Principles and Applications of Asymmetric Synthesis
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8.2 MISCELLANEOUS METHODS |
463 |
Scheme 8±12
Based on this method,39 several chiral axial aryls such as 29, 30, 31, and 32 have been prepared.31a,41 The diastereomeric alkaloids …ÿ†-ancistrocladine 29 and …‡†-hamatine 30 are also obtainable from the plants.
In fact, compounds 31 and 32 from Ancistrocladus hamatus have the same con®guration in the axial stereogenic unit (atriousiners) but opposite con®guration for the two stereogenic centers of the tetrahydroisoquinoline ring.
Lipshuz et al.42 have developed a new approach to the chiral biaryls mediated by cyanocuprate. The diastereoselective coupling depends on the proper choice of the tether (Scheme 8±13).
The bromo-aryl groups are ®rst linked by (S,S)-stilbene diol to form the dibromide 33. Compound 33 is then dilithiated with t-BuLi at ÿ78 C, followed by addition of CuCN. Intermediate 34 is presumably formed during the reaction. Reductive elimination promoted by molecular oxygen provides compound 35 at 77% yield with 93:7 diasteroselectivity. The ®nal biaryl compound ellagi-
464 ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES
Scheme 8±13
tannin (tellimagrandrin II) can be obtained upon removal of the tether in 35 (the chiral stilbene diol) via catalytic hydrogenation over Pd/C in MeOH.
8.2.4The Asymmetric Kharasch Reaction
In 1959, Kharasch et al.43 reported an allylic oxyacylation of ole®ns. In the presence of t-butyl perbenzoate and a catalytic amount of copper salt in re- ¯uxing benzene, ole®n was oxidized to allyl benzoate, which could then be converted to an allyl alcohol upon hydrolysis. It is desirable to introduce asymmetric induction into this allylic oxyacylation because allylic oxyacylation holds great potential for nonracemic allyl alcohol synthesis. Furthermore, this reaction can be regarded as a good supplement to other asymmetric ole®nic reactions such as epoxidation and dihydroxylation.
The mechanism of the reaction involves initiating the reaction by forming a t-butoxy radical via copper(I)-mediated reductive homolysis of the perester O±O bond. The t-butoxy radical then abstracts an allylic hydrogen atom to give t-butanol and an allylic radical, followed by a rapid addition of copper(II) to the allylic radical to generate copper(III) benzoate with an allyl fragment. Rearrangement of the copper(III) intermediate gives the allylester product with the regeneration of Cu(I) catalyst. It has been found that copper(III) coordinated with a suitable ligand can induce the asymmetric formation of the allyl benzoate product (Scheme 8±14).
Andrus et al.44 employed a C2-symmetric bis(oxazoline) copper catalyst in the Kharasch reaction. When cyclohexene was used as the reaction substrate, yields ranging from 34% to 62% and ee from 30% to 81% were observed (Scheme 8±15).
DattaGupta and Singh45 report the results of bis(oxazolinyl)pyridine induced asymmetric allylic oxidation. The reaction proceeds with 59% yield and 56% ee (Scheme 8±16).
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8.2 MISCELLANEOUS METHODS |
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Scheme 8±14. Mechanism of allylic ole®n oxidation with Cu(I) and perester.
Scheme 8±15. Enantioselective allylic oxidation of ole®ns.
Scheme 8±16
8.2.5 Optically Active Lactones from Metal-Catalyzed Baeyer-Villiger± Type Oxidations Using Molecular Oxygen as the Oxidant
The Baeyer-Villiger reaction refers to the oxidation of a ketone to an ester or lactone by peracids or other oxidants. Highly oxidized reagents such as peracids or other peroxy compounds are generally used as the typical oxygen source, but applying molecular oxygen as a simple oxidant in the asymmetric oxidation reaction has recently drawn much attention. Bolm et al.46 were the ®rst to develop the metal complex±catalyzed Baeyer-Villiger oxidation using molecular
466 ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES
Scheme 8±17
oxygen as oxidant to transform cyclic ketones to lactones in the presence of an aldehyde (Scheme 8±17).
Best results were obtained when the reaction was carried out in benzenesaturated water using p-nitro±substituted copper complex 38 as the catalyst and pivaldehyde as the oxygen acceptor (co-reducing reagent). Using 1 mol% of (S,S)-38, the reaction proceeds at 6 C under an oxygen atmosphere, providing the product lactone (R)-40 at 41% yield with 69% ee. Because the unreacted ketone is thus enriched in (S)-con®guration, this reaction can also be regarded as a kinetic resolution process. Dependence of the reactivity on ring size is found to be similar to that observed for peroxides. A six-membered ring substrate was oxidized faster, a ®ve-membered ring reacted more slowly, and a seven-membered ring substrate did not react.
8.2.6Recent Progress in Asymmetric Wittig-Type Reactions
The essence of asymmetric synthesis is producing a new stereogenic center in such a manner that the product consists of stereoisomers in unequal amount. In most cases, this can be achieved by the formation of a new sp3 stereocenter. There is also another type of asymmetric reaction in which the employed substrates contain either a stereogenic unit or a pro-stereogenic unit apart from the functional group, and asymmetric synthesis occurs even though the nature of the reaction is not directly related to the newly formed sp3 stereocenter. The Wittig reaction is invoked for the asymmetric synthesis of such molecules.47
Di¨erent types of the reagents (see Fig. 8±4) have been applied in asymmetric Wittig-type reactions. Because no new sp3 stereocenter is formed in a Wittingtype reaction, a substrate containing a stereogenic or pro-stereogenic unit apart from the carbonyl group is usually required to induce an asymmetric process.
