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(+)-Amphidinolide T1
CHAPTER FIVE
(+)-Amphidinolide T1 Abbreviations Ar argon (ClCO)2 oxalyl chloride Bn benzyl BnOH benzylalcohol CH2Cl2 dichloromethane Cp2TiMe2 dimethyltitanocene (Petasis reagent) DAMP 4-dimethylaminopyridine DIBAL diisobutylaluminum hydride DMSO dimethylsulfoxide DTBMP 2,6-di-tert-butyl-4-methylpyridine Et3N triethylamine EtOAc ethyl acetate HMPA hexamethylphosphoramide HSO2Ph phenylsulfinic acid i-Pr2NEt diisopropylethylamine LAH lithium aluminum hydride LiHMDS lithium hexamethyl disilazide n-BuLi n-butyllithium NMO N-methylmorpholine-N-oxide p-TsOH p-toluenesulfonic acid Py pyridine TBS/TBDMS tert-butyldimethylsilyl THF tetrahydrofuran TiCl4 titanium(IV) chloride TIPS triisopropylsilyl TMS(CH2)2OH trimethylsilylethanol TPAP tetra-n-propylammonium perruthenate Tris-Cl/Tris-HCl tris(hydroxymethyl)aminomethane hydrochloride [NH₂C(CH₂OH)₃HCl] Ts 4-methylphenylsulfonyl (p-toluenesulfonyl)
Systematic name: (1S,6S,9R,13R,14S,17R,19S)-14-hydroxy-6,13, 19-trimethyl-11-methylene-9-propyl-8,20-dioxabicyclo[15.2.1]icosane-7, 15-dione
Total Synthesis of Bioactive Natural Products https://doi.org/10.1016/B978-0-08-102822-3.00005-5
© 2019 Elsevier Ltd. All rights reserved.
25
26
Goutam Brahmachari
Compound class: A 19-membered macrolide Structure:
Natural source: Y-56 strain of the marine dinoflagellate Amphidinium sp. [1–3] Pharmaceutical potential: Anticancer (showed potent activity against murine lymphoma L1210 and human epidermoid carcinoma KB cell lines) [2, 4, 5] Synthetic route: The significant biological activity, low abundance, and unique structural features of amphidinolide T1 (1) attracted the synthetic community for its total synthesis, and as a result four total syntheses have appeared so far in the literature. The first total synthesis of amphidinolide T1 was accomplished by Ghosh and Liu [6]; later on the other three total syntheses were reported by F€ urstner et al. [7], Jamison et al. [8], and Yadav and Reddy [9] using different strategies to effect the macrocycle formation. The first total synthesis of amphidinolide T1 (1) reported by Ghosh and Liu is outlined herein. The retrosynthetic approach conceived by the investigators is outlined in Scheme 1. Their stereocontrolled and convergent synthetic strategy for the macrolide 1 involves the assembly of the C1–C10 sulfone segment 2 and the C11–C21 segment 3 by an oxocarbenium ion-mediated alkylation and macrolactonization sequence. They planned to synthesize fragment 2 using cross-metathesis and a hydrogenation sequence between the terminal olefins of 5 and 6, and enol ether 4 was designed to be the surrogate of fragment 3. The synthesis of C1–C10 segment 2 is outlined in Scheme 2. Aldol condensation of (1R,2S)-(4-methylphenylsulfonamido)-2,3-dihydro-1Hinden-2-yl propionate (7) with 3-(benzyloxy)propanal (8) at 78°C furnished the aldol adduct 9 as a single diastereomer in 90% yield [10, 11].
(+)-Amphidinolide T1
27
Scheme 1 Ghosh’s retrosynthetic approach for (+)-amphidinolide T1 [6].
