Aldehydes achiral reactions

Sn(OTf)2 can function as a catalyst for aldol reactions, allylations, and cyanations asymmetric versions of these reactions have also been reported. Diastereoselective and enantioselective aldol reactions of aldehydes with silyl enol ethers using Sn(OTf)2 and a chiral amine have been reported (Scheme SO) 338 33 5 A proposed active complex is shown in the scheme. Catalytic asymmetric aldol reactions using Sn(OTf)2, a chiral diamine, and tin(II) oxide have been developed.340 Tin(II) oxide is assumed to prevent achiral reaction pathway by weakening the Lewis acidity of Me3SiOTf, which is formed during the reaction. 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Reactions with Achiral Aldehydes. The reaction of tartrate allylboronates with achiral aldehydes proceeds with moderate to excellent enantioselectivity (60-92% ee) and high yield (80-90%). Simple aliphatic aldehydes give good enantioselectiv-ities (decanal 86% ee, CyCHO 87% ee, eq 2), while p-alkoxy and conjugated aldehydes give diminished selectivities (60-80% ee) (eq 3). The enantioselectivity is highly temperature and solvent dependent. Best results for reactions with the vast majority of aldehydes are obtained in toluene at —78 °C. 4°A molecular sieves are included to ensure that the reaction is anhydrous. Other tartrate esters (e.g. diethyl tartrate) may also be used without loss of enantioselectivity. 

New auxiliaries and reaction methods are now available for the stereoselective synthesis of all members of the stereochemical family of propionate aldol additions. These also include improvements on previously reported methods that by insightful modification of the original reaction conditions have led to considerable expansion of the versatility of the process. In addition to novel auxiliary-based systems, there continue to be unexpected observations in diastereoselective aldol addition reactions involving chiral aldehyde/achiral enolate, achiral aldehyde/chir-al enolate, and chiral aldehyde/chiral enolate reaction partners. These stereochemical surpri.ses underscore the underlying complexity of the reaction process and how much we have yet to understand. 

Stable pentacoordinated allylsiliconates have been employed in aldehyde addition reactions. These reagents require no activation by Lewis acids or Lewis bases, but have found only limited applications in synthesis to date. The use of these agents in addition to aldehydes was first described in 1987 by Corriu [59] and Hosomi [60] and by Kira and Sakurai [61] in 1988. In these reactions, the addition of a catechol or 2,2 -biphenol-derived allylsiliconate to an achiral aldehyde led to the highly regio- and stereoselective formation of homoallylic alcohols. For example, the addition of the catechol-derived 2-butenylsiliconate 81 (90/10 E Z) provided a diastereomeric mixture of homoallylic alcohols 74 and 75 in a 90/10 ratio (Scheme 10-33) [60c]. 

Achiral allylic boranes and chiral aldehydes. The reaction of pinacol-derived al-lylboronate 175 with a number of chiral aldehydes proceeds in only modest selectivity (Scheme 10-73) [120], Almost all of the aldehydes examined demonstrate a weak preference for the syn or Cram product. Almost no change in selectivity was observed when the protecting group on the alcohol is changed from a /-butyl-siloxy to a methoxymethyl group. 

Scheme 1.5. Examples of single and double asymmetric induction in the aldol addition reaction, (a) Reaction of a chiral enolate and an achiral aldehyde (b) Reaction of an achiral enolate with a chiral aldehyde (c) Matched pair double asymmetric induction with a chiral enolate and a chiral aldehyde (d) Mismatched pair double asymmetric induction with a chiral enolate and the aldehyde enantiomeric to that shown in (a). (After ref. [58]).

Dr Reddy s Laboratories claimed the diastereoselective hydroformylation of an enantiopure bicyclic lactam by means of a Rh[(/ ,/ )-Kelliphite] catalyst (Scheme 4.59) [18]. The olefinic substrate that is produced on a multi-ton scale by Chirotech gives after hydroformylation and a single crystallization step the almost pure aldehyde. Noteworthy, (S,S)-Kelliphite or other ligands, such as (/J,/ ,S)-Bisdiazaphos or (achiral) BIPHEPHOS, induced mainly the formation of the undesired regioisomeric aldehyde. The reaction has been upscaled to 15 g of substrate and used eventually for the production of multifunctionalized... 

The aldehyde structures and the tosylhydrazone salts were varied in an extensive study of scope and limitations, with use of both achiral and chiral sulfur ylides [73]. Aromatic aldehydes were excellent substrates in the reaction with benzaldehyde-derived ylides, whereas aliphatic aldehydes gave moderate yields and transxis ratios. 

The addition of an achiral organometallic reagent (R M) to a chiral carbonyl compound 1 (see Section 1.3.1.1.) leads to a mixture of diastercomers 2 (syn/anti) which can be either racemic, or enantiomerically enriched or pure, depending on whether the substrates are race-mates or pure enantiomers. This section incorporates only those reactions starting from optically pure a-amino aldehydes, however, optical purity of the starting material has not been demonstrated in all cases. 

I.3.3.3.3.I.2. Simple Diastereosclectivity Reactions with Achiral Aldehydes and Ketones... 

In contrast to the 2-butenylboranes, 2-butcnylboronates have found widespread application in acyclic diastereoselective synthesis owing to their ease of preparation (Section 1.3.3.3.3.1.1.), configurational stability and highly stereoselective reactions with aldehydes3 4. The results of reactions of substituted allylboronates and representative achiral aldehydes are summarized in Table 1. 

I.3.3.3.3.I.3. Relative Asymmetric Induction Reactions of Chiral Aldehydes with Achiral Allylboron Reagents... 

Several detailed studies of reactions of achiral aiiylboronates and chiral aldehydes have been reported4,52 - 57. Diastereofacial selectivity in the reactions of 2-(2-propenyl)- or 2-(2-butenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolanes with x-methyl branched chiral aldehydes are summarized in Table 252, 53, while results of reactions with a-heteroatom-substituted aldehydes are summarized in Table 34,52d 54- 57. 

Finally, 2-allyl-4,5-tra ,s-diphenyl-l,3-bis(4-methylphenylsulfonyl)-l,3,2-diazaborolidincs have been used74. The 2-propenyl derivative undergoes highly stereoselective reactions with achiral aldehydes (95 - 97% ee) the ( )-2-butenyl derivatives (91-95% ee) and the analogous 2-chloro- and 2-bromo-2-propenyl derivatives (84-99% ee) also give excellent results in reactions with achiral aldehydes. 

The enantioselectivities of the reactions of representative achiral aldehydes and chiral allylboron reagents arc compared in Table 4. A comparison of the enantioselectivities of the (Z )-2-butenyl reagents appears in Table 5, while Table 6 provides a similar summary of the reactions of the (Z)-2-butenyl and 3-methoxy-2-propcnyl reagents. A 3-diphenylamino-2-propenyl reagent was recently reported102. 

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