Concise Total Synthesis of Curvulone B

Key words

curvulone B - natural products - Mukaiyama–aldol reaction - Friedel–Crafts acylation reaction

Marine fungi have been long recognized as a rich source of novel secondary metabolites with such biological properties as antitumor, phytotoxic, or antifungal activities, as well as cytotoxicity against human cancer cell lines.[1] In connection with the search for biologically active metabolites from fungi, Krohn and Kurtán and their co-workers isolated two new curvularin-type metabolites, curvulone A (1) and curvulone B (2; Figure [1]) from a Curvularia sp. obtained from the marine alga Gracilaria folifera.[1] Curvulone B (2) features a 2,6-disubstituted cis-tetrahydropyran ring, and displays antitumor, antifungal, and cytotoxic activities.[2]

Figure 1 Structures of curvulone A (1) and curvulone B (2)

The structure of curvulone B was determined by 2D NMR spectroscopy, and its absolute configuration was deduced by comparison of the experimental electronic circular dichroism spectra in acetonitrile with the Boltzman-averaged spectrum.[3] Total syntheses of curvulone B (2) have been reported by the groups of Takahashi,[2] Bates,[4] and, more recently, He.[5] None of these syntheses involved fewer than ten linear steps, and all employed an intramolecular oxa-Michael addition for the formation of THP ring.

We recently reported the synthesis of 2,6-trans-disubstituted tetrahydropyrans with a keto functionality by means of a Mukaiyama-type aldol reactions of 1-phenyl-1-(trimethylsiloxy)ethylene with six-membered cyclic hemiacetals in the presence of iodine.[6] As a further application of this Mukaiyama-type aldol reaction, and as a part of our ongoing research on the total synthesis of biologically active natural products containing pyran rings,[7] we report an efficient and convergent synthesis of curvulone B in seven steps.

Scheme 1 Retrosynthetic analysis of curvulone B (2)

Our retrosynthetic analysis of curvulone B is outlined in Scheme [1]. It was envisaged that curvulone B might be prepared by a Friedel–Crafts acylation reaction of aromatic ester 3 and the acid fragment 4 (Scheme [1]). We planned to obtain intermediate 4 from the trans-2,6-disubstituted dihydropyran 5 that, in turn, would be accessed from a δ-hydroxy α,β-unsaturated aldehyde through tandem isomerization followed by C–O and C–C bond-forming reactions of a silyl enol ether under Mukaiyama-type aldol reaction conditions. The δ-hydroxy α,β-unsaturated aldehyde would be obtained from the commercially available chiral homoallylic alcohol 6.

The synthesis of the key intermediate 5 began with the commercially available homoallylic alcohol 6 and acrolein, which, on treatment with the Hoveyda–Grubbs catalyst (10 mol%) in CH₂Cl₂ gave the cross-metathesis[8] product, the δ-hydroxy α,β-unsaturated aldehyde 7, in 87% yield (Scheme [2]). Tandem isomerization followed by a C–O and C–C bond-formation protocol under Mukaiyama-type conditions was performed by treating 7 with trimethyl(vinyloxy)silane in the presence of a catalytic amount of molecular iodine in anhydrous CH₂Cl₂ at room temperature to furnish the trans-2,6-disubstituted-3,4-dihydropyran 5 as the sole product in 81% yield.[6] [9] [10]

Scheme 2 Synthesis of compound 5

The next task was to reduce the internal double bond and then to perform the isomerization reaction. Accordingly, the double bond in compound 5 was reduced in the presence of a catalytic amount of Adams’s catalyst under hydrogen in anhydrous ethyl acetate to furnish compound 8 in excellent yield (Scheme [3]). Epimerization was performed by a retro-oxa-Michael/oxa-Michael reaction with potassium tert-butoxide in THF at 0 °C; this reaction was highly stereoselective, favoring the desired C-β-epimer 9, which was obtained in 92% yield.[11] Acid 4, a key fragment for the Friedel–Crafts acylation strategy, was then synthesized in 86% yield from cis-pyran aldehyde 9 by Pinnick oxidation[12] with NaClO₂, NaH₂PO₄, t-BuOH–H₂O (1:1), and 2-methylbut-2-ene.

