메뉴 건너뛰기




Volumn 13, Issue 19, 2007, Pages 5515-5538

Total synthesis of potent antifungal marine bisoxazole natural products bengazoles A and B

Author keywords

Antifungal agents; Cycloaddition; Heterocycles natural products; Total synthesis

Indexed keywords

ANTIFUNGAL AGENTS; HETEROCYCLES NATURAL PRODUCTS; NATURAL PRODUCTS; POTENT ANTIFUNGAL MARINE BISOXAZOLE; TOTAL SYNTHESIS;

EID: 34547467756     PISSN: 09476539     EISSN: 15213765     Source Type: Journal    
DOI: 10.1002/chem.200700033     Document Type: Article
Times cited : (61)

References (121)
  • 3
  • 6
    • 0000314051 scopus 로고
    • c) P. Wipf, Chem. Rev. 1995, 95, 2115;
    • (1995) Chem. Rev , vol.95 , pp. 2115
    • Wipf, P.1
  • 9
  • 11
    • 0022551475 scopus 로고
    • For selected examples and solutions, in the synthesis of the calyculin natural products see: a
    • For selected examples and solutions, in the synthesis of the calyculin natural products see: a) Y. Kato, N. Fusetani, S. Matsunaga, K. Hashimoto, J. Am. Chem. Soc. 1986, 108, 2780;
    • (1986) J. Am. Chem. Soc , vol.108 , pp. 2780
    • Kato, Y.1    Fusetani, N.2    Matsunaga, S.3    Hashimoto, K.4
  • 18
    • 0000331564 scopus 로고
    • For oxazoline formation, using Burgess reagent see: a
    • For oxazoline formation, using Burgess reagent see: a) G. M. Atkins Jr. , E. M. Burgess, J. Am. Chem. Soc. 1968, 90, 4744;
    • (1968) J. Am. Chem. Soc , vol.90 , pp. 4744
    • Atkins Jr., G.M.1    Burgess, E.M.2
  • 19
    • 0026604531 scopus 로고
    • 907; using (diethylamino)sulfur trifluoride (DAST) see
    • b) P. Wipf, C. P. Miller, Tetrahedron Lett. 1992, 33, 907; using (diethylamino)sulfur trifluoride (DAST) see:
    • (1992) Tetrahedron Lett , vol.33
    • Wipf, P.1    Miller, C.P.2
  • 52
    • 33750160748 scopus 로고    scopus 로고
    • Angew. Chem. Int. Ed. 2006, 45, 6714.
    • (2006) Chem. Int. Ed , vol.45 , pp. 6714
    • Angew1
  • 57
  • 61
    • 34547453415 scopus 로고    scopus 로고
    • 1H NMR.
    • 1H NMR.
  • 62
    • 34547445765 scopus 로고    scopus 로고
    • For experimental procedures and characterisation data for known compounds 9, 37, 39, and 40, see Supporting Information.
    • For experimental procedures and characterisation data for known compounds 9, 37, 39, and 40, see Supporting Information.
  • 63
    • 34547439958 scopus 로고    scopus 로고
    • See Supporting Information for characterisation data for alcohols 12 and 13 and for NOE data
    • See Supporting Information for characterisation data for alcohols 12 and 13 and for NOE data.
  • 66
    • 34547393990 scopus 로고    scopus 로고
    • 3·THF present at the start of the reaction. It was necessary to add aliquots of the catalyst periodically to achieve the desired conversion, which could be monitored by GC of the crude product (Agilent 6890N GC, Varian Chirasil Dex-CB column (25 m × 0.25 mm) using Helium as the carrier gas, 25 psi, 19:1 split, 100°C, retention times: 26.5 min (10), 24.5 min (11)).
    • 3·THF present at the start of the reaction. It was necessary to add aliquots of the catalyst periodically to achieve the desired conversion, which could be monitored by GC of the crude product (Agilent 6890N GC, Varian Chirasil Dex-CB column (25 m × 0.25 mm) using Helium as the carrier gas, 25 psi, 19:1 split, 100°C, retention times: 26.5 min (10), 24.5 min (11)).
  • 69
    • 34547405421 scopus 로고    scopus 로고
    • See Supporting Information for characterisation of nitrile oxide dimer 17, which was confirmed by X-ray crystallography. CCDC-630712 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
    • See Supporting Information for characterisation of nitrile oxide dimer 17, which was confirmed by X-ray crystallography. CCDC-630712 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
  • 73
    • 34547427582 scopus 로고    scopus 로고
    • See Supporting Information for further details of the coupling constant calculations for major and minor cycloadducts
    • See Supporting Information for further details of the coupling constant calculations for major and minor cycloadducts.
  • 76
    • 34547490899 scopus 로고    scopus 로고
    • See Supporting Information for full characterisation of the minor cycloadduct diastereomer 16a. CCDC630709 contains the supplementary cristallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.
    • See Supporting Information for full characterisation of the minor cycloadduct diastereomer 16a. CCDC630709 contains the supplementary cristallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.
  • 80
    • 34547468577 scopus 로고    scopus 로고
    • Mosher's esters of 19 were prepared, which showed that no epimerisation had occurred at the CIO centre during deprotection of the BDA group. See Supporting Information for full procedures and characterisation.
