A Short and Efficient Total Synthesis of

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Jul 26, 2018 - Keywords: ficuseptamines A and B; cross metathesis; total synthesis ... and B, is frequently found in natural products [2,3] and biologically active.
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Efficient Total TotalSynthesis Synthesisof of A Short and Efficient Ficuseptamines A and B Hani Mutlak Mutlak A. A. Hassan Hassan Hani King Fahd Fahd Medical Medical Research Research Center, Center, King King King Abdulaziz Abdulaziz University, University,P.O. P.O.Box Box80216, 80216,Jeddah Jeddah21589, 21589,Saudi SaudiArabia; Arabia; [email protected] [email protected]  

Received: Received: 11 11 July July 2018; 2018; Accepted: Accepted: 23 23 July July 2018; 2018; Published: Published: 26 26 July July 2018 2018

Abstract: A A rapid rapid and and efficient efficient total total synthesis synthesis of of ficuseptamines ficuseptamines A A and and B B by a cross metathesis strategy is described. ficuseptamines A and B; cross metathesis; total synthesis Keywords: ficuseptamines

1. Introduction Introduction 1. FicuseptaminesA, A, B, B, and and C C (1a–c) (1a–c) were were isolated isolated from from the the leaves leaves of of Ficus and reported reported by by Ficuseptamines Ficus septica septica and Shin-ya and co-workers in 2009 (Figure 1) [1]. Ficuseptamines A and B possess an aminocaprophenone Shin-ya and co-workers in 2009 (Figure 1) [1]. Ficuseptamines A and B possess an aminocaprophenone structure, while while ficuseptamine ficuseptamine C C contains contains aa pyrrolidine pyrrolidine moiety moiety in in its its structure. structure. After After their their isolation, isolation, structure, these alkaloids alkaloidswere wereevaluated evaluated cytotoxicity against HeLa (human cervical carcinoma) and these forfor cytotoxicity against HeLa (human cervical carcinoma) and ACCACC-MESO-1 (malignant pleural mesothelioma) cancer cell lines. Ficuseptamine A displayed IC 50 MESO-1 (malignant pleural mesothelioma) cancer cell lines. Ficuseptamine A displayed IC50 values values of and 57 µM µM against HeLa and ACC-MESO-1 cells lines, respectively. Ficuseptamine B of 57 μM 160and μM160 against HeLa and ACC-MESO-1 cells lines, respectively. Ficuseptamine B showed showed better cytotoxicity against the same cell lines (IC : 23 µM for HeLa; 72 µM for ACC-MESO-1), 50 better cytotoxicity against the same cell lines (IC50: 23 μM for HeLa; 72 μM for ACC-MESO-1), while while ficuseptamine C showed no activity either cell line. aryl motif, ketonewhich motif,iswhich is ficuseptamine C showed no activity againstagainst either cell line. The arylThe ketone present present in ficuseptamines B, is frequently found in natural products [2,3]and andbiologically biologically active active in ficuseptamines A andAB,and is frequently found in natural products [2,3] molecules [4]. We were interested in devising a novel strategy targeting ficuseptamines A and B for for molecules [4]. We were interested in devising a novel strategy targeting ficuseptamines A and B their first total synthesis. We thought that designing an efficient and facile strategy for their rapid total their first total synthesis. We thought that designing an efficient and facile strategy for their rapid synthesis wouldwould offer the possibility of synthesizing ficuseptamine A and B A analogues for biological total synthesis offer the possibility of synthesizing ficuseptamine and B analogues for evaluation, given the commercial availability of a wide variety of functionalized terminal olefins, which biological evaluation, given the commercial availability of a wide variety of functionalized terminal could bewhich utilized in library design synthesis. addition, the In incorporation ofincorporation fluorine atom(s) olefins, could be utilized inand library design In and synthesis. addition, the of into ficuseptamines A and B to synthesize fluorinated analogues could also significantly improve their fluorine atom(s) into ficuseptamines A and B to synthesize fluorinated analogues could also biological activity [5,6]. significantly improve their biological activity [5,6].

