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Article Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX

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Highly Enantioselective Semisynthesis of (+)/(−)-Gossypol Schiff Base Derivatives from Ground Plant Material Mohamed V. Sidi Boune,†,‡ Brahim Elemine,‡ Ahmed Aliyenne,†,§ Abderrahmane Hadou,‡ Adam Daïch,† Mohamed Othman,† and Ata M. Lawson*,† †

Normandie Université France, UNILEHAVRE, URCOM, EA 3221, FR 3038 CNRS, F-76600 Le Havre, France Université de Nouakchott Al-Aasriya, Nouakchott, Mauritanie, UCME, BP 5026 Nouakchott, Mauritanie § Département des Sciences Exactes, Ecole Normale Supérieure de Nouakchott, BP 90 Ksar, BP 990 Nouakchott, Mauritanie Downloaded via BUFFALO STATE on July 24, 2019 at 02:39:49 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

‡

S Supporting Information *

ABSTRACT: We have recently developed a one-pot process for simultaneous extraction and chemical modification (SECheM) on Cienfuegosia digitata, a Mauritanian Malvaceae called locally “Izide”. On the basis of this innovative methodology that consisted of using ground plant roots as starting material in gossypol Schiff base semisynthesis, we now report how this concept can be used to access enantiomerically pure Schiff base atropisomer derivatives of gossypol in only two steps. This study has been envisioned since enantiomerically pure Schiff base atropisomer derivatives of gossypol are generally more potent biologically when compared to racemic gossypol Schiff bases.

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ossypol is a natural phenolic pigment known to be sensitive to solvents, high temperature, and light. For these reasons, gossypol is frequently transformed into Schiff base derivatives, less subjected to degradation. Moreover, both gossypol and its Schiff base derivatives suffer from atropoisomerism, slow in the dark and greatly accelerated by sunlight or light.1 These parameters complicate the extraction and isolation processes of gossypol. This pigment is also known for its various biological activities.2−7 Indeed, the biological importance of gossypol and its Schiff base derivatives is well established.8−10 However, gossypol is known to be toxic, and its formyl group is presumed to be responsible for this toxicity.11 Thus, to decrease the toxicity and enhance the biological activity, gossypol is frequently derivatized into diverse Schiff base derivatives, necessary for structure−activity relationship (SAR) studies (Figure 1).10b,12,13 Through the improvement of biological activities, Schiff base derivatives of gossypol resulted in a substantial and growing scientific interest compared to gossypol.14,15 Therapeutic effects of enantiomerically pure gossypol Schiff base derivatives have been recognized as effective against serious disorders such as cancer, HIV (human immunodeficiency virus), and bacterial diseases, through their cytotoxic effect, antibacterial activity, and antiproliferative and antioxidant activities.16−19 This biological potential has prompted the scientific community to access enantiomerically pure gossypol Schiff base derivatives starting from the expensive gossypol usually obtained by an extraction process. Enantiomerically pure Schiff base derivatives of gossypol are prepared via a three-step procedure from racemic gossypol. Several research groups working on this topic resolve (±)-gossypol by © XXXX American Chemical Society and American Society of Pharmacognosy

Figure 1. Modulation of gossypol into corresponding Schiff base derivatives of biological interest.

treatment with chiral amino acid derivatives such as Lphenylalaninol, L-tryptophane methyl ester, or (+)-phenylalanine methyl ester.20,21 The resulting diastereomeric adducts were separated by selective crystallization or by chromatography.22 After their separation, every single diastereomeric adduct was subjected to hydrolysis, leading to the generation of the resolved free gossypol. The resulting (+)- and (−)-enantiomers of gossypol were treated with different amines to access enantiomerically pure Schiff base derivatives. The hydrolysis step is sensitive and requires a specific ratio between HCl (37%) and HOAc (1:22).22,23 Indeed, the HCl− HOAc ratio was maintained during the hydrolysis reaction in order to prevent precipitation of gossypol together with tryptophan methyl ester salt that would require supplementary Received: December 10, 2018

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DOI: 10.1021/acs.jnatprod.8b01045 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

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Scheme 1. Literature Methods and the New Two-Step Process to Generate Gossypol-Derived Enantiomerically Pure Schiff Bases

treatments for the critical step of gossypol purification. Another major drawback of this three-step approach is that the instability inherent to gossypol makes this procedure less efficient. To overcome these limitations, we report herein a new methodology based on a short two-step process starting from a Cienfuegosia digitata root extract as a source of (±)-gossypol. The first step is based on the recently published SECheM concept24 using chiral amino alcohols. After a flash chromatographic separation of diastereomeric adducts, a transamination reaction was used to obtain enantiomerically pure Schiff base derivatives without proceeding through the critical hydrolysis step. This two-step methodology is the most practical route to access enantiomerically pure Schiff base derivatives of gossypol with both good overall yield and high enantiomeric purities.

preventing laborious separation and purification steps. As this pragmatic “one-pot” semisynthesis approach is simple to handle, the same concept was applied in the semisynthesis of enantiomerically pure gossypol Schiff base derivatives by using chiral amines. To evaluate the feasibility of the strategy, several chiral amines were used in the SECheM concept. Chiral amines were used to prepare diastereomeric gossypol Schiff base derivatives; these mixtures were separated using normalphase flash chromatography. In the case of a successful separation, every pure diastereomeric adduct was analyzed by chiral-phase HPLC in order to evaluate and quantify the purity through the diastereomeric excess (de) determination. Finally, the [α]D values of separated diastereomeric adducts were used to identify (−)- or (+)-isomers. As shown in Table 1, the use of a chiral amine such as (S)-1phenylethanamine (entry 1) led to two inseparable diastereomeric enamines 1a, since no difference in Rf was observed between 1a′ and 1a″ by using cyclohexane/EtOAc (1:1) as a thin-layer chromatography (TLC) solvent. However, when a chiral amino alcohol such as (S)-2-amino-3-methylbutan-1-ol was used in SECheM, the resulting diastereomeric enamines 1b (1b′ and 1b″) were separated on TLC (ΔRf = 0.25), allowing their separation via flash chromatography (entry 2).

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RESULTS AND DISCUSSION In the previous paper,24 a SECheM (simultaneous extraction and chemical modification) concept that permitted the successful transformation of gossypol into more stable Schiff base derivatives was described. More widely known as reactive extraction, this strategy applied to C. digitata roots allowed instantaneous trapping of freshly extracted gossypol, thus B



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Table 1. Experimental Screening Conditions with Chiral Amines24,25

a

TLC solvent: cyclohexane/EtOAc (1:1). bTLC solvent: cyclohexane/EtOAc (9:1). cThe eluted compound sign was determined by the sign of the [αD] value. dDiastereomeric excess (de) was furnished by chiral-phase HPLC analysis. eNot realized. fOverall isolated yield = yield of first eluted + yield of second eluted.

same, with 100% de for the first eluted and >97% de for the second. An amino alcohol with one more hydroxy group [(1S,2S)-2-amino-1-phenylbutane-1,3-diol, entry 3] led to

Indeed, the flash chromatography led to the separation of 1b′ and 1b″ in 37% isolated yield for 1b′ and 23% for 1b″. For both adducts, diastereomeric excesses are substantially the C



Article

to produce diastereomerically pure Schiff base derivatives. As the (+)-isomer of the Shiff base derived from (R)-phenylglycinol was obtained in high yield (43%) and de (>99%) (Table 1, entry 7), this derivative was used as a valuable platform for the preparation of enantiomerically pure Schiff base gossypol derivatives through a transamination reaction. In this regard, p-methylbenzylamine was selected as a partner to test the transamination reaction. Several parameters such as the number of equivalents of the amine, temperature, and acid catalysis conditions were studied (Table 2). The reaction was first tested at reflux in CH2Cl2 for 2.5 h. The use of 2 equiv of p-methylbenzylamine (MBA) surprisingly led to two products. Besides the target product 2 (38%), a partially substituted Schiff base 3 (25%) was also obtained. To decrease the yield of the unwanted product 3, the number of equivalents of the amine was increased to 10. As displayed in Table 2, when the number of equivalents increased, the yield of purified compound 3 declined from 25% to 6%, while 2 varies from 38% to 65%. As the use of 10 equiv of amine led to a good yield (65%) of targeted compound 2, this equivalent number was used for further screening. The effect of catalysts such as Brönsted acids to improve the yield of compound 2 was next investigated. Thus, the use of a catalytic amount of TFA (trifluoroacetic acid) led to full conversion in only 30 min. In this case, 77% of 2 was obtained, whereas only traces of 3 were recovered (entry 6). The yield of 2 was slightly lowered (72%) when PTSA (ptoluene sulfonic acid) was used as Brönsted acid (entry 7). The same yield of 72% was obtained when EtOH was used at reflux in the presence of TFA (entry 8). It is important to notice that the latter conditions as well as previously tested conditions of CH2Cl2 under reflux (entry 1 to entry 8) led to racemization of compound 2. To avoid the racemization, the transamination reaction was carried out at room temperature in EtOH. Under these conditions in the presence of a catalytic amount of TFA, the reaction successfully provided the expected product 2 (entry 9). However, longer reaction time (2 h) was needed for full conversion of 1g′, and satisfactorily, racemization of 2 was not observed and only traces of 3 were generated. A slight decrease of the yield (67% to 65%) was observed when the same reaction was performed without TFA (entry 9 vs entry 10). Conditions of entry 9 were then chosen as the best conditions for the reaction. After the optimization of the transamination reaction leading to enantiomerically pure Schiff base derivatives, the scope of the reaction was further studied for diversification. This study showed that the reaction conditions were conducive to the use of different primary amines. The diversification on diastereomerically pure (R)-(+)-1g′ led to a large number of different enantiomerically pure (+)-Schiff base derivative in good yields ranging from 39% for (+)-4f to 82% for (+)-4b. It is important to note that sterically hindered amines also generated monosubstituted Schiff base derivatives. This behavior could be one of the reasons for the low yield observed for (+)-4f (39%) and (+)-4i (40%). However, due to its weak nucleophilicity, aniline failed to provide Schiff base derivatives, and only starting material was recovered. Since the diastereomeric excesses of enantiomerically pure (−)-Schiff base derivatives are slightly lower, only five examples were synthesized. Notably, for both the synthesized (+)- and (−)-enantiomer series, the HPLC and [α]D analyses were rapidly performed, as some of Schiff base derivatives can be subjected to photoepimerization as previously demonstra-