LAH reduction of 9 followed by selective sulfonylation of the primary hydroxyl group of diol 10, displacement of the resulting sulfonate with cyanide, and acid-promoted lactonization ultimately afforded 11 in 81% overall yield as colorless oil. DIBAL reduction of the γ-lactone 11 followed by its reaction with trimethylsilylethanol and p-TsOH gave acetal 12 and its isomer as a 3.5:1 mixture, which was separated by column chromatography after removal of the benzyl group by hydrogenolysis. Swern oxidation of the resulting alcohol followed by Wittig olefination furnished alkene 5, one of the substrates for cross-metathesis. Afterward the investigators carried out cross-metathesis reaction between the terminal alkenes 5 and 6 [12] to form the C4–C5 carbon–carbon bond [13] in the presence of 5 mol% of second-generation Grubbs’ catalyst [14] whereby a 1:1 mixture (E:Z) of cross-metathesis product 13 was obtained. Catalytic hydrogenation of the alkene mixture followed by treatment of the saturated derivative with lithium phenylmethoxide furnished benzyl ester 14 in 85% yield. Exposure of 14 to phenylsulfinic acid and CaCl2 afforded sulfone derivative 2 and its isomer as a 7:1 mixture in 95% yield [15]. Synthesis of the C11–C21 segment is outlined in Scheme 3. Aldol reaction of (1S,2R)-(4-methylphenylsulfonamido)-2,3-dihydro-1H-inden-2-yl propionate (15) with benzyloxyacetaldehyde (16) afforded a single syn-diastereomer (17) in 95% yield [10, 11]. Protection of the resulting alcohol 17 as a TIPS ether followed by DIBAL-H reduction produced alcohol 18, which was readily converted into the corresponding iodide (19). Preparation of aldehyde 21 was achieved from glycidyl tosylate 20 [14]. Treatment of
28
Goutam Brahmachari
Scheme 2 Synthesis of the C1–C10 segment (2) [6].
iodide 19 with t-BuLi generated the corresponding alkanyllithium, which was reacted with aldehyde 21 to obtain a 1:1 diastereomeric mixture of alcohols; this mixture upon TPAP oxidation yielded ketone 22 [16]. Olefination of 22 utilizing Petasis conditions [17] furnished alkene 23. Reductive removal of the benzyl and TIPS ethers [18] followed by reaction of the resulting diol with NBS eventually resulted in the formation of bromotetrahydrofuran 25 as a 3:1 diastereomeric mixture. The investigators prepared this bromolactone to protect the C13-alcohol as well as to protect
(+)-Amphidinolide T1
29
Scheme 3 Synthesis of the C11–C21 segment (4) [6].
the sensitive exo-methylene group during the oxocarbenium ion-mediated alkylation process. The hydroxymethyl group of 25 was then converted to methyl ketone 26 in 60% overall yield. Treatment of 26 with LiHMDS followed by reaction of the resulting enolate with TBSCl afforded the vinyl ether segment (4) as pale yellow oil.
30
Goutam Brahmachari
Scheme 4 Assembly of segments 2 and 4 to form (+)-amphidinolide T1 (1) [6].
The assembly of the sulfone segment 2 and enol ether segment 4 is depicted in Scheme 4. The investigators achieved this assembly of fragments 2 and 4 by an oxocarbenium ion-mediated alkylation reaction using modified Ley’s protocol [19]. Treatment of 2 and 4 in the presence of excess AlCl3 (6 equiv.) and DTBMP (1.2 equiv.) at 35°C resulted in the coupling product 27 as colorless oil in 73% yield as a single isomer. The C18-silyl ether was then removed by exposure to HF-Py, and subsequent hydrogenolysis removed the benzylester. Macrolactonization of the resulting hydroxy acid under Yamaguchi conditions [20] afforded macrolactone 28 in 71% yield over three steps. Reductive unmasking of the bromoether with Zn dust and NH4Cl in ethanol provided amphidinolide T1 (1), whose spectral data were found to be in agreement with those of natural compound [1–3].
