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Volumn 9, Issue 19, 2007, Pages 3825-3828

Two syntheses of (-)-kainic acid via highly stereoselective zinc-ene cyclizations

Author keywords

[No Author keywords available]

Indexed keywords

CHLORIDE; KAINIC ACID; PALLADIUM; SULFONE; ZINC DERIVATIVE;

EID: 34848876647     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol701733u     Document Type: Article
Times cited : (32)

References (55)
  • 16
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    • For reviews, see: a
    • For reviews, see: (a) Parsons, A. F. Tetrahedron 1996, 52, 4149.
    • (1996) Tetrahedron , vol.52 , pp. 4149
    • Parsons, A.F.1
  • 17
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    • 597. For recent syntheses, see
    • (b) Moloney, M. G. Nat. Prod. Rep. 2002, 19, 597. For recent syntheses, see:
    • (2002) Nat. Prod. Rep , vol.19
    • Moloney, M.G.1
  • 29
    • 0028135651 scopus 로고
    • For previous examples of zinc-ene cyclizations, see: a
    • For previous examples of zinc-ene cyclizations, see: (a) Oppolzer, W.; Schröder, F. Tetrahedron Lett. 1994, 35, 7939.
    • (1994) Tetrahedron Lett , vol.35 , pp. 7939
    • Oppolzer, W.1    Schröder, F.2
  • 34
    • 34848818270 scopus 로고    scopus 로고
    • Protection of the amine was probably necessary because attempted cyclization of the N-unprotected version of the cyclization substrate shown in Scheme 1 was unsucessful
    • Protection of the amine was probably necessary because attempted cyclization of the N-unprotected version of the cyclization substrate shown in Scheme 1 was unsucessful.
  • 36
    • 84961981775 scopus 로고    scopus 로고
    • 2O quenching after lithiation. For an example of such a proton transfer, see: Cheng, D.; Zhu, S.; Liu, X.; Norton, S.H.; Cohen, T. J. Am. Chem. Soc. 1999, 121, 10241. Standard precautions to prevent the formation of 9 (e.g., reverse quench) were ineffective. Excess 'BuLi (>5 equiv) improved the yield of 8 slightly, but this measure is impractical for a scalable process.
    • 2O quenching after lithiation. For an example of such a proton transfer, see: Cheng, D.; Zhu, S.; Liu, X.; Norton, S.H.; Cohen, T. J. Am. Chem. Soc. 1999, 121, 10241. Standard precautions to prevent the formation of 9 (e.g., reverse quench) were ineffective. Excess 'BuLi (>5 equiv) improved the yield of 8 slightly, but this measure is impractical for a scalable process.
  • 37
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    • Our original plan, designed to both facilitate the cyclization and save steps, was to use the conjugated unsaturated methyl ester as the enophile, readily prepared by using the suitable Wittig reagent, instead of the alkene in 6. However, the result was a surprise. The cyclization was considerably more sluggish, requiring an elevated temperature, and the major product had a trans C3-C4 relationship. The sluggish cyclization suggests that this Zn-ene reaction should be considered an ambiphilic rather than a nucleophilic addition. The origin of the trans selectivity is not yet fully understood, but optimizing this transformation provides a route to other kainoid stereoisomers
    • Our original plan, designed to both facilitate the cyclization and save steps, was to use the conjugated unsaturated methyl ester as the enophile, readily prepared by using the suitable Wittig reagent, instead of the alkene in 6. However, the result was a surprise. The cyclization was considerably more sluggish, requiring an elevated temperature, and the major product had a trans C3-C4 relationship. The sluggish cyclization suggests that this Zn-ene reaction should be considered an ambiphilic rather than a nucleophilic addition. The origin of the trans selectivity is not yet fully understood, but optimizing this transformation provides a route to other kainoid stereoisomers.
  • 39
    • 34848865291 scopus 로고    scopus 로고
    • See Supporting Information for details
    • See Supporting Information for details.
  • 40