more polar diastereomeric enamines 1c (ΔRf = 0.33). In this case, the separation of 1c′ and 1c″ requires a longer time since both isomers are strongly retained on the solid-phase system. Subsequently, the yield of isolated diastereomeric adducts of 1c declined, with 32% for 1c′ and 21% for 1c″. To summarize, the use of a chiral amino alcohol with at least one free hydroxy group is imperative for efficient chromatographic separation. This hypothesis was confirmed by the use of protected chiral amino alcohols that failed to provide pure enamines 1d and 1e through flash chromatography separation by using cyclohexane/EtOAc (1:1) as the solvent system (entries 4 and 5). By using a less polar eluent (cyclohexane/EtOAc, 9:1), the separation of 1d′ and 1d″ remained unsuccessful, while 1e efficiently provided 1e′ and 1e″ with almost the same de as those of entry 2 (entry 5). Inseparable diastereomeric adducts of 1f were also obtained by using a secondary amino alcohol with the stereogenic center in the β-position to the nitrogen atom (entry 6). Finally, the use of (R)- or (S)-2-phenylglycinol allowed separation of 1g and 1h in terms of yield and purity, as shown in entries 7 and 8. The (R)-2-phenylglycinol furnished the first eluted Schiff base 1g′, which was assigned as the (+)-isomer with >99% de, and 1g″, as the (−)-isomer (78.5% de). The elution order was reversed by considering the (S)-2phenylglycinol adducts, 1h′ and 1h″, with higher purity for the first eluted (de > 99%) that was determined as the (−)-isomer. The first eluted adduct of both Schiff bases 1g′ and 1h′ displayed the highest de, while the de of the second one remained lower due to contamination induced by the peaktailing effect of previous isomers. As reported by Matlin et al., this contamination is one of the main problems in the separation of gossypol Schiff base atropisomers.26 From these observations, the latter result remains interesting, as the first eluted compounds from (R)- and (S)-2-phenylglycinol Schiff base derivatives provided by acidic hydrolysis an efficient access to both enantiopure free (+)- and (−)-gossypol in quantitative yields (Scheme 2). This inversion in elution order results in circumvention of contamination problems in accessing both pure gossypol atropisomers. Based on these results (R)-phenylglycinol was chosen as the best chiral amine Scheme 2. Access to Enantiomerically Pure (+)- and (−)-Gossypol by Changing the Configuration of the Amino Alcohol

D



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Table 2. Screening of Transamination Reaction Conditions

a

MBA: methlybenzylamine. bSum of compounds 2 and 3 isolated yield. rt = room temperature.

ted.1,27 This phenomenon seems to occur very rapidly for (+)-4g. Such behavior could potentially explain the 95.5% ee obtained for this compound, which is, however, somewhat lower than those in the same series (>98% ee). Mechanistically, the transamination reaction would proceed through a 1,4-aza-Michael addition assisted by Brönsted acid catalysis on the enaminone unit. This first step led to intermediate A, which could be transformed into B by simple proton exchange. Finally, the enaminone unit was regenerated through a 1,4-retro-aza-Michael addition, leading to the release of the amino alcohol moiety. This mechanism was proposed on the basis of publications dealing with the influence of protonation on molecular structures of gossypol Schiff bases.28 In conclusion, we have successfully developed a new twostep procedure for the rapid synthesis of enantiomerically pure Schiff base derivatives of (+)- and (−)-gossypol in good yields and excellent ee. This procedure has been inspired by the recently developed SECheM methodology by using (R)phenylglycinol as chiral amine. Indeed, chiral amino alcohol diastereomeric adducts of gossypol were exploited, resulting in an easy and practical preparative chromatographic separation that takes advantage of SiO2 as the stationary phase. As a result, a large amount of both atropisomers of gossypol Schiff base derivatives can be achieved contrary to the existing methods that employed analytical HPLC. Furthermore, a simple transamination reaction provides enantiomerically pure Schiff base derivatives. This two-step atroposelective transformation can be considered as an atom-economic and green alternative procedure. The reaction was performed directly on ground plant material containing gossypol, and the critical step

of Schiff base hydrolysis was avoided. As derivatization of gossypol and related compounds leads to enhanced activity and eudysmic ratio,29 the methodology developed herein represents a practical and powerful route for the semisynthesis of a library of biologically relevant compounds. Finally, the methodology allows quantification of both atropisomers of gossypol in the plant material. Consequently, the (+)-gossypol proportion (55%) is estimated as slightly higher than the (−)-gossypol (45%) in C. digitata. This gossypol atropisomer ratio is close to those obtained from Gossypium hirsutum cottonseeds.30

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EXPERIMENTAL SECTION

General Experimental Procedures. Unless otherwise specified, reagents used in gossypol Schiff base synthesis were purchased from traditional suppliers (Sigma-Aldrich, Acros, or Alfa Aesar) and were used without further purification. Transamination reactions were carried out in standard glassware. Melting points were recorded on a Stuart Scientific Analyzer SMP 10 apparatus and are uncorrected. Infrared spectra were performed neat on a PerkinElmer FT-IR spectrophotometer, and only broad or strong signals are reported. Optical rotations were measured on a 241 polarimeter. NMR spectra were recorded at 300 MHz for 1H, 75 MHz for 13C, and 282 MHz for 19 F at room temperature in CDCl3 or DMSO-d6 using tetramethylsilane as internal standard (δ = 0). High-resolution ESI mass spectra were measured on a 6530 Q-TOF Agilent System spectrometer. Separation procedures were carried out using an Interchim PuriFlash 430 system equipped with a UV detector. Silicon dioxide (SiO2) (30 to 50 μm) was used as the solid phase, and a mixture of cyclohexane/ EtOAc or a gradient from cyclohexane to variable mixtures of cyclohexane/EtOAc was used as the eluent. Chiral-phase HPLC E



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Scheme 3. Scope of the Reaction

analyses were performed using a CHIRALPAK(R) IC column (250 × 4.66 mm, 5 μm) as stationary phase. Plant Material. C. digitata was collected in the region of Adala (Hodh Ech Chargui, Mauritania, N 18°11′38.8″; O 7°5′31.794″) in August 2015. The plant was identified by Prof. Ahmed Ismail̈ Boumediana in the Botany Laboratory of the Ecole Normale Supérieure de Nouakchott, Mauritania, and a voucher specimen

(HNM 02349) was deposited in the National Herbarium of Mauritania. General Procedure for Racemic Gossypol Schiff Base Derivative Semisynthesis Using Chiral Amines. The racemic diastereomeric gossypol Schiff base derivatives were synthesized according to a published procedure.24 To 200 mL of Et2O was added the corresponding amine (6 equiv). After assembling the Soxhlet system with 20 g of dried and ground roots in the cartridge (34 × 37 F



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Scheme 4. Proposed Mechanism of Transamination Reaction

