Total Synthesis and Full Structural Assignment of Namenamicin

Jun 22, 2018 - The synthesis of glycosyl donor 8 was accomplished starting with hydroxy ... (9) Selective mono-desulfurization(10) of 13 with zinc dus...
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Total Synthesis and Full Structural Assignment of Namenamicin K. C. Nicolaou,*,† Ruofan Li,† Zhaoyong Lu,† Emmanuel N. Pitsinos,†,‡ and Lawrence B. Alemany#,† †

Department of Chemistry, BioScience Research Collaborative, Rice University, 6100 Main Street, Houston, Texas 77005, United States ‡ Laboratory of Natural Products Synthesis & Bioorganic Chemistry, Institute of Nanoscience and Nanotechnology, National Centre for Scientific Research “Demokritos”, 153 10 Agia Paraskevi, Greece # Shared Equipment Authority, Rice University, 6100 Main Street, Houston, Texas 77005, United States Downloaded via STONY BROOK UNIV SUNY on June 22, 2018 at 14:46:42 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: Namenamicin is a rare natural product possessing potent cytotoxic properties that may prove useful as a lead compound for payloads of antibody−drug conjugates (ADCs). Its scarcity, coupled with the uncertainty of its full absolute configuration, elevates it to an attractive synthetic target. Herein we describe the total synthesis of the two C7′-epimers of namenamicin and assign its complete structure, opening the way for further chemical and biological studies toward the discovery of potent payloads for ADCs directed toward targeted cancer therapies.

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eported in 1996, namenamicin is a rare naturally occurring compound isolated from the orange-colored ascidian Polysyncraton lithostrotum collected off the coast of the Fijian island Namenalala.1 It was speculated that it is most likely produced by a micromonospora bacterium species living symbiotically within this ascidian.1 Namenamicin exhibited potent in vitro cytotoxicity (mean IC50 = 3.5 nM)1 and in vivo antitumor properties [P388 leukemia model in mice; increase life span (ILS) 40% @ 3 μg/kg].1 It also demonstrated antimicrobial properties against numerous microbes (e.g., Staphylococcus aureus, MIC = 0.001 μM; Enterococcus faecium, MIC = 0.03 μM; Ustilago maydis, MIC = 0.004 μM).1 The same compound was later isolated by the Fusetani group who reported impressive potencies against certain cancer cell lines (3Y1, IC50 = 13 pM; HeLa, IC50 = 34 pM; P388, IC50 = 3.3 pM).2 Its structural assignment, however, remained ambiguous as to the stereochemical configuration at C7′, leaving structures 1a and 1b (Figure 1) as the two likely candidates for this intriguing marine natural product. The absolute configuration of the rest of the molecule was assigned by analogy to the related marine natural product shishijimicin A (2, Figure 1).2,3 Because of its low picomolar potencies against several cancer cell lines,2 namenamicin presents a lead compound for antibody−drug conjugate (ADC) payloads. This potential, coupled with the scarcity of the molecule and the need to assign its full structure, elevates namenamicin to a high value target for total synthesis.4 In this Communication, we report the total synthesis of both C7′ epimers of namenamicin (1a, 1b, Figure 1) and elucidation of its complete molecular structure as 1a. © XXXX American Chemical Society

Figure 1. Molecular structures of (7′S)-namenamicin (1a), (7′R)namenamicin (1b), and shishijimicin A (2).

Figure 2 outlines, in retrosynthetic format, the designed strategy for the synthesis of the targeted compounds 1a and 1b. This strategy was directed toward the construction of both C7′ (namenamicin numbering) isomers of advanced intermediates 3a/3b, 5a/5b, and 6a/6b, and defined building blocks 4,3 7,4 and 8 as the starting materials, the latter derivable from known compound 9.5 The construction of the required disaccharide epimers 6a and 6b is summarized in Scheme 1. Thus, addition of aldehyde 74 to the organometallic species generated from stannane 10,6 n-BuLi, and LaCl3·2LiCl7 at −78 °C furnished alcohol 6b as the major product in 54% combined yield and ca. 4.5:1 dr, from which mixture pure 6b was obtained chromatographically. Oxidation of diastereoisomer 6b (DMP, 25 °C, 92% yield) followed by Red-Al reduction of the resulting ketone (11) at −78 °C afforded alcohol 6a as the major isomer in 87% combined yield (ca. 3.8:1 dr), the latter obtained pure chromatographically. The stereochemical identities of the two isomers 6a and 6b were deciphered by their conversions to rigidified pentacyclic derivatives and by 1H NMR spectroscopic analysis of the latter (see Supporting Information for details). The synthesis of glycosyl donor 8 was accomplished starting with hydroxy compound 95 as summarized in Scheme 2. Thus, Received: May 3, 2018

