Aldol-type reaction stereoselective

A study of the kinetics and products of the thermolysis of a series of diaryl-phosphinic azides has been reported.119 Diethyl 1-diazomethylphosphonates undergo an aldol-type reaction with aldehydes to give l-diazo-2-hydroxyalkylphosphonates (152).120 Acidification of the diazophosphonates (153) possessing a chiral phosphorus centre yields mixtures of diastereoisomers (154) and epimers at C. For given R1 and R2, the reaction becomes increasingly stereoselective for X= OAc < Cl < OTs. It may be argued that protonation of (153) will yield a mixture of diastereoisomeric di-... 

Novel aldol-type reactions under Cinchona-deriwed chiral thiourea catalysis was reported by Wang et al. [78]. In their report, a novel cascade Michael-aldol reaction was presented. The reaction involves a tandem reaction catalyzed via hydrogen-bonding with as little as 1 mol% catalyst loading to generate a product with three stereogenic centers (Scheme 28). hi the reaction of 2-mercaptobenzaldehyde 128 and a,P-unsatnrated oxazolidinone 129, the desired benzothiopyran 130 was formed smoothly in high yield and excellent stereoselectivity. 

From the illustrated (S)-valinol imide (175), the derived dibutylboryl enolates undergo condensation with a broad range of aldehydes in greater than 99% asymmetric induction for both newly formed asymmetric centers 180). Evans et al. have shown that the propionyl sidely chain in (175) may be replaced by other alkanoyl substituents without loss of stereoselectivity in the aldol type reaction 180). 

Thioamide enolates are also interesting substrates for the stereoselective aldol-type reactions. The aldol stereochemistry is very sensitive to the conditions of preparation of magnesium thioamide enolates and it generally gives different results depending on the procedure used. Illustrations of some aspects of the reactivity are provided in the examples presented below. 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

In contrast to titanium enolates of ketones, titanium enolates of aldehydes exhibit practically no stereoselectivity in aldol reactions. However, titanation of dimethylhy-drazones of aldehydes with 1 results in substrates (2) that show high eryt/iro-selecti v i ty in aldol-type reactions with aldehydes (equation I). Bromotitanium tris(diethylamide) can be used in place of 1, but is less efficient, as is Ti(IV) isopropoxide.6... 

Asymmetric aldol reactions.1 This diamine (1) when coordinated with tin(II) triflate and dibutyltin diacetate promotes highly stereoselective aldol-type reactions between silyl enol ethers and aldehydes. 

Tandem radical addition-aldol-type reaction of a,/3-unsaturated oxime ethers bearing an Oppolzer sultam auxiliary leads to stereoselective incorporation of alkyl groups in the 5- and 3-positions in tetrahydrofurans (Scheme 77) <2005AGE6190>. The observed /ra r,/ra r-stereoselectivity was explained by invoking a cyclic six-membered ring transition state. 

Yamamoto and co-workers found that 27 is an excellent chiral promoter not only for the aza Diels-Alder reaction of aldimines [40] but also for the stereoselective aldol-type reaction of aldimines with ketene silyl acetals [55]. The reaction of (5)-benzyli-dene a-methylbenzylamine with trimethylsilyl ketene acetal derived from terf-butyl acetate in the presence of (R)-27 produces the (R) adduct in > 92 % diastereomeric excess (de), whereas reaction with (5)-27 gives the adduct in 74 % de. In a similar way, (5)-butylidene a-methylbenzylamine, an aliphatic imine, can be converted to the (R)-)3-amino ester in 94 % de by use of (R)-27 (Eq. 73). 

Mukaiyama and Kobayashi et al. have developed the use of Sn(OTf)2 in diastereose-lective and enantioselective aldol-type reactions [26,27]. Initially, the stereoselective aldol reactions were performed with a stoichiometric amount of Sn(OTf)2 [28], The reaction between 3-acylthiazolidine-2-thione and 3-phenylpropionaldehyde is a representative example of a diastereoselective syn-aldol synthesis (Eq. 17). 

