Concise and Convergent Enantioselective Total Syntheses of (+)- and

acid unit into a natural product,6 ii) the use of highly substituted vinyl .... Brønsted acid catalyst, such as the tris(pentafluorophenyl)borane‐a...
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Concise and Convergent Enantioselective Total Syntheses of (+)- and (–)-Fumimycin Michele Retini, Silvia Bartolucci, Francesca Bartoccini, Michele Mari, and Giovanni Piersanti J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02020 • Publication Date (Web): 03 Sep 2019 Downloaded from pubs.acs.org on September 3, 2019

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The Journal of Organic Chemistry

Concise and Convergent Enantioselective Total Syntheses of (+)- and (–)-Fumimycin Michele Retini, Silvia Bartolucci, Francesca Bartoccini, Michele Mari, and Giovanni Piersanti* Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, P.zza Rinascimento 6, 61029 Urbino, PU, Italy *[email protected]

ABSTRACT: The concise and convergent total syntheses of (+)- and (–)-Fumimycin have been achieved by taking advantage of strategies for the asymmetric aza-Friedel–Crafts reaction of a highly substituted hydroquinone and Nfumaryl ketimine generated from the corresponding dehydroalanine. The enantiomerically pure natural product and its enantiomer were prepared in seven steps and 22% overall yield by employing both enantiomers of a BINOL‐derived chiral phosphoric acid (CPA) catalyst.

The micotoxin (–)-fumimycin (1) was isolated from Aspergillus fumisynnematus in 2007.1 Soon after its discovery, the syntheses of racemic fumimycin and its immediate precursors were reported in the literature.2 This natural product continues to attract considerable interest from the synthetic community due to its strong antibacterial activity against resistant S. aureus strains and its inhibition of peptide deformylases (PDFs) (Scheme 1).3 However, despite this attention, the asymmetric synthesis of (+)-fumimycin (ent-1) together with its absolute configuration assignment have only recently been accomplished in 18 steps, 90% ee, and 1.6 % overall yield from commercially available material.4 Herein, we report the concise, highly convergent, and efficient syntheses of natural (–)-fumimycin (1) and its enantiomer (+)-fumimycin (ent-1). The key step in this synthesis is the asymmetric aza-Friedel–Crafts reaction5 of a densely functionalized hydroquinone and N-fumaryl ketimine, which is generated from the corresponding dehydroalanine. Our approach to (–)-fumimycin (1) and (+)-fumimycin (ent-1) is depicted in Scheme 1. We envisioned that both enantiomers of fumimycin would be accessed via a late-stage, chiral phosphoric acid (CPA)-catalyzed, domino azaFriedel−Crafts/lactonization process between hydroquinone 6 and dehydroalanine 10 to form the congested benzofuranone 11 bearing an aza-quaternary stereocenter, followed by cleavage of the two methyl groups. The synthesis of hydroquinone 6 would be accomplished in four steps starting from vanillin (2) and employing Dakin oxidation and Claisen rearrangement. Dehydroalanine 10, the precursor of N-fumaryl ketimine (A), would in turn be generated from the condensation of serine with monomethyl fumarate followed by dehydration. In view of the stereochemical and structural complexity of 1, this powerful

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disconnection of the natural product presented an opportunity to highlight the following: i) the utility of functionalized dehydroalanine 10 as a surrogate for unstable ketimine A, as the electrophilic component, to introduce the quaternary amino acid unit into a natural product,6 ii) the use of highly substituted vinyl hydroquinone 6 as the nucleophilic component in the relatively poorly investigated chemo-, regio-, and enantioselective domino aza-Friedel−Crafts/lactonization reaction,7 iii) the versatility of the CPA organocatalyst in enantioselective transformations of highly dense substrates, iv) the clear advantage for the availability of CPAs in both enantiomeric forms, and v) merging the structural design and synthetic design for possible natural product analogues and derivatives. 8 It must be stressed that even if the aza-Friedel–Crafts reaction between the π-aryl nucleophile and simple α,β-dehydroamino acids under stoichiometric and catalytic acidic conditions has been developed by us and others,9 related catalytic enantioselective transformations are less explored and their application to the synthesis of natural products has only recently emerged as an environmentally friendly and indispensable tool for the construction of relevant bioactive molecules.10

Scheme 1. Retrosynthetic Analysis of (–)-Fumimycin (1) and Challenges in the Catalytic Asymmetric Domino aza-Friedel−Crafts/Lactonization Reaction.

The synthesis ultimately commenced with the preparation of 2,6-disubstituted hydroquinone 6 by quantitative allylation of vanillin (2) under standard conditions.2a,b Installation of the third oxygen group at the aromatic core was feasible in excellent yield and with complete chemoselectivity by slight modification of Dakin oxidation (Scheme 2a). Indeed, oxidation of the aldehyde was accomplished using a catalytic amount (5 mol %) of diphenyl selenide as the activator of H 2O2, according to the procedure developed by Syper.11 Subsequent treatment of the formate intermediate with 5 equiv NH3 in DCM at 0 °C gave the desired phenol 4 in a gratifying yield of 92%. Claisen rearrangement of allyl ether 4 in DMF at 180 °C smoothly provided compound 5.2b Isomerization of the terminal double bond in the conjugated product 6 was achieved in good yield and with complete E-selectivity under relatively mild conditions by employing 5 mol % RhCl 3 in refluxing methanol.12 The entire sequence could be performed routinely on a multigram scale (Scheme 2a). Despite the fact that the synthesis of dehydroalanine 10 from racemic serine methyl ester (7) and monomethyl fumarate (8) in a one-pot amidation/dehydration procedure employing thionyl chloride has already been reported, 3c in our hands, we were able to detect the product but repeatedly obtained an unacceptable yield of 10 using these conditions. Therefore, we changed the reagent to the inexpensive and largely used 1-ethyl-