× 130 mm), the device was heated at reflux for 7 h. The reaction mixture was evaporated under vacuum, and Schiff base atropisomers were separated by flash column chromatography (gradient from 100% cyclohexane to variable mixtures of cyclohexane/EtOAc). The separated gossypol Schiff base atropisomer fractions were collected and evaporated to two-thirds. Addition of cyclohexane led to the precipitation of the compound after cooling to room temperature and then to 10 °C. Finally, the corresponding Schiff base derivative was recovered by filtration. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl8,8′-bis{[(S-1-phenylethyl)amino]methylene}-[2,2′-binaphthalene]7,7′(8H,8′H)-dione (1a): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 8:2), Rf = 0.5 (TLC eluent: cyclohexane/EtOAc, 8:2), mp = 97−98 °C, 127.54 μL of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 111 mg was isolated, 93% yield; IR (νmax/cm−1) 3273 (νO−H), 1606 (νCO), 1492 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.75 (br s, 4NH), 9.67 (d, J = 8.4 Hz, 4H), 7.99 (br s, 4OH), 7.56 (s, 2H), 7.55 (s, 2H), 7.37−7.16 (m, 20H), 5.54 (br s, 4OH), 4.67 (m, 4H), 3.70 (m, 4H), 2.07 (s, 6H), 2.04 (s, 6H), 1.68 (d, J = 6.9, Hz, 6H), 1.66 (d, J = 6.9, Hz, 6H), 1.50 (d, J = 7.2, 12H), 1.49 (d, J = 7.2, 12H); 13C NMR (75 MHz, CDCl3) δC 172.8 (C-7), 161.3 (C-11), 149.0 (C-1), 147.2 (C6), 141.8 (C-18), 131.8 (C-3), 2 × 129.1 (C-20, C-22), 129.0 (C-10), 128.0 (C-21), 127.5 (C-5), 2 × 126.0 (C-19, C-23), 118.2 (C-4), 115.8 (C-2), 114.7 (C-9), 103.4 (C-8), 59.8 (C-17), 27.5 (C-12), 23.2 (C-16), 20.4 (C-13), 20.4(C-14), 20.1 (C-15); HRMS (ESI+) calcd for C46H48N2O8 [M + H]+ 725.3585, found 725.3585. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-8,8′-bis{[(S-1-hydroxy-3-methylbutan-2-yl)amino]methylene}-5,5′-diisopropyl-3,3′-dimethyl-[2,2′binaphthalene]-7,7′(8H,8′H)-dione. First eluted Schiff base atropisomer 1b′: yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 6:4) followed by selective precipitation in cyclohexane, Rf = 0.4 (TLC eluent: cyclohexane/ EtOAc, 6:4), mp = 150−151 °C, 110.22 μL of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 42 mg was isolated, 37% yield; [α]D = −251 (c 0.0002 CH2Cl2); HPLC tR = 4.96 min (de = 99%, i-PrOH/nheptane, 50:50); IR (νmax/cm−1) 3276 (νO−H), 1616 (νCO), 1490 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.42 (br s, 2NH), 9.67 (d, J = 5.4 Hz, 2H), 7.97 (br s, 2OH), 7.59 (s, 2H), 5.59 (br s, 2OH), 3.86−3.68 (m, 6H), 3.21−3.15 (m, 2H), 2.10 (s, 6H), 2.00 (hept, J = 6.6 Hz, 2H), 1.52 (d, J = 7.0 Hz, 6H), 1.51 (d, J = 7.0 Hz, 6H), 0.99 (d, J = 6.9 Hz, 6H), 0.98 (d, J = 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 172.5 (C-7), 163.4 (C-11), 149.0 (C-1), 147.1 (C6), 131.9 (C-3), 128.9 (C-10), 127.6 (C-5), 118.1 (C-4), 115.8 (C2), 114.7 (C-9), 103.3 (C-8), 69.5 (C-17), 63.6 (C-16), 29.6 (C-18), 27.4 (C-12), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15), 19.7 (C-19), 18.3 (C-20); HRMS (ESI+) calcd for C40H52N2O8 [M + H]+ 689.3796, found 689.3816. Second eluted Schiff base atropisomer 1b″: yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 5:5) followed by selective precipitation in cyclohexane, Rf = 0.3 (TLC eluent: cyclohexane/EtOAc, 6:4), mp = 154−155 °C, 110.22 μL of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 25.85 mg was isolated, 23% yield, [α]D = +139 (c 0.0002 CH2Cl2); HPLC tR = 6.04 min (de = 99%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3276 (νO−H), 1616 (νCO), 1490 (νC C); NMR (300 MHz, CDCl3) δH 13.35 (br s, 2NH), 9.65 (d, J = 5.4 Hz, 2H), 7.94 (br s, 2OH), 7.58 (s, 2H), 5.72 (br s, 2OH), 3.82−3.63 (m, 6H), 3.15 (br s, 2H), 2.11 (s, 6H), 1.98−1.91 (m, 2H), 1.52 (d, J

= 6.7 Hz, 6H), 1.50 (d, J = 6.7 Hz, 6H), 0.97 (d, J = 7.1 Hz, 6H), 0.95 (d, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 172.4 (C-7), 163.5 (C-11), 149.0 (C-1), 147.1 (C-6), 131.9 (C-3), 128.8 (C-10), 127.6 (C-5), 118.1 (C-4), 116.0 (C-2), 114.8 (C-9), 103.3 (C-8), 69.6 (C-17), 63.6 (C-16), 29.5 (C-18), 27.4 (C-12), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15), 19.6 (C-19), 18.2 (C-20); HRMS (ESI+) calcd for C40H52N2O8 [M + H]+ 689.3796, found 689.3812. (8Z,8′Z)-8,8′-Bis{[(1S,2S-1,3-dihydroxy-1-phenylpropan-2-yl)amino]methylene}-1,1′,6,6′-tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl-[2,2′-binaphthalene]-7,7′(8H,8′H)-dione. First eluted Schiff base atropisomer 1c′: yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 6:4) followed by selective precipitation in cyclohexane, Rf = 0.4 (TLC eluent: cyclohexane/ EtOAc, 6:4), mp = 146−147 °C, 165.4 mg of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 43.5 mg was isolated, 32% yield; IR (νmax/cm−1) 3279 (νO−H), 1609 (νCO), 1492 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.48 (br s, 2NH), 9.54 (br s, 2H), 7.97 (br s, 2OH), 7.56 (s, 2H), 7.23 (d, J = 7.5 Hz, 4H), 7.18−7.13 (m, 6H), 5.43 (br s, 2OH), 3.92−3.41 (m, 6H), 3.06−2.84 (m, 4H), 2.07 (s, 6H), 1.52 (d, J = 7.2 Hz, 12H).; 13C NMR (75 MHz, CDCl3) δC 172.8 (C-7), 162.4 (C-11), 148.9 (C-1), 147.1 (C-6), 136.6 (C-19), 131.9 (C-3), 2 × 129.2 (C-20, C-24), 129.0 (C-10), 2 × 128.8 (C-21, C-23), 127.6 (C-5), 126.9 (C-22), 118.1 (C-4), 115.7 (C-2), 114.6 (C-9), 103.3 (C-8), 64.5 (C-17), 64.4 (C-16), 38.3 (C-18), 27.4 (C12), 20.4 (C-13), 20.3 (C-14), 20.0 (C-15); HRMS (ESI+) calcd for C48H52N2O10 [M + H]+ 817.3695, found 817.3650. Second eluted Schiff base atropisomer 1c″: yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 6:4) followed by selective precipitation in cyclohexane, Rf = 0.3 (TLC eluent: cyclohexane/EtOAc, 6:4), mp = 142−143 °C, 165.4 mg of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 28.5 mg was isolated, 21% yield, [α]D = +134 (c 0.0002 CH2Cl2); IR (νmax/cm−1) 3308 (νO−H), 1611 (νCO), 1494 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.32 (br s, 2NH), 9.43 (br s, 2H), 7.55 (s, 2H), 7.18 (m, 6H), 7.10 (m, 4H), 3.75−3.55 (m, 6H), 2.98−2.84 (m, 4H), 2.05 (s, 6H), 1.52 (d, J = 7.4 Hz, 12H), 1.49 (d, J = 7.4 Hz, 12H); 13C NMR (75 MHz, CDCl3) δC 172.5 (C-7), 162.7 (C-11), 148.9 (C-1), 147.1 (C-6), 136.5 (C-19), 131.8 (C-3), 2 × 129.3 (C-20, C-24), 128.9 (C10), 2 × 128.8 (C-21, C-23), 127.7 (C-5), 126.9 (C-22), 118.0 (C-4), 115.9 (C-2), 114.7 (C-9), 103.3 (C-8), 64.7 (C-17), 64.4 (C-16), 38.3 (C-18), 27.4 (C-12), 20.4 (C-13), 20.3 (C-14), 20.0 (C-15); HRMS (ESI−) calcd for C48H52N2O10 [M − H]− 815.3549, found 815.3536. (8Z,8′Z)-8,8′-Bis{[(R-1-(benzyloxy)butan-2-yl)amino]methylene}1,1′,6,6′-tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl-[2,2′-binaphthalene]-7,7′(8H,8′H)-dione (1d): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 6:4), Rf = 0.3 (TLC eluent: cyclohexane/EtOAc, 8/2), mp = 179−180 °C, 177.34 mg of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 102 mg was isolated, 74% yield; IR (νmax/cm−1) 3262 (νO−H), 1605 (νC O), 1492 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.42 (br s, 4NH), 9.71 (d, J = 9.3 Hz, 4H), 8.05 (br s, 4OH), 7.60 (s, 4H), 7.29−7.11 (m, 20H), 5.47 (s, 2OH), 5.46 (s, 2OH), 4.53 (d, J = 2.5 Hz, 4H), 4.51 (br s, 4H), 3.76 (hept, J = 7.1 Hz, 4H), 3.66−3.52 (m, 4H), 3.48 (br s, 4H), 2.11 (s, 6H), 2.10 (s, 6H), 1.82−1.67 (m, 8H), 1.56 (d, J = 6.9 Hz, 12H), 1.54 (d, J = 6.9 Hz, 12H), 1.05−0,95 (m, 12H); 13C NMR (75 MHz, CDCl3) δC 172.5 (C-7), 162.7 (C-11), 149.0 (C-1), 147.2 (C-6), 137.6 (C-21), 131.7 (C-3), 128.9 (C-10), 2 G



