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DOI: 10.1055/a-2538-2999
Synthesis of Sparsomycin via Regioselective Oxidation of Disulfide Intermediate Employing Titanium–Mandelate Complex
This work was financially supported by JSPS KAKENHI Grant Number 22K05469 (Japan), and The Meijo Research Promotion Organization for Carbon Neutrality.
Dedicated to Prof. Takayuki Shioiri on the occasion of his 88th birthday
Abstract
The total synthesis of sparsomycin, a natural bioactive compound with both antitumor and antibiotic activities, was achieved using a titanium–mandelate complex that regioselectively oxidizes one of the sulfide moieties in a synthetic intermediate containing a disulfide structure. This oxidation process exhibited a regioselectivity of 73:27, preferentially oxidizing the sterically hindered sulfur atom at the desired internal position. Using the single diastereomer of the purified monosulfoxide, the synthesis of sparsomycin was then accomplished.
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Sparsomycin (1) is a biologically active natural compound, isolated from the metabolic products of Streptomyces sparsogenes, with antitumor and antibiotic activities (Scheme [1a]).[1] This compound features an interesting structure, containing both sulfide and sulfoxide moieties in its structure.[2] Reports on the total synthesis of this compound indicate that regioselective oxidation of the precursor disulfide compound 2 was unsuccessful[3] (Scheme [1b]). Consequently, in all previously reported synthetic examples, the total synthesis has been achieved by first constructing the sulfoxide fragment and then introducing the sulfide moiety.[3] [4]
Among the two sulfide sites within the same molecule, methods for the selective chemical oxidation of one sulfide have been scarcely reported, with a few examples involving an enzymatic reaction.[5] Previously, we reported the asymmetric oxidation of pseudo-homoallylic sulfides, facilitated by adjacent hydroxyl groups on the substrate, using chiral titanium–mandelate complexes.[6] In disulfide 2, which is a component of sparsomycin (1), selectively oxidizing the pseudo-homoallylic sulfide site using this method could potentially enable the efficient synthesis of the sulfoxide fragment 3a, a crucial intermediate in the synthesis of 1 (Scheme [1]). In this paper, we describe the total synthesis of sparsomycin (1) utilizing regioselective oxidation of a synthetic precursor that contains a disulfide moiety.
First, the amino group of methyl d-cysteinate (5) was Boc-protected, after which condensation with chloromethyl methyl sulfide was carried out, followed by reduction with sodium borohydride to yield compound (S)-2 (Scheme [2]).
On the other hand, 2-methyluracil fragment 4 was prepared following the route shown in Scheme [3]. Initially, 6-methylpyrimidine-2,4(1H,3H)-dione (7) was treated with an aqueous formaldehyde solution under alkaline conditions to induce hydroxymethylation.[4a] [e] This was followed by oxidation using potassium persulfate and silver nitrate, yielding the formyl compound 8.[3] Subsequently, compound 8 was converted into E-olefin 4 employing a Wittig reaction via a stabilized ylide.[4a]
The regioselective oxidation of disulfide fragment (S)-2 was conducted based on previously reported conditions[6] for the asymmetric oxidation of pseudo-homoallyl sulfides utilizing a titanium mandelate complex. Consistent with the established Kagan oxidation[7] conditions for prochiral sulfides, preliminary experiments revealed that adding a small amount of water to the reaction system slightly improved the regioselectivity.[8] Therefore, oxidation was carried out using 0.4 equivalents of titanium tetraisopropoxide, 0.6 equivalents of mandelic acid, 1.0 equivalent of cumene hydroperoxide, and 0.4 equivalents of H2O along with MS 4 Å.[9] When DCM was used as the solvent, the desired monosulfoxide 3a, in which only the inner sulfide was oxidized, was preferentially obtained in a ratio of 71:29. The diastereoselectivity of the obtained 3a was for the (S C,R S)-isomer with 33% de (Table [1], entry 1). Lowering the reaction temperature to 0 °C slightly increased the regioselectivity and conversion, respectively (73:27, 92%; entry 2). When DMF, toluene, or acetonitrile was used as the solvent, the regioselectivity was significantly decreased, and the selectivity was reversed in all cases (entries 3–5). In the reaction using disulfide (S)-2, which contains an asymmetric center, matching and mismatching of the asymmetric source due to substrate control may influence diastereoselectivity. Therefore, although more expensive than the natural form, the reaction using the non-natural (+)-mandelic acid was also examined, and the regioselectivity was found to be 3a/3b = 67:33, which was slightly reduced. The diastereoselectivity of the obtained 3a was for the (S C,R S)-isomer with 19% de (entry 6). The reaction using natural (–)-mandelic acid is inferior in diastereoselectivity compared to the case with non-natural (+)-mandelic acid (entry 1 vs entry 6). However, it exhibits slightly better regioselectivity and, importantly, is less expensive, which led to the decision to use natural (–)-mandelic acid as the chiral source. Using optically active (+)-DET as the chiral source, similar to Kagan's oxidation conditions,[7] resulted in a preference for the desired regioisomer, but with lower regioselectivity compared to using (–)-mandelic acid (entry 7 vs. entry 1).
