Cyclopentane, trans-1,2-disubstituted

The viscidanes exhibit an antipodal configuration at C7 compared to the bisabolane, serrulatane and decipiane diterpenes. This difference may reflect the involvement of a 3/ ,6 -acyclic precursor (211), or 3S,6E-, which cyclizes to the lS,7/ -intermediate (212) (Scheme 51). A 1,2-hydride shift with displacement of X would generate the tertiary carbocation (213) which could alkylate the Re-facc of CIO. The spiro-ring system produced (214) contains the 1,4-trans-disubstitution on the cyclopentane ring observed for the viscidane nucleus. A 1,5-hydride shift of the quasi-a ial allylic hydrogen in 214 and allylic rearrangement, with net yn-addition of water, completes the elaboration of the nucleus. Circumstantial support for the last step can be enlisted... 

Silylcarbocyclization of Dienes. The Pd-catalyzed silylcarbocyclizations of 1,6- and 1,7-dienes (30,41-49) have been extensively studied. The reaction of dimethyl diallylmalonate 33 with EtsSiH catalyzed by [(phen)PdMe(0Et)2]" "-BAr4 gave trans-disubstituted cyclopentane 34 in 93% yield (Scheme 17) (41). 

In the ring closures of the 1,2-disubstituted 1,3-difunctional cyclohexane, cycloheptane, and cyclooctane derivatives discussed in Sections II,A,B, and C, no appreciable differences were found in the reactivities of the cis and trans isomers. In contrast, very significant differences were observed in the cyclization reactivities of the cis and trans 1,2-disubstituted 1,3-difunctional cyclopentane derivatives, such as 1,3-amino alcohols, 2-hydroxy-l-carboxamides or /S-amino acids. Whereas the cis isomers reacted readily, their trans counterparts did not undergo ring closure in most cases. This difference was manifested in the formation of both d - and e -fused derivatives. 

The use of 13C-NMR spectroscopy in stereochemical assignment of disubstituted cyclopentanes has been investigated using dimethylcyclopentanes and mcthylcyclopentanols495. In 1,2-disubstituted derivatives the chemical shifts of the substituted and the methyl carbons are significantly smaller (2 to 5 ppm) in the cis than in the trans series. In 1,3-disubstituted cyclopentanes the sequence is the same, but the differences are often so small that a reliable assignment is possible only if both isomers are available. 

Thus, the hydroboration of 1-phenylcyclopentene with (—)-IpcBH, (99% produces, after crystallization, the chiral organoborane 126 with 94% ee. The reaction of 126 with Et2BH replaces the isopinocamphenyl group with an ethyl substituent (50 C, 16 h) and provides, after the addition of i-Pr2Zn (25 °C, 5 h), the mixed diorganozinc 127. Its stereoselective allylation leads to the fraw5-disubstituted cyclopentane 128 in 44% yield (94% ee trans cis = 98 2) see Scheme 43 ° . This sequence can be extended to open-chain alkenes and Z-styrene derivative 129 is converted to the anf/ -zinc reagent 130, which provides after allylation the alkene 131 in 40% yield and 74% ee (dr = 8 92). 

Although the fate of the zinc ligands was not unambiguously ascertained, it appeared clearly that palladium to zinc transmetallation occurred prior to cyclization. Indeed, palla-dium-ene reactions are known but generally require higher temperatures and, when run in association with a subsequent Stille cross-coupling, trans- 1,2-disubstituted cyclopentanes were generated (equation 81)115,116. 

Michael intramolecular alkylation. The reaction of f-butyl lithioacetate (1) with ethyl 6-iodo-2-hexenoate 2 in the presence of potassium t-butoxide in THF at - 78° results in a single trans-1,2-disubstituted cyclopentane (3). Reaction of 2 with f-butyl lithiopropionate (4) under the same conditions results mainly in syn-5, but when HMPT is also present anti-5 is mainly formed. Similar stereoselectivity is observed in reaction of 1 and 4 with ethyl 6-iodo-2-heptenoate in formation of... 

Cyclization of dienes.3 Cp2Zr also promotes cyclization of 1,6-dienes to trans-1,2-disubstituted cyclopentanes. Thus 1,6-heptadiene (1) on treatment with Cp2Zr followed by bromination affords the trans-dibromide 2. In contrast, use of a related reagent, Cp ZrCl (Cp = pentamethylcyclopentadienyl), effects cyclization to the isomeric ds-dibromide (equation I). Electrophiles other than bromine can... 

Cyclization of trienes.1 In combination with 2,2-bipyridyl (bpy), an iron(O) species prepared by reduction of iron(III) 2,4-pentanedionate with A1(C2H5)3 (3 equiv.) promotes cyclization of trienes (1) in which a 1,3-diene unit is tethered to an ally lie or homoallylic ether group. vic-Disubstituted cyclopentanes or cyclohexanes are formed, and the cisltrans disposition of the substituents is controlled by the geometry of the allylic double bond. Thus (Z,E-)1 is cyclized to trans-2, whereas (E,E)-1 is cyclized to cis-2. 

