Hongbin Zhai

Expedient synthesis of the tetracyclic core of ent-nakadomarin A.

An efficient eight-step assembly of the tetracyclic core (ABCD rings) of ent-(+)-nakadomarin A, a bioactive hexacyclic marine alkaloid, has been realized with Sonogashira coupling, platinum(II)-promoted cascade cyclizations, and saturation of a challenging carbon-carbon double bond through a hydroboration/oxidation/xanthate formation/Barton-McCombie deoxygenation sequence as key transformations.

Efficient Total Synthesis of Marine Alkaloid (−)‐Nakadomarin A

In 1997, Kobayashi and co-workers disclosed the isolation of ( )-nakadomarin A (1, Scheme 1) from an Okinawan marine sponge Amphimedon sp. Its unique 8/5/5/5/15/6 hexacyclic full-ring structure containing four stereogenic centers and an imbedded furan was shown with extensive NMR spectroscopic analyses including NOE and proton coupling data. The biological properties of 1 range from prominent cytotoxicity against murine lymphoma L1210 cells to outstanding antimicrobial and CDK4 inhibitory activities. Since 2003, elegant total and formal syntheses of 1 have been accomplished by the laboratories of Nishida, Kerr, Dixon, Mukai, and Funk, and relevant synthesis studies have been reported by an array of research teams. Having communicated a rapid construction of the tetracyclic core (ABCD rings) of ent-1 by showcasing the power of a Pt-promoted cascade reaction sequence, we report herein a novel total synthesis of ( )-nakadomarin A with higher practicality and efficiency. The synthesis features: 1) the assembly of the tetracyclic core through the PtCl2-catalyzed cascade cyclization strategy [3i] (4!3, Scheme 1) followed by saturation of the C8=C9 double bond (3!2), and 2) CSA-assisted Z-selective olefin ringclosing metathesis (RCM; within 2!1) involving a monoamine precursor (17, Scheme 2) used to replace Dixon s more polar diamine substrate (19b) for the F ring generation. For the rest of our synthesis plan (Scheme 1), the E ring can be forged by typical olefin RCM (within 2! 1) prior to the F ring formation. Enyne 4 can be obtained through Sonogashira coupling of terminal alkyne 5 with iodofuran 7. While reductive amination of aldehyde 6 can be implemented to form alkyne 5, furan 7 can be accessible from cyclization/iodination of conjugated ynone 8 in the presence of hydriodic acid. Finally, ketone 8 can be prepared from 9 and 10. The synthesis of disubstituted furan 7 is described in Scheme 3. Propargyl alcohol THP ether (9) was deprotonated and then treated with g-butyrolactone (10) in the presence of BF3·OEt2 to give ynone 8, treatment [5] of which with hydriodic acid (3m) effected the desired cyclization/iodination to afford a mixture containing alcohol 11 and its THP ether (generated due to THP migration). Subjecting the above mixture to TsOH in MeOH led to 11 (52%, from 9) as the sole product, which was silylated to furnish iodofuran 7 in 89% yield. Unsaturated aldehyde 6 was converted into compound 5 (54%, overall yield) by stepwise reductive amination (propargylamineHCl, TEA, tBuOH, evaporation, NaBH4, MeOH) followed by N-sulfonylation (BsCl, TEA, DCM). [Pd ACHTUNGTRENNUNG(PPh3)2Cl2]/CuI-catalyzed Sonogashira coupling of terminal alkyne 5 with furan 7 in degassed TEA/DMF at room temperature gave rise to the key molecule 4 (87%), in which the enecarbamate, alkyne and furan functionalities [a] Dr. B. Cheng, F. Wu, Y. Zhou Hefei National Laboratory for Physical Science at Microscale and Department of Chemistry University of Science and Technology of China Hefei 230026 (P.R. China)

Total Synthesis of (±)-Sculponeatin N

The first total synthesis of the (±)-sculponeatin N (a 6,7-seco-ent-kaurane diterpenoid discovered by Sun and co-workers) has been achieved. The features include a regio- and stereoselective aldol reaction to form a lactone, an intramolecular Diels-Alder reaction to install B and C rings simultaneously, and a radical cyclization to forge the D ring.

Concise Synthesis of the Oxapentacyclic Core of Cortistatin A

A concise synthetic approach for constructing the oxapentacyclic framework of cortistatin A is described. The synthesis features a furan-oxyallyl [4 + 3] cycloaddition and double-intramolecular aldol reactions. In addition, an interesting core structure was obtained in 11 steps from furan by using our method.

One-Step Construction of Tetrahydro-5H-indolo[3,2-c]quinolines from Benzyl Azides and Indoles via a Cascade Reaction Sequence

A novel one-step assembly of tetrahydro-5H-indolo[3,2-c]quinolines from benzyl azides and indoles via a formal [4 + 2] cycloaddition is described. A cascade reaction sequence, which involves benzyl azide-to-iminium rearrangement followed by two sequential Pictet-Spengler reactions, generates the tetracycles in moderate to excellent yields. The current method is applicable to a broad substrate scope and holds significant potential in constructing polycyclic indolines with tertiary and/or quaternary carbon centers.

Enantiocontrolled synthesis of (-)-9-epi-pentazocine and (-)-aphanorphine.

We have developed novel asymmetric routes to (-)-9- epi-pentazocine and (-)-aphanorphine from a d-tyrosine derivative. The tricyclic frameworks of (-)-9- epi-pentazocine and (-)-aphanorphine were assembled stereoselectively via intramolecular Friedel-Crafts reaction of the corresponding bicyclic precursors, generated with titanium-promoted enyne cyclization and indium-initiated atom-transfer radical cyclization, respectively.

Synthesis of Polysubstituted Pyridines via a One-Pot Metal-Free Strategy.

An efficient strategy for the one-pot synthesis of polysubstituted pyridines via a cascade reaction from aldehydes, phosphorus ylides, and propargyl azide is reported. The reaction sequence involves a Wittig reaction, a Staudinger reaction, an aza-Wittig reaction, a 6π-3-azatriene electrocyclization, and a 1,3-H shift. This protocol provides quick access to the polysubstituted pyridines from readily available substrates in good to excellent yields.

Facile Synthesis of 2-Arylphenols via Palladium-Catalyzed Cross-Coupling of Aryl Iodides with 6-Diazo-2-cyclohexenones

2-Arylphenols were conveniently synthesized from aryl iodides and 6-diazo-2-cyclohexenones, in moderate to excellent yields, via tandem Pd-catalyzed cross-coupling/aromatization. The preliminary results for the corresponding enantioselective version showed that the coupling products could be generated in up to 72% ee.

Fast and Protecting-Group-Free Synthesis of (±)-Subincanadine C

The first total synthesis of (±)-subincanadine C has been accomplished in a protecting-group-free fashion. This pentacyclic indole alkaloid was synthesized in six steps from the known intermediate 4, featuring Ni(COD)(2)-mediated intramolecular Michael addition as a key transformation.

SmI2-Mediated Carbon−Carbon Bond Fragmentation in α-Aminomethyl Malonates

A new and efficient samarium diiodide-promoted carbon-carbon bond fragmentation reaction of alpha-aminomethyl malonates, taking place normally at room temperature and generating the corresponding deaminomethylation products in 74-94% yields, is reported. The presence of the amino group is necessary for the success of the current transformation.