate and hydroxy alkenes using second generation Grubbs catalyst and copper (I) iodide gave the substituted phosphonates in good yield. Stereospecific palladium (0)-catalyzed cyclization gave tetrahydrofuran and tetrahydropyran vinyl phosphonates. Regioselective Wacker oxidation of the vinyl phosphonate gave the β-keto phosphonate, which underwent HWE reaction with benzaldehyde to yield the unsaturated ketone. The utility of the cross metathesis/cyclization protocol was further demonstrated by a formal synthesis of centrolobine.

Allylic hydroxy phosphonates and their derivatives can be interconverted by using cross metathesis with second generation Grubbs catalyst. The absolute stereochemistry of the starting phosphonate is conserved in the product. Cross metathesis reaction of the acrolein-derived phosphonate 2a yields a series of functionalized allylic hydroxy phosphonates. However, the cross metathesis reaction is often accompanied by competing dimerization and alkene migration reactions leading to a reduction in yield. The cinnamaldehyde- and crotonaldehyde-derived phosphonates 2b and 2c were also examined. In general, the metathesis reactions of phosphonates 2b and 2c are considerably slower than those for phosphonate 2a leading to mixtures. Several hydroxyl-protected derivatives of the phosphonate 2a (methyl carbonate 3a, acetate 4a, N-tosyl carbamate 5a, TBDMS 6a, and acetoacetate 7a) undergo metathesis without competing side reactions to give substituted allylic phosphonates in good to excellent yield.