Allyl carbonates diastereoselectivity

Reactions with seven- to nine-membered cydic allylic carbonates or halides give the corresponding cydic allyltitanium compounds. These reagents add to aldehydes and imines with moderate to excellent diastereoselectivities [59]. The allyltitanium compound generated from 1-vinylcyclopropyl carbonate reacts regioselectively with aldehydes and ketones at the less substituted carbon atom to provide alkylidenecydopropane derivatives, as shown in Scheme 13.29 [60], The regiochemical outcome of the reaction can be rationalized by assuming an equilibrium between two allyltitanium spedes that favors the less strained tertiary structure. 

Trons-divinyl-pyrrolidines and -piperidines were prepared by sequential intermolecular and intramolecular aminations of bis-allylic carbonates (Scheme 9.21) [22aj. Due to double stereoselection, these reactions proceeded with high diastereoselectivity and enantioselectivity. 

The regio- and diastereoselective rhodium-catalyzed sequential process, involving allylic alkylation of a stabilized carbon or heteroatom nucleophile 51, followed by a PK reaction, utilizing a single catalyst was also described (Scheme 11.14). Alkylation of an allylic carbonate 53 was accomplished in a regioselective manner at 30 °C using a j-acidic rhodium(I) catalyst under 1 atm CO. The resulting product 54 was then subjected in situ to an elevated reaction temperature to facilitate the PK transformation. 

Palladium(0)-catalyzed a-allylation of silyl ethers is a reaction which can be carried out with ketones as well as with aldehydes91. It is highly regiospecific when applied to ketones. a-Allylations can also be performed with enol acetates using allyl carbonates in the presence of catalytic amounts of palladium(O) complexes and (tributyl)methoxytin92,93. The steric course of the reaction has not been studied systematically but a high level of diastereoselectivity is expected and possibilities for asymmetric induction by the use of chiral auxiliaries are envisaged. 

The reaction of PhCH=C(CN)2 with the hydroxy allylic carbonate in the presence of catalytic amounts of Pd2dba3 in CHCI3 and (o-tolyl)3P in THF at 100°C gives the cycloaddition product, the oxepane, in 31% yield with low diastereoselectivity (dba = dibenz[ , ] anthracene) <2001JOC7142>. 

Rhodium(ll)-catalyzed etherification of an allylic carbonate with enantiopure alkenyl alcohols 246 followed by RCM proceeds with excellent diastereoselectivity to afford syn-247 or /f-3,6-dihydropyrans 248 in high yield (Scheme 68) <2004AGE4788>. This methodology can be extended to the preparation of chiral 2,3,6-trisubstituted 3,6-dihydropyrans <2004JA8642>. 

The reaction of benzaldehyde with unsymmetrical allylic bromides in the ionic liquid bmim also proceeds regioselectively to realize a carbon-carbon bond formation at the more substituted allylic carbon (Scheme 5). In the coupling of crotyl bromide with benzaldehyde, the product is a nearly 50 50 mixture of antilsyn diastereomers. Cinnamyl bromide predominantly gives the //-diastereomer. The regio- and diastereoselectivity is similar to that observed for these in aqueous media.104... 

Najera and coworkers introduced a new class of cyclic alanine templates (227, equation 59), the structure of which was anchored on Schollkopf s bislactim ether . Palladium-catalyzed allylations of the chiral pyrazinone derivative 227 with allylic carbonates (228) as substrates led to the formation of y,i5-unsaturated amino acids (229a-c) under very mild and neutral reaction conditions, whereas the required base for enolate preparation has been generated in situ from the allylic carbonate during jr-allyl complex formation. With this protocol in hand, the alkylated pyrazinones 229 were obtained with excellent regio- and diastereoselectivities (>98% ds). Finally, hydrolysis with 6 N aqueous HCl under relatively drastic conditions (150 °C) led to the free amino acids. 

The scalable total synthesis of the cytotoxic natural product (+)-FR182877 was accomplished in the laboratory of E.J. Sorensen.The key steps of the synthetis were an intramolecular Tsuji-Trost allylation to prepare the 19-membered macrocyclic pentaene followed by a double transannular DIels-Alder cycloadditlon to obtain the desired pentacyclic structure. The allylic carbonate was exposed to 10 mol% of the Pd-catalyst under high dilution conditions in THF. The new bond between Cl and Cl 9 was formed with complete diastereoselectivity and in good yield, although the configuration at Cl 9 was not determined. 

In comparison, the iodolactonization of 49 proceeds with very high diastereos-electivity and a 95 5 mixture of the products 50 and 51 is obtained [27, 28]. The diastereoselectivity is tightly controlled by A(1,3) strain between the methyl group on the terminal olefinic carbon and the other methyl group on the allylic carbon so much so that it allows the reaction to proceed primarily through the transition state 50a. 

Khand reaction with CO in the presence of rhodium catalyst. Evans and Robinson reported that the regio-and diastereoselective tandem allylic alkylation/ Pauson-Khand annulation reaction of the propargylic derivatives 99 with the allylic carbonate 100 and CO took place in the presence of a rhodium catalyst only (Scheme 34).113... 

Proton acceptor. In the displacement reaction of allyl carbonates with nitro-alkanes, the presence of this silylated acetamide affords good diastereoselectivity. 

Retention of geometry, perfect chirality transfer, and high reactivity have been observed by the reaction of the chelated Zn enolate of amino acid ester 53 even when PPhs was used [23]. In addition, the non-stabilized enolate 53 was found to be very reactive. Reaction of the allylic carbonates 54 and 56 with the enolate 53 gave 55 and 57 with perfect chirality transfer and high diastereoselectivity. The carbonates and the enolates are highly reactive and the reaction starts even at —78 °C. Lower selectivity was observed by the reaction of the corresponding allylic acetate. 

