A concise protecting-group-free synthesis of cephalosporolides E and F

Abstract

A concise protecting-group-free synthesis of cephalosporolides E and F has been described. The key steps involve the one-pot conversion of L-mannonic-γ-lactone to γ-vinyl-β-hydroxy-γ-lactone, cross-metathesis and Wacker-type oxidative spiroketalization. The internal olefin served as a latent keto functionality with excellent delivery of a regioselective keto group for spiroketalization. The synthetic strategy is protecting-group-free and marks the shortest route so far to cephalosporolides E and F.

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Introduction

The 5,5-spiroketal natural products cephalosporolides E 1 and F 2 (Fig. 1) were isolated in 1985 by Hanson and co-workers^1a from the fungus Cephalosporium aphidicola and later by Rukachaisirikul and co-workers from the entomopathogenic fungus Cordyceps militaris BCC 2816.^1b These are epimers at the spirocenter with other features being common. They belong to a bigger family of 5,5-spiroketal natural products like penisporolides A and B,² cephalosporolides H and I (3 and 4, Fig. 1),³ symbiospirol A⁴ and ascospiroketal B⁵ to name a few. These molecules with a rigid spiroketal structure are known to exhibit significant biological activities. This has prompted many to design new strategies toward their total synthesis. The total synthesis of unnatural enantiomers of cephalosporolides E and F was first reported by Ramana and co-workers⁶ followed by our first synthesis of the natural antipodes.⁷ Since then a few more syntheses of 1 and 2 or analogs are reported,⁸ the significant being the chelation-controlled epimerization to the spiroketals involving Zn-salts giving a diasteroselectivity as high as 20 : 1 ^8b for the spiroketal center.

Fig. 1 The cephalosporolides E, F, H, and I.

With our continued interest in the synthesis of several γ-lactone based natural products,⁹ our own synthesis^7,10 of cephalosporolides E, F and H and inclination to protecting-group-free synthesis^9f,h we embarked on a concise strategy to achieve the synthesis of cephalosporolides E and F from L-mannonic-γ-lactone without involving protecting groups.

Results and discussion

As shown in our retrosynthetic design (Scheme 1), we visualized the γ-vinyl-β-hydroxy-γ-lactone 8 (obtained by a one-pot procedure from L-mannonic-γ-lactone, 9)^11a to represent the lactone portion of 1 and 2. If the spirocenter can be generated through ketalization by suitably placed hydroxyl groups, the compound 6 seemed the obvious choice as the required keto group (of 5) can be generated in situ through Wacker-type oxidation. Our recent hetero-atom directed regioselective Wacker-type oxidation of related olefin supported the anticipated regioselectivity for keto group.¹² The olefin compound 6 can easily be obtained by cross-metathesis of 7 with 8. The synthetic design would prove to be the shortest route known so far for cephalosporolides E and F synthesis and is notably protecting-group-free.

Scheme 1 Retrosynthesis of cephalosporolides E 1 and F 2.

The forward synthesis is shown in Scheme 2. The allyl magnesium chloride/CuI opening of known epoxide 10¹³ delivered the olefin partner 7 in excellent yield of 92%. The γ-vinyl-β-hydroxy-γ-lactone 8 was prepared from L-mannonic-γ-lactone following our reported literature procedure for its enantiomer.¹¹ The cross-metathesis of 8 with 7 using the Grubbs-II catalyst (2.0 mol%) provided the key olefin compound 6 in 78% yield with E-selectivity.¹⁴ The compound 6 was prepared on 2.4 g scale. The olefin 6 was subjected to Wacker-type oxidation with concomitant spiroketalization as shown in Table 1. We screened four Pd-catalysts (10 mol%, entries 1–4) using CuCl (1.5 equiv.) in DMF : H₂O (4 : 1) as solvent at 60 °C and found PdCl₂ to be superior (entry 1). Pd/C did not work for this reaction and compound 6 was recovered over 75% with partial decomposition. The screening of common solvents used in Wacker oxidation (entries 5–8) showed DMF : H₂O to be better (entry 1). We also considered changing PdCl₂ loading (entries 9–11) and found 20 mol% to give improved yield of 1 and 2 in 60% and 28% respectively (entry 9). The increase in catalyst loading to 30 mol% did not affect the yield much (entry 10), while the lowering to 5 mol% gave diminished yields (entry 11). The lowering of CuCl concentration to 1.0 equiv. gave inferior results (entry 12). Thus the use of PdCl₂ (20–30 mol%) and CuCl (1.5 equiv.) gave the best results. A reaction of 6 (4.0 mmol scale) using the reaction conditions as in entry 9 delivered 1 and 2 in 56% and 25% yields respectively, indicating a good scalability of the reaction (entry 13).