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DOI: 10.1021/jacs.8b04592 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society Scheme 2. Synthesis of Glycosyl Donor 8a

Reagents and conditions: (a) DMP (1.2 equiv), CH2Cl2, 0 → 25 °C, 2 h; (b) (MeS)3CH (1.2 equiv), n-BuLi (1.2 equiv), −78 °C, 0.5 h; then LaCl3·2LiCl (0.7 equiv), 5 min; then ketone (1.0 equiv), −78 °C, 10 min, 70% for the two steps; (c) n-BuLi (1.0 equiv), −78 °C, 0.5 h; then Cu(MeCN)4PF6 (3.0 equiv), −78 → 25 °C; then 2,6-ditert-butylpyridine (1.0 equiv), 42−45 °C, 0.5 h, 72%; (d) Zn dust (15 equiv), sat. aq. NH4Cl:THF (1:1, v/v), 25 °C, 6 h; (e) (R)-CBS catalyst (0.2 equiv), BH3·THF (2.0 equiv), THF, 0 °C, 0.5 h, 72% for the two steps (ca. 5.8:1 dr at C4); (f) Ac2O (1.5 equiv), pyridine (2.0 equiv), DMAP (0.1 equiv), CH2Cl2, 25 °C, 24 h; (g) AcOH:H2O (1:2.5, v/v), 80 °C, 4 h; (h) 15 (1.5 equiv), EDCI (3.0 equiv), iPr2NEt (3.0 equiv), DMAP (0.1 equiv), CH2Cl2, 24 h, 81% for the three steps. DMAP = N,N-dimethylpyridin-4-amine, EDCI = 1-ethyl3-(3-(dimethylamino)propyl)carbodiimide. a

Figure 2. Retrosynthetic analysis of C7′ epimers of namenamicin (1a and 1b). Ac = acetyl; TES = triethylsilyl; TDS = thexyldimethylsilyl; Alloc = allyloxycarbonyl; Nap = 2-naphthylmethyl; NB = onitrobenzyl.

Scheme 1. Synthesis of Epimers 6a and 6b and Ketone 11a

With disaccharides 6a and 6b and glycosyl donor 8 in hand, we attempted their coupling toward their corresponding trisaccharides (i.e., 16a and 16b). As shown in Scheme 3A, we were disappointed to find that the coupling of isomer 6a with donor 8 under a variety of conditions (see Supporting Information) failed to give the desired β-anomer. Instead, the undesired α-anomer (16a-α) was formed exclusively. On the Scheme 3. Synthesis of Glycosyl Donor 5ba a

Reagents and conditions: (a) 10 (5.5 equiv), n-BuLi (5.5 equiv), −78 °C, 30 s; then LaCl3·2LiCl (2.9 equiv), −78 °C, 1 min; then 7 (1.0 equiv), −78 °C, 1 min, 54% (ca. 4.5:1 dr); (b) DMP (1.5 equiv), CH2Cl2, 25 °C, 1 h, 92%; (c) Red-Al (5.0 equiv), THF, −78 °C, 20 min, 87% (ca. 3.8:1 dr). DMP = Dess−Martin periodinane, THF = tetrahydrofuran.

