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Volumn 74, Issue 12, 2009, Pages 4447-4454

Rational design of aldol reactions that proceed via kinetic resolution with switchable enantioselectivity

Author keywords

[No Author keywords available]

Indexed keywords

ALDOL REACTIONS; BORON ENOLATES; CHEMICAL EQUATIONS; DESIGN STRATEGIES; DIASTEREOMERIC ADDUCTS; DIASTEREOMERS; DIASTEREOSELECTIVE; ENANTIOSELECTION; ENOLATES; KINETIC RESOLUTION; RATIONAL DESIGN; REACTION CONDITIONS; STEREOCONTROL; SWITCHABLE;

EID: 67249127134     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo900716a     Document Type: Article
Times cited : (23)

References (66)
  • 11
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    • note
    • For each combination of reactant enantiomers, four diastereomeric aldol adducts are possible when two new stereocenters are formed in the reaction. When only one new stereocenter is created (e.g. aldol of a methyl ketone), two diastereomeric adducts are generally possible; nonetheless, four diastereotopic transition states are possible.
  • 13
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    • For examples of aldol reactions proceeding with significant KR see refs 3a,3c, and
    • For examples of aldol reactions proceeding with significant KR see refs 3a,3c, and: Shinoyama, M.; Shirokawa, S.-i.; Nakazaki, A.; Kobayashi, S. Org. Lett. 2009, 11, 1277-1280.
    • (2009) Org. Lett. , vol.11 , pp. 1277-1280
    • Shinoyama, M.1    Shirokawa, S.-I.2    Nakazaki, A.3    Kobayashi, S.4
  • 15
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    • For examples of aldol reactions with significant MKE, see refs 3a, 3c, and
    • For examples of aldol reactions with significant MKE, see refs 3a, 3c, and: (a) Ward, D. E.; Guo, C.; Sasmal, P. K.; Man, C. C.; Sales, M. Org. Lett. 2000, 2, 1325-1328.
    • (2000) Org. Lett. , vol.2 , pp. 1325-1328
    • Ward, D.E.1    Guo, C.2    Sasmal, P.K.3    Man, C.C.4    Sales, M.5
  • 20
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    • note
    • As explained in ref 1a, this approach will necessarily be qualitative. The selectivities of the three stereocontrol elements (E, A, and R) are not fixed values but will vary depending on the other reactants. Moreover, they do not act independently but mutually interact in ways that are difficult to predict and are not necessarily the same in competing transition states. Nonetheless, this qualitative approach provides a simple paradigm to guide the design of reactions with desirable properties.
  • 21
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    • For a derivation see
    • For a derivation see: Nakayama, K. J. Chem. Educ. 1990, 67, 20-23.
    • (1990) J. Chem. Educ. , vol.67 , pp. 20-23
    • Nakayama, K.1
  • 24
    • 67249109858 scopus 로고    scopus 로고
    • note
    • The like and unlike descriptors specify the relationship between the absolute configurations of the reactant enantiomers (see Scheme 12 in ref 6). Matched and mismatched are terms widely used to describe double stereodifferentiation in reactions of chiral reactants; that is, where the matched pair of reactant enantiomers gives enhanced diastereoselectivity relative to the mismatched pair (ref 1a). Alternatively, these terms are defined according to the diastereoselectivities of the individual reactants (for example, as determined in an analogous reaction with an achiral reactant) that can be either reinforcing (matched) or counteracting (mismatched). In the present context, matched and mismatched can become ambiguous, especially in cases where both combinations of reactant enantiomers lead to highly diastereoselective reactions (ref 3c). Moreover, these terms are specifically defined without reference to kinetics (see footnote ** in ref 1a). Thus, because like vs unlike and fast vs slow are unambiguously defined based on the structures of the reactant enantiomers and their relative facility for reaction, respectively, we have used these descriptors in preference to matched and mismatched. Nonetheless, application of the multiplicativity rule suggests that reaction of the matched pair of enantiomers will be more facile than reaction of the mismatched pair (ref 1a).
  • 25
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    • Mahrwald, R., Ed.; Wiley-VGH: Weinheim
    • Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VGH: Weinheim, 2004; Vols. 1 and 2.
    • (2004) Modern Aldol Reactions , vol.1-2
  • 26
    • 67249090341 scopus 로고    scopus 로고
    • note
    • The like (same configuration) and unlike (opposite configuration) reactions are defined here with respect to the stereochemical configurations at C-3 of 1 and C-6 of 2; see ref 6. Each reaction can produce four unique diastereomers (i.e., R or S at C-5 and C-1″). For each diastereomer of 1, the aldol adducts 3 and 4 have the same configurations at C-1′, C-3, and C-6′ as those in 1.
  • 31
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    • note
    • 2 reagent was calibrated with the reaction of cyclohexanone with benzaldehyde which gave >90% of aldol adduct using 1 equiv of reagent; see ref 19b.
  • 32
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    • note
    • Lower reactivity of the enolates was implicated as good conversions were obtained using propanal in place of (±)-2 under the same conditions.
  • 34
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    • For an excellent discussion of the various transition states for aldol reactions, see
    • For an excellent discussion of the various transition states for aldol reactions, see: Denmark, S. E.; Henke, B. R. J. Am. Chem. Soc. 1991, 113, 2177-2194.
    • (1991) J. Am. Chem. Soc. , vol.113 , pp. 2177-2194
    • Denmark, S.E.1    Henke, B.R.2
  • 35
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    • Computational studies on aldol reactions of ethanal with simple acyclic (E)-enolborinates (e.g., from butanone) suggest that the major anti adduct is derived predominantly from a boatlike transition state (boat A) and the minor syn adduct from a different boatlike transition state (boat B).
    • Computational studies on aldol reactions of ethanal with simple acyclic (E)-enolborinates (e.g., from butanone) suggest that the major anti adduct is derived predominantly from a boatlike transition state (boat A) and the minor syn adduct from a different boatlike transition state (boat B). (a) Goodman, J. M.; Paton, R. S. Chem Commun. 2007, 2124-2126.
    • (2007) Chem Commun. , pp. 2124-2126
    • Goodman, J.M.1    Paton, R.S.2
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    • This DFT computational study on the diastereoselectivity of boron-mediated aldol reactions of β-alkoxy ketones suggests the importance of a formyl H-bond between the β-O and the aldehyde H. In the present context, this interaction would necessarily produce 3,5-cis products and can be neglected
    • Paton, R. S.; Goodman, J. M. J. Org. Chem. 2008, 73, 1253-1263. This DFT computational study on the diastereoselectivity of boron-mediated aldol reactions of β-alkoxy ketones suggests the importance of a formyl H-bond between the β-O and the aldehyde H. In the present context, this interaction would necessarily produce 3,5-cis products and can be neglected. .
    • (2008) J. Org. Chem. , vol.73 , pp. 1253-1263
    • Paton, R.S.1    Goodman, J.M.2
  • 40
  • 41
    • 67249149994 scopus 로고    scopus 로고
    • note
    • Structure labels with a (+) or (-) prefix refer to enantioenriched compounds with absolute configuration as illustrated for the structure with the same number without a prefix; labels with an ent prefix refer to enantioenriched compounds with absolute configuration opposite to that illustrated for the structure with that label. The (+) and (-) prefixes also indicate the sign of the [R]D for the indicated absolute configuration.
  • 42
    • 18244400404 scopus 로고    scopus 로고
    • With a sufficient excess of (±)-2, the ratio and yield of products from the reaction of enantioenriched 1 should approach those obtained with (±)-1 under the same conditions; however, the product ratio (and perhaps yield) will be diminished using less (±)-2 due to depletion of the fast-reacting enantiomer (see ref 29 for a sample calculation of this effect). We found that 3 equiv of (±)-2 gave a satisfactory compromise between selectivity and convenience. The moderate enantioenrichment of recovered 2 is consistent with that predicted from a kinetic resolution (see ref 29 for the calculated enrichment under various scenarios) indicating that racemization of 2 is slow under these conditions. The recovered enantioenriched 2 can be readily racemized for reuse. For the facile racemization of 2 in the presence of proline, see