Figure Figure 1. 1. Structures Structures of of ficuseptamine ficuseptamine A, A, B, B, and and C C (1a–c). (1a–c).

Olefin metathesis is one of the most useful carbon–carbon bond-forming reactions, and it has Olefin metathesis is one of the most useful carbon–carbon bond-forming reactions, and it has found tremendous use in organic chemistry for the construction of a myriad of organic molecules found tremendous use in organic chemistry for the construction of a myriad of organic molecules [7–10]. [7–10]. This highly powerful transformation has also been elegantly utilized in the total synthesis of Molecules 2017, 22, x; doi: Molecules 2018, 23, 1865; doi:10.3390/molecules23081865

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This highly powerful transformation has also been elegantly utilized in the total synthesis of numerous natural products Olefin metathesis catalysts that promote transformation are displayed numerous natural[11,12]. products [11,12]. Olefinmetathesis metathesis catalysts thatthis promote thistransformation transformation are numerous natural products [11,12]. Olefin catalysts that promote this are in Figure 2.inCross metathesis (CM) is one of the most popular transformations for connecting two displayed Figure 2. Cross metathesis (CM) is one of the most popular transformations for displayed in Figure 2. Cross metathesis (CM) is one of the most popular transformations for independent olefins together to form a more complex olefinic product, which could require several connectingtwo twoindependent independentolefins olefinstogether togetherto toform formaamore morecomplex complexolefinic olefinicproduct, product,which whichcould could connecting steps toseveral synthesize iftoa synthesize different methodology was employed. Although ring-closing metathesis require steps if a different methodology was employed. Although ring-closing require several steps to synthesize if a different methodology was employed. Although ring-closing (RCM) has found use in the total synthesis of synthesis numerousofnatural products, CM has become metathesis (RCM)extensive hasfound found extensive usein inthe thetotal total numerous natural products, CM metathesis (RCM) has extensive use synthesis of numerous natural products, CM increasingly popular in the field of total synthesis [13–15], particularly after the discovery of Z-selective has become increasingly popular in the field of total synthesis [13–15], particularly after the has become increasingly popular in the field of total synthesis [13–15], particularly after the olefin metathesis catalysts [16].metathesis As part ofcatalysts our interest inAs the power of interest olefin metathesis to facilitate discovery of Z-selective olefin [16]. part of our in the power of olefin discovery of Z-selective olefin metathesis catalysts [16]. As part of our interest in the power of olefin useful transformations [17], wetransformations report herein a [17], highly methodology forefficient the totalmethodology synthesis of metathesis tofacilitate facilitateuseful useful weefficient reportherein herein highly metathesis to transformations [17], we report aahighly efficient methodology ficuseptamines A and B, utilizing a cross metathesis approach. forthe thetotal totalsynthesis synthesisof officuseptamines ficuseptaminesAAand andB, B,utilizing utilizingaacross crossmetathesis metathesisapproach. approach. for

Figure2.2. 2.Ruthenium-based Ruthenium-basedolefin olefinmetathesis metathesiscatalysts. catalysts. Figure Figure Ruthenium-based olefin metathesis catalysts.

2.Results Resultsand andDiscussion Discussion 2. 2. Results and Discussion Aretrosynthetic retrosyntheticanalysis analysis ofofficuseptamines ficuseptamines and isdepicted depicted inScheme Scheme We commenced the A AAand BBisB in 1.1.We commenced the A retrosynthetic analysisof ficuseptamines A and is depicted in Scheme 1. We commenced synthetic work by first targeting ficuseptamine A for total synthesis. Aryl ketone 9a was prepared in two synthetic work by firstby targeting ficuseptamine A for total A synthesis. Aryl ketone 9a Aryl was prepared in two the synthetic work first targeting ficuseptamine for total synthesis. ketone 9a was sequential in steps from commercially available alcohol 11 11available via halogenation halogenation andvia dehydrohalogenation sequential steps commercially available alcohol via dehydrohalogenation prepared twofrom sequential steps from commercially alcohol and 11 halogenation and reactions(Scheme (Scheme2). 2). reactions (Scheme 2). reactions dehydrohalogenation

Scheme 1. Retrosyntheticanalysis analysis officuseptamines ficuseptamines Aand and B. Scheme Scheme1.1.Retrosynthetic Retrosynthetic analysisof of ficuseptaminesA A andB. B.

