Divergent Synthesis of Revised Apratoxin E, 30-epi-Apratoxin E, and

Article pubs.acs.org/joc

Cite This: J. Org. Chem. 2017, 82, 10830-10845

Divergent Synthesis of Revised Apratoxin E, 30-epi-Apratoxin E, and 30S/30R‑Oxoapratoxin E Zhuo-Ya Mao,†,‡ Chang-Mei Si,† Yi-Wen Liu,‡ Han-Qing Dong,‡,§ Bang-Guo Wei,*,† and Guo-Qiang Lin†,‡ †

Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China Institute of Biomedical Sciences, Fudan University, 130 Dongan Road, Shanghai 200433, China

‡

S Supporting Information *

ABSTRACT: In this report, originally proposed apratoxin E (30S-7), revised apratoxin E (30R-7), and (30S)/(30R)oxoapratoxin E (30S)-38/(30R)-38 were efficiently prepared by two synthetic methods. The chiral lactone 10, recycled from the degradation of saponin glycosides, was utilized to prepare the key nonpeptide fragment 9. Our alternative convergent assembly strategy was applied to the divergent synthesis of revised apratoxin E and its three analogues. Moreover, ring-closing metathesis (RCM) was for the first time found to be an efficient strategy for the macrocyclization of apratoxins.

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Additional marine secondary metabolites of apratoxins,7 isolated from the Lyngbya species of cyanobacteria, exhibit highly potent cytotoxicity against some cancer cell lines. Structurally, they possess a novel thiazoline ring in the macrocycle. Apratoxin A7c (4), isolated from the remarkably prolific Lyngbya majuscula collected in Guam, is sensitive toward acid-induced dehydration leading to (E)-dehydroapratoxin A (6).7d The dehydration resulted in two conformers, which showed 3:2 ratio in NMR (CDCl3). Apratoxin D7e (5), obtained from the same species collected in Papua New Guinea, contains a longer polyketide sequence than other apratoxins by an acetate group. All members of apratoxins exhibit potent in vitro cytotoxicity against LoVo cell lines (IC50 = 0.38−10.8 nM) and the KB (IC50 = 0.52−21.3 nM) or other cell lines by inducing G1 phase specific cell cycle arrest and apoptosis. Because of their unique scaffolds and interesting biological activities, tremendous efforts have been devoted to the asymmetric synthesis of apratoxins A, C, D, F and corresponding analogues,8 as well as the studies on their mechanism of action9 and biosynthetic pathways.10 Apratoxin E (7),7f which was isolated from Lyngbya bouillonii collected in Guam by the Luesch group, contains a different peptide− polyketide hybrid. The absolute configuration at C30 of

INTRODUCTION Secondary metabolites derived from marine cyanobacteria are a promising class of compounds for drug discovery due to their interesting biological activities, including antifungal, antimicrobial, antimalarial, cytotoxic, and neurotoxic properties.1 Among them, cyanobacterial cyclodepsipeptides, predominantly with structural skeletons as depsipeptides and peptide−polyketide hybrids, have attracted significant attention in recent years.2 Several of them were selected as novel pharmaceuticals and are currently being evaluated in human clinical trials for cancer treatment.3 As most cyanobacterial metabolites are not well studied, further investigation is required to understand their modes of actions.4 For example, lagunamide A5 (1), which was isolated from the marine cyanobacterium Lyngbya majuscula collected in Pulau Hantu Beser, Singapore, displayed potent cytotoxic activity against P388 murine leukemia cell lines (IC50 = 6.4 nM, 20.5 nM, and 24.4 nM, respectively) and selective growth inhibitory activities against a panel of other cancer cell lines, including A549, PC3, HCT8, and SK-OV3 (IC50 = 1.6− 3.8 nM) (Figure 1). Hoiamides A (2) and B (3), which were isolated from an environmental assemblage of the marine cyanobacteria Moorea producens and Phormidium gracile collected in Papua New Guinea,6 showed stimulation of sodium influx in mouse neocortical neurons (EC50 values are 1.7 and 3.9 μM, respectively) and exhibited modest cytotoxicity to cancer cells. © 2017 American Chemical Society

Received: June 27, 2017 Published: September 21, 2017 10830

DOI: 10.1021/acs.joc.7b01598 J. Org. Chem. 2017, 82, 10830−10845

Article

The Journal of Organic Chemistry

Figure 1. Structures of the representative secondary metabolites.

apratoxin E was originally assigned as 30S, which was based on its biosynthetic path. In 2016, we completed the asymmetric synthesis of 30S-7. 8e Due to the complexity in the spectroscopic NMR of the two conformers, we incorrectly claimed our synthetic 30S-7 as the natural product. Right after the publication of our partial work,8e our colleague Li and the Zhang and Luesch group jointly published the revision of its structure from 30S to 30R.8f As a continuation of our interest in developing divergent syntheses of natural products isolated from cyanobacteria and investigating their structure−activity relationships,5d,f,11 we quickly looked into the synthesis of 30R7, which confirmed the revised stereochemistry. Herein we present the effective approach to synthesize the revised apratoxin E (30R-7) and its three non-natural analogues.

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RESULTS AND DISCUSSION First, we aimed to synthesize the proposed apratoxin E (30S-7). Our initial strategy for asymmetric synthesis of 30S-7 is illustrated in Figure 2, with stereoselective synthesis of nonpeptide fragment 8 and effective macrocyclization as our main focus in constructing this target molecule. We plan to use a cross-metathesis (CM)12 reaction to form the double bond between C34 and C35 and explore macrolactamization at two different connection points for the final ring closure. Moreover, the concept of “f rom nature to nature” was applied in our asymmetric synthesis of proposed apratoxin E (30S-7). In other words, the key fragment 9 could be prepared from industrial waste13 10, and another fragment 11 could be derived from glutamic acid. The preparation of nonpeptide fragment 9 is shown in Scheme 1. Chiral lactone 10 was isolated from the industrial wastewater during the degradation of saponin glycosides13 in 22% yield. Treatment of 10 with benzyl chloride (BnCl) and NaOH in toluene under refluxing conditions resulted in the ring opening and simultaneous selective benzylation of the primary alcohol.14 Upon protection of the carboxylic acid, the crude ester 12 was reduced with LiAlH4 and the resulting diol

Figure 2. Our strategy to access proposed apratoxin E (30S-7).

was subjected to oxidative cleavage (NaIO4) to provide the aldehyde. The introduction of the tert-butyl group was achieved by nucleophilic addition with a solution of tert-butylmagnesium chloride, which obviously gave a mixture of two diasteromers (dr = 1:1). This new stereocenter could be enriched through an 10831


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The Journal of Organic Chemistry Scheme 1. Preparation of Fragment 9a

Scheme 2. Preparation of Fragment (S)-11a

a

Reagents and conditions: (a) (1) Boc2O, NaHCO3, H2O/dioxane, 0 °C to rt, overnight; (2) 4-methylmorpholine, ethyl chloroformate, −10 °C, 1 h then NaBH4, THF, rt, 1 h, 69% (two steps); (b) (1) MsCl, TEA, DCM, 0 °C, 40 min, (2) NaH, TrtSH, DMF, 0 °C to rt, overnight, 79% (two steps); (c) (1) TFA, DCM, 0 °C, 30 min, (2) acrylic acid, HATU, DIPEA, DCM, 5 h, 71% (two steps).

thiazoline (4S)-8 in 86% yield. Finally, the deprotection of the allyl group in thiazoline (4S)-8 was achieved by treatment with catalytic amount of Pd(PPh3)4 in N-methylaniline to give the acid (4S)-24 in 88% yield.23 The final assembly to proposed apratoxin E (30S-7) was shown in Scheme 4. Tripeptide 25 was prepared by sequential condensation of N-methylisoleucine allyl ester with N-Boc-Nmethylalanine and N-Fmoc-O-methyltyrosine according to the known method.8e Upon the removal of Fmoc in 25 with Et2NH, the resulting free amine was coupled with carboxylic acid (4S)-24 using pentafluorophenyl diphenylphophinate (FDPP)24 in acetonitrile to afford the amide (30S)-26 in 75% yield. The sequential cleavage of allyl ester by Pd(PPh3)4 in N-methylaniline and removal of the Fmoc protecting group with Et2NH/CH3CN afforded the crude cyclization precursor, which was subjected to macrolactamization (HATU/DIPEA)20 to give proposed apratoxin E (30S-7) in 19% overall isolated yield. In order to improve the yield of final macrolactamization, we turned our attention to the final amidation between the less hindered carboxylic acid and primary amino group, i.e., C27−N (Scheme 5). After the removal of the allyl protection in tripeptide fragment 25 and the N-Fmoc protecting group in nonpeptide fragment (4S)-8, the resulting free carboxylic acid 27 and free amine 28 were coupled in the presence of HATU/ DIPEA to generate 29 in 73% overall yield. Similar sequential cleavage of allyl ester by Pd(PPh3)4 in N-methylaniline and removal of the Fmoc protecting group with Et2NH/CH3CN gave the cyclization precursor, which underwent subsequent macrolactamization using FDPP25 as condensation reagent to afford proposed apratoxin E (30S-7) in 43% overall isolated yield. The product could be further purified by RP C18 HPLC with 80% aqueous CH3CN (Sepax-tech Amethyst C18 semipreparative column, 250 mm × 150 mm, 10 mL/min, refractive index detection) [[α]D23 −150.4 (c 0.24, MeOH), lit.8f [α]D20 −163.4 (c 0.106, MeOH)], to afford >99% purity. Both 1H and 13C NMR spectroscopic data are consistent with those in the literature for the proposed structure.8f After the successful synthesis of proposed apratoxin E (30S7), we turned our attention to the asymmetric synthesis of revised apratoxin E (30R-7) according to the similar synthetic route by using (R)-11 derived from D-glutamate (Scheme 6). It is worth noting that the amide coupling of free acid from (4R)8 and free amine from 25 is very interesting. Although HATU

a

Reagents and conditions: (a) (1) BnCl, NaOH, toluene, reflux, 12 h; (2) MeOH, H2SO4, reflux, 4 h; (b) (1) LiAlH4, THF, 10 h, (2) NaIO4, H2O, 1.5 h, (3) t-BuMgCl, THF, overnight, 47% (five steps); (c) DMP, NaHCO3, DCM, 3 h, 87%; (d) (R)-CBS, BH3·DMS, toluene, −20 °C to +35 °C, 10 h, 72%; (e) (1) TBSOTf, 2,6-lutidine, DCM, 0 °C, 3 h, (2) Pd/C, Pd(OH)2, H2, MeOH, 3 h, 76% (two steps); (f) (1) I2, imidazole, PPh3, DCM, 15 min, (2) CH2CHMgBr, Li2CuCl4, THF, −78 °C to rt, overnight, 84% (two steps).

oxidative and stereoselective reduction process. Thus, compound 13 was oxidized with Dess−Martin periodinane (DMP)15 to give the desired ketone 14, which was then reduced with BH3·DMS and a catalytic amount of Corey’s chiral borane, R-CBS catalyst.16 This sequence led to the enhancement of the desired isomer with syn/anti = 88:12, and both isomers could be separated by silica gel chromatography. The subsequent transformations were straightforward. Protection (TBSOTf, 2,6-lutidine) of the single isomer 15 and subsequent hydrogenation (Pd/C, H2) generated the desired primary alcohol 16 in 76% overall yield. Iodination of the alcohol 16, followed by a copper-catalyzed Grignard coupling reaction17 with vinylmagnesium bromide, successfully led to the olefin 9 in 84% overall yield. The synthesis of another chiral fragment (S)-11 of proposed apratoxin E (30S-7) was described in Scheme 2. Protection (Boc2O) and subsequent reduction18 (NaBH4) of the glutamic acid derivative (S)-17 gave the desired alcohol (S)-18 in 69% overall yield, which was conveniently converted to its sulfide (S)-19 according to the known method19 in 79% yield. Deprotection (TFA) of (S)-19 and subsequent coupling with acrylic acid using HATU20 generated amide (S)-11 in 71% yield. With both fragments 9 and (S)-11 in hand, we began to construct the thiazoline unit (4S)-24 (Scheme 3). (4S)-20 was obtained by CM reaction in 60% yield (E/Z > 99:1). After the benzyl ester was switched to allylic protection through hydrolysis (LiOH) and subsequent alkylation (AllylBr/ K2CO3), the resulting compound (4S)-21 was subjected to a solution of HCl (6 N)/EtOAc to produce the secondary alcohol (4S)-22 in 82% isolated yield, which was coupled with N-Fmoc-proline under Yamaguchi conditions21 to give (4S)-23 in 89% yield. Then, compound (4S)-23 was treated with POPh3/Tf2O22 in CH2Cl2 at 0 °C to form the desired 10832


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The Journal of Organic Chemistry Scheme 3. Preparation of the Nonpeptide Fragment (4S)-24a

Reagents and conditions: (a) Grubbs 2nd, DCM, reflux, 24 h, 60%; (b) (1) LiOH, THF/MeOH/H2O, 0 °C to rt, 7 h, (2) AllylBr, K2CO3, DMSO, rt, 4 h, 84% (two steps); (c) HCl, EtOAc, 0 °C to rt, 3 h, 82%; (d) N-Fmoc-proline, 2,4,6-trichlorobenzoyl chloride, DIPEA, DMAP, toluene, 3 h, 89%; (e) Ph3PO, Tf2O, DCM, 0 °C, 20 mim, 86%; (f) Pd(PPh3)4, N-methylaniline, THF, 1 h, 88%.

a

Scheme 4. Synthesis of Proposed Apratoxin E (30S-7) by Macrolactamization at C6−Na

a

Reagents and conditions: (A) (1) Et2NH, MeCN, 30 min, (2) (4S)-24, FDPP, DIPEA, MeCN, overnight, 75%; (b) (1) Pd(PPh3)4, Nmethylaniline, THF, 30 min, (2) Et2NH, MeCN, 30 min, (3) HATU, DIPEA, DCM, 40 h, 19%.

As shown in Scheme 7, compounds (S)-30/(R)-30 were prepared from glutamic acid derivatives (S)-18/(R)-18. After the protection of (S)-18/(R)-18 as corresponding siloxanes (S)-32/(R)-32 in 84% yield, the removal of N-Boc and subsequent amidation with acrylyl chloride resulted in (S)-30/ (R)-30 in 78% yield. Then the benzyl esters were hydrolyzed to give the corresponding carboxylic acids (S)-33/(R)-33. With fragments (S)-33/(R)-33, tripeptide 25, and compound 9 in hand, we focused on the above convergent assembly strategy for divergent synthesis of apratoxin E and its analogues. As shown in Scheme 8, desilylation of compound 9 and subsequent coupling with N-Fmoc-proline under Yamaguchi conditions afforded 31 in 80% overall yield. Amidation (HATU/DIPEA) with free amine of 25, which was obtained under Et2NH/CH3CN conditions, was conducted to give compound 34 in 73% yield. Further couplings with the acids (S)-33/(R)-33 using FDPP, upon the treatment of 34 with Et2NH/CH3CN, produced (30S)-35 (75%) and (30R)-35 (77%), respectively. RCM macrocyclization28 of (30S)-35/ (30R)-35 successfully produced the desired (30S)-36/(30R)36 (70% for (30S)-36, 67% for (30R)-36) with high selectivity (E:Z > 99:1). With the macrocyclic structure in hand, the formation of the oxazoline ring was straightforward. The removal of the TBS group in 36 gave the alcohols (30S)-37 (82%) and (30R)-37 (76%), respectively. Finally, the treatment of 37 with DAST29 in CH2Cl2 at −78 °C led to the desired oxoapratoxin E ((30S)-38) [α]D18 −64 (c 0.15, CHCl3), ((30R)-38) [α]D25 −53.2 (c 0.25, CHCl3), in good yields (77%

could effectively promote the amidation, compound (30R)-26 was observed to be relatively unstable during the repeated purification by flash chromatography on silica gel, and partial decomposition was also observed in CDCl3 solution for 2 days. Therefore, the crude (30R)-26 from FDPP coupling was quickly purified by flash chromatography on short silica gel, and the resulted pure product was treated sequentially with Pd(PPh3)4/N-methylaniline and Et2NH/CH3CN for the removal of allyl ester and Fmoc, respectively. The resulting crude cyclization precursor was quickly subjected to macrolactamization (HATU/DIPEA) to provide revised apratoxin E (30R-7) [[α]D17 = −59 (c 0.25, MeOH), lit.7f [α]D20 = −69 (c 0.12, MeOH); lit.8f [α]D20 = −68 (c 0.182, MeOH)] in 21% overall isolated yield. The spectroscopic and physical data of the synthetic (30R)-apratoxin E (30R-7) were identical to the reported data.7f,8f Although the originally proposed and revised apratoxin (30S7, 30R-7) were successfully synthesized, we proposed an alternative convergent strategy26 using a ring-closure metathesis (RCM)27 reaction to form the double bond between C34 and C35 in the final stage as macrocyclization (Figure 3). This new approach assembles fragments 25, (S)-30/(R)-30, and 31, allowing for the synthesis of diverse new apratoxin E analogues which are not quickly accessible through traditional step-bystep methods.7b More importantly, the key (S)-30/(R)-30 and 31 fragments are simple chemical subunits which could be prepared on the basis of our concept of “f rom nature to nature”. 10833


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The Journal of Organic Chemistry Scheme 5. Synthesis of Proposed Apratoxin E (30S-7) by Macrolactamization at C27−Na

a

Reagents and conditions: (a) Pd(PPh3)4, N-methylaniline, THF, 1 h; (b) Et2NH, MeCN, 30 min; (c) HATU, DIPEA, DCM, overnight, 73%; (d) (1) Pd(PPh3)4, N-methylaniline, THF, 30 min, (2) Et2NH, MeCN, 30 min, (3) FDPP, DIPEA, MeCN, 40 h, 43%.

