MBH reaction intramolecular

Enones with a pendant aldehyde, RC(=0)-CH=CH-(CH2)2-CH0, have been cyclized via an intramolecular MBH reaction in a study of the influence of Michael acceptor stereochemistry on yield.164 Using triphenylphosphine as catalyst, the Z-isomer consistently gave 2.5-8.5 times higher yield of the product (55), using reaction times of 1-3 days. It is unclear whether this is due to the relative accessibility of the /3-positions of the isomers to the nucleophilic catalyst, or differential stability in the enolate intermediates. 

Scheme 5.14 The aldol cycloisomerization by pipecolinic acid and NMI-catalyzed asymmetric intramolecular MBH reaction followed by a kinetic resolution quench .

A modification of this system was also used in intramolecular MBH reactions (also called as aldol cycloisomerization) [71, 74]. In this reaction, optically active pipecolinic acid 61 was found to be a better co-catalyst than proline, and allowed ee-values of up to 80% to be obtained, without a peptide catalyst. The inter-molecular aldol dimerization, which is an important competing side-reaction of the basic amine-mediated intramolecular MBH reaction, was efficiently suppressed in a THF H20 (3 1) mixture at room temperature, allowing the formation of six-membered carbocycles (Scheme 5.14). The enantioselectivity of the reaction could be improved via a kinetic resolution quench by adding acetic anhydride as an acylating agent to the reaction mixture and a peptide-based asymmetric catalyst such as 64 that mediates a subsequent asymmetric acylation reaction. The non-acylated product 65 was recovered in 50% isolated yield with ee >98%. 

Table 5.5 Proline-catalyzed intramolecular MBH reaction of hept-2-endial with and without imidazole additive.

The stereochemistry of the Michael acceptor plays an important role in the efficiency of the phosphine-mediated intramolecular MBH reactions. Enones having (Z)-alkenes (e.g., 83) afforded a higher yield in the desired product than did the... 

Another example of intramolecular MBH reaction has been reported by Drewes et al. In the presence of DABCO, the acrylate ester of salicylaldehyde (230) afforded crystalline coumarin salt 231 (Scheme 1.88). The chloride ion in salt 231 originally comes from the solvent (CH2CI2). Formation of this... 

At the same time, Roush and co-workers reported phosphine-mediated intramolecular MBH reactions of di-activated 1,6-heptadienes 240 and 1,5-hexadienes 241 to provide an attractive synthesis of functionalized cyclohexene 242 and cyclopentene derivatives 243, respectively. They also extended this... 

Keck and Welch have examined the intramolecular MBH reaction of ot, 3-unsaturated esters/thioesters containing an enolizable aldehyde group, under... 

Krishna et al. have developed the first diastereoselective intramolecular MBH reaction of chiral substrates 259 and 260, wherein both aldehyde and... 

Koo et al. have developed an efficient method for the preparation of diverse co-formyl-a,p-unsaturated carbonyl compounds 268 and 273 that relied on the Pb(OAc)4-promoted oxidative ring cleavage of cyclic 1,2-diols 267 and 272, respectively, which in turn can be readily obtained by the 1,2-addition of various nucleophiles to a cx -acetoxy-substituted conjugated cycloalkenones 266 and a-acetoxy cyclohexanone 271. The authors also optimized the conditions for the intramolecular MBH reactions of 268 and 273. The utility of this sequence is demonstrated by the syntheses of chromones 270 and the precursor (274) of the compound containing the 6,8-dioxabicyclo[3.2.1]octane ring (Scheme 1.98). ... 

In addition, we have found that the stereochemistry of the Michael acceptor also plays an important role in the efficiency of phosphine-mediated intramolecular MBH reactions. In all examined cases with PPhs or polymer-supported phosphine as the catalyst, cyclization substrates enones 275 possessing (Z)-alkenes afforded the desired product 276 in a higher yield than ( )-275 under identical conditions (Scheme 1.99). The reason for this difference in reactivity is most likely steric in nature, as substrates where the p-substituent is ds to the electron-withdrawing substituent are more accessible to reaction with the nucleophilic catalyst than their trans counterparts. 