    • With a sufficient excess of (±)-2, the ratio and yield of products from the reaction of enantioenriched 1 should approach those obtained with (±)-1 under the same conditions; however, the product ratio (and perhaps yield) will be diminished using less (±)-2 due to depletion of the fast-reacting enantiomer (see ref 29 for a sample calculation of this effect). We found that 3 equiv of (±)-2 gave a satisfactory compromise between selectivity and convenience. The moderate enantioenrichment of recovered 2 is consistent with that predicted from a kinetic resolution (see ref 29 for the calculated enrichment under various scenarios) indicating that racemization of 2 is slow under these conditions. The recovered enantioenriched 2 can be readily racemized for reuse. For the facile racemization of 2 in the presence of proline, see: Ward, D. E.; Jheengut, V.; Akinnusi, O. T. Org. Lett. 2005, 7, 1181-1184.
    • (2005) Org. Lett. , vol.7 , pp. 1181-1184
    • Ward, D.E.1    Jheengut, V.2    Akinnusi, O.T.3
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    • note
    • slow) 15, the ratio of products from the fast and slow reactions (at 90% conversion of A) as a function of the amount of (±)-B used is calculated to be: 7.9 (2 equiv of B; remaining B, 63% ee); 10.2 (3 equiv of B; remaining B, 35% ee); 11.8 (4 equiv of B; remaining B, 24% ee); 13.8 (10 equiv of B; remaining B, 8.5% ee). See ref 2a for the equations used for this computation.
  • 44
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    • 2 and N-ethylpiperidine) with PhCHO is highly syn-selective
    • 2 and N-ethylpiperidine) with PhCHO is highly syn-selective: Mukaiyama, T.; Stevens, R. W.; Iwasawa, N. Chem. Lett. 1982, 353-356.
    • (1982) Chem. Lett. , pp. 353-356
    • Mukaiyama, T.1    Stevens, R.W.2    Iwasawa, N.3
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    • For aldol reactions of Ti(IV) "ate" enolates, see
    • For aldol reactions of Ti(IV) "ate" enolates, see: (a) Reetz, M. T.; Peter, R. Tetrahedron Lett. 1981, 22, 4691-4694.
    • (1981) Tetrahedron Lett. , vol.22 , pp. 4691-4694
    • Reetz, M.T.1    Peter, R.2
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    • For other reactions of Ti(IV) "ate" enolates, see
    • For other reactions of Ti(IV) "ate" enolates, see: (e) Bernardi, A.; Dotti, P.; Poli, G.; Scolastico, C. Tetrahedron 1992, 48, 5597-5606.
    • (1992) Tetrahedron , vol.48 , pp. 5597-5606
    • Bernardi, A.1    Dotti, P.2    Poli, G.3    Scolastico, C.4
  • 57
    • 67249094870 scopus 로고    scopus 로고
    • note
    • 3Cl (ref 31a), and in the absence of Ti(IV) additives, the reactions were moderately anti-slective.
  • 61
    • 67249109448 scopus 로고    scopus 로고
    • note
    • 3Ti(IV) enolate that reacts via a closed chair-like transition state (syn relative topicity). Reactions of 1 via such a transition state would give anti relative topicity, contrary to our results.
  • 62
    • 67249101496 scopus 로고    scopus 로고
    • note
    • The structure and aggregation state of Ti "ate" enolates are uncertain (refs 31k,l) and it is not clear whether the competing transition states for the like and unlike reactions are the same type (e.g., "closed" chair vs twist-boat) or different types (e.g., "closed" vs "open"). Thus, differentiating among the various mechanistic possibilities (see ref 23) is not feasible at present.
  • 63
    • 67249143858 scopus 로고    scopus 로고
    • note
    • If R = H, 20 diastereomers are possible; if R ≠ H, 32 diastereomers are possible. From the perspective of diversity of relative configurations, here we are considering the 32 R≠H diastereomers to be "synthetically equivalent" to the 20 R = H diastereomers. Because one diastereomer is produced from two reactions (i.e, 3a (R = H) ≡ 4b (R = H)), 11 (rather than 12) unique diastereomers are generated.
  • 64
    • 67249131890 scopus 로고    scopus 로고
    • note
    • See the Supporting Information for general methods and procedures.
  • 66
    • 67249084633 scopus 로고    scopus 로고
    • note
    • See the Supporting Information for the complete characterization data for this racemic adduct obtained via the same procedure but using (±)-1.


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.