Synthesis of the Key Skeleton of Phosphoeleganin

Abstract

The asymmetric synthesis of the key skeleton of phosphoeleganin has been achieved for the first time by using a convergent approach. The salient features of this synthesis include amidation to install a glycine amide at the C-1 position, Wittig olefination to access the C5–C6 bond, Julia–Kocienski olefinations to prepare the C9–C10 and C13–C14 bonds, and a Takai olefination and a Sonogashira coupling to construct the C17–C18 and C18–C19 bonds, respectively. The route disclosed is highly modular, which will permit the synthesis of various analogues, useful for structure–activity relationship studies on phosphoeleganins.

Phosphorylated polyketides are an important class of natural products that possess challenging structural features and potent bioactivities. Calyculins A and B,[1a] fostriecin,[1b] ieustroducsins B and H,[1c] phosdiecins A and B,[1d] phospholactamycins A and B,[1e] and enigmazole A[1f] are among the members of this class that have been synthesized,[2] and the biological potencies of few compounds of this type have been investigated extensively by the scientific community.[1c] [3] The discovery of such natural products, as well as their chemical synthesis, remain important. During a search for novel secondary metabolites from the Mediterranean ascidian Sidnyum elegans in 2016, Menna and co-workers became the first to discover the new phosphorylated polyketide phosphoeleganin[4a] (1; Figure [1]). The same group later reported the absolute configuration[ ^4b ] of this natural product, together with spectroscopic data for various synthesized model compounds. Phosphoeleganin possesses a C-30 linear lipid-like structure bearing an amide of glycine at one terminal. There are five stereogenic secondary hydroxy centers, of which one is phosphorylated. Phosphoeleganin exhibits significant inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), a crucial regulator of a human signaling pathway. Our continuing interest in the total synthesis of bioactive natural products[ ⁵ ] prompted us to envisage a chemical synthesis of the structurally interesting and biologically potent natural product phosphoeleganin. Here, we report the first stereoselective chemical synthesis of the key skeleton of this natural product.

Our retrosynthetic analysis of phosphoeleganin (1) is shown in Scheme [1]. 1 might be accessed from the protected key precursor 2 through global deprotection. Compound 2 could further be synthesized from compound 3 by hydrogenation followed by phosphorylation protocols. Compound 3, in turn, could be constructed by coupling alcohol 4 and phosphine 5 by a Wittig protocol and subsequent amidation with protected glycine. Alcohol 4 could be dissected into two major coupling partners, sulfone 6 and alcohol 7, through a Julia–Kocienski olefination as one of the key strategic steps.

Our synthesis of sulfone 6 commenced from the known alcohol 8, prepared from d-arabinose by following the reported procedure.[5a] [6] Sulfone 6 was then benzylated by using BnBr/NaH/TBAI and then subjected to oxidative cleavage in the presence of NaIO₄/OsO₄ to give the corresponding aldehyde, which was subsequently reduced with NaBH₄ to obtain alcohol 9. This was then treated with 1-phenyl-1H-tetrazole-5-thiol (10) by following a Mitsunobu protocol[5a] [b] [h] ^, [7] to give the corresponding sulfide which further was oxidized with (NH₄)₆Mo₇O₂₄·4H₂O/H₂O₂ [5b] [h] ^, [8] to provide sulfone 11 in a good overall yield.

The known epoxide 12, obtained from d-aspartic acid by following the reported methods.[5a] [b] ^, [9] was subjected to epoxide opening in the presence of Me₃SI/BuLi[5h] [10] to give the corresponding allyl alcohol, which was protected as its TBS ether 13 by using TBSCl/imidazole. Selective deprotection of the TBDPS ether of compound 13 by using NH₄F, followed by pivaloyl protection of the resultant primary alcohol, provided compound 14 in 79% yield (over two steps). Next, compound 14 was subjected to oxidative cleavage with NaIO₄/OsO₄ to obtain the corresponding aldehyde, which was treated further with sulfone 11 through a Julia–Kocienski olefination protocol[5b] [h] [11] to access compound 15 together with its inseparable Z-isomer (E/Z = 5:1). Next, compound 15 was hydrogenated to give alcohol 16 that, on treatment with 1-phenyl-1H-tetrazole-5-thiol (10) in the presence of Ph₃P/DIAD,[5a] [b] ^, [7] followed by oxidation with (NH₄)₆Mo₇O₂₄·4H₂O/H₂O₂ gave sulfone 6 in a good overall yield.

The synthesis of alcohol 7 is shown in Scheme [3]. The known compound 17 was prepared from l-arabinose by following the reported procedures.[5a] [6] Alcohol 19 (55%) was obtained along with triol 18 (20%) by treatment of compound 17 with CSA in MeOH at room temperature for two hours; some starting material (25%) was also recovered in this reaction. Later, the undesired triol 18 was converted into the requisite compound 19 in 98% yield by treatment with 2,2-dimethoxypropane (2,2-DMP) in CH₂Cl₂. The free hydroxy group of compound 19 was then protected as a benzyl ether by using BnBr/NaH/TBAI, and the resultant compound was treated with 80% AcOH/H₂O to give diol 20 in 84% yield (over two steps). Diol 20 was then treated sequentially with PivCl/Et₃N/DMAP and TBSOTf/2,6-lutidine to produce compound 21 in good yield. This was subjected to NaIO₄/OsO₄-mediated oxidative cleavage, and the resultant aldehyde reacted concomitantly with Ph₃PCH₂I₂/NaHMDS, giving a smooth transformation into the iodo-Wittig[12] products 22 as an inseparable mixture of geometrical isomers (E/Z = 4:1). Finally, iodides 22 were coupled with alkyne 23 through a Sonogashira reaction[5a] [d] ^, [13] in the presence of Pd(Ph₃P)₂Cl₂/CuI/Et₃N; this was followed by reduction with DIBAL-H to yield an inseparable mixture of alcohols 7 in a very good yield.

The synthesis of key skeleton of phosphoeleganin is shown in Scheme [4]. The mixture of alcohols 7 was oxidized under Swern conditions[5e] [g] [h] ^, [14] and then treated with sulfone 6 in the presence of NaHMDS by following a Julia–­Kocienski olefination protocol[5b] [f] [g] ^, [11] to give a mixture of alkenes 24 in 75% yield (over two steps). It is important to mention that we did not pay attention to the separation of those olefins of similar polarities, even in the advanced stages, as a hydrogenation at a later stage would provide a single compound. Next, the pivaloyl ester of compound 24 was removed by using DIBAL-H, and the mixture of resultant alcohols was oxidized further to the corresponding aldehydes under Swern conditions; the aldehydes were subsequently subjected to Wittig olefination[15] with compound 5 in the presence of NaHMDS to provide a mixture of acids 25 in 68% yield (over two steps). Next, an amidation of the mixture of acids 25 with tert-butyl glycinate was attempted (Table [1]). The use of DCC/DMAP (Table [1], entry 1) and DIC/DMAP (entry 2) resulted a mixture of coupling products 3 in yields of 30 and 55%, respectively, whereas EDC·HCl (entry 3) gave a superior yield of 87%.

Compound 3 mixed with its geometrical isomers was subjected to hydrogenation to provide the corresponding saturated debenzylated product in 58% yield. The stage was then set for the crucial phosphorylation of the C-16 hydroxy group. The phosphorylating agents PCl₃/Me₃SiCH₂CH₂OH/H₂O₂/py, 4-methoxybenzyl alcohol/PCl₃/H₂O₂/py, and (4-methoxybenzyl alcohol/PCl₃/py) were tested under various conditions, and we were delighted to find that that PO(OPh)₂Cl₂/py functioned best in this case and provided the suitably protected complete skeleton 2 of phosphoeleganin in a good yield (72%) for future studies.

In summary, we have accomplished a synthesis of the suitably protected key skeleton of structurally intriguing and biologically potent phosphoeleganin for the first time in 17 longest linear steps starting from known compound 12 with a 4.0% overall yield.[16] All five chiral hydroxy centers were installed by using a chiral-pool approach. We believe that the synthesized key skeleton could be manipulated to access the isolated phosphoeleganin. The developed route is flexible, which should permit access to a large number variants of phosphoeleganin ideally suited for structure–activity relationship assays. Efforts are currently in progress in our laboratory to transform the key intermediate 2 into phosphoeleganin and its various analogues, as will be disclosed in due course.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgements

G.H.M., D.S., and S.S.A. thank the Indian Association for the Cultivation of Science, Kolkata and the Council of Scientific and Industrial Research, New Delhi, for research fellowships.

• References and Notes

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  Thieme Connect
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• 16 Compound 2 10% Pd/C (111 mg) was added to a stirred solution of 3 (370 mg, 0.4 mmol) in EtOAc (10 mL), under H₂ (balloon) at rt, and the mixture was stirred for 40 h. The mixture was then filtered through a short pad of Celite that was washed with EtOAc (30 mL). The combined organic layers were concentrated under reduced pressure and purified by flash column chromatography [silica gel (100–200 mesh), 20% EtOAc–hexane] to give the corresponding saturated compound as a colorless oil; yield: (202 mg, 58%). Diphenylphosphoryl chloride (30 μl, 0.11 mmol) was added slowly to a solution of the saturated compound (50 mg, 0.055 mmol) in anhyd pyridine (5 mL) at 0 °C under argon, and the mixture was stirred at rt for 48 h. The reaction was quenched with ice–water, and the mixture was extracted with EtOAc (20 mL). The combined organic layers were washed successively with ice–water, 1 N aq HCl, sat. aq NaHCO₃, and brine, then dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by column chromatography [silica gel (100–200 mesh), 15–20% EtOAc–hexane] to give compound 2 as a liquid; yield: 47 mg (72%); [α]_D ²⁵ +7 (c 0.8, CHCl₃). IR (neat): 3302, 2931 2872, 1733, 1612, 1454, 1388, 1067, 993 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.42–7.05 (m, 12 H), 6.15 (s, 1 H), 4.64–4.46 (m, 1 H), 3.93 (dt, J = 13.0, 5.1 Hz, 4 H), 3.74–3.47 (m, 2 H), 2.62 (t, J = 7.5 Hz, 2 H), 1.77–1.66 (m, 5 H), 1.42–1.20 (m, 62 H), 0.89–0.86 (m, 15 H), 0.15–0.06 (m, 12 H). ¹³C NMR (75 MHz, CDCl3): δ = 158.0, 155.8, 151.0, 150.9, 150.8, 129.8, 125.3, 125.2, 120.4, 120.3, 120.2, 108.0, 107.6, 84.9, 84.8, 83.4, 78.6, 78.4, 77.4, 74.4, 74.3, 72.3, 37.4, 33.8, 32.1, 30.4, 30.3, 30.2, 29.9, 29.8, 29.8, 29.7, 29.6, 29.5, 29.3, 28.8, 28.7, 28.2, 27.0, 26.4, 26.1, 26.1, 25.9, 25.5, 25.2, 22.9, 18.4, 18.3, 14.3, 1.2, 0.2, –4.1, –4.2, –4.3, –4.4. HRMS (ESI): m/z [M + H + Na]⁺ calcd for C₆₃H₁₁₂NNaO₁₁PSi₂: 1169.7487; found: 1169.779.

Corresponding Author

Publication History

Received: 13 May 2022

Accepted after revision: 21 June 2022

Accepted Manuscript online:
21 June 2022

Article published online:
19 July 2022

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• References and Notes

• 1a Kato Y, Fusetani N, Matsunaga S, Hashimoto K, Fujita S, Furuya T. J. Am. Chem. Soc. 1986; 108: 2780
  CrossrefSearch in Google Scholar
• 1b Boger DL, Hikota M, Lewis BM. J. Org. Chem. 1997; 62: 1748
  CrossrefSearch in Google Scholar
• 1c Kohama T, Enokita R, Okazaki T, Miyaoka H, Torikata A, Inukai M, Kaneko I, Kagasaki T, Sakaida Y, Satoh A, Shiraishi A. J. Antibiot. 1993; 46: 1503
  CrossrefPubMedSearch in Google Scholar
• 1d Thomasi SS, Ladeira C, Ferreira D, da Fontoura Sprenger R, Badino AC, Ferreira AG, Venâncio T. Helv. Chim. Acta 2016; 99: 281
  CrossrefSearch in Google Scholar
• 1e Ozasa T, Tanaka K, Sasamata M, Kaniwa H, Shimizu M, Matsumoto H, Iwanami M. J. Antibiot. 1989; 42: 1339
  CrossrefPubMedSearch in Google Scholar
• 1f Oku N, Takada K, Fuller RW, Wilson JA, Peach ML, Pannell LK, McMahon JB, Gustafson KR. J. Am. Chem. Soc. 2010; 132: 10278
  CrossrefPubMedSearch in Google Scholar
• 1g Ai Y, Kozytska MV, Zou Y, Khartulyari AS, Smith AB. III. J. Am. Chem. Soc. 2015; 137: 15426
  CrossrefPubMedSearch in Google Scholar
• 1h Ahlers A, de Haro T, Gabor B, Fürstner A. Angew. Chem. 2016; 128: 1428
  CrossrefSearch in Google Scholar
• 1i Meissner A, Kishi T, Fujisawa Y, Murai Y, Takamura H, Kadota I. Tetrahedron Lett. 2018; 59: 4492
  CrossrefSearch in Google Scholar
• 1j Sakurai K, Sakamoto K, Sasaki M, Fuwa H. Chem. Asian J. 2020; 15: 3494
  CrossrefPubMedSearch in Google Scholar
• 2a Matsuhashi H, Shimada K. Tetrahedron 2002; 58: 5619
  CrossrefSearch in Google Scholar
• 2b Shimada K, Kaburagi Y, Fukuyama T. J. Am. Chem. Soc. 2003; 125: 4048
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• 2c Della-Felice F, Sarotti AM, Krische MJ, Pilli RA. J. Am. Chem. Soc. 2019; 141: 13778
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• 2d Wang Y.-G, Takeyama R, Kobayashi Y. Angew. Chem. Int. Ed. 2006; 45: 3320
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• 2e Sakurai K, Sasak M, Fuwa H. Angew. Chem. Int. Ed. 2018; 57: 5143
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• 2f Evans DA, Gage JR, Leighton JL. J. Am. Chem. Soc. 1992; 114: 9434
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• 2g Reddy YK, Falck JR. Org. Lett. 2002; 4: 969
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• 3a Swingle MB, Amable L, Lawhorn BG, Buck SB, Burke CP, Ratti P, Fisher KL, Boger DL, Honkanen RE. J. Pharmacol. Exp. Ther. 2009; 45: 331
  Search in Google Scholar
• 3b Paulson JR, Mause ER. V. Adv. Biol. Chem. 2013; 3: 36
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• 3c Fabian L, Troscianczuk J, Forer A. Cell Chromosome 2007; 6: 1
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• 3d Lewy DS, Gauss C.-M, Soenen DR, Boger DL. Curr. Med. Chem. 2002; 9: 2005
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• 4a Imperatore C, Luciano P, Aiello A, Vitalone R, Irace C, Santamaria R, Li J, Guo Y, Menna M. J. Nat. Prod. 2016; 79: 1144
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• 5b Saha D, Mandal GH, Goswami RK. J. Org Chem. 2021; 86: 10006
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• 5c Kuilya TK, Goswami RK. Org. Lett. 2017; 19: 2366
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• 5d Paul D, Saha S, Goswami RK. Org. Lett. 2018; 20: 4606
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• 5f Guchhait S, Chatterjee S, Ampapathi RS, Goswami RK. J. Org. Chem. 2017; 82: 2414
  CrossrefPubMedSearch in Google Scholar
• 5g Das S, Paul D, Goswami RK. Org. Lett. 2016; 18: 1908
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  CrossrefPubMedSearch in Google Scholar
• 6a Thompson DK, Hubert CH, Wightman RH. Tetrahedron 1993; 49: 3827
  CrossrefSearch in Google Scholar
• 6b Phaosiri C, Proteau PJ. Bioorg. Med. Chem. Lett. 2004; 14: 5309
  CrossrefPubMedSearch in Google Scholar
• 7a Candy M, Audran G, Bienaymé H, Bressy C, Pons J.-M. J. Org. Chem. 2010; 75: 1354
  CrossrefPubMedSearch in Google Scholar
• 7b Mitsunobu O. Synthesis 1981; 1
  Thieme Connect
• 8a Cichowicz NR. Nagorny P. Org. Lett. 2012; 14: 1058
  CrossrefPubMedSearch in Google Scholar
• 8b Crimmins MT, Haley MW, O’Bryan EA. Org. Lett. 2011; 13: 4712
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• 9 Volkmann RA, Kelbaugh PR, Nason DM, Jasys VJ. J. Org. Chem. 1992; 57: 4352
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• 10 Alcaraz L, Harnett JJ, Mioskowski C, Martel JP, Le Gall T, Shin D.-S, Falck JR. Tetrahedron Lett. 1994; 35: 5449
  CrossrefPubMedSearch in Google Scholar
• 11a Julia M, Paris J.-M. Tetrahedron Lett. 1973; 14: 4833
  CrossrefSearch in Google Scholar
• 11b Blakemore PR, Cole WJ, Kocieński PJ, Morley A. Synlett 1998; 26
  Thieme Connect
• 11c Lee J.-L, Lin C.-F, Hsieh L.-Y, Lin W.-R, Chiu H.-F, Wu Y.-C, Wang K.-S, Wu M.-J. Tetrahedron Lett. 2003; 44: 7833
  CrossrefSearch in Google Scholar
• 12a Stork G, Zhao K. J. Am. Chem. Soc. 1990; 112: 5875
  CrossrefSearch in Google Scholar
• 12b Williams GM, Roughley SD, Davies JE, Holmes AB, Adams JP. J. Am. Chem. Soc. 1999; 121: 4900
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• 12c Crimmins MT, Powell MT. J. Am. Chem. Soc. 2003; 125: 7592
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• 13a Sonogashira K. J. Organomet. Chem. 2002; 653: 46
  CrossrefSearch in Google Scholar
• 13b Crimmins MT, She J. J. Am. Chem. Soc. 2004; 126: 12790
  CrossrefPubMedSearch in Google Scholar
• 14 Mancuso A, Huang S.-L, Swern D. J. Org. Chem. 1978; 43: 2480
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• 15a Hurem D, Dudding T. RSC Adv. 2014; 4: 15552
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• 15c Brinkmann Y, Oger C, Guy A, Durand T, Galano J.-M. J. Org. Chem. 2010; 75: 2411
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• 16 Compound 2 10% Pd/C (111 mg) was added to a stirred solution of 3 (370 mg, 0.4 mmol) in EtOAc (10 mL), under H₂ (balloon) at rt, and the mixture was stirred for 40 h. The mixture was then filtered through a short pad of Celite that was washed with EtOAc (30 mL). The combined organic layers were concentrated under reduced pressure and purified by flash column chromatography [silica gel (100–200 mesh), 20% EtOAc–hexane] to give the corresponding saturated compound as a colorless oil; yield: (202 mg, 58%). Diphenylphosphoryl chloride (30 μl, 0.11 mmol) was added slowly to a solution of the saturated compound (50 mg, 0.055 mmol) in anhyd pyridine (5 mL) at 0 °C under argon, and the mixture was stirred at rt for 48 h. The reaction was quenched with ice–water, and the mixture was extracted with EtOAc (20 mL). The combined organic layers were washed successively with ice–water, 1 N aq HCl, sat. aq NaHCO₃, and brine, then dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by column chromatography [silica gel (100–200 mesh), 15–20% EtOAc–hexane] to give compound 2 as a liquid; yield: 47 mg (72%); [α]_D ²⁵ +7 (c 0.8, CHCl₃). IR (neat): 3302, 2931 2872, 1733, 1612, 1454, 1388, 1067, 993 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.42–7.05 (m, 12 H), 6.15 (s, 1 H), 4.64–4.46 (m, 1 H), 3.93 (dt, J = 13.0, 5.1 Hz, 4 H), 3.74–3.47 (m, 2 H), 2.62 (t, J = 7.5 Hz, 2 H), 1.77–1.66 (m, 5 H), 1.42–1.20 (m, 62 H), 0.89–0.86 (m, 15 H), 0.15–0.06 (m, 12 H). ¹³C NMR (75 MHz, CDCl3): δ = 158.0, 155.8, 151.0, 150.9, 150.8, 129.8, 125.3, 125.2, 120.4, 120.3, 120.2, 108.0, 107.6, 84.9, 84.8, 83.4, 78.6, 78.4, 77.4, 74.4, 74.3, 72.3, 37.4, 33.8, 32.1, 30.4, 30.3, 30.2, 29.9, 29.8, 29.8, 29.7, 29.6, 29.5, 29.3, 28.8, 28.7, 28.2, 27.0, 26.4, 26.1, 26.1, 25.9, 25.5, 25.2, 22.9, 18.4, 18.3, 14.3, 1.2, 0.2, –4.1, –4.2, –4.3, –4.4. HRMS (ESI): m/z [M + H + Na]⁺ calcd for C₆₃H₁₁₂NNaO₁₁PSi₂: 1169.7487; found: 1169.779.

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