Seven-membered carbocycles

Seven-membered carbocycles are also available from the reaction of alkenylcarbene complexes of chromium and lithium enolates derived from methyl vinyl ketones [79b] (Scheme 65). In this case, the reaction is initiated by the 1,2-addition of the enolate to the carbene complex. Cyclisation induced by a [1,2]-migration of the pentacarbonylchromium group and subsequent elimination of the metal fragment followed by hydrolysis leads to the final cyclo-heptenone derivatives (Scheme 65). 

The cobalt-catalyzed cooligomerization of diynes with nitriles allows a simple one-step synthesis222 of condensed pyridine derivatives including difficultly accessible 5,6,7,8-tetrahydroisoquinolines223 The synthesis is a versatile one in that pyridines condensed with five- and seven-membered carbocyclic rings can also be achieved in moderate yield in similar fashion. Additional attractive features of this simple synthesis are the formation of condensed isoquinolines by the use of functionalized nitriles and the pronounced regioselectivity observed when dissymmetrical diacetylenes are employed (Scheme 148).222... 

A variety of functionalities, tether lengths, and alkene substitution patterns were tolerated (Equation (35)).52,53 Of particular significance is the synthesis of a-methylene-y-butyrolactone 55, as only Zhang had reported successfully using Alder-ene chemistry to gain access to this novel system (see Section 10.12.4.3). The reaction was sensitive to the length of the tether, since there was a marked decrease in yield for the formation of the six- and seven-membered carbocycles (53 and 54, respectively) compared to the five-membered case 52. 

A method for highly efficient asymmetric cyclopropanation with control of both relative and absolute stereochemistry uses vinyldiazomethanes and inexpensive a-hydroxy esters as chiral auxiliaries263. This method was also applied for stereoselective preparation of dihydroazulenes. A further improvement of this approach involves an enantioselective construction of seven-membered carbocycles (540) by incorporating an initial asymmetric cyclopropanation step into the tandem cyclopropanation-Cope rearrangement process using rhodium(II)-(5 )-N-[p-(tert-butyl)phenylsulfonyl]prolinate [RhjtS — TBSP)4] 539 as a chiral catalyst (equation 212)264. 

Evans and Kennedy later combined the regioselective rhodium-catalyzed allylic alkylation, using a-substituted malonates, with ring-closing metathesis for the construction of five-, six-, and seven-membered carbocycles (Scheme 10.2) [13]. The combination of these methodologies allowed for the rapid and flexible assembly of carbocycles possessing vicinal ternary-quaternary or quaternary-quaternary stereogenic centers. 

Synthesis of 2-amino-4H-pyrans, annulated with five- 201 to seven-membered carbocycles... 

In recent years, a wealth of information has been accumulated on RCM reactions leading to five-, six-, and seven-membered carbocycles and heterocycles, so that it is impossible to refer to all the new, natural-product directed work. Therefore, we will concentrate here on a few selected examples that can illustrate (i) the progress made by the advent of the second generation ruthenium catalysts G-E, (ii) the use of RCM in concert with other innovative methodology, and (iii) the use of RCM in total syntheses of newly discovered natural products, which due to an outstanding biological profile have attracted specific interest from the synthetic community. 

The N-(bicycloalkenyl)nitrone (37) afforded the tetracyclic isoxazolidine (38) in 67% yield none of the regioisomeric isoxazolidine was observed (Scheme 9).17 The authors attributed this to non-bonded C—H interactions as shown, but the observed isoxazolidine was also entropically favored, forming via a six-membered, as opposed to a seven-membered, carbocyclic transition state. The N-(bicycloalkenyl)ni-trone formed from (39) and furfural cyclized in 45% yield predominantly to the tetracyclic product (40b), but some (41b) was also produced (95 5 ratio).18 Reaction of (39) and formaldehyde gave a mixture of (40a) and (41a) (62 38 ratio). The authors attribute the somewhat higher regioselectivity for (40b) in part to non-bonded interaction of the 2-furyl substituted methylene with the C-8 endocyclic C—H bond. 

Nitrones can be generated by Michael reaction of oximes with appropriate conjugated substrates.25 If a generated nitrone has a built-in dipolarophile, cyclization can ensue (Scheme 15). There are three synthetic variations on this theme.25a,b First, the oxime may contain the dipolarophile as in (56). Reaction of (56) with phenyl vinyl sulfone provided a quantitative yield of the tandem product as one stereoisomer. Alternatively, die dipolarophile can reside in the Michael substrate as in (57). Reaction of (57) with cyclohexanone oxime produced two isoxazolidines from competitive cyclization of the intermediate nitrone through six- and seven-membered carbocyclic transition states. It is also possible to carry out an intramolecular Michael addition followed by an intramolecular nitrone cyclization as in thermolysis of (58) to produce a tricyclic isoxazolidine. Very recently several examples of a tandem Diels-Alder, Michael addition, nitrone cyclization sequence have been reported.250... 

