Synthetic Routes to (+)-Cassiol and (-)-Cassioside

This review summarizes the sequences recently developed for the total synthesis of the antiulcerogenic compounds (+)-cassiol and its glucoside (-)-cassioside. The discussion is focused on synthetic strategies and on methodologies for the construction of quaternary carbon stereocenters.


Introduction
As the result of a pharmacological analysis of the aqueous extract of the dried stem bark of Cinnamomum cassia Blume, one of the constituents of the traditional chinese prescription ''goreisan'' (''kennan keihi'' in Japanese) that displayed a potent antiulcerogenic activity in rats, Fukaya et al. 1 isolated in 1988 three pure compounds responsible for this pharmacological effect.One of these compounds comprised 1 x 10 -5 % of the stem bark and was named cassioside (1).

S
of this comparison, it can be conclude that the absolute configuration at C-4 of (-)-cassioside is also S.
A careful analysis of the structure of (+)-cassiol (2) reveals a rather simple molecular framework that accommodates a functionalized cyclohexenone moiety with a quaternary stereocenter (C-4) and a 2-ethenyl-1,3propanediol side chain which is connected at C-3.These structural features and pharmacological activity of cassiol have aroused the interest of synthetic organic chemists and several valuable contributions to its synthesis have appeared in the literature in recent years.In this Report we have summarized this body of published material, focusing our attention on synthetic strategies and on new methodologies for the construction of quaternary carbon stereocenters 2 .
The discussion is organized into three primary sections: 1) strategies based on the assembly of a chiral cyclohexenone/cyclohexanone intermediate and its coupling with a side-chain precursor 2) the chiral Diels-Alder strate-gies and 3) the palladium catalyzed cycloisomerization strategy

Strategies Based on the Assembly of a Chiral Cyclohexenone/Cyclohexanone Intermediate and its Coupling with a Side Chain Precursor
In 1989, Fukaya et al., who had determined the structure of (+)-cassiol (2) just one year earlier, reported also its total synthesis.Fukaya's strategy 3 , outlined retrosynthetically in Scheme 1, was based on the selective vinylation of the chiral enone intermediate 6 to furnish the allylic alcohol 5 which, through an 1,3-oxidative rearrangement and deprotection would afford (+)- (2).
Starting with the commercially available chiral ketoester 8, of known absolute configuration, and following the degradative sequence described in Scheme 2, the required enone 6 was obtained in enantiomerically pure form {[α]D 24 -23.6 (c 1.8, MeOH)}.
For the crucial selective vinylation reaction of (-)-6, the (E)-vinyllithium reagent 7 was generated in situ by the transmetalation of 14 with butyllithium, following the methodology previously described by Corey et al. 4 , to afford the allylic alcohol 5 in 94% yield (see next page).
By following a strategy conceptually similar to that outlined in Scheme 1, several authors developed sequences towards cassiol (2), using, however, a variety of interesting methodologies for the construction of the quaternary stereocenter present in the required cyclohexenone/cyclohexanone intermediate.
That the configuration of this ester is the one shown in 18, was deduced on the basis of previous observations that the alkylation of the dianion of 16 (or its methylated product) gives preferentially the anti-product 6 .The ester 18 was then transformed into the vinylogous ester 21 by the sequence of functional group interconversions followed by Claisen condensation, esterification and column chromatography, as described in Scheme 4.
Finally, addition of 7, generated from 14, to 21 followed by cleavage of the protecting groups gave (+)-2 in 5.6% overall yield and 99.2% ee.A similar strategy to that described by Mori et al. 5 for the synthesis of (+)-cassiol (2) was reported in 1996 by Taber et al. 7 However, a completely different approach was used by these authors for the construction of the vinylogous ester 23, with a defined absolute configuration, as illustrated in retrosynthetic format in Scheme 5.The key transformation in this approach is the stereospecific conversion of an acyclic stereocenter into a cyclic quaternary one (26 → 25) by an intramolecular alkylidene carbene methine insertion reaction 8 .
Starting with (-)-norcitronellol (27) prepared from geraniol by a known procedure 9 , and by a series of functional group manipulations, enantiomerically pure 26 was obtained (Scheme 6).
The cyclization of 26 into 25 was carried out with the lithium derivative of (trimethylsilyl)-diazomethane (29), generated in situ, and by α-elimination at the vinyl chlorides 30 according to Scheme 7. The yield of the two-step route was similar to that of the one-pot procedure with 29.
For the preparation of 23, cyclopentene 25 was first submitted to ozonolysis followed by oxidation to the methyl ester 24 which, upon Claisen condensation and esterification with 2-diazopropane, afforded a mixture of regioisomers (23 and 31) separable by column chromatography (Scheme 8).
The catalytic hydrogenation of 23 gave alcohol 32 which, by vinylation, under essentially the same conditions  These authors envisioned, on the basis of molecular mechanic calculations, that the stereochemistry of the two contiguous chiral centers of oxime 33 was crucial to constraint the conformation of the transition state of the dipolar cycloaddition reaction to the more favorable chair-like one leading, consequently, to the diasteroselective formation of 35 (Fig. 1).
The preparation of oxime 33 with the required relative and absolute stereochemistry was carried out following the asymmetric aldol methodology of Evans 11 and further functional group interconversions, as shown in Scheme 10.
The nitrile oxide intermediate 34, generated from oxime 33, on treatment with sodium hypochlorite afforded, as expected, exclusively the isoxazoline 35 in 88% yield.That the stereochemistry of the newly generated center is S as depicted in 35, was established by NOE experiments on the free alcohol 41a and further, by analysis of the 1 H-NMR spectrum of the corresponding MTPA ester 41b, it was shown that the optical purity of 35 was more than 99%.
The isoxazoline ring of 35 was smoothly cleaved by hydrogenolysis to afford 36 in good yield.By protection of the free hydroxyl group of 36 followed by vinylation, the intermediate 42 was obtained.Starting with 42 and following the sequence depicted in Scheme 11, the synthesis of (+)-cassiol (2) was completed.
More recently, in 1998, Banerjee et al. 12 reported a short and efficient synthesis of (-)-6, the key intermediate  enone which had been prepared by Fukaya an co-workers in the first synthesis of (+)-cassiol (2) 3 .
In 1994, Corey and co-workers 14 demonstrated the synthetic power of their oxazaborolidine-catalyzed enantioselective Diels-Alder reaction 15 by the development of a remarkable short and efficient route to (+)-cassiol (2).After an appropriate choice of protecting groups for the diene, small structural modifications in the catalyst and an experimentally oriented selection of reaction solvents, Corey et al. discovered that the cycloaddition reaction of the electron-rich triene 51, prepared as depicted in Scheme 13, and 2-methylacrolein in the presence of the chiral oxazaborolidine derived from tryptophan (54) afforded 52 in 83% yield and 97% ee (see next page).
Finally, by the four-step sequence also described in Scheme 13, (+)-cassiol (2) {[α]D 20 8.5 (c 0.27, MeOH)} was obtained in ca.40% overall yield.More recently, in 1996, Boeckman et al. 16 reported the construction of the quaternary carbon stereocenter present in (-)-cassioside (1) by an asymmetric Diels Alder reaction of the oxygenated triene 55, identical to triene 51, previously described by Corey et al. 14   The preparation of 55, carried out by two consecutive Wittig reactions, is described in Scheme 14, together with the preparation of the chiral dienophile 58.
To avoid decomposition of the acid-sensitive triene 55, under the usual conditions of the Lewis acid-catalyzed cycloaddition reaction, the TiCl4-SbPh3 complex was employed as promoter and further, one equivalent of trimethylalminum was added as proton scavenger.Under these conditions a 11:1 mixture of two diasteroisomeric cycloadducts 59 and 60, endo and exo respectively, was obtained in 89% yield.The X-ray analysis of the crystalline acetonide derivative 61, prepared as described also in Scheme 14, confirmed the structure and absolute stereochemistry of the major diastereoisomer.
The reduction of the mixture of cycloadducts 59 and 60 followed by column chromatography, allowed the isolation of the major alcohol 62 and recovery of the chiral auxiliary (56).Finally, glycosidation of the hydroxyl group of 62 following Kahne's procedure gave intermediate 64 which, by generation of the enone moiety and deprotection afforded (-)-1 {[α]D 25 -25.1 (c 0.6, MeOH)}, this work represents the first total synthesis of (-)-cassioside (1) (Scheme 15).

