Total Synthesis of (−)-Mucocin

A highly convergent, modular strategy for the total synthesis of the annonaceous acetogenin (−)-mucocin is reported. The remarkable features are the endo-selective formation of the tetrahydropyran ring from an activated epoxide and the stability of the butenolide in the coupling with an organomagnesium compound.     

Enantiospecific Total Synthesis of (−)-D-Noviose

(−)-D -Noviose ((−)- 22 ), a rare sugar, was synthesized starting from the optically active building block (−)- 1 in seven steps. The first step of this route, the introduction of a methyl-ether group under Lewis-acidic conditions, left the acetoxy group untouched and thereby preserved the absolute configuration in the product 2 (Scheme 2). Next, the double bond of methyl ether 2 was cis-dihydroxylated leading selectively to 3 . After saponification of the acetoxy group of 3 the two vicinal cis OH groups of 17 were selectively protected as the cyclic carbonate 18 (Scheme 4). This kind of protection was essential to achieve the proper regioselectivity in the Baeyer-Villiger rearrangement of the cyclopentanone derivative 19 that was obtained after oxidation of the remaining OH group of 18 . Lactone 20 was the major product of this rearrangement. Final reduction to the corresponding lactol (cyclic hemiacetal) with diisobutylaluminium hydride (DIBAH) at low temperature was accompanied by reductive cleavage of the protecting cyclic carbonate moiety thereby leading directly to (−)-D -noviose ((−)- 22 ).     

Synthese von (−)-(R)-Nephthenol und (−)-(R)-Cembren A

Synthesis of (?)-(R)-Nephthenol and (?)-(R)-Cembren A Starting for L -serine,(?)-(R)-nephthenol((?)- 2 ) and (?)-(R)-cembren A((?)- 3 ) were synthesized.     

Total Synthesis of (−)‐Daphenylline

Total synthesis of (?)‐daphenylline, a hexacyclic Daphniphyllum alkaloid, was achieved. Construction of the tricyclic DEF ring system was initiated by asymmetric Negishi coupling followed by an intramolecular Friedel–Crafts reaction. Installation of a side chain onto the tricyclic core was carried out through Sonogashira coupling, stereocontrolled Claisen rearrangement by taking advantage of the characteristic conformation of the tricyclic DEF core, and the stereoselective alkylation of a lactone. After the introduction of a glycine unit, the ABC ring system was stereoselectively constructed through intramolecular cycloaddition of the cyclic azomethine ylide.     

Total Synthesis of (−)‐Bauhinin

The total synthesis of the naturally occurring cyanoglucoside (−)‐bauhinin ( 1 ) was achieved starting from the optically pure oxatrinorbornenone 2 in 12 steps and 8% overall yield. The aglycone of (−)‐bauhinin was easily obtained from the optically pure oxatrinorbornenone derivative 6 by a Wittig‐Horner reaction followed by the opening of the oxa bridge. Glycosidation with tetra‐O‐isobutyryl‐D ‐glucosyl bromide 9 as the reagent in the Koenigs‐Knorr reaction afforded glucoside 10 in 58% yield, which, after photoisomerization and deprotection, gave (−)‐bauhinin ( 1 ).     

Total Synthesis of (−)‐Lithospermoside

The total synthesis of the naturally occurring noncyanogenic cyanoglucoside (?)‐lithospermoside ( 1 ) was achieved starting from optically pure oxatrinorbornenone (+)‐ 2 in 12 steps and 10% overall yield. The key step of the synthesis, the glycosidation, turned out to be very sensitive to steric hindrance, and we had, therefore, to optimize the choice of the protection used for the two other OH functions of the aglycone. Finally, the desired β‐D ‐glucoside 15 was obtained in a very good yield (72%) under Koenigs–Knorr‐glycosidation conditions, closely related to those used for the total synthesis of (?)‐bauhinin.     

Total Synthesis of (−)‐Vindorosine

Outlined herein is a novel and scalable synthesis of (−)‐vindorosine based on two key transformations. A highly diastereoselective vinylogous Mannich addition of dioxinone‐derived lithium dienolates with indolyl N ‐tert‐butanesulfinyl imines has been developed. In addition, an intramolecular Heathcock/aza‐Prins cyclization was introduced to construct both the C, and the highly substituted E rings for the synthesis of (−)‐vindorosine and related alkaloids.     

Total Synthesis of (−)‐Spiroleucettadine

One of a number of intriguing new alkaloids isolated from the Leucetta sp. sponge in 2004, spiroleucettadine displayed unique structural features on a restricted scaffold: a trans ‐fused 5,5‐bicyclic ring system together with an amino hemiketal moiety. Attempts to synthesize the initially proposed structure failed, raising questions as to its veracity, and structure revision ensued in 2008; no successful synthetic approach has been reported to date. Herein, we describe the enantiospecific total synthesis of (−)‐spiroleucettadine by a highly efficient biomimetic approach starting from l ‐tyrosine. One of two key hypervalent‐iodine‐mediated oxidation reactions forged the spirocyclic center, and the other enabled the installation of the methylamine side chain in the penultimate step. Our approach provides synthetic access to a new class of spiroannulated natural products and will enable future studies of the structure–biological‐activity relationships of these antibacterial compounds.     

Total Synthesis of (−)‐Cleistenolide

An efficient and short total synthesis of (?)‐cleistenolide ( 1 ) from D ‐mannitol with an overall yield of 23.6% is described. The chiron approach for the synthesis of (?)‐cleistenolide involves a one‐C‐atom Wittig olefination, a selective allylic triethylsilyl protection, and a Grubbs‐catalyzed ring‐closure‐metathesis (RCM) reaction as the key steps.     

Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (?)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO₄)₂‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (?)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.     

Total Synthesis of (−)‐Norzoanthamine

No bones about it : (?)‐Norzoanthamine, a promising candidate for an anti‐osteoporotic drug, was the target of a total synthesis (see scheme). The final bisaminal formation with AcOH/H₂O gave the DEFG ring, while the cyclization precursor was prepared by installing the remaining bisaminal unit after oxidative cleavage of the cyclopentanol moiety.

     

Total Synthesis of (−)‐Morphine

We have developed an efficient total synthesis of (?)‐morphine in 5 % overall yield with the longest linear sequence consisting of 17 steps from 2‐cyclohexen‐1‐one. The cyclohexenol unit was prepared by means of an enzymatic resolution and a Suzuki–Miyaura coupling as key steps. Construction of the morphinan core features an intramolecular aldol reaction and an intramolecular 1,6‐addition. Furthermore, mild deprotection conditions to remove the 2,4‐dinitrobenzenesulfonyl (DNs) group enabled the facile construction of the morphinan skeleton. We have also established an efficient synthetic route to a cyclohexenol unit containing an N‐methyl‐DNs‐amide moiety.