Evolution of a Cycloaddition–Rearrangement Approach to the Squalestatins: A Quarter-Century Odyssey

Abstract

The highs, lows, and diversions of a journey leading to two syntheses of 6,7-dideoxysqualestatin H5 is described. Both syntheses relied on highly diastereoselective n-alkylations of a tartrate acetonide enolate and subsequent oxidation–hydrolysis to provide an asymmetric entry to β-hydroxy-α-ketoester motifs. The latter were differentially elaborated to diazoketones which underwent stereo- and regioselective Rh(II)-catalysed cyclic carbonyl ylide formation–cycloaddition and then acid-catalysed transketalisation to generate the 2,8-dioxabicyclo[3.2.1]octane core of the squalestatins/zaragozic acids at the correct tricarboxylate oxidation level. The unsaturated side chain was either protected with a bromide substituent during the transketalisation or introduced afterwards by a stereoretentive Ni-catalyzed Csp³–Csp² cross-electrophile coupling.

1 Introduction  

2 Racemic Model Studies to the Squalestatin/Zaragozic Acid Core

3 Asymmetric Model Studies to a Keto α-Diazoester

3.1 Dialkyl Squarate Desymmetrisation

3.2 Tartrate Alkylation

3.2.1 Further Studies on Seebach’s Alkylation Chemistry 

4 Failure at the Penultimate Step to DDSQ 

5 Second-Generation Approach to DDSQ: A Bromide Substituent Strategy 

5.1 Stereoselective Routes to E-Alkenyl Halides via β-Oxido Phosphonium Ylides 

5.2 Back to DDSQ Synthesis

6 An Alternative Strategy to DDSQ: By Cross-Electrophile Coupling

7 Alkene Ozonolysis in the Presence of Diazo Functionality: Accessing α-Ketoester Intermediates

8 Summary

Key words

zaragozic acid - squalestatin - tartrate alkylation - squarate - α-ketoester - cross-coupling - alkene protection - ozonolysis