Scheme 6. Synthesis of Revised Apratoxin E (30R-7) by Macrolactamization at C6−Na

a

Reagents and conditions: (a) (1) Pd(PPh3)4, N-methylaniline, THF, 1 h, (2) 25, Et2NH, MeCN, 30 min, (3) FDPP, DIPEA, MeCN, overnight, 72%; (b) (1) Pd(PPh3)4, N-methylaniline, THF, 30 min, (2) Et2NH, MeCN, 30 min, (3) HATU, DIPEA, DCM, 40 h, 21%.

for (30S)-38, 81% for (30R)-38, respectively). The structures of oxoapratoxin E ((30S)-38 and (30R)-38) were unambiguously confirmed by two-dimensional NMR and the spectroscopic data of 1H and 13C NMR data. In order to effectively synthesize apratoxin E and its analogues through the above convergent assembly strategy, we prepared the thiazoline fragments (S)-39/(R)-39 (Scheme 9). Upon hydrolysis (LiOH) of (S)-11/(R)-11 and subsequent alkylation (AllylBr/K2CO3), the benzyl ester was switched to allylic ester (S)-40/(R)-40 in 72% yield. Then, compounds (S)-40/(R)-40 were treated with Ph3PO/Tf2O in CH2Cl2 at 0 °C to form the desired thiazolines (S)-39/(R)-39 in 56% yield.

After the Fmoc protecting group of 34 and the Allyl protecting group of (S)-39/(R)-39 were removed, the resulted crude amine and acid were subjected to amidation (FDPP/ DIPEA) to give compounds (30S)-42/(30R)-42 in 57% and 52% yields, respectively (Scheme 10). Finally, the RCM macrocyclization28 afforded the desired revised apratoxin E (30R-7) [α]D17 = −59 (c 0.25, MeOH) [lit.7f [α]D20 = −69 (c 0.12, MeOH); lit.8f [α]D20 = −68 (c 0.12, MeOH)] and originally proposed apratoxin E (30S-7) [[α]D23 = −150.4 (c 0.24, MeOH); lit.8f [α]D20 = −163.4 (c 0.106, MeOH)] with high selectivity (E/Z > 99:1) and in moderate yields (38% for 30S-7, 41% for 30R-7). 10834


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laboratory to synthesize other analogues of apratoxin E. The chemistry and related biological data will be published in due course.

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EXPERIMENTAL SECTION

General Methods. THF was distilled from sodium/benzophenone. Reactions were monitored by thin-layer chromatography (TLC) on glass plates coated with silica gel with fluorescent indicator. Flash chromatography was performed on silica gel (300−400) with petroleum/EtOAc as eluent. Optical rotations were measured on a polarimeter with a sodium lamp. HRMS spectra were measured on a LCMS-IT-TOF or LTQ-Orbitrap-XL apparatus. IR spectra were recorded using film on a Fourier transform infrared spectrometer. NMR spectra were recorded at 400, 500 or 600 MHz, and chemical shifts are reported in δ (ppm) referenced to an internal TMS standard for 1H NMR and CDCl3 (77.16 ppm) for 13C NMR. Methyl (2S,4R)-5-(Benzyloxy)-2-hydroxy-4-methylpentanoate 12. The lactone 10 (5.00 g, 38.43 mmol) was dissolved in toluene (60 mL), and then NaOH (6.15 g, 153.72 mmol) and BnCl (8.80 mL, 76.86 mmol) were added. After the mixture was refluxed for 12 h, water was added. Extraction were performed with Et2O three times, and the aqueous phase was acidified with hydrochloric acid. The resulting mixture was extracted with EtOAc (60 mL × 3), and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the crude acid without further purification. The above crude acid was dissolved in MeOH (60 mL), and then H2SO4 (1.00 mL, 98%) was carefully added dropwise. After the mixture was refluxed for 4 h, the reaction was quenched with water. The mixture was extracted with EtOAc (50 mL × 3), and the combined organic layers were washed with brine. The product was dried, filtrated, and concentrated to give the crude ester without further purification: [α]D23 = +6.2 (c 1.00, CHCl3); IR (film) νmax 3450, 2958, 2851, 2359, 1737, 1458, 1211, 1092, 740, 701 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.17−7.05 (m, 5H), 4.35−4.27 (m, 2H), 4.14−4.03 (m, 1H), 3.57 (s, 3H), 3.17−3.15 (m, 1H), 3.15−3.12 (m, 1H), 1.97−1.85 (m, 1H), 1.60−1.42 (m, 2H), 0.82−0.78 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 175.8, 138.2, 133.6, 130.2, 128.4, 127.6, 75.9, 73.1, 69.3, 52.4, 39.3, 30.6, 16.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H20O4H 253.1434, found 253.1434. (R)-6-(Benzyloxy)-2,2,5-trimethylhexan-3-one 14. A solution of the above ester 12 in THF (30 mL) was carefully dropped onto a suspension of LAH (1.75 g, 46.15 mmol) in THF (30 mL). After being stirred for 10 h, the resulting mixture was carefully quenched with water (0.5 mL) and filtrated. The filtrate was concentrated to give the crude diol without further purification. The above diol was dissolved in water (50 mL), and then the mixture was acidified with hydrochloric acid to pH = 6 at 0 °C. NaIO4 (9.87 g, 46.15 mmol) was added in one portion and the resulting mixture stirred for 1.5 h. The mixture was extracted with EtOAc (30 mL × 3), and the combined organic layers were washed with brine. The product was dried, filtrated, and concentrated to give the aldehyde without further purification. The above crude aldehyde was dissolved in dry THF (60 mL), the mixture was cooled to 0 °C, and then a solution of tertbutylmagnesium chloride (1 M in THF, 58.0 mL, 58.00 mmol) was slowly added dropwise. After the mixture was stirred for overnight, the reaction was quenched with an aqueous solution of saturated NH4Cl, and the resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 10:1) to give 13 (4.52 g, 47%, five steps) as a colorless oil. The above alcohol (4.17 g, 16.65 mmol) was dissolved in cooled DCM (60 mL, 0 °C), and then DMP (10.60 g, 24.98 mmol) was added in several portions. After being stirred for 3 h, the mixture was carefully quenched with a solution of saturated aqueous NaHCO3 and solid Na2S2O3. The resulting mixture was extracted with DCM (30 mL × 3), and the combined organic layers were washed with brine, dried, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 20:1) to give 14 (3.60 g, 87%) as a colorless oil: [α]D23 = +6.7 (c 4.00, CHCl3); IR (film) νmax 2966,

Figure 3. Our convergent strategy to access revised apratoxin E and its analogues.

Scheme 7. Synthesis of 33a

a

Reagents and conditions: (a) TBSCl, imid. DMAP, DMF, 12 h, 84%; (b) (1) TMSOTf, 2,6-lutidine, DCM, 0 °C, 5 h, (2) acryl chloride, TEA, DCM, 0 °C, 8 h, 78% (two steps); (c) LiOH, THF/MeOH/ H2O, 0 °C to rt, 7 h, 77%.

The structures of originally proposed apratoxin E (30S-7) and revised apratoxin E (30R-7) were unambiguously confirmed by two-dimensional NMR, and all of the physical data of the originally proposed and revised apratoxin E were in excellent agreement with those reported for the originally proposed apratoxin E (30S-7)8f and revised apratoxin E.7f,8f In analytical reversed-phase HPLC, the isolated apratoxin E provided by Luesch and our synthetic (30R)-apratoxin E 30R-7 were identical by retention time and coeluted under two different sets of conditions (see the Supporting Information).

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CONCLUSION In summary, our concept of “f rom nature to nature” was successfully applied to synthesize revised apratoxin E (30R-7) and its three analogues (30S-7, 30R-38, and 30S-38). It is worth mentioning that the convergent assembly process was an effective approach to divergently synthesize revised apratoxin E (30R-7) and its three analogues. Moreover, ring-closing metathesis (RCM) proved to be an alternative approach for the macrocyclization of analogues of apratoxin E. Further efforts on the extension of this strategy are ongoing in our 10835


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The Journal of Organic Chemistry Scheme 8. Synthesis of the Oxoapratoxin E (30S)-38/(30R)-38a

a Reagents and conditions: (a) (1) TBAF, THF, 2 h, (2) N-Fmoc-proline, 2,4,6-trichlorobenzoyl chloride, DIPEA, DMAP, toluene, 3 h, 80%, two steps; (b) (1) Et2NH, MeCN, 30 min, (2) 25, Pd(PPh3)4, N-methylaniline, THF, 1 h then HATU, DIPEA, DCM, overnight, 73%; (c) (1) Et2NH, MeCN, 30 min, (2) (S)-33 or (R)-33, FDPP, DIPEA, MeCN, overnight, 75% for (30S)-35, 77% for (30R)-35; (d) Grubbs 2nd, DCM, reflux, 24 h, 70% for (30S)-36, 67% for (30R)-36; (e) TBAF, THF, 30 min, 82% for (30S)-37, 76% for (30R)-37; (f) DAST, DCM, −78 °C, 2 h, 77% for (30S)38, 81% for (30R)-38.

Scheme 9. Preparation of Fragment (S)-41/(R)-41a

(3S,5R)-6-(Benzyloxy)-2,2,5-trimethylhexan-3-ol 15. A solution of (R)-CBS (1 M in toluene, 1.23 mL, 1.23 mmol) was dissolved in dry toluene (15 mL) and cooled to −20 °C, and then BH3·DMS (0.23 mL, 2.43 mmol) was slowly added dropwise. After the mixture was stirred for 30 min at the same temperature, a solution of 14 (0.61 g, 2.44 mmol) in toluene (4 mL) was slowly added dropwise. After being stirred for 10 h at −20 to 35 °C, the mixture was concentrated and diluted with MeOH. The resulting mixture was concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 10:1) to give 15 (0.44 g, 72%) as a colorless oil: [α]D23 = −26.2 (c 1.00, CHCl3); IR (film) νmax 3447, 2959, 2093, 1636, 1085, 697, cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.37−7.24 (m, 5H), 4.54 (brs, 2H), 3.41−3.35 (m, 1H), 3.30−3.25 (m, 2H), 2.52 (brs, 1H), 1.97 (ddd, J = 13.6, 12.8, 6.4 Hz, 1H), 1.42−1.36 (m, 2H), 0.95−0.91 (m, 3H), 0.90 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 137.6, 127.8, 127.1, 127.0, 77.4, 75.9, 72.4, 36.2, 34.2, 31.0, 25.2, 17.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H26O2H 251.2006, found 251.2005. (2R,4S)-4-((tert-Butyldimethylsilyl)oxy)-2,5,5-trimethylhexan-1-ol 16. A cooled (0 °C) DCM (30 mL) solution of 15 (1.62 g, 6.47 mmol) and 2,6-lutidine (1.13 mL, 9.72 mmol) was carefully treated with TBSOTf (2.28 mL, 9.72 mmol) for 3 h. Then the mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with DCM (15 mL × 3). The combined organic layers were washed with brine, dried, filtrated, and concentrated to give the crude product without further purification. The above product, 10% Pd/C (150 mg),

Reagents and conditions: (a) (1) LiOH, THF/MeOH/H2O, 0 °C to rt, 7 h; (2) AllylBr, K2CO3, DMSO, rt, 4 h, 72%, two steps; (b) Ph3PO, Tf2O, DCM, 0 °C, 20 mim, 56%; (c) Pd(PPh3)4, Nmethylaniline, THF, 30 min, 87%. a

1705, 1477, 1454, 1365, 1097, 738, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38−7.24 (m, 5H), 4.49 (brs, 2H), 3.37−3.26 (m, 2H), 2.65 (dd, J = 16.8, 4.8 Hz, 1H), 2.46−2.30 (m, 2H), 1.12 (s, 9H), 0.94−0.92 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 214.6, 138.0, 127.7, 126.9, 126.8, 74.3, 72.2, 43.6, 39.8, 28.6, 25.7, 16.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H24O2H 249.1849, found 249.1849. 10836


Article

The Journal of Organic Chemistry Scheme 10. Synthesis of Proposed Apratoxin E (30S-7) and Revised Apratoxin E (30R-7)a

a Reagents and conditions: (a) (1) Et2NH, MeCN, 30 min; (2) (S)-41 or (R)-41, FDPP, DIPEA, MeCN, overnight, 57% for (30S)-42, 52% for (30R)-42; (b) Grubbs 2nd, DCM, reflux, 24 h, 38% for the originally proposed apratoxin E (30S-7), 41% for the revised apratoxin E (30R-7).

