Total Syntheses of (+)-Chloropuupehenone and (+)-Chloropuupehenol and Their Analogues and Evaluation of Their Bioactivities

• Published in: Journal of organic chemistry Vol. 69; no. 18; pp. 6065 - 6078
• Main Authors: Hua, Duy H, Huang, Xiaodong, Chen, Yi, Battina, Srinivas K, Tamura, Masafumi, Noh, Sang K, Koo, Sung I, Namatame, Ichiji, Tomoda, Hiroshi, Perchellet, Elisabeth M, Perchellet, Jean-Pierre
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 03.09.2004; Amer Chemical Soc
• Subjects: Alicyclic compounds, terpenoids, prostaglandins, steroids; Animals; Carrier Proteins - antagonists & inhibitors; Chemistry; Chemistry, Organic; Cholesterol Ester Transfer Proteins; Cyclization; Exact sciences and technology; Glycoproteins - antagonists & inhibitors; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Heterocyclic Compounds, 4 or More Rings - chemical synthesis; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; Inhibitory Concentration 50; Leukemia L1210; Molecular Structure; Organic chemistry; Physical Sciences; Preparations and properties; Pyrans - chemical synthesis; Pyrans - chemistry; Pyrans - pharmacology; Rats; Science & Technology; Sesquiterpenes - chemical synthesis; Stereoisomerism; Structure-Activity Relationship; Terpenoids; IN-VITRO; ESTER TRANSFER PROTEIN; ENANTIOSPECIFIC SYNTHESIS; EFFICIENT SYNTHESIS; ORDER VERONGIDA; WIEDENDIOL-A; ALPHA-TOCOPHEROL; LYMPHATIC ABSORPTION; BIOLOGICAL-PROPERTIES; MARINE NATURAL-PRODUCTS; Rat; Leukemia; Oxygen heterocycle; Stereoselectivity; Ester; Absorption; Lithium Organic compounds; Sesquiterpenes; Inhibition; Terpenoid; Diol; Condensation reaction; Quinone; Rodentia; Pyran derivatives; Tetracyclic compound; Aldehyde; Oxides selenides; Organic chlorine compounds; Naphthalene derivatives; Biological activity; Cholesterol; Desilylation; Protein; Total synthesis; L1210 cell line; Vertebrata; Terpene; Mammalia; Cyclization; Benzenic compound
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0491399

Tetracyclic pyrans (+)-chloropuupehenone (1) and (+)-chloropuupehenol (5) and its C8-R-isomer (+)-3 were synthesized via a one-pot condensation of 1-chloro-2-lithio-3,5,6-tris(tert-butyldimethylsilyloxy)benzene (8) with (4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethylnaphthalene-1-carboxaldehyde (7). The major condensation product, (4aS,6aR,12bS)-2H-9,10-bis(tert-butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene (4), after desilylation provided tetracyclic pyran (+)-(4aS,6aR,12bS)-2H-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene-9,10-diol (3). At a dosage of 42 mg/rat over 8 h, pyran diol 3 inhibited the intestinal absorption of cholesterol by 71% in rats. Tetracyclic pyran 4 was also converted to o-quinone 28, which inhibited cholesteryl ester transfer protein (CETP) activity and L1210 leukemic cell viability with IC50 values of 31 and 2.4 μM, respectively. Diol (+)-5 inhibited CETP activity with an IC50 value of 16 μM. The minor condensation product, (4aS,6aS,12bS)-2H-9,10-bis(tert-butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene (6), was transformed into (+)-5 and (+)-1. A stepwise stereoselective synthesis of (+)-1 was also developed utilizing an oxyselenylation ring-closure reaction. The synthetic sequence also produced four biologically active naturally occurring drimanic sesquiterpenes, (+)-drimane-8α,11-diol (34), (−)-drimenol (38), (+)-albicanol (39), and (−)-albicanal (31) as intermediates.