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. 2024 Jun 17;146(26):17757–17764. doi: 10.1021/jacs.4c02969

Enantioselective Synthesis of Sealutomicin C

Stuart M Astle †, Sean Guggiari †, James R Frost ‡, Hamish B Hepburn §, David J Klauber ∥, Kirsten E Christensen †, Jonathan W Burton †,*
PMCID: PMC11228992  PMID: 38885121

Abstract

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The sealutomicins are a family of anthraquinone antibiotics featuring an enediyne (sealutomicin A) or Bergman-cyclized aromatic ring (sealutomicins B–D). Herein we report the development of an enantioselective organocatalytic method for the synthesis of dihydroquinolines and the use of the developed method in the total synthesis of sealutomicin C which features a transannular cyclization of an aryllithium onto a γ-lactone as a second key step.

Introduction

A recent report from Igarashi, Sawa, and co-workers described the isolation of four novel anthraquinone-fused natural products, the sealutomicins A–D 1–4, from fermentation of the marine actinomycete Nonomuraea sp. MM565M-173N2 (Figure 1a).1 In addition to the anthracene-9,10-dione motif shared by all four natural products, sealutomicin A 1 contains a bicyclo[7.3.1]-tridecadiynene core, placing it in the anthraquinone-fused enediyne (AFE) subfamily of natural products which includes dynemicin A, tiancimycin A, yangpumicin A, and uncialamycin 5.2−6 AFEs have attracted considerable attention from the synthetic and medicinal chemistry communities owing to their potent antibiotic and antitumor activities, with notable contributions coming from the Myers, Danishefsky, and Nicolaou groups,7−15 including the synthesis of numerous analogues to develop structure–activity relationships.7,8,13,14 In contrast, sealutomicins B–D 2–4 all possess a bridging aryl ring in place of the enediyne core, proposed to be formed biosynthetically via Bergman cyclization of an enediyne precursor, such as sealutomicin A 1. Such reactivity has previously been implicated in the biosynthesis of the natural product unciaphenol 6 from its enediyne precursor uncialamycin 5.16 In both cases, aryl ring formation is thought to be preceded by syn-hydrolysis of an epoxide unit, bringing the two alkyne units close enough together to trigger the cyclization. Igarashi, Sawa, and co-workers note in the isolation paper that sealutomicin C 3 may be identical to a compound isolated by Shen and co-workers, namely, the Bergman cyclization product of tiancimycin B 7.17

Figure 1.

Figure 1

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(a) Sealutomicin family of natural products, along with uncialamycin, unciaphenol, and tiancimycin B. (b) Retrosynthetic analysis of sealutomicin C.

The sealutomicins 1–4 all display in vitro antibacterial activity against Gram-positive bacteria with sealutomicin A 1 being more potent than the cycloaromatized sealutomicins B–D 2–4. Sealutomicin A 1 also shows similar effects against Gram-negative bacteria. The antibacterial activity of sealutomicin A 1 is proposed to arise from the ability of the enediyne warhead to form a benzenoid biradical that triggers bacterial DNA scission via hydrogen atom abstraction from the DNA backbone, in the same manner as other AFEs such as uncialamycin 5 and dynemicin A. Sealutomicins B–D all lack this key enediyne motif capable of inducing DNA damage, and as such, the mechanism of action by which they exert their antimicrobial effects is currently unknown. Sealutomicins B–D 2–4 share strong structural similarities with the natural product unciaphenol 6, which was found to display in vitro anti-HIV activity against both wild-type and antiretroviral-resistant strains of HIV.16 This raises the possibility that sealutomicins B–D 2–4 may also display similar antiviral properties. In light of the biological activities and intriguing chemical structures, we sought to develop a synthetic route to the sealutomicins. Herein, we report the development of an organocatalytic enantioselective dihydroquinoline synthesis which, along with a transannular cyclization of an aryl lithium onto a γ-lactone, feature as key steps in our total synthesis of sealutomicin C 3. Additionally, our successful synthesis of 3 demonstrates that the Bergman cyclization product of tiancimycin B, isolated by Shen and co-workers,17 and sealutomicin C 3 have the same structure.

Results and Discussion

Our strategy for the synthesis of sealutomicin C 3 is shown retrosynthetically in Figure 1b. We reasoned that the anthraquinone moiety of sealutomicin C 3 could be installed via a Hauser–Kraus annulation on an iminoquinone formed from oxidation of an alkoxy aniline such as 8, as previously utilized by Nicolaou et al. in the syntheses of uncialamycin 5,11−13 leading to a protected triol derivative from which 3 could be formed on global deprotection.

The α,β-unsaturated ester functionality in 8 was to be introduced from terminal alkyne 9, which itself would be derived ultimately from ketone 10. The key disconnection in our proposed route to sealutomicin C was to be a 6-exo-trig cyclization of an arylmetal derived from 11 (X = halide) onto a γ-lactone to yield ketone 10. The initial aim was to conduct a lithium–halogen exchange reaction of the bromide 11 (X = Br) given the precedent for lithium–halogen exchange to outcompete addition of alkyllithium reagents to carbonyl groups.18−20 The key cyclization substrate was to be prepared from the dihydroquinoline 12, which we envisaged would be synthesized by condensation of a cinnamaldehyde 14 and an aniline 13 bearing an α-ketoester under enantioselective organocatalysis.

