Frontalin

Benzylidination of methyl a-D-glucopyranoside (8 a) gives the diol (35) which can be converted to the oxirane (37) in excellent yield 37). This process is accomplished in one step, but the 2-0-tosyl ester (36) 

A much more lengthy route from glucose giving only the (—)-enantio-mer of frontalin has been reported by Ohrui and Emoto (66). This synthesis, as well as that reviewed above share the common defect that some of the original carbons of the sugar are lost during periodate oxidations. If it is considered that the formation of C-C bonds is nine-tenths of synthetic organic chemistry, then the need for reticence in the use of sodium meta-periodate is warranted. This has been of prime consideration in the approaches to exo-brevicomin which follow. 

The title compound is one of the sex pheromones of the Dutch Elm beetle Scolytus scolytus. For maximum biological activity it is essential for the pheromone to have a high degree of enantiomeric purity. This 

8 EPOXIDE HYDROLASES AND THEIR APPLICATION IN ORGANIC SYNTHESIS 

---

The syntheses of brevicomin (67)[109,110] and frontalin[l 11] have been achieved as an elegant application of the intramolecular acetal formation with the diol 66 in dry DME. Optically active frontalin (68) has been synthesized by this cyclization in triglymejl 12]. 

The cyclic enol ether 255 from the functionalized 3-alkynoI 254 was converted into the furans 256 by the reaction of allyl chloride, and 257 by elimination of MeOH[132], The alkynes 258 and 260, which have two hydroxy groups at suitable positions, are converted into the cyclic acetals 259 and 261. Carcogran and frontalin have been prepared by this reaction[124]. 

Fritting From squalene Frontal Frontal chromatography Frontalin [28401-39-0] Froth Froth ers... 

The western pine beetle Dendroctonus brevicomis is perhaps the most destmctive insect enemy of western pine forests. The aggregation pheromone is a mixture of the terpenoid myrcene [123-35-3J (163) from the tree and the frass pheromones exo-hsevicomki [20290-99-7] (164) and frontalin [28401-39-0] (165). The Norway spmce beede Ips tppopraphus converts the tree terpenoid myrcene into the frass pheromone ipsdienol [33628-00-3] (166) and the beedes also produce 2-methyl-3-buten-2-ol [115-18-4] and rir-verbenol [473-67-6] (167), all of which are components of the aggregation pheromone. 

Recognising the acetal in frontalin (3), a pheromone of the western pine beetle," is not so easy. Nevertheless, it is Important to look for the two oxygen atoms joined to the same carbon atom ( in 3a) and disconnect the acetal before considering any other steps. 

Intramolecular acetal formation is so favourable that any attempt to make (4) leads at once to frontalin. 

Frontalin (18), the pheromone of the western pine beetle, is an acetal (atom has two single bonds to oxygen). Disconnection reveals diol ketone (19). 

Some insect pheromones are internal ketals. We have already mentioned multistriatin (pp T 2 and 99) and frontalin p 193). Brevicomin (22) is another example. Disconnection of the ketal gives (23) containing a 1,2-diol. Among other syntheses, hydroxy-lation of protected enone (24) by epoxidation and acid catalysed rearrangement gives brevicomin stereo-specifically,... 

This ligand has also been used by the same authors to promote the addition of ZnMe2 to a functionalised a,(3-unsaturated ketone in the asymmetric key step of the first enantioselective synthesis of (-)-frontalin. This synthesis started with the naphthalene-catalysed lithiation of a chlorinated ketal (Scheme 4.15) that, after several transmetalation processes, was trapped by reaction... 

Fig. 4 Proposed biosynthetic pathways for the production of ipsdienol in I. pini and frontalin in D. spp. Both pathways utilize an isoprenoid biosynthetic pathway to produce geranyl diphosphate...

Evidence for de novo synthesis of pheromone components was obtained by showing that labeled acetate and mevalonate were incorporated into ipsdienol by male Ips pini [103,104]. Similarly, labeled acetate and other labeled intermediates were shown to be incorporated into frontalin in a number of Dendroctonus species [105]. Possible precursors to frontalin include 6-methyl-6-hep-ten-2-one, which was incorporated into frontalin by D. ruffipennis [106]. The precursor 6-methyl-6-hepten-2-one also was shown to be converted to bre-vicomin in the bark beetle, Dendroctonus ponderosae [107]. In addition, the expression patterns of HMG-CoA reductase and HMG-CoA synthase are tightly correlated with frontalin production in Dendroctonus jeffreyi [108, 109]. A geranyl diphosphate synthase cDNA from I. pini was also isolated, functionally expressed, and modeled [110]. These data indicate that the de novo isoprenoid biosynthetic pathway is present in bark beetles. A variety of other monoterpene alcohols such as myrcenol, pityol, and sulcitol are probably synthesized through similar pathways [111]... 

Rasmussen, L.E.L. and Greenwood, D.R. (2003) Frontalin A chemical message of musth in Asian elephants (Elephas maximus). Chem. Senses 28,433-446. 

Abstract A relatively small number of mammalian pheromones has been identified, in contrast to a plethora of known insect pheromones, but two remarkable Asian elephant/insect pheromonal linkages have been elucidated, namely, (Z)-7-dodecen-1-yl acetate and frontalin. In addition, behavioral bioassays have demonstrated the presence of a chemical signal in the urine of female African elephants around the time of ovulation. Our search for possible ovulatory pheromones in the headspace over female African elephant urine has revealed for the first time the presence of a number of known insect pheromones. This search has been facilitated by the use of a powerful new analytical technique, automated solid phase dynamic extraction (SPDE)/GC-MS, as well as by novel macros for enhanced and rapid comparison of multiple mass spectral data files from Agilent ChemStation . This chapter will focus on our methodologies and results, as well as on a comparison of SPDE and the more established techniques of solid phase microextraction (SPME) and stir bar sorptive extraction (SBSE). 

Use of automated headspace SPDE/GC-MS not only enabled the identification in female African elephant urine of a number of known insect pheromones (compounds 2-6, Fig. 2.1), but also revealed the presence of the beetle biochemical precursors to frontalin (2), exo-brevicomin (3) and ent/o-brevicomin (4), thus suggesting a common biosynthetic pathway (Goodwin et al. 2006). Extensive behavioral bioassays must be performed to determine whether any of these compounds is functioning as a pheromone among African elephants. 

Enantiomerically pure tetrahydro-l//-pyrrolo[2, l -acrylamides derived from proline (see Section 11.11.7.4), are versatile intermediates for the synthesis of natural products or drugs. Compound 86a was submitted to debromination with Bu3SnH followed by ring opening in KOH and further reduction with BHj to give diol 89 that was then easily transformed into (A)-4-(2,2,4-trimethyl-l,3-dioxolan-4-yl)-lT>utanol 90, a key intermediate for )-frontalin, <2002TA155>,... 

More recently, the deracemization of ( )-2c (Scheme 16) with Nocardia EHl and sulfuric acid in dioxane containing a trace amount of water (see above) afforded (S)-2-methyl-hept-6-ene-l,2-diol in 97% yield and 99% ee [83]. This intermediate was successfully applied in a short synthesis of (S)-(-)-frontalin, a central aggregation pheromone of pine beetles of the Dendroctonus family [81]. 

Scheme 16. Chemoenzymatic synthesis of (S)-(-)-frontalin using bacterial epoxide hydrolase...

---