oxidation of 9 (DMP) followed by sequential addition of (MeS)3CLi and LaCl3·2LiCl7 to the resulting ketone, at −78 °C, gave tertiary alcohol 12 in 70% overall yield. Treatment of the latter with n-BuLi (−78 °C), Cu(MeCN)4PF6 (−78 → 25 °C), and 2,6-di-tert-butylpyridine (25 → 42−45 °C) furnished α,α-bis(methylthio)ketone 13,8 presumably via transient epoxide (12a), through semipinacol rearrangement of the latter.9 Selective mono-desulfurization10 of 13 with zinc dust and NH4Cl, followed by stereoselective reduction of the resulting monomethylthioether with (R)-CBS−BH3·THF11 gave hydroxy methylthioether 14 as predominant product (72% overall yield; ca. 5.8:1 dr at C4). Chromatographically purified 14 was converted to glycosyl donor 8 (β-anomer exclusively) through a sequence involving (i) acetylation (Ac2O, pyridine, DMAP), (ii) hydrolysis of the resulting methyl pyranoside (AcOH, H2O), and (iii) esterification with carboxylic acid 1512 (EDCI, i-Pr2NEt, DMAP), in 81% overall yield, as shown in Scheme 2.

a

Reagents and conditions: (a) 6a (1.0 equiv), 8 (3.0 equiv), Ph3PAuNTf2 (0.2 equiv), 4 Å MS, CH2Cl2, −40 → 0 °C, 1 h, 84% (α exclusively); (b) 6b (1.0 equiv), 8 (3.0 equiv), Ph3PAuOTf (0.2 equiv), 4 Å MS, CH2Cl2, −40 °C, 1 h, 82% (β:α ca. 2.3:1); (c) hν, THF:H2O (10:1, v/v), 0 → 25 °C; (d) DDQ (4.0 equiv), CH2Cl2:H2O (10:1, v/v), 35 °C, 3 h; (e) 15 (4.0 equiv), EDCI (4.0 equiv), i-Pr2NEt (10 equiv), DMAP (2.0 equiv), CH2Cl2, 24 h, 68% (β:α ca. 3:1) for the three steps. B

DOI: 10.1021/jacs.8b04592 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society Scheme 5. Synthesis of Glycosyl Donor 5aa

other hand, isomer 6b reacted with glycosyl donor 8 in the presence of Ph3PAuOTf13 to afford the targeted trisaccharide (16b-β, Scheme 3B) as a mixture with its α-anomer counterpart (82% combined yield, 16b-β:16b-α ca. 2.3:1). Chromatographically purified 16b-β was then elaborated to the desired trisaccharide donor (5b) through sequential removal of the o-nitrobenzyl (hν) and 2-naphthylmethyl groups (DDQ), and selective coupling of the resulting hydroxy lactol with benzoic acid derivative 1512 (EDCI, i-Pr2NEt, DMAP) in 68% overall yield and β:α ca. 3:1 (at the anomeric position) as shown in Scheme 3B. The synthesized trisaccharide donor 5b was then coupled with the enediyne fragment 4 3 in the presence of Ph3PAuNTf214 to afford advanced intermediate 3b as the major product (34% combined yield, β:α ca. 3:2) as shown in Scheme 4. Chromatographically purified thioacetate 3b was

a

Scheme 4. Synthesis of (7′R)-Namenamicin (1b)a

Reagents and conditions: (a) Ac2O (2.0 equiv), pyridine (3.0 equiv), DMAP (0.1 equiv), CH2Cl2, 25 °C, 24 h; (b) DDQ (4.0 equiv), CH2Cl2:H2O (10:1, v/v), 35 °C, 3 h, 83% for the two steps; (c) DIBAL-H (2.0 equiv), CH2Cl2, −78 °C, 0.5 h, 94%; (d) 8 (8.0 equiv), Ph3PAuOTf (0.8 equiv), 4 Å MS, −20 → 0 °C, 45 min, 78% (β:α ca. 1:2.6); (e) hν, THF:H2O (10:1, v/v), 0 → 25 °C; (f) 15 (4.0 equiv), EDCI (4.0 equiv), i-Pr2NEt (10 equiv), DMAP (2.0 equiv), CH2Cl2, 25 °C, 24 h, 77% for the two steps.

