High-harmonic generation is a universal response of matter to strong femtosecond laser fields, coherently upconverting light to much shorter wavelengths. Optimizing the conversion of laser light into soft x-rays typically demands a trade-off between two competing factors. Because of reduced quantum diffusion of the radiating electron wave function, the emission from each species is highest when a short-wavelength ultraviolet driving laser is used. However, phase matching--the constructive addition of x-ray waves from a large number of atoms--favors longer-wavelength mid-infrared lasers. We identified a regime of high-harmonic generation driven by 40-cycle ultraviolet lasers in waveguides that can generate bright beams in the soft x-ray region of the spectrum, up to photon energies of 280 electron volts. Surprisingly, the high ultraviolet refractive indices of both neutral atoms and ions enabled effective phase matching, even in a multiply ionized plasma. We observed harmonics with very narrow linewidths, while calculations show that the x-rays emerge as nearly time-bandwidth-limited pulse trains of ~100 attoseconds.

Despite the longstanding importance of polyketide natural products in human medicine, nearly all commercial polyketide-based drugs are prepared through fermentation or semi-synthesis. The paucity of manufacturing routes involving de novo chemical synthesis reflects the inability of current methods to concisely address the preparation of these complex structures. Direct alcohol C-H bond functionalization via “C-C bond forming transfer hydrogenation” provides a powerful, new means of constructing type I polyketides that bypasses stoichiometric use of chiral auxiliaries, premetallated C-nucleophiles, and discrete alcohol-to-aldehyde redox reactions. Using this emergent technology, the total syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, and formal syntheses of rifamycin S and scytophycin C, were accomplished. These syntheses represent the most concise routes reported to any member of these respective natural product families.

The 14-membered macrolide 6-deoxyerythronolide B is prepared in 14 steps (longest linear sequence) and 20 total steps. Two different methods for alcohol CH-crotylation via transfer hydrogenation are deployed for the first time in target-oriented synthesis. Enyne metathesis is used to form the 14-membered ring. The present approach represents the most concise construction of any erythronolide reported, to date.

The cyclometallated iridium complex (S)-I derived from [Ir(cod)Cl]2, 4-cyano-3-nitrobenzoic acid, allyl acetate and (S)-SEGPHOS is conveniently isolated by precipitation or through conventional silica gel flash chromatography. This single component precatalyst allows alcohol mediated carbonyl crotylations to be performed at significantly lower temperature, resulting in enhanced levels of anti-diastereo- and enantioselectivity. Most significantly, the chromatographically isolated precatalyst (S)-I enables carbonyl crotylations that are not possible under previously reported conditions involving in situ generation of (S)-I.

Under the conditions of transfer hydrogenation employing a cyclometallated iridium catalyst (R)-I derived from [Ir(cod)Cl]2, allyl acetate, 4-cyano-3-nitrobenzoic acid and the chiral phosphine ligand (R)-SEGPHOS, α-methyl allyl acetate engages 1,3-propanediol 1a and 2-methyl-1,3-propanediol 1b in double carbonyl crotylation from the alcohol oxidation level to deliver the C2-symmetric and pseudo-C2-symmetric stereopolyads 2a and 3a, respectively, with exceptional control of anti-diastereo- and enantioselectivity. Notably, the polypropionate stereopentad 3a is formed predominantly as 1 of 16 possible stereoisomers. Desymmetrization of polypropionate stereopentad 3a is readily achieved upon iodoetherification to form pyran 4. Direct generation of polypropionate stereopentad 3a enables a dramatically simplified approach to previously prepared polypropionate substructures, as demonstrated by the synthesis of C19–C27 of rifamycin S (8 steps, originally prepared in 26 steps) and C19–C25 of scytophycin C (8 steps, originally prepared in 15 steps). The present transfer hydrogenative protocol represents an alternative to chiral auxiliaries, chiral reagents and premetallated nucleophiles in polyketide construction.

(+)-Zincophorin methyl ester is prepared in 13 steps (longest linear sequence). A bidirectional redox-triggered double anti-crotylation of 2-methyl-1,3-propane diol directly assembles the triketide stereopolyad spanning C4-C12, significantly enhancing step-economy and enabling construction of (+)-zincophorin methyl ester in nearly half the steps previously required.

Parallel synthesis and high-throughput ee screening.

Using the ortho-cyclometallated π-allyl iridium precatalyst (R)-I derived from [Ir(cod)Cl] 2 , 4-cyano-3-nitrobenzoic acid, (R)-SEGPHOS and allyl acetate, enantioselective transfer hydrogenation of α-(trimethylsilyl)allyl acetate in the presence of aldehydes 2a-2i mediated by isopropanol delivers products of (trimethylsilyl)allylation 4a-4i in good isolated yields and with exceptional levels of anti-diastereoselectivity and enantioselectivity (90-99% ee). In the absence of isopropanol, but under otherwise identical reaction conditions, carbonyl (trimethylsilyl)allylation is achieved directly from alcohol oxidation level to furnish an equivalent set of adducts 4a-4i with roughly equivalent isolated yields and stereoselectivities. To evaluate the synthetic utility of the reaction products 4a-4i, adduct 4g was converted to the 1,4-ene-diol 5g via dioxirane mediated oxidative desilylation with allylic transposition, the allylic alcohol 6g via protodesilylation with allylic transposition, and the γ-lactam 7g via chlorosulfonyl isocyanate mediated cycloaddition.