Cycloisomerization acetals

Another useful class of palladium-catalyzed cycloisomerizations is based on the general mechanistic pathway shown in Scheme 13. In this chemistry, a hydridopalladium acetate complex is regarded as the catalytically active species.27b-29 According to this pathway, coordination of a generic enyne such as 59 to the palladium metal center facilitates a hydropalladation reaction to give intermediate 60. With a pendant alkene, 60 can then participate in a ring-form-... 

Scheme 13. Trost s hydridopalladium acetate catalyzed cycloisomerization chemistry.

Scheme 14. Trost s approach to [3.3.3]propellane 67 by hydridopalladium acetate-catalyzed sequential cycloisomerization.

In addition to the reactions discussed above, there are still other alkyne reactions carried out in aqueous media. Examples include the Pseudomonas cepacia lipase-catalyzed hydrolysis of propargylic acetate in an acetone-water solvent system,137 the ruthenium-catalyzed cycloisomerization-oxidation of propargyl alcohols in DMF-water,138 an intramolecular allylindination of terminal alkyne in THF-water,139 and alkyne polymerization catalyzed by late-transition metals.140... 

Silane reduces the palladium acetate in 119 to the palladium hydride 120, which undergoes reductive elimination to provide the organic product and the catalytic Pd(II) species. This mechanistic hypothesis was supported by the use of EtsSiD as the reductant product was formed with D incorporation at only the methyl group [70]. This reaction is best performed with a Pd(0) precatalyst in the presence of acetic acid and 10 eq. of silane, which suppresses the competitive cycloisomerization reaction [70]. 

The ruthenium-based reaction conditions were, however, demonstrated to be acidic in acetone. Tandem acetal hydrolysis was observed in the cycloisomerization of 56 (Equation (36)) and unexpected 1,5-diene 59 arose from the... 

The Diels-Alder reaction outlined above is a typical example of the utilization of axially chiral allenes, accessible through 1,6-addition or other methods, to generate selectively new stereogenic centers. This transfer of chirality is also possible via in-termolecular Diels-Alder reactions of vinylallenes [57], aldol reactions of allenyl eno-lates [19f] and Ireland-Claisen rearrangements of silyl allenylketene acetals [58]. Furthermore, it has been utilized recently in the diastereoselective oxidation of titanium allenyl enolates (formed by deprotonation of /3-allenecarboxylates of type 65 and transmetalation with titanocene dichloride) with dimethyl dioxirane (DMDO) [25, 59] and in subsequent acid- or gold-catalyzed cycloisomerization reactions of a-hydroxyallenes into 2,5-dihydrofurans (cf. Chapter 15) [25, 59, 60],... 

The first example involving a rhodium catalyst in an ene reaction was reported by Schmitz in 1976. An intramolecular cyclization of a diene occurred to give a pyrrole when exposed to rhodium trichloride in isobutanol (Eq. 2) [15]. Subsequently to this work, Grigg utilized Wilkinson s catalyst to effect a similar cycloisomerization reaction (Eq. 3) [16]. Opplozer and Eurstner showed that a n -allyl-rhodium species could be formed from an allyl carbonate or acetate and intercepted intramolecularly by an alkene to afford 1,4-dienes (Eq. 4). Hydridotetrakis(triphenylphosphine)rhodium(l) proved to be the most efficient catalyst for this particular transformation. A direct comparison was made between this catalyst and palladium bis(dibenzylidene) acetone, in which it was determined that rhodium might offer an additional stereochemical perspective. In the latter case, this type of reaction is typically referred to as a metallo-ene reaction [17]. 

C-H activation pathway cannot be ruled out for this transformation, however. They subsequently observed C-H insertion of a cis substituent by means of isotope studies [32], The cycloheptene product was observed as the major product when cis- or tri-substituted enyne and acetylenic ester termini were present. Ruthenium hydride catalysts reported by Mori and Dixneuf can also initiate the cycloisomerization of 1,5- and 1,6-enynes and dienes [33, 34], The vinylruthenium hydride can be obtained from RuClH(CO)(PPh3)3 or in the presence of acetic acid or ethanol. 

Jt-allyl complex can be generated after cyclization, as suggested by Takacs in a Fe(0)-catalyzed cyclization of polyenes. It also can be preformed if an active functional group is present in the allylic position. The palladium-catalyzed intramolecular cycloisomerization reaction of allylic acetates is an efficient method for constructing five- or six-membered rings [56, 57]. An asymmetric approach to this transformation has been studied and so far only poor enantioselectivity has been achieved (0-20% ee) [58]. Very recently, Zhang et al. also reported a Rh-catalyzed cycloisomerization involving a Jt-allylrhodium intermediate formed from an allylic halide [59]. 