Thus,primary primaryalcohol alcohol11 11was wastransformed transformedinto intoits itsbromo bromocounterpart counterpart(i.e., (i.e.,12), 12),under underthe theinfluence influence Thus, Thus, primary alcohol 11 was transformed into itsSubsequent bromo counterpart (i.e., 12), under the influence of hydrobromic acid to furnish 12 in high yield (93%). treatment of the brominated product of hydrobromic acid to furnish 12 in high yield (93%). Subsequent treatment of the brominated product of hydrobromic acid to furnish 12 in high yield (93%). Subsequent treatment of the brominated 12 with with DBU DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (1,8-diazabicyclo[5.4.0]undec-7-ene) delivered delivered CM CM precursor precursor 9a 9a in in 69% 69% yield yield through through 12 dehydrobromination. dehydrobromination.

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product 12 with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) delivered CM precursor 9a in 69% yield through dehydrobromination. Molecules2017, 2017, Molecules 22,22, xx 3 3ofof9 9

Scheme2.2. 2. Brominationofof of1111 11 followed by dehydrobromination with DBUtoto togive giveCM CM precursor 9a. Scheme Bromination followed byby dehydrobromination with DBU precursor 9a. Scheme Bromination followed dehydrobromination with DBU give CM precursor 9a.

Next,we weexplored exploredthe thekey keyCM CMreaction reactionbetween between9a9aand andN,N-dimethyl-4-pentene-1-amine N,N-dimethyl-4-pentene-1-amine1010toto Next, Next, we explored the key CM reaction between 9a and N,N-dimethyl-4-pentene-1-amine 10 to affordthe theα,β-unsaturated α,β-unsaturatedCM CMproduct product8a. 8a.We Weinitially initiallyperformed performedthe theCM CMreaction reactionusing usingGrubbs GrubbsI I afford afford the α,β-unsaturated CM product 8a. We initially performed the CM reaction using Grubbs I catalyst 4 (5 mol %) with CH 2 Cl 2 as a solvent to afford CM product 8a in 22% yield (entry Table catalyst 4 (5 mol %) with CH2Cl2 as a solvent to afford CM product 8a in 22% yield (entry 1,1,Table catalyst 4 (5 mol %) with CH2 Cl2 as a solvent to afford CM product 8a in 22% yield (entry 1, Table 1). Increasingthe theGrubbs GrubbsI catalyst I catalyst4 4loading loading(10 (10mol mol%)%)provided provided8a8ainina adisappointing disappointing15% 15%yield yield 1).1).Increasing Increasing the Grubbs I catalyst 4 loading (10 mol %) provided 8a in a disappointing 15% yield (entry (entry2,2,Table Table1).1).We Wethen thenturned turnedour ourattention attentiontotoGrubbs GrubbsIIIIcatalyst catalyst5,5,which whichgave gavethe theCM CMproduct product (entry 2, Table 1). We then turned our attention to Grubbs II catalyst 5, which gave the CM product 8a in modest3737and and41% 41%yields yieldsusing using5 5mol mol%%and and1010mol mol%%catalyst catalystloading loadingininCH CH 2Cl , respectively 8a8aininmodest 2Cl 2, 2respectively modest 37 and 41% yields using 5 mol % and 10 mol % catalyst loading in CH2 Cl2 , respectively (entries 2Cl 2 to tolueneand andperforming performingthe thereaction reaction (entries3 3and and4,4,Table Table1).1).Switching Switchingthe thesolvent solventfrom fromCH CH 2Cl 2 to toluene (entries 3 and 4, Table 1). Switching the solvent from CH2 Cl2 to toluene and performing the reaction with with Grubbs II catalyst 5 (10 mol %) at 80 °C improved the yield to 47% (entry 5, Table 1). with Grubbs II catalyst 5 (10 mol %) at◦ 80 °C improved the yield to 47% (entry 5, Table 1). Grubbs II catalyst 5 (10 mol %) at 80 C improved the yield to 47% (entry 5, Table 1). Table1.1. Optimizationofof theCM CMreaction. reaction. Table Optimization the Table 1. Optimization of the CM reaction.