Numerous methods for the enantioselective synthesis of 1,2-dihydroquinolines have been reported including kinetic resolution of 1,2-dihydroquinolines;21−26 additions to quinolines and 1,2-dihydroquinolines and their derivatives;27−36 and direct enantioselective synthesis of 1,2-dihydroquinolines.37−40 Two early examples involving 1,2-dihydroquinoline synthesis, from the groups of Wang and Córdova et al., utilized diarylprolinol silyl ether catalysts to effect an aza-Michael/aldol cascade coupling of 2-aminobenzaldehydes with cinnamaldehydes in order to access aryl-substituted 1,2-dihydroquinolines in high yields and >90% ee.37,38 We sought to adapt these methods to the synthesis of a variety of dihydroquinolines 18 by replacing the 2-aminobenzaldehyde component with the analogous α-ketoester 15 (Table 1). To investigate the proposed modified organocatalytic cascade, representative α-ketoesters 15 were readily prepared from the analogous isatins in two steps (see the Supporting Information, p S3). Using (E)-cinnamaldehyde 16a and α-ketoester 15a, the conditions of Wang et al.,38 namely, catalyst (S)-17a in DCE with 4 Å molecular sieves and sodium acetate as additive, gave poor conversion of reactants to a mixture of the desired 1,2-dihydroquinoline (−)-18a (structure confirmed by single-crystal X-ray diffraction—see the Supporting Information, p S52 and CIF) and a single diastereomer of aldol product (−)-19a [Table 1, entry 1, the configuration of (±)-19a was assigned from 1H–1H NMR coupling constant and 1H–1H NOESY analysis—see the Supporting Information, pp S16–S17 and p S116]. Pleasingly, (−)-18a was isolated in high enantiomeric excess, and dehydration of (−)-19a under the reaction conditions both with and without chiral catalyst (S)-17a provided (−)-18a with similarly high enantiomeric excess.

Table 1. Optimization of the Dihydroquinoline Synthesis.

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entrya catalyst additive solvent yield of (−)-18a/(−)-19a (%)b ee of (−)-18a (%)c
1 17a NaOAc ClCH2CH2Cl 8/10 98
2 17b NaOAc ClCH2CH2Cl 12/13 88
3 17a none ClCH2CH2Cl 9/6 96
4 17a PhCO2H ClCH2CH2Cl 98/0 97
5d 17a PhCO2H ClCH2CH2Cl 23/42 99
6e 17a PhCO2H ClCH2CH2Cl 91/0 97
7e 17b PhCO2H ClCH2CH2Cl 83/0 99
8e 17c PhCO2H ClCH2CH2Cl <5/0 n.d.
9e 17a PhCO2H CH2Cl2 98/0 99
10e 17a PhCO2H PhCH3 97/0 98
11e 17a PhCO2H THF 43/24 98
12f 17a PhCO2H CH2Cl2 92/0 98g
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a

General conditions: 15a (3.0 equiv), 16a (1.0 equiv, 0.15 mmol), (S)-17a (20 mol %), additive (50 mol %), 4 Å MS (75 mg), solvent (0.5 M), RT.

b

Isolated yield based on cinnamaldehyde starting material.

c

ee determined by chiral HPLC.

d

Molecular sieves omitted.

e

15a (2.0 equiv).

f

15a (2.0 equiv), 16a (1.0 equiv, 3.0 mmol), (R)-17a 20 mol %, in place of (S)-17a, PhCO2H (50 mol %), 4 Å MS (1.0 g), CH2Cl2 (0.5 M).

g

(+)-18a [enantiomer of (−)-18a formed as using (R)-17a].

It was found that the additive played a vital role in the catalyst turnover, with benzoic acid in place of sodium acetate resulting in complete consumption of 16a without accumulation of 19a, while requiring a lower excess of 15a (Table 1, entries 3, 4, and 6). Meanwhile, the absence of molecular sieves considerably reduced the turnover (Table 1, entry 5). While the TMS-protected diphenylprolinol catalyst (S)-17b gave the product (−)-18a with notably lower enantiomeric excess in the presence of a basic additive (Table 1, entry 2), with an acidic additive, the product was formed with similar enantiomeric excess as when using catalyst (S)-17a (Table 1, entries 6 and 7). Catalyst (S)-17c bearing a free alcohol resulted in an almost complete lack of reactivity (Table 1, entry 8). With catalyst (S)-17a, the reaction worked similarly well in other chlorinated solvents as well as toluene, but more polar solvents resulted in lower yields and incomplete dehydration to give (−)-18a (Table 1, entries 9–11). Reduction in the loading of molecular sieves was possible and resulted in the optimal reaction conditions which were readily performed on an up to 3 mmol scale (Table 1, entry 12).

