Enals cyclic

Fig. 16 [3 -I- 2] cycloaddition reactions of cyclic nitrones with enals catalyzed by 29a...

Homoenolate Reactivity The ability to generate homoenolates from enals and its application to the preparation of y-butyrolactones 30, through reaction with an aldehyde or aryl trifluoromethyl ketone, was reported independently by Glorius [8], and Bode and Burstein [9] (Scheme 12.4). A sterically demanding NHC catalyst is required to promote reactivity at the d terminus and to prevent competitive benzoin dimerisation. Nair and co-workers have reported a similar spiro-y-lactone formation reaction using cyclic 1,2-diones, including cyclohexane-1,2-dione and substituted isatin derivatives [10]. 

Bode and co-workers have used NHCs to form y-butyrolactams 34 from enals 27 and saccharin-derived cyclic sulfonylimines 32. A range of [3-alkyl and [3-aryl substituted enals, and a variety of substituted imines, are tolerated in this reaction,... 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

NHC-promoted enolate formation from an enal, followed by a desymmetrising aldol event to generate P-lactones and loss of CO, has been exploited by Scheidt and co-workers to generate functionalised cyclopentenes 240 in high ee from enal substrates 238 (Scheme 12.52) [94]. Interestingly, the use of alkyl ketones in this reaction manifold allows the isolation of the p-lactone intermediates with acyclic diketones, P-lactones 239 are formed with the R group anti- to the tertiary alkox-ide, while with cyclic diketones the P-lactone products have the R group with a syn relationship to the alkoxide [95]. 

The enantioselective catalytic 1,3-dipolar cycloaddition of linear or cyclic nitrones to enals was accomplished using the half-sandwich rhodium(III) complex S, Rc)-[(ri -C5Me5)Rh (/ )-Prophos (H20)](SbF6)2 as catalyst precursor [33, 34]. At —25°C, quantitative conversions to the cycloadducts, with up to 95% ee, were achieved (Scheme 10). The intermediate with the dipolarophile coordinated to the rhodium has been isolated and completely characterized, including the X-ray determination of its molecular structure [33, 34]. 

Triethylammonium hydrogen fluorides (Et,N - nHF complexes, n = 4 6) allow the fluorocyclization of unsaturated aldehydes such as 2,6-dimethylhcpt-5-enal (7) to livc-mem-bered cyclic fluoro alcohols, such as 8 and 9 (yields 55-81 %).39s... 

Generally, two stereoisomers are formed however, the diastereomer 8 is always favored [ratio (8/9) 83-93 17-7 dependent on the fluorinating agent], Fluorocyclizations of alk-6-enals to six-membered cyclic fluoro alcohols proceed less stereoselectively. 

It is noticeable that neither the most commonly used less acidic triethylamine tris(hydrogen fluoride) nor the more acidic Olah s reagent (70% HF/pyridine) lead to the generation of a cyclic fluoro alcohol from 2,6-dimethylhept-5-enal (7).395... 

Although the use of cyclic enals improved the overall product distribution by suppressing the 1,4-addition pathway,33 34 a general solution remained elusive. To solve the competing reaction pathway problem or to improve the pathway that would ultimately lead to the 2H-pyran 33 involved extensive experimental modifications. Our solution eventually involved the utilization of preformed a,P-unsaturated iminium salts instead of generating them in situ.35-38... 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

Scheme 82 Cycloisomerization of alkynyl allyl alcohols to cyclic enals [148]...

The synthesis of complex polycyclic molecules has been achieved by Montgomery et al. by cascade cyclization processes involving nickel enolates [40]. Up to three cycles could be generated in the intramolecular version of the reaction. Alkynyl enal or enone were first converted into their corresponding seven-membered cyclic enolates in the presence of Ni(cod)2/TMEDA [41 ]. These species could be trapped by electrophiles such as aldehydes. For example, upon treatment with the nickel catalyst, dialdehyde 32 afforded spiro-cycle 35 in 49% yield as a single diastereomer (Scheme 17). 

Thiosalicylaldehydes afford chiral thiochromene-3-carbaldehydes 39 on reaction with a,P-unsaturated aldehydes catalysed by a chiral pyrrolidine silyl ether. Initial activation of the enal triggers sequential Michael and aldol reactions and dehydration completes the highly enantioselective synthesis <06JA10354, 06TL8547>. In a similar manner, cyclic enones afford cycloalkanone[ ]thiochromenes <06TL8679>. 

Most chiral organoboron Lewis acids reported to date are based on an organoborane that is attached to a chiral organic moiety such as a diol, aminoalcohol, or other readily available chiral substrates.Organoboron derivatives recently used as catalysts in enantioselective Diels-Alder reactions include the family of chiral acyloxyboranes (CAB) with (196) and (197) as representative examples and various cyclic boronic esters such as (198) and (199). An interesting system that combines the favorable Lewis acid properties of fluorinated arylboranes with a chiral Bronsted acid has been developed by Ishihara and Yamamoto. The Bronsted acid-assisted chiral Lewis acids (BLA) (200) was found to be highly effective in enantioselective cycloadditions of Q ,jS-enals with various dienes. The presence of the Bronsted acid functionality leads to significant acceleration of the reaction. 

Decomposition of cyclic hydroperoxides. Cyclohexyl hydroperoxide (1) is decomposed mainly to (E)-2-hexenal by this salt and a trace of FeSO -VHaO in a two-phase system of water and an organic solvent. Highest yields (58%) are obtained with nitrobenzene. Na2PdCl4 is the most satisfactory water-soluble eomplexof PdX, for this purpose. The reaction is general, but yields are low from Cg-Ci2 cyclic hydroperoxides. Cyclopentyl hydroperoxide is converted into the corresponding enal in 73.6% yield. 

Another important example of the Michael addition in biochemistry and molecnlar biology is the reaction of 4-hydroxynon-2-enal with amines and snlfydryl gronps (Winter, C.K., Segall, H.J., and Haddon, W.F., Formation of cyclic addncts of deoxygnanosine with the aldehyde trans-4-hydroxy-2-hexenal and fran.y-4-hydroxy-2-nonenal in vitro. Cancer Res. 46, 5682-5686, 1986 Sayre, L.M., Arora, P.K., Iyer, R.S., and Salomon, R.G., Pyrrole formation from 4-hydroxynonenal and primary amines, Chem. Res. Toxicol. 6, 19-22, 1993 Hartley, D.P, Ruth, J.A., and Petersen,... 

DIBAL-H has often proved effective in 1,2-reduction of enones and the ate complex generated with n-butyllithium is a powerful and selective reducing agent, which has been used in toluene-hexane to reduce cyclic enones and in toluene-THF to reduce acyclic examples. 1-Pyrrolylborane-THF complex, which may be prepared from pyrrole and borane-THF, is a reactive aminoborane and has been used to reduce enones and enals to the corresponding allylic alcohols, but its scope remains to be established. "... 

The Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

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