Asymmetric enol ether substrate

Stoltz reported the extension of their methodology to silyl enol ether substrates (Scheme 4.18) [36]. In many cases these enolate precursors are easier to prepare compared to their enol carbonate counterpart. The addition of diallyl carbonate was necessitated to generate the enol carbonate in situ. Tetrabutylammonium difluoro-triphenylsiUcate (TBAT) was also required to activate the cleavage of the enol silane in situ at a temperature for asymmetric induction to occur. Nearly identical levels of enantioselectivity were obtained with this system. 

Extremely sterically demanding Br0nsted acid catalyst 13 indeed efficiently catalyzed the asymmetric conversion of small and further unfunctionalized hydroxy enol ether substrates. Various spiroacetals were obtained with high enantios-electivity independent of the ring size of the enol ether by the formation of either 6- or 5-membered rings (Table 4) [57]. Catalyst 13 also enabled the first catalytic asymmetric synthesis of the natural product olean (entry 2). AU these small spiroacetals in Table 4 are core stmcmres of many natural products [6-8]. 

Table 8 Silyl enol ether substrates in asymmetric allylic alkylation...

The first asymmetric Mn(salen)-catalyzed epoxidation of silyl enol ethers was carried out by Reddy and Thornton in 1992. Results from the epoxidation of various silyl enol ethers gave the corresponding keto-alcohols in up to 62% ee Subsequently, Adam and Katsuki " independently optimized the protocol for these substrates yielding products in excellent enantioselectivity. 

In 1992, Thornton et al. reported that Mn(salen) (43) catalyzed the asymmetric oxidation of silyl enol ethers to give a mixture of a-siloxy and a-hydroxy ketones, albeit with moderate enantioselectivity (Scheme 28).135 Jacobsen et al. examined the oxidation of enol esters with Mn(salen) (27) and achieved good enantioselectivity.136 Adam et al. also reported that the oxidation of enol ethers with (27) proceeded with moderate to high enantioselectivity.137 Good substrates for these reactions are limited, however, to conjugated enol ethers and esters. Based on the analysis of the stereochemistry,137 enol ethers have been proposed to approach the oxo-Mn center along the N—Mn bond axis (trajectory c, vide supra). 

Another useful method for the asymmetric oxidation of enol derivatives is osmium-mediated dihydroxylation using cinchona alkaloid as the chiral auxiliary. The oxidation of enol ethers and enol silyl ethers proceeds with enantioselectivity as high as that of the corresponding dihydroxylation of olefins (vide infra) (Scheme 30).139 It is noteworthy that the oxidation of E- and Z-enol ethers gives the same product, and the E/Z ratio of the substrates does not strongly affect the... 

MeOC6H4, respectively. The titanium enolates were converted into silyl enol ethers 54 by treatment with chlorotrimethylsilane and lithium isopropoxide. Additionally, cyclic enones lb and Ic, and linear enones Id and le, are also good substrates for the asymmetric conjugate addition of phenyltitanium triisopropoxide, giving the corresponding arylation products with over 97% enantioselectivity. 

Enantiotopos discrimination, 93, 128, 142, 234, 235, 331 Ene reactions asymmetric, 223 binaphthol, 222 chiral metal complexes, 222 intramolecular, 226 methyl glyoxylate, 290 Enol silyl ether substrates, 128, 228, 230 Enol substrates, 28 Enolates ... 

The range of alkenes that may be used as substrates in these reactions is vast Suitable catalysts may be chosen to permit use of ordinary alkenes, electron deficient alkenes such as a,(3-unsaturated carbonyl compounds, and very electron rich alkenes such as enol ethers. These reactions are generally stereospecific, and they often exhibit syn stereoselectivity, as was also mentioned for the photochemical reactions earlier. Several optically active catalysts and several types of chiral auxiliaries contained in either the al-kene substrates or the diazo compounds have been studied in asymmetric cyclopropanation reactions, but diazocarbonyl compounds, rather than simple diazoalkanes, have been used in most of these studies. When more than one possible site of cyclopropanation exists, reactions of less highly substituted alkenes are often seen, whereas the photochemical reactions often occur predominantly at more highly substituted double bonds. However, the regioselectivity of the metal-catalyzed reactions can be very dependent upon the particular catalyst chosen for the reaction. 

An interesting use of the nickel-catalyzed allylic alkylation has prochiral allylic ketals as substrate (Scheme 8E.47) [206]. In contrast to the previous kinetic-resolution process, the enantioselectivity achieved in the ionization step is directly reflected in the stereochemical outcome of the reaction. Thus, the commonly observed variation of the enantioselectivity with respect to the structure of the nucleophile is avoided in this type of reaction. Depending on the method of isolation, the regio- and enantioselective substitution gives an asymmetric Michael adduct or an enol ether in quite good enantioselectivity to provide further synthetic flexibility. 