difficulties encountered to the steric hindrance of the bulky Nap protecting group. We, therefore, decided to remove this moiety before the pending glycosylation. Scheme 5 depicts the steps that led to the conversion of intermediate 6a to the desired glycosyl donor 5a. Thus, acetylation of 6a (Ac2O, py), followed by cleavage of the Nap group (DDQ), furnished hydroxy acetate 18 in 83% overall yield. Exposure of 18 to DIBAL-H at −78 °C gave the required hydroxy disaccharide (19, 94% yield), whose glycosylation with carbohydrate donor 8 under gold-promoted conditions (Ph3PAuOTf,13 4 Å MS) produced, albeit as the minor product, desired trisaccharide 20, (β-anomer at C1″) as a mixture with its α-anomer (78% yield, β:α ca. 1:2.6), from which it was separated chromatographically. Photolytic cleavage of the o-nitrobenzyl group from 20, followed by coupling of the resulting hydroxy lactol with benzoic acid derivative 1512 (EDCI, i-Pr2NEt, DMAP) afforded the trisaccharide donor 5a, in 77% overall yield as shown in Scheme 5. The final stages of the synthesis of namenamicin (1a) are shown in Scheme 6. Thus, gold-facilitated coupling of enediyne aglycone 43 with carbohydrate donor 5a (Ph3PAuNTf2,14 4 Å MS) led to a mixture of the desired 1′-β-glycoside anomer 3a and its 1′-α-glycoside counterpart (33% combined yield, β:α ca. 1:2.2), which were chromatographically separated. Attempts to improve the yield and the anomeric ratio of these glycosides failed, presumably due to the challenging nature of fragment 5a as a donor. Particularly unfavorable appeared to be the steric crowding and sensitivity under the reaction conditions of the various functionalities residing on this intermediate (particularly on the A ring). The trisulfide structural motif was then installed into the growing structure (3a) through sequential treatment of the latter with (i) DIBAL-H (−78 °C), (ii) AcOH/MeOH (−78 °C), (iii) PhthNSSMe3,15 (−78 → 25 °C), and (iv) MeOH (25 °C) furnishing hydroxy methyltrisulfide 17a, in 80% overall yield. Finally, the targeted namenamicin structure (1a) was generated from precursor 17a, in 55% overall yield, through a three-step global deprotection sequence involving exposure

Reagents and conditions: (a) 5b (1.0 equiv, β:α ca. 3:1), 4 (4.0 equiv), Ph3PAuNTf2 (2.5 equiv), CH2Cl2, 25 °C, 20 min, 34% (β:α ca. 1.5:1); (b) DIBAL-H (10 equiv), CH2Cl2, −78 °C, 20 min; then AcOH (10 equiv), MeOH, −78 °C, 1 min; then PhthNSSMe (7.0 equiv), −78 → 25 °C; then MeOH, 25 °C, 24 h, 75%; (c) HF· py:THF (1:20, v/v), 25 °C, 10 h; (d) Pd(PPh3)4 cat. (0.5 equiv), morpholine (20 equiv), THF, 0 °C, 2 h; (e) p-TsOH (5.0 equiv), THF:H2O (20:1, v/v), 50% for the three steps. DIBAL-H = diisobutylaluminum hydride. a

converted to precursor trisulfide 17b by sequential treatment with (i) DIBAL-H (−78 °C), (ii) AcOH/MeOH (−78 °C), (iii) PhthNSSMe3,15 (−78 → 25 °C), and (iv) MeOH (25 °C) in 75% overall yield. Finally, global deprotection of 17b [(i) HF·py, (ii) Pd(PPh3)4 cat., morpholine, and (iii) p-TsOH] generated (7′R)-namenamicin (1b) in 50% overall yield as summarized in Scheme 4. Although consistent with its structure (1b, Scheme 4), the 1H and 13C NMR spectroscopic data of synthetic 1b (Scheme 4) did not match those of the natural product, thereby leading us to assign its structure as 7′epi-namenamicin (1b, Figure 1). In pursuit for the alternative, and by then most-likely correct structure of namenamicin [i.e., 1a, Figure 1], we embarked on its synthesis from disaccharide 6a, via trisaccharide 5a, the latter becoming our next targeted intermediate, as shown in Scheme 5. Having failed to prepare trisaccharide 16a-β directly from disaccharide 6a (see Scheme 3A), we attributed the C