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× 128.3 (C-23, C-25), 127.7 (C-24), 2 × 127.6 (C-22, C-26), 127.2 (C-5), 118.1 (C-4), 115.7 (C-2), 114.9 (C-9), 103.1 (C-8), 73.4 (C20), 72.2 (C-19), 62.6 (C-18), 27.4 (C-12), 25.0 (C-17), 20.4 (C13), 20.3 (C-14), 20.1 (C-15), 10.4 (C-16); HRMS (ESI+) calcd for C52H60N2O8 [M + H]+ 841.4422, found 841.4451. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-5,5′-diisopropyl-8,8′-bis{[(R-2methoxy-1-phenylethyl)amino]methylene}-3,3′-dimethyl-[2,2′-binaphthalene]-7,7′(8H,8′H)-dione. First eluted Schiff base atropisomer 1e′: yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 9:1), Rf = 0.3 (TLC eluent: cyclohexane/EtOAc, 8:2), mp = 99−100 °C, 149.6 mg of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 50.5 mg was isolated, 40% yield; [α]D +377 (c 0.0002 CH2Cl2); HPLC tR = 06.867 min (de > 99%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3280 (νO−H), 1607 (νCO), 1493 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.93 (br s, 2NH), 9.67 (br s, 2H), 8.05 (br s, 2OH), 7.58 (s, 2H), 7.39−7.27 (m, 10H), 5.45 (br s, 2OH), 4.70 (d, J = 6.2 Hz, 2H), 3.80−3.68 (m, 6H), 3.40 (s, 6H), 2.09 (s, 6H), 1.54 (d, J = 6.9 Hz, 6H), 1.52 (d, J = 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 173.0 (C-7), 162.5 (C-11), 149.0 (C-1), 147.1 (C-6), 137.5 (C-18), 131.9 (C-3), 129.1 (C-10), 2 × 129.0 (C-20, C-22), 128.4 (C-21), 127.5 (C-5), 2 × 126.8 (C-19, C-23), 118.1 (C-4), 115.7 (C-2), 114.7 (C9), 103.6 (C-8), 76.0 (C-16), 64.4 (C-17), 59.4 (C-24), 27.4 (C-12), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15); HRMS (ESI+) calcd for C48H52N2O8 [M + H]+ 785.3796, found 785.3790. Second eluted Schiff base atropisomer 1e″: yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 7:3), Rf = 0.3 (TLC eluent: cyclohexane/EtOAc, 7:3), mp = 100−101 °C, 149.6 mg of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 40 mg was isolated, 31% yield; [α]D −302 (c 0.0002 CH2Cl2); HPLC tR = 08.099 min (de > 98%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3280 (νO−H), 1607 (νCO), 1493 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.96 (br s, 2NH), 9.69 (br s, 2H), 7.56 (s, 2H), 7.42− 7.29 (m, 10H), 5.48 (br s, 2OH), 4.72 (t, J = 6.3 Hz, 2H), 3.76−3.65 (m, 6H), 3.41 (s, 6H), 2.05 (s, 6H), 1.53 (d, J = 7.2 Hz, 6H), 1.52 (d, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 172.9 (C-7), 162.5 (C-11), 149.0 (C-1), 147.2 (C-6), 137.4 (C-18), 131.9 (C-3), 2 × 129.1 (C-20, C-22), 129.0 (C-10), 128.5 (C-21), 127.5 (C-5), 2 × 126.9 (C-19, C-23), 118.1 (C-4), 115.7 (C-2), 114.7 (C-9), 103.6 (C8), 76.1 (C-16), 64.4 (C-17), 59.4 (C-24), 27.4 (C-12), 20.4 (C-13), 20.3 (C-14), 20.0 (C-15); HRMS (ESI+) calcd for C48H52N2O8 [M + H]+ 785.3796, found 785.3784. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-8,8′-bis{[(S-2-hydroxypropyl)amino]methylene}-5,5′-diisopropyl-3,3′-dimethyl-[2,2′-binaphthalene]-7,7′(8H,8′H)-dione (1f): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 4:6) followed by selective precipitation in cyclohexane, Rf = 0.3 (TLC eluent: cyclohexane/EtOAc, 3/7), mp = 145−146 °C, 77.89 μL of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 45 mg was isolated, 43% yield; IR (νmax/cm−1) 3280 (νO−H), 1616 (νCO), 1490 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.27 (br s, 4NH), 9.63 (br s, 4H), 7.93 (br s, 4OH), 7.57 (s, 4H), 5.70 (br s, 4OH), 4.03− 3.97 (m, 4H), 3.71 (hept, J = 7.1 Hz, 4H), 3.52 (dd, J = 13.3, 3.8 Hz, 4H), 3.33 (dd, J = 13.4, 7.4 Hz, 4H), 2.10 (s, 12H), 1.51 (d, J = 7.1 Hz, 12H), 1.50 (d, J = 7.1 Hz, 12H), 1.25−1.20 (m, 12H); 13C NMR (75 MHz, CDCl3) δC 172.7 (C-7), 163.8 (C-11), 149.0 (C-1), 147.1 (C-6), 132.0 (C-3), 128.9 (C-10), 127.7 (C-5), 118.1 (C-4), 115.9 (C-2), 114.7 (C-9), 103.4 (C-8), 67.0 (C-18), 57.7 (C-17), 27.4 (C12), 20.6 (C-19), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15); HRMS (ESI+) calcd for C36H44N2O8 [M + H]+ 633.3170, found 633.3165. 8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-8,8′-bis{[(R-2-hydroxy-1phenylethyl)amino]methylene}-5,5′-diisopropyl-3,3′-dimethyl[2,2′-binaphthalene]-7,7′(8H,8′H)-dione. First eluted Schiff base atropisomer 1g′: yellow-orange solid obtained by flash column chromatography (gradient from 100% cyclohexane to cyclohexane/ EtOAc, 5:5) followed by selective precipitation in cyclohexane, Rf = 0.4 (TLC eluent: cyclohexane/EtOAc, 6:4), mp = 176−177 °C, 135.7 mg of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 53.25 mg was isolated, 43% yield; [α]D = +617 (c 0.0002 CH2Cl2); HPLC tR = 06.724 min (de > 99%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1)

3300 (νO−H), 1616 (νCO), 1494 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.94 (br s, 2NH), 9.70 (br s, 2H), 7.95 (br s, 2OH), 7.57 (s, 2H), 7.37−7.28 (m, 10H), 5.49 (br s, 2OH), 4.61 (t, J = 6.1 Hz, 2H), 3.97−3.95 (m, 4H), 3.72 (hept, J = 7.1 Hz, 2H), 2.07 (s, 6H), 1.52 (d, J = 7.1 Hz, 6H), 1.51 (d, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 173.0 (C-7), 162.6 (C-11), 149.0 (C-1), 147.1 (C6), 137.1 (C-18), 132.0 (C-3), 2 × 129.1 (C-20, C-22), 129.1 (C-10), 128.5 (C-21), 127.9 (C-5), 2 × 126.7 (C-19, C-23), 118.2 (C-4), 115.8 (C-2), 114.6 (C-9), 103.8 (C-8), 66.6 (C-17), 66.5 (C-16), 27.4 (C-12), 20.3 (C-13), 20.3 (C-14), 20.0 (C-15); HRMS (ESI+) calcd for C46H48N2O8 [M + H]+ 757.3483, found 757.3464. Second eluted Schiff base atropisomer 1g″: yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 5:5) followed by selective precipitation in cyclohexane, Rf = 0.3 (TLC eluent: cyclohexane/EtOAc, 5:5), mp = 149−150 °C, 135.7 mg of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 44 mg was isolated, 35% yield; [α]D = −242 (c 0.0002 CH2Cl2); HPLC tR = 11.266 min (de > 93%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3298 (νO− H), 1616 (νCO), 1494 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.86 (br s, 2NH), 9.72 (br s, 2H), 7.53 (s, 2H), 7.36−7.29 (m, 10H), 4.54 (t, J = 6.1 Hz, 2H), 3.82 (d, J = 6.0 Hz, 4H), 3.68 (hept, J = 7.1 Hz, 2H), 2.04 (s, 6H), 1.49 (dd, J = 7.1 Hz, 12H), 1.48 (d, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 172.7 (C-7), 162.8 (C11), 149.1 (C-1), 147.0 (C-6), 136.9 (C-18), 132.1 (C-3), 2 × 129.1 (C-20, C-22), 128.9 (C-10), 128.5 (C-21), 128.1 (C-5), 2 × 126.6 (C-19, C-23), 118.1 (C-4), 116.2 (C-2), 114.7 (C-9), 103.8 (C-8), 66.8 (C-17), 66.3 (C-16), 27.4 (C-12), 20.3 (C-13), 20.3 (C-14), 20.1 (C-15); HRMS (ESI+) calcd for C46H48N2O8 [M + H]+ 757.3483, found 757.3471. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-8,8′-bis{[(S-2-hydroxy-1phenylethyl)amino]methylene}-5,5′-diisopropyl-3,3′-dimethyl[2,2′-binaphthalene]-7,7′(8H,8′H)-dione. First eluted Schiff base atropisomer 1h′: yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 6:4) followed by selective precipitation in cyclohexane, Rf = 0.4 (TLC eluent: cyclohexane/ EtOAc, 6:4), mp = 170−171 °C, 135.7 mg of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 53.5 mg was isolated, 43% yield; [α]D = −401 (c 0.0002 CH2Cl2); HPLC tR = 06.381 min (de = 99%, iPrOH/n-heptane, 50:50); IR (νmax/cm−1) 3300 (νO−H), 1616 (νCO), 1492 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.94 (br s, 2NH), 9.69 (br s, 2H), 7. 96 (br s, 2OH), 7.57 (s, 2H), 7.36−7.27 (m, 10H), 5.50 (br s, 2OH), 4.60 (t, J = 6.0 Hz, 2H), 3.96−3.94 (m, 4H), 3.70 (hept, J = 7.0 Hz, 2H), 2.07 (s, 6H), 1.52 (d, J = 6.9 Hz, 6H), 1.51 (d, J = 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 172.9 (C-7), 162.7 (C-11), 149.0 (C-1), 147.1 (C-6), 137.1 (C-18), 132.1 (C-3), 2 × 129.1 (C-20, C-22) 129.1 (C-10), 128.5 (C-21), 128.0 (C5), 2 × 126.7 (C-19, C-23), 118.2 (C-4), 115.8 (C-2), 114.6 (C-9), 103.8 (C-8), 66.5 (C-17), 66.4 (C-16), 27.5 (C-12), 20.3 (C-13), 20.3 (C-14), 20.1 (C-15); HRMS (ESI+) calcd for C46H48N2O8 [M + H]+ 757.3483, found 757.3480. Second eluted Schiff base atropisomer 1h″: yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 5:5) followed by selective precipitation in cyclohexane, Rf = 0.3 (TLC eluent: cyclohexane/EtOAc, 5:5), mp = 146−147 °C, 135.7 mg of amine (6 equiv) in 200 mL of Et2O for 7 h at 60 °C, 45 mg was isolated, 36% yield; [α]D = +259 (c 0.0002 CH2Cl2); HPLC tR = 06.611 min (de = 99%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3300 (νO−H), 1616 (νCO), 1493 (νC C); 1H NMR (300 MHz, CDCl3) δH 13.86 (br s, 2NH), 9.73 (br s, 2H), 7.86 (br s, 2OH), 7.53 (s, 2H), 7.38−7.30 (m, 8H), 7.24 (d, J = 5.9 Hz, 2H), 4.54 (t, J = 6.2 Hz, 2H), 3.81−3.79 (m, 4H), 3.67 (hept, J = 7.0 Hz, 2H), 2.04 (s, 6H), 1.48 (d, J = 7.2 Hz, 6H), 1.45 (d, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 172.8 (C-7), 162.7 (C11), 149.1 (C-1), 147.0 (C-6), 136.9 (C-18), 132.1 (C-3), 2 × 129.2 (C-20, C-22), 129.0 (C-10), 128.5 (C-21), 128.1 (C-5), 2 × 126.6 (C-19, C-23), 118.1 (C-4), 116.2 (C-2), 114.6 (C-9), 103.8 (C-8), 66.8 (C-17), 66.3 (C-16), 27.5 (C-12), 20.3 (C-13), 20.3 (C-14), 20.1 (C-15); HRMS (ESI+) calcd for C46H48N2O8 [M + H]+ 757.3483, found 757.3492. General Procedure for Enantiomerically Pure Gossypol Schiff Base Derivative Synthesis. The enantiomerically pure H



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15); HRMS (ESI+) calcd for C42H48N6O6 [M + H]+ 733.3708, found 733.3747. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl8,8′-bis{[(pyridin-2-ylmethyl)amino]methylene}-[2,2′-binaphthalene]-7,7′(8H,8′H)-dione (4d): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 4:6), Rf = 0.3, (TLC eluent: cyclohexane/EtOAc, 3:7), mp = 239−240 °C, 68 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2h at room temperature, 24 mg was isolated, 52% yield; HPLC tR = 5.681 min (ee > 99%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3228 (νO−H), 1608 (νCO), 1489 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.65 (br s, 2NH), 9.74 (br s, 2H), 8.51 (d, J = 5.1 Hz, 2H), 7.93 (br s, 2OH), 7.64 (dd, J = 7.5, 7.2 Hz, 2H), 7.55 (s, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.17 (dd, J = 7.8, 7.5 Hz, 2H), 5.85 (br s, 2OH), 4.74 (s, 4H), 3.69 (hept, J = 7.2 Hz, 2H), 2.09 (s, 6H), 1.50 (d, J = 7.2 Hz, 6H), 1.49 (d, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 173.2 (C-7), 163.2 (C-11), 155.8 (C-17), 149.8 (C-21), 149.1 (C-1), 147.1 (C-6), 137.1 (C-19), 132.0 (C-3), 129.0 (C-10), 127.7 (C-5), 122.9 (C-20), 121.3 (C-18), 118.2 (C-4), 116.2 (C-2), 114.7 (C-9), 103.7 (C-8), 55.7 (C-16), 27.4 (C-12), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15); NMR chemical shifts are comparable with data from the literature;15 HRMS (ESI+) calcd for C42H42N4O6 [M + H]+ 699.3177, found 699.3172. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl8,8′-bis{[(4-methylbenzyl)amino]methylene}-[2,2′-binaphthalene]7,7′(8H,8′H)-dione (4e): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 8:2), Rf = 0.4 (TLC eluent: cyclohexane/EtOAc, 8/2), mp = 144−145 °C, 84 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2h at room temperature, 32 mg was isolated, 67% yield; HPLC tR = 11.777 min (ee > 98%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3199 (νO−H), 1606 (νCO), 1487 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.56 (br s, 2NH), 9.72 (d, J = 12.4 Hz, 2H), 7.96 (br s, 2OH), 7.59 (s, 2H), 7.18 (d, J = 8.4 Hz, 4H), 7.14 (d, J = 8.4 Hz, 4H), 5.57 (s, 2OH), 4.62 (d, J = 5.1 Hz, 4H), 3.72 (hept, J = 6.9 Hz, 2H), 2.33 (s, 6H), 2.11 (s, 6H), 1.53 (d, J = 7.0 Hz, 6H), 1.52 (d, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 172.9 (C-7), 162.8 (C11), 149.0 (C-1), 147.1 (C-6), 138.0 (C-20), 133.2 (C-17), 131.9 (C3), 2 × 129.7 (C-19, C-21), 129.0 (C-10), 2 × 127.4 (C-18, C-22), 127.4 (C-5), 118.2 (C-4), 115.8 (C-2), 114.7 (C-9), 103.4 (C-8), 54.3 (C-16), 27.4 (C-12), 21.1 (C-23), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15); NMR chemical shifts were previously described in DMSO;17 HRMS (ESI+) calcd for C46H48N2O6 [M + H]+ 725.3585, found 725.3579. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl8,8′-bis{[(3,4,5-trimethoxybenzyl)amino]methylene}-[2,2′-binaphthalene]-7,7′(8H,8′H)-dione (4f): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 7:3), followed by selective precipitation in cyclohexane, Rf = 0.5, (TLC eluent: cyclohexane/EtOAc, 7:3), 58 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 17 mg was isolated, 39% yield; IR (νmax/cm−1) 3279 (νO−H), 1610 (νCO), 1456 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.57 (br s, 2NH), 9.71 (d, J = 12.5 Hz, 2H), 7.95 (br s, 2OH), 7.60 (s, 2H), 6.50 (s, 4H), 5.57 (br s, 2OH), 4.59 (d, J = 5.6 Hz, 4H), 3.83 (s, 12H), 3.81 (s, 6H), 3.72 (hept, J = 7.1 Hz, 2H), 2.12 (s, 6H), 1.53 (d, J = 7.0 Hz, 6H), 1.52 (d, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 173.1 (C-7), 162.6 (C-11), 153.7 (C-20), 148.9 (C-1), 147.1 (C-6), 2 × 137.7 (C-19, C-21), 131.9 (C-3), 131.7 (C-17), 129.1 (C-10), 127.6 (C-5), 118.3 (C-4), 115.8 (C-2), 114.6 (C-9), 2 × 104.7 (C-18, C-22), 103.4 (C-8), 60.8 (C-24), 2 × 56.3 (C-23, C25), 54.7 (C-16), 27.5 (C-12), 20.4 (C-13), 20.3 (C-14), 20.0 (C15); HRMS (ESI+) calcd for C50H56N2O12 [M + H]+ 877.3906, found 877.3919. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl8,8′-bis{[(thiophen-2-ylmethyl)amino]methylene}-[2,2′-binaphthalene]-7,7′(8H,8′H)-dione (4g): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 7:3), Rf = 0.3 (TLC eluent: cyclohexane/EtOAc, 8/:2), mp = 186−187 °C, 68 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 27.5 mg was isolated, 60% yield; HPLC tR =

gossypol Schiff base derivatives were synthesized through a transamination procedure. To 2.5 mL of EtOH containing 1g′ (50 mg) were added the corresponding amine (10 equiv) and a catalytic amount (0.5 equiv) of TFA. The mixture was stirred for 2 h at room temperature, and the progress of the reaction was monitored by SiO2 TLC. After the reaction was completed, the solvent was evaporated under vacuum and the Schiff base atropisomers were separated by flash column chromatography (gradient from 100% cyclohexane to variable mixtures of cyclohexane/ethyl acetate). (+)-Enantiomers of Schiff Bases. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy5,5′-diisopropyl-3,3′-dimethyl-8,8′-bis{[2-(trifluoromethyl)benzyl]amino}methylene)-[2,2′-binaphthalene]-7,7′(8H,8′H)-dione (4a): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 8:2), Rf = 0.4 (TLC eluent: cyclohexane/ EtOAc, 8:2), mp = 150−151 °C, 93 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 39 mg was isolated, 71% yield; HPLC tR = 06.609 min (ee > 99%, iPrOH/n-heptane, 50:50); IR (νmax/cm−1) 3296 (νO−H), 1606 (νCO), 1491 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.66 (br s, 2NH), 9.73 (d, J = 12.2 Hz, 2H), 7.93 (br s, 2OH), 7.69 (d, J = 7.8 Hz, 2H), 7.60 (s, 2H), 7.55 (d, J = 7.8 Hz, 2H), 7.52 (dd, J = 7.4, 7.2 Hz, 2H), 7.43 (dd, J = 7.6, 7.5 Hz, 2H), 5.60 (br s, 2OH), 4.86 (d, J = 5.6 Hz, 4H), 3.73 (hept, J = 7.0 Hz, 2H), 2.12 (s, 6H), 1.54 (d, J = 7.0 Hz, 6H), 1.53 (d, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 173.4 (C-7), 163.2 (C-11), 149.0 (C-1), 147.1 (C-6), 134.9 (C-17, q, J = 1.4 Hz), 132.7 (C-21), 132.2 (C-3), 129.2 (C-22), 129.1 (C-10), 128.3 (C-20), 127.9 (C-5), 127.9 (C-18, q, J = 30.5 Hz),126.4 (C-19, q, J = 5.6 Hz), 124.2 (C-23, q, J = 272.2 Hz), 118.3 (C-4), 115.9 (C2), 114.5 (C-9), 103.7 (C-8), 51.1 (C-16, q, J = 2.6 Hz), 27.5 (C-12), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15); 19F NMR (282 MHz, CDCl3) δF −59.8 (s, 3F); HRMS (ESI+) calcd for C46H42F6N2O6 [M + H]+ 833.3020, found 833.3003. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl8,8′-bis{[(1,2,3,4-tetrahydronaphthalen-1-yl)amino]methylene}[2,2′-binaphthalene]-7,7′(8H,8′H)-dione (4b): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 9:1), Rf = 0.3 (TLC eluent: cyclohexane/EtOAc, 9:1), mp = 141−142 °C, 95 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 42 mg was isolated, 82% yield; IR (νmax/cm−1) 3296 (νO−H), 1616 (νCO), 1490 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.66 (br s, 2NH), 9.81 (d, J = 12.4 Hz, 2H), 7.96 (br s, 2OH), 7.61 (s, 2H), 7.27−7.13 (m, 8H), 5.59 (br s, 2OH), 4.66 (q, J = 6.8 Hz, 2H), 3.73 (hept, J = 7.1 Hz, 2H), 3.10− 2.70 (m, 4H), 2.30−1.80 (m, 2H), 2.14 (s, 6H), 1.54 (d, J = 7.0 Hz, 6H), 1.52 (d, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 172.7 (C-7), 161.4 (C-11), 149.0 (C-1), 147.2 (C-6), 137.2 (C-24), 134.2 (C-25), 131.8 (C-3), 129.5 (C-23), 129.0 (C-10), 128.5 (C-22), 128.1 (C-21), 127.3 (C-5), 126.6 (C-20), 118.2 (C-4), 115.7 (C-2), 114.8 (C-9), 103.2 (C-8), 59.4 (C-16), 31.7 (C-17), 28.9 (C-19), 27.4 (C-12), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15), 19.7 (C-18); HRMS (ESI+) calcd for C50H52N2O6 [M + H]+ 777.3898, found 777.3906. (8Z,8′Z)-8,8′-Bis{[(3-(1H-imidazol-1-yl)propyl)amino]methylene}-1,1′,6,6′-tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl[2,2′-binaphthalene]-7,7′(8H,8′H)-dione (4c): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 7:3), Rf = 0.5 (TLC eluent: cyclohexane/EtOAc, 8:2), mp = 214−215 °C, 79 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 30 mg was isolated, 62% yield; HPLC tR = 05.798 min (ee = 100%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3238 (νO−H), 1606 (νCO), 1486 (νCC); 1H NMR (300 MHz, DMSO-d6) δH 13.22 (br s, 2NH), 9.71 (br s, 2H), 8.40 (br s, 2OH), 7.63 (s, 2H), 7.44 (s, 2H), 7.18 (s, 2H), 6.87 (s, 2H), 4.04 (t, J = 7.0 Hz, 4H), 3.70 (hept, J = 7.2 Hz, 2H), 3.45 (t, J = 7.1 Hz, 4H), 2.13−2.08 (m, 4H), 1.93 (s, 6H), 1.44 (d, J = 6.9 Hz, 6H), 1.42 (d, J = 6.9 Hz, 6H); 13C NMR (75 MHz, DMSO) δC 172.3 (C-7), 162.8 (C-11), 150.2 (C-1), 146.7 (C-6), 137.7 (C-21), 131.7 (C-3), 129.0 (C-20), 127.3 (C-10), 127.0 (C-5), 120.8 (C-4), 119.7 (C-19), 117.0 (C-2), 116.4 (C-9), 103.7 (C-8), 47.6 (C-16), 43.7 (C18), 31.9 (C-17), 27.0 (C-12), 20.8 (C-13), 20.8 (C-14), 20.7 (CI



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10.380 min (ee = 95.5%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3431 (νO−H), 1610 (νCO), 1489 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.58 (br s, 2NH), 9.72 (d, J = 11.5 Hz, 2H), 7.92 (br s, 2OH), 7.59 (s, 2H), 7.29−7.27 (m, 2H), 7.04−7.02 (m, 2H), 7.00− 6.90 (m, 2H), 5.57 (br s, 2OH), 4.82 (d, J = 4.3 Hz, 4H), 3.71 (hept, J = 7.1 Hz, 2H), 2.11 (s, 6H), 1.53 (d, J = 7.1 Hz, 6H), 1.51 (d, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 173.3 (C-7), 162.3 (C11), 149.0 (C-1), 147.1 (C-6), 138.5 (C-17), 132.1 (C-3), 129.1 (C10), 127.7 (C-5), 127.3 (C-19), 126.7 (C-18), 126.2 (C-20), 118.3 (C-4), 115.8 (C-2), 114.6 (C-9), 103.5 (C-8), 48.9 (C-16), 27.5 (C12), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15); HRMS (ESI+) calcd for C40H40N2O6S2 [M + H]+ 709.2401, found 709.2401. (8Z,8′Z)-8,8′-Bis{[(furan-2-ylmethyl)amino]methylene}-1,1′,6,6′tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl-[2,2′-binaphthalene]7,7′(8H,8′H)-dione (4h): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 7:3), Rf = 0.4 (TLC eluent: cyclohexane/EtOAc, 7:3), mp = 191−192 °C, 58 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 28.5 mg was isolated, 64% yield; HPLC tR = 08.962 min (ee > 99%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3431 (νO−H), 1615 (νCO), 1496 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.47 (br s, 2NH), 9.70 (br s, 2H), 7.92 (br s, 2OH), 7.59 (s, 2H), 7.38 (br s, 2H), 6.34−6.31 (m, 4H), 5.57 (br s, 2OH), 4.62 (d, J = 4.5 Hz, 4H), 3.72 (hept, J = 7.1 Hz, 2H), 2.11 (s, 6H), 1.53 (d, J = 6.9 Hz, 6H), 1.51 (d, J = 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 173.2 (C-7), 162.8 (C-11), 149.1 (C-17), 149.0 (C-1), 147.1 (C-6), 143.3 (C-19), 132.0 (C-3), 129.1 (C-10), 127.7 (C-5), 118.3 (C-4), 115.8 (C-2), 114.6 (C-9), 110.6 (C-18), 108.8 (C-20), 103.6 (C-8), 46.9 (C-16), 27.5 (C-12), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15); NMR chemical shifts are comparable with data from the literature;12 HRMS (ESI+) calcd for C40H40N2O8 [M + H]+ 677.2857, found 677.2871. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-8,8′-bis{[(1-hydroxy-2-methylpropan-2-yl)amino]methylene}-5,5′-diisopropyl-3,3′-dimethyl[2,2′-binaphthalene]-7,7′(8H,8′H)-dione (4i): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 5:5), Rf = 0.3, (TLC eluent: cyclohexane/EtOAc, 4:6), mp = 219− 220 °C, 58 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 17.5 mg was isolated, 40% yield; HPLC tR = 05.123 min (ee > 99%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3312 (νO−H), 1614 (νCO), 1491 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.58 (br d, J = 13.2 Hz, 2NH), 9.81 (d, J = 12.1 Hz, 2H), 7.98 (br s, 2OH), 7.60 (s, 2H), 5.63 (br s, 2OH), 3.71 (hept, J = 6.9 Hz, 2H), 3.58 (s, 4H), 2.11 (s, 6H), 1.52 (d, J = 7.2 Hz, 6H), 1.51 (d, J = 7.2 Hz, 6H), 1.38 (s, 12H); 13C NMR (75 MHz, CDCl3) δC 172.1 (C-7), 159.6 (C-11), 148.9 (C-1), 147.2 (C6), 131.7 (C-3), 129.0 (C-10), 127.4 (C-5), 118.2 (C-4), 115.8 (C2), 114.9 (C-9), 103.3 (C-8), 70.4 (C-17), 57.9 (C-16), 27.4 (C-12), 24.0 (C-18), 23.9 (C-19), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15); HRMS (ESI+) calcd for C38H48N2O8 [M + H]+ 661.3483, found 661.3479. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl8,8′-bis[(prop-2-yn-1-ylamino)methylene]-[2,2′-binaphthalene]7,7′(8H,8′H)-dione (4j): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 8:2), Rf = 0.4 (TLC eluent: cyclohexane/EtOAc, 7/3), mp = 130−131 °C, 42 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 20.5 mg was isolated, 52% yield; HPLC tR = 08.957 min (ee > 98%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3430 (νO− H), 1608 (νCO), 1491 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.53 (br s, 2NH), 9.84 (d, J = 9.9 Hz, 2H), 7.90 (br s, 2OH), 7.60 (s, 2H), 5.62 (br s, 2OH), 4.30 (br s, 4H), 3.72 (hept, J = 7.1 Hz, 2H), 2.48 (t, J = 2.9 Hz, 2H), 2.11 (s, 6H), 1.53 (d, J = 7.2 Hz, 6H), 1.52 (d, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 173.2 (C-7), 162.2 (C-11), 149.1 (C-1), 147.0 (C-6), 132.2 (C-3), 129.2 (C-10), 128.0 (C-5), 118.3 (C-4), 115.9 (C-2), 114.5 (C-9), 103.8 (C-8), 76.5 (C-18), 75.8 (C-17), 38.9 (C-16), 27.5 (C-12), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15); NMR chemical shifts are comparable with data from the literature;15 HRMS (ESI+) calcd for C36H36N2O6 [M + H]+ 593.2646, found 593.265.

(8Z,8′Z)-8,8′-Bis[(allylamino)methylene]-1,1′,6,6′-tetrahydroxy5,5′-diisopropyl-3,3′-dimethyl-[2,2′-binaphthalene]-7,7′(8H,8′H)dione (4k): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 9:1), Rf = 0.3 (TLC eluent: cyclohexane/ EtOAc, 8:2), mp = 244−245 °C, 50 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 23 mg was isolated, 58% yield; HPLC tR = 06.405 min (ee > 98%, iPrOH/n-heptane, 50:50); IR (νmax/cm−1) 3436 (νO−H), 1616 (νCO), 1491 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.34 (br s, 2NH), 9.62 (d, J = 12.2 Hz, 2H), 7.99 (br s, 2OH), 7.59 (s, 2H), 5.92 (ddt, J = 15.8, 10.5, 5.4 Hz, 2H), 5.57 (s, 2OH), 5.32 (d, J = 15.0 Hz, 2H), 5.27 (d, J = 10.8 Hz, 2H), 4.10 (br s, 4H), 3.72 (hept, J = 7.0 Hz, 2H), 2.11 (s, 6H), 1.53 (d, J = 7.0 Hz, 6H), 1.52 (d, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 172.9 (C-7), 163.0 (C-11), 148.9 (C-1), 147.1 (C-6), 132.7 (C-17), 131.9 (C-3), 129.0 (C-10), 127.4 (C-5), 118.4 (C-18), 118.2 (C-4), 115.7 (C-2), 114.6 (C-9), 103.4 (C-8), 52.5 (C-16), 27.4 (C-12), 20.4 (C-13), 20.3 (C-14), 20.0 (C-15); NMR chemical shifts are comparable with data from the literature;14,15,28 HRMS (ESI+) calcd for C36H40N2O6 [M + H]+ 597.2959, found 597.2943. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl8,8′-bis[(pentylamino)methylene]-[2,2′-binaphthalene]7,7′(8H,8′H)-dione (4l): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 8:2), Rf = 0.5 (TLC eluent: cyclohexane/EtOAc, 8:2), mp = 140−141 °C, 77 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 29.5 mg was isolated, 71% yield; HPLC tR = 07.650 min (ee = 99%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3272 (νO− H), 1616 (νCO), 1490 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.36 (br s, 2NH), 9.64 (d, J = 12.7 Hz, 2H), 8.02 (br s, 2OH), 7.60 (s, 2H), 5.59 (br s, 2OH), 3.74 (hept, J = 7.1 Hz, 2H), 3.48 (q, J = 6.7 Hz, 4H), 2.12 (s, 6H), 1.73−1.69 (m, 4H), 1.54 (d, J = 6.9 Hz, 6H), 1.53 (d, J = 6.9 Hz, 6H), 1.41−1.31 (m, 8H), 0.90 (t, J = 6.9 Hz, 6H); 13 C NMR (75 MHz, CDCl3) δC 172.4 (C-7), 162.9 (C-11), 148.9 (C1), 147.2 (C-6), 131.7 (C-3), 128.9 (C-10), 127.1 (C-5), 118.2 (C4), 115.6 (C-2), 114.7 (C-9), 103.0 (C-8), 50.9 (C-16), 30.3 (C-17), 28.7 (C-18), 27.4 (C-12), 22.2 (C-19), 20.4 (C-13), 20.4 (C-14), 20.1 (C-15), 13.9 (C-20); HRMS (ESI+) calcd for C40H52N2O6 [M + H]+657.3898, found 657.3918. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl8 ,8 ′-bis[(o ctylamino)methylene]-[2,2 ′-binaphthale ne ]7,7′(8H,8′H)-dione (4m): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 8:2), Rf = 0.3 (TLC eluent: cyclohexane/EtOAc, 9:1), mp = 110−111 °C, 109 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 29.5 mg was isolated, 62% yield; HPLC tR = 07.337 min (ee > 98%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3269 (νO−H), 1616 (νCO), 1490 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.35 (br s, 2NH), 9.64 (d, J = 12.7 Hz, 2H), 8.03 (br s, 2OH), 7.60 (s, 2H), 5.58 (br s, 2OH), 3.73 (hept, J = 7.2 Hz, 2H), 3.47 (q, J = 6.7 Hz, 4H), 2.12 (s, 6H), 1.75−1.65 (m, 4H), 1.54 (d, J = 6.7 Hz, 6H), 1.52 (d, J = 6.7 Hz, 6H), 1.41−1.25 (m, 20H), 0.85 (t, J = 6.5 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 172.4 (C-7), 162.9 (C-11), 148.9 (C-1), 147.2 (C-6), 131.7 (C-3), 128.9 (C-10), 127.1 (C-5), 118.3 (C-4), 115.6 (C-2), 114.7 (C-9), 103.0 (C-8), 50.9 (C16), 31.7 (C-17), 30.6 (C-18), 2 × 29.1 (C-19, C-20), 27.4 (C-12), 26.6 (C-21), 22.6 (C-22), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15), 14.1 (C-23); HRMS (ESI+) calcd for C46H64N2O6 [M + H]+ 741.4837, found 741.4844. (−)-Enantiomers of Schiff Bases. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy5,5′-diisopropyl-3,3′-dimethyl-8,8′-bis{[(2-(trifluoromethyl)benzyl)amino]methylene}-[2,2′-binaphthalene]-7,7′(8H,8′H)-dione (5a): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 8:2), Rf = 0.4 (TLC eluent: cyclohexane/ EtOAc, 8:2), mp = 119−120 °C, 93 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 26 mg was isolated, 47% yield; HPLC tR = 09.178 min (ee > 94%, iPrOH/n-heptane, 50:50); IR (νmax/cm−1) 3296 (νO−H), 1606 (νCO), 1491 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.66 (br s, 2NH), 9.72 (d, J = 12.3 Hz, 2H), 7.92 (br s, 2OH), 7.70 (d, J = 7.8 Hz, 2H), 7.60 (s, 2H), 7.55 (d, J = 7.4 Hz, 2H), 7.52 (dd, J = 7.4, 7.2 J



Article

General Procedure for Gossypol Schiff Base Derivative Hydrolysis. To a solution of Schiff base derivative 1g′ or 1g″ (100 mg) in Et2O (6 mL) were added in portions HOAc (0.9 mL) and 3− 4 drops of HCl (37%). The mixture was then heated at reflux overnight. The Et2O solution was treated with water until the aqueous phase showed neutrality (pH ≈ 7) and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to furnish 68.55 mg of gossypol (90% yield). NMR chemical shift data are in accordance with literature values.21,24

Hz, 2H), 7.43 (dd, J = 7.6, 7.4 Hz, 2H), 5.59 (br s, 2OH), 4.86 (d, J = 5.9 Hz, 4H), 3.72 (hept, J = 7.0 Hz, 2H), 2.11 (s, 6H), 1.54 (d, J = 7.2 Hz, 6H), 1.53 (d, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 173.4 (C-7), 163.2 (C-11), 149.0 (C-1), 147.1 (C-6), 134.9 (C-17, q, J = 1.4 Hz), 132.7 (C-21), 132.2 (C-3), 129.2 (C-22), 129.1 (C-10), 128.3 (C-20), 127.9 (C-5), 127.9 (C-18, q, J = 30.5 Hz),126.4 (C-19, q, J = 5.6 Hz), 124.2 (C-23, q, J = 272.2 Hz), 118.3 (C-4), 115.9 (C2), 114.5 (C-9), 103.7 (C-8), 51.1 (C-16, q, J = 2.6 Hz), 27.5 (C-12), 20.4 (C-13), 20.3 (C-14), 20.1 (C-15); 19F NMR (282 MHz, CDCl3) δF −59.8 (s, 3F); HRMS (ESI+) calcd for C46H42F6N2O6 [M + H]+ 833.3020, found 833.3032. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl8,8′-bis{[(4-methylbenzyl)amino]methylene}-[2,2′-binaphthalene]7,7′(8H,8′H)-dione (5b): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 8:2); Rf = 0.4 (TLC eluent: cyclohexane/EtOAc, 8:2), mp = 129−130 °C, 84 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 18 mg was isolated, 38% yield; HPLC tR = 15.034 min (ee > 92.5%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3285 (νO−H), 1610 (νCO), 1490 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.57 (br s, 2NH), 9.73 (d, J = 11.4 Hz, 2H), 7.97 (br s, 2OH), 7.60 (s, 2H), 7.19 (d, J = 8.5 Hz, 4H), 7.17 (d, J = 8.5 Hz, 4H), 5.59 (br s, 2OH), 4.62 (br s, 4H), 3.73 (hept, J = 7.1 Hz, 2H), 2.33 (s, 6H), 2.12 (s, 6H), 1.54 (d, J = 7.2 Hz, 6H), 1.53 (d, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 172.9 (C-7), 162.8 (C-11), 149.0 (C-1), 147.1 (C-6), 138.0 (C-20), 133.2 (C-17), 131.9 (C-3), 2 × 129.7 (C-19, C-21), 129.0 (C-10), 127.4 (C-5), 2 × 127.4 (C-18, C-22), 118.2 (C-4), 115.8 (C-2), 114.7 (C-9), 103.4 (C-8), 54.3 (C16), 27.4 (C-12), 21.1 (C-23), 20.4 (C-13), 20.3 (C-14), 20.1 (C15); HRMS (ESI+) calcd for C46H48N2O6 [M + H]+ 725.3585, found 725.3612. (8Z,8′Z)-8,8′-Bis[(allylamino)methylene]-1,1′,6,6′-tetrahydroxy5,5′-diisopropyl-3,3′-dimethyl-[2,2′-binaphthalene]-7,7′(8H,8′H)dione (5c): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 8:2), Rf = 0.3 (TLC eluent: cyclohexane/ EtOAc, 8:2), mp = 201−202 °C, 49.5 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 10 mg was isolated, 25% yield; HPLC tR = 07.533 min (ee > 88%, iPrOH/n-heptane, 50:50); IR (νmax/cm−1) 3280 (νO−H), 1606 (νCO), 1490 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.34 (br s, 2NH), 9.62 (d, J = 12.1 Hz, 2H), 7.98 (br s, 2OH), 7.59 (s, 2H), 5.93 (ddt, J = 15.7, 10.5, 5.4 Hz, 2H), 5.57 (br s, 2OH), 5.32 (d, J = 15.1 Hz, 2H), 5.27 (d, J = 10.5 Hz, 2H), 4.10 (br s, 4H), 3.72 (hept, J = 7.1 Hz, 2H), 2.11 (s, 6H), 1.54 (d, J = 6.9 Hz, 6H), 1.53 (d, J = 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 173.0 (C-7), 163.0 (C-11), 148.9 (C-1), 147.1 (C-6), 132.7 (C-17), 131.9 (C-3), 129.0 (C-10), 127.4 (C-5), 118.4 (C-18), 118.2 (C-4), 115.7 (C-2), 114.6 (C-9), 103.4 (C-8), 52.5 (C-16), 27.4 (C-12), 20.4 (C-13), 20.3 (C-14), 20.0 (C-15); HRMS (ESI+) calcd for C36H40N2O6 [M + H]+ 597.2959, found 597.2969. (8Z,8′Z)-1,1′,6,6′-Tetrahydroxy-5,5′-diisopropyl-3,3′-dimethyl8,8′-bis[(pentylamino)methylene]-[2,2′-binaphthalene]7,7′(8H,8′H)-dione (5d): yellow-orange solid obtained by flash column chromatography (cyclohexane/EtOAc, 8:2), Rf = 0.5 (TLC eluent: cyclohexane/EtOAc, 8:2), mp = 103−104 °C, 77 μL of amine (10 equiv), 2.5 μL (0.5 equiv) of TFA, in 2.5 mL of EtOH for 2 h at room temperature, 13 mg was isolated, 31% yield; HPLC tR = 09.178 min (ee > 93%, i-PrOH/n-heptane, 50:50); IR (νmax/cm−1) 3271 (νO−H), 1615 (νCO), 1491 (νCC); 1H NMR (300 MHz, CDCl3) δH 13.36 (br s, 2NH), 9.63 (d, J = 12.5 Hz, 2H), 8.02 (br s, 2OH), 7.60 (s, 2H), 5.57 (br s, 2OH), 3.73 (hept, J = 7.2 Hz, 2H), 3.48 (q, J = 6.7 Hz, 4H), 2.12 (s, 6H), 1.73−1.63 (m, 4H), 1.54 (d, J = 7.2 Hz, 6H), 1.53 (d, J = 7.2 Hz, 6H), 1.40−1.30 (m, 8H), 0.90 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC 172.4 (C-7), 162.9 (C-11), 148.9 (C-1), 147.2 (C-6), 131.7 (C-3), 128.9 (C-10), 127.1 (C-5), 118.2 (C-4), 115.6 (C-2), 114.7 (C-9), 103.0 (C-8), 50.9 (C16), 30.3 (C-17), 28.7 (C-18), 27.4 (C-12), 22.2 (C-19), 20.4 (C13), 20.3 (C-14), 20.1 (C-15), 13.9 (C-20); HRMS (ESI+) calcd for C40H52N2O6 [M + H]+ 657.3898, found 657.3912.

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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.jnatprod.8b01045.

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Experimental details, product characterization data including 1 H, 13 C, and 19 F NMR descriptions, compound numbering, spectra, and HPLC analyses (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ahmed Aliyenne: 0000-0002-5818-0994 Adam Daïch: 0000-0002-6942-0519 Ata M. Lawson: 0000-0002-1641-4190 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to Marie José Tranchant for HRMS acquisition, the SCAC “Service de Coopération et d’Action Culturelle de l’Ambassade de France en Mauritanie” for the Graduate Fellowship awarded to one of us (S.B.M.V.), and the “Université Le Havre Normandie” for financial and technical help. We also thank “La Région Normandie” and “Fédération INC3M”.

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