and Pd(OH)2 (150 mg) were stirred in MeOH (70 mL) for 3 h under H2 atmosphere. Then the mixture was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 30:1) to give 16 (1.35 g, 76%, two steps) as a colorless oil: [α]D23 = +25.2 (c 2.00, CHCl3); IR (film) νmax 2345, 2082, 1635, 1249, 1084, 1031, 772 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.50−3.37 (m, 2H), 3.32 (dd, J = 8.4, 1.2 Hz, 1H), 1.84− 1.72 (m, 1H), 1.46−1.35 (m, 2H), 1.25−1.17 (m, 1H), 0.93−0.87 (m, 12H), 0.85 (s, 9H), 0.05 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 77.6, 68.7, 36.2, 35.1, 32.0, 25.8, 25.6, 17.9, 15.6, −3.9, −4.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H34O2SiH 275.2401, found 275.2402. tert-Butyldimethyl((3S,5S)-2,2,5-trimethyloct-7-en-3-yloxy)silane 9. To a stirred solution of 16 (1.08 g, 3.93 mmol) in DCM (20 mL) were added PPh3 (1.34 g, 5.11 mmol) and imidazole (0.54 g, 7.86 mmol), and then I2 (1.30 g, 5.11 mmol) was added in several portions. After the mixture was stirred for 15 min, the reaction was quenched with a saturated aqueous solution of Na2SO3 and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried, filtrated, and concentrated to give the crude product without further purification. The above crude compound was dissolved in dry THF (20 mL) and cooled to −78 °C. Once a solution of vinylmagnesium bromide (0.7 M in THF, 28.07 mL, 19.65 mmol) was added dropwise, a solution of Li2CuCl4 (0.1 M in THF, 3.90 mL, 0.39 mmol) was slowly added dropwise. After being stirred for overnight at −78 °C to room temperature, the mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (PE) to give 9 (0.94 g, 84%, two steps) as a colorless oil: [α]D25 = −14.8 (c 1.00, CHCl3); IR (film) νmax 3493, 2946, 1742, 1581, 1519, 1453, 1411, 1312, 1216, 1172, 1001, 767 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.88−5.74 (m, 1H), 5.08−5.01 (m, 2H), 3.36 (dd, J = 7.6, 2.8 Hz, 1H), 2.26−2.17 (m, 1H), 1.84− 1.65 (m, 2H), 1.49 (ddd, J = 14.4, 9.2, 2.8 Hz, 1H), 1.23 (ddd, J = 14.4, 7.6, 4.4 Hz, 1H) 0.96−0.84 (m, 21H), 0.09 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 137.1, 116.0, 78.5, 40.9, 40.4, 35.8, 29.7, 26.4, 26.2, 20.7, 18.5, −3.4, −3.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H36OSiH 285.2608, found 285.2609. General Procedure for the Synthesis of (S)-18 and (R)-18. To a stirred solution of (S/R)-2-amino-5-(benzyloxy)-5-oxopentanoic acid (S)-17/(R)-17 (5.00 g, 21.08 mmol) in H2O/dioxane (30 mL/30 mL) were added NaHCO3 (1.99 g, 23.64 mmol) and Boc2O (5.52 g, 25.30 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for overnight. After concentration, the aqueous phase was acidified with hydrochloric acid, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were dried, filtrated, and concentrated to give the crud acid as a colorless oil without further purification. The above crude acid was dissolved in THF (100 mL) at room temperature, and then 4methylmorpholine (2.32 mL, 21.08 mmol) was added dropwise. After being stirred for 10 min, the mixture was cooled to −10 °C, and ethyl chloroformate (2.42 mL, 25.30 mmol) was added dropwise. The

reaction mixture was stirred for another 1 h at the same temperature and filtrated. Then a solution of NaBH4 (2.39 g, 63.24 mmol) in H2O (20 mL) was added dropwise to the filtrate and stirred for 1 h at room temperature. The mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 2:1) to give the desired product: white solid (4.71 g, 69%, two steps); mp 76−77 °C (lit.18 mp 75−76 °C); [α]D25 = −10.3 (c 1.00, CHCl3) for (S)-18 [lit.18 [α]D25 = −10.0 (c 1.00, MeOH)]; [α]D17 = +11.2 (c 2.00, CHCl3) for (R)-18; IR (film) νmax 3346, 2985, 2947, 1727, 1682, 1523, 1451, 1368, 1298, 1167, 1070, 1021, 748, 697 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.42−7.33 (m, 5H), 5.15 (s, 2H), 4.86 (d, J = 6.8 Hz, 1H), 3.71−3.62 (m, 2H), 3.61−3,54 (m, 1H), 2.60 (brs, 1H), 2.52−2.45 (m, 2H), 1.99−1.88 (m, 1H), 1.86−1.75 (m, 1H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.4, 156.1, 135.6, 128.4, 128.2, 128.1, 79.5, 66.4, 65.0, 52.1, 30.7, 28.2, 26.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H25NO5Na 346.1625, found 346.1613. General Procedure for the Synthesis of (S)-19 and (R)-19. Compound (S)-18/(R)-18 (2.50 g, 7.73 mmol) and TEA (2.20 mL, 15.46 mmol) were stirred in dry DCM (30 mL) for 10 min at 0 °C. MsCl (0.90 mL, 11.60 mmol) was added dropwise, and the resulting mixture was stirred for another 30 min. Then the reaction was quenched with a saturated aqueous solution of NH4Cl and then extracted with DCM (30 mL × 3). The organic layers were washed with brine, dried over MgSO4, filtrated, and concentrated to give the intermediate without further purification. A suspension of NaH (60%) (0.35 g, 9.26 mmol) in DMF (10 mL) was treated with a solution of TrtSH (2.35 g, 8.50 mmol) in DMF (5 mL) at 0 °C. After the mixture was stirred for 45 min, a solution of the above intermediate in DMF (15 mL) was slowly added dropwise, and the resulting mixture was stirred overnight at 0 °C to room temperature. The resulting mixture was quenched with water and diluted with EtOAc. The mixture was separated, the aqueous layer was extracted with EtOAc (30 mL × 3), and the combined organic layers were washed with water and brine, respectively. The product was dried, filtrated, and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 10:1) to give the desired product. Benzyl (S/R)-4-((tert-butoxycarbonyl)amino)-5-(tritylthio)pentanoate (S)-19/ (R)-19: white amorphous solid (3.55 g, 79%); [α]D25 = −10.5 (c 1.00, CHCl3); [α]D17 = +9.7 (c 2.00, CHCl3); IR (film) νmax 3364, 3058, 3031, 2924, 2851, 1713, 1494, 1366, 1247, 1169, 1028 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.45−7.20 (m, 20H), 5.15−5.05 (m, 2H), 4.49 (d, J = 8.8 Hz, 1H), 3.75−3.60 (m, 1H), 2.38−2.33 (m, 1H), 2.32−2.27 (m, 2H), 1.85−1.65 (m, 2H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.8, 155.0, 144.4, 135.7, 129.4, 128.4, 128.1, 127.8, 126.6, 79.2, 66.5, 66.2, 49.2, 37.0, 30.8, 29.4, 28.2; HRMS (ESI-TOF) m/z [M + Na+] calcd for C36H39NO4SNa 604.2492, found 604.2470. General Procedure for the Synthesis of (S)-11/(R)-11. A cooled (0 °C) solution of (S)-19/ (R)-19 (2.36 g, 4.05 mmol) in DCM (7 mL) was treated with TFA (7 mL) for 30 min, and then the 10837


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chromatography on silica gel (PE/EA = 6:1) to give the desired product. Allyl (S)-4-((5S,7S,E)-7-((tert-Butyldimethylsilyl)oxy)-5,8,8-trimethylnon-2-enamido)-5-(tritylthio)pentanoate (4S)-21: white amorphous solid (747 mg, 84%, two steps); [α]D25 = −22.4 (c 1.00, CHCl3); IR (film) νmax 3059, 2956, 2857, 1712, 1662, 1493, 1362, 1256, 1084, 1032, 832, 758 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.46−7.41 (m, 6H), 7.35−7.20 (m, 9H), 6.81 (ddd, J = 15.2, 8.0, 6.8 Hz, 1H), 5.96−5.85 (m, 1H), 5.70 (d, J = 15.2 Hz, 1H), 5.49 (d, J = 8.8 Hz, 1H), 5.35−5.28 (m, 1H), 5.27−5.22 (m, 1H), 4.58−4.52 (m, 2H), 4.15−4.05 (m, 1H), 3.35 (dd, J = 7.6, 2.8 Hz, 1H), 2.52−2.40 (m, 2H), 2.34−2.23 (m, 2H), 1.95−1.75 (m, 4H), 1.54−1.45 (m, 1H), 1.34−1.25 (m, 2H), 0.97−0.93 (m, 12H), 0.89 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 173.0, 165.2, 144.6, 143.6, 132.1, 129.6, 128.0, 126.8, 125.0, 118.3, 78.4, 66.8, 65.2, 48.1, 41.2, 38.7, 36.7, 31.0, 29.7, 29.1, 26.4, 26.2, 21.0, 18.5, −3.3, −3.8; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C45H63NO4SSiNa 764.4139, found 764.4127. Allyl (R)-4-((5S,7S,E)-7-((tert-Butyldimethylsilyl)oxy)-5,8,8-trimethylnon-2-enamido)-5-(tritylthio)pentanoate (4R)-21: white amorphous solid (791 mg, 89%, two steps); [α]D16 = −3.8 (c 3.00, CHCl3); IR (film) νmax 3059, 2956, 2857, 1712, 1662, 1493, 1362, 1256, 1084, 1032, 832, 758 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.42−7.37 (m, 6H), 7.30−7.17 (m, 9H), 6.81−6.72 (m, 1H), 5.93−5.81 (m, 1H), 5.65 (d, J = 15.2 Hz, 1H), 5.47 (d, J = 8.4 Hz, 1H), 5.32−5.19 (m, 2H), 4.56−4.50 (m, 2H), 4.10−4.02 (m, 1H), 3.32−3.28 (m, 1H), 2.47−2.35 (m, 2H), 2.27−2.20 (m, 2H), 1.85−1.74 (m, 4H), 1.48− 1.41 (m, 1H), 1.29−1.23 (m, 1H), 0.93−0.91 (m, 3H), 0.89 (s, 9H), 0.84 (s, 9H), 0.05 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 172.4, 164.6, 143.9, 143.0, 131.4, 128.9, 127.3, 126.2, 124.3, 117.7, 77.8, 66.1, 64.6, 47.5, 40.6, 38.1, 36.1, 35.2, 30.3, 29.0, 25.8, 25.6, 20.4, 17.9, −3.9, −4.4; HRMS (ESI-Orbitrap) m/z [M + H] + calcd for C45H63NO4SSiH 742.4320, found 742.4320. General Procedure for the Synthesis of (4S)-22 and (4R)-22. Compound (4S)-21/(4R)-21 (747 mg, 1.01 mmol) was stirred in EtOAc (6 mL) at 0 °C, then hydrochloric acid (6 N, 4 mL) was dropped, and the reaction was stirred for 3 h at 0 °C to room temperature. The resulting mixture was extracted with EtOAc (10 mL × 3), and the combined organic layers were washed with a saturated aqueous solution of NaHCO3 and brine, respectively. The mixture was dried over MgSO4, filtrated, and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 2:1) to give the desired product. Allyl (S)-4-((5S,7S,E)-7-hydroxy-5,8,8-trimethylnon-2-enamido)-5(tritylthio)pentanoate (4S)-22: white amorphous solid (521 mg, 82%); [α]D25 = −27.7 (c 1.00, CHCl3); IR (film) νmax 3391, 3059, 2955, 2869, 1708, 1660, 1626, 1493, 1448, 1256, 1083, 989, 756 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.45−7.39 (m, 6H), 7.33−7.27 (m, 6H), 7.26−7.20 (m, 3H), 6.86−6.77 (m, 1H), 5.95−5.84 (m, 1H), 5.70 (d, J = 15.2 Hz, 1H), 5.49 (d, J = 8.8 Hz, 1H), 5.33−5.27 (m, 1H), 5.26−5.21 (m, 1H), 4.56−4.52 (m, 2H), 4.14−4.03 (m, 1H), 3.35−3.28 (m, 1H), 2.50−2.35 (m, 3H), 2.32−2.20 (m, 2H), 2.05− 1.95 (m, 1H), 1.83−1.73 (m, 2H), 1.48−1.39 (m, 2H), 1.32−1.22 (m, 2H), 1.02−0.98 (m, 3H), 0.91 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.9, 165.1, 144.4, 143.5, 131.9, 129.4, 127.8, 126.7, 124.7, 118.2, 66.6, 65.1, 47.9, 38.4, 37.9, 36.6, 34.9, 30.8, 29.6, 28.9, 25.5, 20.9, 20.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C39H49NO4SNa 650.3275, found 650.3257. Allyl (R)-4-((5S,7S,E)-7-hydroxy-5,8,8-trimethylnon-2-enamido)5-(tritylthio)pentanoate (4R)-22: white amorphous solid (521 mg, 82%); [α]D16 = −8.0 (c 3.00, CHCl3); IR (film) νmax 3391, 3059, 2955, 2869, 1708, 1660, 1626, 1493, 1448, 1256, 1083, 989, 756 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.42−7.36 (m, 6H), 7.29−7.23 (m, 6H), 7.23−7.17 (m, 3H), 6.79 (ddd, J = 15.2, 7.6, 6.8 Hz, 1H), 5.93−5.82 (m, 1H), 5.68 (d, J = 15.6 Hz, 1H), 5.56 (d, J = 8.8 Hz, 1H), 5.33− 5.18 (m, 2H), 4.56−4.50 (m, 2H), 4.07−3.99 (m, 1H), 3.29 (d, J = 10.4 Hz, 1H), 2.45−2.36 (m, 2H), 2.35−2.30 (m, 1H), 2.28−2.20 (m, 2H), 2.02−1.94 (m, 1H), 1.93−1.84 (m, 1H), 1.78−1.72 (m, 2H), 1.45−1.37 (m, 1H), 1.30−1.23 (m, 1H), 0.99−0.95 (m, 3H), 0.88 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 173.1, 165.4, 144.7, 143.7,

mixture was concentrated under reduced pressure. The residue was dissolved in dry DCM (15 mL), and HATU (2.31 g, 6.08 mmol), DIPEA (2.10 mL, 12.15 mmol), and acrylic acid (0.33 mL, 4.86 mmol) were added under N2 atmosphere. After the mixture was stirred for 5 h at room temperature, the reaction was quenched with a saturated aqueous solution of NH4Cl and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 3:1) to give the desired product. Benzyl (S/R)-4-Acrylamido-5-(tritylthio)pentanoate (S)-11/(R)-11: white amorphous solid (1.53 g, 71%); [α]D25 = −23.5 (c 1.00, CHCl3); [α]D17 = +23.7 (c 1.00, CHCl3); IR (film) νmax 3272, 3059, 3031, 2953, 1735, 1656, 1627, 1540, 1490, 1243, 1181, 983 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.47−7.21 (m, 20H), 6.27 (dd, J = 17.2, 1.6 Hz, 1H), 5.99 (dd, J = 17.2, 10.4 Hz, 1H), 5.79 (d, J = 8.8 Hz, 1H), 5.64 (dd, J = 10.4, 1.2 Hz, 1H), 5.10 (s, 2H), 4.16−4.05 (m, 1H), 2.50 (dd, J = 12.4, 5.6 Hz, 1H), 3.67 (dd, J = 12.4, 5.2 Hz, 1H), 2.39−2.25 (m, 2H), 1.90−1.77 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 173.2, 165.0, 144.6, 135.8, 130.8, 130.2, 129.6, 128.6, 128.3, 128.0, 127.1, 126.9, 126.7, 66.8, 66.5, 48.3, 36.6, 31.0, 29.0; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C34H33NO3SNa 558.2073, found 558.2053. General Procedure for the Synthesis of (4S)-20 and (4R)-20. Compound (S)-11/(R)-11 (1.20 g, 2.24 mmol), compound 10 (637 mg, 2.24 mmol), and Grubbs second (cat.) were refluxed in DCM (80 mL) under Ar atmosphere for 24 h to give crude product, which was purified by flash chromatography on silica gel (PE/EA = 8:1) to give the desired product. Benzyl (S)-4-((5S,7S,E)-7-((tert-Butyldimethylsilyl)oxy)-5,8,8-trimethylnon-2-enamido)-5-(tritylthio)pentanoate (4S)-20: white amorphous solid (1.06 g, 60%, E/Z > 99:1); [α]D25 = −19.0 (c 1.00, CHCl3); IR (film) νmax 3272, 3031, 3060, 2926, 2855, 1738, 1667, 1630, 1539, 1445, 1361, 1257, 1081, 1031 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.46−7.20 (m, 20H), 6.87−6.78 (m, 1H), 5.69 (d, J = 15.2 Hz, 1H), 5.51 (d, J = 8.8 Hz, 1H), 5.17−5.08 (m, 2H), 4.18−4.06 (m, 1H), 3.36 (dd, J = 7.2, 2.4 Hz, 1H), 2.52−2.41 (m, 2H), 2.40−2.28 (m, 3H), 1.95−1.77 (m, 4H), 1.55−1.45 (m, 1H), 1.35−1.30 (m, 1H), 0.98 (s, 3H), 0.95 (s, 9H), 0.90 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 173.2, 165.2, 144.6, 143.6, 135.9, 129.6, 128.6, 128.3, 128.2, 128.0, 126.8, 125.0, 78.5, 66.8, 66.4, 48.1, 41.2, 38.7, 36.7, 35.9, 31.1, 29.7, 29.1, 26.4, 26.2, 21.0, 18.5, −3.2, −3.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C49H65NO4SSiNa 814.4296, found 814.4290. Benzyl (R)-4-((5S,7S,E)-7-((tert-butyldimethylsilyl)oxy)-5,8,8-trimethylnon-2-enamido)-5-(tritylthio)pentanoate (4R)-20: white amorphous solid (0.99 g, 56%, E/Z > 99:1); [α]D16 = −1.3 (c 5.00, CHCl3); IR (film) νmax 3272, 3031, 3060, 2926, 2855, 1738, 1667, 1630, 1539, 1445, 1361, 1257, 1081, 1031 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.40−7.16 (m, 20H), 6.81−6.73 (m, 1H), 5.63 (d, J = 15.2 Hz, 1H), 5.47 (d, J = 8.8 Hz, 1H), 5.10−5.03 (m, 2H), 4.10−4.01 (m, 1H), 3.30 (dd, J = 7.2, 2.4 Hz, 1H), 2.45−2.34 (m, 2H), 2.33−2.24 (m, 3H), 1.84−1.72 (m, 4H), 1.45−1.42 (m, 1H), 1.26−1.22 (m, 1H), 0.93−0.92 (m, 3H), 0.89 (s, 9H), 0.84 (s, 9H), 0.05 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 173.3, 165.3, 144.7, 143.7, 135.9, 129.7, 128.6, 128.3, 128.3, 128.1, 126.9, 125.0, 78.5, 66.9, 66.5, 48.2, 41.3, 38.8, 36.8, 35.9, 31.1, 29.8, 29.2, 26.5, 26.3, 21.1, 18.6, −3.2, −3.7; HRMS (ESIOrbitrap) m/z [M + H]+ calcd for C49H65NO4SSiH 792.4476, found 792.4477. General Procedure for the Synthesis of (4S)-21 and (4R)-21. Compound (4S)-20/(4R)-20 (0.95 g, 1.20 mmol) was dissolved in a mixture of THF, MeOH, and H2O (12 mL v/v/v = 1:1:1), and then LiOH·H2O (75 mg, 1.80 mmol) was added in one portion. After being stirred for 7 h, the mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over MgSO4, filtrated, and concentrated. The residue was dissolved in DMSO (4 mL), and K2CO3 (332 mg, 2.40 mmol) and AllylBr (0.13 mL, 1.80 mmol) was added. After being stirred for 4 h, the reaction was diluted with water and extracted with EtOAc (25 mL × 3). The combined organic layers were washed with water and brine, respectively, dried over MgSO4, filtrated, and concentrated. The residue was purified by flash 10838


