Ring-closing approach

The Diels-Alder reaction can be used to create rings in many situations that would be difficult to accomplish by ring closing approaches. Consider product P. This product can be made by a Diels-Alder reaction between diene D and acrylate A. 

In a reiterative approach, enol ether epoxidation with DM DO has been coupled with C-C bond fonnation and ring-closing metathesis to provide trans-fused THP ring systems [82],... 

With a-monosubstituted ylides the oxidation results in the formation of alkenes (by subsequent Wittig reaction on the intermediate aldehyde). A recent example of such synthesis is found in the preparation of all-(Z)-cyclododecate-traene by oxidation of the appropriate bis-ylide [33]. It must be pointed out that an approach of the same macrocycle based on ring closing metathesis was found ineffective. 

Close approaches of arene. solvents to metalloporphyrins have been observed by crystallography. For example. Mn(TPP) crystallizes as a toluene. solvate with a toluene solvent molecule lying on either side of the porphyrin plane. The dihedral angle between the porphyrin plane and toluene plane is 10.7 (reduced to 6.7 for one of the pyrrole rings). The average perpendicular distance between the toluene ring and the mean 24-atom plane of the porphyrin is 3.30 A. One aromatic C—C bond of toluene approximately eclipses one N—Mn—N axis, with IVln- C distances of 3.05 and 3.25 There has been considerable effort invested in the... 

Until now, the most efficient approach to synthesize Freidinger lactams 147 started from a resin-bound cinnamylamine 144. A Fukuyama-Mitsunobu reaction to 145 followed by sulfonamide cleavage and a consecutive appropriate acylation built up the diene 146, which underwent ring-closing metathesis involving Grubb s catalyst 123 to generate the desired lactams 147 (Scheme 27, Table 5) [35d]. 

In a more recent approach, the same group synthesized macrocycles using a Passerini reaction followed by a ring-closing metathesis [23], but the final cycliza-tion gave only low yields. 

High oxidation state alkylidene complexes in which a heteroatom is bound to the alkylidene carbon atom are extremely rare [41]. Since the approach shown in Eq. 43 failed, the related approach shown in Eq. 44 was taken to prepare the medium-sized ring subunits [222]. The latter product was formed in good yield when n=2, R H, R2=Et, but only poor yield when n=2, R =Et, R2=H, possibly due to unfavorable interactions between the ethyl substituent and transannular groups in the transition state for cyclization of the allyl ether [222]. Ruthenium catalysts either failed or gave low yields, presumably because of the steric hindrance associated with ring-closing dienes of this type. 

The ring-closing metathesis (RCM) approach is useful for the synthesis of indolizidinone derivatives. The procedures published are based on the use of compound 103, an amide of a pyrrolidine derivative bearing on C-l the second unsaturated branch ready for the cyclization. The reaction proceeded smoothly with high yields in both examples (Scheme 27) <2001JOC9056, 2004JOC3968>. 

The most common bicyclic 5-6 system with one bridgehead N-O and one extra heteroatom described in the period covered in this chapter has been the diketopiperazine derived from proline as it is present in natural products, in biologically active synthetic molecules, and has been used as starting material for the preparation of conformationally constrained peptidomimetics. The classical approach to this class of molecule is the ring closing of the dipeptide derived from proline and another amino acid via nucleophilic attack of the NH2 to the activated carboxylic group. This method has been applied several times to prepare different diketopiperazines for different uses. 

Smalley et al. reported the synthesis of the cyano-containing keto ester 98 by reaction of o-azidobenzoyl chloride 97 with cyanoacetic ester in the presence of triethylamine. This keto ester was then heated in acetonitrile for 30 min and gave the ring closed product 99 which was isolated in the fully aromatic tautomeric form 100 <1997S773>. A similar approach to tetrazolo[l,5- ]quinolines has been applied by a Korean research group in this case a reflux of the cyano-azido compound 101 for a longer period was needed in order to accomplish the cyclization to 4-acetoxymethyl-tetrazolo[l,5- ]quinoline 102 <2003JHC1103>. 

Vercek and co-workers described an effective approach to some 3-cyano-4-amino[l,2,3]triazolo[l,5-tf]pyrazines starting from the N-substituted triazole derivatives 396 <2002H(56)353>. This compound when treated either with acetic acid or triethylamine gave rise to the ring-closed products 397 in acceptable yield (55-66%). 

Ring closure to the 5//-tetrazolo[5,l-t][l,3]oxazine skeleton has been reported by Hoornaert and co-workers <1996T8813>. These authors treated variously substituted 2,4-dichloro[l,4]oxazin-2-ones 133 with sodium azide. The fused tetrazoles 135 obtained were formed via the formation of their azide valence bond isomer intermediate 134. A similar approach proved to be suitable for the benzologues of these compounds. Thus, the benzoxazinone compounds 136 gave the tricyclic ring-closed tetrazoles 137. Both reactions yielding 135 and 137 proceeded in high yields (80-90%). 

Novel bicyclic imidazo-oxazaphosphinines have been synthesized in high diastereoselectivity by Marsault and Just <1996TL977>. In the first step, iV-tritylimidazole 209 was lithiated and, subsequently, treated with (.S )-propylcnc oxide as a chiral auxiliary and acetic acid to give the intermediate 210, which was reacted with alkyl dichlorophos-phite to yield the ring-closed product 211 as a single diastereomer (Scheme 33). Extension of these approaches for further derivatives 212 has also been published <1998NN939>. 

Scheme 4.71 Iterative ring-closing glycosylation approach to mannooctulsonic acid derivatives.

Scheme 13 Ring-closing metathesis approach for the synthesis of Cl-glycals.

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