Scheme 2 Synthesis of cephalosporolides E and F.

Table 1 Wacker-type oxidative-spiroketalization of 6 to 1 and 2^a

Entry	Pd-catalyst (x mol%)	CuCl (y equiv.)	Solvent	Isolated yield of 1 and 2
a Reaction conditions: substrate 6 (0.5 mmol), Pd-catalyst (x mol%), CuCl (y equiv.), DMF : H2O (4 : 1, 5.0 mL), at 60 °C under O2, 2 h.b Reaction on 4.0 mmol of 6.
1	PdCl2 (10)	1.5	DMF : H2O	1 (42%), 2 (18%)
2	Pd(OAc)2 (10)	1.5	DMF : H2O	1 (18%), 2 (8%)
3	Pd/C (10)	1.5	DMF : H2O	—
4	Pd(OCOCF3)2 (10)	1.5	DMF : H2O	1 (22%), 2 (10%)
5	PdCl2 (10)	1.5	DMA : H2O	1 (32%), 2 (12%)
6	PdCl2 (10)	1.5	THF : H2O	1 (12%), 2 (8%)
7	PdCl2 (10)	1.5	CH2Cl2 : H2O	1 (28%), 2 (16%)
8	PdCl2 (10)	1.5	tBuOH : H2O	1 (30%), 2 (18%)
9	PdCl2 (20)	1.5	DMF : H2O	1 (60%), 2 (28%)
10	PdCl2 (30)	1.5	DMF : H2O	1 (61%), 2 (28%)
11	PdCl2 (5)	1.5	DMF : H2O	1 (32%), 2 (15%)
12	PdCl2 (20)	1.0	DMF : H2O	1 (48%), 2 (23%)
13^b	PdCl2 (20)	1.5	DMF : H2O	1 (56%), 2 (25%)

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Conclusions

In conclusion an efficient and concise strategy for the synthesis of cephalosporolides E and F has been developed. The Wacker-type oxidative-spiroketalization efficiently delivered both 1 and 2 in good yields. The internal olefin served as latent keto functionality offering excellent heteroatom directed regioselectivity in Wacker-type oxidation. The synthesis is completed in 22.8% and 10.5% over all yields for 1 and 2 respectively from 9 and marks the shortest route to these molecules. It is also notably a protecting-group-free synthesis. The strategy has potential for synthesis of other 5,5-spiroketal natural products.

Experimental section

General information

Flasks were oven- or flame-dried and cooled in a desiccator. Dry reactions were carried out under an atmosphere of N₂. Solvents and reagents were purified by standard methods. Thin-layer chromatography was performed on EM250 Kieselgel 60 F254 silica gel plates. The spots were visualized by staining with KMnO₄ or by UV lamp. ¹H NMR and ¹³C NMR were recorded with Bruker AVANCE III 400 or 500 and 100 or 125 MHz, respectively, and chemical shifts are based on TMS peak at δ = 0.00 ppm for proton NMR and CDCl₃ peak at δ = 77.00 ppm (t) in carbon NMR. IR samples were prepared by evaporation from CHCl₃ on CsBr plates. High-resolution mass spectra were obtained using positive electrospray ionization by TOF method. Optical rotations were measured with a Jasco P-2000 digital polarimeter.

