- Structural elucidation of cisoid and transoid cyclization pathways of a sesquiterpene synthase using 2-fluorofarnesyl diphosphates
-
Sesquiterpene skeletal complexity in nature originates from the enzyme-catalyzed ionization of (trans,trans)-farnesyl diphosphate (FPP) (1a) and subsequent cyclization along either 2,3-transoid or 2,3-cisoid farnesyl cation pathways. Tobacco 5-epi-aristolochene synthase (TEAS), a transoid synthase, produces cisoid products as a component of its minor product spectrum. To investigate the cryptic cisoid cyclization pathway in TEAS, we employed (cis,trans)-FPP (1b) as an alternative substrate. Strikingly, TEAS was catalytically robust in the enzymatic conversion of (cis,trans)-FPP (1b) to exclusively (?99.5%) cisoid products. Further, crystallographic characterization of wild-type TEAS and a catalytically promiscuous mutant (M4 TEAS) with 2-fluoro analogues of both all-trans FPP (1a) and (cis,trans)-FPP (1b) revealed binding modes consistent with preorganization of the farnesyl chain. These results provide a structural glimpse into both cisoid and transoid cyclization pathways efficiently templated by a single enzyme active site, consistent with the recently elucidated stereochemistry of the cisoid products. Further, computational studies using density functional theory calculations reveal concerted, highly asynchronous cyclization pathways leading to the major cisoid cyclization products. The implications of these discoveries for expanded sesquiterpene diversity in nature are discussed.
- Noel, Joseph P.,Dellas, Nikki,Faraldos, Juan A.,Zhao, Marylin,Hess, B. Andes,Smentek, Lidia,Coates, Robert M.,O'Maille, Paul E.
-
body text
p. 377 - 392
(2011/02/23)
-
- Bisabolyl-derived sesquiterpenes from tobacco 5-epi-aristolochene synthase-catalyzed cyclization of (2Z,6E)-farnesvl diohosohate
-
We report the structures and stereochemistry of seven bisabolyl-derived sesquiterpenes arising from an unprecedented 1,6-cyclization (cisoid pathway) efficiently catalyzed by tobacco 5-epi-aristolochene synthase (TEAS). The use of (2Z,6E)-farnesyl diphosphate as an alternate substrate for recombinant TEAS resulted in a robust enzymatic cyclization to an array of products derived exclusively (≥99.5%) from the cisoid pathway, whereas these same products account for ca. 2.5% of the total hydrocarbons obtained using (2E,6E)-farnesyl diphosphate. Chromatographic fractionations of extracts from preparative incubations with the 2Z,6E substrate afforded, in addition to the acyclic allylic alcohols (2Z,6E)-farnesol (6.7%) and nerolidol (3.6%), five cyclic sesquiterpene hydrocarbons and two cyclic sesquiterpene alcohols: (+)-2-epiprezizaene (44%), (-)-α-cedrene (21.5%), (R)-(-)-β-curcumene (15.5%), R-acoradiene (3.9%), 4-epi-α-acoradiene (1.3%), and equal amounts of α-bisabolol (1.8%) and epi-R-bisalolol (1.8%). The structures, stereochemistry, and enantiopurities were established by comprehensive spectroscopic analyses, optical rotations, chemical correlations with known sesquiterpenes, comparisons with literature data, and GC analyses. The major product, (+)-2-epi-prezizaene, is structurally related to the naturally occurring tricyclic alcohol, jinkohol (2-epi-prezizaan-7 β-ol). Cisoid cyclization pathways are proposed by which all five sesquiterpene hydrocarbons are derived from a common (7R)-β-bisabolyl+/pyrophosphate - ion pair intermediate. The implications of the cisoid catalytic activity of TEAS are discussed.
- Faraldos, Juan A.,O'Maille, Paul E.,Dellas, Nikki,Noel, Joseph P.,Coates, Robert M.
-
experimental part
p. 4281 - 4289
(2010/05/15)
-
- Stereocontrolled Synthesis of (+/-)-Acorenone B Based on New Ring Conversion
-
On the basis of a new ring conversion reaction from the bicyclooctane ring to the spirodecane ring, (+/-)-acorenone B was synthesized in a stereocontrolled fashion.
- Nagumo, Shinji,Suemune, Hiroshi,Sakai, Kiyoshi
-
p. 1778 - 1779
(2007/10/02)
-
- Synthetic Studies on Acorane-Alaskane Sesquiterpenes. II. Total Synthesis of (+/-)-Acorenone
-
The metal-ammonia reduction of the cyclopentabenzofuran derivative (2b) afforded a mixture of 4-epi-β-acorenol (5), a disubstituted olefin (8) as the main product, and a perhydro compound (9).Compound 8 was converted to 5 via the exo-diene (15).Dehydration of 5 afforded the 4-epi-β-acoradiene (6), selective reduction of which gave the monoolefin (7), and then the allylic oxidation of 7 gave (+/-)-acorenone (3) in good yield.Keywords - acorane-alaskane sesquiterpene; acorenone; cyclopentabenzofuran; total synthesis; 4-epi-β-acorenol; 4-epi-α-acorenol; 4-epi-β-acoradiene; metal-ammonia reduction; conjugate reduction; terminal olefin reduction.
- Iwata, Chuzo,Fusaka, Takafumi,Maezaki, Naoyoshi,Nakamura, Shizou,Shinoo, Yasutaka,et al.
-
p. 1638 - 1645
(2007/10/02)
-
- Synthetic Studies on Acorane-Alaskane Sesquiterpenes. I. Total Synthesis of (+/-)-β-Acorenol
-
(+/-)-β-Acorenol (2) was synthesized by the methal-ammonia reduction of (1R*,3aR*,5aR*,9aR*)-2,3,3a,4-tetrahydro-1,4,4,7-tetramethyl-1H,5aH-cyclopentabenzofuran (11a), which was prepared from the spirodienone
- Iwata, Chuzo,Nakamura, Shizuo,Shinoo, Yasutaka,Fusaka, Takafumi,Okada, Hideko,at al.
-
p. 1961 - 1968
(2007/10/02)
-
- Novel Cyclopentabenzofuran Intermediates for the Synthesis of Acorane-Alaskane Sesquiterpenes: Total Synthesis of (+/-)-β-Acorenol and (+/-)-Acorenone
-
Cyclopentabenzofuran derivatives (5a) and (5b) were synthesized from spirodienone esters (6a) and (6b), respectively, and the utility of these intermediates in acorane-alaskane sesquiterpene synthesis is illustrated by their conversion into (+/-)-β-acorenol (4a) and (+/-)-acorenone (1).
- Iwata, Chuzo,Nakamura, Shizuo,Shinoo, Yasutaka,Fusaka, Takafumi,Kishimoto, Michie,et al.
-
p. 781 - 782
(2007/10/02)
-