E

Substrate 9a (equiv.)

Substrate 10 (equiv.)

Catalyst (Loading)

Solvent

T (◦ C)

Yield % a

TT a a Substrate (equiv.) Substrate1010(equiv.) Catalyst (Loading) Yield 1 2 1 (equiv.) Catalyst G I 4 (5 (Loading) mol %) CH Cl2 40 22 % E E Substrate 9a9a(equiv.) Substrate Solvent 2Solvent (°C) Yield % (°C) 2 2 1 G I 4 (10 mol %) CH2 Cl2 40 15 4 (5 mol 2Cl 3 2 GG II mol %) Cl22Cl 40 3722 G I 45I (5 (5 mol %)%) CH 11 22 111 CH 2 2 4040 22 2CH 4 2 GG II mol %) Cl22Cl 40 4115 4 (10 mol 2Cl 2CH G I 45I (10 (10 mol %)%) CH 22 22 111 CH 2 2 4040 15 5 2 1 G II 5 (10 mol %) Toluene 80 47 5 (5 mol%)%) 2Cl 37 CH GG IIIIII57(5 2Cl 2 2 4040 37 33 22 111 CH 6 2 H-G (5 mol mol %) CH 40 68 2 Cl2 5(10 (10 mol 2Cl 2 40 41 CH GG IIIIII57(10 mol %)%) CH 2 Cl 2 40 41 44 22 111 CH 7 2 H-G mol %) Cl 40 76 2 2 8 2 H-G mol %) 5247 5(10 (10 mol Toluene 80 GG IIIIII57(10 mol %)%) Toluene 55 22 111 Toluene 8080 47 9 1 2 H-G II 7II(10 mol %) %) CH2CH Cl 2Cl2 4040 42 H-G mol H-G II 7 7(5(5 mol %) 2 40 6868 66 22 11 CH22Cl H-GII II (10 mol %) CH 1 mmol), 10 (1 mmol), CH 2Cl 2 76 H-G 7 7(10 mol 7 7 a All reactions 2 2 were performed using 9a1 (2 2Cl 2 10 4040 entry 76 solvent, and%) temperature for h, except 9, in H-G 7(10 (10 mol %) Toluene 2 Toluene was carried out using 10 II (2II E =%) entry. H-G 7mmol). mol 8 8 which the 2reaction 1 19a (1 mmol) and 8080 5252 H-GII II7 7(10 (10 mol%)%) CH 2Cl CH H-G mol 2Cl 2 2 4040 4242 99 11 22 a All reactions were performed using 9a (2 mmol), 10 (1 mmol), solvent, and temperature for 10 h, a All reactions were performed using 9a (2 mmol), 10 (1 mmol), solvent,ofand 10 h,(PCy3 ) A report by Grubbs and co-workers described how the presence thetemperature phosphine for ligand exceptentry entry whichthe the reactionwas wascarried carriedout out using mmol)and and1010(2(2 mmol). = entry. except 9,9, ininwhich reaction using 9a9a(1(1mmol) mmol). EE = entry.