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1-((9H-Fluoren-9-yl)methyl) 2-((3S,5S,E)-8-((S)-4-(3-(allyloxy)-3oxopropyl)-4,5-dihydrothiazol-2-yl)-2,2,5-trimethyloct-7-en-3-yl)(S)-pyrrolidine 1,2-dicarboxylate (4S)-8. White amorphous solid (265 mg, 86%). [α]D25 = −102.7 (c 1.00, CHCl3); IR (film) νmax 3018, 2961, 1706, 1580, 1419, 1357, 1245, 1217, 1177, 1122, 990 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.81−7.76 (m, 2H), 7.68−7.64 (m, 1.6H), 7.60−7.57 (m, 0.4H), 7.45−7.38 (m, 2H), 7.37−7.30 (m, 2H), 6.37−6.25 (m, 1.6H), 6.21−6.13 (m, 0.4H), 5.99−5.87 (m, 1H), 5.37−5.30 (m, 1H), 5.27−5.22 (m, 1H), 4.94− 4.86 (m, 1H), 4.63−4.58 (m, 2H), 4.56−4.37 (m, 3.6H), 4.32−4.27 (m, 0.6H), 4.24−4.16 (m, 0.8H), 3.77−3.65 (m, 1H), 3.63−3.55 (m, 1H), 3.37−3.30 (m, 0.4H), 3.27−3.21 (m, 0.6H), 2.92−2.85 (m, 0.4H), 2.80−2.74 (m, 0.6H), 2.63−2.46 (m, 2.6H), 2.40−2.25 (m, 1H), 2.12−1.87 (m, 6H), 1.58−1.49 (m, 1H), 1.46−1.40 (m, 1H), 0.95−0.89 (m, 12H), 0.74−0.71 (m, 1H); 13C NMR (100 MHz, CDCl3, mixture of rotamers) δ 173.0, 172.6, 172.5, 166.7, 166.4, 154.7, 154.3, 144.4, 144.2, 144.1, 144.0, 143.8, 143.0, 141.3, 132.2, 127.7, 127.6, 127.1, 127.0, 126.9, 126.4, 125.3, 125.2, 120.0, 118.2, 79.6, 79.1, 76.0, 75.9, 67.7, 67.5, 65.2, 59.5, 59.3, 47.3, 47.0, 46.5, 38.6, 38.3, 37.1, 37.0, 36.7, 34.7, 31.5, 31.3, 30.3, 30.0, 29.7, 29.3, 28.7, 25.9, 24.5, 23.3, 20.9, 20.6; HRMS (ESI-TOF) m/z [M + H] + calcd for C40H50N2O6SH: 687.3462, found 687.3459. 1-((9H-Fluoren-9-yl)methyl) 2-((3S,5S,E)-8-((R)-4-(3-(allyloxy)-3oxopropyl)-4,5-dihydrothiazol-2-yl)-2,2,5-trimethyloct-7-en-3-yl) (S)-pyrrolidine-1,2-dicarboxylate (4R)-8: white amorphous solid (259 mg, 84%); [α]D17 = −3.1 (c 3.00, CHCl3); IR (film) νmax 3018, 2961, 1706, 1580, 1419, 1357, 1245, 1217, 1177, 1122, 990 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.78−7.73(m, 2H), 7.66− 7.55 (m, 2H), 7.42−7.36 (m, 2H), 7.33−7.28 (m, 2H), 6.32−6.27 (m, 1.5H), 6.18−6.10 (m, 0.5H), 5.97−5.84 (m, 1H), 5.34−5.27 (m, 1H), 5.25−5.20 (m, 1H), 4.91−4.83 (m, 1H), 4.60−4.55 (m, 2H), 4.52− 4.47 (m, 1H), 4.46−4.40 (m, 2H), 4.40−4.34 (m, 1H), 4.30−4.24 (m, 1H), 4.23−4.15 (m, 1H), 3.73−3.64 (m, 1H), 3.61−3.52 (m, 1H), 3.33−3.14 (m, 1H), 2.87−2.74 (m, 1H), 2.57−2.50 (m, 2H), 2.36− 2.24 (m, 1H), 2.10−1.92 (m, 6H), 1.87−1.82 (m, 1H), 1.56−1.47 (m, 1H), 1.43−1.38 (m, 1H), 0.93−0.90 (m, 2H), 0.88 (s, 9H), 0.73−0.68 (m, 1H); 13C NMR (150 MHz, CDCl3, mixture of rotamers) δ 173.1, 173.0, 172.7, 172.6, 166.8, 166.4, 154.8, 154.4, 144.5, 144.3, 144.2, 144.2, 143.1, 141.4, 127.7, 127.2, 127.1, 125.4, 125.4, 120.1, 120.0, 118.3, 118.3, 79.7, 79.6, 79.6, 79.2, 76.1, 76.0, 67.8, 67.6, 65.2, 59.7, 59.6, 59.4, 47.4, 47.1, 46.5, 38.7, 38.4, 37.2, 37.1, 36.8, 34.8, 31.6, 31.4, 30.4, 30.1, 29.4, 28.9, 26.0, 26.0, 24.5, 23.4, 21.1, 20.7, 19.2, 19.0; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C40H50N2O6SH 687.3462, found 687.3461. General Procedure for the Synthesis of (30S)-26 and (30R)26. To a solution of (4S)-8/(4R)-8 (265 mg, 0.39 mmol) in THF (5 mL) were added Pd(PPh3)4 (46 mg, 0.04 mmol) and N-methylaniline (0.10 mL, 0.96 mmol). After being stirred for 1 h, the mixture was concentrated and purified by flash chromatography on silica gel (DCM/MeOH = 10:1) to give acid (4S)-24/(4R)-24 (221 mg, 88%) as a white amorphous solid. Tripeptide 25 (228 mg, 0.34 mmol) was dissolved in MeCN (5 mL), and then Et2NH (2.50 mL) was added. After being stirred for 30 min, the reaction mixture was concentrated. The residue and above acid (4S)-24/(4R)-24 (221 mg, 0.34 mmol), FDPP (142 mg, 0.37 mmol) and DIPEA (0.08 mL, 0.51 mmol) was stirred in MeCN (2 mL) for overnight at room temperature. The resulting mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated and concentrated. The residue was purified by flash chromatography on silica gel (PE/Acetone = 2:1) to give the desired product. 1-((9H-Fluoren-9-yl)methyl) 2-((3S,5S,E)-8-((S)-4-((5S,8S,11S)-11((S)-sec-butyl)-5-(4-methoxybenzyl)-7,8,10-trimethyl-3,6,9,12-tetraoxo-13-oxa-4,7,10-triazahexadec-15-en-1-yl)-4,5-dihydrothiazol2-yl)-2,2,5-trimethyloct-7-en-3-yl)-(S)-pyrrolidine 1,2-dicarboxylate (30S)-26: white amorphous solid (274 mg, 75%); [α]D25 = −117.3 (c 1.00, CHCl3); IR (film) νmax 2111, 2958, 2924, 1738, 1704, 1645, 1514, 1355, 1247, 1179, 1088 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.82−7.75 (m, 2H), 7.71−7.60 (m, 2H), 7.45− 7.37 (m, 2H), 7.36−7.30 (m, 2H), 7.21−7.13 (m, 2H), 6.85−6.75 (m, 2H), 6.15−6.09 (m, 0.5H), 5.98−5.77 (m, 1.5H), 5.59−5.45 (m, 1H),

132.2, 129.6, 128.1, 126.9, 124.9, 118.4, 77.4, 66.8, 65.3, 48.2, 38.7, 38.2, 36.8, 35.1, 31.1, 29.9, 29.2, 25.7, 21.2; HRMS (ESI-Orbitrap) m/ z [M + H]+ calcd for C39H49NO4SH: 628.3455, found 628.3455. General Procedure for the Synthesis of (4S)-23 and (4R)-23. A cooled (0 °C) toluene solution (5 mL) of N-Fmoc-proline (536 mg, 1.59 mmol) and DIPEA (0.40 mL, 2.38 mmol) was carefully treated with 2,4,6-trichlorobenzoyl chloride (0.37 mL, 2.38 mmol) for 30 min, and then a solution of compound (4S)-22/(4R)-22 (498 mg, 0.79 mmol) in toluene and DMAP (194 mg, 1.59 mmol) was added separately. After being stirred for 3 h, the mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 3:1) to give the desired product. 1-((9H-Fluoren-9-yl)methyl) 2-((3S,5S,E)-9-(((S)-5-(allyloxy)-5oxo-1-(tritylthio)pentan-2-yl)amino)-2,2,5-trimethyl-9-oxonon-7en-3-yl)-(S)-pyrrolidine 1,2-dicarboxylate (4S)-23: white amorphous solid (669 mg, 89%). [α]D25 = −47.1 (c 1.00, CHCl3); IR (film) νmax 3066, 3015, 2959, 2928, 1708, 1662, 1633, 1450, 1419, 1366, 1253, 1180, 1122, 989 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.82−7.74 (m, 2H), 7.68−7.65 (m, 1.6H), 7.60−7.57 (m, 0.4H), 7.45−7.37 (m, 7H), 7.34−7.18 (m, 12H), 6.85−6.70 (m, 1H), 5.95−5.77 (m, 2H), 5.67−5.47 (m, 1H), 5.32−5.25 (m, 1H), 5.25− 5.18 (m, 1H), 4.95−4.80 (m, 1H), 4.56−4.42 (m, 4H), 4.35−4.15 (m, 2H), 4.10−4.00 (m, 1H), 3.70−3.64 (m, 1H), 3.61−3.47 (m, 1H), 2.49−2.29 (m, 3H), 2.28−2.06 (m, 4H), 2.04−1.90 (m, 3H), 1.69− 1.62 (m, 2H), 1.60−1.51 (m, 0.8H), 1.48−1.40 (m, 1.2H), 1.28 (s, 1H), 1.02−0.96 (m, 2H), 0.90 (s, 9H), 0.80−0.75 (m, 1H); 13C NMR (100 MHz, CDCl3, mixture of rotamers) δ 172.9, 172.8, 172.7, 172.2, 165.5, 165.2, 154.8, 154.4, 144.6, 144.2, 144.1, 143.9, 143.7, 143.0, 142.7, 141.3, 132.1, 129.6, 128.0, 127.9, 127.7, 127.6, 127.1, 127.0, 126.8, 126.7, 125.5, 125.3, 125.3, 125.2, 119.9, 118.2, 79.5, 79.0, 67.7, 67.5, 66.8, 66.7, 65.2, 59.6, 59.4, 48.1, 47.9, 47.3, 47.2, 47.0, 46.4, 37.1, 36.8, 36.6, 36.4, 34.9, 34.7, 31.3, 30.9, 30.0, 29.8, 29.7, 29.4, 29.3, 29.2, 25.9, 24.3, 23.3, 20.9, 20.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C59H66N2O7S Na 969.4483, found 969.4459. 1-((9H-Fluoren-9-yl)methyl) 2-((3S,5S,E)-9-(((R)-5-(allyloxy)-5oxo-1-(tritylthio)pentan-2-yl)amino)-2,2,5-Trimethyl-9-oxonon-7en-3-yl)-(S)-pyrrolidine 1,2-dicarboxylate (4R)-23: white amorphous solid (669 mg, 89%); [α]D17 = −30.8 (c 3.00, CHCl3); IR (film) νmax 3066, 3015, 2959, 2928, 1708, 1662, 1633, 1450, 1419, 1366, 1253, 1180, 1122, 989 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.77−7.73 (m, 2H), 7.65−7.54 (m, 2H), 7.40−7.33 (m, 8H), 7.34−7.15 (m, 11H), 6.83−6.65 (m, 1H), 5.90−5.72 (m, 2H), 5.65−5.53 (m, 1H), 5.29−5.22 (m, 1H), 5.21−5.16 (m, 1H), 4.93− 4.85 (m, 1H), 4.52−4.45 (m, 3H), 4.40−4.31 (m, 1H), 4.26−4.10 (m, 2H), 4.04−3.94 (m, 1H), 3.67−3.58 (m, 1H), 3.56−3.44 (m, 1H), 2.40−2.31 (m, 3H), 2.25−2.16 (m, 3H), 2.13−2.07 (m, 1H), 2.00− 1.90 (m, 3H), 1.77−1.65 (m, 2H), 1.53−1.45 (m, 1H), 1.43−1.37 (m, 1H), 1.30−1.24 (m, 1H), 0.97−0.93 (m, 2H), 0.90−0.87 (m, 9H), 0.75−0.70 (m, 1H); 13C NMR (150 MHz, CDCl3, mixture of rotamers) δ 173.0, 172.8, 172.4, 165.7, 165.3, 154.9, 154.5, 144.7, 144.3, 144.1, 143.1, 142.8, 141.4, 132.2, 129.7, 128.0, 127.8, 126.9, 120.1, 120.0, 118.4, 118.3, 79.7, 79.2, 67.8, 67.6, 67.5, 66.8, 65.3, 60.5, 59.7, 59.4, 48.2, 47.4, 47.4, 47.1, 46.5, 36.8, 36.7, 36.6, 34.9, 31.1, 30.1, 29.8, 29.2, 26.0, 24.4, 21.0, 14.3; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C59H66N2O7SH 947.4664, found 947.4666. General Procedure for the Synthesis of (4S)-8 and (4R)-8. Triphenylphosphine oxide (746 mg, 2.70 mmol) was dissolved in DCM (3 mL) and cooled to 0 °C, and then trifluoromethanesulfonic anhydride (0.23 mL, 1.35 mmol) was added at 0 °C. After the solution was stirred for 10 min, a solution of compound (4S)-23/(4R)-23 (423 mg, 0.45 mmol) in DCM (2 mL) was added dropwise, and the mixture was stirred for 10 min. Then the mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 4:1) to give the desired product. 10839


