Enantioselective construction of quaternary stereogenic carbons by the Lewis base catalyzed additions of silyl ketene imines to aldehydes

Silyl ketene imines derived from a variety of alpha-branched nitriles have been developed as highly useful reagents for the construction of quaternary stereogenic centers via the aldol addition reaction. In the presence of SiCl4 and the catalytic action of chiral phosphoramide (R,R)-5, silyl ketene imines undergo extremely rapid and high yielding addition to a wide variety of aromatic aldehydes with excellent diastereo- and enantioselectivity. Of particular note is the high yields and selectivities obtained from electron-rich, electron-poor, and hindered aldehydes. The nitrile function serves as a useful precursor for further synthetic manipulation.     

Lewis base activation of Lewis acids: catalytic, enantioselective vinylogous aldol addition reactions

The generality of Lewis base catalyzed, Lewis acid mediated, enantioselective vinylogous aldol addition reactions has been investigated. The combination of silicon tetrachloride and chiral phosphoramides is a competent catalyst for highly selective additions of a variety of alpha,beta-unsaturated ketone-, 1,3-diketone-, and alpha,beta-unsaturated amide-derived dienolates to aldehydes. These reactions provided high levels of gamma-site selectivity for a variety of substitution patterns on the dienyl unit. Both ketone- and morpholine amide-derived dienol ethers afforded high enantio- and diastereoselectivity in the addition to conjugated aldehydes. Although alpha,beta-unsaturated ketone-derived dienolate did not react with aliphatic aldehydes, alpha,beta-unsaturated amide-derived dienolates underwent addition at reasonable rates affording high yields of vinylogous aldol product. The enantioselectivities achieved with the morpholine derived-dienolate in the addition to aliphatic aldehydes was the highest afforded to date with the silicon tetrachloride-chiral phosphoramide system. Furthermore, the ability to cleanly convert the morpholine amide to a methyl ketone was demonstrated.     

Lewis base activation of lewis acids. Addition of silyl ketene acetals to aldehydes

The weak Lewis acid silicon tetrachloride can be activated by catalytic amounts of the chiral bisphosphoramide (R,R)-3 to form a highly reactive, chiral trichlorosilyl cation which is an extremely effective promoter of aldol addition reactions between aldehydes and silyl ketene acetals. The tert-butyldimethylsilyl ketene acetal of methyl acetate adds nearly instantaneously to aromatic and olefinic aldehydes as well as aliphatic aldehydes (albeit more slowly) with excellent enantioselectivity. The homologous tert-butyldimethylsilyl ketene acetal of tert-butyl propanoate adds with nearly exclusive anti diastereoselectivity to a similar range of aldehydes also with excellent enantioselectivity. The origin of the slower reaction rate with aliphatic aldehydes is revealed to be the formation of chlorosilyl ether adducts.     

Lewis base activation of Lewis acids: catalytic, enantioselective addition of glycolate-derived silyl ketene acetals to aldehydes

A catalytic system involving silicon tetrachloride and a chiral, Lewis basic bisphosphoramide catalyst is effective for the addition of glycolate-derived silyl ketene acetals to aldehydes. It was found that the sense of diastereoselectivity could be modulated by changing the size of the substituents on the silyl ketene acetals. In general, the trimethylsilyl ketene acetals derived from methyl glycolates with a large protecting group on the alpha-oxygen provide enantiomerically enriched alpha,beta-dihydroxy esters with high syn-diastereoselectivity, whereas the tert-butyldimethylsilyl ketene acetals derived from bulky esters of alpha-methoxyacetic acid provide enantiomerically enriched alpha,beta-dihydroxy esters with high anti-diastereoselecitvity.     

Lewis base activation of Lewis acids. Catalytic enantioselective addition of silyl enol ethers of achiral methyl ketones to aldehydes

A highly enantioselective addition of silyl enol ethers derived from simple methyl ketones is described. The catalyst system of silicon tetrachloride activated by a chiral bisphosphoramide (R,R)-7 effectively promotes the addition of a variety of unsubstituted silyl enol ethers to aromatic, olefinic, and heteroaromatic aldehydes in excellent yield. [reaction: see text]     

A convenient method for the synthesis of (Z)-α-haloacrylates: Lewis base-catalyzed carbonyl olefination using α-halo-C,O-bis(trimethylsilyl)ketene acetals

A highly useful method for the stereoselective synthesis of (Z)-α-haloacrylates from various aldehydes that uses α-halogenated ethyl-C,O-bis(trimethylsilyl)ketene acetals in the presence of a Lewis base catalyst such as acetate salts was established. This procedure gives the corresponding α-halo-α,β-unsaturated esters in high yields with excellent stereoselectivity from E/Z mixtures of ketene silyl acetals under mild conditions.     

