A,P-Unsaturated enol esters

Total Synthesis of (—)-7-Deoxyloganin Exploiting N-Heterocyclic Carbene Catalysis with a,p-Unsaturated Enol Esters... 

Prior to this study, the NHC-catalyzed rearrangement had never been attempted on a,p-unsaturated enol esters in which the a-position was substituted (as in enol ester 51). To overcome the lack of reactivity we proposed that a less bulky, but highly electron rich, Af-alkyl-substituted NHC might allow access to the required reactivity. Thus, tetramethyl NHC 12, which had previously been observed to activate unreactive substrates when used stoi-chiometrically, was trialed. Using 40 mol% of 12, pyranone 52b, along with diastereomeric 52b, were isolated in 40% yield in a 2 1 ratio (Table 2, entry 3). Pleasingly, formation of the desired diastereoisomer 52b was favored, however, the low yield suggested the catalyst was unable to turn over. When 30 mol% N-isopropyl catalyst 60 was trialed, cyclopenta[c]pyran 52b was... 

Candish L, Lupton DW (2010) The Total Synthesis of (-)-7-Deoxyloganin via N-Heterocy-clic Carbene Catalyzed Rearrangement of a, P-Unsaturated Enol Esters. Org Lett 12 4836... 

Scheme 18.33 Rearrangement of a,P-unsaturated enol esters, according to Lupton and coworkers.

Carbonyl transposition.1 Tetrafluoroboric acid is the most effective acid for rearrangement of a-hydroxy ketene dithioketals to a,p-unsaturated thiol esters. This rearrangement is particularly useful for rearrangement of the tertiary allylic alcohols formed by addition of organometallic reagents to a-keto ketene dithioketals, which are readily available by reaction of ketone enolates with carbon disulfide followed by alkylation with methyl iodide. 

Section 1.1.1 described the formation of enolates, silyl enol ethers and enamines and their alkylation reactions. An alternative type of alkylation occurs on addition of these nucleophiles to electrophilic alkenes, such as a,p-unsaturated ketones, esters... 

Based on our experiences with the NHC-catalyzed synthesis of dihydropyra-nones, we thought it conceivable that ot,p-unsaturated enol ester 51a could be converted to the iridoid cyclopenta[c]pyran core (i.e., 52a) (Scheme 11). In turn, it was envisaged that the required unsaturated enol ester 51a could be prepared via acylation of methyl formyl acetate (53a) with enantioenriched acyl chloride 54. The NHC-catalyzed rearrangement would only prove viable if it proceeded with chemoselectivity, due to the presence of additional ester functionality in enol ester 51a, and stereoselectively, to provide the correct diastereomer of 52a for the natural product. Although it was unclear whether these selectivities could be achieved, or whether the reaction would proceed with substrates annulated about the a,p-unsaturation, it was envisaged that this study would, at the very least, allow the limitations of the NHC catalysis to be examined. From the iridoid core 52a, completion of the total synthesis would require the chemo- and stereoselective reduction of the lactone to the lactol, followed by glycosylation. 

Hayashi and Miyaura pioneered the enantioselective rhodium-catalyzed conjugate addition of arylboronic acids to a variety of Michael acceptors a,P-unsaturated ketones, esters, lactones, amides, and lactams [215]. Generally, water is used as a cosolvent and plays a key role in the catalytic cycle, illustrated in Scheme 5.111 (cycle A) for the conjugate addition of phenylboronic acid to cyclohexenone that, when catalyzed by the Rh(I)-(S)-BINAP complex, leads to 3-phenylcyclohexanone in 97% ee and 93% chemical yield [205a]. The key intermediates of the catalytic cycle, the hydroxorhodium complex 433, the phenylrhodium complex 434, and -bound rhodium enolate 435 were characterized by NMR spectroscopy. The reaction of the hydrorhodium complex 433 with phenylboronic acid leads to a transmetallation to give the phenylrhodium complex 434. Then, the insertion of the carbon-carbon double bond of cyclohexenone into the phenylrhodium bond leads to the formation of the... 