Having established optimized conditions for the modified dihydroquinoline synthesis, using unsubstituted α-ketoester 15a and cinnamaldehyde 16a, the scope of the method was investigated, using catalyst (S)-17a derived from l-proline. The scope included variation of the aniline protecting group and substitution on the aromatic rings of both aniline and cinnamaldehyde. Carbamate protection of the aniline nitrogen atom was well-tolerated with both Boc and methyl carbonate groups giving the desired products in good yields and enantiomeric excesses with cinnamaldehyde 16a (Chart 1, entries 1–4, (−)-18a–d, 69–88% yield, 98–99% ee). Using Cbz-protected anilines, a brief scope of the substitution on the aniline ring was investigated with numerous substituents being well-tolerated including 4-chloro, 4-methyl, 4-nitro, and 4-methoxy [Chart 1, entries 5–8, (−)-18e–h, yields 77–94%, ee, 97–98%]. 2-Fluoro- and 3,5-dichloro-substituted anilines gave the corresponding products (−)-18i, 78% yield, 97% ee and (−)-18j, 98% yield, 78% ee, respectively (Chart 1, entries 9 and 10). Substitution on the aromatic ring of the cinnamaldehyde was also accommodated. 4-Chloro-, methoxy-, and nitro-substituted cinnamaldehydes gave the corresponding dihydroquinolines in good yields and enantiomeric excesses [Chart 1, entries 11–13, (−)-18k–m 74–92% yield, 93–98% ee], with 3,4-disubstitution also tolerated giving (−)-18n in 90% yield and 98% ee (Chart 1, entry 14). 2-Substitution on the aromatic ring of the cinnamaldehyde gave the dihydroquinolines in high enantiomeric excesses (91–96%) and yields ranging from 39 to 70% [Chart 1, entries 15–17, (−)-18o–q]. Importantly, for the synthesis of sealutomicin C (3), dihydroquinoline (−)-18r, bearing the necessary functionality on both aromatic rings for the synthesis of the natural product, could be readily formed in 89% yield and 98% ee (Chart 1, entry 18). Overall, this methodology provided the desired dihydroquinoline products in good yields and with high enantiomeric excesses.

Chart 1. Substrate Scope for Enantioselective Organocatalytic Dihydroquinoline Synthesis.

Chart 1

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a Yield based on cinnamaldehyde starting material.

b Incomplete conversion to a dihydroquinoline product.

The absolute configuration of dihydroquinoline (−)-18k was determined to be (R) by single-crystal X-ray diffraction (see the Supporting Information, p S53, and CIF), with the configuration of all other products assigned by analogy. Having identified 18r as having the appropriate core from which to construct sealutomicin C 3, we now embarked on our synthesis of the natural product.

