Acid-promoted Cycloadditions

Use of allylsilanes as 1,2-dipole equivalents is valuable also for the construction of six-membered rings. f3-Oxyaldehydes undergo Lewis acid-promoted cycloadditions with allylsilanes to provide substituted tetrahydropyrans (Equation (52)). 3 A similar [4 + 2]-cycloaddition of /V-/-butoxycarbonyl-0,Ar-acetals is available for the synthesis... 

It is proposed that these cycloadditions are also reactions of the alkyne triplet state, and this seems reasonable in the light of the non-concerted nature of the reaction indicated by the fact that dimethyl acetylenedicarboxylate gives a mixture of the same four stereoisomers of the bicyclohexane product with either cis- or /ra i5-but-2-ene (equation 44) . This is in contrast to the stercospecific nature of the Lewis acid promoted cycloaddition of alkenes and alkynes to give cyclobutenes . ... 

Among many Lewis acid-promoted cycloadditions Diels-Alder reactions have been most widely investigated to date. Simple silicon Lewis acids such as la do not, unfortunately, catalyze the standard Diels-Alder reaction of acrylate and cyclopenta-diene. Accordingly, silicon Lewis acids are generally not very suitable for the related cycloaddition reaction. Few reports on silicon Lewis acid-promoted cycloaddition reactions are thus shown herein. 

The cycloaddition using allylsilanes as 1,2-dipole equivalents is apphcable to fhe construction of six-membered rings. j5-Oxyaldehydes as well as u-oxyaldehydes undergo Lewis acid-promoted cycloaddition with allylsilanes to provide substituted THP derivatives in moderate yields (Scheme 10.190) [509]. When N-t-butoxycarbo-nyl-O,N-acetals are used as the substrates, silylated oxazinones are obtained as major products [510]. In this reaction the t-butoxycarbonyl group adds to a /7-silyl-carbenium ion intermediate for ring-closure. 

The Denmark laboratory has developed an elegant tandem [4 + 2]/[3 + 2]-cyclo-addition strategy for the synthesis of a variety of alkaloid natural products (96CR137). Nitroethylene (166) readily undergoes a Lewis acid promoted cycloaddition with vinyl ethers that contain a chiral auxiliary group to give nitronates 168... 

Scheme 8.10 Lewis acid-promoted cycloaddition of VDCPs with aldehyde.

The synthesis of the projected W-acyliminium ion precursor (208) began with a cycloaddition between cyclohexenone (202) and 1,3-butadiene. This acid-promoted cycloaddition initially gave the m-cycloadduct, but the acid also promoted epimerization of the ring juncture to a thermodynamic 9 1 mixtrue of products from which 203 was isolated in reasonable yield. Reduction of 203 occurred with the expected axial delivery of hydride to provide largely 204. A Mitsunobu reaction gave succinimide 205. 

As the examples in Scheme 16.18 illustrate, one of the problems with cycloadditions that are not promoted by Lewis acids is that the isolation of the nitronate intermediate after the [4 + 2] step is not always possible. Lewis-acid promoted cycloadditions often allow for the isolation of the nitronate because such [4 + 2] cycloadditions usually proceed at temperatures too low for the nitronate to react further. Moreover, the nitronate is usually the strongest Lewis base in the reaction mixture. Thus, the nitronate successfully competes for the Lewis acid (which is used stoichiometrically) and becomes deactivated toward the [3 + 2] cycloaddition step. The [3 + 2] cycloadditions of... 

High-pressnre promoted cycloadditions of nitroalkenes and enol ethers eliminate the nse of Lewis acids fEq 8 106 "Thus, even sterically hmdered nitroalkenes react with 2,3-thhydro-furan to give the exo cyclic nitronates stereoselecdvely without using Lewis acids... 

