Asymmetric Synthesis of ( 7 a S )-7 a-Methyl-4 , 5 , 7 , 7 a-tetrahydro-1 H-indene-2 , 6-dione and Useful Derivatives Thereof

The enantioselective synthesis of the title compound, using Meyers' bicyclic lactam methodology, is described. This compound and a few of its derivatives are useful intermediates in natural product synthesis.


Introduction
In the context of the development of structural analogs of calcitriol, the hormonally active metabolite of vitamin D 3 [1], we required the cis-fused perhydrindanone 7 (Scheme 1) [2].We herein describe in detail the enantioselective synthesis of the potentially useful dione 5 and its further conversion to 7.

Results and Discussion
The synthesis of 7, a cis-fused angularly substituted perhydrindane dione, in which one of the carbonyl groups is protected as cyclic ketal, involves two phases.First Meyers' methodology for the enantioselective synthesis of hydrindenones is applied in the preparation of 5 [3].In a second phase, the cyclohexanone carbonyl group of 5 is protected as an ethylene ketal and the cis-fusion in 7 is obtained by stereoselective catalytic hydrogenation of 6.
Meyers' approach for the asymmetric synthesis of angularly substituted hydrinden-2-ones proceeds in 3 stages: (i) the asymmetric introduction of the quaternary center using a chiral bicyclic lactam such as 1; (ii) the reductive intramolecular alkylation in which the 1,4-diketone is generated; (iii) the intramolecular aldolisation of the latter to the hydrinden-2-one.We chose to introduce the second carbonyl group in 5 via oxidative cleavage of the exocyclic double bond in 4. Following Meyers' methodology the latter is obtained from diastereomer 2a.
To stereoselectively obtain the correct configuration at the 6-position in 2a, the methyl group and the unsaturated side chain need to be introduced sequentially and in that precise order.Indeed, the prior introduction of the unsaturated side chain could eventually lead to the formation of spirocyclic derivatives [4].On the other hand, the preferred endo-alkylation of Meyers' bicyclic lactam template has been well documented [5].Hence, enantiomerically pure (+)-1 was required as starting material [6].(ii) The methylation of 1 led to a 9:1 diastereomeric mixture, which was not separated.After further deprotonation with LDA (DMPU, THF) and alkylation with the known dibromide 8 [7], a 7:3 mixture of 2a and 2b was obtained, which was separated by chromatography.The preferred formation of the endo-isomer 2a was proven by 1 H-NMR nOe signal-enhancement studies establishing the relative positions of the Me groups and H atoms indicated in Figure 1.The major isomer 2a was subjected to Meyers' protocol (KH, t-BuLi) yielding diketone 3. Basic treatment (KOH, EtOH) led to hydrinden-2one 4. Selective cleavage of the exocyclic double bond in 4 (ozone, Me 2 S) gave diketone 5 in which the saturated carbonyl group was further protected to afford the ketal 6.Finally, catalytic hydrogenation of the latter occurred exclusively from the convex side of the bicyclic molecule leading to the cis-fused perhydrindanone 7, the structure of which was confirmed by 1 H-NMR structural analysis: upon irradiation of the angular Me group a clear nOe enhancement of the signal of the bridgehead hydrogen was observed, confirming the cis-fusion of the hydrindane (Figure 1).

Conclusions
Angularly substituted perhydrindanones are useful intermediates in synthesis.The asymmetric synthesis of 7, in which an additional carbonyl group in protected ketal form is present (overall yield 33%), following a sequence of 7 steps starting from commercially available (+)-1 provides a useful example of the general applicability of Meyers' methodology.

General
Tetrahydrofuran (THF) was distilled from benzophenone ketyl.Dichloromethane (DCM) was distilled from CaH 2 .Toluene was distilled from sodium.TLC were run on glass plates precoated with silica gel (Merck, 60F-254).Column chromatography was performed on silica gel (Merck, 230-400 mesh).IR spectra were recorded on a Perkin-Elmer series 1600 FT-IR spectrometer. 1 H-NMR and 13 C-NMR spectra were recorded on a Bruker AM-500 spectrometer.Hydrogen chemical shifts δ are reported in ppm relative to CDCl 3 (7.26ppm) as an internal reference.J values are given in Hz.Carbon chemical shifts δ are reported in ppm relative to CDCl 3 (77.16ppm) as an internal reference.Mass spectra (EI) were recorded on a Hewlett-Packard 5898A spectrometer at 70 eV.