Twistanes

Fujikura, Y. Inamoto, N. Takaishi, and H. Ikeda, Synth. Comm., 1976, 6, 199. 

Inamoto, N. Takaishi, Y. Fujikura, K. Aigami, and K. Tsuchihashi, Chem. Letters, 1976, 631. 

Full details have now appeared of a previously reported synthesis of iceane.  

Finally, a solvolytically initiated 7T-route ring closure to a protoadamantyl cation has been found to give minor amounts of protoadamantyl products (Eq.(25))84 . 

Twistane derivatives (tricyclo [4.4.0.03 8 ] decanes) may be prepared in one step from the readily available ds-decal in-2,7-dione (Eq. (26)) 85, 86.  

The functional groups of the resulting l-acetoxy 5-twistanone may be selectively removed, enabling the preparation of a wide variety of 1- 86 87 and 4- 8S) substituted twistanes by conventional techniques. Table 2 summarizes all twistane derivatives which have been reported. 

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 

Pyrolysis of the sodium salt of the tosylhydrazone of 10-bicyclo[5.2.1 ]deca-none provides a remarkably easy synthesis of tricyclo [5.2.1.0 4 10] decane 

The optically active endo-bicyclo-octene aldehyde (800), prepared by standard reactions from (798) via (799), is converted on u.v. irradiation into the cyclic ether (801) which can be reductively cleaved regiospeciGcally with LiAlH4 in JV-methylmorpholine to the alcohol (802). Net reduction of the alcohol (802) was achieved by the standard sequence (802)- (803)- (804). The final hydrocarbon product, (+)-twistbrendane (804), is in effect a nortwistane chiroptical data confirms (804) to be the enantiomer of the previously prepared (—)-twistbrendane.  

Internal aldol cyclization of compounds (805) is greatly enhanced by the presence of a trans (but not a cis) methyl group at C-10 (i.e. R = Me instead of H), and leads to the predominance of the twistanone (806 R = Me) in the base-catalysed equili-brium. The trans-methyl group is likely to destabilize conformation (807) relative to (808) which is more suited to the condensation, requiring relatively minor rotational motion to give the necessary boat-form. A general review of twistane chemistry has appeared. 

A synthesis of [8]di-isotwistane-2,8-dione (809) has been achieved by standard transformation of trans-anti-2,5-dioxo-7,8-diethoxycarbonylbicyclo[2,2,2]octane, itself obtained as a minor product of the cycloaddition of diethyl fumarate to hydro-quinone. A related approach was also used to effect the synthesis of the benzoiso-twistanone (810), and from thence the benzoisotwistane itself.  

The epimeric 2-hydroxymethyl-5,6-exo-trimethylenenorbomanes on reaction with sulphuric acid in pentane yield 4-homoisotwistane (811). Seychellene, which possesses the homoisotwistane skeleton, on conversion to its unstable epoxide, which was stored in the presence of light and air before reduction with LiAlH4, was transformed into the abnormal oxidation product norseychelanol (812) a scheme based on dioxetan formation was proposed. Bromination or Koch-Haaf carboxylation of (811) produces the appropriate 3-substituted derivative, indicating that C-3 in (811) is at least as reactive as the 1-position in adamantane, while the 1- and 8-positions in (811) are unreactive. The 3-bromo-derivative (813) is solvolytically more reactive than 1-bromoadamantane, and reaction with sodamide in boiling toluene yielded the anti-Bredt olefin (815) which could be isolated in 52% yield (815) exhibited typical 

Nakazaki, K. Naemura, and H. Yoshihara, Bull. Chem. Soc. Japan, 175,48, 3278. 

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In some molecules, the twist conformation is actually preferred. In all cis-2,5-di-fert-butyl-l,4-cyclohexanediol, hydrogen bonding stabilizes the otherwise high-energy form and 1,3-dioxane 89 exists largely as the twist conformation shown. Of course, in certain bicyclic compounds, the six-membered ring is forced to maintain a boat or twist conformation, as in norbornane or twistane. 