Scheme 3 Synthesis of compound 4

The aromatic coupling fragment 3 was synthesized by methylation of commercially available methyl 2-(3,5-dihydroxyphenyl)acetate (10) with potassium carbonate and dimethyl sulfate in acetone to afford methyl 2-(3,5-dimethoxyphenyl)acetate (3) in 95% yield (Scheme [4]).[13]

Scheme 4 Synthesis of fragment 3

With cis-pyran acid 4 and methyl 2-(3,5-dimethoxyphenyl)acetate (3) in hand, our next objective was to combine both fragments by using the key Friedel–Crafts acylation reaction. Accordingly, treatment of cis-pyran acid 4 with methyl 2-(3,5-dimethoxyphenyl)acetate (3) in TFA/TFAA, afforded the desired ketone 11 in 93% yield (Scheme [5]).[14]

Scheme 5 Completion of the total synthesis of curvulone B (2)

The structure of compound 11 was confirmed by extensive NMR experiments, including DQF-COSY, TOCSY, NOESY, HSQC, and HMBC experiments. The distinctive AB spin system of double doublets at δ = 2.97 and 3.04 ppm, due to 10-H and 10-H′ displaying a HMBC correlation with the carbonyl carbon (δ = 204.3 ppm), was used to initiate the assignments. The DQF-COSY experiment helped us to assign the protons from 11-H to 15-H and the 16-CH₃ protons. The 2-CH₂ protons appear as a broad singlet at δ = 3.60 ppm. The nOe correlations 11-H/15-H, 11-H/13-H, 13-H/15-H, and 12-H′/14-H′ strongly supported the syn orientation of the 11-H and 15-H protons, as well as the ¹⁴C₁₁ chair conformation of the six-membered ring. Furthermore, nOe correlations between 10-H/2-CH₂, 2-CH₂/4-H, and 7′-OCH₃/10-H provided strong evidence that the pyran ring occupies an position ortho to methyl ester of the benzene ring, providing firm support for the proposed structure of 11 (Figure [2]).

Figure 2 Energy-minimized structure of 11, along with key nOe correlations (double-headed arrows)

Finally, demethylation of the methoxy group of 11 was successfully achieved under Maier’s conditions (AlI₃, TBAI, phloroglucinol)[15] in benzene at 0 °C to furnish curvulone B (2) in 91% yield.[16] The spectroscopic and analytical data for synthetic compound 2 were in good agreement with those reported for the natural product.[1]

In summary, a concise and stereoselective synthesis of the curvulone B (2) was achieved in seven steps and a 46% overall yield by using iodine-catalyzed tandem isomerization followed by C–O and C–C bond-formation through a Mukaiyama-type aldol reaction for the construction of the trans-2,6-disubstituted dihydropyran ring system as the key step. The other important reactions involved in the current synthetic approach were cross-metathesis, epimerization, and Friedel–Crafts acylation reactions.