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The Journal of Organic Chemistry

3-(3′-dimethylaminopropyl)carbodiimide (EDCI) for both dehydration steps.13 Thus, the amide bond formation was carried out by using EDCI and N-hydroxybenzotriazole (HOBt) under standard basic amide coupling conditions between commercially available racemic serine methyl ester (7) and monomethyl fumarate (8) to give 9, and the conjugated double bond was obtained by using a combination of EDCI and catalytic copper (I) chloride. Finally, the water-soluble byproduct urea from EDCI could be removed by simple aqueous workup, and dehydroalanine 10 was obtained in high yield on a multigram scale. With the substrates for the key reaction in hand, we explored the organocatalytic enantioselective aza-Friedel−Crafts/lactonization sequence (Table 1).

Scheme 2. Syntheses of 2,6-Disubstituted Hydroquinone 6 and Dehydroalanine 10

We started this study by reacting hydroquinone 6 (1 equiv) with dehydroalanine 10 (1.2 equiv) in the presence of BINOL‐ derived CPA catalyst 12a at 5 mol % loading. Although the first attempt using toluene as the solvent at 85 °C and a reaction time of 72 h gave only poor conversion to the regioselective desired lactone 11, the enantioselectivity was decent (Table 1, entry 1, er 65:35). Under these conditions, we tested some drying agents, which are standard additives in phosphoric acid-catalyzed reactions.14 As shown in Table 1 (entries 2–3), the presence of molecular sieves (4 Å or 3 Å) was surprisingly detrimental to catalyst activity.15 In addition, lower conversion and enantioselectivity, compared to the reaction performed in their absence, were observed when the drying agent Na2SO4 or MgSO4 was used as an additive (Table 1, entries 4–5). Also, the use of an achiral urea as a co-catalyst, which has been reported to provide both a greater reactivity and a higher selectivity, 16 failed to improve the conversion when used with 12a in our reaction; however, a slightly better enantioselectivity (er 82:18) was detected (Table 1, entry 7). At this point, we envisioned that the addition of an achiral Lewis acid to form a bulky chiral supramolecular Brønsted acid catalyst, such as the tris(pentafluorophenyl)borane‐assisted CPA catalyst proposed by Ishihara,17 would be a highly promising and practical catalyst system to achieve both better conversion and enantioselectivity (Table 1, entries 8–13). Ultimately, complete conversion accompanied by good enantioselectivity (er 70:30) was achieved using the additive B(C6F5)3

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with 20 mol % loading, a reaction temperature of 85 °C, and a reaction time of 24 h (Table 1, entry 10).18 Under these conditions, the negative effect displayed by molecular sieves was confirmed. Low yields and enantioselectivities were observed in DCM and DCE at 23 °C, respectively (data not shown). Monitoring this reaction by TLC and 1H NMR spectroscopic analysis in situ revealed excellent conversion of the starting materials into the alkylated product. The yield of the isolated lactone 11 (Table 1) was diminished as a result of its partial sensitivity to chromatography on silica gel and, more likely, minimal polymerization of vinyl hydroquinone 6. In terms of further catalyst screening with examination of substituents at the 3,3′‐positions of 12a–d with different bulkiness and skeletons for asymmetric induction, 13a,b and 14a (Table 1, entries 15–20) were evaluated.19 No significant improvement in the er value or yield was observed with these catalysts. Therefore, the use of catalyst 12a (5 mol %) in the presence of the additive B(C6F5)3 with 20 mol % loading in toluene at 85 °C for 24 h gave the best results. Pleasingly, intermediate 11 could be enantioenriched by one single recrystallization using 7:1 iPr2O:DCM, furnishing 96:4 er in the mother liquor. In modern asymmetric catalysis, chiral Brønsted acid catalysts with (R)- or (S)-binaphthyl skeletons have found widespread applications, and both enantiomers of 12a are commercially available. Repeating the reaction and crystallization with the catalyst ent-12a, we were able to obtain 11 with the same yield and almost opposite enantioselectivity.

Table 1. Catalyst and Condition Optimization.

entrya 1d 2d 3d 4d 5d 6 7 8d 9

CPA (mol %) 12a (5) 12a (5) 12a (5) 12a (5) 12a (5) 12a (5) 12a (5) 12a (5) 12a (5)

additive (mol %) / MS, 4 Å MS, 3 Å Na2SO4 MgSO4 H2O Urea-(CF3)2 (5)e B(C6F5)3 (5) B(C6F5)3 (10)

T (° C) 85 85 85 85 85 85 85 85 85

conv. (%) 48 0 0 100 100 100 52 72 52

yield (%)b 38 / / 14 24 15 30 38 48

10

12a (5)

B(C6F5)3 (20)

85

100

68

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er (%)c 65:35 / / 61:39 61:39 64:36 82:18 75:25 77:23 70:30 (96:4)f

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The Journal of Organic Chemistry

11 12 13g 14 15 16 17 18 19 20

12a (10) 12a (5) 12a (5) / 12b (5) 12c (5) 12d (5) 13a (5) 13b (5) 14a (5)

B(C6F5)3 (20) B(C6F5)3 (20) B(C6F5)3 (20) B(C6F5)3 (20) B(C6F5)3 (20) B(C6F5)3 (20) B(C6F5)3 (20) B(C6F5)3 (20) B(C6F5)3 (20) B(C6F5)3 (20)

85 65 85 85 85 85 85 85 85 85

100 74 90 68 50 100 52 61 51 100

74 40 62 20 20 54 24 34 20 58

21

ent 12a (5)

B(C6F5)3 (20)

85

100

68

a

71:29 67:33 57:43 / 38:62 40:60 51:49 55:45 61:39 62:38 30:70 (13:87)f

Reaction conditions: 6 (0.25 mmol), 10 (0.3 mmol), CPA (5–10 mol %), additive (5–20 mol %), toluene (0.25 M), 85

°C, 24 h. bIsolated yield. cDetermined by chiral HPLC on a Chiralpack OD-H column. d72 h. e1,3-bis(3,5bis(trifluoromethyl)phenyl)urea. fIn the mother liquor by recrystallization with 7:1 iPr2O/DCM. Crystals were racemic. g

6 (0.3 mmol), 10 (0.25 mmol) were used. To complete the synthesis of (+)-fumimycin and (–)-fumimycin, only the removal of the two methyl groups of 11 remained.