In disubstituted cyclopropanes, cyclobutanes and cyclopentanes, assignment of configuration, cis or trans, is made with respect to a plane through the molecule. Cyclopentanes and most cyclobutanes are not planar, but this does not pose a significant problem. Cyclohexanes are also non-planar. Using the above method it can take a while to decide whether the relative configurations of some disubstituted cyclohexanes are cis or trans. For these compounds we employ an alternative method based on dihedral angles. 

Hashimoto and coworkers have reported a highly diastereo- and enantioselective synthesis of 1,2-disubstituted cyclopentanes 53 that also avoids competing 1,2 hydride migration with appropriate choice of catalyst (Fig. 4) [68], Phthalimide-based Rh2(5-PTTL)4 (29a) was found to be the optimal catalyst for insertion into the benzylic position of the precursors to 53, and was effective for both electron poor and electron rich systems. The diastereoselectivity for the 1,2 cis product was excellent as long as the reaction was conducted at -78 °C, and enantioselectivities of up to 95% were achieved. An additional example demonstrated that insertion into a fully aliphatic position could also proceed with high ee (94%), but the resulting product was the trans diastereomer. 

The alkylidene-1,3-dicarbonyl moiety is also a highly reactive enophile. Thus, the Knoevenagel adduct (223) obtained from aldehyde (222) and dimethyl malonate in the presence of piperidinium acetate, cy-clizes by treatment with Lewis acids such as FeCb on AI2O3 exclusively to the rranr-substituted cyclohexane (224 trans.cis > 99.5 0.5 Scheme 44).7 °3 The sesquiterpene veticadinol (225) has been synthesized in enantiomerically pure form by this method.Contrary to the expectation, rranr-sub-stituted cyclopentanes can also be obtained with excellent induced and noninduced dia-stereoselectivities. Similarly, aldehydes containing an allylsilane moiety can be used for a highly stereoselective formation of rran.r-l,2-disubstituted cyclopentanes and cyclohexanes by a Knoevenagel... 

Simple model studies show that substitution at C-l or C-3 of the 5-hexenyl radical gives mainly c/.v-disubstituted cyclopentanes, whereas substitution at C-2 or C-4 leads mainly to tran.v-disub-stituted cyclopcntanes. A variety of theoretical treatments L 2 and experimental results now aid in the planning of highly stereoselective reactions, and allow predictions according to Beckwith s guidelines. 

The ene reaction where both partners are simple alkenes is quite useful when the partners are linked so as to provide for an intramolecular ene reaction. There is a preference for the formation of cw-disubstituted cyclopentane and frans-disubstituted cyclohexane systems resulting from thermally induced, intramolecular ene reactions. For example, levels of transjcis control of 92 8 to > 99 1 were found for the intramolecular cyclization of methyl 2-cyano-9-methyl-3,8-decadienoate23 24. Furthermore, the same tran. -stereochemical relationship was obtained when the reaction was carried out at room temperature in the presence of zinc(II) bromide with control consistently at the 99 1 level for R and R2 either methoxycarbonyl or cyano groups24, This preference for trans fusion does not appear to be greatly altered by added substituents on the chain connecting the reacting partners (vide infra). 

It is noteworthy that the ring closures of 1,2-disubstituted cyclohexane, cycloheptane and cyclooctane derivatives revealed no appreciable differences in the reactivities of the cis and trans isomers in the formation of six-membered 1,3-heterocycles [117]. In contrast, striking differences were observed in the cyclizations of the cis and trans cyclopentane derivatives. For instance, the above cyclizations to pyrimidinones, starting from the trans counterparts, were unsuccessful. The attempted ring closure from 104 did not result in the cyclized products, but gave hydrolysed derivatives 105 and 106 [111]. 

As an extension of hydrosilylation of alkenes, cyclization-hydrosilylation of 1,6-dienes occurs by the reaction with HSiRs [23]. The cationic complex 37, generated in situ from (phen)Pd(Me)Cl and NaBAr4, is an active catalyst, catalyzing the reaction of dimethyl diallylmalonate (36) with HSiCl3 to give the disubstituted cyclopentane 38 with 98% trans selectivity in 92% yield [24]. A mechanism different from that of usual hydrosilylation, which postulates formation of H-Pd-SiR3 and hydropalladation of alkene, was proposed by Widenhoefer... 

Molecules of cyclobutane, cyclopentane, and cyclohexane are nonplanar. Besides determining configuration at each carbon atom in these compounds, conformational aspects of the whole molecule should also be considered. Figure 2.15 shows the most stable conformations of rings in these molecules. Of course, such molecules can also exist in any intermediary conformations between those shown. In monosubstituted rings of cyclobutane, cyclopentane, and cyclohexane there is no asymmetric carbon atom. In disubstituted isomers of these cyclic compounds, optical activity can appear even if the substituents are identical. The cis forms will not be optically active in any case since they exist in meso form. On the other hand, the trans forms will be optically active (they occur as two... 

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