Enantioselective synthesis. See

Because of the nature of the transition state in the pericyclic mechanism, optically active substrates with a chiral carbon at C-3 or C-4 transfer the chirality to the product, making this an enantioselective synthesis (see p. 1451 for an example in the mechanistically similar Claisen rearrangement). ... 

For a discussion of this approach to enantioselective synthesis, see S. Hanessian, Total Synthesis of Natural Products The Chiron Approach, Pergamon Press, New York, 1983. 

These reflections are of special interest in the case of industrial syntheses in which the economic aspects are important. In these syntheses there is another factor to be kept in mind that may be illustrated by considering the industrial syntheses of steroids developed by Velluz and his coworkers in 1960 [18]. In contrast with other syntheses in which the intermediates are racemates and are only resolved into their optical active forms in the last step, the industrial syntheses require the resolution of the racemic mixture at the first possible opportunity, in order to exclude the unwanted isomer and thus avoiding the expenses of its processing. For recent advances in enantioselective synthesis see Heading 9.3. 

In 1998, Kawahara and Nagumo reported the first total synthesis of a member of the TAN1251 series [63] and five years later both authors revisited the TAN1251A alkaloid by means of a new enantioselective synthesis (see Section 5.6). The retro synthetic analysis of TAN 1251A is outlined in Scheme 37. The target compound could be obtained by aldol reaction of tricyclic lactam 119, whose disconnection at the amide bond led to the bicyclic amino acid 120, which could be prepared from azaspirocyclic compound 121 by means of alkylation of the secondary amine and Mitsunobu-type chemistry. Azabicycle 121 may be prepared by an intramolecular alkylation of 122, which in turn could be available from allyl derivative 123. The latter can be prepared from carboxylic acid 124 by alkylation and subsequent Curtius rearrangement. 

In the area of enantioselective synthesis see Enantio selectivit ), the development of catalytic carbon-carbon bond-forming reactions that proceed under mild conditions in an enantioselective fashion (ee > 95%) remains a challenging objective.Among a great variety of metallic complexes, Zr-containing chiral catalysts can promote efficient and highly enantioselective additions of nucleophilic fragments such as alkylmetals and cyanides to C=0 and C=N bonds. Moreover, Zr-based metallocenes promote additions of alkylmetals to carbon-carbon double bonds, reactions that do not easily occur with other catalysts. One another important feature is that the product of the asymmetric addition of an alkylmetal to an alkene produces a chiral alkylmetal that can be further functionalized. 

Soon after the disclosure of the total synthesis of ( )-gingkolide B, (see ref. 8a) Corey reported a concise, enantioselective synthesis of tetracyclic lactone 23, see Corey, E. J. Gavai, A. V. Tetrahedron Lett. 1988, 29, 3201. Thus, in principle, gingkolide B could be synthesized in its naturally occurring enantiomeric form. 

Schemes 16-19 present the details of the enantioselective synthesis of key intermediate 9. The retrosynthetic analysis outlined in Scheme 5 identified aldoxime 32 as a potential synthetic intermediate the construction of this compound would mark the achievement of the first synthetic objective, for it would permit an evaluation of the crucial 1,3-dipolar cycloaddition reaction. As it turns out, an enantioselective synthesis of aldoxime 32 can be achieved in a straightforward manner by a route employing commercially available tetronic acid (36) and the MEM ether of allyl alcohol (74) as starting materials (see Scheme 16).

Since the addition of dialkylzinc reagents to aldehydes can be performed enantioselectively in the presence of a chiral amino alcohol catalyst, such as (-)-(1S,2/ )-Ar,A -dibutylnorephedrine (see Section 1.3.1.7.1.), this reaction is suitable for the kinetic resolution of racemic aldehydes127 and/or the enantioselective synthesis of optically active alcohols with two stereogenic centers starting from racemic aldehydes128 129. Thus, addition of diethylzinc to racemic 2-phenylpropanal in the presence of (-)-(lS,2/ )-Ar,W-dibutylnorephedrine gave a 75 25 mixture of the diastereomeric alcohols syn-4 and anti-4 with 65% ee and 93% ee, respectively, and 60% total yield. In the case of the syn-diastereomer, the (2.S, 3S)-enantiomer predominated, whereas with the twtf-diastereomer, the (2f ,3S)-enantiomer was formed preferentially. 