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2214, 1736, 1640, 1513, 1450, 1247, 1180, 1142, 1075, 1034, 742 cm−1; 1H NMR (600 MHz, CDCl3, mixture of rotamers) δ 7.69−7.65 (m, 2H), 7.48−7.43 (m, 2H), 7.33−7.27 (m, 2H), 7.05−7.01 (m, 2H), 6.74−6.67 (m, 2H), 6.30−6.17 (m, 2H), 5.87−5.79 (m, 1H), 5.52 (d, J = 9.0 Hz, 1H), 5.37 (dd, J = 13.8, 6.6 Hz, 1H), 5.25−5.21 (m, 1H), 5.16−5.12 (m, 1H), 4.98 (d, J = 11.4 Hz, 1H), 4.84−4.78 (m, 2H), 4.51−4.49 (m, 2H), 4.44−4.40 (m, 1H), 4.36 (dd, J = 5.6, 3.2 Hz, 1H), 4.28 (dd, J = 7.2, 4.8 Hz, 1H), 4.18 (dd, J = 7.2, 4.8 Hz, 1H), 4.07 (dd, J = 7.2, 6.6 Hz, 1H), 3.84−3.77 (m, 1H), 3.70−3.64 (m, 1H), 3.65 (s, 3H), 3.26 (dd, J = 10.8, 8.4 Hz, 1H), 2.98−2.88 (m, 4H), 2.85 (s, 2.5H), 2.80 (dd, J = 10.8, 8.4 Hz, 1H), 2.77−2.70 (m, 1.5H), 2.53− 2.42 (m, 3H), 2.16−2.05 (m, 2H), 1.95−1.83 (m, 5H), 1.81−1.73 (m, 2H), 1.52−1.46 (m, 1H), 1.32−1.26 (m, 1H), 1.20−1.14 (m, 5H), 0.92−0.88 (m, 3H), 0.82−0.76 (m, 15H); 13C NMR (150 MHz, CDCl3, mixture of rotamers) δ 171.9, 171.4, 170.8, 170.5, 168.3, 165.6, 157.6, 154.7, 143.8, 142.8, 142.7, 140.2, 131.2, 129.3, 126.9, 126.7, 126.0, 125.3, 124.1, 124.0, 118.9, 117.2, 112.9, 77.8, 77.4, 74.9, 66.0, 64.1, 59.4, 58.1, 56.7, 54.1, 51.3, 48.7, 46.3, 46.1, 37.5, 37.1, 36.0, 35.8, 33.6, 32.3, 30.4, 29.5, 29.4, 29.3, 28.3, 27.2, 24.9, 23.9, 23.7, 19.9, 13.7, 13.5, 9.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C61H81N5O10SH 1076.5777, found 1076.5778. General Procedure for the Synthesis of Proposed Apratoxin E (30S-7) and Revised Apratoxin E (30R-7) through Macrolactamization at C6−N. A solution of compound (30S)-26/(30R)26 (220 mg, 0.20 mmol) and Pd(PPh3)4 (24 mg, 0.02 mmol) in dry THF (5 mL) was treated with N-methylaniline (0.06 mL, 0.50 mmol) for 30 min. The mixture was concentrated, and the residue was purified by flash chromatography (DCM/MeOH = 20:1) to give the acid. The above acid was dissolved in MeCN (2 mL), and then Et2NH (1 mL) was added. After the mixture was stirred for 30 min at room temperature, the mixture was concentrated and dissolved in DCM (200 mL). HATU (114 mg, 0.30 mmol) and DIPEA (0.66 mL, 4.00 mmol) were added, and the mxiture was stirred for 40 h. The mixture was concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 1:1) to give the desired product. Proposed Apratoxin E (30S-7): white amorphous solid (30.2 mg, 19%, three steps); [α]D23 = −150.4 (c 0.24, MeOH) [lit.8f [α]D20 −163.4 (c 0.106, MeOH)]; 1H NMR (600 MHz, CDCl3, mixture of rotamers) δ 7.16−7.12 (m, 2H), 6.83−6.75 (m, 2H), 6.60 (d, J = 15.6 Hz, 0.67H), 6.44−6.35 (m, 1.33H), 6.09 (d, J = 9.0 Hz, 0.67H), 5.79 (d, J = 10.2 Hz, 0.33H), 5.26−5.20 (m, 1H), 5.18−5.13 (m, 0.33H), 4.99−4.95 (m, 0.33H), 4.93−4.87 (m, 1H), 4.65 (dd, J = 13.2, 6.6 Hz, 0.67H), 4.42−4.35 (m, 0.67H), 4.34−4.30 (m, 1H), 4.26−4.23 (m, 0.33H), 4.15−4.12 (m, 0.33H), 4.08−4.04 (m, 0.67H), 3.77 (s, 1H), 3.77 (s, 2H), 3.70−3.62 (m, 1H), 3.34−3.29 (m, 1.33H), 3.10−3.06 (m, 1H), 2.98 (s, 2H), 2.92−2.89 (m, 1.67H), 2.84 (s, 1H), 2.82 (s, 1H), 2.62 (s, 2H), 2.50−2.40 (m, 2.33H), 2.27−2.20 (m, 1.67H), 2.09−2.03 (m, 1.67H), 1.97−1.86 (m, 5H), 1.77−1.69 (m, 2H), 1.46− 1.44 (m, 1H), 1.30−1.23 (m, 5H), 1.06−1.02 (m, 3H), 0.94−0.92 (m, 3H), 0.91−0.88 (m, 9H), 0.87−0.84 (m, 2H), 0.57−0.54 (m, 2H); 13C NMR (150 MHz, CDCl3, mixture of rotamers) δ 172.9, 172.4, 172.2, 171.77, 171.3, 170.6, 170.43, 170.3, 170.1, 169.7, 166.7, 166.4, 158.9, 158.7, 145.0, 144.8, 132.3, 132.2, 130.7, 130.6, 128.7, 128.7, 128.6, 128.5, 126.3, 126.2, 114.3, 114.0, 77.7, 77.7, 76.6, 76.5, 60.7, 59.5, 59.3, 58.0, 57.3, 55.5, 55.4, 54.2, 50.8, 50.0, 47.6, 47.5, 39.9, 38.5, 37.8, 37.5, 37.5, 37.2, 36.9, 35.3, 34.9, 34.3, 33.7, 33.4, 33.2, 31.0, 30.7, 30.5, 29.7, 29.6, 29.5, 29.4, 28.9, 26.2, 26.1, 25.7, 25.4, 25.3, 20.7, 19.5, 15.1, 14.3, 14.3, 14.1, 14.1, 10.4, 10.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C43H65N5O7SH 796.4683, found 796.4679. Revised Apratoxin E (30R-7): white amorphous solid (33.3 mg, 21%); [α]D17 = −59 (c 0.25, MeOH) [lit.7f [α]D20 = −69 (c 0.12, MeOH); lit.8f [α]D20 = −68 (c 0.182, MeOH)]; 1H NMR (600 MHz, CDCl3, mixture of rotamers) δ 7.16−7.13 (m, 2H), 6.82−6.78 (m, 2H), 6.55−6.52 (m, 0.4H), 6.47−6.40 (m, 1.6H), 6.16 (d, J = 8.4 Hz, 0.4H), 5.88 (d, J = 9.6 Hz, 0.6H), 5.25 (d, J = 10.8 Hz, 0.6H), 5.23− 5.17 (m, 0.6H), 5.07 (dd, J = 15.0, 7.8 Hz, 0.4H), 4.98 (dd, J = 12.0, 1.8 Hz, 0.6H), 4.91 (dd, J = 11.4, 2.4 Hz, 0.4H), 4.87 (d, J = 10.8 Hz, 0.4H), 4.68 (dd, J = 16.8, 7.8 Hz, 0.4H), 4.62 (dd, J = 13.2, 6.6 Hz, 0.4H), 4.37−4.32 (m, 1H), 4.22−4.18 (m, 0.6H), 4.17−4.13 (m, 0.6H), 4.07−4.02 (m, 0.4H), 3.77−3.76 (m, 3H), 3.70−3.61 (m, 1H),

5.35−5.23 (m, 2H), 4.97−4.78 (m, 2H), 4.65−4.57 (m, 2H), 4.55− 4.40 (m, 3H), 4.39−4.32 (m, 1H), 4.31−4.19 (m, 1.5H), 4.13−4.07 (m, 0.5H), 3.80−3.74 (m, 3H), 3.70−3.63 (m, 1H), 3.61−3.52 (m, 1H), 3.10−2.98 (m, 2H), 2.95−2.88 (m, 1H), 2.86−2.77 (m, 3H), 2.71 (s, 3H), 2.63−2.60 (m, 0.5H), 2.53−2.50 (m, 1.5H), 2.36−2.17 (m, 3H), 2.10−1.89 (m, 4H), 1.86−1.79 (m, 1H), 1.58−1.51 (m, 1H), 1.46−1.37 (m, 2H), 1.36−1.17 (m, 8H), 0.98−0.81 (m, 18H); 13C NMR (125 MHz, CDCl3, mixture of rotamers) δ 172.6, 172.0, 171.9, 171.5, 170.7, 158.6, 154.7, 154.3, 144.2, 144.1, 141.3, 131.8, 130.4, 130.3, 128.2, 128.1, 127.7, 127.6, 127.0, 126.9, 126.3, 125.3, 125.2, 119.9, 118.6, 113.9, 79.6, 79.1, 75.9, 75.6, 67.7, 67.6, 66.0, 65.4, 60.5, 59.5, 59.3, 55.2, 50.3, 49.6, 47.3, 47.0, 46.4, 38.6, 38.1, 37.8, 37.1, 37.0, 36.7, 34.7, 33.6, 33.5, 33.3, 31.3, 31.0, 30.5, 30.0, 29.7, 29.5, 29.3, 28.7, 25.9, 25.0, 24.4, 23.3, 20.9, 20.6, 15.8, 14.3, 10.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C61H81N5O10SNa 1098.5596, found 1098.5602. 1-((9H-fluoren-9-yl)methyl) 2-((3S,5S,E)-8-((R)-4-((5S,8S,11S)-11((S)-sec-butyl)-5-(4-methoxybenzyl)-7,8,10-trimethyl-3,6,9,12-tetraoxo-13-oxa-4,7,10-triazahexadec-15-en-1-yl)-4,5-dihydrothiazol2-yl)-2,2,5-trimethyloct-7-en-3-yl)-(S)-pyrrolidine 1,2-dicarboxylate (30R)-26: white amorphous solid (263 mg, 72%); [α]D17 = −27.4 (c 0.25, CHCl3); IR (film) νmax 2111, 2958, 2924, 1738, 1704, 1645, 1514, 1355, 1247, 1179, 1088 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.77−7.73 (m, 2H), 7.67−7.55 (m, 2H), 7.41− 7.36 (m, 2H), 7.33−7.28 (m, 2H), 7.18−7.09 (m, 2H), 6.78−6.72 (m, 2H), 6.04−5.92 (m, 1H), 5.91−5.83 (m, 1H), 5.55−5.48 (m, 0.4H), 5.41−5.37 (m, 0.6H), 5.33−5.27 (m, 1H), 5.25−5.21 (m, 1H), 4.95− 4.87 (m, 1.4H), 4.79−4.75 (m, 0.6H), 4.62−4.53 (m, 2H), 4.54−4.43 (m, 2H), 4.40−4.31 (m, 2H), 4.27−4.15 (m, 2H), 3.88−3.81 (m, 1H), 3.77−3.73 (m, 3H), 3.65−3.60 (m, 1H), 3.56−3.51 (m, 1H), 3.30− 3.20 (m, 1H), 3.03−2.91 (m, 2H), 2.90−2.83 (m, 2H), 2.82−2.78 (m, 2H), 2.77−2.76 (m, 1H), 2.74−2.63 (m, 2H), 2.61−2.59 (m, 1H), 2.52−2.49 (m, 1H), 2.32−2.16 (m, 3H), 2.12−2.06 (m, 1H), 2.06− 2.01 (m, 1H), 1.98−1.91 (m, 2H), 1.82−1.78 (m, 1H), 1.39−1.38 (m, 1H), 1.31−1.25 (m, 4H), 1.24−1.20 (m, 3H), 1.18−1.13 (m, 1H), 0.95−0.91 (m, 3H), 0.89−0.83 (m, 12H), 0.83−0.79 (m, 3H); 13C NMR (150 MHz, CDCl3, mixture of rotamers) δ 175.1, 173.9, 172.3, 172.2, 172.0, 171.9, 170.9, 170.8, 170.0, 169.8, 158.4, 158.2, 154.8, 154.5, 154.4, 144.7, 144.4, 144.2, 144.0, 143.9, 141.5, 141.4, 131.9, 130.5, 127.9, 127.8, 127.2, 125.7, 125.6, 125.5, 125.4, 125.3, 120.0, 118.8, 118.7, 113.8, 113.8, 113.7, 80.5, 80.3, 80.2, 68.0, 67.8, 67.5, 65.9, 65.6, 65.5, 65.4, 60.6, 60.0, 59.7, 59.4, 57.2, 57.0, 56.9, 55.8, 55.7, 55.6, 55.3, 50.0, 49.9, 49.7, 47.4, 47.1, 46.5, 46.4, 43.4, 43.3, 43.2, 39.5, 38.6, 38.4, 38.3, 38.1, 37.6, 37.5, 37.3, 37.2, 35.3, 35.2, 35.1, 34.9, 33.4, 33.3, 31.7, 31.6, 31.4, 31.3, 30.9, 30.3, 30.1, 30.0, 29.8, 29.6, 29.2, 28.3, 27.7, 27.6, 27.0, 26.9, 26.0, 25.7, 25.6, 25.1, 24.5, 24.4, 23.5, 23.0, 22.8, 21.3, 21.2, 21.1, 21.0, 15.9, 15.2, 15.1, 14.5, 14.3, 10.7, 10.5; HRMS (ESIOrbitrap) m/z [M + H]+ calcd for C61H81N5O10SH 1076.5777, found 1076.5780. (3S,5S,E)-8-((S)-4-(3-(Allyloxy)-3-oxopropyl)-4,5-dihydrothiazol-2yl)-2,2,5-trimethyloct-7-en-3-yl N-(N-((S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoyl)-Nmethyl-L-alanyl)-N-methyl-L-isoleucyl-L-prolinate 29. A solution of tripetide 25 (120 mg, 0.18 mmol) and Pd(PPh3)4 (24 mg, 0.02 mmol) in THF (3 mL) was treated with N-methylaniline (0.05 mL, 0.45 mmol) for 1 h. The mixture was concentrated and purified by flash chromatography on silica gel (DCM/MeOH = 15:1) to give the crude acid without further purification. Compound (4S)-8 (124 mg, 0.18 mmol) was dissolved in MeCN (2 mL), and then Et2NH (1 mL) was added. After being stirred for 30 min, the reaction mixture was concentrated. The residue was azeotroped with toluene three times and dissolved in DCM (2 mL), and then the above acid, HATU (103 mg, 0.27 mmol), and DIPEA (0.09 mL, 0.54 mmol) were added. After the resulting mixture was stirred overnight at room temperature, the reaction was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/ acetone = 2:1) to give 29 (141 mg, 73%) as a white amorphous solid: [α]D23 = −108.3 (c 1.00, CHCl3); IR (film) νmax 3800, 3320, 2958, 10840


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Benzyl (S/R)-4-Acrylamido-5-((tert-butyldimethylsilyl)oxy)pentanoate (S)-30 or (R)-30: white solid (1.53 g, 78%); [α]D16 = −13.5 (c 1.00, CHCl3) for (S)-30, [α]D16 = +10.7 (c 2.00, CHCl3) for (R)-30; IR (film) νmax 3434, 2932, 2844, 1655, 1556, 1260,1167 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.39−7.26 (m, 5H), 6.29−6.21 (m, 1H), 6.08−5.99 (m, 1H), 5.90 (d, J = 8.8 Hz, 1H), 5.65−5.59 (m, 1H), 5.11−5.09 (m, 2H), 4.13−4.03 (m, 1H), 3.67−3.61 (m, 2H), 2.55−2.34 (m, 2H), 1.96−1.88 (m, 2H), 0.89 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 172.5, 164.1, 134.9, 129.9, 127.5, 127.2, 127.2, 125.4, 65.4, 63.7, 49.2, 30.1, 25.7, 24.8, 17.3, −6.5; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C21H33NO4SiH 392.2252, found 392.2250. 1-((9H-Fluoren-9-yl)methyl) 2-((3R,5R)-2,2,5-trimethyloct-7-en-3yl)-(S)-pyrrolidine 1,2-Dicarboxylate 31. Compound 9 (4.20 g, 8.6 mmol) was dissolved in THF, and then TBAF was added. After being stirred for 2 h, the mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated, and concentrated to give the crude alcohol without further purification. A cooled (0 °C) toluene solution (50 mL) of N-Fmocproline (5.36 g, 15.9 mmol) and DIPEA (4.0 mL, 23.8 mmol) was carefully treated with 2,4,6-trichlorobenzoyl chloride (3.7 mL, 23.8 mmol) for 30 min, and then a solution of the above alcohol in toluene and DMAP (1.94 g, 15.9 mmol) was added separately. After being stirred for 3 h, the mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 10:1) to give 31 (3.37 g, 80%) as a white amorphous solid: [α]D23 = −57.5 (c 3.00, CHCl3); IR (film) νmax 3477, 2958, 1708, 1450, 1415, 1195, 1112, 762, 729 cm−1; 1 H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.77−7.73 (m, 2H), 7.66−7.54 (m, 2H), 7.42−7.36 (m, 2H), 7.34−7.27 (m, 2H), 5.82−5.57 (m, 1H), 5.05−4.85 (m, 3H), 4.55−4.40 (m, 2H), 4.33− 4.24 (m, 1H), 4.22−4.13 (m, 1H), 3.71−3.63 (m, 1H), 3.60−3.50 (m, 1H), 2.37−1.79 (m, 6H), 1.61−1.35 (m, 3H), 0.94−0.90 (m, 2H), 0.70−0.65 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 172.5, 154.7, 154.4, 144.3, 144.2, 144.0, 143.8, 141.3, 141.3, 136.9, 136.4, 127.8, 127.7, 127.1, 127.1, 127.0, 125.4, 125.3, 125.2, 120.0, 116.5, 116.2, 79.9, 79.6, 67.8, 67.5, 59.7, 59.4, 47.3, 47.0, 46.4, 39.6, 39.3, 36.5, 36.5, 34.9, 34.8, 31.4, 30.1, 29.3, 29.1, 26.0, 24.4, 23.4, 20.8, 20.5; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C31H39NO4H 490.2957, found 490.2957. (3S,5S)-2,2,5-Trimethyloct-7-en-3-yl N-(N-((S)-2-((((9H-Fluoren-9yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoyl)-Nmethyl-L-alanyl)-N-methyl-L-isoleucyl-L-prolinate 34. To a solution of 25 (1.13 g, 1.8 mmol) in THF (30 mL) were added Pd(PPh3)4 (212 mg, 0.18 mmol) and N-methylaniline (0.46 mL, 4.42 mmol). After being stirred for 1 h, the mixture was concentrated and purified by flash chromatography on silica gel (DCM/MeOH = 30:1) to give the crude acid. Compound 31 (880 mg, 1.8 mmol) was dissolved in MeCN (10 mL), and then Et2NH (5 mL) was added. After being stirred for 30 min, the reaction mixture was concentrated. The residue was azeotroped with toluene three times and dissolved in DCM (20 mL), and then the above crude acid, HATU (1.03 g, 2.7 mmol), and DIPEA (0.9 mL, 5.4 mmol) were added. After being stirred overnight at room temperature, the resulting mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 1:1) to give 34 (1.15 g, 73%) as a white amorphous solid: [α]D23 = −90.0 (c 2.50, CHCl3); IR (film) νmax 2961, 1721, 1640, 1513, 1450, 1247, 1182, 1079, 1036, 745 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.70−7.65 (m, 2H), 7.50−7.45 (m, 2H), 7.35−7.30 (m, 2H), 7.25−7.20 (m, 2H), 7.08−7.00 (m, 2H), 6.75−6.69 (m, 2H), 5.74−5.61 (m, 1H), 5.47−5.42 (m, 1H), 5.35 (dd, J = 13.6, 6.4 Hz, 1H), 4.97−4.86 (m, 3H), 4.85−4.77 (m, 2H), 4.41 (dd, J = 8.4, 3.6 Hz, 1H), 4.33−4.26 (m, 1H), 4.23−4.17 (m, 1H), 4.12−4.07 (m, 1H), 3.80−3.72 (m, 1H), 3.67 (s, 3H), 3.64−3.60 (m,

3.42 (dd, J = 10.8, 7.8 Hz, 0.4H), 3.32 (dd, J = 10.8, 7.8 Hz, 0.6H), 3.28 (dd, J = 13.2, 6.6 Hz, 0.6H), 3.10−3.03 (m, 1.4H), 3.03 (s, 1H), 2.81 (s, 2H), 2.79−2.77 (m, 0.6H), 2.77−2.75 (m, 0.4H), 2.75 (s, 2H), 2.63 (s, 1H), 2.60−2.55 (m, 0.6H), 2.53−2.47 (m, 0.6H), 2.46−2.44 (m, 0.4H), 2.43−2.37 (m, 1H), 2.26−2.12 (m, 2H), 2.07−2.03 (m, 0.6H), 1.98−1.84 (m, 4H), 1.71−1.64 (m, 2H), 1.59−1.54 (m, 1.4H), 1.27−1.22 (m, 4H), 1.11−1.07 (m, 3H), 1.04−1.00 (m, 2H), 0.96− 0.93 (m, 3H), 0.88−0.86 (m, 9H), 0.86−0.83 (m, 3H), 0.51−0.49 (m, 1H); 13C NMR (150 MHz, CDCl3, mixture of rotamers) δ 172.7, 172.1, 172.0, 171.5, 170.7, 170.4, 170.3, 170.1, 170.0, 166.6, 166.4, 158.9, 158.8, 144.3, 143.6, 132.3, 132.2, 132.1, 128.8, 128.7, 128.6, 128.5, 126.7, 126.4, 114.3, 114.0, 77.8, 76.1, 75.5, 60.7, 59.5, 59.1, 58.2, 56.8, 55.5, 55.4, 53. 8, 51.5, 49.8, 47.6, 47.5, 39.9, 38. 6, 38.1, 37. 9, 37.7, 37.5, 37.4, 36.8, 35.2, 35.0, 34.4, 33.6, 33.5, 32.7, 31.7, 31.7, 31.1, 31.0, 30.2, 29.9, 29.6, 29.5, 29.4, 28.9, 26.2, 26.2, 25.8, 25.7, 25.5, 25.3, 20.8, 20. 5, 14.8, 14.3, 14.1, 14.0, 10.28, 10.2; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C43H65N5O7SH 796.4678, found 796.4678. Method of Synthesis for Proposed Apratoxin E (30S-7) by Macrolactamization at C27−N. A solution of compound 29 (110 mg, 0.10 mmol) and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in dry THF (3 mL) was treated with N-methylaniline (0.03 mL, 0.25 mmol) for 30 min. Then the reaction was concentrated and purified by flash chromatography on silica gel (DCM/MeOH = 20:1) to give the acid, which was dissolved in MeCN (2 mL), and Et2NH (1 mL) was added. After being stirred for 30 min at room temperature, the mixture was concentrated, and the residue was dissolved in MeCN (100 mL). Then FDPP (57.6 mg, 0.15 mmol) and DIPEA (0.33 mL, 2.00 mmol) were added, and the reaction was stirred for 40 h. The mixture was concentrated and purified by flash chromatography silica gel (PE/EA = 1:1) to give proposed apratoxin E (30S-7) (34.2 mg, 43%, three steps). General Procedure for the Synthesis of (S)-32 and (R)-32. (S)-18/(R)-18 (3.23 g, 10 mmol) was dissolved in DMF (20 mL), and then TBSCl (2.25 g, 15 mmol), imidazole (1.36 g, 20 mmol), and DMAP (122 mg, 1 mmol) were added. After being stirred for 12 h at room temperature, the resulting mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water and brine, dried over MgSO4, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 20:1) to give the desired compound. Benzyl (S/R)-4-((tert-Butoxycarbonyl)amino)-5-((tertbutyldimethylsilyl)oxy)pentanoate (S)-32 or (R)-32: white solid (3.67g, 84%); [α]D15 = −20.0 (c 2.00, CHCl3) for (S)-32, [α]D15 = +22.5 (c 1.00, CHCl3) for (R)-32; IR (film) νmax 3436, 2964, 2854, 1682, 1627, 1523, 1167, 1118, 723 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.35−7.20 (m, 5H), 5.08−5.00 (m, 2H), 4.65−4.56 (m, 1H), 3.60−3.47 (m, 3H), 2.39−2.33 (m, 2H), 1.85−1.65 (m, 2H), 1.36 (s, 9H), 0.81 (s, 9H), −0.03 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 172.3, 154.6, 135.0, 127.5, 127.1, 78.2, 65.2, 64.0, 50.4, 30.1, 27.4, 26.1, 24.9, 17.3, −6.5; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C23H39NO5SiH 438.2670, found 438.2671. General Procedure for the Synthesis of (S)-30 and (R)-30. A solution of (S)-32 or (R)-32 (2.19 g, 5 mmol) in DCM (20 mL) was treated with 2.6-lutidine (3.49 mL, 30 mmol) and TMSOTf (2.71 mL, 15 mmol) at 0 °C. After being stirred for 5 h at 0 °C to room temperature, the resulting mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted with DCM (20 mL × 3). The combined organic layers were dried over MgSO4, filtrated, and concentrated to give the crude product without further purification. The above crude product was dissolved in DCM under Ar atmosphere, and then TEA (1.39 mL, 10 mmol) and acrylyl chloride (0.81 mL, 10 mmol) were added at 0 °C. After being stirred for 8 h at 0 °C to room temperature, the resulting mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 5:1) to give the desired compound. 10841


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115.7, 114.1, 79.7, 65.1, 59.2, 58.0, 55.3, 50.9, 50.3, 50.0, 47.3, 42.7, 37.7, 36.7, 34.8, 33.4, 33.0, 30.6, 30.4, 29.4, 28.7, 28.2, 27.0, 26.1, 26.0, 24.9, 24.8, 18.8, 18.4, 14.9, 14.5, 10.4, −5.3, −5.4; HRMS (ESIOrbitrap) m/z [M + H]+ calcd for C51H85N5O9SiH 940.6189, found 940.6191. General Procedure for the Synthesis of (30S)-36 and (30S)36. Compound (30S)-35/(30R)-35 (300 mg, 0.32 mmol) and Grubbs second (cat.) were refluxed in DCM (320 mL) under Ar atmosphere for 24 h to give the crude product, which was purified by flash chromatography on silica gel (PE/acetone = 3:1) to give the desired compound. (3S,5S,11S,16S,19S,22S,27aS,E)-22-((S)-sec-Butyl)-3-(tert-butyl)11-(((tert-butyldimethylsilyl)oxy)methyl)-16-(4-methoxybenzyl)5,18,19,21-tetramethyl-5,6,10,11,12,13,15,16,18,19,21,22,25,26,27,27a-hexadecahydro-1H,3H-pyrrolo[2,1-c][1]oxa[4,7,10,13,18]pentaazacyclopentacosine-1,9,14,17,20,23(4H)-hexaone (30S)-36: white amorphous solid (204 mg, 70%); [α]D18 = −78.8 (c 0.50, CHCl3); IR (film) νmax 3432, 1636, 1238, 1172, 1091 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.49−7.47 (m, 2H), 7.19−7.14 (m, 2H), 7.11− 7.01 (m, 1H), 6.80 (d, J = 7.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 6.21 (d, J = 15.6 Hz, 1H), 5.68−5.56 (m, 1H), 5.30−5.20 (m, 2H), 5.09− 5.01 (m, 1H), 4,69−4.62 (m, 1H), 4.45−4.38 (m, 1H), 4.12 (s, 3H), 4.08−4.03 (m, 1H), 4.01−3.94 (m, 1H), 3.93−3.87 (m, 1H), 3.46− 3.37 (m, 1H), 3.28 (s, 3H), 3.26−3.20 (m, 1H), 3.19−3.09 (m, 1H), 2.97 (s, 3H), 2.81−2.74 (m, 1H), 2.74−2.65 (m, 1H), 2.65−2.57 (m, 1H), 2.50−2.35 (m, 3H), 2.30−2.24 (m, 3H), 2.21 (s, 3H), 2.17−2.10 (m, 2H), 2.08−2.03 (m, 1H), 1.83−1.77 (m, 1H), 1.61 (s, 3H), 1.43− 1.37 (m, 3H), 1.28−1.26 (m, 3H), 1.24 (s, 9H), 1.22 (s, 9H), 0.99− 0.94 (m, 3H), 0.41 (s, 3H), 0.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5, 172.0, 170.2, 171.9, 167.3, 143.7, 130.5, 128.4, 125.2, 114.3, 64.0, 59.5, 58.1, 55.5, 54.6, 51.1, 50.3, 47.5, 40.0, 37.5, 37.1, 35.3, 34.1, 32.9, 30.7, 29.8, 29.5, 29.4, 28.9, 26.4, 26.1, 26.0, 25.9, 25.5, 19.6, 18.4, 15.3, 14.2, 10.0, −5.2, −5.3; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C49H81N5O9SiH 912.5876, found 912.5877. (3S,5S,11R,16S,19S,22S,27aS,E)-22-((S)-sec-Butyl)-3-(tert-butyl)11-(((tert-butyldimethylsilyl)oxy)methyl)-16-(4-methoxybenzyl)5,18,19,21-tetramethyl-5,6,10,11,12,13,15,16,18,19,21,22,25,26,27,27a-hexadecahydro-1H,3H-pyrrolo[2,1-c][1]oxa[4,7,10,13,18]pentaazacyclopentacosine-1,9,14,17,20,23(4H)-hexaone (30R)-36: white amorphous solid (195 mg, 67%); [α]D18 = −46.9 (c 1.00, CHCl3); IR (film) νmax 3432, 1636, 1238, 1172, 1091 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.13−7.09 (m, 2H), 6.93−6.86 (m, 1H), 6.83− 6.81 (m, 2H), 6.67−6.63 (m, 1H), 6.22 (d, J = 9.0 Hz, 1H), 5.92 (d, J = 15.6 Hz, 1H), 5.32−5.27 (m, 1H), 4.93 (d, J = 11.4 Hz, 1H), 4.80 (d, J = 9.6 Hz, 1H), 4.73 (dd, J = 13.2, 6.6 Hz, 1H), 4.31−4.27 (m, 1H), 4.04−3.98 (m, 2H), 3.84 (dd, J = 10.2, 4.8 Hz, 1H), 3.78 (s, 3H), 3.67−3.62 (m, 1H), 3.42 (dd, J = 10.2, 6.6 Hz, 1H), 3.05 (dd, J = 13.2, 9.0 Hz, 1H), 2.95 (s, 3H), 2.92−2.87 (m, 1H), 2.66 (s, 3H), 2.42−2.35 (m, 1H), 2.33−2.26 (m, 1H), 2.24−2.20 (m, 1H), 2.15−2.10 (m, 1H), 2.08−2.03 (m, 1H), 2.03−1.97 (m, 1H), 1.95−1.84 (m, 5H), 1.61− 1.57 (m, 1H), 1.43 (s, 3H), 1.42−1.40 (m, 1H), 0.96−0.94 (m, 3H), 0.93−0.91 (m, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.84−0.82 (m, 3H), 0.76−0.73 (m, 3H) 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 172.7, 172.6, 172.0, 170.1, 169.8, 166.5, 159.0, 143.4, 130.5, 128.3, 124.7, 114.3, 79.8, 63.0, 59.6, 58.1, 55.5, 54.8, 50.3, 50.2, 47.6, 40.3, 39.8, 38.0, 34.6, 34.1, 31.8, 31.4, 30.6, 29.8, 29.5, 29.1, 29.0, 27.1, 26.1, 26.0, 25.6, 25.4, 19.4, 18.3, 15.6, 14.2, 10.2, −5.1, −5.3; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C49H81N5O9SiH 912.5876, found 912.5877. General Procedure for the Synthesis of (30S)-37 and (30R)37. (30S)-36/(30R)-36 (160 mg, 0.18 mmol) was dissolved in THF (2 mL), and then TBAF (0.26 mL, 0.26 mmol, 1 M in THF) was added under Ar atmosphere. After being stirred for 30 min, the mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over MgSO4, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (DCM/MeOH = 30:1) to give the desired compound. (3S,5S,11S,16S,19S,22S,27aS,E)-22-((S)-sec-Butyl)-3-(tert-butyl)11-(hydroxymethyl)-16-(4-methoxybenzyl)-5,18,19,21-tetramethyl5,6,10,11,12,13,15,16,18,19,21,22,25,26,27,27a-hexadecahydro-

