Thioketene acetals

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

This reaction occurs through a TS in which the aldehyde is chelated, but the silyl thioketene acetal is not coordinated to the Ti (open TS). 

Entries 3 and 8 show additions of a silyl thioketene acetal to a-substituted... 

E- and Z-silyl thioketene acetals give the 2,3-anti product. The 3,4-syn ratio is 50 1, and is consistent with the Felkin model. When this nucleophile reacts with 2-benzyloxypropanal (Entry 8), a chelation product results. The facial selectivity with respect to the methyl group is now reversed. Both isomers of the silyl thioketene acetal give mainly the 2,3-syn-3A-syn product. The ratio is higher than 30 1 for the Z-enolate but only 3 1 for the F-enolate. 

The (3-methoxy group in Entry 12 has a similar effect. The aldehydes in Entries 13 and 14 also have a-methyl-(3-oxy substitution and the reactions in these cases are with a silyl ketene acetal and silyl thioketene acetal, respectively, resulting in a 3,4-syn relationship between the newly formed hydroxyl and a-methyl substituents. 

This and similar catalysts are effective with silyl ketene acetals and silyl thioketene acetals.155 One of the examples is the tridentate pyridine-BOX-type catalyst 18. The reactivity of this catalyst has been explored using a- and (3-oxy substituted aldehydes.154 a-Benzyloxyacetaldehyde was highly enantioselective and the a-trimethylsilyoxy derivative was weakly so (56% e.e.). Nonchelating aldehydes such as benzaldehyde and 3-phenylpropanal gave racemic product. 3-Benzyloxypropanal also gave racemic product, indicating that the (i-oxy aldehydes do not chelate with this catalyst. 

Several catalysts based on Ti(IV) and BINOL have shown excellent enantiose-lectivity in Mukaiyama aldol reactions.156 A catalyst prepared from a 1 1 mixture of BINOL and Ti(0-i-Pr)4 gives good results with silyl thioketene acetals in ether, but is very solvent sensitive.157... 

The enantioselectivity of Sn(II) enolate reactions can be controlled by chiral diamine additives. These reagents are particularly effective for silyl thioketene acetals.162 Several diamines derived from proline have been explored and l-methyl-2-(l-piperidinomethyl)pyrrolidine 21 is an example. Even higher enantioselectivity can be achieved by attachment of bicyclic amines to the pyrrolidinomethyl group.163... 

Silyl acetals of thiol esters have also been studied. With TiCl4 as the Lewis acid, there is correspondence between the configuration of the silyl thioketene acetal and the adduct stereochemistry.314 L-Isomers show high anti selectivity, whereas Z-isomers are less selective. 

A number of other chiral catalysts can promote enantioselective conjugate additions of silyl enol ethers, silyl ketene acetals, and related compounds. For example, an oxazaborolidinone derived from allothreonine achieves high enantioselectivity in additions of silyl thioketene acetals.323 The optimal conditions for this reaction also include a hindered phenol and an ether additive. 

More recently, Kobayashi and co-workers reported on Zr-catalyzed additions of ketene and thioketene acetals to a range of aromatic and aliphatic aldehydes (Scheme 6.25) [83], As in the Erker study, the presence of protic additives proved critical here as well. As the example in Scheme 6.25 illustrates, the addition of larger amounts of iPrOH improved the yield and ee it was reported that in the absence of the alcohol additive much lower yield and enantioselectivities" were attained. The proposed catalytic cycle, depicted in Scheme 6.25, provides a plausible rationale for the role of the additive Si transfer is facilitated by iPrOH to regenerate the chiral catalyst. Finally, it is worthy of mention... 

In contrast to titanium(IV) tetrachloride, which causes polymerization of a,3-unsaturated esters, aluminum triflate88 or aluminum-impregnated montmorillonite87b are excellent promoters of silyl ketene acetal additions to a,(3-unsaturated esters (Scheme 35). Similarly, the addition of silyl ketene acetals and enol silyl ethers to nitroalkenes, followed by Nef-type work-up, affords y-keto esters (216) and y-di-ketones (218), respectively (Scheme 35).89a>89b Mechanistically, the y-diketones (218) arise from Nef-type hydrolysis of an initial nitronate ester (217).89e 89d Mukaiyama reports that SbCls-Sn(OTf)2 catalyzes diastereoselective anti additions of silyl ketene acetals, silyl thioketene acetals and enol silyl ethers to a,(3-unsaturated thioesters (219).90... 