DOI: 10.1021/jacs.8b04592 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Scheme 6. Synthesis of (7′S)-Namenamicin (1a)a

ACKNOWLEDGMENTS We thank Dr. Q. Kleerekoper (Rice University) for NMR spectroscopic assistance, and Drs. C. Pennington (Rice University) and I. Riddington (University of Texas at Austin) for mass spectrometric assistance. This work was supported by the Cancer Prevention Research Institute of Texas (CPRIT), The Welch Foundation (grant C-1819), AbbVie Stemcentrx, and Rice University.

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to (i) HF·py (desilylation/deformylation), (ii) Pd(PPh3)4 cat., morpholine (Alloc removal), and (iii) p-TsOH (ketal cleavage), as shown in Scheme 6. The 1H and 13C NMR data16 of synthetic namenamicin (1a) matched those expected for the structure of the natural product.1,17 However, in the course of this investigation we noticed in the literature, and provided answers to, a number of chemical shift assignment inconsistencies and missing signals in the 13C NMR spectra (i.e., wrong peak assigned to certain carbons) of the enediyne domains of not only namenamicin,1 but also esperamicin A118 and calicheamicin γI119 (i.e., C3, C6, C8, C9, C10, C12, C13, and C17, see Supporting Information for details). In conclusion, the described chemistry led to the total synthesis of both 7′-epimers of namenamicin, 1a and 1b, and the assignment of the (7′S)-epimer (1a) as the structure of the naturally occurring substance.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b04592. Experimental procedures and characterization data (PDF)

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REFERENCES

(1) For isolation of namenamicin, see: McDonald, L. A.; Capson, T. L.; Krishnamurthy, G.; Ding, W.-D.; Ellestad, G. A.; Bernan, V. S.; Maiese, W. M.; Lassota, P.; Kramer, R. A.; Ireland, C. M. J. Am. Chem. Soc. 1996, 118, 10898−10899. (2) For isolation of shishijimicins A, B, and C and namenamicin, see: Oku, N.; Matsunaga, S.; Fusetani, N. J. Am. Chem. Soc. 2003, 125, 2044−2045. (3) For the total synthesis of shishijimicin A, see: Nicolaou, K. C.; Lu, Z.; Li, R.; Woods, J. R.; Sohn, T. J. Am. Chem. Soc. 2015, 137, 8716−8719. (4) For a synthetic study on the namenamicin disaccharide, see: Weinstein, D. S.; Nicolaou, K. C. J. Chem. Soc., Perkin Trans. 1 1999, 1, 545−557. (5) Soll, R. M.; Seitz, S. P. Tetrahedron Lett. 1987, 28, 5457−5460. (6) Antonsen, Ø.; Benneche, T.; Undheim, K. Acta Chem. Scand. 1992, 46, 757−760. (7) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 497−500. (8) (a) Cohen, T.; Kuhn, D.; Falck, J. R. J. Am. Chem. Soc. 1975, 97, 4749−4751. (b) Knapp, S.; Trope, A. F.; Ornaf, R. M. Tetrahedron Lett. 1980, 21, 4301−4304. (c) Knapp, S.; Theodore, M. S.; Hirata, N.; Barchi, J. J.; Trope, A. F. J. Org. Chem. 1984, 49, 608−614. (d) Israel, R. J.; Murray, R. K. J. Org. Chem. 1985, 50, 1573−1577. (e) Trost, B. M.; Mikhail, G. K. J. Am. Chem. Soc. 1987, 109, 4124− 4127. (f) Corey, E. J.; Desai, M. C.; Engler, T. A. J. Am. Chem. Soc. 1985, 107, 4339−4341. (9) For reviews on the semipinacol rearrangement, see: (a) Song, Z.; Fan, C.; Tu, Y. Chem. Rev. 2011, 111, 7523−7556. (b) Leemans, E.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2011, 111, 3268−3333. (10) Mahmud, T.; Xu, J.; Choi, Y. J. Org. Chem. 2001, 66, 5066− 5073. (11) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861−2863. (12) Li, Y.; Yang, W.; Ma, Y.; Sun, J.; Shan, L.; Zhang, W.; Yu, B. Synlett 2011, 7, 915−918. (13) (a) Li, Y.; Yang, Y.; Yu, B. Tetrahedron Lett. 2008, 49, 3604− 3608. (b) Tang, Y.; Li, J.; Zhu, Y.; Li, Y.; Yu, B. J. Am. Chem. Soc. 2013, 135, 18396−18405. (c) Yu, B. Acc. Chem. Res. 2018, 51, 507− 516. (14) (a) Li, Y.; Yang, X.; Liu, Y.; Zhu, C.; Yang, Y.; Yu, B. Chem. Eur. J. 2010, 16, 1871−1882. (b) Zhang, Q.; Sun, J.; Zhu, Y.; Zhang, F.; Yu, B. Angew. Chem., Int. Ed. 2011, 50, 4933−4936. (15) (a) Harpp, D. N.; Ash, D. K. Int. J. Sulfur Chem. Part A 1971, 1, 57−59. (b) Haseltine, J. N.; Danishefsky, S. J. J. Org. Chem. 1990, 55, 2576−2578. (16) While the 1H NMR spectrum of 1a matched perfectly the reported 1H NMR spectrum of the natural product (ref 1), a number of the 13C NMR chemical shifts of our synthetic material (1a) differed from those reported in the literature (ref 1). For a detailed analysis and chemical shift assignments of the 13C signals of synthetic 1a, see Supporting Information. (17) We were unable to compare optical rotation values of our synthetic namenamicins 1a ([α]20 D = −144, c = 0.023, CHCl3) and 1b ([α]20 D = −138, c = 0.014, CHCl3) with those of the natural namenamicin due to the absence of optical rotation data in the literature (refs 1 and 2). The absolute configuration shown in refs 1 and 2 and in this Communication are used by analogy to the shishijimicin structures, whose absolute configurations was originally

