Masashi Yokoya

A general method for the asymmetric synthesis of both enantiomers of 1-substituted 1,2,3,4-tetrahydro-β-carbolines employing pyroglutamic acid derivatives as chiral auxiliaries

9-(S)-Pyroglutaminyl-β-carbolines were allowed to react with a nucleophile (allyltributyltin or a silyl enol ether) in the presence of 2,2,2-trichloroethyl chloroformate to give 1,2-addition products in good yields and high diastereoselectivity. The chiral auxiliary at N-9 was readily removed by a mild hydrolysis. The same chiral source afforded both enantiomers by simply altering a protecting group of the amide nitrogen. That is, (S)-pyroglutaminyl groups which had an N-alkyl group afforded the (S) isomer, whereas the ones having an N-acyl group produced the (R) isomer of the addition products.

SYNTHESIS OF TETRAHYDROISOQUINOLINE ANTITUMOR NATURAL PRODUCTS : CONSTRUCTION OF TRICYCLIC LACTAMS THROUGH PICTET-SPENGLER-TYPE CYCLIZATION OF N-METHYL-3-ARYLMETHYLPIPERAZINE-2,5-DIONE WITH ETHYL DIETHOXYACETATE

6-Hydroxymethyl-7,8,10-trimethoxy-2,6-dimethyl-3,6,11,11a-tetrahydro-2H-pyrazino[1,2-b]isoquinoline-1,4-dione (10) was prepared stereoselectively by Pictet-Spengler-type cyclization of the O,N-acetal of 3-arylmethylpiperazine-2,5-dione (8) in high yield. This procedure provides an efficient route for the total synthesis of renieramycin G and cribrostatin 4.

Stereoselective Total Synthesis of (−)-Renieramycin T

A stereoselective total synthesis of (-)-Renieramycin T (1t) from a key tetrahydroisoquinoline intermediate previously utilized in our formal total synthesis of Ecteinascidin 743 is described. The synthesis features a concise approach for construction of the pentacyclic framework using a Pictet-Spengler cyclization of bromo-substituted carbinolamine 17, which obviates the regioselectivity problem of the Pictet-Spengler cyclization. The results of cytotoxicity studies are also presented.

Microarray-Based Transcriptional Profiling of Renieramycin M and Jorunnamycin C, Isolated from Thai Marine Organisms

Renieramycin M and jorunnamycin C, two isoquinolinequinone compounds differing only at the C-22 ester side chain, were evaluated for their cytotoxic effects on human colon (HCT116) and breast (MDA-MB-435) cancer cell lines. These two compounds displayed potent cancer cell growth inhibition, their IC50 values reaching nanomolar order. To examine their effects on transcription, we carried out oligonucleotide microarray analysis with focus on the similarities and differences between the two compounds in terms of transcriptional profiles. We found that the down-regulation of PTPRK (protein tyrosine phosphatase receptor type K) can be considered as a biomarker responsive to the cytotoxic effects of this class of antitumor marine natural products.

Chemistry of Renieramycins. Part 14: Total Synthesis of Renieramycin I and Practical Synthesis of Cribrostatin 4 (Renieramycin H)

The first total synthesis of (±)-renieramycin I, which was isolated from the Indian bright blue sponge Haliclona cribricutis, is described. The key step is the selenium oxide oxidation of pentacyclic bis-p-quinone derivative (3) stereo- and regioselectively. We also report a large-scale synthesis of cribrostatin 4 (renieramycin H) via the C3-C4 double bond formation in an early stage based on the Avendaño’s protocol, from readily available 1-acetyl-3-(3-methyl-2,4,5-trimethylphenyl)methyl-piperazine-2,5-dione (8) in 18 steps (8.3% overall yield). The synthesis provides unambiguous evidence supporting the original structure of renieramycin I.