Stereoselective total synthesis of (±)-7-deoxy-trans-dihydronarciclasine, a potent antineoplastic phenanthridone alkaloid

A short and efficient stereoselective total synthesis of (±)-7-deoxy-trans-dihydronarciclasine, a highly potent antineoplastic agent and constituent of the Amaryllidaceae alkaloids, is described. Starting from a known arylcyclohexylamine-type precursor 6, the C-ring with the required stereochemistry is constructed using a chemo- and stereoselective enone reduction (NaBH₄/CaCl₂ system) and a Mitsunobu reaction. For the B-ring closure, the Banwell modification of the Bischler-Napieralski reaction was applied.     

An expedient total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide

[reaction: see text] A highly convergent and efficient total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide is reported.     

Enantioselective synthesis of R-(+)-α and S-(−)-α-lipoic acid

An efficient synthesis of α-lipoic acid from the readily available cis-2-butene-1,4-diol employing a Claisen orthoester rearrangement and Sharpless asymmetric dihydroxylation as the key steps, is described.     

Total synthesis of ent-(−)-azonazine using a biomimetic direct oxidative cyclization and structural reassignment of natural product

A biomimetic approach has been investigated and developed for the total synthesis of azonazine, an unusual marine natural cyclopeptide containing a rigid transannular 10-membered ring. A hypervalent iodine-mediated direct oxidative cyclization was successfully developed and applied to construct the highly strained core, which was the key step in the first total synthesis of ent-(−)-azonazine. Based on the physical evidences of synthesized diastereomer and enantiomer of azonazine, both the relative and absolute configurations of the natural product were revised. Two fluorinated azonazine derivatives were also synthesized in short convenient steps utilizing the same intermediate in this work. The established total synthesis opens a potential opportunity to study the structure–activity relationship of natural azonazine.     

An efficient total synthesis of (−)-anamarine

An efficient synthesis of (−)-anamarine is described using d(+)-mannitol and (R)-epichlorohydrin. The synthesis is achieved starting from easily accessible d(+)-mannitol using a selective benzoylation, regioselective epoxide ring opening, a selective acetonide deprotection, tosylation and cross metathesis reaction.     

Stereospecific total synthesis of (−)-8-epi-hyperaspine

Condensation of protected δ-hydroxy-β-amino ester 7 with a β-keto ester provides vinylogous urethane 8, which is cyclized under the action of t-BuOK followed by decarboxylation to afford enone 12. Hydrogenation of 12 or its N,O-diprotected derivative 13 gives 2,6-cis-disubstituted piperdines. Using these intermediates, (−)-8-epi-hyperaspine is synthesized.     

Synthesis of ent-ambrox® from (−)-nidorellol

Using ozonolysis of the acid-catalyzed cyclized products of (−)-nidorellol and air-autoxidation as the key steps, (+)-ambrox was obtained in 53% overall yield. In the course of our synthesis, we discovered that (−)-nidorellol provided (+)-ambrox instead of the expected product, (−)-ambrox. Thus the absolute configuration of (−)-nidorellol was proved to be trans-(5R^∗,7R^∗,8R^∗,9S^∗,10R^∗)-labda-12,14-diene-7α,8β-diol, which is opposite to that illustrated in a previous report.     

Enantioselective total synthesis of (S)-(−)-quinolactacin B

The enantioselective total synthesis of (−)-quinolactacin B (−)-1 was performed in seven steps and 33% overall yield from tryptamine. The synthesis features the use of ruthenium catalytic asymmetric hydrogen reaction to introduce the chirality in dihydro-β-carboline 2. Based on Noyori’s work, the hydrogenation using the (R,R)-TsDPEN-Ru complex produces dihydro-β-carbolines possessing the (S) absolute configuration, the corrected asymmetric center of the natural product. The synthetic quinolactacin B displayed optical rotations that was in accordance with that of the natural product, thereby supporting the (S) configuration for natural quinolactacin B. The final product’s stereochemical assignment is in agreement with that proposed by Nakagawa and co-workers.     

A practical enantioselective total synthesis of (−)-(S)-stepholidine

A convergent enantioselective total synthesis of (−)-(S)-stepholidine, a drug candidate for the treatment of schizophrenia and/or drug abuse, was described, which represented the first example of successful auxiliary-assisted Bischler–Napieralski cyclization of amide bearing bromine atom at 2-position of the C ring, followed by an introduction of the aryl methyl ester via Br–Li exchange. (−)-(S)-Stepholidine was synthesized in 6 steps, with 52% overall yield and >99% ee. The reported synthesis is practically free from chromatographic separation.     

