Butyrolactone natural products synthesis

Chiral butenolides are valuable synthons towards y-butyrolactone natural products [37] and have also been successfully applied to the synthesis of paraconic acids. The lactone 91, readily available from the hydroxyamide (rac)-90 by enzymatic resolution [38] followed by iodolactonization, proved to be an especially versatile key intermediate. Copper(I)-catalyzed cross coupling reactions with Grignard reagents allowed the direct introduction of alkyl side chains, as depicted in 92a and 92b (Scheme 13) [39, 40]. Further... 

Bromoetherification of alkenes can be achieved using NBS in the desired alcohol as the solvent. The reaction of 1,3-dichloropro-pene with NBS in methanol yields an a-bromo dimethyl acetal in the first step in a convenient synthesis of cyclopropenone. Using propargyl alcohol the reaction depicted in eq 22 has been extended to an annulation method for the synthesis of a-methy-lene-y-butyrolactones. Intramolecular bromoetherification and bromoamination reactions are generally very facile (eq 23). In natural products synthesis, bromoetherification has been used for the synthesis of cyclic ethers (by subsequent debromination, see... 

Recently, the group extended this methodology to a-substituted acroleins and applied their reaction nicely to the short synthesis of various enantio-enriched y-butyrolactone natural products [35aj. 

B.V.C. Natural Product Synthesis. With these methodologies, natural products a-alkyUdene-y butyrolactone structure unit are readily synthesized for examnt T factor,[5 i ( )-isohinokinin,[ ° (+)- or ( )-methylenolactocin (.P,y-trans) i62 phaseoUnic add (/3,y-cw),t isopilocarpine (formal synthesis), ]. 7 ... 

An obvious way to target chiral compounds is to start with a compound in which the chiral center is already present. Here natural products and derivatives offer a rich pool of generally inexpensive starting materials. Examples include L-hydroxy and amino adds. Sometimes, just one out of many chiral centers is predestined to remain, as in the synthesis of vitamin C from D-glucose, or in the preparation of (S)-3-hydroxy-y-butyrolactone from ladose. 

Both enantiomers of the bicyclic enone 78 and their derivatives have been proved to be useful chiral building blocks for the synthesis of natural products [29], among them y-butyrolactones. 78 is readily available in either enantiomeric form by a Diels-Alder reaction of furan with a-acetoxyacry-lonitrile and subsequent hydrolysis, followed by a resolution of the racemate... 

This methodology was expanded to the synthesis of (-)-amabiline (145)(/42c). Namely, 2-aza-allylstannane 189 (derived from 25,35-0-isopropylidene-y-butyrolactone) was exposed to butyllithium in THF at -78"C to provide 3a-(3,4-methylenedioxy)phenylhexahydroindoline (190) along with a diastereomer in 74% yield (a 5 1 mixture of two diastereo-mers). The Pictet-Spengler cyclization of 190, followed by acid treatment, afforded (-)-amabiline (145), confirming the absolute stereochemistry of the natural product (Scheme 17). 

Chiral a-methylene-y-butyrolactones An asymmetric synthesis of a-mcthylcne- y-butyrolactones such as 7 utilizes the benzoate (2) of (1R,2S)-1, which on reaction with 1,1-dibromohexane and Zn-TiCU TMKDA forms the (Z)-cnol ether 3. Thus this product reacts with dichlorokctcnc to form the cyclobutanonc (—)-4. Bacyer-Villiger oxidation of 4 followed by oxidation with chromium(ll) perchlorate provides the a-chlorobutenolide (+)-5. Hydrogenation and oxidation provides the /3-carboxy-y-butyrolactone (—) 6. The final step involves introduction of a methylene group to provide (—)-7, mcthylcnolactocin, a natural antitumor antibiotic. 

Specific examples of the synthesis of natural products containing a-methylene-butyrolactone functions are to be found in the full reports from Danishefsky s group" and from Grieco s group " on the total synthesis of ( )-vernolepin (79) and its isomer, vernomenin Grieco et al. have also reported a synthesis of ( )-desoxyvernolepin " and demonstrated the use of the selenenation method for the introduction of an a-methylene substituent with a neat total synthesis of (+)-costunolide (80) from santonin," together with a general, stereochemically-... 

Lactonization of a hydroxy-acid to a butyrolactone is achieved, using dimethyl-formamide dineopentyl acetal, during a synthesis of oxygenated nor-heliango-lides. The chiral lactone (164) is prepared from (iJ)-malic acid, its dianion is alkylated at carbon to give the /ra/i5-disubstituted lactone (165) in moderate yield, and this is used in a synthesis of (—)-aplysistatin (Scheme 94). An independent, biogenetically patterned synthesis of this natural product, using tetronic acid intermediates, has been described. ... 

The product allyl alcohols have been employed in the synthesis of various biologically active compounds, such as the anti-tumor agent Saikomycin ester (5) and a-methylene-y-butyrolactones (6). These lactones constitute 10% of all natural products, including mecUcinals for cardio-vascular diseases (7). In materials chemistry, the Morita-Baylis-Hillman products have been applied to prepare novel side chains of liquid crystal polymers (8). 

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