Asymmetric reactions sesquiterpenes

The (S)-leucine derivative (215) was allowed to react with diene (216) to afford the threo isomer (217) as the major product (d.s. = 80%) 213). Mukaiyama et al. 215) have reported the total synthesis of the sesquiterpene (-l-)-farnesiferol, starting from (R)-phenylglycinol, a derivative of the amino acid (R)-phenylglcine. They key step of this synthesis was an asymmetric Diels-Alder reaction. 

With Tartrate-Derived Chiral 1,4-Diol/Ti Complexes A catalytic asymmetric Diels-Alder reaction is promoted by the use of a chiral titanium catalyst prepared in situ from (Pr O TiC and a tartrate-derived (2.R,3.R)-l,l>4,4-tetraphenyl-2,3-0-(l-phenylethylidene)-l,2,3,4-butanetetrol. This chiral titanium catalyst, developed by Narasaka, has been successfully executed with oxazolidinone derivatives of 3-borylpropenoic acids as P-hydroxy acrylic acid equivalents [40] (Eq. 8A.21). The resulting chiral adduct can be utilized for the first asymmetric total synthesis of a highly oxygenated sesquiterpene, (-i-)-Paniculide. 

Asymmetric double alkylation of a, -enaldimines. A synthesis of (+ )-ivalin, an antileukemic sesquiterpene (4), is based on this stereoselective reaction. The... 

In addition, allenes can act as the olefinic part of the reaction [32], Al-lenynes like 12 may react with both double bonds. Brummond established the substitution patterns for the reaction with either the external or the internal bond of the allenic fragment, that give products with different ring sizes (13— 14) [33]. This group has applied these studies to the synthesis of hydroxy-methylfulvalene (17), a potent anticancer agent related with illudines, a natural sesquiterpene family. The key step was the synthesis of 16 from 15 with a PKR mediated by molybdenum carbonyl (Scheme 6) [34,35]. In addition they have developed an asymmetric version of the reaction. They have transferred efficiently chirality from a non-racemic allene to an a-alkylidene and an a-silylidene cyclopentenone in a molybdenum mediated reaction [36-38]. 

Trost BM, Haffner CD, Jebaratnam DJ, Krische MJ, Thomas AP (1999) The Palladium-Catalyzed Enyne Cycloisomerization Reaction in a General Approach to the Asymmetric Syntheses of the Picrotoxane Sesquiterpenes. Part. I. First-Generation Total Synthesis of Corianin and Formal Syntheses of Picrotoxinin and Picrotin. J Am Chem Soc 121 6183... 

The protic Bamford-Stevens reaction has been successfully utilized in the asymmetric synthesis of the naturally occurring sesquiterpenes (+)-a-eudesmol and (-)-a-selinene. Here, the more-substituted alkene was formed preferentially (equation 4,1). ... 

An asymmetric intramolecular Michael-aldol reaction which leads to nonracemic tricyclic cyclobutanes is performed by using TMSOTf andbis[(/ )-l-phenylethyl]amine as chiral amine, but only moderate enantioselectivities are reached (eq 68). A similar reaction sequence can also be carried out with TMSOTf and HMDS as base, with (—)-8-phenylmenthol as the chiral auxiliary however, the iodotrimethylsilane-HMDS system is more efficient in terms of yield and diastereoselectivity. The combination EtsN/TMSOTf (or some other trialkylsilyl triflates) has been used to accomplish an intramolecular Michael reaction, which was the key step for the synthesis of sesquiterpene (=E)-ricciocarpin A. ... 

The non-classical version of the intermediate carbenium ion (also referred to as a carbonium ion) resulting upon dissociation of the pyrophosphate anion from famesylpyrophosphate explains the cyclization to several cyclic carbenium ions as demonstrated for some sesquiterpenes (Fig. 3). Additional diversity arises from 1,2-hydride and 1,2-alkyl shifts (Wagner-Meerweest rearrangements) sbA sigmatropic reactions (COPE rearrangements) on the one hand, and on the other hand from the formation of diastereomers and enantiomers provided that the cyclizations generate new asymmetric carbon atoms (Fig. 3)... 