The α-ketoester 15r and bromocinnamaldehyde 16r required for the key catalytic enantioselective dihydroquinoline synthesis were both prepared on a scale in a single step from cheap, commercially available starting materials. Carbamate protection of 5-methoxyisatin 20 followed by alcoholysis in acidic isopropanol gave 15r in 78% yield, while Wittig homologation of 2-bromobenzaldehyde 21 using the ylide derived from 22 followed by subsequent acetal hydrolysis gave 16r in 79% yield (Scheme 1).41,42 Under the optimized organocatalytic conditions, using (R)-17a as the catalyst, dihydroquinoline (+)-18r was obtained in 89% on a 7 g scale with an enantiomeric excess of >98%. Subsequent Luche reduction of (+)-18r gave α,β-unsaturated lactone 23.43 It was found that the addition of CeCl3·7H2O was crucial for suppressing unwanted over-reduction to the corresponding saturated lactone. With lactone 23 in hand, we turned our attention to the installation of the 1,2-syn diol. Ruthenium(VIII)-catalyzed dihydroxylation of 23 gave the syn-diol 24 as a single diastereomer in 88% yield, which was assigned as the (R,R) diastereomer in the expectation that dihydroxylation had occurred from the less hindered face of the fully substituted alkene (vide infra).44 Protection of 24 as the bis-paramethoxybenzyl (PMB) ether 25 under basic conditions now set the stage for the crucial cyclization to form the bridged bicyclic core of sealutomicin C. Treatment of bromide 25 in THF with a slight excess of n-butyllithium at −78 °C and subsequent warming to room temperature gave the desired ketone 26 in 94% yield on a 1 g scale. By 1H NMR, the ketone 26 was formed as a mixture with the corresponding lactol, resulting in a complex spectrum; however, simple oxidation of 26 with the Dess–Martin periodinane gave the aldehyde 27 with a much simplified 1H NMR spectrum. Aldehyde 27 showed a 1H–13C HMBC correlation between the indicated aromatic proton (δH 7.88 ppm) and the ketone carbonyl carbon (δC 190 ppm) demonstrating that successful cyclization had occurred which also demonstrated that dihydroxylation had indeed occurred on the less hindered face of the α,β-unsaturated-γ-lactone 23. The aldehyde 27 was readily converted into the terminal acetylene 28 under standard conditions in the presence of the aromatic ketone.45,46 Reduction of the aromatic ketone 28 with lithium borohydride gave the corresponding secondary alcohol 29 as a single diastereomer whose configuration was tentatively assigned by 1H–1H NOESY analysis and later confirmed by 1H–1H ROESY analysis of anthraquinone 33. Following protection of the benzylic alcohol as its PMB ether, the terminal alkyne was carboxylated under basic conditions with methyl chloroformate to give alkynyl ester 30. Exposure of propargylic ester 30 to an excess of the organocuprate derived from methyllithium and copper(I) cyanide at 0 °C gave alkenyl ester 31 in 47% yield with the double bond configuration assigned through 1H–1H NOESY and ROESY experiments on later synthetic intermediates. Our endgame strategy centered around the conversion of the p-methoxyaniline motif of 31 into a suitable electrophile which could be used in the anthraquinone-forming Hauser–Kraus annulation.47−49 To this end, hydrogenolysis using palladium on carbon enabled selective cleavage of the benzyloxycarbamate protecting group to give the corresponding aniline, which on treatment with cerium(IV) ammonium nitrate (CAN) gave iminoquinone 32 in 75% yield over two steps.50 Treatment of 32 with the anion generated from 3-cyanophthalide and LiHMDS resulted in rapid iminoquinone consumption, giving anthraquinone 33 in 86% yield; 1H–1H ROESY analysis of 33 was entirely in keeping with the depicted configuration. Attempts to remove the three PMB ether groups from 33 using Lewis-acidic boron trichloride dimethyl sulfide complex51 led to degradation of the starting material which also occurred when attempting the deprotection with CAN. Global deprotection was ultimately achieved upon treatment of 33 with excess 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), yielding sealutomicin C 3 in 70% yield. The 1H and 13C NMR data (DMSO-d6) for the synthetic sealutomicin C were in good agreement with those reported for the natural product.1 Additionally, the circular dichroism spectrum of our synthetic material matched closely with that of the isolated natural product, indicating that the natural enantiomer of sealutomicin C had been synthesized. The 1H and 13C NMR spectra (acetone-d6) for synthetic sealutomicin C were in agreement with those reported by Shen and co-workers for the Bergman cyclization product of tiancimycin B 7, indicating that sealutomicin C and cycloaromatized tiancimycin B have the same structure.

Scheme 1. Total Synthesis of Sealutomicin C.

Scheme 1

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P = 4-methoxybenzyl. Reagents and conditions: (a) (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide 22, LiHMDS (1.0 M in THF), THF, 0 °C then RT 15 min, then aldehyde 21 was added in THF, refluxed for 40 h, then 2 M HCl was added at RT, 15 h, 79%; (b) NaH, THF, 0 °C, RT 30 min, then benzyl chloroformate was added, RT 3 h, workup, i-PrOH, H2SO4, refluxed, 61 h, 78%; (c) (R)-2-{[(triethylsilyl)oxy]diphenylmethyl} pyrrolidine (R)-17a (20 mol %), 2-bromocinnamaldehyde 16r (1 equiv), isopropyl 2-(2-{[(benzyloxy)carbonyl]amino}-5-methoxyphenyl)-2-oxoacetate 15r (2.0 equiv), 4 Å molecular sieves, RT, 72 h, 89%, 98% ee; (d) NaBH4, CeCl3·7H2O, MeOH, RT, 1 h, 95%; (e) NaIO4, CeCl3·7H2O, water, 35 °C, 10 min, then cooled to 0 °C, then EtOAc, MeCN, and RuCl3·3H2O were added, then γ-lactone 23 was added, 0 °C, 10 min, 88%; (f) NaHMDS (1.0 M in THF, 3.0 equiv), DMF, 0 °C, 30 min, then 4-methoxybenzyl bromide was added, RT, 12 h, 76%; (g) n-BuLi, (1.6 M in hexane), THF, −78 °C, 5 min, then warmed to RT, 30 min, 94%; (h) Dess–Martin periodinane, NaHCO3, CH2Cl2, 0 °C then RT, 1 h, 90%; (i) dimethyl (1-diazo-2-oxopropyl)phosphonate, MeOH, RT, 20 h, 85%; (j) LiBH4, THF, 0 °C, then RT, 18 h, 86%; (k) NaH, DMF, 0 °C, then RT, 15 min, then 4-methoxybenzyl bromide was added, 14 h, 87%; (l) LiHMDS (1.0 M in toluene), THF, HMPA, 15 min, −78 °C, then methyl chloroformate was added, −78 °C, 2 h, 80%; (m) Cu(I)CN, MeLi (1.7 M in Et2O), Et2O, −78 °C, then propiolate ester 30 was added in Et2O at 0 °C, 3h, 47%; (n) H2, Pd/C, MeOH, EtOAc, RT, 3 h, 89%; (o) (NH4)2Ce(NO3)6, MeCN, water, RT, 15 min, 84%; (p) 3-cyanophthalide, LiHMDS (1.0 M in toluene), THF, −78 °C, 15 min, then iminoquinone 32 was added in THF, −78 °C to RT, 15 min, 86%; (q) DDQ, CH2Cl2, water, RT, 16 h, 70%.