• References and Notes

• 1 Dai J, Krohn K, Flörke U, Pescitelli G, Kerti G, Papp T, Kövér KE, Bényei AC, Draeger S, Schulz B, Kurtán T. Eur. J. Org. Chem. 2010; 6928 ; and references therein
• 2 Takahashi S, Akita Y, Nakamura T, Koshino H. Tetrahedron: Asymmetry 2012; 23: 952 ; and references therein
• 3 Guo Y.-W, Kurtán T, Krohn K, Pescitelli G, Zhang W. Chirality 2009; 21: 561
• 4 Bates RW, Wang K, Zhou G, Kang DZ. Synlett 2015; 26: 751
• 5 Allu SR, Banne S, Jiang J, Qi N, Guo J, He Y. J. Org. Chem. 2019; 84: 7227
• 6 Bharath Y, Choudhury UM, Sadhana N, Mohapatra DK. Org. Biomol. Chem. 2019; 17: 9169
• 7a Mallampudi NA, Srinivas B, Reddy JG, Mohapatra DK. Org. Lett. 2019; 21: 5952
• 7b Srinivas B, Reddy DS, Mallampudi NA, Mohapatra DK. Org. Lett. 2018; 20: 6910
• 7c Reddy GS, Padhi B, Bharath Y, Mohapatra DK. Org. Lett. 2017; 19: 6506
• 7d Maity S, Kanikarapu S, Marumudi K, Kunwar AC, Yadav JS, Mohapatra DK. J. Org. Chem. 2017; 82: 4561
• 7e Banoth S, Maity S, Kumar SR, Yadav JS, Mohapatra DK. Eur. J. Org. Chem. 2016; 2300
• 7f Thirupathi B, Mohapatra DK. Org. Biomol. Chem. 2016; 14: 6212
• 7g Padhi B, Reddy DS, Mohapatra DK. Eur. J. Org. Chem. 2015; 542
• 7h Reddy DS, Padhi B, Mohapatra DK. J. Org. Chem. 2015; 80: 1365
• 8a Garber SB, Kingsbury JS, Gray BL, Hoveyda AH. J. Am. Chem. Soc. 2000; 122: 8168
• 8b Dinh M.-T, Bouzbouz S, Peglion J.-L, Cossy J. Tetrahedron 2008; 64: 5703
• 9 Mohapatra DK, Das PP, Pattanayak MR, Yadav JS. Chem. Eur. J. 2010; 16: 2072
• 10 [(2R,6R)-6-Methyl-5,6-dihydro-2H-pyran-2-yl]acetaldehyde (5) I₂ (0.89 g, 3.51 mmol) was added to a stirred solution of aldehyde 7 (2.0 g, 17.54 mmol) and trimethyl(vinyloxy)silane (3.85 mL, 26.31 mmol) in anhyd CH₂Cl₂ (50 mL) at 0 °C, and the mixture was allowed to warm to rt. When the reaction was complete (TLC), it was quenched with sat. aq Na₂S₂O₃ (30 mL), and the mixture was extracted with CH₂Cl₂ (2 × 50 mL). The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:5)] to give a pale-yellow liquid; yield: 1.99 g (81%); [α]_D ²⁰ –68.0 (c = 0.85, CHCl₃). IR (neat): 3033, 2971, 2928, 1721, 1636, 1373, 1187, 1137, 1090 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 9.81 (s, 1 H), 5.87 (m, 1 H), 5.70 (d, J = 11.7 Hz, 1 H), 4.78 (m, 1 H), 3.83 (m, 1 H), 2.76 (ddd, J = 16.2, 8.8, 3.0 Hz, 1 H), 2.55 (dd, J = 16.2, 4.7 Hz, 1 H), 2.06–1.91 (m, 2 H), 1.21 (d, J = 6.2 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 201.0, 127.5, 125.2, 67.6, 64.1, 47.9, 31.5, 20.6. HRMS (ESI): m/z [M + Na]⁺ calcd for C₈H₁₂NaO₂: 163.0728; found: 163.0724.
• 11 Yakambram P, Puranik VG, Gurjar MK. Tetrahedron Lett. 2006; 47: 3781
• 12a Ballakrishna SB, Childers WE. Jr, Pinnick HW. Tetrahedron 1981; 37: 2091
• 12b Dalcanale E, Montanari F. J. Org. Chem. 1986; 51: 567
• 13 Liang Q, Zhang J, Quan W, Sun Y, She X, Pan X. J. Org. Chem. 2007; 72: 2694
• 14 Tauber J, Rudolph K, Rohr M, Erkel G, Opatz T. Eur. J. Org. Chem. 2015; 3587
• 15 Rink C, Sasse F, Zubrienė A, Matulis D, Maier ME. Chem. Eur. J. 2010; 16: 14469
• 16 Curvulone B (2) A suspension of Al powder (192 mg, 7.37 mmol) in anhyd benzene (5 mL) was treated with I₂ (0.7 g, 2.74 mmol) under argon, and the violet mixture was stirred under reflux for 30 min until the mixture became colorless. The mixture was then cooled to 0 °C, and TBAI (12.7 mg, 0.034 mmol) and phloroglucinol (108 mg, 0.85 mmol) were added, followed by a solution of 11 (60 mg, 0.17 mmol) in anhyd benzene (2 mL) added in one portion. The resulting green–brown suspension was stirred for 30 min at 0 °C. When the reaction was complete (TLC), it was quenched with sat. aq aqueous Na₂S₂O₃ (10 mL), and the mixture was diluted with EtOAc (15 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine (25 mL), filtered, dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:1)] to give a colorless liquid; yield: 50 mg (91%); [α]_D ²⁰ –18.2 (c = 0.2, EtOH). IR (neat): 3410, 2928, 1713, 1613, 1451, 1334, 1166 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.79 (s, 1 H), 6.28 (d, J = 2.3 Hz, 1 H), 6.22 (d, J = 2.3 Hz, 1 H), 6.08 (br s, 1 H), 4.13 (brtt, J = 10.5, 2.3 Hz, 1 H), 3.92 (d, J = 16.5 Hz, 1 H), 3.70 (s, 3 H), 3.57 (m, 1 H), 3.51 (d, J = 16.6 Hz, 1 H), 3.30 (dd, J = 14.3, 10.1 Hz, 1 H), 2.56 (dd, J = 14.3, 3.1 Hz, 1 H), 1.85 (m, 1 H), 1.65–1.50 (m, 3 H), 1.42 (m, 1 H), 1.25 (m, 1 H), 1.17 (d, J = 6.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 204.2, 172.4, 159.4, 135.7, 120.7, 111.7, 104.0, 77.8, 74.8, 52.0, 49.0, 39.7, 32.6, 30.7, 23.1, 21.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₃O₆: 323.1489; found: 323.1494.