(R)-(−)-5-Hexen-2-ol (7)

Allyl magnesium chloride (61 mL, 121.55 mmol, 2.0 M solution in THF) was added dropwise to a suspension of CuI (579 mg, 3.04 mmol, 5.0 mol%) in dry ether (75 mL) at −60 °C. It was stirred at the same temperature for 30 min. The solution of epoxide 10 (3.53 g, 60.78 mmol) in ether (5 mL) was added. It was stirred for 2 h and then quenched with saturated aq. NH₄Cl solution (10 mL). The reaction mixture was extracted with ether (2 × 60 mL). The combined organic extracts were washed with brine (15 mL), dried (Na₂SO₄) and concentrated. The residue was purified by silica gel column chromatography using petroleum ether/Et₂O (2 : 1) to give 7 (5.6 g, 92%) as colorless oil. [α]²⁵_D −10.2 (c 2.0, CHCl₃). IR (neat): ν_max = 3440, 3021, 1585, 1410, 1221, 1115, 669 cm⁻¹. ¹H NMR (400 MHz, CDCl₃/TMS) δ = 5.89–5.77 (m, 1H), 5.06–4.92 (m, 2H), 3.81 (quin, J = 6.2 Hz, 1H), 2.15–2.09 (m, 2H), 1.99 (br. s, 1H), 1.57–1.48 (m, 2H), 1.17 (d, J = 6.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ = 138.5, 114.7, 67.6, 38.2, 30.1, 23.4 ppm.

(4S,5S)-4-Hydroxy-5-vinyldihydrofuran-2(3H)-one (8)

The title compound was prepared from L-mannonic-γ-lactone 9 following similar one-pot procedure reported by us for its enantiomer.^9h,11 A reaction on 9 (4.5 g, 25.26 mmol) delivered 8 (1.55 g, 48%) as colorless oil. [α]²⁵_D −46.1 (c 1.0, CHCl₃). Lit.^11a −44 (c 1.56, CHCl₃). Other spectral data is same as its enantiomer.^9h

(4S,5S)-4-Hydroxy-5-[(R,E)-5-hydroxyhex-1-enyl]dihydrofuran-2(3H)-one (6)

To a degassed solution of 8 (1.97 g, 15.37 mmol) and 7 (2.31 g, 23.06 mmol, 1.5 equiv.) in dry CH₂Cl₂ (200 mL) was added Grubbs-II catalyst (261 mg, 0.307 mmol, 2.0 mol%) at room temperature and the mixture refluxed for 48 h. The mixture was cooled and filtered through a small pad of celite and the filtrate concentrated. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc (3 : 2) to give 6 (2.4 g, 78%) as colorless oil. [α]²⁵_D = −24.3 (c = 1.75, CHCl₃). IR (CHCl₃): ν_max = 3435, 3018, 2969, 2931, 1769, 1404, 1376, 1327, 1163, 1076, 1014, 968, 907, 847, 667 cm⁻¹. ¹H NMR (400 MHz, CDCl₃/TMS) δ = 5.97–5.90 (m, 1H), 5.66–5.61 (m, 1H), 4.82 (dd, J = 3.6 Hz, 1H), 4.44 (t, J = 4.9 Hz, 1H), 3.78 (q, J = 6.2 Hz, 1H), 2.77 (dd, J = 17.7, 5.4 Hz, 1H), 2.57 (dd, J = 17.7, 1.0 Hz, 1H), 2.23 (q, J = 6.4 Hz, 2H), 1.60–1.51 (m, 2H), 1.18 (d, J = 6.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ = 176.1, 137.7, 122.3, 85.0, 69.7, 67.5, 38.8, 37.5, 28.9, 23.6 ppm. HRMS (ESI-TOF) calcd for [C₁₀H₁₆O₄ + Na]⁺ 223.0938, found 223.0944.

Cephalosporolides E and F (1 and 2)

Reaction conditions as in Table 1, entry 9: to a suspension of PdCl₂ (17.7 mg, 0.1 mmol, 20 mol%) and CuCl (74.3 mg, 0.75 mmol, 1.5 equiv.) in DMF/H₂O (5 mL, 4 : 1) under oxygen atmosphere at room temperature was added 6 (100.1 mg, 0.5 mmol). The reaction mixture was stirred at 60 °C for 2 h. The mixture was cooled and filtered through a short pad of silica gel and the filtrate concentrated. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc (4 : 1) to afford 2 (27.7 mg, 28%). Further elution with petroleum ether/EtOAc (3 : 1) gave 1 (59.5 mg, 60%). The reaction on 6 (801 mg, 4.0 mmol, Table 1, entry 13) delivered 1 (444 mg, 56%) and 2 (198.2 mg, 25%).