a Determined by 1H NMR spectroscopy.
b Determined by HPLC analysis (TSKgel ODS-80Ts column, MeOH/H2O = 40:60, 6.0 mL/min).
c Conducted at 0 °C.
d CHP of 1.2 equiv was used.
e (+)-Mandelic acid was used as the asymmetric source.
f (+)-DET was used as the asymmetric source.
g (R)-2 was used instead of (S)-2.
h In the absence of MS 4 Å.
i For (S C,S S)-3a.
j For (S C,R S)-3a.
Incidentally, oxidation of substrate (S)-2 at room temperature using the common oxidants mCPBA[10] or NaIO4 [11] yielded product ratios of 3a and 3b as 39:61 and 28:72, respectively (Scheme [4]). These results suggest that the less sterically hindered terminal sulfide is preferentially oxidized to form 3b as the major product in both cases. This indicates that regioselective oxidation using titanium mandelate complexes is particularly effective for synthesizing fragment 3a, the oxidized product of the non-terminal sulfide moiety, which is otherwise difficult to achieve.
The isolation and purification of 3a were carried out using a mixture of 3a and 3b obtained from Table [1], entry 1 (3a/3b = 71:29). After isolating 3a as a mixture of diastereomers (33% de) via column chromatography, the diastereomers were further separated using preparative high-performance liquid chromatography to give the desired (S c,R S)-3a in 28% yield and its epimer (S c,S S)-3a in 56% recovery yield (Scheme [5]). The stereochemistry of the optical active sulfoxides was determined by comparing them with the previously reported 1H NMR spectral data of (S c,R S)-3a and (S c,S S)-3a.[12]
During the deprotection of the Boc group in (S c,R S)-3a using TFA, some substrate degradation was observed, likely due to a Pummerer-type[13] reaction. To avoid this, deprotection was performed under neutral conditions. Specifically, the Boc group in compound (S c,R S)-3a was quantitatively removed by treatment in water at 100 °C.[14] The target compound sparsomycin (1) was then obtained in 75% yield by coupling the deprotected compound (S c,R S)-9 with uracil fragment 4 using EDCI in the presence of HOBt (Scheme [6]).[4d]
On the other hand, compound 10, an epimer of sparsomycin regarding its sulfur center, was prepared from (S C,S S)-3a through the same reactions (Scheme [7]). This epimer is also known to exhibit several biological activities.[4d] [15]
In summary, we successfully synthesized sparsomycin (1) using the key reaction of the regioselective oxidation of the disulfide fragment (S)-2 with a titanium–mandelate complex. Compound (S)-2 contains two sulfide sites within the molecule, and oxidation using conventional methods has proven difficult, leading to the absence of previous examples of synthesis via this route. This study represents the first example of the synthesis of sparsomycin utilizing regioselective sulfide oxidation.
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Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2538-2999.
- Supporting Information
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References and Notes
- 1a Argoudelis AD, Herr RR. Antimicrob. Agents Chemother. 1962; 780
- 1b Cordell A, Geoffrey S-kDaley. Heterocycles 2022; 105: 287
- 2a Wiley PF, Mackellar FA. J. Am. Chem. Soc. 1970; 92: 417
- 2b Wiley PF, Mackellar FA. J. Org. Chem. 1976; 41: 1858
- 3 Ottenheijm HC. J, Liskamp RM. J, Van Nispen SP. J. M, Boots HA, Tijhuis MW. J. Org. Chem. 1981; 46: 3273
- 4a Hwang DR, Helquist P, Shekhani MS. J. Org. Chem. 1985; 50: 1264
- 4b Nakajima N, Enomoto T, Matsuura N, Ubukata M. Bioorg. Med. Chem. Lett. 1998; 8: 3331
- 4c Nakajima N, Enomoto T, Watanabe T, Matsuura N, Ubukata M. Biosci., Biotechnol., Biochem. 2003; 67: 2556
- 4d Li S, Cheng X, Zhou Y, Xi Z. ChemBioChem 2011; 12: 2801
- 4e Zhang J, Suzuki K, Ohmori K. Org. Lett. 2023; 25: 9036
- 5a Boyd DR, Sharma ND, Haughey SA, Malone JF, King AW. T, McMurray BT, Alves-Areias A, Allen CC. R, Holt R, Dalton H. J. Chem. Soc., Perkin Trans. 1 2001; 24: 3288
- 5b Dell’Anna MM, Mastrorilli P, Nobile CF, Taurino MR, Calò V, Nacci A. J. Mol. Catal. A: Chem. 2000; 151: 61
- 6a Matsugi M, Fukuda N, Minamikawa J, Otsuka S. Tetrahedron Lett. 1998; 39: 5591
- 6b Matsugi M, Fukuda N, Muguruma M, Yamaguchi T, Minamikawa J, Otsuka S. Tetrahedron 2001; 57: 2739
- 7a Pitchen P, Dunach E, Deshmukh N, Kagan HB. J. Am. Chem. Soc. 1984; 106: 8193
- 7b Diter P, Samuel O, Taudien S, Kagan HB. Tetrahedron: Asymmetry 1994; 5: 549
- 7c Brunei J-M, Diter P, Duetsch M, Kagan HB. J. Org. Chem. 1995; 60: 8086
- 7d Brunei J-M, Kagan HB. Synlett 1996; 404
- 8 In preliminary experiments conducted under anhydrous conditions using DCM as the solvent, the product ratio of 3a to 3b was 64:36.
- 9 General Procedure To a suspension of (–)-mandelic acid (68.3 mg, 0.449 mmol, 0.6 equiv) and MS 4 Å (520 mg) in anhydrous solvent (3 mL), titanium tetraisopropoxide (89.5 μL, 0.299 mmol, 0.4 equiv) and H₂O (5.39 μL, 0.299 mmol, 0.4 equiv) were added at room temperature. The mixture was stirred for 0.5 h. Then, (S)-2 (200 mg, 0.748 mmol, 1.0 equiv) in anhydrous solvent (3 mL) was added to the mixture, stirred for 1 h, and then cumene hydroperoxide (137–164 μL, 0.748 mmol, 1.0–1.2 equiv) was added. The mixture was stirred for 48 h. After Celite filtration, 10% (+)-tartaric acid solution (2 mL) was added and stirred for 1 h. Then, 20% NaOH solution (1 mL) and 8.3% sodium thiosulfate solution (1 mL) were added in succession to the reaction mixture. The mixture was further stirred for 0.5 h at room temperature. The reaction mixture was then extracted three times with CHCl3 and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. ¹H NMR spectra of the crude product determined the conversion and regioselectivity.
- 10 Madesclaire M. Tetrahedron 1986; 42: 5459
- 11 Sudalai A, Khenkin A, Neumann R. Org. Biomol. Chem. 2015; 13: 4374
- 12 Xi Z, Cheng X.-F, Chen W.-B, Cao L.-Q. Tetrahedron Lett. 2006; 47: 3337
- 13a Pummerer R. Ber. Dtsch. Chem Ges. 1909; 42: 2282
- 13b Pummerer R. Ber. Dtsch. Chem Ges. 1910; 43: 1401
- 14 Wang J, Liang Y.-L, Qu J. Chem. Commun. 2009; 5144
For a review, see:
Corresponding Author
Publication History
Received: 24 January 2025
Accepted after revision: 12 February 2025
Accepted Manuscript online:
12 February 2025
Article published online:
01 April 2025
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References and Notes
- 1a Argoudelis AD, Herr RR. Antimicrob. Agents Chemother. 1962; 780
- 1b Cordell A, Geoffrey S-kDaley. Heterocycles 2022; 105: 287
- 2a Wiley PF, Mackellar FA. J. Am. Chem. Soc. 1970; 92: 417
- 2b Wiley PF, Mackellar FA. J. Org. Chem. 1976; 41: 1858
- 3 Ottenheijm HC. J, Liskamp RM. J, Van Nispen SP. J. M, Boots HA, Tijhuis MW. J. Org. Chem. 1981; 46: 3273
- 4a Hwang DR, Helquist P, Shekhani MS. J. Org. Chem. 1985; 50: 1264
- 4b Nakajima N, Enomoto T, Matsuura N, Ubukata M. Bioorg. Med. Chem. Lett. 1998; 8: 3331
- 4c Nakajima N, Enomoto T, Watanabe T, Matsuura N, Ubukata M. Biosci., Biotechnol., Biochem. 2003; 67: 2556
- 4d Li S, Cheng X, Zhou Y, Xi Z. ChemBioChem 2011; 12: 2801
- 4e Zhang J, Suzuki K, Ohmori K. Org. Lett. 2023; 25: 9036
- 5a Boyd DR, Sharma ND, Haughey SA, Malone JF, King AW. T, McMurray BT, Alves-Areias A, Allen CC. R, Holt R, Dalton H. J. Chem. Soc., Perkin Trans. 1 2001; 24: 3288
- 5b Dell’Anna MM, Mastrorilli P, Nobile CF, Taurino MR, Calò V, Nacci A. J. Mol. Catal. A: Chem. 2000; 151: 61
- 6a Matsugi M, Fukuda N, Minamikawa J, Otsuka S. Tetrahedron Lett. 1998; 39: 5591
- 6b Matsugi M, Fukuda N, Muguruma M, Yamaguchi T, Minamikawa J, Otsuka S. Tetrahedron 2001; 57: 2739
- 7a Pitchen P, Dunach E, Deshmukh N, Kagan HB. J. Am. Chem. Soc. 1984; 106: 8193
- 7b Diter P, Samuel O, Taudien S, Kagan HB. Tetrahedron: Asymmetry 1994; 5: 549
- 7c Brunei J-M, Diter P, Duetsch M, Kagan HB. J. Org. Chem. 1995; 60: 8086
- 7d Brunei J-M, Kagan HB. Synlett 1996; 404
- 8 In preliminary experiments conducted under anhydrous conditions using DCM as the solvent, the product ratio of 3a to 3b was 64:36.
- 9 General Procedure To a suspension of (–)-mandelic acid (68.3 mg, 0.449 mmol, 0.6 equiv) and MS 4 Å (520 mg) in anhydrous solvent (3 mL), titanium tetraisopropoxide (89.5 μL, 0.299 mmol, 0.4 equiv) and H₂O (5.39 μL, 0.299 mmol, 0.4 equiv) were added at room temperature. The mixture was stirred for 0.5 h. Then, (S)-2 (200 mg, 0.748 mmol, 1.0 equiv) in anhydrous solvent (3 mL) was added to the mixture, stirred for 1 h, and then cumene hydroperoxide (137–164 μL, 0.748 mmol, 1.0–1.2 equiv) was added. The mixture was stirred for 48 h. After Celite filtration, 10% (+)-tartaric acid solution (2 mL) was added and stirred for 1 h. Then, 20% NaOH solution (1 mL) and 8.3% sodium thiosulfate solution (1 mL) were added in succession to the reaction mixture. The mixture was further stirred for 0.5 h at room temperature. The reaction mixture was then extracted three times with CHCl3 and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. ¹H NMR spectra of the crude product determined the conversion and regioselectivity.
- 10 Madesclaire M. Tetrahedron 1986; 42: 5459
- 11 Sudalai A, Khenkin A, Neumann R. Org. Biomol. Chem. 2015; 13: 4374
- 12 Xi Z, Cheng X.-F, Chen W.-B, Cao L.-Q. Tetrahedron Lett. 2006; 47: 3337
- 13a Pummerer R. Ber. Dtsch. Chem Ges. 1909; 42: 2282
- 13b Pummerer R. Ber. Dtsch. Chem Ges. 1910; 43: 1401
- 14 Wang J, Liang Y.-L, Qu J. Chem. Commun. 2009; 5144
For a review, see:
