Dienolate Additions to Aldehydes

Catalytic enantioselective dienolate additions to aldehydes were realized by Tol-BINAP-Cu(ll) fluoride complexes as shown by an example in Equation (131). 

Singer RA, Carreira EM. Catalytic, enantioselective dienolate additions to aldehydes preparation of optially active acetoa-cetonate aldol adducts. J. Am. Chem. Soc. 1995 117(49) 12360-12361. 

Regio-, enantio-, and diastereo-selective vinylogous aldol additions of silyl dienol ethers to aldehydes use a Lewis base (a chiral bis-BINAP-phosphoramide) to activate a Lewis acid (silicon tetrachloride).139... 

In the previous synthesis, two asymmetric aldol reactions using dienyl silyl ethers were described, one using a chiral Lewis acid for stereoinduction while the other used substrate control from a chiral aldehyde. This can be compared with the use of chiral dienolate 131 in the synthesis of a Ci-Cie fragment of the bryo-statins (Scheme 9-41) [59J. Here, the menthyl-derived auxiliary is covalently attached to the enolate, and again an excellent level of asymmetric induction was achieved on addition to aldehyde 132 to give adduct 133. 

The lithium dienolate anions derived from 2-bromocrotonates undergo addition to aldehydes and some ketones to furnish vinyloxiranes 1 at low temperature. ... 

Carreira and co-workers have described a Cu-mediated process that effects the catalytic, enantioselective addition of silyl dienolates 87 to aldehydes [24]. The active complex that is believed to initiate the reaction is readily prepared in situ upon mixing optically active bisphosphine, Cu(OTf)2 and (Bu4)NPh3SiF2 in THE (Eq. 58). The addition reactions catalyzed by this system proceed with a broad range of aldehydes to afford adducts 88 in up to 95% ee and 98% yield. Moreover, the reaction may be conducted on a preparative multigram scale utilizing as little as 0.5 mol % of 273 without deleterious effects on the product enantiomeric excess or yields. 

Denmark SE, Heemstra JR Jr (2004) Lewis base activation of lewis acids vinylogous aldol additions of dienol ethers to aldehydes. Synlett 2411-2416... 

Table 1 summarizes the yields and selectivities of the addition of dienolate 2 to various aldehydes. It can be seen that the yield and enantioselectivity very much depend on the solvent, with THF being the best tested. The best results were obtained with pentanal (55% yield, 92% ee). On the other hand, when spiro dienolate 1 was used in these aldol reactions, benzaldehyde gave the best... 

To start with the addition of y-dienolates to aldehydes, the so-called vinylogous Mukaiyama aldol reaction, Campagne et al. studied the applicability of different types of catalyst when using the silyldienolate 115 as nucleophile [121]. In general, many products obtained by means of this type of reaction are of interest in the total synthesis of natural products. It should be added that use of CuF-(S)-TolBinap (10 mol%) as metal-based catalyst led to 68% yield and enantioselectivity up to... 

Catalytic, enantioselective addition of silyl ketene acetals to aldehydes has been carried out using a variant of bifunctional catalysis Lewis base activation of Lewis acids.145 The weakly acidic SiCU has been activated with a strongly basic phor-phoramide (the latter chiral), to form a chiral Lewis acid in situ. It has also been extended to vinylogous aldol reactions of silyl dienol ethers derived from esters. 

The catalytic system using 62 is applicable to highly enantioselective preparation of acetoacetate aldol adducts (Scheme 10.55) [152]. The use of 1-3 mol% 62 and 0.4 equiv. 2,6-lutidine promotes the aldol reaction of a variety of aldehydes with silyl dienolate 64 in good to high optical yields. The dienolate addition provides a convergent and enantioselective route to 1,3-polyols by appending a protected acetoacetate in a single step. The 62-catalyzed aldol reactions of methyl acetate TMS enolate and dienolate 64 have been used in the total syntheses of Rofla-mycoin [153] and Macrolactin A [154], respectively. In the latter both enantiomers... 

In addition to the efficiency exhibited by catalyst 165 with a broad spectrum of aldehydes in acetate aldol addition reactions, this catalyst has been shown to function competently in enantioselective additions of dienol silane 87. The requisite dienolate is readily synthesized from 2,2,6-trimethyl-4H-l,3-dioxin-4-one 84 (diketene-i-acetone adduct) by deprotonation with LDA and quenching with MejSiCl (Eq. 24). Dioxinone 84 is commercially available at a nominal price in addition, the silyl dienolate 87 is easily purified by distillation and stable to prolonged storage. The addition reactions of 87 with aldehydes were conducted with 1-3 mol % of 165 at 0 °C (Eq. 25). A variety of aldehydes serve as substrates and give aldol adducts in 79-97% yields and up to 99% ee after a single recrystallization. 