Initial attempts to remove both of the protecting groups with a single reagent were unsuccessful. Treatment with a large excess of HBr or BBr3 at 23 °C resulted in cleavage of both the methyl ether and methyl ester as well as multiple other side products. On the other hand, lithium hydroxide in 2:1 THF/water proved to be a mild and highly effective method for the selective hydrolysis of the methyl ester to give (+)- and (–)-methoxyfumimicyn 15, itself a target for synthesis (Scheme 3). As expected,2,3 we encountered many difficulties in the deprotection of the catechol moiety at a late stage. Following a very recent report describing clean demethylation of various ortho-methoxyphenols to catechol by treatment with a combination of AlCl3 and NaI in acetonitrile using N,N′-diisopropylcarbodiimide (DIC) as the acid scavenger, the reaction failed and 11 was recovered almost quantitatively. 20 However, inspired by this work and our previous results, we decided to treat 11 with BBr3 (5 equiv) in DCM in the presence of DIC (2 equiv) to prevent side reactions probably due to byproducts of the reaction such as methyl bromide, hydrobromic acid, and boronic acid. Pleasingly, (+)- and (–)-fumimycin methyl ester 16 were obtained cleanly and in very good yield. The ability to selectively deprotect either functional group provides great flexibility for possible subsequent synthetic approaches to derivatives. Unfortunately, the one-pot double-deprotection, in either order, resulted in the formation of a complex mixture. This result indicated that both of the deprotection steps must be carried out under mild and controlled conditions. For example, when 16 was treated with LiOH under the same conditions used for 11, only a complex mixture was obtained; whereas when 15 was subjected to the methoxy ether cleavage reaction, only starting material was recovered. Pleasingly, cleavage of the methyl ester in 16 was achieved with trimethyltin hydroxide, yielding (+)- and (–)fumimycin (1) in decent yields, without the decomposition of base-sensitive moieties (Scheme 3).

Scheme 3. Selective Ester/Ether C–O Cleavage of (–)-11.

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In summary, we have developed a concise and convergent route to both enantiomers of fumimycin (1) in 7 steps and 22% overall yield. The synthesis is considerably shorter and higher yielding than the previously reported asymmetric synthesis 4 and provides rapid access to significant quantities of (–)-fumimycin. The use of a bulky chiral supramolecular Brønsted acid catalyst, such as the tris(pentafluorophenyl)borane‐assisted CPA catalyst, was crucial to achieve full conversion for the regio- and enantioselective domino aza-Friedel−Crafts/lactonization reaction. This novel methodology and enantioenrichment by recrystallization enabled the asymmetric synthesis of (+)-fumimycin and (–)-fumimycin. The chemoselective cleavage of the ester/ether C–O of methyl anisates in the context of natural product synthesis, under relatively mild conditions, was also reported. The application of this highly convergent strategy for the synthesis of novel analogues of fumimycin by simply changing the phenol and/or the dehydroalanine component as well as their full biological evaluation on various bacterial PDFs are of ongoing interest in our group.

Experimental Section General methods. All reagents were purchased from best-known commercial suppliers and used without further purification. All reactions were run in air unless otherwise noted. Column chromatography purifications were performed in flash conditions using 230-400 Mesh silica gel. 1H NMR and 13C NMR were recorded on a 400 spectrometer, using CDCl3 and CD3OD as solvents. Chemical shifts (δ scale) are reported in parts per million (ppm) relative to the central peak of the solvent. Coupling constants (J values) are given in Hertz (Hz). Enantiomeric excesses were determined on an HPLC instrument (chiral column OD-H; mobile phase n-hexane/i-PrOH 85:15, flow 1.0 mL min−1, λ = 220 nm). Optical rotation analysis was performed with a polarimeter using a sodium lamp (λ 589 nm, D-line); [α]D20 values are reported in 10−1 deg cm2 g−1; concentration (c) is in g for 100 mL. HRMS analysis was performed using a Q-TOF micro TM mass spectrometer. 4-(Allyloxy)-3-methoxybenzaldehyde (3): To a suspension of vanillin 2 (3.04 g, 20 mmol, 1 equiv) and K2CO3 (3.86 g, 28 mmol, 1.4 equiv) in acetone (30.0 mL) allyl bromide (2.38 mL, 4.37 g, 26 mmol, 1.3 equiv) was added. The mixture was heated to reflux in oil bath for 2 h. After filtration, the filtrate was concentrated under reduced pressure and purified by flash chromatography (cyclohexane/EtOAc 9:1) to afford the allylether 3 as a colorless oil (3.80 g, 19.8 mmol, 99%).