References [1] [2] [3] [4] [5] [6] [7] [8] [9]
M. Tsuda, T. Endo, J. Kobayashi, J. Org. Chem. 65 (2000) 1349. J. Kobayashi, T. Kubota, T. Endo, M. Tsuda, J. Org. Chem. 66 (2001) 134. T. Kubota, T. Endo, M. Tsuda, M. Shiro, J. Kobayashi, Tetrahedron 57 (2001) 6175. T.K. Chakraborty, S. Das, Curr. Med. Chem. Anti-Cancer Agents 1 (2001) 131 (Review). J. Kobayashi, M. Tsuda, Nat. Prod. Rep. 21 (2004) 77 (Review). A.K. Ghosh, C. Liu, J. Am. Chem. Soc. 125 (2003) 2374. A. F€ urstner, C. Aissa, J. Ragot, J. Am. Chem. Soc. 125 (2003) 15512. E.A. Colby, K.C. O’Brien, T.F. Jamison, J. Am. Chem. Soc. 127 (2005) 4297. Y.S. Yadav, C.S. Reddy, Org. Lett. 11 (2009) 1705.
(+)-Amphidinolide T1
[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]
31
A.K. Ghosh, S. Fidanze, M. Onishi, K.A. Hussain, Tetrahedron Lett. 38 (1997) 7171. A.K. Ghosh, S. Fidanze, C.H. Senanayake, Synthesis (1998) 937. D. Schinzer, A. Bauer, J. Schiber, Chem. Eur. J. 5 (1999) 2492. H.E. Blackwell, D.J. O’Leary, A.K. Chatterjee, R.A. Washenfelder, D.A. Bussmann, R.H. Grubbs, J. Am. Chem. Soc. 122 (2000) 58 (and references therein). F. Yokokawa, T. Asano, T. Shioiri, Org. Lett. 26 (2000) 4169. L.A. Paquette, J. Tae, J. Org. Chem. 61 (1996) 7860. E.J. Corey, D.C. Ha, Tetrahedron Lett. 29 (1998) 3171. N.A. Petasis, E.I. Bzowej, J. Am. Chem. Soc. 112 (1990) 6394. E.J. Corey, G.B. Jones, J. Org. Chem. 57 (1992) 1028. S.V. Ley, B. Lygo, A. Wonnacott, Tetrahedron Lett. 26 (1989) 535. J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull. Chem. Soc. Jpn. 52 (1979) 1989.
(+)-Amphidinolide T1 Abbreviations Ar argon (ClCO)2 oxalyl chloride Bn benzyl BnOH benzylalcohol CH2Cl2 dichloromethane Cp2TiMe2 dimethyltitanocene (Petasis reagent) DAMP 4-dimethylaminopyridine DIBAL diisobutylaluminum hydride DMSO dimethylsulfoxide DTBMP 2,6-di-tert-butyl-4-methylpyridine Et3N triethylamine EtOAc ethyl acetate HMPA hexamethylphosphoramide HSO2Ph phenylsulfinic acid i-Pr2NEt diisopropylethylamine LAH lithium aluminum hydride LiHMDS lithium hexamethyl disilazide n-BuLi n-butyllithium NMO N-methylmorpholine-N-oxide p-TsOH p-toluenesulfonic acid Py pyridine TBS/TBDMS tert-butyldimethylsilyl THF tetrahydrofuran TiCl4 titanium(IV) chloride TIPS triisopropylsilyl TMS(CH2)2OH trimethylsilylethanol TPAP tetra-n-propylammonium perruthenate Tris-Cl/Tris-HCl tris(hydroxymethyl)aminomethane hydrochloride [NH₂C(CH₂OH)₃HCl] Ts 4-methylphenylsulfonyl (p-toluenesulfonyl)
Systematic name: (1S,6S,9R,13R,14S,17R,19S)-14-hydroxy-6,13, 19-trimethyl-11-methylene-9-propyl-8,20-dioxabicyclo[15.2.1]icosane-7, 15-dione
Total Synthesis of Bioactive Natural Products https://doi.org/10.1016/B978-0-08-102822-3.00005-5
© 2019 Elsevier Ltd. All rights reserved.
25
26
Goutam Brahmachari
Compound class: A 19-membered macrolide Structure:
Natural source: Y-56 strain of the marine dinoflagellate Amphidinium sp. [1–3] Pharmaceutical potential: Anticancer (showed potent activity against murine lymphoma L1210 and human epidermoid carcinoma KB cell lines) [2, 4, 5] Synthetic route: The significant biological activity, low abundance, and unique structural features of amphidinolide T1 (1) attracted the synthetic community for its total synthesis, and as a result four total syntheses have appeared so far in the literature. The first total synthesis of amphidinolide T1 was accomplished by Ghosh and Liu [6]; later on the other three total syntheses were reported by F€ urstner et al. [7], Jamison et al. [8], and Yadav and Reddy [9] using different strategies to effect the macrocycle formation. The first total synthesis of amphidinolide T1 (1) reported by Ghosh and Liu is outlined herein. The retrosynthetic approach conceived by the investigators is outlined in Scheme 1. Their stereocontrolled and convergent synthetic strategy for the macrolide 1 involves the assembly of the C1–C10 sulfone segment 2 and the C11–C21 segment 3 by an oxocarbenium ion-mediated alkylation and macrolactonization sequence. They planned to synthesize fragment 2 using cross-metathesis and a hydrogenation sequence between the terminal olefins of 5 and 6, and enol ether 4 was designed to be the surrogate of fragment 3. The synthesis of C1–C10 segment 2 is outlined in Scheme 2. Aldol condensation of (1R,2S)-(4-methylphenylsulfonamido)-2,3-dihydro-1Hinden-2-yl propionate (7) with 3-(benzyloxy)propanal (8) at 78°C furnished the aldol adduct 9 as a single diastereomer in 90% yield [10, 11].
(+)-Amphidinolide T1
27
Scheme 1 Ghosh’s retrosynthetic approach for (+)-amphidinolide T1 [6].
LAH reduction of 9 followed by selective sulfonylation of the primary hydroxyl group of diol 10, displacement of the resulting sulfonate with cyanide, and acid-promoted lactonization ultimately afforded 11 in 81% overall yield as colorless oil. DIBAL reduction of the γ-lactone 11 followed by its reaction with trimethylsilylethanol and p-TsOH gave acetal 12 and its isomer as a 3.5:1 mixture, which was separated by column chromatography after removal of the benzyl group by hydrogenolysis. Swern oxidation of the resulting alcohol followed by Wittig olefination furnished alkene 5, one of the substrates for cross-metathesis. Afterward the investigators carried out cross-metathesis reaction between the terminal alkenes 5 and 6 [12] to form the C4–C5 carbon–carbon bond [13] in the presence of 5 mol% of second-generation Grubbs’ catalyst [14] whereby a 1:1 mixture (E:Z) of cross-metathesis product 13 was obtained. Catalytic hydrogenation of the alkene mixture followed by treatment of the saturated derivative with lithium phenylmethoxide furnished benzyl ester 14 in 85% yield. Exposure of 14 to phenylsulfinic acid and CaCl2 afforded sulfone derivative 2 and its isomer as a 7:1 mixture in 95% yield [15]. Synthesis of the C11–C21 segment is outlined in Scheme 3. Aldol reaction of (1S,2R)-(4-methylphenylsulfonamido)-2,3-dihydro-1H-inden-2-yl propionate (15) with benzyloxyacetaldehyde (16) afforded a single syn-diastereomer (17) in 95% yield [10, 11]. Protection of the resulting alcohol 17 as a TIPS ether followed by DIBAL-H reduction produced alcohol 18, which was readily converted into the corresponding iodide (19). Preparation of aldehyde 21 was achieved from glycidyl tosylate 20 [14]. Treatment of
28
Goutam Brahmachari
Scheme 2 Synthesis of the C1–C10 segment (2) [6].
iodide 19 with t-BuLi generated the corresponding alkanyllithium, which was reacted with aldehyde 21 to obtain a 1:1 diastereomeric mixture of alcohols; this mixture upon TPAP oxidation yielded ketone 22 [16]. Olefination of 22 utilizing Petasis conditions [17] furnished alkene 23. Reductive removal of the benzyl and TIPS ethers [18] followed by reaction of the resulting diol with NBS eventually resulted in the formation of bromotetrahydrofuran 25 as a 3:1 diastereomeric mixture. The investigators prepared this bromolactone to protect the C13-alcohol as well as to protect
(+)-Amphidinolide T1
29
Scheme 3 Synthesis of the C11–C21 segment (4) [6].
the sensitive exo-methylene group during the oxocarbenium ion-mediated alkylation process. The hydroxymethyl group of 25 was then converted to methyl ketone 26 in 60% overall yield. Treatment of 26 with LiHMDS followed by reaction of the resulting enolate with TBSCl afforded the vinyl ether segment (4) as pale yellow oil.
30
Goutam Brahmachari
Scheme 4 Assembly of segments 2 and 4 to form (+)-amphidinolide T1 (1) [6].
The assembly of the sulfone segment 2 and enol ether segment 4 is depicted in Scheme 4. The investigators achieved this assembly of fragments 2 and 4 by an oxocarbenium ion-mediated alkylation reaction using modified Ley’s protocol [19]. Treatment of 2 and 4 in the presence of excess AlCl3 (6 equiv.) and DTBMP (1.2 equiv.) at 35°C resulted in the coupling product 27 as colorless oil in 73% yield as a single isomer. The C18-silyl ether was then removed by exposure to HF-Py, and subsequent hydrogenolysis removed the benzylester. Macrolactonization of the resulting hydroxy acid under Yamaguchi conditions [20] afforded macrolactone 28 in 71% yield over three steps. Reductive unmasking of the bromoether with Zn dust and NH4Cl in ethanol provided amphidinolide T1 (1), whose spectral data were found to be in agreement with those of natural compound [1–3].
References [1] [2] [3] [4] [5] [6] [7] [8] [9]
M. Tsuda, T. Endo, J. Kobayashi, J. Org. Chem. 65 (2000) 1349. J. Kobayashi, T. Kubota, T. Endo, M. Tsuda, J. Org. Chem. 66 (2001) 134. T. Kubota, T. Endo, M. Tsuda, M. Shiro, J. Kobayashi, Tetrahedron 57 (2001) 6175. T.K. Chakraborty, S. Das, Curr. Med. Chem. Anti-Cancer Agents 1 (2001) 131 (Review). J. Kobayashi, M. Tsuda, Nat. Prod. Rep. 21 (2004) 77 (Review). A.K. Ghosh, C. Liu, J. Am. Chem. Soc. 125 (2003) 2374. A. F€ urstner, C. Aissa, J. Ragot, J. Am. Chem. Soc. 125 (2003) 15512. E.A. Colby, K.C. O’Brien, T.F. Jamison, J. Am. Chem. Soc. 127 (2005) 4297. Y.S. Yadav, C.S. Reddy, Org. Lett. 11 (2009) 1705.
(+)-Amphidinolide T1
[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]
31
A.K. Ghosh, S. Fidanze, M. Onishi, K.A. Hussain, Tetrahedron Lett. 38 (1997) 7171. A.K. Ghosh, S. Fidanze, C.H. Senanayake, Synthesis (1998) 937. D. Schinzer, A. Bauer, J. Schiber, Chem. Eur. J. 5 (1999) 2492. H.E. Blackwell, D.J. O’Leary, A.K. Chatterjee, R.A. Washenfelder, D.A. Bussmann, R.H. Grubbs, J. Am. Chem. Soc. 122 (2000) 58 (and references therein). F. Yokokawa, T. Asano, T. Shioiri, Org. Lett. 26 (2000) 4169. L.A. Paquette, J. Tae, J. Org. Chem. 61 (1996) 7860. E.J. Corey, D.C. Ha, Tetrahedron Lett. 29 (1998) 3171. N.A. Petasis, E.I. Bzowej, J. Am. Chem. Soc. 112 (1990) 6394. E.J. Corey, G.B. Jones, J. Org. Chem. 57 (1992) 1028. S.V. Ley, B. Lygo, A. Wonnacott, Tetrahedron Lett. 26 (1989) 535. J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull. Chem. Soc. Jpn. 52 (1979) 1989.