A challenging goal is the development of catalytic asymmetric induction processes. Denmark et al.48 have reported an asymmetric Wittig reaction using
8.2 MISCELLANEOUS METHODS |
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8.2.7Asymmetric Reformatsky Reactions
As a kind of nucleophilic addition reaction similar to the Grignard reaction, the Reformatsky reaction can a¨ord useful b-hydroxy esters from alkyl haloacetate, zinc, and aldehydes or ketones. Indeed, this reaction may complement the aldol reaction for asymmetric synthesis of b-hydroxy esters.
The earliest enantioselective Reformatsky reaction was reported in 1973.52 Compound …ÿ†-spartein was used as the chiral ligand, but the reaction gave rather low yield. Almost 20 years later, in 1991, Soai and Kawase53 reported an enantioselective Reformatsky reaction in which chiral amino alcohol 58 or 59 was used as the ligand. Aliphatic and aromatic b-hydroxy esters were obtained with moderate to good yields.
Chiral b-hydroxylester 61 cannot be satisfactorily obtained through the reaction between a prochiral ketone and the enolate. It can, however, be synthesized via the chiral ligand-induced asymmetric Reformatsky reaction of ketones (Scheme 8±21).
Scheme 8±21
Moreover, Soai et al.53c found that the enantioselective addition of Reformatsky reagents to prochiral ketones proceeds well when N,N- dialkylnorephedine 59 is used as the chiral ligand. When (1S,2R)-59a is used, the b-hydroxyl ester is obtained in 74% ee and 65% yield with (S)-con®guration predominant. When (1R,2S)-59a is used, the product is obtained in 74% ee and at 47% yield with (R)-con®guration prevailing.
Similarly, compound 58 [in both (R)- and (S )-forms] has been found to be a good ligand for the enantioselective addition of cyanomethyl zinc bromide to various aldehydes. Products with up to 93% ee are obtained.53b Scheme 8±22 shows one example. When R ˆ Ph, product is obtained in 78% ee.
470 ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES
Scheme 8±22
Pini et al.54 and Mi et al.55 reported the promotion of the enantioselective Reformatsky reaction by using stoichiometric and/or catalytic amounts of amino alcohols. Moderate yields were obtained.
Samarium(II) iodide often exerts good chelation control with an oxygen or nitrogen moiety in organic molecules, and this results in highly stereoselective intraor intermolecular 1,2- and 1,3-asymmetric inductions.56 Fukuzawa et al.57 demonstrated a highly diastereoselective intermolecular samarium iodide± mediated Reformatsky reaction using a-bromoacetyl-2-oxazolidinone 62 as the chiral auxiliary. This example is shown in Scheme 8±23. The yields for product 63 are good to excellent, and de values are high for the straight chain and branched aliphatic aldehydes as well as aromatic aldehydes. When X ˆ i-Pr in 62, the product obtained (RCHO ˆ t-butyl aldehyde) has 99% de.
Scheme 8±23
8.2.8Catalytic Asymmetric Wacker Cyclization
Wacker cyclization has proved to be one of the most versatile methods for functionalization of ole®ns.58,59 However, asymmetric oxidative reaction with palladium(II) species has received only scant attention. Using chiral ligand 1,10-binaphthyl-2,20-bis(oxazoline)±coordinated Pd(II) as the catalyst, high enantioselectivity (up to 97% ee) has been attained in the Wacker-type cyclization of o-alkylphenols (66a±f ) (Scheme 8±24).
It is worth noting, however, that chiral phosphine±palladium complexes generated from palladium salts and BINAP or MOP cannot be used for this oxidation because phosphines will be readily oxidized to phosphine oxides under the reaction conditions, leading to the deactivation of the catalyst. As reaction without the chiral catalyst will give a racemic product, this deactivation of the catalyst will cause a drop in the enantioselectivity of the whole process.
Besides the function of the 1,10-binaphthyl backbone, which is very important for high enantioselectivity, con®guration of the central chirality on the
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Scheme 8±24
oxazoline attached to binaphthyl also has a great in¯uence on enantioselectivity and catalytic activity. In Scheme 8±24, when (S,S)-i-Pr-boxax 65a is used as the catalyst, the resulting products 67a±c are obtained with (S)-con®guration in 90±97% ee. The diastereoisomer (R,S)-i-Pr-boxax 65a0 is much less active and less enantioselective (3% yield, 18% ee (R)-con®guration). Compounds 65b and 65c show almost the same high stereoselectivity as 65a.
8.2.9Palladium-Catalyzed Asymmetric Alkenylation of Cyclic Ole®ns
Palladium-catalyzed arylation of ole®ns and the analogous alkenylation (Heck reaction) are the useful synthetic methods for carbon±carbon bond formation.60 Although these reactions have been known for over 20 years, it was only in 1989 that the asymmetric Heck reaction was pioneered in independent work by Sato et al.60d and Carpenter et al.61 These scientists demonstrated that intramolecular cyclization of an alkenyl iodide or tri¯ate yielded chiral cyclic compounds with approximately 45% ee. The ®rst example of the intermolecular asymmetric Heck reaction was reported by Ozawa et al.60c Under appropriate conditions, the major product was obtained in over 96% ee for a variety of aryl tri¯ates.62
Treating 2,3-dihydrofuran 68 with aryl tri¯ate 69 in the presence of a base and a palladium catalyst generated in situ from Pd(OAc)2 and (R)-BINAP