Lewis base activation of Lewis acids: catalytic, enantioselective addition of silyl ketene acetals to aldehydes

The concept of Lewis base activation of Lewis acids has been reduced to practice for catalysis of the aldol reaction of silyl ketene acetals and silyl dienol ethers with aldehydes. The weakly acidic species, silicon tetrachloride (SiCl4), can be activated by binding of a strongly Lewis basic chiral phosphoramide, leading to in situ formation of a chiral Lewis acid. This species has proven to be a competent catalyst for the aldol addition of acetate-, propanoate-, and isobutyrate-derived silyl ketene acetals to conjugated and nonconjugated aldehydes. Furthermore, vinylogous aldol reactions of silyl dienol ethers are also demonstrated. The high levels of regio-, anti diastereo-, and enantioselectivity observed in these reactions can be rationalized through consideration of an open transition structure where steric interactions between the silyl cation complex and the approaching nucleophile are dominant.     

Lewis base catalyzed, enantioselective aldol addition of methyl trichlorosilyl ketene acetal to ketones

The catalytic enantioselective addition of an acetate enolate equivalent to ketones is described. Methyl trichlorosilyl ketene acetal reacts with a wide range of ketones in the presence of pyridine N-oxide to afford the aldol addition products in excellent yields. Chiral 2,2'-pyridyl bis-N-oxides bearing various substituents at the 3,3'- and 6,6'-positions also provide excellent yields of the aldol products with variable enantioselectivities ranging from 94/6 er for aromatic ketones to nearly racemic for aliphatic ketones. An X-ray crystal structure of the complex between a catalyst and silicon tetrachloride (((P)-(R,R)-19.SiCl(4))) has been obtained. Extensive computational analysis provides a stereochemical rationale for the observed trends in enantioselectivities.     

Mechanistic investigations of the ZnCl2-mediated tandem Mukaiyama aldol lactonization: evidence for asynchronous, concerted transition states and discovery of 2-oxopyridyl ketene acetal variants

The ZnCl(2)-mediated tandem Mukaiyama aldol lactonization (TMAL) reaction of aldehydes and thiopyridyl ketene acetals provides a versatile, highly diastereoselective approach to trans-1,2-disubstituted β-lactones. Mechanistic and theoretical studies described herein demonstrate that both the efficiency of this process and the high diastereoselectivity are highly dependent upon the type of ketene acetal employed but independent of ketene acetal geometry. Significantly, we propose a novel and distinct mechanistic pathway for the ZnCl(2)-mediated TMAL process versus other Mukaiyama aldol reactions based on our experimental evidence to date and further supported by calculations (B3LYP/BSI). Contrary to the commonly invoked mechanistic extremes of [2+2] cycloaddition and aldol lactonization mechanisms, investigations of the TMAL process suggest a concerted but asynchronous transition state between aldehydes and thiopyridyl ketene acetals. These calculations support a boat-like transition state that differs from commonly invoked Mukaiyama "open" or Zimmerman-Traxler "chair-like" transition-state models. Furthermore, experimental studies support the beneficial effect of pre-coordination between ZnCl(2) and thiopyridyl ketene acetals prior to aldehyde addition for optimal reaction rates. Our previously proposed, silylated β-lactone intermediate that led to successful TMAL-based cascade sequences is also supported by the described calculations and ancillary experiments. These findings suggested that a similar TMAL process leading to β-lactones would be possible with an oxopyridyl ketene acetal, and this was confirmed experimentally, leading to a novel TMAL process that proceeds with efficiency comparable to that of the thiopyridyl system.     

Synthesis of Ethyl 2-Cyano-3-Methylthio-3'-Arylaminoacrylate From Low Nucleophilic Amine

The synthesis of ketene N,S-acetals has attracted a considerable attention as building blocks in organic synthesis, especially in the preparation of heterocycles^[1]. The addition reaction of ketene S,S-acetals with highly nucleophilic amines, such as alkylamines, can easily afford the corresponding ketene N,S-acetals, under gentle condition, which could be converted into conjugated ketene aminals by reaction with a second equivalent of the same or a different amine^[2,3]. However, this addition reaction with low nucleophilic amines, such as arylamine or heterocyclic amine, can hardly give the corresponding ketene N,S-acetals under gentle conditions. If under powerful condition,such as refluxing, the addition reaction affords a mixture of the N,S-acetals and conjugated ketene aminals^[4]. Recent studies showed that this addition reaction with low nucleophilic amines affords the corresponding ketene N,S-acetals in the presence of a catalyst^[5].     