1H), 2.97−2.92 (m, 1H), 2.89 (s, 3H), 2.78−2.70 (m, 4H), 2.24−2.16 (m, 1H), 2.14−2.05 (m, 1H), 2.00−1.85 (m, 5H), 1.76−1.69 (m, 1H), 1.64−1.56 (m, 1H), 1.44−1.31 (m, 2H), 1.20−1.06 (m, 3H), 1.15− 1.07 (m, 1H), 0.90−0.86 (m, 3H), 0.85−0.82 (m, 3H), 0.81 (s, 9H), 0.78−0.75 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2, 171.6, 171.4, 169.2, 158.7, 155.7, 143.8, 143.8, 141.3, 137.2, 130.4, 127.9, 127.7, 127.1, 125.1, 120.0, 115.8, 114.0, 79.4, 67.0, 59.1, 57.8, 55.2, 52.2, 49.8, 47.2, 47.1, 39.4, 38.2, 34.7, 33.4, 30.5, 29.3, 28.5, 26.0, 24.8, 20.8, 14.8, 14.5, 10.4; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C52H70N4O8H 879.5266, found 879.5266. General Procedure for the Synthesis of (30S)-35 and (30R)35. Compound (S)-30/(R)-30 (470 mg, 1.20 mmol) was dissolved in a mixture of THF, MeOH, and H2O (12 mL v/v/v = 1:1:1), and then LiOH·H2O (75 mg, 1.80 mmol) was added in one portion. After being stirred for 7 h, the mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over MgSO4, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (DCM/MeOH = 20:1) to give the crude acid (S)-33/(R)-33 (278 mg, 77%). Compound 34 (571 mg, 0.65 mmol) was dissolved in MeCN (4 mL), and then Et2NH (2 mL) was added. After being stirred for 30 min, the reaction mixture was concentrated. The residue was azeotroped with toluene three times and dissolved in MeCN (5 mL), and then (S)-33/(R)-33 (196 mg, 0.65 mmol), FDPP (327 mg, 0.85 mmol), and DIPEA (0.21 mL, 1.28 mmol) were added. After being stirred overnight at room temperature, the resulting mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/acetone = 3:1) to give the desired compound. (3S,5S)-2,2,5-Trimethyloct-7-en-3-yl N-(N-((S)-2-((S)-4-acrylamido-5-((tert-butyldimethylsilyl)oxy)pentanamido)-3-(4-methoxyphenyl)propanoyl)-N-methyl-L-alanyl)-N-methyl-L-isoleucyl-L-prolinate (30S)-35: white amorphous solid (458 mg, 75%); [α]D18 = −111.0 (c 1.00, CHCl3); IR (film) νmax 3463, 2948, 2926, 1635, 1255, 1184, 1074, 1041 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.15−7.11 (m, 2H), 6.81−6.77 (m, 2H), 6.34−6.25 (m, 1H), 6.14−6.04 (m, 2H), 5.81−5.67 (m, 1H), 5.66 (d, J = 10.4 Hz, 1H), 5.42 (dd, J = 13.2, 6.4 Hz, 1H), 5.20 (dd, J = 14.8, 7.2 Hz, 1H), 5.06−4.94 (m, 3H), 4.89 (d, J = 10.4 Hz, 1H), 4.50−4.46 (m, 1H), 3.84−3.81 (m, 1H), 3.77 (s, 3H), 3.74−3.67 (m, 1H), 3.55−3.51 (m, 2H), 3.09−3.01 (m, 1H), 2.98 (s, 3H), 2.90−2.82 (m, 1H), 2.80 (s, 3H), 2.32−2.22 (m, 1H), 2.22−2.14 (m, 3H), 2.04−1.98 (m, 3H), 1.94−1.90 (m, 2H), 1.86− 1.73 (m, 3H), 1.50−1.35 (m, 3H), 1.27−1.22 (m, 4H), 0.98−0.93 (m, 3H), 0.92−0.86 (m, 24H), 0.04 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 171.6, 171.5, 170.9, 170.7, 168.4, 164.8, 157.8, 136.4, 130.2, 129.6, 127.4, 125.8, 115.0, 113.1, 78.7, 64.3, 58.3, 57.1, 54.4, 49.5, 49.2, 49.0, 46.4, 38.6, 36.8, 35.7, 34.0, 32.6, 32.2, 29.7, 29.5, 28.5, 27.8, 27.4, 25.2, 25.1, 24.0, 23.9, 20.0, 17.5, 14.0, 13.7, 9.6, −6.2, −6.3; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C51H85N5O9SiH 940.6189, found 940.6191. (3S,5S)-2,2,5-Trimethyloct-7-en-3-yl N-(N-((S)-2-((R)-4-acrylamido-5-((tert-butyldimethylsilyl)oxy)pentanamido)-3-(4-methoxyphenyl)propanoyl)-N-methyl-L-alanyl)-N-methyl-L-isoleucyl-L-prolinate (30R)-35: white amorphous solid, (470 mg, 77%); [α]D18 = −65.6 (c 2.00, CHCl3); IR (film) νmax 3463, 2948, 2926, 1635, 1255, 1184, 1074, 1041 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.14−7.10 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.82−6.77 (m, 2H), 6.28 (d, J = 17.2 Hz, 1H), 6.20 (d, J = 8.4 Hz, 1H), 6.13−6.04 (m, 1H), 5.85−5.74 (m, 1H), 5.66 (d, J = 10.0 Hz, 1H), 5.41 (dd, J = 13.6, 6.8 Hz, 1H), 5.13− 5.05 (m, 1H), 5.05−4.97 (m, 3H), 4.87 (d, J = 10.4 Hz, 1H), 4.50− 4.45 (m, 1H), 4.14−4.04 (m, 1H), 3.86−3.78 (m, 1H), 3.77 (s, 3H), 3.72−3.67 (m, 1H), 3.66−3.62 (m, 2H), 3.06−2.98 (m, 1H), 2.96 (s, 3H), 2.88−2.81 (m, 1H), 2.76 (s, 3H), 2.31−2.22 (m, 1H), 2.21−2.16 (m, 2H), 2.05−1.97 (m, 5H), 1.94−1.92 (m, 2H), 1.66−1.58 (m, 2H), 1.44−1.42 (m, 2H), 1.25−1.16 (m, 5H), 0.95−0.93 (m, 3H), 0.91− 0.87 (m, 24H), 0.05 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 172.8, 172.5, 171.8, 171.7, 169.3, 165.7, 137.7, 131.1, 130.4, 128.3, 126.6, 10842


Article

The Journal of Organic Chemistry 1H,3H-pyrrolo[2,1-c][1]oxa[4,7,10,13,18]pentaazacyclopentacosine-1,9,14,17,20,23(4H)-hexaone (30S)-37: white amorphous solid (118 mg, 82%); [α]D18 = −74.6 (c 0.50, CHCl3); IR (film) νmax 3821, 3427, 2935, 2256, 1634, 1513, 1180 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.17−7.13 (m, 1H), 7.12−7.08 (m, 2H), 6.85−6.80 (m, 3H), 6.57−6.50 (m, 1H), 5.93 (d, J = 15.6 Hz, 1H), 5.35−5.25 (m, 1H), 4.94−4.86 (m, 2H), 4.75 (dd, J = 12.8, 6.4 Hz, 1H), 4.36− 4.32 (m, 1H), 4.25−4.16 (m, 1H), 4.09−4.03 (m, 1H), 3.78 (s, 3H), 3.67−3.64 (m, 3H), 3.08−3.01 (m, 1H), 2.94 (s, 3H), 2.91−2.82 (m, 2H), 2.65 (s, 3H), 2.44−2.35 (m, 2H), 2.27−2.23 (m, 1H), 2.18−2.14 (m, 1H), 1.98−1.93 (m, 3H), 1.92−1.84 (m, 6H), 1.75−1.66 (m, 2H), 1.56−1.49 (m, 1H), 1.33−1.21 (m, 3H), 1.08−1.03 (m, 3H), 0.97− 0.93 (m, 3H), 0.87 (s, 9H), 0.69−0.64 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 172.6, 172.0, 171.7, 170.3, 170.1, 168.8, 159.1, 145.5, 130.5, 128.1, 124.3, 114.4, 77.7, 66.2, 59.5, 58.2, 55.5, 54.9, 53.7, 50.2, 47.5, 40.1, 37.4, 36.9, 35.3, 34.1, 32.7, 30.7, 30.0, 29.5, 29.0, 26.1, 25.9, 25.3, 19.3, 15.4, 14.3, 10.0; HRMS (ESI-Orbitrap) m/z [M + H+] calcd for C43H67N5O9H 798.5012, found 798.5012. (3S,5S,11R,16S,19S,22S,27aS,E)-22-((S)-sec-Butyl)-3-(tert-butyl)11-(hydroxymethyl)-16-(4-methoxybenzyl)-5,18,19,21-tetramethyl5,6,10,11,12,13,15,16,18,19,21,22,25,26,27,27a-hexadecahydro1H,3H-pyrrolo[2,1-c][1]oxa[4,7,10,13,18]pentaazacyclopentacosine-1,9,14,17,20,23(4H)-hexaone (30R)-37: white amorphous solid (109 mg, 76%); [α]D18 = −34.3 (c 1.00, CHCl3); IR (film) νmax 3821, 3427, 2935, 2256, 1634, 1513, 1180 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.57 (d, J = 6.6 Hz, 1H), 7.12−7.09 (m, 2H), 6.89− 6.84 (m, 1H), 6.83−6.80 (m, 2H), 6.59 (d, J = 9.6 Hz, 1H), 6.09 (d, J = 15.6 Hz, 1H), 5.29−5.26 (m, 1H), 5.17−5.13 (m, 1H), 5.04 (d, J = 11.4 Hz, 1H), 4.80−4.75 (m, 2H), 4.38 (dd, J = 8.4, 4.8 Hz, 1H), 4.03−3.97 (m, 2H), 3.87−3.84 (m, 1H), 3.78 (s, 3H), 3.74−3.69 (m, 2H), 3.15 (dd, J = 13.2, 9.6 Hz, 1H), 2.91 (s, 3H), 2.86 (dd, J = 12.6, 4.8 Hz, 1H), 2.62 (s, 3H), 2.47−2.38 (m, 2H), 2.28−2.22 (m, 2H), 2.15−2.10 (m, 1H), 2.09−2.04 (m, 1H), 2.03−1.94 (m, 4H), 1.80− 1.74 (m, 1H), 1.64−1.57 (m, 1H), 1.43−1.37 (m, 1H), 1.32−1.27 (m, 1H), 1.15 (dd, J = 14.4, 10.8 Hz, 1H), 1.05−0.99 (m, 1H), 0.97−0.03 (m, 6H), 0.88 (s, 9H), 0.84−0.80 (m, 3H), 0.77−0.74 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 172.5, 172.0, 170.4, 169.9, 168.6, 159.0, 143.0, 130.5, 128.2, 123.8, 114.3, 80.8, 63.6, 59.3, 57.6, 55.5, 55.4, 53.0, 50.0, 47.7, 39.9, 39.1, 37.3, 34.8, 34.1, 32.1, 30.3, 29.5, 29.1, 28.0, 26.3, 26.0, 25.5, 24.8, 20.1, 15.6, 14.1, 9.8; HRMS (ESI-Orbitrap) m/z [M + H+] calcd for C43H67N5O9H 798.5012, found 798.5012. General Procedure for the Synthesis of (30S)-38 and (30R)38. (30S)-37/(30R)-37 (80 mg, 0.10 mmol) was dissolved in DCM at −78 °C, and then DAST (26 μL, 0.20 mmol) was added. After being stirred for 2 h, the mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted with DCM (10 mL × 3). The combined organic layers were dried over MgSO4, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/acetone = 3:1) to give the desired compound. 30S-Oxoapratoxin E (30S)-38: white amorphous solid (60 mg, 77%); [α]D18 = −64.0 (c 0.15, CHCl3); 1H NMR (600 MHz, CDCl3, mixture of rotamers) δ 7.16−7.10 (m, 1.65H), 6.82−6.78 (m, 1.65H), 6.71−6.63 (m, 0.65H), 6.63−6.56 (m, 1H), 6.35 (d, J = 15.6 Hz, 0.65H), 6.11 (d, J = 8.4 Hz, 0.65H), 5.95 (d, J = 16.2 Hz, 0.35H), 5.82 (d, J = 10.2 Hz, 0.35H), 5.25−5.22 (m, 1H), 5.18−5.13 (m, 0.35H), 5.00−4.97 (m, 0.35H), 4.95−4.87 (m, 1.65H), 4.66 (dd, J = 12.6, 6.0 Hz, 0.65H), 4.35−4.29 (m, 0.65H), 4.28−4.23 (m, 1H), 4.23−4.19 (m, 0.35H), 4.13−4.07 (m, 1H), 4.02−3.96 (m, 1H), 3.85−3.82 (m, 1H), 2.98−2.75 (m, 3H), 3.68−3.66 (m, 0.35H), 3.66−3.61 (m, 1H), 3.32−3.27 (m, 0.35H), 3.12−3.08 (m, 0.65H), 3.04 (s, 2H), 2.95−2.91 (m, 1H), 2.86 (s, 1H), 2.80 (s, 1H), 2.80−2.76 (m, 0.65H), 2.63 (s, 2H), 2.62−2.56 (m, 1H), 2.42−2.38 (m, 2H), 2.27−2.22 (m, 1H), 2.10−2.02 (m, 2H), 2.00−1.96 (m, 1H), 1.94−1.89 (m, 2H), 1.88− 1.83 (m, 2H), 1.55−1.50 (m, 1H), 1.44−1.41 (m, 1H), 1.26−1.23 (m, 2H), 1.08−1.02 (m, 4H), 0.93−0.90 (m, 3H), 0.87 (s, 9H), 0.85−0.81 (m, 3H), 0.55−0.51 (m, 2H); 13C NMR (150 MHz, CDCl3, mixture of rotamers) δ 172.9, 172.5, 172.2, 171.7, 171.4, 170.6, 170.5, 170.4, 170.1, 169.9, 163.5, 163.4, 158.9, 158.7, 143.9, 143.8, 130.7, 130.6, 128.8, 128.5, 119.4, 118.7, 114.3, 114.0, 77.7, 77.7, 71.8, 67.0, 65.7, 60.7, 59.6, 59.3, 58.0, 57.1, 55.5, 55.4, 54.2, 50.8, 49.9, 47.5, 40.0, 38.3,