    • Mosher's esters of 19 were prepared, which showed that no epimerisation had occurred at the CIO centre during deprotection of the BDA group. See Supporting Information for full procedures and characterisation.
  • 82
    • 34547447846 scopus 로고    scopus 로고
    • For the syn-reduction different batches gave variable yields and diastereoselectivities. It is believed that molybdenum salts residual from the previous reaction enhanced the diastereoselectivity the hydroxyketone starting material showed levels of a pink colouration that varied from batch to batch which could be ascribed to residual metal contamination
    • For the syn-reduction different batches gave variable yields and diastereoselectivities. It is believed that molybdenum salts residual from the previous reaction enhanced the diastereoselectivity (the hydroxyketone starting material showed levels of a pink colouration that varied from batch to batch which could be ascribed to residual metal contamination).
  • 88
    • 34547393989 scopus 로고    scopus 로고
    • Hydrolysis under conditions similar to those used by Molinski (see ref. [15]) for the corresponding ethyl acetal but 10 equivalents of water were required. The aldehyde product is volatile and care is needed when handling under reduced pressure.
    • Hydrolysis under conditions similar to those used by Molinski (see ref. [15]) for the corresponding ethyl acetal but 10 equivalents of water were required. The aldehyde product is volatile and care is needed when handling under reduced pressure.
  • 93
    • 34547478928 scopus 로고    scopus 로고
    • See Supporting Information for selected results of the catalyst screen
    • See Supporting Information for selected results of the catalyst screen.
  • 95
    • 34547486626 scopus 로고    scopus 로고
    • For cyanohydrin 41 and α-hydroxyester 42, the ee was assessed by formation of the Mosher's esters. See Supporting Information for experimental procedures and full characterisation of the Mosher's esters.
    • For cyanohydrin 41 and α-hydroxyester 42, the ee was assessed by formation of the Mosher's esters. See Supporting Information for experimental procedures and full characterisation of the Mosher's esters.
  • 96
    • 34547420360 scopus 로고    scopus 로고
    • Unfortunately, attempts to scale up the enantioselective addition of TMSCN caused a significant decrease of the ee value (10 mmol: 52% ee, 70% yield). Any attempt to enrich the ee of the cyanohydrin by recrystallisation returned material with the same ee (cold PE/ethyl acetate 4:1) or completely destroyed the ee (13% ee, from hot cydohexane/ethyl acetate 4:1).
    • Unfortunately, attempts to scale up the enantioselective addition of TMSCN caused a significant decrease of the ee value (10 mmol: 52% ee, 70% yield). Any attempt to enrich the ee of the cyanohydrin by recrystallisation returned material with the same ee (cold PE/ethyl acetate 4:1) or completely destroyed the ee (13% ee, from hot cydohexane/ethyl acetate 4:1).
  • 97
    • 34547433294 scopus 로고    scopus 로고
    • The corresponding bromide analogue of 46 is reported to be very unstable, see references [45] and [48].
    • The corresponding bromide analogue of 46 is reported to be very unstable, see references [45] and [48].
  • 99
    • 34547460800 scopus 로고    scopus 로고
    • Using the, -oxaziridines the unnatural (R)-configured α-hydroxy ester was formed preferentially
    • Using the (+)-oxaziridines the unnatural (R)-configured α-hydroxy ester was formed preferentially.
  • 101
    • 34547459735 scopus 로고    scopus 로고
    • Attempts to form the CIO stereochemistry by an enantioselective reduction of the α-ketoester formed by the oxidation of rac-48 gave low yields and ee. See Supporting Information for characterisation of the ketone intermediate
    • Attempts to form the CIO stereochemistry by an enantioselective reduction of the α-ketoester formed by the oxidation of rac-48 gave low yields and ee. See Supporting Information for characterisation of the ketone intermediate.
  • 104
    • 34547460799 scopus 로고    scopus 로고
    • The ee value for 51, 52, and 62 was determined using HPLC on a chiral stationary phase (see Experimental Section for further details). Both CIO epimers (from amides 25 and 44) were progressed through the same steps to aid determination of retention times for the enantiomers.
    • The ee value for 51, 52, and 62 was determined using HPLC on a chiral stationary phase (see Experimental Section for further details). Both CIO epimers (from amides 25 and 44) were progressed through the same steps to aid determination of retention times for the enantiomers.
  • 106
    • 34547432762 scopus 로고    scopus 로고
    • These studies were performed with the enantiomer of enamide 52, ent-52.