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1

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H NMR (CDCl3, 400 MHz) δ 3.94 (s, 3H), 4.69-4.71 (m, 2H), 5.32-5.35 (m, 1H), 5.41-5.46 (m, 1H) 6.04-6.11 (m, 1H),

6.97 (d, J = 8.5 Hz, 1H), 7.40-7.44 (m, 2H), 9.84 (s, 1H). The chemical-physical data are according to those published the literature.2a 4-(Allyloxy)-3-methoxyphenol (4): To a 0.5 M solution of 3 (3.80 g, 19.8 mmol) in CH2Cl2 was added a catalytic amount of diphenylselenide (231 mg, 0.99 mmol, 0.05 equiv) followed by the addition of 5 mL of 30% H2O2. The reaction mixture was stirred at 23 °C for 60 h. Water was added and the aqueous layer was extracted with CH 2Cl2. The solvent was removed under reduced pressure and the residue was dissolved in CH2Cl2 (198 mL) and cooled to 0 °C. 47.4 mL of NH 3 (2N in EtOH) were added and the reaction was stirred for 1 h at 0 °C. The reaction mixture was concentrated, dissolved in CH2Cl2 (50 ml), washed with a saturated solution of NaHCO3 aqueous (50 ml) and water (50 ml). The organic phase was dried over Na2SO4, concentrated and the residue purified by flash chromatography (cyclohexane/EtOAc 8:2) to give the phenol 4 as a brown oil (3.28 g, 18.2 mmol, 92%). 1H NMR (CDCl3, 400 MHz) 3.84 (s, 3H), 4.52-4.55 (m, 2H), 4.61 (br s, 1H), 5.25-5.27 (m, 1H), 5.39-5.40 (m, 1H), 6.03-6.06 (m, 1H), 6.31 (dd, J = 8.5, 3.0 Hz, 1 H), 6.47 (d, J = 3.0 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H); HRMS (ESI-TOF) m/z: [M+H]+ calcd for C10H13O3 181.0859; found 181.0866. The chemicalphysical data are according to those published the literature.2a 2-Allyl-6-methoxybenzene-1,4-diol (5)2b: A solution of 4 (3.28 g, 18.2 mmol) in DMF (300 mL) was heated in oil bath at 180 °C for 18 h. The solvent was removed under reduced pressure; water (800 mL) was added to residue and the mixture was extracted with EtOAc (3 x 800 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient from cyclohexane/EtOAc 9:1 to 7:3) to give 5 as a white solid (2.79 g, 15.5 mmol, 85%). 1H NMR (CDCl3, 400 MHz) δ 3.353.37 (m, 2H), 3.86 (s, 3H), 4.44 (br s, 1H), 5.06–5.11 (m, 2H), 5.28 (br s, 1H) 5.94 -6.01(m, 1H) 6.22 (d, J = 3.0 Hz, 1 H), 6.35 (d, J = 3.0 Hz, 1H); 13C1H NMR (CDCl3, 100 MHz) δ 33.8, 56.0, 97.6, 107.8, 115.7, 126.0, 136.3, 137.3, 146.9, 148.4; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C10H13O3 181.0859; found 181.0876. (E)-2-Methoxy-6-(prop-1-enyl)benzene-1,4-diol (6): A mixture of 5 (2.78 g, 15.5 mmol, 1 equiv) and RhCl3·3H2O (176 mg, 0.77 mmol, 0.05 equiv) in methanol (282 mL) was heated to reflux in oil bath for 24 h. The reaction mixture was allowed to cool to 23 °C and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and purified by flash chromatography (gradient from cyclohexane/EtOAc 9:1 to 7:3) to give 6 as a white solid (2.51 g, 14.0 mmol, 90%). 1H NMR (CD3OD, 400 MHz) δ 1.85 (dd, J = 6.5, 1.5 Hz, 3H), 3.79 (s, 3H), 6.15 (dq, J = 16.0, 6.5 Hz, 1H), 6.30 (d, J = 2.5 Hz, 1H), 6.40 (d, J = 2.5 Hz, 1H), 6.65 (ddd, J = 16.0, 3.5, 1.5 Hz, 1H); 13C1H NMR (CD3OD, 100 MHz) δ 18.5, 56.0, 99.2, 103.8, 125.6, 125.8, 126.5, 137.2, 149.3, 150.6; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C10H13O3 181.0859; found 181.0871. (E)-Methyl 4-(3-hydroxy-1-methoxy-1-oxopropan-2-ylamino)-4-oxobut-2-enoate (9): DIPEA (6.97 mL, 40 mmol, 2