The ferrocenylphosphine-silver complex catalyzes the aldol-type reaction of tosylmethyl isocyanide 71 with aldehydes with higher stereoselectivity than the gold complex (Scheme 2-59) [84]. The reaction with several aldehydes produces trans-4-tosyloxazolines 72 in up to 86% ee, which can be converted into optically active l-alkyl-2-aminoethanols by reduction with LiAlH4. 

The aldol-type reaction of a-bromo ketones with aldehydes, mediated by CrCh, has been studied by Dubois and coworkers. The reaction is carried out by addition of (241 equation 80) to a solution of (242) and CrCh in THF. The reaction proceeds with high levels of syn selectivity with bulky bromo ketones (241), independent of the substrate aldehyde used (Table 11, entries 1-6). However, the reaction is stereorandom with bromoacetophenone (entry 7) and selectively anti with 2-bromocyclohexanone (entry 8). No explanation of the stereoselectivity has been advanced, but the reaction is believed not to proceed via a simple chromium enolate since no condensation reaction is obtained by addition of (242) to a solution of (241) and CrCh. Moreover, Nozaki and coworkershave demonstrated that chro-mium(II) chloride treatment of 1-bromocyclododecanone followed by treatment with either methyl iodide or TMS-Cl produces only cyclododecanone. 

Stereoselectivity. See Asymmetric induction Axial/equatorial-, Cis/trans-, Enantio-, Endo/exo- or Erythro/threo-Selectivity Inversion Retention definition (e.e.), 107 footnote Steric hindrance, overcoming of in acylations, 145 in aldol type reactions, 55-56 in corrin synthesis, 261-262 in Diels-Alder cyclizations, 86 in Michael type additions, 90 in oiefinations Barton olefination, 34-35 McMurry olefination, 41 Peterson olefination, 33 in syntheses of ce-hydrdoxy ketones, 52 Steric strain, due to bridges (Bredt s rule) effect on enolization, 276, 277, 296, 299 effect on f3-lactam stability, 311-315 —, due to crowding, release of in chlorophyll synthesis, 258-259 in metc-cyclophane rearrangement, 38, 338 in dodecahedrane synthesis, 336-337 in prismane synthesis, 330 in tetrahedrane synthesis, 330 —, due to small angles, release of, 79-80, 330-333, 337... 

In the synthesis of aspyrone (994), an antibiotic isolated from the culture broth of Aspergillus species, lactaldehyde 990 supplies the asymmetric centers of the epoxide in the side chain (Scheme 134). The molecule is assembled convergently by addition of the lithium enolate of D-rhamnose-derived a-phenylseleno- -lactone 991 to aldehyde 990. After an initial aldol-type reaction, the intermediate alkoxide displaces tosylate to provide epoxide 992 with >99.8% stereoselectivity. Peroxide-induced elimination of phenylselenide furnishes TBS-protected aspyrone 993 in 61% overall yield from 990. 

Stereoselective reactions with acetals. Noyori et al. (10,438) have used this Lewis acid to promote an aldol-type reaction between enol silyl ethers and acetals and have noted high. syn-selectivity in this process. Molander and Haar report that reaction of acetals with cyanotrimethylsilane promoted by TMSOTf results in a-alkoxy cyanides and that this reaction can be diastereoselective when the acetal is substituted at the 4-position by an alkoxy group. The diastereoselectivity depends on the nature of the acetal and the 4-alkoxy group. Dimethoxy acetals show slight diastereoselectivity, but diisopropoxy and dibenzyl acetals can show diastereoselectivity of 5-10 1. The diastereoselectivity also depends on the type of 4-substituent. Acetoxy and t-butyldimethylsilyloxy groups have no effect on the diastereoselectivity, but methoxy, benzyloxy, and allyloxy groups promote anri-selectivity. Since a metal template is not involved, the diastereoselectivity... 

TMSOTf mediates a stereoselective aldol-type condensation of silyl enol ethers and acetals (or orthoesters). The nonbasic reaction conditions are extremely mild. TMSOTf catalyzes many aldol-type reactions in particular, the reaction of relatively non-nucleophilic enol derivatives with carbonyl compounds is facile in the presence of the silyl triflate. The activation of acetals was first reported by Noyori and has since been widely employed (eq 14). ... 