37.7, 37.6, 37.4, 36.8, 35.3, 34.8, 34.2, 33.4, 32.8, 32.6, 31.7, 31.0, 29.9, 29.9, 29.6, 29.5, 29.0, 28.8, 27.1, 26.2, 26.1, 25.8, 25.5, 25.4, 20.8, 19.6, 15.0, 14.3, 14.1, 14.0, 10.0; HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C43H65N5O8H 780.4906, found 780.4907. 30R-Oxoapratoxin E (30R)-38: white amorphous solid (63 mg, 81%); [α]D20 = −53.2 (c 0.25, CHCl3); 1H NMR (600 MHz, CDCl3, mixture of rotamers) δ 7.16−7.09 (m, 2H), 6.82−6.79 (m, 2H), 6.78− 6.74 (m, 0.75H), 6.67−6.63 (m, 0.25H), 6.26 (d, J = 16.8 Hz, 0.25H), 6.17 (d, J = 8.4 Hz, 0.75H), 6.00 (d, J = 15.6 Hz, 0.75H), 5.87 (d, J = 9.0 Hz, 0.25H), 5.24 (d, J = 10.8 Hz, 0.25H), 5.18−5.13 (m, 1H), 4.98 (d, J = 11.4 Hz, 0.75H), 4.94 (d, J = 11.4 Hz, 0.25H), 4.88 (d, J = 10.8 Hz, 0.75H), 4.65 (dd, J = 13.2, 6.0 Hz, 0.75H), 4.36−4.32 (m, 1H), 4.29−4.25 (m, 1.75H), 4.18−4.13 (m, 0.25H), 4.07−4.04 (m, 0.25H), 3.93−3.87 (m, 0.75H), 3.77−3.75 (m, 3H), 3.72−3.63 (m, 2H), 3.32− 3.29 (m, 0.25H), 3.10−3.05 (m, 1H), 2.98−2.95 (m, 0.75H), 2.92 (s, 2.25H), 2.86 (s, 0.75H), 2.83−2.81 (m, 0.25H), 2.75 (s, 0.75H), 2.63 (s, 2.25H), 2.49−2.44 (m, 0.75H), 2.42−2.40 (m, 0.25H), 2.39−2.33 (m, 1H), 2.18−2.16 (m, 2H), 2.10−2.02 (m, 3H), 1.97−1.93 (m, 1H), 1.92−1.85 (m, 2H), 1.68−1.62 (m, 1H), 1.58−1.54 (m, 1H), 1.43− 1.41 (m, 0.75H), 1.30−1.24 (m, 4H), 1.18−1.13 (m, 1H), 1.03−1.00 (m, 1H), 0.95−0.91 (m, 4H), 0.88 (s, 9H), 0.86−0.82 (m, 3H), 0.61− 0.59 (m, 2.25H); 13C NMR (150 MHz, CDCl3, mixture of rotamers) δ173.7, 173.3, 172.0, 171.8, 171.4, 170.4, 170.2, 169.9, 169.8, 168.7, 163.8, 163.3, 158.9, 158.7, 143.5, 142.7, 130.7, 130.5, 128.7, 128.6, 118.6, 117.4, 114.2, 114.0, 79.6, 78.9, 72.0, 72.0, 64.8, 64.7, 60.7, 59.5, 59.3, 57.8, 57.4, 55.5, 55.4, 54.4, 54.0, 51.1, 50.0, 47.5, 47.3, 41.5, 40.9, 39.9, 38.3, 38.1, 36.8, 34.5, 34.1, 33.8, 31.9, 31.8, 31.7, 31.5, 31.1, 30.2, 30.1, 30.0, 29.6, 29.4, 29.3, 29.1, 26.1, 25.6, 25.3, 25.1, 20.3, 18.4, 15.3, 14.2, 14.2, 14.1, 10.6, 10.3.; HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C43H65N5O8H 780.4906, found 780.4907. General Procedure for the Synthesis of (S)-40 and (R)-40. Compound (S)-11/(R)-11 (1.30 g, 2.42 mmol) was dissolved in a mixture of THF, MeOH, and H2O (20 mL v/v/v = 1:1:1), and then LiOH·H2O (152 mg, 3.64 mmol) was added in one portion. After being stirred for 7 h, the mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over MgSO4, filtrated, and concentrated. The residue was dissolved in DMSO (10 mL), and K2CO3 (670 mg, 4.84 mmol) and AllylBr (0.26 mL, 3.64 mmol) were added. After being stirred for 4 h, the reaction was diluted with water and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water and brine, respectively, dried over MgSO4, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 2:1) to give the desired compound. Allyl (S/R)-4-acrylamido-5-(tritylthio)pentanoate (S)-40 or (R)40: white amorphous solid (845 mg, 72%); [α]D20 = −23.4 (c 2.00, CHCl3) for (S)-40; [α]D20 = +20.3 (c 2.00, CHCl3) for (R)-40; IR (film) νmax 3272, 3059, 3031, 2953, 1735, 1656, 1627, 1540, 1490, 1243, 1181, 983 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.42−7.37 (m, 6H), 7.30−7.24 (m, 6H), 7.23−7.18 (m, 3H), 6.27−6.18 (m, 1H), 6.03−5.93 (m, 1H), 5.93−5.81 (m, 1H), 5.67−5.59 (m, 2H), 5.32− 5.19 (m, 2H), 4.53−4.48 (m, 2H), 4.10−3.99 (m, 1H), 2.48−2.43 (m, 1H), 2.42−2.35 (m, 1H), 2.32−2.20 (m, 2H), 1.78−1.73 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 172.1, 164.1, 143.6, 131.1, 129.9, 128.6, 127.1, 125.9, 125.7, 117.5, 65.9, 64.4, 47.3, 35.7, 30.0, 28.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C30H31NO3S H 486.2097, found 486.2097. General Procedure for the Synthesis of (S)-39 and (R)-39. Triphenylphosphine oxide (2.24 g, 8.10 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C, and then trifluoromethanesulfonic anhydride (0.69 mL, 4.05 mmol) was added at 0 °C. After being stirred for 10 min, a solution of compound (S)-40/(R)-40 (655 mg, 1.35 mmol) in DCM (5 mL) was dropped, and the mixture was stirred for 10 min. Then the mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, filtrated, and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 4:1) to give the desired compound. 10843


Article

The Journal of Organic Chemistry Allyl (S/R)-3-(2-vinyl-4,5-dihydrothiazol-4-yl)propanoate (S)-39 or (R)-39: white amorphous solid (170 mg, 56%); [α]D20 = −10.7 (c 1.00, CHCl3) for (S)-39, [α]D25 = +12.3 (c 1.00, CHCl3) for (R)39; IR (film) νmax 3275, 3031, 2953, 1735, 1637, 1540, 1243, 1181, 983 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.61 (dd, J = 17.2, 10.4 Hz, 1H), 5.97−5.87 (m, 1H), 5.84−5.73 (m, 2H), 5.32 (dd, J = 17.2, 1.6 Hz, 1H), 5,24 (dd, J = 10.4, 1.2 Hz, 1H), 4.62−4.53 (m, 3H), 3.41 (dd, J = 11.2, 8.8 Hz, 1H), 2.96 (dd, J = 11.2, 8.4 Hz, 1H), 2.62−2.56 (m, 2H), 2.07−2.02 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 173.0, 167.1, 132.3, 132.0, 126.7, 118.4, 76.5, 65.3, 37.3, 31.6, 30.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C11H15NO2SH 226.0896, found 226.0896. General Procedure for the Synthesis of (30S)-42 and (30R)42. To a solution of (S)-39 or (R)-39 (88 mg, 0.39 mmol) in THF (5 mL) were added Pd(PPh3)4 (46 mg, 0.04 mmol) and N-methylaniline (0.10 mL, 0.96 mmol). After being stirred for 1 h, the mixture was concentrated and purified by flash chromatography on silica gel (DCM/MeOH = 30:1) to give crude acid (S)-41/(R)-41 (63 mg, 87%). Compound 34 (237 mg, 0.27 mmol) was dissolved in MeCN (2 mL), then Et2NH (1 mL) was added. After being stirred for 30 min, the reaction mixture was concentrated. The residue was azeotroped with toluene three times and dissolved in MeCN (3 mL), then (S)-41/ (R)-41 (50 mg, 0.27 mmol), FDPP (155 mg, 0.41 mmol) and DIPEA (0.14 mL, 0.81 mmol) was added. After being stirred for overnight at room temperature, the resulting mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated and concentrated. The residue was purified by flash chromatography on silica gel (DCM/MeOH = 40:1) to give the desired compound. (3S,5S)-2,2,5-Trimethyloct-7-en-3-yl N-(N-((S)-3-(4-methoxyphenyl)-2-(3-((S)-2-vinyl-4,5-dihydrothiazol-4-yl)propanamido)propanoyl)-N-methyl- L -alanyl)-N-methyl-L -isoleucyl- L-prolinate (30S)-42: white amorphous solid (127 mg, 57%); [α]D20 = −127.6 (c 0.50, CHCl3); IR (film) νmax 2347, 2351, 1512, 1249, 1167, 1112, 782 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.25−7.23 (m, 1H), 7.10−7.07 (m, 2H), 6.79−6.73 (m, 2H), 6.76−6.74 (m, 1H), 6.73−6.68 (m, 1H), 6.41−6.33 (m, 1H), 5.83−5.72 (m, 2H), 5.44−5.39 (m, 1H), 5.22− 5.18 (m, 1H), 5.05−5.03 (m, 1H), 5.02−4.95 (m, 2H), 4.91−4.88 (m, 1H), 4.49−4.46 (m, 1H), 4.26−4.20 (m, 1H), 3.86−3.81 (m, 1H), 3.76 (s, 3H), 3.68−3.66 (m, 1H), 3.33−3.27 (m, 1H), 3.03−3.00 (m, 1H), 3.00−2.97 (m, 2H), 2.96−2.95 (m, 2H), 2.84−2.83 (m, 2H), 2.79−2.76 (m, 1H), 2.72−2.70 (m, 1H), 2.40−2.33 (m, 2H), 2.28− 2.24 (m, 1H), 2.19−2.16 (m, 1H), 2.04−1.97 (m, 3H), 1.96−1.87 (m, 3H), 1.82−1.78 (m, 2H), 1.49−1.44 (m, 1H), 1.42−1.39 (m, 1H), 1.26−1.23 (m, 3H), 0.97−0.95 (m, 3H), 0.92−0.90 (m, 3H), 0.88 (s, 9H), 0.86−0.83 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 172.4, 172.0, 171.8, 171.7, 169.4, 168.1, 158.8, 148.8, 137.3, 132.0, 130.5, 129.4, 128.1, 126.7, 116.8, 115.9, 114.1, 112.6, 79.6, 76.4, 59.3, 58.0, 55.3, 50.7, 50.3, 49.9, 47.3, 39.7, 38.7, 38.3, 38.0, 36.6, 34.9, 33.8, 33.5, 31.5, 31.0, 30.7, 30.5, 29.4, 28.7, 26.1, 24.9, 24.8, 20.9, 14.9, 14.6, 10.5; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for: C45H69N5O7SH 824.4991, found 824.4991. (3S,5S)-2,2,5-Trimethyloct-7-en-3-yl N-(N-((S)-3-(4-methoxyphenyl)-2-(3-((R)-2-vinyl-4,5-dihydrothiazol-4-yl)propanamido)propanoyl)-N-methyl- L -alanyl)-N-methyl-L -isoleucyl- L-prolinate (30R)-42: white amorphous solid (116 mg, 52%); [α]D20 = −87.4 (c 1.00, CHCl3); IR (film) νmax 2347, 2351, 1512, 1249, 1167, 1112, 782 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.24−7.22 (m, 1H), 7.10−7.07 (m, 2H), 6.80−6.77 (m, 2H), 6.75−6.69 (m, 2H), 6.50−6.35 (m, 1H), 5.83−5.76 (m, 1H), 5.41 (dd, J = 13.2, 6.6 Hz, 1H), 5.17 (dd, J = 15.0, 7.2 Hz, 1H), 5.05−4.97 (m, 3H), 4.87−4.85 (m, 1H), 4.48 (dd, J = 9.0, 3.6 Hz, 1H), 4.36−4.33 (m, 1H), 3.84−3.80 (m, 1H), 3.77−3.75 (m, 3H), 3.68−3.65 (m, 1H), 3.36−3.31 (m, 1H), 3.04−2.99 (m, 1H), 2.97 (s, 3H), 2.95−2.94 (m, 2H), 2.82−2.80 (m, 2H), 2.72−2.69 (m, 1H), 2.35−2.33 (m, 1H), 2.17−2.13 (m, 1H), 2.05−1.97 (m, 4H), 1.97−1.80 (m, 5H), 1.65−1.60 (m, 2H), 1.26−1.23 (m, 3H), 1.22− 1.16 (m, 2H), 0.95−0.93 (m, 3H), 0.89−0.86 (m, 12H), 0.85−0.83 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 172.5, 172.0, 171.8, 171.6, 169.3, 168.2, 158.8, 148.8, 137.7, 131.9, 130.5, 129.4, 128.1, 126.8,

116.8, 115.7, 114.1, 112.6, 79.7, 76.6, 59.3, 58.0, 55.3, 50.7, 50.3, 49.9, 47.3, 42.7, 38.7, 38.3, 37.9, 36.7, 34.8, 33.5, 31.5, 30.9, 30.6, 30.4, 29.4, 28.7, 26.1, 24.9, 24.8, 18.8, 14.9, 14.6, 10.5; HRMS (ESI-Orbitrap) m/ z [M + H]+ calcd for C45H69N5O7SH 824.4991, found 824.4991. General Procedure for the Synthesis of Proposed Apratoxin E (30S-7) and Revised Apratoxin E (30R-7). Compound (30S)42/(30R)-42 (82 mg, 0.10 mmol) and Grubbs second (cat.) were refluxed in DCM (10 mL) under Ar atmosphere for 24 h to give the crude product, which was purified by flash chromatography on silica gel (PE/EA = 1:1) to give proposed apratoxin E (30S-7) (30 mg, 38%) and revised apratoxin E (30R-7) (33 mg, 41%).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01598. 1 H and 13C NMR spectra of related compounds; comparison of NMR data of natural and synthetic apratoxin E; comparison HPLC data of isolated apratoxin E and synthetic apratoxin E (30R 7); comparison HPLC data of our synthetic 30R/S-oxoapratoxin E (30R/S-38) and Zhang’s synthetic 30R/S-oxoapratoxin E; comparison HPLC data of (30S)-apratoxin E (30S 7)/(30R)apratoxin E (30R 7) and (30S)-oxoapratoxin E (30S 38)/(30R)-oxoapratoxin E (30R 38) (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Bang-Guo Wei: 0000-0003-3470-6741 Present Address §

(H.-Q.D.) Arvinas, Inc., 5 Science Park, New Haven, CT 06511. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21472022, 21272041, 21072034) for financial support. We thank Dr. Jing-Yi Ma for the preparation of several synthetic intermediates. We thank Prof. Wei-Sheng Tian and Prof. ZhenTing Du for providing the lactone 10. We thank Dr. Zhu Zhou for structure analysis of synthetic compounds. Moreover, we thank Prof. Hendrik Luesch for providing isolated apratoxin E.

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DEDICATION Dedicated to Prof. Jin-Xian Wang on the occasion of his 80th birthday. REFERENCES

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