Denmark and coworkers have found that methylaluminum bis (2,6-di-tert-butyl-4-methyl-phenoxide) (MAD) or methylaluminum bis(2,6-diphenylphenoxide) (MAPh) is effective as the Lewis acid promoter for cycloaddition of 2,2-disubstituted 1-nitroalkenes (Eq. 8.100).158 Other Lewis acids such as SnCl4, TiCl4, and TiCl2(Oi-Pr)2 fail to promote the cycloaddition of 2,2-disubstituted 1-nitroalkenes. The products are converted into 3,3-disubstituted pyrrolidines via hydrogenolysis.158 Reductive cleavage of N-0 bonds produces oxime hemiacetals, which are further reduced to amido aldehydes and finally to pyrrolidines. This reaction provides a useful synthetic method for pyrrolidines, which is discussed later. 

The strategy based on tandem cycloaddition leads to a short and efficient asymmetric synthesis of the pyrrolizidine necine base (-)-hastanecine, as shown in Scheme 8.32.163 Pyrrolizidine alkaloids have a long history for attracting the interest of synthetic chemists because of their physiological properties. The method of Denmark shown in this scheme is very simple and applied to synthesis of various alkaloids. The Lewis acid-promoted [4+2] cycloaddition between 2-acyloxy nitroalkene and chiral vinyl ether gives a nitronate that... 

The simplest nitroalkene, nitroethene, undergoes Lewis acid-promoted [4+2] cycloaddition with chiral vinyl ethers to give cyclic nitronates with high diastereoselectivity. The resulting cyclic nitronates react with deficient alkenes to effect a face-selective [3+2] cycloaddition. A remote acetal center controls the stereochemistry of [3+2] cycloaddition. This strategy is applied to synthesis of the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine (Scheme 8.33).165... 

The synthesis of (+)-crotanecine is accomplished in 10 steps in a 10.2% overall yield, as shown in Scheme 8.42. The key step in the asymmetric synthesis is a Lewis acid-promoted, tandem inter [4+2]/intra [3+2] cycloaddition between a (fumaroyloxy)nitroalkene and chiral [J-silylvinyl ether, in which the substituted silanes are used as hydroxy synthons.181... 

Dicyclohexyl ether [Brpnsted acid promoted ketone reduction, symmetrical ether], 123 Diels-Alder cycloaddition-cycloreversion pathway, alkene to alkane reductions, trisubstituted alkenes, 39-40 3,5-Dimethyl-1 -cyclohexen-1 -yl... 

Cycloadditions and cyclization reactions are among the most important synthetic applications of donor-substituted allenes, since they result in the formation of a variety of carbocyclic and heterocyclic compounds. Early investigations of Diels-Alder reactions with alkoxyallenes demonstrated that harsh reaction conditions, e.g. high pressure, high temperature or Lewis acid promotion, are often required to afford the corresponding heterocycles in only poor to moderate yield [12b, 92-94]. Although a,/3-unsaturated carbonyl compounds have not been used extensively as heterodienes, considerable success has been achieved with activated enone 146 (Eq. 8.27) or with the electron-deficient tosylimine 148 (Eq. 8.28). Both dienes reacted under... 

The Lewis acid-promoted [4+ 2]-cycloaddition reaction of the allenic ester 103 having a camphor-derived chiral auxiliary with cydopentadiene provided the adduct with excellent Jt-facial selection, leading to an enantioselective synthesis of (-)-/l-san-talene [92]. 

The reaction of allenylsilanes with a,/8-unsaturated acylsilanes presents a new [3 + 3]-cycloaddition approach to a six-membered carbocycle [189]. Lewis acid-promoted ring expansion of the [3 + 2]-annulation product 260 is followed by a second cationic 1,2-silyl migration to produce the cyclohexenone 261 after desilylation. 

Our preliminary experiments have provided the first example of Lewis acid promoted C-C bond heterolysis of epoxides and productive cycloaddition (eq 7). Under the influence of TiCl4-(THF)2 (2 equiv), epoxide 26 reacts with methyl pyruvate to provide acetal 27 (52% isolated yield), along with C-O cleavage product 28 (23 °C, 3 h). The diaste-reoselectivity for formation of 27 is 2.3 1. We have performed the analogous reaction in the absence of a Lewis acid the thermal reaction requires several days at 110 °C and gives a diastereomer ratio (dr) of ca. 1.3 1... Although not optimized from the standpoint of chemoselectivity, these results are promising because of the relatively low reaction temperature and potential for enhanced diastereocontrol. 

Lewis acid-promoted [3+2] cycloadditions of aziridines and epoxides proceeding via carbon-carbon bond cleavage of three-membered ring heterocycles are demonstrated for the first time. This proposal details plans for extending these initial results into a general synthetic method for the enantioselective synthesis of structurally diverse pyrrolidine- and tetrahydrofuran-containing organic compounds. Expected outcomes of the proposed work will include... 

The reaction of vinyl ethers and enamines with nitroalkenes is highly regiose-lective, with only the head-to-head adduct observed. The endo approach of the dienophile is preferred in the thermal cycloaddition, however, the mode of approach can be controlled by the choice of the Lewis acid promoter (214). Facial discrimination has been obtained by the use of chiral groups on the both the nitroalkene (215,216) and the enamine (217) or vinyl ether (218), as well as with chiral Lewis acids (46,66,94,219,220). 

The synthesis of fenozan BO-7 4 involves two key steps, the first of which employs a 4 + 2 cycloaddition of singlet oxygen to the diene 83a122-20 123. This provides the endoper-oxide 83b that can be transformed into the target cis-fused 1,2,4-trioxane by treatment with the Lewis acid, TMSOTf, in the presence of a carbonyl compound. The reaction proceeds by Lewis acid promoted heterolysis of the C—O bond to give an intermediate peroxy allyl cation 83c that is captured by the carbonyl compound (in this case, cyclopen-tanone) to give the product (Scheme 30). A number of different carbonyls have been used in this reaction along with a number of different endoperoxide templates and detailed SAR have been developed (Scheme 30). 

The 2 + 2-cycloaddition reaction of a-alkoxyketene-derived imines yields /l-lactams with quaternary stereogenic centres at C(4).33 The 2 + 2-cycloaddition of chiral aminoketenes with chiral imines yields cis-fi-lactams with the absolute stereochemistry of file C(3) and C(4) positions being controlled by the ketene partner only.34 The 2 + 2-cycloaddition of ketenes with (W)-2-/-butyldihydrooxazole (19) yields predominately the regioisomer (20) from steric control rather than the expected electronic control (Scheme 7).35 The double 2 + 2-cycloaddition reaction between ketenylidenetriphe-nylphosphorane (21) and carbon suboxide (22) produces the bis(ylidic) spirocyclobut-anedione (23) (Scheme 8).36 Semiempirical and ab initio calculations have been used to investigate the Lewis acid-promoted 2 + 2-cycloaddition leading to the formation of jS-lactones.37... 

The Lewis acid-promoted tandem inter[4 + 2]/intra[3 + 2]-cycloaddition of the (fumaroyloxy)nitroalkene (124) with the chiral /i-silylvinyl ether (125) is the key step in the total synthesis of (+)-crotanecine (126), the necine base of a number of pyrrolizidine alkaloids (Scheme 46).237 The tandem inter[4 + 2]/intra[3 + 2]-cycload-ditions of nitroalkenes (127) with dipolarophiles attached to the /f-carbon of a vinyl ether (128) provides a method of asymmetric synthesis of highly functionalized aminocyclopentanes (129) (Scheme 47).238 trans-2-( 1 -Methyl-phenylethyl)cyclohex-anol has been developed as a new auxiliary in tandem 4 + 2/3 + 2-cycloadditions of nitroalkenes.239 The scope and limitations of the bridged mode tandem inter-[4 + 2]/intra[3 + 2]-cycloadditions involving simple penta-1,4-dienes are described in detail.240 A tandem intermolecular/intramolecular Diels-Alder cycloaddition was successfiilly used to synthesize a B/C cA-fused taxane nucleus (130) in 50% overall... 

The SnCLrpromoted 2 + 1-cycloaddition of l-seleno-2-silylethene with 2-phos-phonoacrylates yields highly functionalized cyclopropanephosphonic acid ester products.271 The Lewis acid-promoted 2 + 1-cycloadditions of l-(phenylseleno)-2-(trimethylsilyl)ethene with tris(alkoxycarbonyl)olefins yields civ-substituted cyclopropanes exclusively.272... 

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