Twistane synthesis

The final twistane synthesis we will consider originates from the one-bond disconnection indicated by Path D in Unnatural Products-1. Just as with Path A, the synthesis uses a Diels-Alder reaction to establish the bicyclo[2.2.2]octane substructure of key intermediate 9. The cycloaddition of cyclohexadiene 43 and methyl propiolate afforded a mixture of regioiso-meric cycloadducts 44 and 45. Catalytic hydrogenation of the mixture occured from the sterically most accessible face of the olefin to afford meso-compound 46 and its diastereomer 9. Diester 9 was subjected to an acyloin condensation, and catalytic hydrogenation of the resulting a-hydroxyketone gave diol 47. A Corey-Winter reaction was used to convert 47 to 49 via thionocarbonate 48. Catalytic hydrogenation completed the synthesis. 

Synthesis of twistane from a bicyclo[2.2.2]octane precursor... 

Although the disconnection of the "strategic bonds" should be in principle the solution of choice in designing a rational synthesis of twistane (see below, 13.1.2), syntheses based in the disconnection of bonds other than those have also been... 

The first synthesis of an optically pure enantiomeric twistane, reported in 1968 [6], also follows this synthetic route with only slight modifications. 

Although this synthesis provides the most direct entry into the twistane polycyclic structure, the adequate balance between the problem of framework construction and the subsequent functional group manipulations, required by the "principle of maximum simplicity", is missed. However, the synthesis represents without doubt an outstanding contribution to the synthesis of polycyclic non-natural products. 

The synthesis of twistane involving an intermediate of type D was reported in 1976 by Hamon and Young [2]. This synthetic approach constitutes a violation of Corey s rule number 4 (which refers to "perimeter" and "core bonds") and involves a bicyclo[3.3.1]nonane precursor in which the relative configuration of the C(6) side-chain is crucial if cyclisation is to occur. The cost of such a "violation" was relatively high and a great number of drawbacks are found in the original article. 

Synthesis of twistane from cis-decalins. Strategic bond... 

Multistep syntheses based on the earlier work of Whitlock 40,89- have also been developed which enable the preparation of optically active twistane and twistene 91X In the latter case, the method of synthesis... 

Synthesis and Chemistry of Polycyclic Hydrocarbons Related to Adamantane Table 2. Twistane derivatives... 

Intramolecular alkylation of a ketone. The key step in Whitlock s synthesis of twistane " was cyclization of the keto-tosylate with solid NaH in dimethylformamide. 

According to Brewster a net P-helicity (P,P,M,P,M) and a net M-helicity (M,M,P,M,P) can be assigned to P-twistane 3b) and M-twistane 3a), respectively. The first synthesis of optically active twistane has been reported by Nakazaki . He postulated — as did shortly afterwards Tichy — an absolute configuration for (-l-)-twistane, which was corrected later by Tichy as follows (-l-)-5Z corresponds to iR,3R,6R,8R), )-3b corresponds to (1S,3S,6S,8S) But even today there are some uncertainties with respect to the absolute configuration in the twistane series . Numerous aliphatic and heterocyclic molecules having helical twistane skeletons have been synthesized and characterized stereotopologically. Some of them are shown in Table 5 together with some chiroptical data. 

Intramolecular acylation. This reaction is the key step in a new synthesis of the twistane ring system By a Canadian group.14 The starting material, decalin-2,7-dione (3), can be prepared easily in quantity by hydrogenation of 2,7-dihydroxynaphthalene to a mixture of isomeric diols (2) and chromic acid oxidation of the mixture.15 16 Treat-... 

C2 symmetry), a high-symmetry chiral cage-shaped tricyclic hydrocarbon closely related to D2 twistane. Wagner-Meerwein rearrangement (144) of the unsaturated carboxylic acid (-)-151 provided the lactone (-)-168, which in turn was converted into the ketone (+)-170 via a series of intermediates, including the mesylate 169 whose intramolecular alkylation was a crucial step in this approach. Removal of the carbonyl group by Wolff-Kishner reduction completed the synthesis of (+)-brexane (171) (145). 

A synthesis involving a Level 2 process is Deslongchamps synthesis of twistane (155), outlined in Scheme 10.1 1. Treatment of 152 with sodium hydride in dioxane gave 153. and intramolecular displacement of the mesylate gave 4-twistanone, 154. The two reacting groups are brought into proper position by the transannular nature of the cyclization. 

The first synthesis of a tricyclo[4.3.1.0 ]decane, namely of pure carbocyclic iso-twistane [G 2 X(2) = CHj, Y(7) = CHj ], was reported by Vogt S in 1968. Almost at the same time 2,7-dihetero-isotwistanes (G 2) and/or derivatives thereof became available. Today a variety of such compounds are known ... 

For the synthesis of 2,7-dihetero-twistanes by bridging a suitable heterobicyclononane with a second heteroatom, only three pathways (N—P) were applied so far, whereby... 

The synthesis of the twistane-ketal 279 using endo-6-hydroxy-9-oxabicyclo[3.3.1]-nonan-2-one (274) or its acetate 227, resp., was nevertheless successful by applying the following route according to a procedure by Inhoffen etal. the keto-acetate 221 was treated with trimethyl orthoformate. From the reaction mixture which contained the dimethoxy-ketals 222 and 223 as well as the enolethers 224 and 225, the acetates 222 (63%) and 224 (5%) were isolated by chromatography. On base-hydrolysis they gave the alcohols 223 and 225. Pyrolysis of the ketal 222 and simultaneous distillation yielded 67% of the enolether 224. Finally by treating the dime-... 

The subsequently applied synthetic scheme was analogous to the one for the corresponding racemic compounds (see 2.2.2.I., 3.2.3. and 3.2.4.). Treatment of the (—)-alcohol 379 with iodine in chloroform yielded the (-)-10° -iodide 383 as sole product. Its reaction with silver tosylate in acetonitrile led to a mixture of 10°(7).tosyloxy-isotwistane 384 and -twistane 386, which was directly treated with LiAlH4 in refluxing dioxane to give a mixture, easily separable by vpc., of (—)-2,7-dioxa-isotwistane 385 [oc]d = —23.3 0.7°) and (-)-2,7-dioxa-twistane 387, see Table 8). The absolute configuration of 387 [(—)-( R, 3R, 6R, 8R), right-handed helix (P)] and of all other compounds involved in its synthesis was determined by chemical correlation with (—)-(2S)-malic acid (559). As relais compounds served the endo-2-hydroxy-9-oxabicyclo[3.3.1]nonanes +)-390 and (—)-J97, (-t)-5-hydroxy-cyclooct-l-ene [ +)-392] and the 4-methoxy-suberic acid dimethylester —) 393 and +)-394. 

We now turn our attention to the terminating synthesis routes discovered by SYNCHEM after a total of approximately twenty minutes of search time (Fig. 6). The twistane ring system was first prepared by Whitlock in 1962 and other syntheses have since been published. Conceptually, the computer discovered all of these approaches, but due to presently severe limitations on our reaction library, they differ in details. SYNCHEM s syntheses need to be further refined by a knowledgeable chemist before they could be considered useful. 

An add-bond strategy via an overbred skeleton offers the possibilities (a) and (b) shown in Scheme 13.31. Choice (a) suggests an intramolecular photocycloaddition between a cyclobutene and a cyclohexene—not really attractive. Choice (b) indicates a well precedented cyclopropanation reaction, that was indeed used [29] to realize a quick synthesis of twistane. However, this faced the problem of the regioselective cleavage of a distinct cyclopropane bond. 

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