Siloxy aldehydes

In most of the successful Diels-Alder reactions reported, dienes containing no heteroatom have been employed, and enantioselective Diels-Alder reactions of multiply heteroatom-substituted dienes, e.g. Danishefsky s diene, are rare, despite their tremendous potential usefulness in complex molecular synthesis. Rawal and coworkers have reported that the Cr(III)-salen complex 15 is a suitable catalyst for the reaction of a-substituted a,/ -unsubstituted aldehydes with l-amino-3-siloxy dienes [21] (Scheme 1.28, Table 1.12). The counter-ion of the catalyst is important and good results are obtained in the reaction using the catalyst paired with the SbFg anion. 

Entry 6 involves a titanium enolate of an ethyl ketone. The aldehyde has no nearby stereocenters. Systems with this substitution pattern have been shown to lead to a 2,2 syn relationship between the methyl groups flanking the ketone, and in this case, the (3-siloxy substituent has little effect on the stereoselectivity. The configuration (Z) and conformation of the enolate determines the 2,3-vyn stereochemistry.113... 

Entry 4 has siloxy substituents in both the (titanium) enolate and the aldehyde. The TBDPSO group in the aldehyde is in the large Felkin position, that is, perpendicular to the carbonyl group.121 The TBDMS group in the enolate is nonchelated but exerts a steric effect that governs facial selectivity.122 In this particular case, the two effects are matched and a single stereoisomer is observed. 

These reagents have been utilized for allyl-, 2-methylallyl-, and E- and Z-2-butenyl derivatives. Enantioselectivity of 90-95% is achieved with alkyl- and aryl-, as well as a- and (3-siloxy aldehydes. 

The addition of carbonyl compounds towards lithiated 1-siloxy-substituted allenes does not proceed in the manner described above for alkoxyallenes. Tius and co-work-ers found that treatment of 1-siloxy-substituted allene 67 with tert-butyllithium and subsequent addition of aldehydes or ketones led to the formation of ,/i-unsaturated acyl silanes 70 (Scheme 8.19) [66]. This simple and convenient method starts with the usual lithiation of allene 67 at C-l but is followed by a migration of the silyl group from oxygen to C-l, thus forming the lithium enolate 69, which finally adds to the carbonyl species. Transmetalation of the lithiated intermediate 69 to the corresponding zinc enolate provided better access to acylsilanes derived from enolizable aldehydes. For reactions of 69 with ketones, transmetalation to a magnesium species seems to afford optimal results. 

Epoxy Silyl Ether MABR P-Siloxy Aldehyde Yield (%)... 

To access anti-l,2-diols, indirect methods are required for the preparation of geometrically pure, chiral E-3-alkoxy reagents. To this end, the isomerization of alkenylboronic esters described above (Eq. 41), provides a reliable route to tartrate-derived E-3-siloxy allylboronate 99 (Fig. 7). The latter shows variable enantioselectivities in additions to aldehydes, with cyclohexanecarboxaldehyde affording the highest selectivity (Eq. 70). ... 

In 1977, an article from the authors laboratories [9] reported an TiCV mediated coupling reaction of 1-alkoxy-l-siloxy-cyclopropane with aldehydes (Scheme 1), in which the intermediate formation of a titanium homoenolate (path b) was postulated instead of a then-more-likely Friedel-Crafts-like mechanism (path a). This finding some years later led to the isolation of the first stable metal homoenolate [10] that exhibits considerable nucleophilic reactivity toward (external) electrophiles. Although the metal-carbon bond in this titanium complex is essentially covalent, such titanium species underwent ready nucleophilic addition onto carbonyl compounds to give 4-hydroxy esters in good yield. Since then a number of characterizable metal homoenolates have been prepared from siloxycyclopropanes [11], The repertoire of metal homoenolate reactions now covers most of the standard reaction types ranging from simple... 

These reagents are also useful for the preparation of 1,2-diols. Upon exposure to Lewis acids such as boron trifluoride etherate (BFa-OEta), the a-alkoxy and oc-siloxyallyl stannanes undergo a stereospecific, intermolecular 1,3-isomerization to give y-alkoxy- and y-siloxy allylic stannanes.3. .7 When tert-butyldimethylsilyl trifluoromethanesulfonate is substituted for chloromethyl methyl ether in the above procedure, the isomeric -y-siloxy allylic stannane can be obtained directly with no loss of enantioselectivity.6 These stannanes can then be added to various aldehydes to give monoprotected 1,2-diols with high diastereoselectivity.8... 

Cyclocondensation of 2-siloxy dienes and aldehydes is catalyzed by 1 mol % of a soluble lanthanide complex, Eu(hfc)3, and gives the hetero-Diels-Alder adduct in up to 58% ee (Scheme 107) (263). Upon treat-... 

The cobalt carbonyl complex is also an effective catalyst for the siloxy-methylation of aromatic aldehydes.110 Arylethane-l,2-diol disilylethers are obtained in good yields, resulting from incorporation of one molecule of CO and two molecules of HSiR3. Good selectivity for the siloxymethylation product is observed at 0°C in hexane. At 15°C, faster reaction rates are observed, but the selectivity for the CO-incorporated product is lower. In contrast, aliphatic aldehydes react under these conditions (1 atm CO, 0°C) to give only a small amount of CO-incorporated product, with a major product resulting from hydrosilylation. 

Murai and co-workers reported the silylformylation of aliphatic aldehydes in 1979.116 In this version of the transition metal-catalyzed reaction of HSiR3 and CO with various substrates, a formyl moiety is always present in the final product of the reaction. Murai utilized the Co2(CO)8 complex with a triphenylphosphine cocatalyst to catalytically form a-siloxy aldehydes from aliphatic aldehydes. An excess of reactant aldehyde is required to obtain the formyl products if silane is in excess, l,2-bis(siloxy)olefins are produced.117... 