Improved total synthesis of (±)-trans-dihydronarciclasine, devised for large-scale preparation

New synthetic route to (±)-trans-dihydronarciclasine, more suitable for a large-scale preparation, has been devised with the early stage incorporation of ester functionality for direct assembly of the B-ring lactam.     

First total synthesis of (−)-8-epi-9-deoxygoniopypyrone

The structure and absolute configuration of natural 8-epi-9-deoxygoniopypyrone have been confirmed by an efficient and highly diastereoselective synthesis in 15 steps from (S)-mandelic acid with an overall yield of 43%.     

Stereoselective total syntheses of (+)-exo- and (−)-exo-brevicomins, (+)-endo- and (−)-endo-brevicomins, (+)- and (−)-cardiobutanolides, (+)-goniofufurone

Stereoselective total syntheses of aggregation pheromones (+)-exo-brevicomin (9a), (−)-exo-brevicomin (9b), (+)-endo-brevicomin (9c), (−)-endo-brevicomin (9d) and styryllactones (+)-cardiobutanolide (14a), (−)-cardiobutanolide (14b), and (+)-goniofufurone (19a) were achieved in good yields from enantiomerically pure highly functionalized furanoid glycal building blocks (1a-d) involving similar synthetic strategies, thus making these furanoid glycals highly useful building blocks in diversity-oriented synthesis (DOS).     

An expedient synthesis of (±)-centrolobine

An expedient synthesis of the antibiotic natural product centrolobine is reported, the key step being the one pot, multi-component construction of a tetrahydropyran-4-one via a ‘revisited’ Maitland-Japp reaction.     

An efficient synthesis of (−)-3-deazaaristeromycin

The coupling reaction of 4-chloro-1H-imidazo[4,5-c]pyridine (6-chloro-3-deazapurine) and (3aS,4S,6R,6aR)-tetrahydro-2,2-dimethyl-6-vinyl-3aH-cyclopenta-[d][1,3]dioxo-4-ol under Mitsunobu reaction conditions provides, after three subsequent straightforward reactions, ready access to the highly biologically active (−)-3-deazaaristeromycin. The versatility of this procedure opens access to a diverse pool of 3-deazapurine carbocyclic nucleosides.     

Stereocontrolled total synthesis of (−)-aspidophytine

The enantioselective stereocontrolled total synthesis of aspidophytine is described. The key indole intermediate was prepared by radical cyclization of 2-alkenylphenylisocyanide, followed by Sonogashira-coupling with a highly functionalized terminal acetylene. The 11-membered cyclic amine, a precursor for the formation of the aspidosperma skeleton, was synthesized using nitrobenzenesulfonamide chemistry. After construction of the pentacyclic skeleton, the lactone ring was formed to complete the total synthesis.     

Stereoflexible total synthesis of (−)-epiquinamide

Hydroxy propiolate rearrangement to conjugated diene, Sharpless asymmetric dihydroxylation and one-pot quinolizine construction have been used as key steps in the total synthesis of (−)-epiquinamide.     

Second-generation total synthesis of (−)-diversifolin

A second-generation total synthesis of (−)-diversifolin has been achieved by a more straightforward strategy, involving a highly stereochemistry-dependent 10-membered ring-closing metathesis and a stereoselective dihydroxylation/lactone transposition sequence. Compared to our previous synthesis, the present synthesis is improved in the yield of the key intermediate 2 (20% in 12 steps from diol 8).     

Stereoselective total synthesis of (−)-pyrenophorol

An efficient stereoselective total synthesis of (−)-pyrenophorol 1 is described. The key steps involved in this synthesis are hydrolytic kinetic resolution (HKR), MacMillan α-hydroxylation, Horner-Wadsworth-Emmons (HWE) reaction, and Mitsunobu cyclization.     

Formal total synthesis of (−)-spongidepsin

The formal total synthesis of (−)-spongidepsin is described. Three fragments I, II, and III were first prepared from readily available starting materials and then assembled to the target compound. The key steps involved in the synthesis are asymmetric α-hydroxylation, Ender's alkylation, and ring-closing metathesis reactions. An alternative route for the fragment II is also achieved involving Sharpless asymmetric epoxidation and Gilman's alkylation as key reactions.     

The total synthesis of (−)-tetrahydrolipstatin

Careful control during the bromolactonisation of β,γ-unsaturated acid 3 was required to afford regioselectively the trans-β-lactone 4 as the major diastereomer. Radical debromination of 4 followed by a three-step sequence of reactions afforded the lipase inhibitor (−)-tetrahydrolipstatin.