Independently, Yamamoto, Yanagisawa, and others reported the asymmetric aldol reaction using trimethoxysilyl enol ethers.19 The reaction was conducted with aldehydes and trimethoxysilyl enol ethers in the presence of Tol-BINAP-AgF to give the corresponding adducts with high enantioselectivities and diastereoselectiv-ities. They obtained vyra-aldol adducts as major products even when silyl enol ethers derived from cyclic ketones were used. Moreover, when a,(3-unsaturated aldehydes were employed as substrates, 1,2 adducts were obtained exclusively (Table 9.10). From an NMR study and correlation between the E Z ratio of the enol ethers and diastereoselectiviy, they proposed a cyclic transition state (Fig. 9.5). Thus, the reaction of E enol ethers proceeded via a boat form, whereas the reaction of Z enol ethers took place via a chair form. 

Yamamoto et al. reported the asymmetric (9-nitrosoaldol reaction using silyl enol ethers in the presence of the silver catalyst.32 In order to achieve this reaction, they developed a novel combination of silver and a chiral phosphite derived from BINOL. The disilanyl enol ether was used to ensure high yield and enantioselectivity. The reaction was conducted with disilanyl enol ether and nitrosobenzene in the presence of AgBF4 and the chiral phosphite ligand in THF to produce the O adduct with high regio- and enantioselectivity (Table 9.14). In addition, a chiral silyl enol ether could be used as a substrate. The reaction was conducted with chiral silyl enol... 

The nitrido complex was applied to the direct asymmetric animation with a silyl enol ether as a substrate. Although several examples for achiral aminations of silyl enol ethers have been reported [32], an asymmetric version of reagent-controlled reaction has not appeared except for the one recent example [33] and the diastereoselective reactions with silyl enol ethers having a chiral auxiliary [34], The amination, which is presumed to take place via an aziridine intermediate [5g, lid,32], proceeded smoothly to give the A-tosylated a-aminoketone in 76% yield with 48% ee. When the same silyl enol ether was treated with complex 15 under Carreira s condition, the TV-trifluoroacetylated a-aminoketone was obtained in 58 % yield with 79 % ee (Scheme 24). 

FMOC-protected amino acid fluorides afford the expected Reissert adducts 160 with a good stereoselectivities, the a-sulfonylamino acid fluorides undergo cycliza-tion to adduct 161 [47, 140, 141], Itho s protocol is amenable to using silyl enol ethers 157 as nucleophiles [142], Gibson has used bulky asymmetric acid chlorides as substrates in a Reissert reaction with TMS-CN the corresponding Reissert compound was then treated with aldehydes and sodium hydride to obtain the enantiopure adducts 4 (Scheme 3) [143],... 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

The first examples of asymmetric Heck cyclizations that form quatemaiy carbon centers with high enantioselectivity came from our development of an asymmetric synthesis of the pharmacologically important alkaloid (—)-physostigmine (184) and congeners (Scheme 6-31) [68]. In the pivotal reaction, (Z)-2-butenanilide iodide 182 was cyclized with Pd-(5)-BINAP to provide oxindole 183 in 84% yield and 95% ee after hydrolysis of the intermediate silyl enol ether. With substrates of this type, cyclizations in the presence of halide scavengers took place with much lower enantioselectivity [68]. 

A library of chiral dihydropyrans (226) [241] was synthesized using asymmetric hetero-Diels-Alder reactions (HAD) on polymer-bound enol ethers (221) and a, 3-unsaturated oxalyl esters (222). A chiral Lewis acidic Cu -bisoxazoline complex was used because of its high efficiency, the high predictability of the reaction outcome, and its broad substrate tolerance [280]. Enol ethers were used as alkene components bearing a hydroxy function for attachment to the resin via a silyl linkage (Scheme 49). The diene components carried allyl-ester groups, which could be readily displaced by amino functions in subsequent steps of the combinatorial synthesis. 

The degree of asymmetric induction in the photocycloaddition reaction can be quite high with substrates containing a stereogenic center. Winkler, Scott and Williard have reported that irradiation of 1-tryptophan-derived vinylogous amide 107 led to the isolation of ketoimine 108 in 91% yield as a single diastereomer . Closure to the tetracyclic portion of the aspidosperma ring system 109 was achieved in two steps by formation of the silyl enol ether with LDA and r-butyl dimethylsilyl triflate followed by treatment with tetrabutylammonium fluoride (TBFA). Conversion of 109 to 110 with >97% optical purity was then achieved. As 110 is an intermediate in Biichi s synthesis of vindorosine, the sequence outlined in Scheme 26 represents a formal total synthesis of vindorosine. 

We pointed out in chapter 27 that Schultz s asymmetric Birch reduction can be developed with iodolactonisation to remove the chiral auxiliary and set up new chiral centres. Now we shall see how he applied that method to alkaloid synthesis.1 The first reaction is the same as in chapter 27 but the alkyl halide is now specified this gave diastereomerically pure acetate in 96% yield and hydrolysis gave the alcohol 4. Mitsunobu conversion of OH to azide and enol ether hydrolysis gave 5, the substrate for the iodolactonisation. Iodolactonisation not only introduces two new chiral centres but cleaves the chiral auxiliary, as described in chapter 27. Reduction of the azide 6 to the amine with Ph3P leads to the imine 7 by spontaneous ring closure. 