The analogous vinyloxirane-dihydrofuran rearrangement has also been developed. Hudliclq et al. reported the thermal deconposition of vinyloxiranes, which were prepared by low-temperature addition of the lithium dienolate of ethyl-2-bromocrotonate to aldehydes. Subsequent pyrolytic rearrangement afforded the corresponding 2,3-dihydroftirans in variable yields fScheme 11.261. ... 

The synthesis of ketone 242 commences with the enantioselective addition of sUyl dienolate 237 to crotonaldehyde 236 catalyzed by Carreira s asymmetric complex [101] to give adduct 238 in 91% ee and 42% yield, albeit with a susceptibihty towards polymerization. Transesterification, sytt-reduction, protection of the corresponding diol, and reduction of the ester afforded aldehyde 239, which was subjected to Horner-Emmons olefination... 

Moving forward from 59, six steps were required to convert this compound to 60. Vicinal dihydroxylation of the olefin was followed by oxidative cleavage of the intermediate diol using lead tetraacetate. Reductive amina-tion of the resulting aldehyde with methylamine, followed by acylation of the intermediate secondary amine gave the desired carbamate. Swern oxidation of the secondary alcohol, followed by enol ether formation gave 60. Elimination of -toluenesulfinic acid from 60 provided 61. Oxidation of this dienol ether to dienone 62 was followed by release of the secondary amine, followed by a conjugate addition reaction to establish the critical C-N bond. The remainder of the synthesis followed known chemistry. The mixture of enones 63 was converted to codeinone (35), codeine (3) and then morphine (1). 

Moreover, the protocol could be used for a vinylogous Mukaiyama aldol addition and offered a solution to the problem of the asymmetric acetoacetate aldol reaction. Thus, 2 mol% of the catalyst 198 is enough to promote the addition of silyl dienolate 214 to various aldehydes to give, after desilylation, O-protected P-keto-5-hydroxy esters [113]. The protocol is illustrated for an addition to P-stannylpropenal 213. Depending on the enantiomer of the catalyst 198 or ent-198 chosen to mediate the aldol addition, enantiomeric products 215 and ent-215 were obtained in 92% ee. In an elegant convergent total synthesis, both enantiomers were incorporated into macrolactin A, as shown in Scheme 5.65 [114,115]. 

Catalysis with BINAP-CuFz, Carreira and co-workers have recently reported a novel aldol addition reaction using a putative Cu(I) fluoride complex as catalyst [32]. The cmiqilex is readily assembled in situ upon dissolving BINAP and CufOTflj, in THF followed by addition of Bu4NPh3SiF2, as an anhydrous fluoride source. Dienolate 105 undergoes addition to a wide range of aldehyde substrates at -78°C with 5 mol % catalyst, giving the protected acetoacetate adducts with up to 94% ee. The reaction has been mechanistically examined in some detail, leading to the postulation that the addition process includes a metalloenolate in the catalytic cycle as relevant reactive intermediate (Scheme 8B2.11) [33]. This perspective contrasts the more traditional role of transition-metal catalysis of the Mukaiyama aldol addition reaction wherein the metal functions as a Lewis acid and activates the electrophilic aldehyde partner. 

Addition reactions of dienolates and aldehydes can also be effected through the use of bisphosphine copper(I) complexes [145, 146]. A mixture of p-Tol-BINAP, Cu(0Tf)2, and (Bu4N)Ph3Sip2 leads to a complex that efficiently promotes rapid aldol addition reactions of acetoacetate-derived dienolates to give adducts with high yields and selectivities. The addition to crotonaldehyde served as an important launch point in Carreira s total syn-... 

An important mechanistic aspect of the Cu-bisphosphine-catalyzed addition reactions of dienolates to aldehydes is worth highlighting. Infra-red spectroscopic studies have collectively provided insight into the details of this process. In this respect, these processes have been suggested to proceed through metaloenolate intermediates [146]. As such, the process complements the traditional Mukaiyama aldol addition reaction, which typically proceeds through Lewis activation of the electrophilic aldehyde partner. 