The Palladium Catalyzed Cycloisomerization Strategy
Also in 1996, based on the strategy outlined retrosynthetically in Scheme 16, Trost et al. 17 reported a new total synthesis of (+)-cassiol (2).The key features of Trost's cassiol synthesis are the new palladium catalyzed cycloisomerization of enyne 66 in an ene type fashion to the cyclohexanone derivative 65, the elaboration of the side chain present in cassiol by a palladium (0) catalyzed reaction (68 → 67) and the generation of the quaternary carbon stereocenter by an enzymatic process.
As shown in Scheme 17, the conjugate addition of the anion of dimethyl methylmalonate 70 to N,N-dimethy- lacrylamide and desymmetrization of the resulting disubstituted malonate by pig liver esterase (PLE) catalyzed hydrolysis led to 69 of 92% ee after recrystallization.Although the absolute configuration of 69 was only tentatively assigned at this juncture, it was confirmed as S after completion of the synthesis.Chemoselective reduction of the carboxylic acid group of 69 furnished alcohol 72 which, by oxidation and addition of vinylmagnesium bromide followed by acetylation gave 68, the substrate required for the elaboration of the side chain of (+)-2.In fact, the Pd (0) catalyzed allylic alkylation of 68 with dimethyl malonate afforded triester 67 in good yield.Starting with 67 and by a sequence involving reduction of the ester groups and protection of the resulting triol, followed by conversion of the N,N-dimethylamide group into an alkynyl ketone, the cyclization precursor 66 was obtained in 18% overall yield in nine steps.
The key cycloisomerization reaction of 66, under the conditions described in Scheme 18, afforded a 3:1 mixture of the diastereisomeric cyclization products 73 and 65 in 83% yield.Finally, by a two-step sequence involving a net double bond migration (74) followed by O and C desilylation (+)-cassiol (2) {[α]D 25 16.1 (c 0.15, MeOH)} was obtained in 42% overall yield for the last three steps.

Concluding Remarks
The application of a variety of synthetic strategies and different methodologies for the construction of quaternary carbon stereocenters can be observed in the description of the sequences towards the synthesis of (+)-cassiol and its glucoside (-)-cassioside.The scarcity of (+)-cassiol together with its promising pharmacological activity and the interesting structural features are likely to stimulate a second generation of short and economical synthetic routes that will soon appear in the literature.
2) {[α]D 8.6 (c 0.25, MeOH)}, showing more potent antiulcer activity than cassioside itself.The absolute configuration of (+)-cassiol (2) was shown to be S by comparison of the CD spectrum of the trimethyl ester 3, prepared by selective hydrogenation, oxidation and methylation of 2, with that of methyl tetrahydrotrisporate C (4), of known absolute configuration.As a consequence Scheme 1.
except by the protecting group, and the chiral dienophile 58.