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%. 

This cascade proved to be quite complex, successively involving a [3,31-sigma-tropic shift of the propargyl acetate, 1,2 migration of this acetate, and cycloisomerization (Scheme 3.47). 

Cycloisomerization of allyl propargyl ethers takes place under mild conditions when performed with a ruthenium hydride catalyst obtained from Cp RuCl(COD) in the presence of acetic acid or ethanol. 3,4-Dialkylidenete-trahydrofurans were produced in good yields [ 71 ] (Eq. 53). It is noteworthy that the C-H and C-C bonds formed are always syn. This is the result of the cis addition of the Ru-H bond to the C=C bond. 

Yet another palladium-catalyzed transformation leading to 1,2-dialkyl-idenecycloalkanes was established by Trost et al. when investigating a catalytic Alder-ene reaction (path D in Scheme 12). They showed that two different catalyst systems are capable of cycloisomerizing enynes 92 to either cyclic 1,4-dienes 96—the products of regular Alder-ene reactions— or the 1,3-dienes 95 (Scheme 15) [66-68]. Starting from palladium acetate, the reaction presumably occurs by coordination of both unsaturated moieties (intermediate 93) and subsequent cycloisomerization to the ring-... 

In the following scheme, the benzo[Z>]furan core of antibiotic erypoegin H was built up by a PtCL-catalyzed cycloisomerization of or// o-alkynylphenyl-0,(9-acetals <07AGE4760>. A similar type of reaction was applied to the syntheses of 2,3-disubstituted bcnzo b furans <07T8670>. A metal-catalyzed cyclization was also used in the syntheses of 5,6-disubstituted furo 2,3-c/]pyrimidines from alkynyl-pyrimidinols and aryl iodides <07T1931>. 

An asymmetric synthesis of aminocyclopentitols 134-137 has been used in the synthesis of trehazolin via free-radical cycloisomerization of enantiomerically pure, alkyne-tethered oxime ethers derived from D-mannose (Scheme 17).84 Treatment of 2,3 5,6-di-(9-isopropylidene-D-mannofuranose (128)85 with ethynylmagnesium bromide gave compound 129, which underwent sequential one-pot acid hydrolysis plus diol cleavage to give 130, oximation of which afforded the radical precursor 131, in 41% overall yield from 129. The free hydroxyl group of 131 was protected as acetate 132 and tert-butyldimethylsilyl ether 133, which were isolated as inseparable... 

However, the transannular reactions are also highly sensitive toward even minimal conformational changes within the substrate. Thus, attempts to perform analogous cycloisomerizations with ethyl 2-(5-cyclopropylidene-4-methylcyclooctylidene)acetate (the 4 -methyl derivative of compound 22) or l-cyclopropylidene-5-(l-methylethylidene)cyclooctane (a geminal dimethyl derivative of 24) have been unsuccessful. ... 

Transformation of 1,2,4-aIkatrienes into cyclopentadienes is catalyzed by PtCl2 at room temperature. Cycloisomerization to break up an acetal unit and re-add the 0/C bonding partners to a conjugated triple bond has been observed. 

Equation 26 illustrates the rare enyne cycloisomerization process which is feasible under relatively mild conditions (in acetic acid at 80 °C for 6 h) in the presence of a palladium (0) catalyst. In the presence of EtAlCl2, alkenes undergo ene reactions with 2-(dialkoxyphosphinoyl)propenoic esters (equation 27 " ) the same catalyst, and other Lewis acids, catalysed the intramolecular reactions of 385 and 386 ( = 0 or 1), which are exemplified by reaction 28 . 

Preparation of an useful synthon, the cyclic carbamate of L-daunosaminal (104), was achieved by sequential catalytic transformations of a key intermediate. Suitably protected propargyl diol 101, which was obtained by diastereoselective addition of allenyl stannate 99 to 0-benzyl (S)-lactyl aldehyde 100, was transformed as depicted in Scheme 18. Cycloisomerization to 3-deoxyglycal 103 was achieved by irradiation in the presence of tungsten hexacarbonyl, and subsequent nitrene insertion was catalyzed by rhodium acetate. Overall yield of the bicyclic daunosaminal (104) derivative from lactic acid derivative amounted to 44% [78]. 