Torn T, Nakamura S (2003) Enantioselective Synthesis by Lithiation Adjacent to Sulfur, Selenium or Phosphorus, or without an Adjacent Activating Heteroatom. 5 177-216 Tunge JA, see Cummings SA (2005) 10 1-39... 

Entries 4 and 5 are examples of use of the Sakurai reaction to couple major fragments in multistage synthesis. In Entry 4 an unusual catalyst, a chiral acyloxyboronate (see p. 126) was used to effect an enantioselective coupling. (See p. 847 for another application of this catalyst.) Entry 5 was used in the construction of amphidinolide P, a compound with anticancer activity. 

Scheme 10.12 gives some examples of enantioselective cyclopropanations. Entry 1 uses the W.s-/-butyloxazoline (BOX) catalyst. The catalytic cyclopropanation in Entry 2 achieves both stereo- and enantioselectivity. The electronic effect of the catalysts (see p. 926) directs the alkoxy-substituted ring trans to the ester substituent (87 13 ratio), and very high enantioselectivity was observed. Entry 3 also used the /-butyl -BOX catalyst. The product was used in an enantioselective synthesis of the alkaloid quebrachamine. Entry 4 is an example of enantioselective methylene transfer using the tartrate-derived dioxaborolane catalyst (see p. 920). Entry 5 used the Rh2[5(X)-MePY]4... 

Section B shows some Hofmann rearrangements. Entry 9, using basic conditions with bromine, provided an inexpensive route to an intermediate for a commercial synthesis of an herbicide. Entry 10, which uses the Pb(OAc)4 conditions (see p. 949), was utilized in an enantiospecific synthesis of the naturally occurring analagesic (-)-epibatidine. Entry 11 uses phenyliodonium diacetate as the reagent. The product is the result of cyclization of the intermediate isocyanate and was used in an enantioselective synthesis of the antianxiety drug (tf)-fluoxetine. 

The main lines of this approach were later embodied in an enantioselective synthesis of (—)-a-allokainic acid (Scheme 34) (179). The sole stereo center of die ene reaction starting material was derived from a glutamic acid derivative (132) to avoid loss of optical activity via double bond migration (see Scheme 33), the a acid function of kainic acid had to be reduced before the pyrolysis step... 

C. W. Johannes, M. S. Visser, G. S. Weatherhead, A H. Hoveyda Zr-Catalyzed Kinetic Resolution of Allylic Ethers and Mo-Catalyzed Chromene Formation in Synthesis. Enantioselective Total Synthesis of the Antihypertensive Agent (SJUUD-Nebivolol J. Am Chem Soc 1998, 120, 8340-8347. For development of the enantioselective methodology, see M. S. Visser, J. P. A. Harrity, A. H. Hoveyda Zirconium-Catalyzed Kinetic Resolution of Cyclic Allylic Ethers. An Enantioselective Route to Unsaturated Medium Ring Systems , J. Am Chem Soc 1996,118, 3779-3780. 

Hoppe D, Marr F, Bruggemann M (2003) Enantioselective Synthesis by Lithiation Adjacent to Oxygen and Electrophile Incorporation. 5 61-138 Hou Z, Wakatsuki Y (1999) Reactions of Ketones with Low-Valent Lanthanides Isolation and Reactivity of Lanthanide Ketyl and Ketone Dianion Complexes. 2 233-253 Hoveyda AH (1998) Catalytic Ring-Closing Metathesis and the Development of Enantioselective Processes. 1 105-132 Huang M, see Wu GG (2004) 6 1-36... 

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