A TMSOTf-initiated cyclization of the dicarbonyl substrate was invoked to explain the reactivity pattern [79]. Selective complexation of the less hindered carbonyl group activates it toward intramolecular nucleophilic attack by the more hindered carbonyl which leads to an oxocarbenium species. Subsequent attack by the enol ether results in addition to the more hindered carbonyl group. The formation of this cyclic intermediate also explains the high stereochemical induction by existing asymmetric centers in the substrates, as demonstrated by Eq. 52, where the stereochemistry at four centers is controlled. A similar reactivity pattern was observed for the bis-silyl enol ethers of / -diketones. The method is also efficient for the synthesis of oxabicyclo[3.3.1] substrates via 1.5-dicarbonyl compounds, as shown in Eq. 53. Rapid entry into more complex polycyclic annulation products is possible starting from cyclic dicarbonyl electrophiles [80]. 

One unique aspect of the carbenoid C-H insertion chemistry is its ability to form products that are typically obtained from more classical organic reactions. One example is the allylic insertion into silyl enol ethers 102 to form products equivalent to those from an asymmetric Michael reaction (Scheme 22) [92], Cyclic substrates provided the desired Michael adducts 103 in the highest ee values for the major isomer (89-96%), but with only moderate de, favoring the diastereomer shown about 1.5 1 to 3 1. The diastereoselectivity was markedly improved to >90% de with acyclic substrate 104 with sterically differentiated substituents, but the enantioselectivity dropped to below 85% ee. Notably, this transformation was limited to aryldiazoacetates. When EDA was utilized as the carbene precursor, cyclo-propanation of the olefin was the major reaction pathway, and only small amounts of the desired C-H insertion were observed. 

A process for the asymmetric cyclopropanation of the enol ethers of cyclic and acyclic ketones has been developed by Tai [109-111]. In this process, a 2-symmetric acetal is isomerized to a hydroxy enol ether which serves as substrate or the Simmons-Smith cyclopropanation, as shown in Scheme 6.29. The stereoselectivity is nearly perfect, but a mechanistic hypothesis has not been proposed. The auxiliary may be removed either by hydrolysis, to give the methyl ketone, or by oxidation of the alcohol and p-elimination [111]. 

An indirect route to a-hydroxy carbonyl compounds uses enol ethers as substrates for dihydroxylations (Scheme 8.24). The primary product is a vicinal hydroxy-hemiacetal which fragments to afford an a-hydroxyketone, rendering the overall route a two-step conversion of ketone to a-hydroxy ketone. The stereochemically important step can use a chiral auxiliary or enantioselective catalysis [64]. The sense of asymmetric induction found in Oppolzer s sulfonamide, shown in Scheme 8.24a... 

Enol ethers are interesting substrates for epoxidations since a-hydroxy ketones or the corresponding acetals are isolated, depending on the choice of solvent. Kat-suki has used enol ethers as substrates, including the cyclic enol ether (4.67), which affords the hydroxy acetal product (4.68). ° Adam has used silyl enol ethers and silyl ketene acetals as substrates. A typical example is provided by the asymmetric oxidation of silyl enol ether (4.69), generating the oi-hydroxy ketone (4.70) after a suitable work up. ... 

Normally, silyl enol ethers are considered to react with aldol substrates via an aldol mechanism, but Mikami and coworkers, in their examples, showed that the reaction involves an ene mechanism. This is clear from the regiochemistry of the product (7.186) that is isolated from the reaction of silyl enol ether (7.184) and aldehyde (7.185) before hydrolysis. The same catalyst system has been used for the asymmetric desymmetrisation of the diene (7.187) with aldehyde (7.183). The ... 

MacMillan and co workers have significantly expanded the scope of this enamine-mediated procedure by the addition of stoichiometric amounts of oxidant that leads to the in situ formation of a radical cation (12.57). This intermediate then undergoes enantioselective radical-based addition with a range of unsaturated substrates (12.58). For example, a-allylation with allylsilanes such as (12.60) can be effected with high ee using CAN as oxidant in the presence of imidazohdinone (12.61) as catalyst, while an a-heteroarylation occurs using N-Boc pyrrole. Furthermore, an asymmetric a-enolation of a range of aldehydes can be achieved by addition of silyl enol ethers such as (12.64). 

As shown in Scheme 17, this alternate approach to 85 woriced beautifully. Thus, adopting an alternate asymmetric reaction as a means to attach the butanone-Iike spacer to 88, this aldehyde was exposed to the indicated (+)-Ipc-derived crotylboration reagent in an event that afforded 133 with complete diastereoselectivity. Subsequent methylation of the newly formed alcohol followed by a Wacker oxidation step then served to create methyl ketone 134. With these steps completing the synthesis of the required four-carbon spacer in 44 % overall yield, the substrate was then treated with LiHMDS and TMSCl to generate a sdyl enol ether (135) in... 

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