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equiv) was added to a 0.25 M stirred solution of serine methyl ester hydrochloride 7 (3.11 g, 20 mmol, 1 equiv) in CH2Cl2 at 0°C under N2. After 10 minutes were added (E)-4-methoxy-4-oxobut-2-enoic acid 8 (2.86 g, 22 mmol, 1.1 equiv), EDCI (4.22 g, 22 mmol, 1.1 equiv) and HOBt (2.7 g, 20 mmol, 1 equiv). The reaction mixture was stirred at 23 °C for 16 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (gradient from cyclohexane/EtOAc 1:1 to EtOAc 100%) to afford 10 (3.65 g, 15.8 mmol, 79%) as white solid. 1H NMR (CDCl3, 400 MHz) δ 2.94 (br s, 1H), 3.75 (s, 3H), 3.76 (s, 3H), 3.88 (dd, J = 11.5, 3.0 Hz, 1H), 4.0 (dd, J = 11.5, 3.5 Hz, 1H), 4.714.74 (m, 1H), 6.79 (d, J = 15.5 Hz, 1H), 7.09 (d, J = 15.5 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H); 13C1H NMR (CDCl3, 100 MHz) δ 52.3, 52.9, 54.9, 63.0, 130.8, 135.8, 163.8, 166.0, 170.7; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C9H14NO6 232.0816; found 232.0823. (E)-methyl 4-(3-methoxy-3-oxoprop-1-en-2-ylamino)-4-oxobut-2-enoate (10): To a solution of 9 (3.65, 15.8 mmol, 1 equiv) in CH2Cl2 dry (105 mL) under N2, were added CuCl (469 mg, 4.74 mmol, 0.3 equiv) and EDCI (3.33 g, 17.38 mmol, 1.1 equiv). After 2 h of stirring at 23 °C, the reaction mixture was filtered through a pad of Celite. The filtrate washed with brine, dried over Na2SO4, concentrated under reduced pressure and purified by flash chromatography (gradient from cyclohexane/EtOAc 9:1 to 7:3) to yield 10 (3.23 g, 15.2 mmol, 96%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 3.82 (s, 3H), 3.88 (s, 3H), 6.01 (d, J = 1.5 Hz, 1H), 6.76 (s, 1H), 6.89 (d, J = 15.5 Hz, 1H), 7.02 (d, J = 15.5 Hz, 1H), 8.11 (br s, 1H); 13C1H NMR (CDCl3, 100 MHz) δ 52.3, 53.2, 110.5, 130.7, 131.3, 136.1, 162.0, 164.2, 165.6; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C9H12NO5 214.0710; found 214.0731. The chemical-physical data are according to those published the literature.2c General procedure for Aza-Friedel-Craft Alkylation/lactonization cascade reaction. A vial was charged with 6 (45 mg, 0.25 mmol, 1 equiv), 10 (64 mg, 0.3 mmol, 1.2 equiv), the appropriate CPA (0.0125 mmol, 0.05 equiv), B(C6F5)3 (26 mg, 0.05 mmol, 0.2 equiv) and toluene (1 mL). The vial was sealed and immersed in a preheated (85 °C) oil bath and stirred at this temperature for 24 h. The solvent was evaporated under reduced pressure, and the residue obtained was purified by flash chromatography. (E)-Methyl 4-((S)-5-hydroxy-6-methoxy-3-methyl-2-oxo-4-((E)-prop-1-enyl)-2,3-dihydrobenzofuran-3-ylamino)4-oxobut-2-enoate ((–)-11): the title compound was synthesized according to the general procedure above from commercially available BINOL‐derived chiral phosphoric acid catalysts (S)-12a. The product was purified by flash chromatography (gradient from cyclohexane/EtOAc 9:1 to 7:3) to give (-)-11 as a pale-yellow solid (61 mg, 0.17 mmol, 68%). 1H NMR (CDCl3, 400 MHz) δ 1.77 (s, 3H), 1.93 (dd, J = 6.5, 1.5 Hz, 3H) 3.80 (s, 3H), 3.92 (s, 3H), 5.82 (s, 1H), 6.31 (dd, J = 16.0, 1.5 Hz, 1H), 6.66 (s, 1H), 6.78 (d, J = 15.5 Hz, 1H), 6.82 (brs, 1H), 6.96 (d, J = 15.5 Hz, 1H); 13C1H NMR (CDCl3, 100 MHz) δ 19.9, 23.4, 52.4, 56.5, 58.3, 93.7, 116.2, 120.3, 121.0, 131.9, 134.0, 134.5, 140.7, 146.2, 147.4, 162.5, 165.8, 175.8; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H20NO7 362.1213; found 362.1223; Chiral

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HPLC analysis: tR (major) = 19.6 min, tR (minor) = 25.2 min, er = 87:13; [α]D20 = -26.6 (c = 0.67, MeOH) (determinated in the mother liquor after recrystallization with iPr2O/DCM 7:1), corresponds to [α]D20 = -35.6 (optically pure). (E)-Methyl 4-((R)-5-hydroxy-6-methoxy-3-methyl-2-oxo-4-((E)-prop-1-enyl)-2,3-dihydrobenzofuran-3-ylamino)4-oxobut-2-enoate ((+)-11): the title compound was synthesized according to the general procedure above from commercially available BINOL‐derived chiral phosphoric acid catalysts (R)-12a. The product was purified by flash chromatography (gradient from cyclohexane/EtOAc 9:1 to 7:3) to give (+)-11 as a pale-yellow solid (61 mg, 0.17 mmol, 68%). The spectroscopic data are identical with those of (–)-11. Chiral HPLC analysis: tR (minor) = 19.6 min, tR (major) = 25.1 min, er = 96:4; [α]D20 = +36.8 (c = 1.27, MeOH) (determinated in the mother liquor after recrystallization with iPr2O/DCM 7:1), corresponds to [α]D20 = +40 (optically pure). (E)-4-((S)-5-Hydroxy-6-methoxy-3-methyl-2-oxo-4-((E)-prop-1-enyl)-2,3-dihydrobenzofuran-3-ylamino)-4oxobut-2-enoic acid ((–)-15): To a 0.1 M solution of (–)-11 (90 mg, 0.25 mmol, 1 equiv.) in THF/H2O (2:1, 2.5 mL) was added LiOH (30 mg, 1.25 mmol, 5 equiv.) and the mixture was stirred at 23 °C for 30 minutes. After completion, the organic solvent was removed in vacuo and the resulting mixture was diluted with H2O, acidifed with 2N HCl, then extracted 3 times with EtOAc. The organic layer was separated, dried over Na 2SO4 and concentrated to provide (–)-15 as a pale-yellow solid (72 mg, 0.21 mmol, 83%). 1H NMR (CD3OD, 400 MHz) δ 1.67 (s, 3H), 1.91 (dd, J = 6.5, 1.5 Hz, 3H), 3.88 (s, 3H), 6.40 (dd, J = 16.0, 1.5 Hz, 1H), 6.61 (d, J = 15.5 Hz, 1H), 6.69-6.78 (m, 2H), 6.95 (d, J = 15.5 Hz, 1H); 13