in olefin metathesis catalysts can attack the carbine through its dissociation from the metal complex via decomposition [18]. This fact turned our attention to Hoveyda-Grubbs II 7, which lacks the PCy3 reportbybyGrubbs Grubbs andco-workers co-workersdescribed describedhow how thepresence presenceofofthe thephosphine phosphineligand ligand AAreport ligand. Pleasingly, the use and of Hoveyda-Grubbs II 7 (5 mol %) the increased the yield significantly, to afford (PCy 3 ) in olefin metathesis catalysts can attack the carbine through its dissociation from the metal (PCy3) in olefin metathesis catalysts can attack the carbine through its dissociation from the metal complexvia viadecomposition decomposition[18]. [18].This Thisfact factturned turnedour ourattention attentiontotoHoveyda-Grubbs Hoveyda-GrubbsIIII7,7,which whichlacks lacks complex the PCy 3 ligand. Pleasingly, the use of Hoveyda-Grubbs II 7 (5 mol %) increased the yield the PCy3 ligand. Pleasingly, the use of Hoveyda-Grubbs II 7 (5 mol %) increased the yield significantly,totoafford afford8a8ainina a68% 68%yield yieldusing usingCH CH 2Cl 2 as thesolvent solvent(entry (entry6,6,Table Table1).1).Treating Treating9a9a significantly, 2Cl 2 as the and1010with withananincreased increasedHoveyda-Grubbs Hoveyda-GrubbsIIII7 7loading loading(10 (10mol mol%)%)ininCH CH 2Cl provided8a8aininanan and 2Cl 2 2provided

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8a in a 68% yield using CH2 Cl2 as the solvent (entry 6, Table 1). Treating 9a and 10 with an increased Hoveyda-Grubbs II 7 loading (10 mol %) in CH2 Cl2 provided 8a in an excellent 76% yield (entry 7, excellent 76% yield (entry 7, Table 1). In contrast, increasing the temperature to 80 °C and changing Table 1). In contrast, increasing the temperature to 80 ◦ C and changing the solvent from CH2 Cl2 to the solvent from CH2Cl2 to toluene diminished the yield to 52% (compare entry 7 vs. 8, Table 1). The toluene diminished the yield to 52% (compare entry 7 vs. 8, Table 1). The double bond geometry of the double bond geometry of the CM product 8a was identified as the (E)-configured isomer, indicating CM product 8a was identified as the (E)-configured isomer, indicating that CM proceeded selectively that CM proceeded selectively to give the thermodynamically stable (E)-isomer exclusively. A change to give the thermodynamically stable (E)-isomer exclusively. A change in molar ratio of the coupling in molar ratio of the coupling partners 9a and 10, and performing the reaction using 10 mol % of partners 9a and 10, and performing the reaction using 10 mol % of Hoveyda-Grubbs II 7 in CH2 Cl2 , Hoveyda-Grubbs II 7 in CH2Cl2, resulted in a reduction of the yield to 42%, with formation of the resulted in a reduction of the yield to 42%, with formation of the homodimer of 10 as a competing homodimer of 10 as a competing side-product (entry 9, Table 1). Grubbs and co-workers categorized side-product (entry 9, Table 1). Grubbs and co-workers categorized olefin metathesis substrates as olefin metathesis substrates as Type I, Type II, Type III, or Type IV [19]. According to Grubbs’ Type I, Type II, Type III, or Type IV [19]. According to Grubbs’ selectivity model, terminal olefin 10 is selectivity model, terminal olefin 10 is a Type I olefin substrate, which usually undergoes fast a Type I olefin substrate, which usually undergoes fast homodimerization, while olefin 9a is a Type homodimerization, while olefin 9a is a Type II olefin, which undergoes slow homodimerization. Thus, II olefin, which undergoes slow homodimerization. Thus, such a change in the ratio of the coupling such a change in the ratio of the coupling partners 9a and 10 has promoted homodimerization of 10 partners 9a and 10 has promoted homodimerization of 10 to occur. to occur. With synthesis of compound 8a accomplished through CM, saturation of the newly formed With synthesis of compound 8a accomplished through CM, saturation of the newly formed double bond (Pd/C, H2 , CH3 OH, r.t., 16 h) proceeded smoothly to provide ficuseptamine A in 62% double bond (Pd/C, H2, CH3OH, r.t., 16 h) proceeded smoothly to provide ficuseptamine A in 62% isolated yield. We then envisioned performing one-pot CM/hydrogenation reactions for the synthesis isolated yield. We then envisioned performing one-pot CM/hydrogenation reactions for the synthesis of ficuseptamine A without isolation of the unsaturated CM product 8a. In fact, a literature screen of ficuseptamine A without isolation of the unsaturated CM product 8a. In fact, a literature screen revealed that such a CM/hydrogenation maneuver had been reported by Cossy and co-workers in revealed that such a CM/hydrogenation maneuver had been reported by Cossy and co-workers in their total synthesis of (-)-centrolobine [20]. One-pot sequential reactions are increasingly being utilized their total synthesis of (‒)-centrolobine [20]. One-pot sequential reactions are increasingly being in organic synthesis to accelerate the synthesis of target molecules [21]. Motivated by Cossy’s work, utilized in organic synthesis to accelerate the synthesis of target molecules [21]. Motivated by we subjected aryl ketone 9a and terminal olefin 10 to our optimized CM conditions, followed by Cossy’s work, we subjected aryl ketone 9a and terminal olefin 10 to our optimized CM conditions, hydrogenation in a one-pot fashion, to afford ficuspetamine A in 65% yield directly from the starting followed by hydrogenation in a one-pot fashion, to afford ficuspetamine A in 65% yield directly materials 9a and 10 (Scheme9a 3).and This10one-pot CM/hydrogenation sequence proved tosequence be fruitful, thus from the starting materials (Scheme 3). This one-pot CM/hydrogenation proved improving the efficiency of the synthesis of ficuseptamine A. to be fruitful, thus improving the efficiency of the synthesis of ficuseptamine A.