    • These studies were performed with the enantiomer of enamide 52, ent-52.
  • 107
    • 34547454442 scopus 로고    scopus 로고
    • Treatment of enamide ent-52 with NBS, and benzyl alcohol formed the desired bromide 56, however, benzyl alcohol ran very close to the desired product by TLC and was problematic to remove. The use of fewer equivalents of the nucleophile resulted in a poor yield of 56 as shown and alcohol 57 was also isolated in 37 % following an aqueous quench.
    • Treatment of enamide ent-52 with NBS, and benzyl alcohol formed the desired bromide 56, however, benzyl alcohol ran very close to the desired product by TLC and was problematic to remove. The use of fewer equivalents of the nucleophile resulted in a poor yield of 56 as shown and alcohol 57 was also isolated in 37 % following an aqueous quench.
  • 110
    • 34547460252 scopus 로고    scopus 로고
    • The ee value was determined by supercritical fluid chromatography on a chiral stationary phase following conversion into the primary alcohol 63 (see Experimental Section for further details).
    • The ee value was determined by supercritical fluid chromatography on a chiral stationary phase following conversion into the primary alcohol 63 (see Experimental Section for further details).
  • 111
    • 34547479470 scopus 로고    scopus 로고
    • Oxime 33 was isolated as a mixture of double bond isomers and the cis/trans ratio depended on the oxidation method. TPAP oxidation gave predominantly cis-oxime (up to 5:1 cis/trans) presumably due to chelation with residual ruthenium salts promoting a cis-conformation, whereas following DMP oxidation the trans-oxime was favoured (up to 1:5 cis/trans, The mixture geometries made the assessment of enantiopurity by chiral HPLC very difficult so a number of batches of bisoxazole 62 (with a range of enantiopurities) were progressed to the oxime and the optical rotation values were recorded. Pleasingly, the different batches gave reproducible and consistent αD values suggesting the stereochemical integrity had been maintained. This was confirmed following the cycloaddition, from which none of the C10 epimer was observed
    • D values suggesting the stereochemical integrity had been maintained. This was confirmed following the cycloaddition, from which none of the C10 epimer was observed.
  • 112
    • 34547417756 scopus 로고    scopus 로고
    • See Supporting Information for selected results in the optimisation of the nitrile oxide cycloaddition between alkene 7 and the nitrile oxide derived from oxime 33
    • See Supporting Information for selected results in the optimisation of the nitrile oxide cycloaddition between alkene 7 and the nitrile oxide derived from oxime 33.
  • 113
    • 34547452919 scopus 로고    scopus 로고
    • The nitrile oxide dimer was also isolated in only 6 %. Excess alkene employed in the reaction was recovered in excellent yields. See Supporting Information for characterisation data for minor cycloadduct diastereomer 3a and nitrile oxide dimer 3b.
    • The nitrile oxide dimer was also isolated in only 6 %. Excess alkene employed in the reaction was recovered in excellent yields. See Supporting Information for characterisation data for minor cycloadduct diastereomer 3a and nitrile oxide dimer 3b.
  • 118
    • 34547424029 scopus 로고    scopus 로고
    • See Supporting Information for characterisation of the minor cycloadduct isoxazoline 69 a. The diastereoselectivity was consistently lower in the 10-epi-series (ent-33) than with oxime 33 (dr 2.5:1 vs 3.5:1). Notwithstanding the distance of the chirality from the reacting centre, this was presumed to be due to a chirality match/mismatch between alkene 7 and the chiral oximes. A similar phenomenon was observed for the enantiomer of the nitrile oxide of Garner's aldehyde oxime (dr 4.1:1 vs 2.5:1) although in this case the chirality is closer to the reacting centres.
    • See Supporting Information for characterisation of the minor cycloadduct isoxazoline 69 a. The diastereoselectivity was consistently lower in the 10-epi-series (ent-33) than with oxime 33 (dr 2.5:1 vs 3.5:1). Notwithstanding the distance of the chirality from the reacting centre, this was presumed to be due to a chirality match/mismatch between alkene 7 and the chiral oximes. A similar phenomenon was observed for the enantiomer of the nitrile oxide of Garner's aldehyde oxime (dr 4.1:1 vs 2.5:1) although in this case the chirality is closer to the reacting centres.
  • 119
    • 34547421411 scopus 로고    scopus 로고
    • See Supporting Information for spectra for bengazole A, 10-epi-bengazole A and bengazole B
    • See Supporting Information for spectra for bengazole A, 10-epi-bengazole A and bengazole B.


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.