C1H NMR (CD3OD, 100 MHz) δ 19.8, 23.4, 57.0, 59.5, 94.9, 118.1, 122.0, 123.0, 134.0, 134.6, 134.7, 142.9, 147.2,

149.7, 165.3, 169.0, 178.1. Chiral HPLC analysis: compound ((–)-15) proved to be too polar for the determination of the enantiomeric excess. Since racemization of the quaternary stereocenter, under mild deprotection conditions can be excluded, the title compound should also possess er = 87:13; [α]D20 = -40.8 (c = 0.44, MeOH), corresponds to [α]D20 = 54 (optically pure); HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H18NO7 348.1078; found 348.1075. The chemicalphysical data are according to those published the literature. 2b (E)-4-((R)-5-Hydroxy-6-methoxy-3-methyl-2-oxo-4-((E)-prop-1-enyl)-2,3-dihydrobenzofuran-3-ylamino)-4oxobut-2-enoic acid (ent-15): Compound ent-15 was synthesized from (+)-11 by following similar procedure for the synthesis of compound ((–)-15). The spectroscopic data are identical with those of ((–)-15). Chiral HPLC analysis: compound (ent-15) proved to be too polar for the determination of the enantiomeric excess. Since racemization of the quaternary stereocenter, under mild deprotection conditions can be excluded, the title compound should also possess er = 96:4; [α]D20 = +50.9 (c = 0.66, MeOH), corresponds to [α]D20 = +55 (optically pure). (E)-Methyl

4-((S)-5,6-dihydroxy-3-methyl-2-oxo-4-((E)-prop-1-enyl)-2,3-dihydrobenzofuran-3-ylamino)-4-

oxobut-2-enoate ((–)-16): To a cooled (0°C) solution of (-)-11 (90 mg, 0.25 mmol, 1 equiv) and 1,3diisopropylcarbodiimide (77 µL, 0.5 mmol, 2 equiv) in CH2Cl2 (4 mL) was added BBr3 (1M in DCM; 1.25 mL, 5 equiv).

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After 30 minutes the resulting mixture was diluted with CH2Cl2, basified by the addition of sat. NaHCO3 solution and the phases were separated. The aqueous layer was acidified with 2N HCl (pH 2-3) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient from CH2Cl2:MeOH 10:0 to 9:1) to afford ((–)-16) (61 mg, 0.175 mmol, 70%) as a pale-yellow solid. 1H NMR (CD3OD, 400 MHz) δ 1.66 (s, 3H), 1.91 (dd, J = 6.5, 1.5 Hz, 3H), 3.77 (s, 3H), 6.38 (dd, J = 16.0, 1.5 Hz, 1H), 6.49 (s, 1H), 6.63 (d, J = 15.5 Hz, 1H), 6.63-6.72 (m, 1H), 7.02 (d, J = 15.5 Hz, 1H); 13C1H NMR (CD3OD, 100 MHz) δ 19.7, 23.5, 52.7, 59.5, 97.6, 117.0, 122.6, 123.2, 131.7, 134.3, 135.8, 141.9, 147.2, 147.4, 164.7, 167.0, 178.1. Chiral HPLC analysis: compound ((–)-16) proved to be too polar for the determination of the enantiomeric excess. Since racemization of the quaternary stereocenter, under mild deprotection conditions can be excluded, the title compound should also possess er = 87:13 [α]D20 = -53.8 (c = 0.65, MeOH), corresponds to [α]D20 = -72.7 (optically pure), HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H18NO7 348.1078; found 348.1082. (E)-Methyl

4-((R)-5,6-dihydroxy-3-methyl-2-oxo-4-((E)-prop-1-enyl)-2,3-dihydrobenzofuran-3-ylamino)-4-

oxobut-2-enoate (ent-16): Compound ent-16 was synthesized from (+)-11 by following similar procedure for the synthesis of compound ((–)-16). The spectroscopic data are identical with those of ((–)-16). Chiral HPLC analysis: compound (ent-16) proved to be too polar for the determination of the enantiomeric excess. Since racemization of the quaternary stereocenter, under mild deprotection conditions can be excluded, the title compound should also possess er = 96:4 [α]D20 = +62.7 (c = 0.76, MeOH), corresponds to [α]D20 = +71 (optically pure). (-)-Fumimycin (1): ((–)-16) (61 mg, 0.175 mmol, 1 equiv) was dissolved in 1,2-dichloroethane (4 mL) and after addition of trimethyltinhydroxide (158 mg, 0.875 mmol, 5 equiv), the mixture was heated in oil bath at 80 °C until TLC analysis indicated a complete reaction. After completion of the reaction, the mixture was concentrated in vacuo, and the residue was taken up in EtOAc and basified by the addition of sat. solution of NaHCO 3. The phases were separated and the aqueous layer was acidified with 2N HCl (pH 2-3) and extracted with EtOAc. The organic layer was dried over Na 2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient from CH2Cl2: MeOH 10:0 to CH2Cl2: MeOH 9:1+ 0.1% acetic acid) to afford (–)-1 (35 mg, 0.10 mmol, 60%). 1H NMR (CD3OD /CDCl3 1:1, 400 MHz) δ 1.38 (s, 3H), 1.61 (dd, J = 6.6, 1.6 Hz, 3H), 6.08 (dq, J = 15.7, 1.7 Hz, 1H), 6.23 (s, 1H), 6.33 (d, J = 15.6 Hz, 1H), 6.36 (dq, J = 15.8, 6.6 Hz, 1H), 6,56 (d, J = 15.5 Hz, 1H); 13C1H NMR (CD3OD /CDCl3 1:1, 100 MHz) δ 19.0, 22.5, 58.1, 96.7, 115.8, 121.1, 121.7, 132.9, 133.3, 133.7, 140.2, 145.6, 145.9, 164.1, 169.7, 177.3. Chiral HPLC analysis: compound (–)-1 proved to be too polar for the determination of the enantiomeric excess. Since racemization of the quaternary stereocenter, under mild deprotection conditions can be excluded, the title compound should also possess er = 87:13 [α]D20 = -91 (c = 0.31, MeOH), corresponds to [α]D20 = -123 (optically pure). The spectroscopic data are