Conclusions

In conclusion, we have developed the first enantioselective synthesis of sealutomicin C 3 and demonstrated that it has the same structure as the Bergman cyclization product of tiancimycin B. The synthesis proceeded in 16 steps (longest linear sequence) from 5-methoxy isatin 20 and required the development of a methodology for the organocatalytic enantioselective synthesis of dihydroquinolines from α-ketoesters and cinnamaldehydes, as well as the use of a key intramolecular cyclization of an aryllithium onto a γ-lactone. Work toward the total synthesis of other members of the sealutomicins is ongoing.

Acknowledgments

S.M.A and S.G. are grateful to the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for a studentship, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c02969.

  • Experimental procedures, characterization data, NMR spectra of reported compounds, and CIF files (PDF)

The authors declare the following competing financial interest(s): D.J.K. was in the employment and a shareholder of Astra- Zeneca during the period of this investigation, which was part-funded by AstraZeneca. The other authors declare no competing financial interests.

Supplementary Material

ja4c02969_si_001.pdf (46.3MB, pdf)

References

  1. Igarashi M.; Sawa R.; Umekita M.; Hatano M.; Arisaka R.; Hayashi C.; Ishizaki Y.; Suzuki M.; Kato C. Sealutomicins, new enediyne antibiotics from the deep-sea actinomycete Nonomuraea sp. MM565M-173N2. J. Antibiot. 2021, 74, 291–299. 10.1038/s41429-020-00402-1. [DOI] [PubMed] [Google Scholar]
  2. Davies J.; Wang H.; Taylor T.; Warabi K.; Huang X.-H.; Andersen R. J. Uncialamycin, A New Enediyne Antibiotic. Org. Lett. 2005, 7, 5233–5236. 10.1021/ol052081f. [DOI] [PubMed] [Google Scholar]
  3. Konishi M.; Ohkuma H.; Matsumoto K.; Tsuno T.; Kamei H.; Miyaki T.; Oki T.; Kawaguchi H.; Vanduyne G. D.; Clardy J. Dynemicin a, a Novel Antibiotic with the Anthraquinone and 1,5-Diyn-3-Ene Subunit. J. Antibiot. 1989, 42, 1449–1452. 10.7164/antibiotics.42.1449. [DOI] [PubMed] [Google Scholar]
  4. Yan X.; Ge H.; Huang T.; Hindra; Yang D.; Teng Q.; Crnovcic I.; Li X.; Rudolf J. D.; Lohman J. R.; Gansemans Y.; Zhu X.; Huang Y.; Zhao L. X.; Jiang Y.; Van Nieuwerburgh F.; Rader C.; Duan Y.; Shen B. Strain Prioritization and Genome Mining for Enediyne Natural Products. mBio 2016, 7, e02104–02116 10.1128/mbio.02104-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Yan X.; Chen J. J.; Adhikari A.; Yang D.; Crnovcic I.; Wang N.; Chang C. Y.; Rader C.; Shen B. Genome Mining of Micromonospora yangpuensis DSM 45577 as a Producer of an Anthraquinone-Fused Enediyne. Org. Lett. 2017, 19, 6192–6195. 10.1021/acs.orglett.7b03120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Yan X. Anthraquinone-fused enediynes: discovery, biosynthesis and development. Nat. Prod. Rep. 2022, 39, 703–728. 10.1039/D1NP00054C. [DOI] [PubMed] [Google Scholar]
  7. Myers A. G.; Tom N. J.; Fraley M. E.; Cohen S. B.; Madar D. J. A Convergent Synthetic Route to (+)-Dynemicin A and Analogs of Wide Structural Variability. J. Am. Chem. Soc. 1997, 119, 6072–6094. 10.1021/ja9703741. [DOI] [Google Scholar]
  8. Myers A. G.; Fraley M. E.; Tom N. J.; Cohen S. B.; Madar D. J. Synthesis of (+)-dynemicin A and analogs of wide structural variability: establishment of the absolute configuration of natural dynemicin A. Chem. Biol. 1995, 2, 33–43. 10.1016/1074-5521(95)90078-0. [DOI] [PubMed] [Google Scholar]
  9. Shair M. D.; Yoon T.-y.; Danishefsky S. J. Total Synthesis of (±)-Dynemicin A. Angew. Chem., Int. Ed. 1995, 34, 1721–1723. 10.1002/anie.199517211. [DOI] [Google Scholar]