As illustrated in Fig. 6, imines serve as important intermediates for a number of solid-phase syntheses. Additional uses for these versatile intermediates are described in Fig. 9. Resin-bound thioketene acetals have been shown to condense with imines to provide, after reductive cleavage, a route to substituted aminoalcohols 6 [45], Aminophosphinic acids 7 were prepared by allowing bis(trimethylsilyl)phosphonite to react with resin-bound imines [46],... 

This peculiar stereoselectivity might be attributed to a memory effect from the approach geometry between the triplet excited benzaldehyde and the alkene. Abe and coworkers have also observed a comparable stereochemical effect in the Paterno-Buchi reaction of 4-cycanobenzalde-hyde with O-silylated thioketene acetals 129 (Sch. 43) resulting in the highly functionalized oxetanes 130 [64]. 

SCHEME 111. Synthesis of y-lactones from tartaric-derivedbis-thioester by aldol reaction and the bis-thioketene acetal obtained by silylation of the intermediate bis-enolate552... 

The addition reaction of thioacetate-derived enoxysilanes to the same substrates has also been investigated (Scheme 8-6). Thus, treatment of /< r/-butyl thioacetate-derived silyl thioketene acetal and benzyloxyacetaldehyde, methyl glyoxylate, or pynivates in the presence of as little as 0.5 mol% 68/69 in CH2CI2 at -78 C affords aldol adducts in up to 99% ee [33]. 

Variation of the thioalkyl group, silyloxy group, counterion of the trityl group, or the geometry of the thioketene acetals influences the stereochemistry of the Michael addition. The optimal substituents depend on the nature of the acceptor. In most instances, however, more bulky silyl groups result in higher selectivity. 

P, P] By using antimony(V) chloride and tin(II) triflate, monothioketene acetals can be induced to add to a,/J-unsaturated thioesters (76). Interestingly, neither antimony(V) chloride nor tin(II) chloride by themselves effectively promote the reaction, implying that the combination of Lewis acids produces a new species. The stereochemistry of these additions is summarized in Scheme 44 and Table 16. For all cases studied, the reaction uniformly provides the anti diastereomers with good selectivity. The selectivity observed is somewhat lower than the optimized results observed with thioketene acetals and enones (vide supra). 

Addition of Thioketene Acetals to a,/ -Unsaturated Thioesters (Scheme 44)... 

The additions of acetate, propionate, and other substituted enolates following the optimized protocol have been reported. The typical set of conditions prescribe the use of 10 to 30 mol % catalyst in propionitrile at -78 °C and slow addition of reactants. For the acetate-derived silyl thioketene acetals 106 adducts are obtained in up to 93% ee and 90% yield (Eq. 9) [8j]. The addition of thiopro-pionate-derived Z-silyl ketene acetal 108 to a range of aldehydes delivered aldol... 

The addition reaction of fert-butyl thioacetate-derived silyl ketene acetal produces the corresponding aldol adducts in 84% yield and up to 96% enantiomeric excess (Eq. 16). The enantioselectivity of the products was observed to be optimal with toluene as solvent the use of the more polar dichloromethane consistently produced adducts with 10-15% lower enantiomeric excess. The bulkier ferf-butylthioacetate-derived enol silane was found to lead to uniformly higher levels of enantioselectivity than the smaller S-ethyl thioketene acetal. This process is impressive in that it tolerates a wide range of aldehyde substrates for instance, the aldol addition reaction has been successfully conducted with aldehydes substituted with polar functionaUty such as N-Boc amides, chlorides, esters, and 0-benzyl ethers. A key feature of this system when compared to previously reported processes was the abiUty to achieve high levels of stereoselectivity at 0 °C, in contrast to other processes that commonly prescribe operating temperatures of -78 °C. 

In acyclic systems, reductions of the ketone group of 1.155 (Y = COR) give poor selectivities. Reactions of o-substituted aldehydes 1.155 (Y = CHO) with organomagnesium reagents, perfluoroalkyllithiums or nitromethane [540] or chloracetophenone [540, 544] anions are very selective. Such is also the case for their reactions with functionalized isonitriles [540], silyl enolethers or thioketene acetals in the presence of Lewis acids [545, 546], or in B aylis-Hillmann reactions [547],... 