More recently, Wright reported the [RhCl(COD)]2-catalyzed silylformylation of aldehydes, with high yields of the a-siloxy aldehydes under mild conditions [Eq. (44)].118... 

Reaction with dimethylphenylsilane is catalyzed at room temperature under 250 psi of carbon monoxide. Other silanes tested, triethyl- and triphenylsi-lane, are not effective reagents in this system. A variety of aldehydes are good substrates for the reaction, including benzaldehyde, substituted benzaldehydes, and heterocyclic aldehydes. Aliphatic aldehydes also yield a-siloxy aldehyde products, but the reaction must be run at higher CO pressure (1000 psi) to avoid hydrosilylation. The reaction does not tolerate substrates bearing strong electron-withdrawing substituents, such as p-nitrobenzaldehyde. 

Ring-opening silylformylation has been observed by Murai and coworkers in reactions of cyclic ethers. When the cobalt complex Co2(CO)8 is used as the catalyst in reactions of epoxides, an excess of substrate is required to prevent further reaction of the product siloxy aldehyde.1192 Further investigation led to the discovery of [RhCl(CO)2]2/l-methyl-pyrazole as an effective catalyst combination for the reaction of oxi-ranes119b and oxetanes.J19c For example, oxetane undergoes silylformylation to give 4-(dimethylphenylsiloxy)butanal in 81% yield [Eq. (45)]. 

Using the rhodium system, siloxy aldehydes are obtained as products in good yield even in the absence of excess substrate. 1-Methylpyrazole was found to be the best cocatalyst, as other amines do not lead to similar product yields. The authors suggest that the role of the amine is to accelerate the rate of carbon monoxide incorporation while suppressing possible side reactions, such as hydrosilylation. 

Methylenesilacyclobutane 61 reacts with aldehydes thermally to give the cyclic siloxy adduct 62105. In the presence of BI Y)Lb. treatment of 61 with 1,4-dicarbonyl compounds yields the corresponding 8-oxabicyclo[3.2.1]octane skeleton 63 (equation 43)106. 

A very useful option for synthesis of a-functional siloxy compounds is the addition of variously substituted (functional) organosilanes. Both aldehydes and ketones react under these reactions although either basic or acidic catalysts are required in some cases (see Scheme 32). 

A procedure for alkylation of C=0 double bonds in the presence of (metal-free) organocatalysts and non-metallic nucleophiles has been reported by the Iseki group for trifluoromethylation of aldehydes and ketones [185]. On the basis of a previous study of the Olah group [186, 187] which showed the suitability of non-chiral phase-transfer catalysts for trifluoromethylation of carbonyl compounds, Iseki et al. investigated the use of N-benzylcinchonium fluoride, 182, as a chiral catalyst. The reaction has been investigated with several aldehydes and aromatic ketones. Trifluoromethyltrimethylsilane, 181, was used as nucleophile. The reaction was, typically, performed at —78 °C with a catalytic amount (10-20 mol%) of 182, followed by subsequent hydrolysis of the siloxy compound and formation of the desired alcohols of type 183 (Scheme 6.82). 

The HDA reaction allows for rapid access to chiral six-membered heterocyclic structures that serve as valuable intermediates in organic synthesis. The first highly enantioselective HDA reaction promoted by a chiral hydrogen bond donor was reported from the Rawal laboratory. While investigating the cycloaddition reactions of amino-siloxy diene 115, it was observed that this diene was exceptionally reactive to heterodienophiles, and underwent HDA reactions with various aldehydes at room temperature, even in the absence of any added catalyst (Scheme 6.14). Subsequent treatment of the intermediate cycloadducts (116) with acetyl chloride afforded the corresponding dihydro-4-pyrones (117) in good overall yields [101]. Further studies of this reaction revealed a pronounced solvent effect,... 

Scheme 6.14 Uncatalyzed HDA reactions of amino-siloxy diene with aldehydes.

Danishefsky et al. [9] reported that stereochemical outcome of cyclocondensation of aldehydes and siloxy dienes was highly dependent on the nature of Lewis acid catalysts. When the reaction of diene 1 and benzaldehyde 2 was performed using BF3 OEt2 consistent tram (threo) selectivity was observed (cis-3/trans-3 = 13) (Sch. 1). High cis specificity was, however, observed in the presence of MgBr2 or ZnCl2 cisitrans = 38 1 and 39 1, respectively). 

This reaction of silyl ketene acetals with aldehydes, using 29 as a stoichiometric chiral reagent (Eq. 46), was reported by Reetz et al. [42]. The aldol addition of l-(trimethyl-siloxy)-l-methoxy-2-methyl-l-propene and 3-methylbutanal provides the aldol in only 57 % yield, but with 90 % ee. 

Kiyooka et al. reported that the 3i-catalyzed aldol reaction of a silyl ketene acetal involving a dithiolane moiety with y3-siloxy aldehyde resulted in the production of syn and anti 1,3-diols with complete stereoselectivity depending on the stereochemistry of the catalyst used [45b]. This methodology was applied to the enantioselective synthesis of the optically pure lactone involving a syn-l,3-diol unit, known to be a mevinic acid lactone derivative of the HMG-CoA reductase inhibitors mevinolin and compac-tin (Sch. 2). 

Aben and Scheeren discovered that bornyloxyaluminum dichloride, which can be easily prepared from bomeol, aluminum chloride, and lithium alanate, acts as an effective catalyst for the hetero Diels-Alder reaction of siloxy dienes and a variety of aldehydes, as illustrated in Sch. 18 [37]. 

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