Stereochemistry folded molecules

The tin hydride reaction is a standard dehalogenation using the radical to sustain a chain reac -je (pp. 1040-1). The stereochemistry is that of the most stable product with the C02Me group on outside of the folded molecule. In fact, this stereochemistry is also unimportant as it disappear. s. the next reaction. 

Though the reagent 273 does have stereochemistry it does not transmit it to the product and the stereoselectivity of the reaction is under substrate control. Folded molecules like the lactone 282 react on the outside as expected to give the exo -product 283. 

The second step is important as it changes the stereochemistry. Ethoxide will form the enolate of the ester reversibly and allow it to move to the outside, convex face of the folded molecule. Though neutral nitrogen is not normally a chiral centre because it undergoes rapid pyramidal inversion, here it is fixed by by the need of the 5/5 fused system to have a cis ring junction. The last step is just reduction of the ester with no change in stereochemistry. 

One element of database generation that is a key consideration is whether to expand the representative compounds to include alternative tautomers, protonated and deprotonated forms of the molecule, and also to enumerate stereochemistry fully if not specified in the input. Depending on the molecules in question and the options considered, these can lead to a 10-fold increase in the size of the database to be explored. However, such an expansion is necessary if methods are used that are sensitive to such chemical precision (e.g., docking). For 3D similarity searching, it is sometimes more efficient to consider various modifications to the query, leading to multiple searches against a smaller database. 

Hirsutine (85) is a corynantheine-type indole alkaloid with a C/D cis ring juncture (pseudo stereochemistry). This compound has recently been found to exhibit highly potent inhibition of the replication of the strains of influenza A (subtype H3N2) [63]. The EC50 of hirsutine was 11- to 20-fold more potent than that of the clinically used ribavirin. Exploration of the important structural features of this molecule revealed that the stereochemistry at C-3 (.R) and C-20 (R) as well as the presence of the Nb lone pair were essential for the anti-influenza A activity. Thus, the C-3 epimer, dihydrocorynantheine (86) (normal stereochemistry), was much less active than hirsutine (85). 

So far, little attention has been given to the stereochemical features of the resultant monoter-pene. Individual enzyme systems present in a particular organism will, of course, control the folding of the substrate molecule and thus define the stereochemistry of the final product. Most... 

The anti-cancer compound coriolin 23 has three fused five-membered rings and two epoxides. Notice that the 3/5 and both 5/5 ring fusions are cis. There have been many syntheses of coriolin, most using stereochemistry from folded precursors.7 We shall feature a couple of examples. Matsomoto s synthesis involves the hydroboration of alkene 24. The addition of borane is cis 25 and the boron is replaced by OH with retention of configuration to give 26. The hydroboration occurred on the outside of the molecule, on the same face as the ring junction hydrogens.8... 

A real example comes in the acylation (Chapter 28) of the enolate from the keto-acetal above and alongside. The molecule is folded downwards and the enolate is essentially planar. Addition presumably occurs entirely from the outside, though the final stereochemistry of the product is controlled thermodynamically because of reversible cnolization of the product whatever the explanation, the black ester group prefers the outside. 

COSY and a C.H-HSC. With only an edited DEPT spectrum and a 2D INADEQUATE spectrum the atomic sequence (structure without stereochemistry) of most molecules can be determined. However, there is a down side the time and effort required to generate the 2D INADEQUATE spectrum. Because we are looking at very weak sidebands of weak signals, it can take days of pulse sequence repetitions to generate the desired information. Moreover, the recycle delay between pulses must be carefully set to exceed (by 1.5- to 3-fold) the longest carbon T, value in the molecule. Also, the experiment... 

The role of the C-3 hydroxyl group has been investigated by comparing a series of enantiomeric chromans and tran -chromanols related to cromakalim (1) and Ro 31-6930 (21), for their relaxant effects in rat isolated portal vein [30]. In the cromakalim (1) series there was an approximate two-fold difference in potency between the enantiomeric chromans, but the difference was increased to about one hundred-fold in the pair of enantiomeric chromanols. Thus, it was shown that the absolute stereochemistry of the hydroxyl group has a eonsiderably greater influence on potency than the absolute stereochemistry of the C-4 substituent in the cromakalim (1) molecule. This effect was less pronounced in the chromans and chromanols related to compound (21). 

The stereochemistry of the reduction is easy to explain as the molecule is folded in such a way tat only the bottom face of the carbonyl group is open to nucleophilic attack. The oxyanion rroduced can immediately cyclize to form the lactone. Clearly, this is possible only if the group - up, but it is also possible only if the C02Me groups are on this side of the molecule. The ijcmation of the lactone does prove the stereochemistry of the cycloaddition. 

Now there is an intramolecular Diels-Alder reaction requiring a high temperature because the dienophUe is not activated. The stereochemistry is not obvious but there is no endo effect so the molecule folds to give the new five-membered ring a ds ring junction with the old. 

Now what will the cation do It could capture the external nucleophile, trifluoroacetate, but that > very weak and there is another nucleophile close at hand the alkene. We know the regioselectivity horn the structure of the product, but it looks as though the alkene prefers to act in an exo manner, rrobably because of better overlap of the orbitals. The stereochemistry of the side chain comes from z transition state already having the side chain on the outside of the molecule as it folds and the lack f control in the SMe group is unimportant as it can be removed with Raney nickel anyway. 

The stereochemistry comes from the way the molecule prefers to fold. The Newman projection below should be clear. The hydrogen atom on the allyl silane tucks under the six-membered ring and the double bond of the allyl silane projects out into space to give the stereochemistry found in the product. The ratio of this and the other diastereoisomer varies from 2 1 to 7.5 1 depending on the conditions so there isn t all that much in it. 

Caryophyllene needs a second cyclization to give a four-membered ring - the stereochemistry is already there as the molecule folds - and a proton loss. The enzymes control which product is formed by providing basic groups to remove protons from specific sites in the molecules and by folding the chain so that the reaction centres are close to each other. 

A more complex example with stereochemistry comes from Schreiber s asteltoxin synthesis.16 Hydroboration of the bicyclic acetal 96 with borane itself occurs on the underside of the folded bicyclic molecule to give 97. But this is not the end of the story. The product of the hydroboration is the THF 98. 

This result shows both the strengths and the weaknesses of such intramolecular aza-Diels-Alder reactions. The stereochemical outcome is controlled by the tether and such considerations as endo/exo selectivity matter very little. The molecule must fold 110 so that the preferred transition state 111 has the newly formed carbocyclic ring (not the ring formed by the cycloaddition itself) in the best chair conformation 112. The reaction is useful only if you want the stereochemistry it naturally gives. 

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