a Reagents and conditions: (a) 5a (1.0 equiv, β only), 4 (4.0 equiv), Ph3PAuNTf2 (2.5 equiv), CH2Cl2, 32 °C, 50 min, 33% (β:α ca. 1:2.2); (b) DIBAL-H (10 equiv), CH2Cl2, −78 °C, 20 min; then AcOH (10 equiv), MeOH, −78 °C, 1 min; then PhthNSSMe (7.0 equiv), −78 → 25 °C; then MeOH, 25 °C, 24 h, 80%; (c) HF· py:THF (1:20, v/v), 25 °C, 10 h; (d) Pd(PPh3)4 (0.5 equiv), morpholine (20 equiv), THF, 0 °C, 2 h; (e) p-TsOH (2.0 equiv), THF:H2O (20:1, v/v), 25 °C, 48 h, 55% for the three steps.

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

K. C. Nicolaou: 0000-0001-5332-2511 Zhaoyong Lu: 0000-0002-9218-6337 Notes

The authors declare no competing financial interest. D

DOI: 10.1021/jacs.8b04592 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Communication

Journal of the American Chemical Society assigned on the basis of circular dichroism study by the Fusetani group (ref 2), and confirmed by us through chemical synthesis (ref 3). (18) Golik, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.; Doyle, T. W. J. Am. Chem. Soc. 1987, 109, 3462−3464. (19) (a) Lee, M. D.; Dunne, T. S.; Siegel, M. M.; Chang, C. C.; Morton, G. O.; Borders, D. B. J. Am. Chem. Soc. 1987, 109, 3464− 3466. (b) Lee, M. D.; Dunne, T. S.; Chang, C. C.; Siegel, M. M.; Morton, G. O.; Ellestad, G. A.; McGahren, W. J.; Borders, D. B. J. Am. Chem. Soc. 1992, 114, 985−997.

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DOI: 10.1021/jacs.8b04592 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX