Homopropargylic

A similar allyl [91] or propargyl [92] Reformatsky reagent has been used to prepare fluormated homoallylic or homopropargylic alcohols, respectively [91, 92] (equations 60 and 61)... 

These mesylates, in turn, can be converted to enantioenriched allenyltin, zinc, and indium reagents which add to aldehydes with excellent diastereo-and enantioselectivity to afford either syn- or anti-homopropargylic alcohols or allenylcarbinols (eq 2, 3, and 4).3 4 Adducts of this type serve as useful intermediates for the synthesis of polyketide and hydrofuran natural products.5... 

Vinyl cations probably are involved as intermediates in the solvolysis of homopropargyl derivatives, 46, extensively investigated by Hanack and coworkers (75-79). The products of reaction are cuclobutanones, 47, cyclo-... 

Formation of rearranged products in the solvolysis of homopropargyl systems need not involve triple-bond participation and vinyl cations in all instances. Ward and Sherman investigated the formolysis of 4-phenyl-1-butyn-l-yl brosylate, 57 (80). At 80°C in the presence of one equivalent of pyridine, they observed formation of phenyl cyclopropyl ketone, 58, and... 

Extended Hiickel calculations have been carried out on the 1-cyclopropylvinyl cation 156 (122). These results show that the most favorable conformation for this ion is the linear bisected structure 156a. However, Hanack et al. (166b), by means of a modified CNDO technique, calculate the most stable geometry of the intermediate ion resulting from homopropargyl participation to be a bridged cyclobutenyl cation rather than 156a. 

It is also difficult to determine exactly the relative stabilities of vinyl cations and the analogous saturated carbonium ions. The relative rates of solvolysis of vinyl substrates and their analogous saturated derivatives have been estimated to be 10 to 10 (131, 134, 140, 154) in favor of the saturated substrates. These rate differences, however, do not accurately reflect the inherent differences in stability between vinyl cations and the analogous carbonium ions, for they include effects that result from the differences in ground states between reactants, as well as possible differences between the intermediate ions resulting from differences in solvation, counter-ion effects, etc. The same difficulties apply in the attempt to estimate relative ion stabilities from relative rates of electrophilic additions to acetylenes and olefins, (218), or from relative rates of homopropargylic and homoallylic solvolysis. 

Besides short ELPS, longer ELPs have also been conjugated to synthetic polymers. In one approach, Cu(I)-catalyzed azide-alkyne cycloaddition click chemistry was applied. For this purpose, ELPs were functionalized with azides or alkynes via incorporation of azidohomoalanine and homopropargyl glycine, respectively, using residue-specific replacement of methionine in ELP via bacterial expression [133]. More recently, an alternative way to site-selectively introduce azides into ELPs was developed. Here, an aqueous diazotransfer reaction was performed directly onto ELP[V5L2G3-90] using imidazole-1-sulfonyl azide [134]. 

In the case of terminal alkynes having oxygenated functions in the linear chain (Scheme 10, route D), Martin, Padron, and coworkers found that homopropargylic alcohols reacted properly, yielding 2-substituted dihydropyrans as sole products, probably via a Prins-type cyclization. This cyclization provides a new approach toward 2-alkyM-halo-5,6-dihydro-2//-pyrans through a concomitant C-C and C-O bond formation (Scheme 21) [35]. 

Scheme 22 Coupling of secondary homopropargylic alcohols and aldehydes promoted by iron (III) halides...

As an extension of this work, the same authors explored such methodology for the synthesis of 2,6-disubstituted dihydropyrans using secondary homopropargylic alcohols (Scheme 10, route E). Surprisingly, the treatment of pent-4-yn-2-ol and 3-methylbutanal in the presence of FeCls led to unsaturated ( )-(3-hydroxyketone and ( )-a,p-unsaturated ketone in 2.5 1 ratio and 65% yield, without any trace of the expected Prins-type cyclic product (Scheme 22) [36]. To test the anion influence in this coupling, FeCE and FeBrs were used in a comparative study for the reaction of pent-4-yn-2-ol (R = R" = H, = Me) and several aldehydes. A range of aldehydes except for benzaldehyde was transformed into unsaturated (3-hydroxy-ketones in moderate to good yields. 

Several ways to suppress the 2-oxonium-[3,3]-rearrangements might be envisioned. Apart from the introduction of a bulky substituent R at the aldehyde (Scheme 23) a similar steric repulsion between R and R might also be observed upon introduction of a bulky auxiliary at R. A proof-of-principle for this concept was observed upon by using of a trimethylsilyl group as substituent R in the alkyne moiety (Scheme 25, R = TMS). This improvement provided an efficient access to polysubstituted dihydropyrans via a silyl alkyne-Prins cyclization. Ab initio theoretical calculations support the proposed mechanism. Moreover, the use of enantiomerically enriched secondary homopropargylic alcohols yielded the corresponding oxa-cycles with similar enantiomeric purity [38]. 

In furtherance of these smdies, the reaction scope was broadened by employing homopropargylic amines to give the corresponding aza-cycles (Scheme 26) [39, 40]. Hence, the alkyne aza-Prins cyclization between homopropargyl tosyl amines... 

Scheme 23 Proposed mechanism for the addition of secondary homopropargylic alcohols to...

Scheme 25 Silyl alkyne-Prins cyclization of secondary homopropargylic alcohols and aldehydes using FeXs as a promoter...

Scheme 26 Synthesis of 2-aikyl-4-halo-1 -tosyl-1,2,5,6-tetrahydropyridines from A-tosyl homopropargyl amine and aldehydes using FeX3 as promotor...

A plausible mechanism for this new alkyne aza-Prins cyclization is outlined in Scheme 27. Thus, reaction of the homopropargyl tosyl amine with an aldehyde promoted by ferric halide generates the W-sulfonyl iminium ion. This intermediate evolves to the corresponding piperidine, via the vinyl carbocation. Ah initio theoretical calculations support the proposed mechanism. 

Cyclization to six-membered rings (Eq. 15) provided modest diastereoselectivity and required the use of bulkier PhMeSiH2 to prevent olefin hy-drosilylation. Propargyl and homopropargyl amines 94 afforded a variety of heterocycles (Scheme 21), if the catalyst was added slowly over the reaction course to diminish side reactions resulting from metal coordination to the basic amine [56]. The reaction procedure was extended to the diastereoselect-ive bicyclization of dienyne substrate 95, giving 96 as product in a cascade fashion (Eq. 16) [57]. 

Intramolecular nucleophilic additions by nitrogen functional groups onto pendant alkynes and allenes represent an important class of type la approaches to functionalized pyrroles. A platinum-catalyzed (PtCl4) cyclization of homopropargyl azides provided an entry to 2,5-disubstituted pyrroles and 4,5,6,7-tetrahydroindoles (fused pyrroles) <06OL5349>. 

Scheme 63 Mn-catalyzed allylmagnesation, alkylmagnesation, and phenylmagnesation of homopropargyl and propargyl alcohol derivatives as well as allenes.

Synthetic transformations of the products of the intramolecular bis-silylation have been examined. The five-membered ring products derived from homopropargylic alcohols were hydrogenated in a stereoselective manner (Scheme ll).90 Oxidation of the products under the Tamao oxidation conditions (H202/F /base)96 leads to the stereoselective synthesis of 1,2,4-triols. This method can be complementary to the one involving intramolecular bis-silylation of homoallylic alcohols (vide infra). 

Interestingly, the [RuCl2(p-cymene)]2 catalyst used for selective synthesis of (Z)-vinylsilanes produces instead the a-vinylsilanes with appropriately positioned hydroxyl groups.57 For the homopropargylic system shown (Scheme 12), the selectivity is 98 2. For propargylic or bishomopropargylic systems, only small amounts (2-13%) of the a-product... 

An alternative disconnection of homopropargylic alcohols substrates for intramolecular hydrosilylation is the opening of an epoxide with an alkynyl anion. This strategy was employed in a total synthesis of the macrolide RK-397 (Scheme 20). Epoxide ring opening serves to establish homopropargylic alcohol C with the appropriate stereochemistry. A hydrosilylation/oxidation protocol affords the diol E after liberation of the terminal alkyne. The... 

The final cyclization manifold has been realized with a different ruthenium catalyst (Scheme 22). The cationic [Cp Ru(MeCN)3]PF6 induces exclusive endo-dig cyclization of both homopropargylic and bis-homopropargylic alcohols.29 73 The clean reaction to form a seven-membered ring is noteworthy for several reasons intramolecular exo-dig cyclization with bis-homopropargylic alcohols is not well established, the platinum-catalyzed case has been reported to be problematic,80 and the selectivity for seven-membered ring formation over the exo-dig cyclization to form a six-membered ring is likely not thermodynamic. The endo-dig cyclization manifold was thus significant evidence that a re-examination of alkyne hydrosilylation mechanisms is necessary (see Section 10.17.2). 

The positive charge in 28 is stabilized by /j-cr-C-C-hyperconj ligation with the C-C-ring bonds of the two cyclopropyl moieties. In the parlance of VB theory this is described by resonance of 28 with non-bonding resonance limiting structures, the homoallenyl cation type structure 28a, the homopropargyl cation type structure 28b and the Dewar-type limiting resonance structure 28c. 

Closely related to both allyl carbenoids and the allenyl carbenoids discussed above, propargyl carbenoids 101 are readily generated in situ and insert into zirconacycles to afford species 102 (Scheme 3.27), which are closely related to species 84 derived from allenyl carbenoids [65], Protonation affords a mixture of allene and alkyne products, but the Lewis acid assisted addition of aldehydes is regioselective and affords the homopropargylic alcohol products 103 in high yield. Bicydic zirconacyclopentenes react similarly, but there is little diastereocontrol from the ring junction to the newly formed stereocenters. The r 3-propargyl complexes derived from saturated zirconacycles are inert towards aldehyde addition. 

In the case of nonracemic homopropargylic ether 17, hydrozirconation/carbonylation was followed by exposure of the intermediate to molecular iodine (Scheme 4.12) [39]. The ( )- and (Z)-forms of the acyl iodide presumed to be formed in situ were seemingly in equilibrium under the reaction conditions and intramolecular attack followed by dealkylation afforded (S)-(+)-parasorbic acid. 

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