Several other types of domino reactions have been employed in the synthesis of natural products. Diastereoselective conversion of allylic carbonate 173 into enone 174 was one key transformation in a total synthesis of (+)-3-isorauniticine 175 (Scheme 27).Treatment of allylic sulfonamide 173 with a palladium catalyst re-gioselectively forms a 7r-allylpalladium intermediate by carbonate displacement. Carbopalladation of the pendant alkene, carbonylation, a second intramolecular alkene insertion, and /3-hydride elimination delivers a 67 22 11 mixture of stereoisomers of which enone 174 is the major product (isolated in 45-53% yield). Carbopalladation products can also undergo anion capture reactions. For instance, during the synthesis... 

The molybdenum and tungsten complexes catalyze reactions of soft nucleophiles, such as malonates, related 1,3-dicarbonyl compoimds, and nitroalkanes. Azlactones are also soft carbanions, and Trost has shown that complexes formed from molybdenum and the bis(pyridine) ligands catalyze enantioselective and diastereoselective allylation of azlactones with allylic phosphates to form quaternary amino acids (Equation 20.40). In these reactions, the nucleophile adds to the more substituted position of the allylic electrophile, and a stereocenter is formed at both the allyl carbon and the azlactone carbon. One route to the protease inhibitor tipranavir by the molybdenum-catalyzed allylation with 1,3-dicarbonyl compounds was demonstrated by Trost (Equation 20.41), and the Merck process group used related allylation chemistry with Trost s bis(pyridine) ligand to prepare the cyclopentanone precursor to various analogs of tipranavir (Equation 20.42). 

Many diastereoselective allylations form a new stereocenter at one of the allylic carbons and at the nucleophilic carbon. For example, an iridium complex containing a phosphite ligand catalyzes enantioselective and diastereoselective formation of products containing two stereocenters, one at the original nucleophile and one at the original allyl electrophile (Equation 20.58). In another example shown in Equation 20.59, Trost s palladium catalyst leads to the reaction of allylic esters with chiral azlactone pronucleophiles with high diastereomeric and enantiomeric excess, as does the related molybdenum catalyst. In these cases, the metal appears to control the new stereocenter at the allyl group, as well as the relationship between this stereocenter and the new stereocenter formed at the nucleophile. 

One possible role for the enzyme may be to populate and provide electrostatic stabilization of the reactive chair conformer 19. The outcome of the Claisen rearrangement can be predicted by evaluating three structural features. The alkene geometry of the allyl and the vinyl moieties will determine the outcome of syn- or a t/-diastereoselection, and the stereogenicity at the allylic carbon determines an outcome featuring 1,3-chirality transfer. 

A reported diastereoselective synthesis of precursor A of vitamin D3 involved the use of 2-methylcyclopent-2-enone as starting material. The Mukaiyama-Michael conjugate addition of ketene acetal 269 in the presence of trityl hexachloroaniimonate afforded the adduct 270. The lateral chain was introduced, according the procedure of Tsuji, by the treatment of crude 270 with allyl carbonate and palladium dibenzylideneacetone " (Scheme 63). The expected product 271 was obtained in 63% yield from 269. Reduction of 271 with LAH afforded a mixture of diols that was selectively tosylated at the primary hydroxy group. The secondary hydroxy group was protected with the methoxymethyl group and further functional modifications afforded the lactone 272. The reaction of lithium dimethyl methylphosphonate with the lactone 272 completed the synthesis of the AB-des-cholestane derivative 273. 

The above aUylic substitution/aldehyde allylation process establishes another allylic carbonate available for another round of exactly the same sequence. For this, an achiral copper(I)-xantphos catalyst was used to yield densely functionalized, highly enantioenriched cyclopentanes with excellent levels of diastereoselection (not shown). It is worthy of mention that the initial enantioselective borylatiOTi step proceeds through an a t/-SN2 -type substitution, whereas the subsequent diastereo-selective displacement is a sy -SN2 -type borylation. 

A complementary functional cyclopropane assembly relies on the utilization of the Tsuji-Trost reaction [101], A highly enantio and diastereoselective cou-pling/cyclopropanation sequence of acyclic amides 85 with allyl carbonates 86 is illustrated in Scheme 5.30 [102], In this reaction, a scarcely described addition of the nucleophilic enolate intermediate onto the central carbon of the i-allyl palladium is involved, which affords the corresponding cyclopropane. 

The use of a chelated enolate, obtained from the corresponding amino ester and zinc dichloride, afforded, in the allylation reaction of optically active allyl carbonate, a single regioisomer with excellent diastereoselectivity and chirality transfer (eq 37). The r-(T-7r-isomerization is suppressed under these reaction conditions. 

More recently, in 2003, Sorensen demonstrated an impressive, scalable synthesis of cytotoxic natural product (+)-FRl 82877 34, which employed an intramolecular Tsuji-Trost allylation reaction to prepare the 19-membered macrocycle 33. Exposure of allylic carbonate 32 to 10 mol% palladium catalyst under high dilution formed the key bond in good yield and complete diastereoselectivity. This key intermediate was subsequently converted to (+)-FRl 82877 34 via an intramolecular Diels-Alder reaction. 

Removal of the unsaturated side-chain appendage from C-8 in 22 provides diol lactone 23 and allylic bromide 24 as potential precursors. In the synthetic direction, a diastereoselective alkylation of a hydroxyl-protected lactone enolate derived from 23 with allylic bromide 24 could accomplish the assembly of 22, an intermediate that possesses all of the carbon atoms of PGF2o- It was anticipated that preexisting asymmetry in the lactone enolate would induce the... 

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