CAB 3a is also an excellent catalyst (20 mol%) for the Mukaiyama condensation of simple enol silyl ethers of achiral ketones with various aldehydes. Furthermore, the reactivity of aldol-type reactions can be improved without reducing the enantioselec-tivity by using 10-20 mol% of 3c. Enantioselectivity can also be improved without reducing the chemical yield by using 20 mol% of 3b. The 3-catalyzed aldol process allows for the formation of adducts in a highly diastereo- and enantioselective manner (up to 99% ee) under mild reaction conditions [41a, cj. These reactions are catalytic, and the chiral source is recoverable and reusable (Equation 41). The observed high syn selectivities, together with their lack of dependence on the stereoselectivity of the silyl enol ethers, in 3-catalyzed reactions are fully consistent with Noyori s TMSOTf-catalyzed aldol reactions of acetals, and thus may reflect the acyclic extended transition state mechanism postulated in the latter reactions. 

Pioneering work by Lubineau and coworkers showed that the aldol type reaction between a silyl enol ether and an aldehyde (the so-called Mukaiyama aldol reaction) occurred in water at room temperature with high syn stereoselectivity, albeit in low yields.However, the development of water-tolerant Lewis acids for this reaction has led to improved rates and chemical yields. Various lanthanides triflates, such as ytterbium triflate [Yb(OTf)3], scandium triflate [Sc(OTf)3], gadolinium triflate [Gd(OTf)3], or lutetium triflate [Lu(OTf)3], have been found to afford the aldol products between various aldehydes and silyl enol ethers in high yields in aqueous media, with good to moderate syn/anti diastereoselectivi-ties (Scheme 8.3, Table 8.1). ... 

Metal enolates play an important role in organic synthesis and metal enolate-mediated aldol type reactions, in particular, are very useful synthetic tools in stereoselective and asymmetric carbon-carbon bond formation. Generation and reactions of different metal enolates have been extensively studied and successful applications to the controlled formation of carbon-carbon bonds have been realized under mild conditions. 

The aldol reaction has long been recognized as one of the most useful synthetic tools. Under classical aldol reaction conditions, in vhich basic media are usually employed, dimers, polymers, self-condensation products, or a,j5-unsaturated carbonyl compounds are invariably formed as byproducts. The lithium enolate-mediated aldol reaction is regarded as one useful synthetic means of solving these problems. Besides the vell-studied aldol reaction based on lithium enolates, very versatile regio- and stereoselective carbon-carbon bond forming aldol-type reactions have been established in our laboratory by use of boron enolates (1971), silicon enolates-Le vis acids (1973), and tin(II) enolates (1982). Here we describe the first t vo topics, boron and silicon enolate-mediated crossed aldol reactions, in sequence. 

Enol stannanes of cyclohexanone and propiophenone have been indicated to take part in r/treo-selective aldol reactions with benzaldehyde at low temperatures e.g. —78 °C), but to be erythro-seAsciiwe at higher temperatures ca 45 °C). Two complementary methods have been described for stereoselection in aldol-type reactions. Whilst a-mercurio-ketones show eryr/wo-selection in their reactions with aldehydes in the presence of boron trifluoride diethyl etherate, pre-formed lithium enolates and aldehydes, in the presence of simple trialkyl-boranes, lead to mixtures that are rich in the more stable threo-d do product. Aldol-type products arise from 1,3-alkyl migrations of alk-l-enyl alkyl acetals and ketals, in a reaction that is catalysed by boron trifluoride diethyl etherate (Scheme 52). Diastereoselection is possible, since (.E)-alkenyl acetals give the... 

Functional group transformations on azetidine rings serve as useful method to synthesize new 2-azetidinones. Toward this endeavor. Alcaide and coworkers have reported sodium azide-catalyzed stereoselective bromo-nitro-aldol type reaction of azetidine-2,3-diones 29 in aqueous environment to synthesize new 3-hydroxy-3-bromonitro-methyl-2-azetidinones 30 (Scheme 9) [38]. The anff-isomer was the major product without exception. 

---