The cycloisomerization of 1,6-enynes proceeds smoothly in the presence of AcOH or HCO2H and the reaction is explained by the following mechanism (hydridopalladium acetate mechanism) [45]. Most importantly, oxidative addition of AcOH to Pd(0) generates H-Pd-OAc 143, and the cyclization of 1,6-enynes starts by insertion of the triple bond to 143 to afford the alkenylpalladium 144. Subsequent intramolecular insertion of the double bond gives the alkylpalladium 145. The termination step is (i-R elimination and either the diene 136 or 138 is formed with regeneration of H-Pd-OAc. It should be noted that the alkenylpalladium 144 is a similar species formed in a Heck reaction by oxidative addition of alkenyl halide to Pd(0). Based on this reaction, alkyne is a useful starter in domino cyclization of polyenynes. 

A range of cyclization and cycloisomerization reactions of enynes, including enynes with heteroatoms in the skeleton, have been reported for which the possibility of Pd(IV) intermediates has been canvassedJ f t t A typical example is shown in Scheme 16, where supporting ligands at palladium include palladacyclopentadienes, acetate, acetate/PPhj, and acetate/P(o-tol)3. An alternative pathway involving a Pd(0)-Pd(II) cycle has been acknowledged (Scheme 16), and different reaction conditions may favor each pathwayJ Alkylidene complexes as intermediates have also been proposed for some reactions of enynes... 

Recently, Alcaide and co-workers have disclosed the Pd-catalyzed domino cycloisomerization/cross-coupling of ot-allenols and MBH acetates. As shown in Scheme 4.88, several types of spiroheterocycles bearing a 2,5-dihydro-furan ring were synthesized in moderate to good yields. 

The corresponding reaction of but-3-yn-l-ols or pent-4-yn-l-ols with primary or secondary alcohols in the presence of catalytic amounts of Ph3PAuBF4 and p-TsOH afforded tetrahydrofuranyl ethers (Scheme 4-76). This tandem 5-endo-cycloisomerization/hydroalkoxylation proceeds via 2,3-dihydrofurans, which then undergo an intermolecular Bronsted acid-catalyzed addition of the external alcohol. The transformation is not restricted to internal alkynols but can be applied to terminal acetylenes as well. Application of the method to the s thesis of bicyclic heterocycles with a P-lactam structure was reported recently.Under the same conditions, epoxyalkynes undergo a sequence of epoxide opening, 6-exo-cycloisomerization, and nucleophilic addition to afford tetrahydropyranyl ethers. In a closely related transformation, cyclic acetals were obtained from alk-2-ynoates bearing a hydroxy group in 6- or 7-position by treatment with AuCU and MeOH. ... 

The cycloisomerization of a- or (3-hydroxyallenes can also be carried out in water, for example with tetrachloroauric acid as catalyst. This system was used for the first example of a tandem lipase/gold-catalyzed transformation. The one-pot kinetic resolution/cycloisomerization of racemic allenic acetates with Burkholderia cepacia lipase (PS Amano SD Amano Enzyme USA Co., Ltd., Elgin, IL) and HAuCU afforded 2,5-dihydrofurans as well as unreacted starting material with 28-50% isolated yield and 86-98% ee (Scheme 4-96). The mutual tolerance of the Lewis-acidic gold catalyst with the Ixwis-basic lipase is maintained as long as low amounts of the former are used. 

Tris( dibenzylideneacet one) dipalladium I acetic acid Cycloisomerization of enynes... 

An in. sZ/w-generated [HPdOAc] species induces enyne cycloisomerization more effectively than does Pd(OAc)2 (cf. Synth. Meth. 41, 671), which in certain respects may prove over-reactive and easily deactivated. E Startg. enyne added to 2.5 mol.% (dba)3Pd2 CHCl3 and 5 moh% acetic acid in benzene, and worked up after 2h at room temp. product. Y 86% (69% with added tri-o-tolylphosphine). Interestingly, cyclohexane ring closure may be performed from 1,7-enynes, and O-allyl functions remain unaffected (as may not be the case with Pd(OAc)2). F.e., and with asym. induction using chiral carboxylic acids, s. B.M. Trost et ah. Tetrahedron Letters 30, 651-4 (1989). 

Propargyl acetates (51) have been shown to be converted into lactones (52) in a reaction catalysed by Pt(IV), as a result of 6-enrf< -dig cycloisomerization in the first step. Interestingly, analogous reaction catalysed by HAUCI4 prefers the 5-exo-dig route (see below). 

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