Brevicomin, exo

It is interesting to speculate that asymmetric induction may be the consequence of the exo anomeric effect, a stereoelectronic effect that favors the conformation 5 that places the aglycone O-C bond antiperiplanar to the pyran C(1) —C(2) bond7fi. Related asymmetric induction has also been observed in aldehyde addition reactions of the related, but racemic, pinacol (Z)-y-(tetrahydropyranyloxy)allylboronate49. As indicated in the examples above, however, the level of diastereoselectivity is modest and the only application in asymmetric synthesis is Wuts exo-brevicomin synthesis75. 

Figure 10.33 Complementary, backbone-inverting approaches for the asymmetric synthesis of the insect pheromone (-l-)-exo-brevicomin.

Naturally occurring chiral compounds provide an enormous range and diversity of possible starting materials. To be useful in asymmetric synthesis, they should be readily available in high enantiomeric purity. For many applications, the availability of both enantiomers is desirable. Many chiral molecules can be synthesized from natural carbohydrates or amino acids. The syntheses of (+)-exo-brevicomin (66) and negamycin (67) illustrate the application of such naturally occurring materials. 

Dioxalicyclo[3.2.1]octane, or (+)-exo-brevicomin (66), is the aggregating pheromone of the western pine beetle. It has been prepared from glucose using a procedure based on the retro synthesis design shown in Figure 1-2884 ... 

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. 

Catalytic olefin metathesis, in only a few years, has risen to be one of the most important and reliable processes in organic synthesis. Recently, several reports by Schrock and Hoveydallsbbond forming transformations efficiently and enan-tioselectively. A recent concise and enantioselective synthesis of exo-brevicomin by Burke utilizes chiral catalyst 91 (Scheme 13) to effect the desymmetriza-tion of 90 through a ring-closing metathesis.11531... 

Scheme 13. Asymmetric Mo-catalyzed ring-closing metathesis used by Burke in a concise total synthesis of exo-brevicomin (1999).

This Payne rearrangement of an optically active epoxide (4) was used for a synthesis of pure (+ )-exo-brevicomin (6) in 31% overall yield. 

An investigation of the stereochemistry of the urinary substances eliciting intermale aggression in the house mouse established that (l ,7.R)-3,4-dehydro-exo-brevicomin is present in the urine. Due to extremely facile racemization under very mild conditions, it was concluded that 2-sec-butyl-4,5-dihydrothi-azole 2 it is present in the urine as the racemate. It was suggested that the acidity of mouse urine probably promotes racemization of the optically active compound derived biosynthetically from an amino acid [36]. The observation that female house mice prefer the urinary odors of males uninfected by the intestinal nematode Heligmosomoidespolygyrus suggests that urine may also be important in conveying information on the infection status of males [37]. 

A very simple synthesis of the pheromone exo-brevicomin (4i) proceeds via an electrochemical Kolbe condensation between the unsaturated carboxylic acid 39 and the ketoacid 40, followed by hydroxylation of the double bond with OSO4, as... 

Draw the structures of twistane, tropinone, exo-brevicomin, patchouli alcohol, longifolene, sativene, luciduline and porantherine and search bifunctional relationships, rings, synthetically significant rings, bridgeheads, core bonds and strategic bonds of each one of them. 

Two compounds in the urine of male mice trigger attacks by other males 3,4-dehydro-exo-brevicomin and 2-5CC-butyl-4,5-dihydrothiazole (Novotny etal., 1985b). The behavior of male mice depends on the context in which they encounter these compounds. When smeared on castrates or females, they release aggressive behavior, but applied to pups, they inhibit infanticide. Therefore, it appears to be more appropriate to consider the these as signals of maleness rather than aggression pheromones (Mucignat-Caretta etal., 2004). 

The concentrations of 16 constituents of male mouse urine vary with the male s dominance status. Dihydrofurans, ketones, and acetates decreased in subordinates. Two sesquiterpene compounds, a- and /3-farnesene, are elevated in dominants urine 1 week after establishing dominance. The bladder or voided urine of dominants contains more 2-5ec-butyl-4,5-dihydrothiazole. Four compounds depend on hormones a- and /5-farnesene, dehydro-exo-brevicomin, and 2-5cc -butyl-4,5-dihydrothiazole. The latter two are absent in urine of immature or castrated males, and testosterone treatment restores their presence. In addition, a-and /3-farnesene do not occur in urine of immature males and are merely reduced in urine of castrates. They are not found in bladder urine and originate in the preputial glands (Harvey etal., 1989). While subordinate male mice have reduced levels of farnesenes, levels of their major urinary proteins remain high (Malone etal, 2001). 

The 6,8-dioxabicyclo[3.2.1]octane skeleton has been a common structural subunit in natural products. A conceptually new strategy affording these structures is described by Burk et al. [Eqs. (6.67) and (6.68)]. For the syntheses of (+)-exo-brevicomin, they used desymmetrization of triene 97, derived from diol 96 with C2 symmetry, via ring-closing metathesis. Enantiomerically enriched (- -)-ent/o-brevicomm... 

DHAP-dependent aldolases have also been used as key step in the synthesis of several complex natural products starting from achiral precursors. Thus, the sex pheromone (+)-exo-brevicomin can be synthesized in a multi-step route starting with the stereospecific aldol addition between DHAP and 5-oxohexanal or its 5-dithiane-protected analog catalyzed by FBPA from rabbit muscle ( RAMA ) as the key step by which the absolute configuration of the target is estabUshed (Scheme 4.16) [40]. 

The insect pheromone exo-brevicomin is a masked diol derivative. The route to the natural enantiomer utilized (7 )-pinanediol as the chiral director15. 

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