It has been pointed out that there is a torsional-angle (t) dependence of 3-SCS (cf. 40) (104). This angular dependence can be adequately described by multiplying the second term in eq. [15] by cos t (0° t 90°) for the appropriate fragment (104). By that treatment the 3-SCS values of methyl, hydroxy, chlorine, and nitro substituents in bomane (93,104,146,152-154) and twistane derivatives (104,155), which cannot be predicted by the simple eq. [15], become understandable. As expected, such an angular dependence does not exist if t is larger (90° < t < 180°) (156). 

Strategies based on some special topological features, such as the presence of "strategic bonds" and/or "common atoms" which apply preferentially to sesquiterpene compounds (as, for instance, longifolene, patchouli alcohol, seychellene, sativene, etc.) and non-natural compounds with a high degree of internal connectivity as, for example, twistane, bullvalene, etc. 

Twistane, as an example of a non-natural product, which is a chiral, bridged polycyclic compound, completely deprived of functionality. 

As it is a bridged polycyclic system, twistane has "strategic bonds" (bonds 11 and 12 in the conventional numbering adopted in structure l), the disconnection of which leads to rather simple intermediate precursors. 

However, as we will see below, twistane has been used as a model for testing the validity of the retrosynthetic analysis approach [2], as well as the soundness and/or limitations of the "strategic bond" concept. 

Owing to the D2 symmetry present in the structure of twistane only four "one single-bond" disconnections are possible (Scheme 13.1.1) ... 

Since twistane is a molecule without functionality, the fragments or synthons resulting from bond disconnections must be properly functionalised in order to create, in the synthetic direction, the corresponding bond. Or alternatively, as stated... 

Altough no syntheses of twistane involving two-bond disconnections have been reported, there is a paper in which such an approach is used for constructing a highly substituted twistane [3]. 

On the other hand, twistane is a chiral molecule and the disconnection of either one of the two identical strategic bonds, 11 and 12, in each one of two possible enantiomers leads to one of the two possible conformationally enantiomeric cis-decalins (Aj and A2), the resolution of which is indeed not possible since they... 

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. 

Acyloin condensation of diester 30a with sodium in liquid ammonia, followed by direct hydrogenation in the presence of Adam s catalyst, furnished the diol 32 in 49% yield. Diol 32 was transformed into the cyclic thiocarbonyl derivative (80% yield) which after heating with trimethylphosphite [14] afforded twistene 33 in 50% yield. Hydrogenation of 33 gave a compound identical in all respects with twistane 1. From the diester (-)-30a (+)-twistene was obtained, m.p. 35.5-36.5 °C, +... 

However, later on, in 1974, a full paper by Tichy describing an alternative approach to optically pure (+)-twistane was published [6b], in which the absolute configuration of twistane, twistene and some of their derivatives were determined in an unequivocal way, chemically. From this work it could be concluded that the absolute configuration was actually opposite to that inferred from CD-measurements. That is to say, the starting diester 30a has in fact the 2R,5R)-configuration and not the (25,55) as previously reported and (+)-twistane must have the configuration (/ )- and not (5j-l as concluded previously [13]. 

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. 

Draw the structures of twistane, tropinone, exo-brevicomin, patchouli alcohol, longifolene, sativene, luciduline and porantherine and search bifunctional relationships, rings, synthetically significant rings, bridgeheads, core bonds and strategic bonds of each one of them. 

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

The comparison of the genuine theoretical results with those predicted by this approximation shows a root-mean-square (rms) deviation of 0.2kcal/mol with those obtained in the HF/6-31G(if) calculations reported in Table 9.1. This result is all the more remarkable as it includes polycychc molecules (15-21), boat-cyclohexane stmctures (15, 21), as well as a twist-boat structure (19, twistane = tricyclo [4.4.00 ]decane). The use of this approximation for ZPE + — Hq in problems... 

In an elegant approach to gelsemine [238] based on a similar strategy the cationic aza-Cope rearrangement was superseded by a simple Mannich reaction because the twistane skeleton is more highly strained. However, the desired transformation is achievable using the anionic version. 

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