  10. Shair M. D.; Yoon T. Y.; Mosny K. K.; Chou T. C.; Danishefsky S. J. The Total Synthesis of Dynemicin A Leading to Development of a Fully Contained Bioreductively Activated Enediyne Prodrug. J. Am. Chem. Soc. 1996, 118, 9509–9525. 10.1021/ja960040w. [DOI] [Google Scholar]
  11. Nicolaou K. C.; Zhang H.; Chen J. S.; Crawford J. J.; Pasunoori L. Total synthesis and stereochemistry of uncialamycin. Angew. Chem., Int. Ed. 2007, 46, 4704–4707. 10.1002/anie.200700917. [DOI] [PubMed] [Google Scholar]
  12. Nicolaou K. C.; Chen J. S.; Zhang H.; Montero A. Asymmetric synthesis and biological properties of uncialamycin and 26-epi-uncialamycin. Angew. Chem., Int. Ed. 2008, 47, 185–189. 10.1002/anie.200704577. [DOI] [PubMed] [Google Scholar]
  13. Nicolaou K. C.; Wang Y.; Lu M.; Mandal D.; Pattanayak M. R.; Yu R.; Shah A. A.; Chen J. S.; Zhang H.; Crawford J. J.; Pasunoori L.; Poudel Y. B.; Chowdari N. S.; Pan C.; Nazeer A.; Gangwar S.; Vite G.; Pitsinos E. N. Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations. J. Am. Chem. Soc. 2016, 138, 8235–8246. 10.1021/jacs.6b04339. [DOI] [PubMed] [Google Scholar]
  14. Nicolaou K. C.; Das D.; Lu Y.; Rout S.; Pitsinos E. N.; Lyssikatos J.; Schammel A.; Sandoval J.; Hammond M.; Aujay M.; Gavrilyuk J. Total Synthesis and Biological Evaluation of Tiancimycins A and B, Yangpumicin, A, and Related Anthraquinone-Fused Enediyne Antitumor Antibiotics. J. Am. Chem. Soc. 2020, 142, 2549–2561. 10.1021/jacs.9b12522. [DOI] [PubMed] [Google Scholar]
  15. Chowdari N. S.; Pan C.; Rao C.; Langley D. R.; Sivaprakasam P.; Sufi B.; Derwin D.; Wang Y.; Kwok E.; Passmore D.; Rangan V. S.; Deshpande S.; Cardarelli P.; Vite G.; Gangwar S. Uncialamycin as a novel payload for antibody drug conjugate (ADC) based targeted cancer therapy. Bioorg. Med. Chem. Lett. 2019, 29, 466–470. 10.1016/j.bmcl.2018.12.021. [DOI] [PubMed] [Google Scholar]
  16. Williams D. E.; Bottriell H.; Davies J.; Tietjen I.; Brockman M. A.; Andersen R. J. Unciaphenol, an Oxygenated Analogue of the Bergman Cyclization Product of Uncialamycin Exhibits Anti-HIV Activity. Org. Lett. 2015, 17, 5304–5307. 10.1021/acs.orglett.5b02664. [DOI] [PubMed] [Google Scholar]
  17. Yan X.; Chen J. J.; Adhikari A.; Teijaro C. N.; Ge H.; Crnovcic I.; Chang C. Y.; Annaval T.; Yang D.; Rader C.; Shen B. Comparative Studies of the Biosynthetic Gene Clusters for Anthraquinone-Fused Enediynes Shedding Light into the Tailoring Steps of Tiancimycin Biosynthesis. Org. Lett. 2018, 20, 5918–5921. 10.1021/acs.orglett.8b02584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Paleo M. R.; Castedo L.; Dominguez D. Synthesis of 2-[N-(9-phenylfluoren-9-yl)amino]-1-indanones by anionic cyclization of phenylalanine-derived oxazolidinones. J. Org. Chem. 1993, 58, 2763–2767. 10.1021/jo00062a018. [DOI] [Google Scholar]
  19. Ollero L.; Castedo L.; Domínguez D. Enantiospecific synthesis of (+)-ribasine. Tetrahedron 1999, 55, 4445–4456. 10.1016/S0040-4020(99)00133-7. [DOI] [Google Scholar]
  20. Zhang Y.-A.; liu Q.; Wang C.; Jia Y. Total Synthesis of Rugulovasine A. Org. Lett. 2013, 15, 3662–3665. 10.1021/ol401541t. [DOI] [PubMed] [Google Scholar]
  21. Kong D.; Han S.; Wang R.; Li M.; Zi G.; Hou G. Kinetic resolution of racemic 2-substituted 1,2-dihydroquinolines via asymmetric Cu-catalyzed borylation. Chem. Sci. 2017, 8, 4558–4564. 10.1039/C7SC01556A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lu R.; Cao L.; Guan H.; Liu L. Iron-Catalyzed Aerobic Dehydrogenative Kinetic Resolution of Cyclic Secondary Amines. J. Am. Chem. Soc. 2019, 141, 6318–6324. 10.1021/jacs.9b00615. [DOI] [PubMed] [Google Scholar]
  23. Cai B.; Yang Q.; Meng L.; Wang J. J. Kinetic Resolution of 2-Substituted 1,2-Dihydroquinolines by Rhodium-Catalyzed Asymmetric Hydroarylation. Chin. J. Chem. 2021, 39, 1606–1610. 10.1002/cjoc.202000742. [DOI] [Google Scholar]
