A synthetic approach to rocaglamide via reductive cyclization of .delta.-keto nitriles

Abstract

The anticancer agent rocaglamide contains a novel bicyclo[3.3.0]octanol structure. The approach to this molecule involved the preparation of a hydroxy ketone intermediate via a samarium-mediated cyclization. This ketone was then converted into an excellent Michael acceptor via novel chemistry. Subsequent steps led to the preparation of an isomer of rocaglamide. An X-ray determination supported our view that cuprate addition occurred with unusual concave selectivity. 77matographed on silica gel (water-saturated ethyl acetate) to yield the product, 0.36 g (31% yield): [ a I z 6~ -21.8' (c 0.40, H20); 'H NMR (200 MHz, D20) 6 1.03, 1.20 (9, 6 H, CH3), 1.37 (dd, J = 13 Hz, J = 11.8 Hz, 1 H, C5-H,), 1.83 (dd, J = 13 Hz, J = 4. To prepare D-fructose, the condition was essentially the same except that no aldehyde was used. Triosephosphate isomerase (500 units) was added to the mixture in addition to the aldolase.The product was identified with HPLC and compared with that of authentic D-fructose.Fuculose-1-phosphate Aldolase Catalyzed Reaction:Preparation of D-Ribulose. To a Tris buffer solution (85 mL, 10 mM, pH 7.5, containing 6 mM KC1, 6 mM CO(NO,)~) were added sodium arsenate (200 mmol), glycoaldehyde (1.7 g, 14.2 mmol), and dihydroxyacetone (3.2 g, 17.8 mmol). The solution was adjusted to pH 7.5 followed by adding 100 mg of the enzyme-containing E. coli cells and 1 mg of lysozyme (51 000 pm) to break the cells. The mixture was stirred for 24 h. TLC showed no glycoaldehyde was present, R, 0.75. The mixture was lyophilized and triturated with 4 X 75 mL of methanol and filtered, and the filtrate was evaporated. The product was purified on Dowex 50 (Ba2+) column with water as a mobile phase to give 1.70 g of product, which was identical with authentic D-ribulose (from Aldrich) by HPLC ( t R = 4.9 min) and NMR analyses. Rhamnulose-1-phosphate Aldolase Catalyzed Reactions.The E. coli cells containing this enzyme were used to prepared L-xylulose from DHA and glycoaldehyde under the same conditions as that for the preparation of D-ribulose. The product obtained (1.60 g, 76% yield based on glycoaldehyde) was identical with authentic L-xylulose (from Aldrich) by HPLC (tR = 5.0 min) and NMR analyses. When L-lactaldehyde (4.75 mmol, prepared by acid hydrolysis of the dimethyl acetal precursor)lB was used as acceptor and dihydroxyacetone (5.56 mmol) as donor, a mixture of L-rhamnulose and L-rhamnose (0.61 g, 71 % yield) was obtained based on 'H NMR, 13C NMR, and HPLC analyses ( t~ rhamnose = 5.2 min; tR rhamnulose = 4.8 min; the ratio of aldose to ketose is 0.6:0.4).Acknowledgment.

Total Synthesis of (±)-Rocaglamide via Oxidation-Initiated Nazarov Cyclization

“…In addition to being the first synthesis of the natural product, it provided confirmation of its absolute stereochemical assignment. An approach pioneered by Taylor 8 and Kraus 9 in the late 1980’s and early 1990’s took advantage of a samarium (II) iodide-mediated intramolecular pinacol coupling to form the cyclopentane ring. Both quaternary fusion stereocenters were formed in the correct relative configuration.…”

Cyclizations in the homolytic reactions of unsaturated nitriles with tert‐butylmercury halides in the presence of proton donors

“…[3][4][5] observed in the oxidative decarboxylation of 3-cyanocarboxylic acids, 6 in Mn(III) oxidations of b-diketones yielding, after an initial cyclization, 4-or 5-cyanoalkyl radicals, 7 and in the intramolecular addition of ketyls, or their trimethylsilyl derivatives, to gor -unsaturated nitriles. 8,9 Initial experiments with t-BuHgX (X = Cl, I) and CH 2 CH(CH 2 ) 3 CN led only to the uncyclized 1:1 adducts in yields comparable to those observed for 1hexene. This was not surprising because the 5-exo cyclization of .…”

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) andN,N-di-iso-propyl ethyl amine (Hünig base): an effective reagent combination for selective silylation and elimination reactions

“…The few examples for which the use of TMSOTf/ i-Pr 2 NEt was reported are concerned with the protection of sterically congested secondary or tertiary alcohols [3 -5]. Two examples are given in Scheme 1 in which the tertiary alcohols 1 and 3 are converted to the corresponding silyl ethers 2 [3] and 4 [4].…”