• References and Notes

• 1 Permanent address: University of Kufa, Najaf Governorate, Iraq.
• 2 Hodgson DM, Bray CD, Humphreys PG. Synlett 2006; 1
• 3 Hoffmann R. Angew. Chem., Int. Ed. Engl. 1988; 27: 1593
• 4 Padwa A. Acc. Chem. Res. 1991; 24: 22
• 5 Sidebottom PJ, Highcock RM, Lane SJ, Procopiou PA, Watson NS. J. Antibiot. 1992; 45: 648
• 6 Wilson KE, Burk RM, Biftu T, Ball RG, Hoogsteen K. J. Org. Chem. 1992; 57: 7151
• 7 Blows WM, Foster G, Lane SJ, Noble D, Piercey JE, Sidebottom PJ, Webb G. J. Antibiot. 1994; 47: 740
• 8a Nadin A, Nicolaou KC. Angew. Chem., Int. Ed. Engl. 1996; 35: 1622
• 8b Armstrong A, Blench TJ. Tetrahedron 2002; 58: 9321
• 9 Hodgson DM, Bailey JM, Harrison T. Tetrahedron Lett. 1996; 37: 4623
• 10 Nicolaou KC, Yue EW, La Greca S, Nadin A, Yang Z, Leresche JE, Tsuri T, Naniwa Y, De Riccardis F. Chem. Eur. J. 1995; 1: 467
• 11 Armstrong A, Barsanti PA. Synlett 1995; 903
• 12 Hodgson DM, Bailey JM, Villalonga-Barber C, Drew MG. B, Harrison T. J. Chem. Soc., Perkin Trans. 1 2000; 3432
• 13 Kataoka O, Kitagaki S, Watanabe N, Kobayashi J, Nakamura S, Shiro M, Hashimoto S. Tetrahedron Lett. 1998; 39: 2371
• 14 Hodgson DM, Villalonga-Barber C. Tetrahedron Lett. 2000; 41: 5597
• 15 Hodgson DM, Villalonga-Barber C, Goodman JM, Pellegrinet SC. Org. Biomol. Chem. 2010; 8: 3975
• 16 Evans DA, Barrow JC, Leighton JL, Robichaud AJ, Sefkow M. J. Am. Chem. Soc. 1994; 116: 12111
• 17 Ohno M. Top. Heterocycl. Chem. 2006; 6: 1
• 18 Sintim HO, Valade A, Harling DC, Hodgson DM. Tetrahedron 2019; 75: 130747
• 19 Naef R, Seebach D. Angew. Chem., Int. Ed. Engl. 1981; 20: 1030
• 20 Seebach D, Aebi JD, Gander-Coquoz M, Naef R. Helv. Chim. Acta 1987; 70: 1194
• 21 Sintim HO, Al Mamari HH, Almohseni HA. A, Fegheh-Hassanpour Y, Hodgson DM. Beilstein J. Org. Chem. 2019; 15: 1194
• 22 Vedejs E, Larsen S. Org. Synth., Coll. Vol. VII . John Wiley & Sons; London: 1990: 277
• 23 Morita H, Arisaka M, Yoshida N, Kobayashi J. Tetrahedron 2000; 56: 2929
• 24 Sintim HO. Dissertation . University of Oxford; UK: 2002
• 25 Soai K, Oyamada H. Synthesis 1984; 605
• 26 Almohseni HA. A, Mamari HH. A, Valade A, Sintim HO, Hodgson DM. Chem. Commun. 2018; 54: 5354
• 27 Boeckman RK, Ko SS. J. Am. Chem. Soc. 1980; 102: 7146
• 28 Smith AB, Beauchamp TJ, LaMarche MJ, Kaufman MD, Qiu Y, Arimoto H, Jones DR, Kobayashi K. J. Am. Chem. Soc. 2000; 122: 8654
• 29 Al-Mamari HH. Dissertation . University of Oxford; UK: 2005
• 30 Barma DK, Kundu A, Zhang H, Mioskowski C, Falck JR. J. Am. Chem. Soc. 2003; 125: 3218
• 31 Schlosser M, Christmann FK, Piskala A, Coffinet D. Synthesis 1971; 29
• 32 Arif T. Dissertation . University of Oxford; UK: 2012
• 33 Hodgson DM, Arif T. J. Am. Chem. Soc. 2008; 130: 16500
• 34 Hodgson DM, Arif T. Chem. Commun. 2011; 47: 2685
• 35 Hodgson DM, Arif T. Org. Lett. 2010; 12: 4204
• 36 Trost BM, Probst GD, Schoop A. J. Am. Chem. Soc. 1998; 120: 9228
• 37 Müller T, Göhl M, Lusebrink I, Dettner K, Seifert K. Eur. J. Org. Chem. 2012; 2323
• 38 Fürstner A, Seidel G. Tetrahedron 1995; 51: 11165
• 39 Naito S, Escobar M, Kym PR, Liras S, Martin SF. J. Org. Chem. 2002; 67: 4200
• 40 Gassman PG, Schenk WN. J. Org. Chem. 1977; 42: 918
• 41 Fegheh-Hassanpour Y, Arif T, Sintim HO, Al Mamari HH, Hodgson DM. Org. Lett. 2017; 19: 3540
• 42 Hon Y.-S, Lin S.-W, Lu L, Chen Y.-J. Tetrahedron 1995; 51: 5019
• 43 Fegheh-Hassanpour Y, Ebrahim F, Arif T, Sintim HO, Claridge TD. W, Amin NT, Hodgson DM. Org. Biomol. Chem. 2018; 16: 3876
• 44 Johnson KA, Biswas S, Weix DJ. Chem. Eur. J. 2016; 22: 7399
• 45 Villalonga-Barber C. Dissertation . University of Oxford; UK: 2001
• 46 Almohseni AA. H, Fegheh-Hassanpour Y, Arif T, Hodgson DM. Synthesis 2019; 51: 4231
• 47a Wang F, Liu X, Zhang Y, Lin L, Feng X. Chem. Commun. 2009; 7297
• 47b Yamashita Y, Yasukawa T, Yoo W.-J, Kitanosono T, Kobayashi S. Chem. Soc. Rev. 2018; 47: 4388
• 48 Gilbert Stork, quoted in: Seeman JI. Angew. Chem. Int. Ed. 2012; 51: 3012
• 49 Hodgson DM, Stupple PA, Johnstone C. Tetrahedron Lett. 1997; 38: 6471
• 50 Hodgson DM, Labande AH, Muthusamy S. Org. React. 2013; 80: 133