  24. Chen Y.; Zhu C.; Guo Z.; Liu W.; Yang X. Asymmetric Synthesis of Hydroquinolines with α,α-Disubstitution through Organocatalyzed Kinetic Resolution. Angew. Chem., Int. Ed. Engl. 2021, 60, 5268–5272. 10.1002/anie.202015008. [DOI] [PubMed] [Google Scholar]
  25. Zhu C.; Liu W.; Zhao F.; Chen Y.; Tao H.; He Y. P.; Yang X. Kinetic Resolution of 2,2-Disubstituted Dihydroquinolines through Chiral Phosphoric Acid-Catalyzed C6-Selective Asymmetric Halogenations. Org. Lett. 2021, 23, 4104–4108. 10.1021/acs.orglett.1c00978. [DOI] [PubMed] [Google Scholar]
  26. Yeo S. H.; Choi A.; Greaves S.; Meijer A.; Silvestri I. P.; Coldham I. Kinetic Resolution of 2-Aryldihydroquinolines Using Lithiation - Synthesis of Chiral 1,2- and 1,4-Dihydroquinolines. Chem.—Eur. J. 2023, 29, e202300815 10.1002/chem.202300815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Yamaoka Y.; Miyabe H.; Takemoto Y. Catalytic Enantioselective Petasis-Type Reaction of Quinolines Catalyzed by a Newly Designed Thiourea Catalyst. J. Am. Chem. Soc. 2007, 129, 6686–6687. 10.1021/ja071470x. [DOI] [PubMed] [Google Scholar]
  28. Black D. A.; Beveridge R. E.; Arndtsen B. A. Copper-Catalyzed Coupling of Pyridines and Quinolines with Alkynes: A One-Step, Asymmetric Route to Functionalized Heterocycles. J. Org. Chem. 2008, 73, 1906–1910. 10.1021/jo702293h. [DOI] [PubMed] [Google Scholar]
  29. Rezgui F.; Mangeney P.; Alexakis A. Asymmetric synthesis of 1,2- and 1,4-dihydroquinolines. Tetrahedron Lett. 1999, 40, 6241–6244. 10.1016/S0040-4039(99)01172-7. [DOI] [Google Scholar]
  30. Amiot F.; Cointeaux L.; Jan Silve E.; Alexakis A. Enantioselective nucleophilic addition of organometallic reagents to quinoline: regio-stereo- and enantioselectivity. Tetrahedron 2004, 60, 8221–8231. 10.1016/j.tet.2004.06.088. [DOI] [Google Scholar]
  31. Cointeaux L.; Alexakis A. Enantioselective addition of organolithium reagents to quinoline catalyzed by 1,2-diamines. Tetrahedron: Asymmetry 2005, 16, 925–929. 10.1016/j.tetasy.2005.01.007. [DOI] [Google Scholar]
  32. Sylvester K. T.; Wu K.; Doyle A. G. Mechanistic investigation of the nickel-catalyzed Suzuki reaction of N,O-acetals: evidence for boronic acid assisted oxidative addition and an iminium activation pathway. J. Am. Chem. Soc. 2012, 134, 16967–16970. 10.1021/ja3079362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Shields J. D.; Ahneman D. T.; Graham T. J.; Doyle A. G. Enantioselective, nickel-catalyzed Suzuki cross-coupling of quinolinium ions. Org. Lett. 2014, 16, 142–145. 10.1021/ol4031364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Pappoppula M.; Cardoso F. S.; Garrett B. O.; Aponick A. Enantioselective Copper-Catalyzed Quinoline Alkynylation. Angew. Chem., Int. Ed. Engl. 2015, 54, 15202–15206. 10.1002/anie.201507848. [DOI] [PubMed] [Google Scholar]
  35. Wang Y.; Liu Y.; Zhang D.; Wei H.; Shi M.; Wang F. Enantioselective Rhodium-Catalyzed Dearomative Arylation or Alkenylation of Quinolinium Salts. Angew. Chem., Int. Ed. 2016, 55, 3776–3780. 10.1002/anie.201511663. [DOI] [PubMed] [Google Scholar]
  36. Jiang Z.-Z.; Jiang Y.-J.; Du J.; Chen D.; Ding C.-H.; Xu B.; Hou X.-L. Palladium-Catalyzed Asymmetric Heck-Matsuda Reaction of 1,4-Dihydroquinolines with Aryl Diazonium Salts. Synthesis 2019, 51, 3269–3276. 10.1055/s-0037-1610712. [DOI] [Google Scholar]
  37. Sundén H.; Rios R.; Ibrahem I.; Zhao G.-L.; Eriksson L.; Córdova A. A Highly Enantioselective Catalytic Domino Aza-Michael/Aldol Reaction: One-Pot Organocatalytic Asymmetric Synthesis of 1,2-Dihydroquinolidines. Adv. Synth. Catal. 2007, 349, 827–832. 10.1002/adsc.200600513. [DOI] [Google Scholar]
