Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Bioinspired Synthesis of Juglorubin from Juglomycin C Shogo Kamo,†,‡ Kouji Kuramochi,*,† and Kazunori Tsubaki‡ †
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan ‡ Graduate School for Life and Environmental Sciences, Kyoto Prefectural University, 1-5 Shimogamo Hangi-cho, Sakyo-ku, Kyoto 606-8522, Japan S Supporting Information *
ABSTRACT: In this paper, the synthesis of juglorubin, a natural red dye, from juglomycin C, a plausible biogenetic precursor, is reported. Sequential intermolecular and intramolecular Michael additions of juglomycin C, oxidation, and skeletal transformation proceeded in phosphate buffer to afford an undehydrated derivative of juglorubin. Subsequent dehydration of the secondary alcohol afforded juglorubin. The one-pot synthesis of juglorubin from juglomycin C was also achieved. The photophysical properties of synthetic juglorubin and its derivatives were evaluated.
Q
uinones are widely distributed and exist in all organisms.1 Naturally occurring quinones mainly arise via polyketide or shikimate pathways. Both enzymatic and nonenzymatic modifications are also involved in their biosynthesis.2 Owing to their wide-ranging structural diversity and biological activities, quinones are attractive synthetic targets.3 Juglorubin (1) is a red dye isolated from the culture of Streptomyces sp. 3094, 815, and GW4184 (Figure 1).4 The
Scheme 1. Proposed Biosynthesis of Juglorubin (1)
Figure 1. Structures of juglorubin (1) and 1-O-acetyljuglorubin dimethyl ester (2).
structure of 1 has been elucidated by X-ray crystallographic analysis of its derivative, 1-O-acetyljuglorubin dimethyl ester (2). Compound 1 has an unusual 6/6/5/9/6-fused pentacyclic ring system containing a 5-hydroxy-1,4-naphthoquinone, a cyclopentadienyl anion, and a nine-membered lactone. The cyclopentadienyl anion is stabilized by a sodium cation (Na+). Lessmann and co-workers proposed that compound 1 might be biogenetically synthesized from juglomycin C (3) via juglocombins A/B (5/6) because they have been isolated from the same Streptomyces strains (Scheme 1).4−6 Sequential intermolecular and intramolecular Michael additions of 3, followed by oxidation of the resultant hydroquinone (4), would give 5/6. Juglocombins A/B (5/6) have been isolated as © XXXX American Chemical Society
a 1:1 inseparable tautomeric mixture. Oxidative formation of a double bond between C9 and C3′ in 6, skeletal transformation of the resultant 7, and dehydration of the secondary alcohol in the Received: December 29, 2017
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DOI: 10.1021/acs.orglett.7b04051 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters side chain might afford 1. The skeletal transformation step involves formation of a cyclopentadienyl anion and ninemembered lactone, together with a C−C bond cleavage reaction of 7. The challenging structure and interesting proposed biosynthesis of 1 motivated our pursuit of the total synthesis of juglorubin (1). In previous work, we accomplished the total synthesis and determined the absolute configuration of 5/6.7 The 6/6/5/6/6-fused core skeleton of 5/6 was constructed through the bioinspired stereoselective dimerization of the juglomycin C derivative, which provided efficient access to 5/6. Next, we envisioned that target molecule 1 could be synthesized from juglomycin C (3). Herein, the bioinspired synthesis of juglorubin from juglomycin C, the mechanism of this transformation, and the optical properties of synthetic juglorubin and its derivatives are reported. Reaction conditions for the dimerization of enantiomerically pure 38 were investigated (Table 1). After testing different
Scheme 2. Plausible Mechanisms for the Formation of 8 (A) and 9 (B)
Table 1. Dimerization of Juglomycin C (3)
Scheme 3. Skeletal Transformation of Juglocombins A/B (5/ 6) into 8
entry
additive
product (yieldc)
1a 2b
NaI, 2-methyl-2-butene
8 (43%), 9 (41%) 8 (72%)
a
Reaction conditions: 3 in 1 M sodium phosphate buffer (pH 8.5), air, rt, 3 days. bReaction conditions: 3 in 1 M sodium phosphate buffer (pH 8.5), NaI (20 equiv), 2-methyl-2-butene (40 equiv), air, rt, 6 days. c Isolated yield.
conditions, we found that treating 3 with phosphate buffer (pH 8.5) under aerobic conditions gave 8 and juglomycin D (9) in 43 and 41%, respectively (entry 1). Compound 8 is an undehydrated derivative of juglorubin. Juglomycin D (9) is a related natural product found in the same Streptomyces sp. as juglorubin (1) and juglomycin C (3).4b,5 Plausible mechanisms for the formation of 8 and 9 are depicted in Scheme 2. Based on the biosynthesis, it is proposed that 3 is oxidatively dimerized to 7, which under basic conditions undergoes skeletal rearrangement to 8 (Scheme 2A). The cyclopentadienyl anion in 8 should be stabilized by the three carbonyl groups adjacent to the cyclopentadienyl ring and act as a good leaving group to promote C−C bond cleavage.9 The formation of 9 is explained by the epoxidation of 3 with hydrogen peroxide generated by the formation of 8, followed by isomerization (Scheme 2B).10,11 Indeed, the addition of sodium iodide (NaI) and 2-methyl-2butene as hydrogen peroxide scavengers12 greatly improved the yield of 8. Compound 8 was obtained in 72% yield as an identified product (Table 1, entry 2). Although several attempts were made to isolate and identify reaction intermediates for transformations from 3 to 8, plausible intermediates, such as compound 4 and juglocombins A/B (5/ 6), were not obtained (Table S1). To determine whether juglocombins A/B (5/6) were reaction intermediates, the skeletal transformation of 5/6 to 8 was examined (Scheme 3).