Activation of C-X Bonds. Even more important than carbonyl activation, ZnBr promotes substitution reactions with suitably active organic halides with a variety of nucleophiles. Alkylation of silyl enol ethers and silyl ketene acetals using benzyl and allyl halides proceeds smoothly (eq 13). Especially useful electrophiles are a-thio halides which afford products that may be desulfurized or oxidatively eliminated to result in a,p-unsaturated ketones, esters, and lactones (eq 14). Other electrophiles that have been used with these alkenic nucleophiles include Chloromethyl Methyl Ether, HC(OMe)3, and Acetyl Chloride... 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

Besides ordinary esters (containing an a hydrogen), the reaction can also be carried out with lactones and, as in 16-38, with the y position of a,p-unsaturated esters (vinylogy). There are also cases, where the enolate anion of an amide was condensed with an aldehyde. ... 

Nitroalkenes react with lithium dianions of carboxylic acids or with hthium enolates at -100 °C, and subsequent treatment of the Michael adducts with aqueous acid gives y-keto acids or esters in a one-pot operation, respectively (Eq. 4.52).66 The sequence of Michael addition to nitroalkenes and Nef reaction (Section 6.1) provides a useful tool for organic synthesis. For example, the addition of carbanions derived from sulfones to nitroalkenes followed by the Nef reaction and elimination of the sulfonyl group gives a,P-unsaturated ketones (Eq. 4.53).67... 

Conversion of ketone 80 to the enol silane followed by addition of lithium aluminum hydride to the reaction mixture directly provides the allylic alcohol 81 [70]. Treatment of crude allylic alcohol 81 with tert-butyldimethylsilyl chloride followed by N-b ro m o s u cc i n i m i de furnishes the a-bromoketone 82 in 84 % yield over the two-step sequence from a.p-unsaturated ester 80. Finally, a one-pot Komblum oxidation [71] of a-bromoketone 82 is achieved by way of the nitrate ester to deliver the glyoxal 71. It is worth noting that the sequence to glyoxal 71 requires only a single chromatographic purification at the second to last step (Scheme 5.10). 

Evans et al. (219, 220) examined the use of electron-poor heterodienes as partners in cycloadditions with electron-rich alkenes under copper catalysis. In particular, a,p-unsaturated acylphosphonates and keto-esters afford hetero-Diels-Alder adducts in high selectivities when treated with enol ethers in the presence of catalysts 269c and 269d. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

In a closely related reaction, silyl enol ethers add to a,p-unsaturated ketones and esters when catalyzed459 by TiCl,, e.g.,460... 

N-Metalated azomethine ylides generated from a-(alkylideneamino) esters can exist as tautomeric forms of the chelated ester enolate (Scheme 11.8). On the basis of the reliable stereochemical and regiochemical selectivities described below, it is clear that the N-metalated tautomeric contributor of these azomethine ylides is important. Simple extension of the above irreversible lithiation method to a-(alkylideneamino) esters is not very effective, and cycloadditions of the resulting lithiated ylides to a,p-unsaturated carbonyl compounds are not always clean reactions. When the a-(alkylideneamino) esters bear a less bulky methyl ester moiety, or when a,P-unsaturated carbonyl compounds are sterically less hindered, these species suffer from nucleophilic attack by the organometallics, or the metalated cycloadducts undergo further condensation reactions (81-85). 

Enol esters.1 In the presence of (CgHn Ru and P(Bu)3 in the molar ratio 1 2, a,p-unsaturated acids add to terminal alkynes to form enol esters as the major product. 

Similarly, organolithiums (or Grignard reagents) add to ester (26) to afford silyl enolates which are intercepted with aldehydes and ketones to give a,p-unsaturated esters (27),434 while addition of the bifunctional aryllithium (28) (MIRC protocol) affords the 2-(trimethylsilyl)tetrahydronaphthoate ester (29 Scheme 7).43b... 

Corriu and coworkers have reported an alternative procedure for the conjugate addition of ketones to a.P-unsaturated acceptors which employs CsF-(RO)4Si (Scheme 56) 126 this procedure affords adducts with a,3-enones, oc.fj-unsaturated esters and a,3-unsaturated amides. Mechanistically, silyl enol ether formation occurs initially, followed by fluoride ion catalyzed enolate formation. 

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