Catalytic, enantioselective alpha-additions of isocyanides: Lewis base catalyzed Passerini-type reactions

[reaction: see text] The generality of catalytic, enantioselective alpha-additions of isocyanides to aldehydes has been demonstrated (Passerini-type reactions). The catalytic system of silicon tetrachloride and a chiral bisphosphoramide (R,R)-1b provided high yields and good to excellent enantioselectivities for the addition of tert-butyl isocyanide to a wide range of aldehydes (aromatic, heteroaromatic, olefinic, acetylenic, aliphatic). Aqueous workup afforded the alpha-hydroxy tert-butyl amides whereas a low-temperature methanol quench followed by basic workup afforded the alpha-hydroxy methyl esters. The reaction is also successful for other isocyanides, albeit with reduced enantioselectivity. Reaction conditions, particularly the rate of addition of the isocyanide was found to be crucial for good yields and high selectivities.     

An amino alcohol ligand for highly enantioselective addition of organozinc reagents to aldehydes: serendipity rules

[reaction: see text] Amino alcohol 4 (or its enantiomer) is prepared in two simple steps. Commercial (1R,2S)-2-amino-1,2-diphenylethanol is dialkylated with bis(2-bromoethyl) ether. Subsequent hydrogenation over 5% Rh on alumina in the presence of morpholine unexpectedly stops at the hexahydro derivative 4. Amino alcohol 4 promotes the enantioselective addition of diethylzinc to aldehydes at room temperature in up to 99% enantiomeric excess.     

One-pot enol silane formation-Mukaiyama aldol reactions: Crossed aldehyde-aldehyde coupling,thioester substrates,and reactions in ester solvents

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) and a trialkylamine base promote both in situ enol silane/silyl ketene acetal formation and Mukaiyama aldol addition reactions between a variety of reaction partners in a single reaction flask. Isolation of the required enol silane or silyl ketene acetal is not necessary. For example, crossed aldol reactions between α-disubstituted aldehydes and non-enolizable aldehydes yield β-hydroxy aldehydes in good yield. In a related reaction, the common laboratory solvent ethyl acetate functions as both an enolate precursor and a green reaction solvent. When thioesters are employed as enolate precursors, high yields for additions to non-enolizable aldehydes are routinely observed.     

Amino‐Claisen Rearrangements and Diels‐Alder Reactions of Ketene N,O‐Acetals: Reactivity Studies. On the Way to a Novel Tandem Process?

We report the synthesis of N‐benzyl‐N‐[(E)‐buta‐1,3‐dienyl]propanamide ( 6 ) and its corresponding O‐silyl‐substituted ketene N,O‐acetal 7 and their Diels‐Alder reaction. Propanamide 6 reacted smoothly, whereas the yield obtained from 7 was low, probably due to polymerization of the dienophile induced by electron transfer. The ketene N,O‐acetals 27a – g were synthesized starting from the corresponding benzamides 25a – e (Scheme 9). The ketene N,O‐acetals 27a – g showed increased stabilities and underwent amino‐Claisen rearrangements under thermal conditions. Using catalysts, interesting side reactions leading either to the annulated systems rac‐ 35 – 37 or to a β‐lactam rac‐ 34 were observed.     

Method for Regio- and Stereoselective Synthesis of (E)-β,γ-Unsaturated Acids from Aldehydes Under Solvent-Free Conditions

Synthesis of (E)-β,γ-unsaturated acids from aldehydes with malonic acid has been explored under solvent-free conditions. The modified Knoevenagel condensation reaction with N-methyl morpholine (NMM) as catalyst exhibits highly β,γ-regioselectivity and exclusively E-stereoselectivity. A mechanism accounting for both regio- and stereoselectivity has been proposed and preliminarily studied.     