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according to those published the literature.1 HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H16NO7 334.0921; found 334.0943. (+)-Fumimycin (ent-1): Compound ent-1 was synthesized from ent-16 by following similar procedure for the synthesis of compound 1. The spectroscopic data are identical with those of (–)-1. Chiral HPLC analysis: compound (ent-1) proved to be too polar for the determination of the enantiomeric excess. Since racemization of the quaternary stereocenter, under mild deprotection conditions can be excluded, the title compound should also possess er = 96:4 [α]D20 = +112 (c = 0.31, MeOH), corresponds to [α]D20 = +121.7 (optically pure), according to data reported by Brase et al.4 Supporting Information Copies of 1H, 13C NMR spectra for all new compounds and HPLC traces of 11. Acknowledgments We would like to thank Prof. Gilberto Spadoni and Prof. Annalida Bedini, University of Urbino “Carlo Bo”, for useful discussions. MR thanks GLUOS for a research fellowship. References (1) Kwon, Y.-J.; Sohn, M.-J.; Zheng, C.-J.; Kim, W.-G. Fumimycin:  A Peptide Deformylase Inhibitor with an Unusual Skeleton Produced by Aspergillus fumisynnematus. Org. Lett. 2007, 9, 2449-2451. (2) (a) Gross, P. J.; Bräse, S. The Total Synthesis of (±) Fumimycin. Chem. Eur. J. 2010, 16, 12660-12667. (b) Gross, P. J.; Hartmann, C. E.; Nieger, M.; Bräse, S. Synthesis of (±)-Methoxyfumimycin with 1,2-Addition to Ketimines. J. Org. Chem. 2010, 75, 229-232. (c) Zhou, Z.; Hu, Y.; Wang, B.; He, X.; Ren, G.; Feng, L. A Concise Synthesis of (±)Methoxyfumimycin Ethyl Ester. J. Chem. Res. 2014, 38, 378-380. (d) Zhou, Z.-W.; Li, W.-C.; Hu, Y.; Wang, B.; Ren, G.; Feng, L.-H. Synthesis of the Intermediate for Fumimycin: a Natural Peptide Deformylase Inhibitor. Res. Chem. Intermediat. 2013, 39, 3049-3054. (3) Zaghouani, M.; Bögeholz, L. A.K.; Mercier, E.; Wintermeyer, W.; Roche, S. P. Total Synthesis of (±)-Fumimycin and Analogues for Biological Evaluation as Peptide Deformylase Inhibitors. Tetrahedron 2019, 75, 3216-3230. (4) Gross, P. J.; Furche, F.; Nieger, M.; Bräse, S. Asymmetric Total Synthesis of (+)-Fumimycin via 1,2-Addition to Ketimines. Chem.Commun. 2010, 46, 9215-9217. (5) For selected reviews enantioselective aza-Friedel–Crafts reactions, see: (a) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M.; Catalytic Enantioselective Formation of C−C Bonds by Addition to Imines and Hydrazones: A Ten-Year Update Chem. Rev. 2011, 111, 2626-2704. (b) Kataja, A. O.; Masson, G. Imine and Iminium Precursors as Versatile Intermediates in Enantioselective Organocatalysis. Tetrahedron 2014, 70, 8783-8815. (c) Montesinos-Magraner, M.; Vila, C.; Blay, G.; Pedro, J. R. Catalytic Enantioselective Friedel–Crafts Reactions of Naphthols and Electron-Rich Phenols.