Independently, Koizumi et al. also reported [160] the use of nonracemic 3-p-tolylsulfinylacrylates as dienophiles in highly diastereoselective Diels-Alder reactions. The functionalized bicyclo[2.2.1]heptane derivatives such as (186), obtained by asymmetric Diels-Alder cycloaddition of ethyl p-tolylsulfinylmethylenepropionate with cyclopentadiene, have been used as intermediates for the synthesis of bicyclic sesquiterpenes such as (+)-epi-P-santalene (187) [161,162] (Scheme 5.61). 

Asymmetric [2 + 2] Photocycloadditions. Intramolecular copper-catalyzed [2 + 2] photocycloaddition is a useful methodology for the preparation of bicyclic cyclobutanes and recent studies deal with its asymmetric version albeit with variable success. Diastereoselective reactions are achieved under the control of stereogenic centers incorporated in the dienic precursors. Both CuOTf and the more stable and easy to handle Cu(OTf)2 are suitable catalysts in this context. In the latter case, it is assumed that the copper(I) species is generated from Cu(OTf)2 under the photochemical conditions. A noteworthy example is the application of the CuOTf-catalyzed [2 + 2] photocycloaddition in the stereoselective total synthesis of the tricyclic sesquiterpene kel-soene (eq 128). ... 

In some cases, zirconium complexes were used for Sharpless epoxidation of allylic alcohols instead of titanium ones. Asymmetric epoxidation of allyl alcohol (176), which is an intermediate in synthesis of Celastraceae sesquiterpene core, was successfully carried out with Zr(Oi-Pr)4 as a promoter to afford epoxy alcohol (177) with excellent enantioselectivity (Equation 77) [82]. When the reaction was carried out with Ti(Oi-Pr)4, the enantioselectivity decreased into 14% ee. The reason is attributed to the longer Zr-O bond length than that of Ti-0 bond, because coordination of hindered tertiary alcohols such as (176) to zirconium seems to be more favored than to titanium. 

Shibasaki has also reported impressive applications of the asymmetric intramolecular Heck reaction. For example, the Shibasaki group have applied their chemistry to the synthesis of compound 64, a key intermediate in the total synthesis of two complex triquinane sesquiterpenes 65 and 66, by making use of a Heck reaction/anion capture cascade sequence. ... 

Scheme 11.31). Indeed, in their synthesis of this attractive sesquiterpene isolated from both marine coral Sinularia mayi and Amazonian tree Xylopia brasiliensis, three different catalytic systems were combined in one pot without decreasing the overall efficiency of the reactions. The catalytic sequence is initiated by cross-metathesis between 2 and 121. Subsequent addition of 120 and (5)-3 in the same vessel allows for the asymmetric Michael addition, and further addition of L-proline induces the final intramolecular Michael addition. The efficiency of the sequence is demonstrated by the high stereoselectivity obtained (5 1 dr, 99% ee) in the construction of this complex skeleton from readily available starting materials. 

SCHEME 13.4. An asymmetric Heck reaction in the total synthesis of the elemanolide sesquiterpene dilactone (- -)-vernoIepin 9. 

SCHEME 13.5. Application an asymmetric Heck reaction/anion-capture cascade process to the total synthesis of marine sesquiterpene capnellenols 14. 

In another example, Shibasaki and co-workers applied an asymmetric Heck reaction/anion-capture cascade process to the total synthesis of marine sesquiterpenes capnellenols 14 and capnellene 17 (Schemes 13.5 and 13.6). The cascade involved the use of prochiral cyclo-pentadienyl systems for the generation of bicyclic 71-allyl-palladium species, which were then trapped by a suitable nucleophile. Initial studies in the total synthesis of capnellenols described the trapping of the 71-allylpalladium... 

---