As mentioned above, although some examples of intramolecular MBH reactions have been reported in the literature, this aspect is still in its infancy. Most known reports are based on the cyclizations of combinations of enone-enone, enone-acrylate, enone-aldehyde, unsaturated thioester-aldehyde, enone-allylic carbonate frameworks, etc. More recently, Krafft et al. have developed a novel, entirely organo-mediated intramolecular MBH reaction by using allyl chloride 277 as an alternative electrophile to afford densely functionalized cyclic enones 278. This reaction tolerates modification of the enone and the use of primary and secondary allylic chlorides and generates both five-and six-membered rings in excellent yields. Both mono- and disubstituted alkenes are formed with excellent selectivity in the absence of a transition metal catalyst (Scheme 1.100). ... 

Later on, they also reported an interesting intramolecular MBH reaction of an enone-epoxide system. Opening of the MBH epoxide 281 afforded homologous aldol products 282 efficiently and embodies a C(sp ) Il(sp ) coupling with concomitant cyclization. Scheme 1.102 shows a representative example. ... 

There have been only a few reports on asymmetric versions of the intramolecular MBH reaction Scheme 1.105 shows one representative example. The intramolecular Morita Baylis Hillman reaction has been achieved with unprecedented levels of enantioselectivity by using a co-catalyst system involving pipecolinic acid and iV-methylimidazole cyclic MBH products 289 were... 

Recently, Gladysz et al. have developed an effective chiral rhenium-containing phosphine (294) catalyzed intramolecular MBH reaction of enone-aldehydes 295 in benzene, affording the corresponding adducts 296 in 88-99% yields with 38-74% ee (Scheme 1.107). Notably, the catalyst loadings can be much lower than those required with organophosphines, presumably due to the transition-metal-enhanced phosphorus nucleophilicities. ... 

Most recently, the same authors have reported the enantioselective intramolecular MBH reaction catalyzed by bifunctional phosphinothiourea CP49, which was derived from L-phenylalanine. The process afforded cyclic hydroxyl enones with up to 84% ee and good yields under mild conditions (Scheme 2.136). " ... 

Krafft et al. have described a new and efficient approach to functionalized hetero- and carbocyclic alkenols, which is a successful alternative route to the highly substrate dependent intramolecular MBH reaction. A quinuclidine-pro-moted MBH reaction of alkenyl aldehydes took place to generate the required... 

This chapter excludes the direct transformations of MBH adduct into cyclic compounds. The synthesis of cyclic compounds by intramolecular MBH reactions has also been omitted. 

Acid-promoted lactonization of y-hydroxy esters is an important way to construct lactones. For example, Scolastico and co-workers first reported the lactonization of MBH adducts 213 using 0.7 m HCl in ACOH-H2O, obtaining cx-methylene-p-hydroxy-5-butyrolactones 215a,b in moderate yields (Scheme 4.65). Trifluoroacetic acid, CSA and sulfuric acid were also used in such lactonizations. In an alternative method, ot-methylene-p-hydroxy-8-butyrolactone 215c was synthesized by the intramolecular MBH reaction in 62% yield (Scheme 4.66). A series of a-alkylidene-8-butyrolactones and multi-substituted a-methylene-8-butyrolactones have been synthesized from MBH adducts (Figure 4.2). 

Recently, Santos and coworkers have studied the mechanism of proline-catalyzed and imidazole-co-catalyzed intramolecular MBH reactions by DFT calculations [24]. They first investigated the catalytic path for the MBH reaction of a, 3-unsaturated dialdehyde catalyzed by L-proline in the absence of imidazole, and found that water acted as an important catalyst when imidazole was not present. When imidazole was used as a co-catalyst, water was still important in the imidazole addition step. Their results rationalized the experimental outcome of the intramolecular MBH reaction, and provided theoretical evidence for some mechanistic proposals. 

The Morita-Baylis-Hillman (MBH) reaction is a powerful carbon-carbon bondforming reaction that has found widespread application in organic synthesis. In 2005, Miller and Hong independently reported the highly enantioselective intramolecular MBH reaction. The Miller group applied a combination of (S)-pipecohc acid 79 and N-methylimidazole to catalyze the cychzation of heptenal derivatives 80 in aqueous THF (Scheme 36.21a) [27a]. In contrast, Hong and coworkers used simple L-proline and imidazole as the catalysts (Scheme 36.21b) [27b]. 

---