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Synthesis 2016, 48, 2151– 2164. For the pioneering work on the enantioselective aza-Friedel–Crafts reaction by chiral phosphoric acid catalysts, see: (d) Uraguchi, D.; Sorimachi, K.; Terada, M. Organocatalytic Asymmetric Aza-Friedel– Crafts Alkylation of Furan. J. Am. Chem. Soc. 2004, 126, 11804-11805. (6) Hager, A.; Vrielink, N.; Hager, D.; Lefranc, J.; Trauner, D. Synthetic Approaches towards Alkaloids Bearing αTertiary Amines. Nat. Prod. Rep. 2016, 33, 491-522. (7) (a) Enders, D.; Grondal, C.; Hüttl, M. R. M. Asymmetrische organokatalytische Dominoreaktionen. Angew. Chem. 2007, 119, 1590-1601.; Asymmetric Organocatalytic Domino Reactions. Angew. Chem. Int. Ed. 2007, 46, 1570-1581. (b) Chanda, T.; Zhao, J. C. G. Recent Progress in Organocatalytic Asymmetric Domino Transformations. Adv.Synth.Catal. 2018, 360, 2-79. (8) Huffman, B. J.; Shenvi, R. A. Natural Products in the “Marketplace”: Interfacing Synthesis and Biology. J. Am. Chem. Soc. 2019, 141, 3332-3346. (9) (a) De la Hoz, A.; Díaz-Ortiz, A.; Gómez, M. V.; J. Mayoral, A.; Moreno, A.; Sánchez-Migallón A. M.; Vázquez, E. Preparation of α- and β-Substituted Alanine Derivatives by α-Amidoalkylation or Michael Addition Reactions under Heterogeneous Catalysis Assisted by Microwave Irradiation. Tetrahedron 2001, 57, 5421-5428. (b) Royo, E.; López, P.; Cativiela, C. Application of a New Methodology for the Synthesis of α-Methyl-α-arylglycines using Methyl Acetamidoacrylate as an α-Methylglycine Cation Equivalent. Arkivoc 2005, 6, 46-61. (c) Angelini, E.; Balsamini, C.; Bartoccini, F.; Lucarini S.; Piersanti, G. Switchable Reactivity of Acylated α, β-Dehydroamino Ester in the Friedel−Crafts Alkylation of Indoles by Changing the Lewis Acid. J. Org. Chem. 2008, 73, 5654-5657. (d) Righi, M.; Bartoccini, F.; Lucarini S.; Piersanti, G. Organocatalytic Synthesis of α-Quaternary Amino acid Derivatives via aza-Friedel–Crafts Alkylation of Indoles with Simple α-Amidoacrylates. Tetrahedron 2011, 67, 7923-7928. (e) Lucarini, S.; Mari, M.; Piersanti, G.; Spadoni, G. Organocatalyzed Coupling of Indoles with Dehydroalanine esters: Synthesis of Bis(indolyl)propanoates and Indolacrylates. RSC Advances 2013, 3, 19135-19143. (f) Pirovano, V.; Facoetti, D.; Dell’Acqua, M.; Della Fontana, E.; Abbiati, G.; Rossi, E. Gold(I) or Silver Catalyzed Synthesis of α-Indolylacrylates. Org. Lett. 2013, 15, 3812-3815. (g) Bartoccini, F.; Mari, M.; Retini, M.; Bartolucci, S.; Piersanti, G. Organocatalytic AzaFriedel-Crafts/Lactonization Domino Reaction of Naphthols and Phenols with 2-Acetamidoacrylate to Naphtho- and Benzofuranones Bearing a Quaternary Center at the C3 Position. J.Org.Chem. 2018, 83, 12275-12283. (10) For an outstanding review about enantioselective phosphoric acids catalysis as a tool for the synthesis of Naturals Products and Pharmaceuticals, see: Merad J.; Lalli C.; Bernadat G.; Maury J.; Masson G. Enantioselective Brønsted Acid Catalysis as a Tool for the Synthesis of Natural Products and Pharmaceuticals. Chem. Eur. J. 2018, 24, 3925-3943. (11) Syper, L. The Baeyer-Villiger Oxidation of Aromatic Aldehydes and Ketones with Hydrogen Peroxide Catalyzed by Selenium Compounds. A Convenient Method for the Preparation of Phenols. Synthesis 1989, 3, 167-172.

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(12) Hassam, M.; Taher, A.; Arnott, G. E.; Green, I. R.; van Otterlo, W. A. L. Isomerization of Allylbenzenes. Chem. Rev. 2015, 115, 5462-5569. (13) Dunetz, J. R.; Magano, J.; Weisenburger, G. A. Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals. Org. Process Res. Dev. 2016, 20, 140-177. (14) Hong, L.; Sun, W.; Yang, D.; Li, G.; Wang, R. Additive Effects on Asymmetric Catalysis. Chem. Rev. 2016, 116, 4006-4123. (15) Molecular sieves contain alkaline and alkaline earth metals. It can be speculated that molecular sieves convert the acidic catalyst to metal phosphate species, which are not able to promote enamine/imine tautomerization. We have also verified that the magnesium salt of catalyst 12a is not efficient in the promotion of these reactions, although we could not reach a decisive conclusion. (16) Maskeri, M. A.; O'Connor, M. J.; Jaworski, A. A.; Davies, A. V.; Scheidt, K. A. A Cooperative Hydrogen Bond Donor–Brønsted Acid System for the Enantioselective Synthesis of Tetrahydropyrans. Angew. Chem. Int. Ed. 2018, 57, 17225-17229. (17) (a) Hatano, M.; Goto, Y.; Izumiseki, A.; Akakura, M.; Ishihara, K. Boron Tribromide-Assisted Chiral Phosphoric Acid Catalyst for a Highly Enantioselective Diels–Alder Reaction of 1,2-Dihydropyridines. J. Am. Chem. Soc. 2015, 137, 13472-13475; (b) Sakamoto, T.; Mochizuki, T.; Goto, Y.; Hatano, M.; Ishihara, K. Boron Tribromide‐Assisted Chiral Phosphoric Acid Catalysts for Enantioselective [2+2] Cycloaddition. Chem. Asian J. 2018, 13, 2373-2377. (c) Hatano, M.; Sakamoto, T.; Mochizuki, T.; Ishihara, K. Tris(pentafluorophenyl)borane‐Assisted Chiral Phosphoric Acid Catalysts for Enantioselective Inverse‐Electron‐Demand Hetero‐Diels‐Alder Reaction of α,β‐Substituted Acroleins. Asian J. Org. Chem. 2019, 8, 1-7. (18) Interestingly, BBr3-(R)-12a did not effectively promote the reaction of 6 with 10, and 11 was obtained only in traces. (19) (a) Melikian, M.; Gramüller, J.; Hioe, J.; Greindla, J.; Gschwind, R.M. Brønsted Acid Catalysis – the Effect of 3,3′-Substituents on the Structural Space and the Stabilization of Imine/Phosphoric acid Complexes. Chem. Sci. 2019, 10, 5226-5234. (b) Reid, J. P.; Simón, L.; Goodman, J. M. A Practical Guide for Predicting the Stereochemistry of Bifunctional Phosphoric Acid Catalyzed Reactions of Imines Acc. Chem. Res., 2016, 49, 1029-1041. (20) Sang, D.; Tu, X.; Tian, J.; He Z.; Yao, M. Anchimerically Assisted Cleavage of Aryl Methyl Ethers by Aluminum Chloride‐Sodium Iodide in Acetonitrile, ChemistrySelect 2018, 3, 10103-10107.

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