Another cyclization has been described using thioketene acetal protonation to initiate annula-tion33. 

The synthesis of the C29-C43 EF segment 479 is summarized in Scheme 68. Methylation of 467 under Prater s conditions stereoselectively afforded 2,3-anti compound 468 (dr = 5-8 1). After TES protection followed by thioester reduction, aldol reaction of the resulting aldehyde with thioketene acetal afforded a-alcohol 469 under Felkin-Anh selectivity. TES deprotection and silver-mediated lactonization followed by TES protection and lactone reduction gave lactol 470. Dehydration, debenzylation, and oxidation furnished aldehyde 471, which was transformed to benzotriazolyl amide 472. 

The synthesis of the E-ring 476 started with aldehyde 473, prepared via boron-mediated aldol reaction. FeUdn-selective Lewis acid-catalyzed aldol reaction of 473 with thioketene acetal afforded a-alcohol 474 (dr = 94 6). Fukuyama reduction of thioester to aldehyde followed by hemiacetalization and TBS protection furnished the E-ring 475, which was converted into phenylsulfone 476 in standard fashion. 

A variation of this method has also been developed for cases in which reactions with (1) give poor results (eq 6). Thus the carbonyl compound is treated with 2-lithio-l,3-dithiane followed by TMSCl to generate the silyl ether. Subsequent addition of a second equivalent of n-butyllithium effects alkenation, affording the thioketene acetal in good yield. ... 

Thioketene Acetals. Anion (1) reacts with aldehydes and ketones to provide the corresponding thioketene acetals aryl and unsaturated aldehydes and ketones are good substrates for this reaction (eqs 3 and 4). Enolizable alkyl ketones also react to provide thioketene acetals (eq 5). Alternative methods for the preparation of these cyclic thioketene acetals involve the use of phospho-nate derivatives, mixed zinc-titanium organometallic reagents, and iV,iV-dimethyl thioamides. The phosphonate reagents are more nucleophilic than (1) and are superior when competitive deprotonation is a problem. 

Cationic and Anionic Cyclizations. The thioketene acetals derived from the reaction of anion (1) have found several applications in cyclization methodology. The thioketene acetals can be used as either electrophiles (eq 7) or nucleophiles (eq 8) in a cyclization process which depends on the experimental conditions. 

Unsaturated Dithioketene Acetals. The reaction of anion (1) with various o ,/3-unsaturated aldehydes and ketones occurs in a 1,2-fashion and provides vinyl thioketene acetals that are acceptable dienes for Diels-Alder reactions (eq 11) dienes of this type are difficult to access using other protocols. This method is also convenient for the introduction of a protected carbonyl group. 

One Carbon Homologation of Aldehydes via a Peterson Olefination. 2-Trimethylsilyl-l,3-dithianes have been widely used in the formation of thioketene acetals. This reaction is the first of a two-step procedure that results in the one carbon homologation of an aldehyde or ketone via a 2-lithio-2-TMS-1,3-dithiane-mediated Peterson olefination, followed by hydrolysis of the dithiane to give the corresponding ester (eq 20). ... 

Vinyl sulfides and ketene dithioacetals are available via treatment of p-hydroxy thioacetals and p-hydroxy orthothioesters with PI3 or P2l4- For example (eq 7), treatment of the p-hydroxy or-thothioester (entry a) with PI3 (CH2Cl2-Et3N, 0 °C, 0.5 h) affords the thioketene acetal (1) in 69% yield. With certain substitution... 

The careful mechanistic studies that have been documented by Evans are a highly attractive aspect associated with these catalyst systems, and the work is well worth consulting for the practical and mechanistic insight it provides [152, 154, 155]. The investigations have permitted an understanding of the structural and coordination chemistry of the metal complexes, which is sure to have a positive impact on the evolution of enantioselective catalysts. For example, Evans has noted that the general addition of TMSOTf can lead to considerable acceleration in the aldol reaction. Thus, the addition reaction of pyruvate and trimethylsilyl tert-butyl thioketene acetal mediated by 2 mol % of copper(bisoxazoline) affords product in 97 % ee over the course of 14 hours when the same reaction is conducted with one equivalent of TMSOTf and Cu catalyst under otherwise identical conditions, reaction is observed to reach completion in 35 minutes, with no deterioration in enan-... 

---