Enals strategy

One of the first synthetic applications of organoboranes in radical chemistry is the conjugate addition to enones (Scheme 23, Eq. 23a) and enals reported by Brown [58-61]. Addition to -substituted enones and enals are not spontaneous and initiation with the oxygen [62], diacetyl peroxide [63], or under irradiation [63] is necessary (Eq. 23b). A serious drawback of this strategy is that only one of the three alkyl groups is efficiently transferred, so the method is restricted to trialkylboranes derived from the hydroboration of easily available and cheap alkenes. To overcome this limitation B-alkylboracyclanes have been used but this approach was not successful for the generation of tertiary alkyl radicals [64,65]. 

The thiazole-substituted homoallylic alcohol 25 (Scheme 6) is a key intermediate, not only for RCM strategies, but also for other routes. Thiazole aldehyde 4 (Chapter 3) after homologation to enal 24 (90 % yield) [ 11,20) was subjected to asymmetric allylation with allylboron and tin reagents. Interestingly 25 with identical absolute stereochemistry was synthesized by Nicolaou et al. with (+)-IpC2B(allyl) in 96 % yield and > 97 % ee [13, 20], and by Danishefsky et al. with the enantiomeric (—)-Ipc2B(allyl) in 83 % yield and > 95 % ee [11], i.e. in one case an er-... 

An alternative strategy for preparing cembrene C (27) by this group is described below. The dicarbonyl precursor keto enal 176 was prepared from geraniol... 

Diels-Alder-based strategy (Scheme 18).90 An analogous route has also been explored by Miller et a/.91 who obtained the acetoxy-aldehyde (152) from the Diels-Alder reaction of 3-methylbuta-l,3-dienyl acetate with 2-methylprop-2-enal. Cyclization of (152) with sodium hydride gave the coumarin derivative (153). Unfortunately, cyclization of the corresponding methyl ketone (154) yielded the chromanone derivative (155) and not the methyl analogue of (153). 

A third synthetic route follows the C5 -1- C5 strategy. In principal, ( )-4-acetoxy-2-methylbut-2-enal is on the one hand oxidised to a dialdehyde, and on the other hand, the same precursor is converted into the correspondingphosphoni-um salt. A Wittig reaction of both of these intermediates gives then the desired... 

This section will focus on the generation and utility of azolium enolates using NHC (N-heterocyclic carbene) catalysts. Azolium enolates are commonly accessed from enals, a-functionalized aldehydes, or aliphatic aldehydes in the presence of a stoichiometric oxidant. This section exclusively concentrates on strategies for the generation of azolium enolate intermediates from alternative, bench-stable starting materials (Scheme 7.66). 

In 2009, Dixon and co-workers [73] developed a nice cascade reaction for the synthesis of cyclohexanes using a similar strategy. Malonates (119), nitroalkenes 28 and a, 3-unsaturated enals 15 reacts in a Michael-Michael-aldol reaction sequence forming the cyclohexanes 122 in good yields and stereoselectivities. The reaction... 

Amine Catalysis (Via Iminium Ion Activation). a,p-Unsaturated aldehydes and ketones are common Michael acceptors susceptible to be activated by an amine catalyst via ion iminium formation [64]. This general activation strategy for enals and enones has been applied to aza-Michael reactions with relative success [65]. One complication of the approach is that both the catalyst and the nucleophile are amine species that could mix their preconceived roles and lead to either catalyst... 

The general catalytic cycle presented in Sdieme 5.38 tqtpears a priori as one of the fundamental strategies for designing MCRs (from 3CR enal + electrophile + nucleophile), and relevant contributions have been already described. 

While the preparation of 12 was secured, the preparation of the dienyl side chain 21 was undertaken according to a biomimetic strategy using an aldol condensation of enal 19, which was synthesized from p-nitrobenzaldehyde and propanal. Since this transformation worked superbly for accessing -19, it was tempting to produce , -dienal 23 by iteration, a procedure that was actually described by Suzuki with modest efficiency (Scheme 17). Despite numerous attempts from Matthias to enhance the process, dienal 23 could not be obtained in yield higher than 22%. 

We decided to evaluate our new strategy with azomethine imines [111-116] as a possible reacting partner with homoenolates [117], Contrary to our findings with the p-protonation of homoenolates, the AfW-dimethyl substituted benzimidazole 4 was observed by NMR spectroscopy to interact irreversibly with the secondary electrophile, the starting azomethine imine [118], The more bulky A -mesityl-Ai-methylbenzimidazolium salt 5 was employed in order to sequester this nonproductive pathway (Scheme 11). The use of 20 mol% of this precatalyst in combination with DBU at 40°C catalyzed the reaction between enals and azomethine imines to afford tetrahydropyridazinones as a single diastereoisomer (all cis). A variety of substituents are tolerated on the azomethine imine. It was found that phenyl... 

In 2012, Zhao and coworkers developed an enantioselective strategy for the synthesis of spiroindolenines 94 by a Michael-hemiaminal formation/Pictet-Spengler cascade reaction [54]. The indoles 93 bearing a ketoamido group in 3-position reacted with the enals 16 in the presence of the Jprgensen-Hayashi catalyst (XXIV) to afford the corresponding spiroindolines in excellent yields and enantioselectivities but moderate diastereoselectivities (Scheme 10.33). 

Under similar conditions the reaction between pyrroles and enals affords C-2-alkylated products, giving access to a wide range of compounds of biological interest. This strategy was used in tandem with a ruthenium-mediated cross-metathesis reaction in the synthesis of a nonsteroidal anti-inflammatory drug (—)-ketorolac (eq 7). ... 

Many P-substituted enals such as 29 and (S)-30 (Scheme 3.7) gave the corresponding (S)-alcohols 31 and 32 with excellent stereoselection and in good yields (also in these cases the in situ SFPR strategy was adopted). The products were exploited for the preparation of a wide range of natural bisabolane and bisabolene sesquiterpenes [59,60]. 

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