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    • For a review discussing the inherent configurational lability of a-amino aldehydes, see
    • For a review discussing the inherent configurational lability of a-amino aldehydes, see: Gryko, D.; Chalko, J.; Jurczak. J. Chirality 2003, 15, 514.
    • (2003) Chirality , vol.15 , pp. 514
    • Gryko, D.1    Chalko, J.2    Jurczak, J.3
  • 42
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    • Ref 11d
    • (b) Ref 11d.
  • 43
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    • Lee, J.; Jeong, Y.; Ji, M.; Baik, W.; Lee, S.; Koo, S. Synlett 2004, 1937. Apparently, a high E/Z ratio is critical in the synthesis of 12. When batches of 11 with low E/Z were used, yields diminished to 80-90%, We suspect that intramolecular ammonium formation of the Z isomer is responsible for the reduced yield in these cases.
    • Lee, J.; Jeong, Y.; Ji, M.; Baik, W.; Lee, S.; Koo, S. Synlett 2004, 1937. Apparently, a high E/Z ratio is critical in the synthesis of 12. When batches of 11 with low E/Z were used, yields diminished to 80-90%, We suspect that intramolecular ammonium formation of the Z isomer is responsible for the reduced yield in these cases.
  • 44
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    • D = -27.2° (c = 0.99) in ref 17. We consider the optical purity of this material suspect.
    • D = -27.2° (c = 0.99) in ref 17. We consider the optical purity of this material suspect.
  • 46
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    • It is conceivable that silyl transfer in 13 contributes to racemization. However, such a transfer in TBS-protected serinols was not observed in several similar substrates. See: (a) Novachek, K. A.; Meyers, A. I. Tetrahedron Lett. 1996, 37, 1743.
    • It is conceivable that silyl transfer in 13 contributes to racemization. However, such a transfer in TBS-protected serinols was not observed in several similar substrates. See: (a) Novachek, K. A.; Meyers, A. I. Tetrahedron Lett. 1996, 37, 1743.
  • 49
    • 84868263806 scopus 로고    scopus 로고
    • It is interesting that no β-elimination of the intermediate allyl zinc is observed. A minor amount (typically 2-5%) of uncyclized, dechlorinated material is also isolated after quenching. This material is likely the result of protonation of the allyl zinc intermediate where a Pd-H species is the proton source. Without excess diethylzinc as a proton scavenger, the amount of this byproduct increases significantly.
    • It is interesting that no β-elimination of the intermediate allyl zinc is observed. A minor amount (typically 2-5%) of uncyclized, dechlorinated material is also isolated after quenching. This material is likely the result of protonation of the allyl zinc intermediate where a Pd-H species is the proton source. Without excess diethylzinc as a proton scavenger, the amount of this byproduct increases significantly.
  • 50
    • 34848856044 scopus 로고    scopus 로고
    • In general, however, allylic sulfones are much more easily prepared than allylic chlorides, See ref 11d
    • In general, however, allylic sulfones are much more easily prepared than allylic chlorides, See ref 11d.
  • 51
    • 34848846832 scopus 로고    scopus 로고
    • The direct cyanation of the dialkylzinc cyclization product was explored with limited success despite some precedence. See: (a) ref 11a
    • The direct cyanation of the dialkylzinc cyclization product was explored with limited success despite some precedence. See: (a) ref 11a.
  • 53
    • 34848844902 scopus 로고    scopus 로고
    • The reduced yield is the result of a competitive E2 elimination.
    • The reduced yield is the result of a competitive E2 elimination.
  • 55
    • 34848845495 scopus 로고    scopus 로고
    • The overall yield for the sulfone route was calculated using the revised conversion of iodide 7 to kainic acid shown in Scheme 4.
    • The overall yield for the sulfone route was calculated using the revised conversion of iodide 7 to kainic acid shown in Scheme 4.


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.