A simple two-step protocol for the generation of a terminal diene is to add allyl magnesium bromide to an aldehyde or a ketone and subsequent acid or base catalysed dehydration (equation 34)72. Cheng and coworkers used this sequence for the synthesis of some indole natural products (equation 35)72a. Regiospecific dienones can be prepared by 1,2-addition of vinyllithium to a,/l-unsaturated carbonyl compounds and oxidative rearrangement of the resulting dienols with pyridinium dichromate (equation 36)73. 

Several other chiral Lewis acids have also been reported to effect asymmetric aldol reactions. Kruger and Carreira59 reported a catalytic aldol addition of silyl dienolate to a range of aldehydes in the presence of a bisphosphanyl-Cu(II) fluoride complex generated in situ from (iS )-Tol-BINAP, Cu(OTf)2, and (Bu4N)Ph3SiF2. Aromatic, heteroaromatic, and a,/ -unsaturated aldehydes provided the aldol adducts with up to 95% ee and 98% yield (Scheme 3-33). 

The conjugate addition of unstabilized enolates to various acceptors was conceptually recognized by early researchers however, complications were encountered depending on the enolates and acceptors employed. Reexamination of this strategy was made possible by the development of techniques for kinetic enolate formation. This discussion is divided into three enolate classes (a) aldehyde and ketone enolates, azaenolates or equivalents, (b) ester and amide enolates, dithioenolates and dienolates and (c) a,0-carboxylic dianions and a-nitrile anions, in order to emphasize the differential reactivity of various enolates with various acceptors."7 The a-nitrile anions are included because of their equivalence to the hypothetical a-carboxylic acid anion. 

The use of aldehyde enolates for conjugate additions is precluded by competing polymerization and al-dolization processes however, introduction of the OfeCHO moiety is accomplished with aldehyde enolate equivalents. For example, dianions of nitroethanes, e.g. 3-phenylnitroethane (165) or methyl 3-nitropropionate (166), add exclusively in the 1,4-mode to ot,3- nones.,36a-b Similarly, the dianion of 4-nitro-1-butene (167) adds in a 1,4-mode exclusively unlike typical dienolates (Section 1.2.2.2.2) which react at the ot-position, this dianion is formally equivalent to the crotonaldehyde >-enolate (Scheme 64).l36c... 

Oxamborolidenes. There are noteworthy advances in the design, synthesis, and study of amino acid-derived oxazaborolidene complexes as catalysts for the Mukaiyama aldol addition. Corey has documented the use of complex 1 prepared from A-tosyl (S)-tryptophan in enantioselective Mukaiyama aldol addition reactions [5]. The addition of aryl or alkyl methyl ketones 2a-b proceeded with aromatic as well as aliphatic aldehydes, giving adducts in 56-100% yields and up to 93% ee (Scheme 8B2.1, Table 8B2.1). The use of 1-trimethylsilyloxycyclopentene 3 as well as dienolsilane 4 has been examined. Thus, for example, the cyclopentanone adduct with benzaldehyde 5 (R = Ph) was isolated as a 94 6 mixture of diastereomers favoring the syn diastereomer, which was formed with 92% ee, Dienolate adducts 6 were isolated with up to 82% ee it is important that these were shown to afford the corresponding dihydropyrones upon treatment with trifuoroacetic acid. Thus this process not only allows access to aldol addition adducts, but also the products of hetero Diels-Alder cycloaddition reactions. 

According to Section 12.3 enamines are just one synthetic equivalent for enols that are not sufficiently represented in equilibrium with a carhonyl compound to allow for a-functional-izations. Enol ethers and silyl enol ethers, which are addressed in this section, are other synthetic equivalents for such enols. An enol ether, for example, is used as an enol equivalent for aldehyde enols, since several aldehydes do not form stable enamines. In addition, enol ethers or silyl enol ethers are usually employed as synthetic equivalents for the enols of ,/i-unsatu-rated carbonyl compounds. The attempt to react ce,/ -unsaturated carhonyl compounds with secondary amines to give a dienamine is often frustrated by a competing 1,4-addition of the amine. The combination of these factors turns the dienol ether B of Figure 12.23 into a species for which there is no analog in enamine chemistry. 

Denmark reported a protocol for the formation of 3-substituted azepines 4 from nitro acylsilanes 3, which were formed by the conjugate addition of an acylsilane-derived dienol-ether 2 to nitroalkenes 1 <07JOC7050>. The reaction of the nitro acylsilane with aluminium-amalgam gave a mixture of azepines and lactams, however, this was overcome by conversion of the acylsilane to an aldehyde prior to the reductive cyclisation. 

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