The azulene-pyridazine derivative 423 has been obtained by attachment of a seven-membered carbocycle to cyclopentadieno[pyridazine derivatives have been similarly obtained (78H387). As for other peri-annelated heterocycles with... 

A RCM-ROM-RCM strategy was employed as the key step to the synthesis of these alkaloids (Scheme 10). Both alkaloids can be derived from the protected bis-hydropyrrole 31 which is the ring rearranged product from the seven-membered carbocycle 32. Compound 32 can be obtained from the enantiomerically pure triol derivative 33, which in turn can be obtained from commercially available tropone 34.34... 

The guanacastepenes are antibiotics from a rare Costa Rican fungus and have the basic skeleton 35. This has five-, six- and seven-membered carbocyclic rings but there is a hint of Diels-Alder possibilities about it in that ring C is a cyclohexene. In fact Shipe and Sorensen8 chose 36 as a key intermediate but no direct Diels-Alder disconnection looks likely. Does it help if we reconnect to the lactone 37 ... 

Annelation-ring cleavage.1 A bifunctional reagent with an acetal and an allylsi-lane group can be used for annulation of silyl enol ethers to six- and seven-membered carbocycles (equation I).2 The reaction involves conjugate addition to give an adduct that undergoes intramolecular cyclization. 

A notable reaction is that between the pyridinesulfur trioxide complex and sodium cyclopentadienide 298 which forms azulene 299 by a sequence involving opening of the pyridinium ring and subsequent closure to the seven-membered carbocyclic ring. 

Both enantiomers of 116b, through the sequence described in Section 14.04.3.4, led to the enantiomeric pair of the seven-membered carbocyclic nucleosides 129 <1997JOC8948, 1999JOC2304, 2003ARK75>. 

The phenylalanine-derived chiral amine catalyst 10 was used to promote the asymmetric [4-1-3] cycloaddition between 2,5-dialkylfurans and trialkylsilyloxypentadienals to generate seven-membered carbocycles with OTrfo-selec-tivity and 81-90% ee, as represented in Equation (46) <2003JA2058>. However, the absolute configurations of the cycloadducts have not been determined. 

The double bond of the cyclohexene ring reacts first with the catalyst with the release of ring strain in a ROM. Now, depending on where the catalyst is bound, either the five- or the seven-membered carbocycle is formed by RCM. Afterwards the catalyst reacts with one of the two remaining terminal double bonds to form the other ring in a third alkene metathesis reaction. Tricycle 31 is obtained in 43 % yield over three steps. 

The intramolecular reaction of the carbene from diazo ester 280, which contains a 1,3-diene moiety in the ester group and a double bond adjacent to the carbene center, leads to the formation of a substituted 1,2-divinyl-cyclopropane, whose CIS isomer then undergoes a Cope rearrangement to give substituted cycloheptadiene. In such a way, bicyclic 281 and tricyclic 282 y-lactones with a neighboring seven-membered carbocycle have been obtained (89JOC930). 

Figure 4 Diesters which give seven-membered carbocyclic acyloins on reduction. Yields (in brackets), where...

Two strategies are available for the synthesis of seven-membered carbocycles starting with methylenecyclopropanes ... 

Furans in synthesis of seven-membered carbocycles 84AG29. 

The transition-metal-catalyzed intramolecular [5 + 2]-cycloaddition of 154 bearing a heteroatom between an alkynyl and a cyclopropylalkenyl group provides the heterocycles 155 bearing a seven-membered carbocycle (Scheme 53).129 Rhodium and ruthenium complexes have been used as catalysts of this [5 + 2]-cycloaddition. Trost and Shen extended this reaction for constructing the tricyclic heterocycle 157 from 156 (Scheme 54).129i... 

The functionalized oxazofine fused with the seven-membered carbocycle 36 has been found to be a key precursor for the synthesis of calystegines (Scheme 4). It has been obtained from methyl a-D-glucopyranoside (29) by conversion to 30 in 65% overall yield. Compound 30 was oxidized, and reacted with Ph3P=CHC02Et to give the ethyleiuc ester... 

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