Data for 1. White solid, mp 97–99 °C. [α]²⁵_D = 49.2 (c = 0.25, CHCl₃). IR (CHCl₃): ν_max = 3020, 2975, 1779, 1460, 1348, 1303, 1193, 1157, 1099, 1057, 919, 826, 667 cm⁻¹. ¹H NMR (400 MHz, CDCl₃/TMS) δ = 5.12 (t, J = 5.8 Hz, 1H), 4.84 (td, J = 6.6, 1.5 Hz, 1H), 4.12–4.16 (m, 1H), 2.71 (dd, J = 18.6, 7.4 Hz, 1H), 2.61 (dd, J = 18.6, 1.5 Hz, 1H), 2.41 (d, J = 14.2 Hz, 1H), 2.01–2.12 (m, 4H), 1.38–1.45 (m, 1H), 1.18 (d, J = 6.1 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ = 175.9, 115.0, 83.4, 77.2, 75.0, 41.6, 37.6, 34.1, 31.2, 20.9 ppm. HRMS (ESI-TOF) calcd for [C₁₀H₁₄O₄ + H]⁺ 199.0970, found: 199.0975.

Data for 2. White solid, mp 61–63 °C. [α]²⁵_D = −69.1 (c = 0.15, CHCl₃). IR (CHCl₃): ν_max = 3016, 2973, 2934, 1779, 1455, 1404, 1338, 1272, 1195, 1167, 1097, 1059, 927, 864, 667 cm⁻¹. ¹H NMR (400 MHz, CDCl₃/TMS) δ = 5.11–5.06 (m, 1H), 4.79 (t, J = 4.4 Hz, 1H), 4.21–4.17 (m, 1H), 2.73 (dd, J = 18.4, 5.3 Hz, 1H), 2.66 (d, J = 18.0 Hz, 1H), 2.51 (dd, J = 14.9, 6.7 Hz, 1H), 2.31 (dd, J = 14.9, 2.1 Hz, 1H), 2.16–2.11 (m, 1H), 2.06–2.01 (m, 1H), 1.96 (dd, J = 12.4, 7.7 Hz, 1H), 1.75–1.67 (m, 1H), 1.27 (d, J = 6.1 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ = 175.7, 115.4, 83.8, 76.8, 76.5, 42.1, 36.9, 35.9, 32.4, 22.7. HRMS (ESI-TOF) calcd for [C₁₀H₁₄O₄ + H]⁺ 199.0970, found 199.0967.

Acknowledgements

We thank the Board of Research in Nuclear Sciences (BRNS), Government of India (Basic Sciences, Grant no. 2013/37C/59/BRNS/2443) for financial support. D.A.C. and P.K. thanks the Council of Scientific and Industrial Research (CSIR), New Delhi for research fellowships.

Notes and references

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10. R. A. Fernandes and M. B. Halle, Asian J. Org. Chem., 2013, 2, 593–599.
11. The lactone 8 is prepared from L-mannonic-γ-lactone, see: (a) J. Song and R. I. Hollingsworth, Tetrahedron: Asymmetry, 2001, 12, 387; (b) It was prepared in 48% yield by us following our modified procedure used for the synthesis of its antipode from D-glucono-δ-lactone.^9h.
12. (a) V. Bethi, P. Kattanguru and R. A. Fernandes, Eur. J. Org. Chem., 2014, 3249–3255; (b) A day before the submission of this work a similar strategy was employed in the synthesis of cephalosporolide H and I, see: J. Li, C. Zhao, J. Liu and Y. Du, Tetrahedron, 2015 DOI:10.1016/j.tet.2015.04.025.
13. The epoxide was prepared on gram scale following literature procedure, see: S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga, K. B. Hansen, A. E. Gould, M. E. Furrow and E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124, 1307–1315.
14. The Z-olefin was seen in trace amount in the ¹H NMR spectra.

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Footnotes

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra for all the compounds. See DOI: 10.1039/c5ra06991b

‡ These authors contributed equally to this work.

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