Highly enantioselective michael addition of silyl nitronates to alpha,beta-unsaturated aldehydes catalyzed by designer chiral ammonium bifluorides: efficient access to optically active gamma-nitro aldehydes and their enol silyl ethers

Highly enantioselective Michael addition of silyl nitronates to alpha,beta-unsaturated aldehydes has been accomplished by the utilization of designer N-spiro C2-symmetric chiral quaternary ammonium bifluoride 1 as an efficient catalyst, providing direct access to both optically active gamma-nitro aldehydes, a very useful precursor to various complex organic molecules including aminocarbonyls, and their enol silyl ethers, a Mukaiyama donor of potential synthetic utility for further selective transformations. For instance, the reaction of trimethylsilyl nitronate 2 (R1 = Me) with trans-cinnamaldehyde (R2 = Ph, R3 = H) in toluene in the presence of (R,R)-1 (2 mol %) proceeded smoothly at -78 degrees C to give the desired enol silyl ether 3 (R1 = Me, R2 = Ph, R3 = H) in 90% isolated yield (anti/syn = 83:17) with 97% ee (anti isomer), and simple treatment of 3 thus obtained with 1 N HCl in THF at 0 degrees C afforded the corresponding gamma-nitro aldehyde 4 quantitatively without loss of diastereo- and enantioselectivity.     

Aminoboranes as "compatible" iminium ion generators in aminative C-C bond formations

Aminoboranes have been shown to be highly efficient and mild iminium ion generators in the Mannich-type aminative coupling of aldehydes with silyl ketene acetals. By using aminoboranes bearing bulky amino groups, such as a diisopropylamino group, free secondary amines can be successfully used as the amino component in a three-component Mannich reaction with aldehydes and silyl ketene acetals.     

Total synthesis of (+)-epilupinine via an intramolecular nitrile oxide-alkene cycloaddition

Total synthesis of (+)-epilupinine was accomplished in nine steps and in 48% overall yield, in which INOC was used as the key step for the construction of the quinolizidine skeleton. We found that it was an extremely difficult task to prepare the key intermediates (R)-N-(3-nitropropyl)-2-vinylpiperidine or (R)-(2-vinylpiperid-1-yl)propanal by routine methods. Thus, by using Fukuyama's oxime synthesis, a general method was developed for highly efficient conversion of 3-(N,N-dialkylamino)propanols into 3-(N,N-dialkylamino)propanal oximes without using the corresponding aldehydes.     

Syntheses and Crystal Structures of Chiral BINOL Derivatives and Their Applications in Enantioselective Lewis Acid Catalyzed Addition of Diethylzinc to Aldehydes

Two novel chiral BINOL derivatives with bis(benzylamine) groups at the 3,3- positions have been synthesized through the condensation reaction between 2,2'-bis(methoxy- methyleneoxy)-1,1'-binaphthyl-3,3'-dicarboxylic acid and benzylamine or N-phenyl benzylamine in the presence of triethylamine. Suitable single crystal of (R)-N,N'-dibenzyl-2,2'-dihydroxy-1, 1'-binaphthly-3,3'-diformamide (R)-3 for X-ray diffraction was obtained by recrystallization at room temperature from the mixture solvents. Crystallographic data of (R)-3: C40H36N2O6, Mr = 640.71, monoclinic, space group P21, a = 6.746(3), b = 21.883(9), c = 11.723(5) , β = 104.605(7)°, Z = 2, V = 1674.7(12) 3, Dc = 1.271 g/cm3, F(000) = 676, R = 0.0729, wR = 0.1687 and μ(MoKα) = 0.086 mm-1. Two chiral BINOL ligands were found to be effective in the enantioselective addition of diethylzinc to aldehydes and much different enantioselectivity was observed both in the presence and absence of Ti(OiPr)4. In the former case, (R)-3 showed moderate enantioselectivity, which was lower than that of (R)-BINOL's; and in the latter case, (R)-4 gave the highest enan- tioselectivity up to 93.3% ee.*     

Highly enantioselective mukaiyama aldol reaction of alpha,alpha-dichloro ketene silyl acetal: an efficient synthesis of a key intermediate for diltiazem

An efficient synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), has been developed on the basis of the highly enantioselective Mukaiyama aldol reaction of p-anisaldehyde (4a) with alpha,alpha-dichloro ketene silyl acetal 5. Thus, the reaction using a stoichiometric amount of chiral oxazaborolidinone catalyst 12a proceeded to excellent yield (83%) and high enantioselectivity (96% ee), together with the chiral ligand 13a in nearly quantitative recovery. The reaction using a substoichiometric amount of 12e (20 mol %) also proceeded to excellent yield (88%), with somewhat lower enantioselectivity (77% ee). The aldol product 3a thus obtained was easily converted to (-)-2 in excellent yield (80%) and high optical purity (>99% ee). The highly enantioselective Mukaiyama aldol reaction with 5 catalyzed by 12a proved to be applicable to various aldehydes. An efficient preparation of 5 from inexpensive starting materials was also described.