  38. Li H.; Wang J.; Xie H.; Zu L.; Jiang W.; Duesler E. N.; Wang W. Chiral Diphenylprolinol TES Ether Promoted Conjugate Addition–Aldol-Dehydration Reactions between α,β-Unsaturated Aldehydes and 2-N-Protected Amino Benzaldehydes. Org. Lett. 2007, 9, 965–968. 10.1021/ol062877u. [DOI] [PubMed] [Google Scholar]
  39. Yoshitomi Y.; Arai H.; Makino K.; Hamada Y. Enantioselective synthesis of martinelline chiral core and its diastereomer using asymmetric tandem Michael-aldol reaction. Tetrahedron 2008, 64, 11568–11579. 10.1016/j.tet.2008.10.032. [DOI] [Google Scholar]
  40. Wu S.; Liu C.; Luo G.; Jin Z.; Zheng P.; Chi Y. R. NHC-Catalyzed Chemoselective Reactions of Enals and Aminobenzaldehydes for Access to Chiral Dihydroquinolines. Angew. Chem., Int. Ed. Engl. 2019, 58, 18410–18413. 10.1002/anie.201909479. [DOI] [PubMed] [Google Scholar]
  41. Yamagishi M.; Yamada Y.; Ozaki K.-i.; Tani J.; Suzuki M. Quinazolin-2ones Having a Spirohydantoin Ring. II. Synthesis of Several Spiro[imidazolidine-4, 4’(1’H)-quinazoline]-2, 2’, 5(3′H)-triones via 5-Hydroxyhydantoin Derivatives. Chem. Pharm. Bull. 1991, 39, 626–629. 10.1248/cpb.39.626. [DOI] [Google Scholar]
  42. Fu H.; Cui M.; Zhao L.; Tu P.; Zhou K.; Dai J.; Liu B. Highly Sensitive Near-Infrared Fluorophores for in Vivo Detection of Amyloid-β Plaques in Alzheimer’s Disease. J. Med. Chem. 2015, 58, 6972–6983. 10.1021/acs.jmedchem.5b00861. [DOI] [PubMed] [Google Scholar]
  43. Janthawornpong K.; Krasutsky S.; Chaignon P.; Rohmer M.; Poulter C. D.; Seemann M. Inhibition of IspH, a [4Fe-4S]2+ enzyme involved in the biosynthesis of isoprenoids via the methylerythritol phosphate pathway. J. Am. Chem. Soc. 2013, 135, 1816–1822. 10.1021/ja309557s. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Plietker B.; Niggemann M. RuCl3/CeCl3/NaIO4: A New Bimetallic Oxidation System for the Mild and Efficient Dihydroxylation of Unreactive Olefins. J. Org. Chem. 2005, 70, 2402–2405. 10.1021/jo048020x. [DOI] [PubMed] [Google Scholar]
  45. Ohira S. Methanolysis of Dimethyl (1-Diazo-2-oxopropyl) Phosphonate: Generation of Dimethyl (Diazomethyl) Phosphonate and Reaction with Carbonyl Compounds. Synth. Commun. 1989, 19, 561–564. 10.1080/00397918908050700. [DOI] [Google Scholar]
  46. Müller S.; Liepold B.; Roth G. J.; Bestmann H. J. An Improved One-pot Procedure for the Synthesis of Alkynes from Aldehydes. Synlett 1996, 1996, 521–522. 10.1055/s-1996-5474. [DOI] [Google Scholar]
  47. Hauser F. M.; Rhee R. P. New synthetic methods for the regioselective annelation of aromatic rings: 1-hydroxy-2,3-disubstituted naphthalenes and 1,4-dihydroxy-2,3-disubstituted naphthalenes. J. Org. Chem. 1978, 43, 178–180. 10.1021/jo00395a048. [DOI] [Google Scholar]
  48. Kraus G. A.; Sugimoto H. An annelation route to quionones. Tetrahedron Lett. 1978, 19, 2263–2266. 10.1016/S0040-4039(01)91508-4. [DOI] [Google Scholar]
  49. Mal D.; Pahari P. Recent Advances in the Hauser Annulation. Chem. Rev. 2007, 107, 1892–1918. 10.1021/cr068398q. [DOI] [PubMed] [Google Scholar]
  50. Wang S.; Guillot R.; Carpentier J. F.; Sarazin Y.; Bour C.; Gandon V.; Leboeuf D. Synthesis of Bridged Tetrahydrobenzo[b]azepines and Derivatives through an Aza-Piancatelli Cyclization/Michael Addition Sequence. Angew. Chem., Int. Ed. 2020, 59, 1134–1138. 10.1002/anie.201911761. [DOI] [PubMed] [Google Scholar]
  51. Burton J. W.; Clark J. S.; Derrer S.; Stork T. C.; Bendall J. G.; Holmes A. B. Synthesis of medium ring ethers.5. The synthesis of (+)-laurencin. J. Am. Chem. Soc. 1997, 119, 7483–7498. 10.1021/ja9709132. [DOI] [Google Scholar]

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