Asymmetric [2+2] photocycloaddition via charge transfer complex for the synthesis of tricyclic chiral ethers

The asymmetric synthesis of chiral polycyclic ethers by an intramolecular [2+2] photocycloaddition is described.

The Acetate Pathway: Biosynthesis of Polyketides and Related Compounds

We saw in the previous chapter how Otto Wallach’s early proposal regarding the structural origin of terpenoid natural products was later refined by the insightful work of Leopold Rudzicka, leading to the biogenetic isoprene rule and all that it implies. In a nearly parallel fashion, we find in our present chapter a second, unrelated class of naturally occurring compounds whose characteristic structural features prompted an initial innovative hypothesis by J. N. Collie near the turn of the 20th century. Collie proposed that certain natural compounds might arise from precursors containing repeated “ketide” (–CH2CO–) units which could then undergo subsequent condensations and other reactions typical of carbonyl compounds to produce some of the observed structures. Unfortunately, Collie’s work was more or less ignored and largely forgotten for nearly a half century, only to be reimagined and expanded in the middle of the century by A. J. Birch, another pioneer whose proposals met with considerable initial resistance. But unlike his predecessor, Birch ultimately prevailed by providing experimental results that supported a comprehensive theory of the biochemical origin of the group of compounds now universally known as “polyketide” natural products. This structurally diverse family includes some of the most useful medicinal agents now known to us, with many members possessing powerful antibacterial, antifungal, anticancer, immunosuppressant, and even cholesterol-lowering biological properties. As we see in Fig. 5.1, such structures range from the relatively simple to the exceedingly complex and may include large macrocyclic lactone rings (macrolides) such as erythromycin, polycyclic ethers such as monensin A, polycyclic structures which may be partly or mostly aromatic as in tetracycline, griseofulvin, or daunorubicin, or nonaromatic polycyclics such as tacrolimus and lovastatin. Some also contain noncyclic linear components that may be saturated, oxygenated, or unsaturated, as seen in different regions of amphotericin B which, like erythromycin, daunorubicin, and many other polyketides, also possesses an aglycone core which has been glycosylated with a carbohydrate component at a specific position. But in spite of this range of structures, many polyketide compounds share some common features that ultimately become more evident upon closer inspection; six-membered rings (either aromatic or nonaromatic) and multiple oxygens which tend to appear in a repeating 1,3-relationship to one another on both acyclic, cyclic, and aromatic structures.

Bismuth(iii) triflate-catalysed tandem cyclisations towards complex polycyclic ethers

A series of complex polycyclic ethers have been synthesised under very mild conditions using a low catalyst loading of bismuth(iii) triflate.

The Overman Synthesis of Briarellin F

Briarellin F 4 is an elegant representative of the complex polycyclic ethers produced by soft corals such as Briareum abestinum. Larry E. Overman of the University of California, Irvine, developed (J. Org. Chem. 2009, 74, 5458) a triply convergent approach to 4, the central feature of which was the Prins-pinacol combination of 1 with 2 to give 3. The aldehyde 2 was assembled by Wittig homologation of the aldehyde 5 with the phosphorane 6, followed by metalation and formylation. The aldehyde 10 was prepared by opening the enantiomerically pure epoxide 8 with the acetylide 9. Hydroboration of carvone 11 could not be effected with sufficient diastereocontrol. As an alternative, the mixture of diols was oxidized to the lactone 12 . Kinetic quench of the derived silyl ketene acetal followed by reduction led to the diastereomerically pure crystalline diol 13. This key intermediate will have many other applications in target-directed synthesis. The ketone 14 was converted to the alkenyl iodide 15 by stannylation of the enol triflate, followed by exposure of the stannane to N-iodosuccinimide. Addition of the alkenyl iodide 15 to the aldehyde 10 gave the diol 1 as an inconsequential 3:1 mixture of diastereomers. This mixture was combined with the aldehyde 2 to give, via Lewis acid–mediated rearrangement of the initially prepared acetal, the aldehyde 3 . The aldehyde 3 was readily decarbonylated by irradiation in dioxane. Face-selective Al-mediated epoxidation of the derived homoallylic alcohol proceeded with 10:1 selectivity, and subsequent MCPBA epoxidation of the cyclohexene was also secured with 10:1 facial control. This set the stage for the triflic anhydride–mediated closure of the six-membered ring ether. The Nozaki-Hiyama-Kishi cyclization of 18 proceeded with remarkable selectivity, delivering briarellin E 19 as a single diastereomer. Dess-Martin oxidation converted 19 into briarellin F 4.