Juglocombins A/B (5/6) were prepared by oxidation of 10 with [bis(trifluoroacetoxy)iodo]benzene in 2,2,2-trifluoroethanol and water, followed by the removal of four methoxymethyl groups using trifluoroacetic acid.7 As 5/6 were an unstable tautomeric equilibrium mixture, the crude compounds were used in the next reaction without purification. When crude 5/6 were treated with phosphate buffer (pH 8.5) under aerobic conditions, the skeletal transformation occurred to afford 8 in 49% yield from 10. Although juglocombins A/B (5/6) were not obtained by treating 3 with phosphate buffer (pH 8.5) under aerobic conditions, these results indicated that juglocombins A/B (5/6) were plausible intermediates in the formation of 8 from 3. Dehydration of 8 proceeded in AcOH and MeOH to afford juglorubin (1) in 54% yield (Scheme 4). Spectroscopic data of synthetic 1 were identical to those reported for natural 1 (Table S2). Synthetic 1 was converted into 1-O-acetyljuglorubin dimethyl ester (2) via juglorubin dimethyl ester (11) according to the method reported by Lessmann4a with slight modifications. Spectroscopic data of synthetic 2 were also identical to those reported for the same compound derived from natural 1 (Table S3). The one-pot synthesis of 1 from 3 was also achieved (Scheme 5). Treatment of 3 with phosphate buffer (pH 8.5) under aerobic B
DOI: 10.1021/acs.orglett.7b04051 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
1, 2, and 11 showed broad emission bands between 550 and 900 nm, with maximum emission wavelengths (λem) of 632, 628, and 631 nm, respectively. Notably, these compounds exhibited fluorescence emission in the near-infrared region (>700 nm) with large Stokes shifts (approximately 130 nm). The absolute quantum yields of 1, 2, and 11 in MeCN were determined to be 1.9, 4.0, and 5.3%, respectively. In conclusion, the chemical synthesis of juglorubin (1) from juglomycin C (3) has been achieved. The sequential double Michael addition, oxidation, and skeletal transformation of 3 in phosphate buffer proceeded to successfully construct the 6/6/5/ 9/6-fused skeleton of juglorubin and give intermediate 8 in a single step. The skeletal transformation of juglocombins A/B (5/ 6) to 8 also proceeded well, further indicating that these compounds were reaction intermediates in the formation of 8 from 3. Dehydration of the secondary alcohol moiety in 8 proceeded in AcOH and MeOH to afford juglorubin (1). Our results suggested that natural juglorubin might be produced by the nonenzymatic transformation of juglomycin C or juglocombins A/B. Synthetic compounds 1, 2, and 11 showed strong absorption at 400−600 nm and exhibited orange-red fluorescence emissions (λem = approximately 630 nm) in MeCN. We believe that this synthesis will accelerate synthetic, biosynthetic, photophysical, and biological studies of juglorubin and its related natural products, which are currently underway and will be reported in due course.
Scheme 4. Synthesis of Juglorubin (1) and 1-OAcetyljuglorubin Dimethyl Ester (2)
conditions in the presence of NaI and 2-methyl-2-butene for 4 days, followed by treatment of the resultant solution with AcOH and MeOH in the presence of sodium sulfate (Na2SO4) as a drying agent, gave 1 in 48% yield.
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Scheme 5. One-Pot Synthesis of Juglorubin (1)
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b04051. Experimental details, characterization of the products, and copies of 1H and 13C NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected].
The photophysical properties of juglorubin (1) and its derivatives 2 and 11 in MeCN were evaluated (Figure 2). Solutions of 1, 2, and 11 in MeCN were reddish-orange due to broad absorption between 400 and 600 nm in the visible region. Furthermore, these solutions showed orange-red fluorescence when exposed to ultraviolet (UV) light. Fluorescence spectra for
ORCID
Kouji Kuramochi: 0000-0003-0571-9703 Kazunori Tsubaki: 0000-0001-8181-0854 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This study was partly supported by a Grant-in Aid from the Japan Society for the Promotion of Science (JSPS) Fellows (No. 16J00542) to S.K., and a Grant-in-Aid for Scientific Research (C) (KAKENHI No. 15K07416) and the Sumitomo Foundation (No. 170183) to K.K. This study was carried out using the Fourier transform ion cyclotron resonance mass spectrometer at the Joint Usage/Research Center, Kyoto University.
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REFERENCES
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Figure 2. Photophysical properties of juglorubin and its derivatives (2 and 11). (a) UV−vis (solid lines) and corresponding normalized fluorescence spectra (dashed lines) of 1 (green), 2 (blue), and 11 (red) in MeCN (c = 1 × 10−5 M). Excitation wavelengths are 502.5, 500.0, and 507.0 nm for 1, 2, and 11, respectively. (b) Photographs of 1, 2, and 11 in MeCN solution (c = 1 × 10−4 M) under white light (top row) and UV irradiation at 365 nm (bottom row). C
DOI: 10.1021/acs.orglett.7b04051 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.7b04051 Org. Lett. XXXX, XXX, XXX−XXX