Scheme 3. 3. Improving Improving ficuseptamine ficuseptamine A A (1a) (1a) synthesis synthesis by by aa one-pot one-potCM/hydrogentation CM/hydrogentation sequence. Scheme sequence.

With ficuseptamine A (1a) synthesis accomplished, we moved forward to target ficuseptamine With ficuseptamine A (1a) synthesis accomplished, we moved forward to target ficuseptamine B (1b). We imagined employing a dual ethenolysis [22] and CM approach for its total synthesis. We B (1b). We imagined employing a dual ethenolysis [22] and CM approach for its total synthesis. envisaged that aryl ketone 9b, which is a different regioisomer to aryl ketone 9a, could be achieved We envisaged that aryl ketone 9b, which is a different regioisomer to aryl ketone 9a, could be achieved by ethenolysis of the Claisen-Schmidt product 17, using a suitable olefin metathesis catalyst to by ethenolysis of the Claisen-Schmidt product 17, using a suitable olefin metathesis catalyst to dissect dissect the internal alkene of 17 to give the desired terminal olefin 9b (Scheme 4). We also thought the internal alkene of 17 to give the desired terminal olefin 9b (Scheme 4). We also thought that this that this method would allow access to styrene derivatives (e.g., compounds such as 18), which are method would allow access to styrene derivatives (e.g., compounds such as 18), which are important important building blocks in organic chemistry. building blocks in organic chemistry.

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Scheme 4. Synthetic plan of aryl arylketone ketone9b9b a Claisen-Schmidt reaction followed Scheme 4. Synthetic planfor forthe thesynthesis synthesis of viavia a Claisen-Schmidt reaction followed Scheme 4. 4. Synthetic ketone 9b 9bvia viaaaClaisen-Schmidt Claisen-Schmidtreaction reaction followed Syntheticplan planfor forthe thesynthesis synthesis of of aryl aryl ketone followed byScheme ethenolysis. by ethenolysis. byby ethenolysis. ethenolysis.

began synthesis towards towards ficuseptamine ficuseptamine B Bbybyfirst preparing the the Claisen-Schmidt We We began thethesynthesis first preparing Claisen-Schmidt began the synthesis towards ficuseptamine B by first preparing the and Claisen-Schmidt product 17. initially combined 3-hydroxy-4-methoxyacetophenone 15 and 3-hydroxy-4WeWe began theWe synthesis towards ficuseptamine B by first preparing the Claisen-Schmidt product 17. product 17. We initially combined 3-hydroxy-4-methoxyacetophenone 15 3-hydroxy-4product 17. We initially combined 3-hydroxy-4-methoxyacetophenone 15 and 3-hydroxy-4methoxybenzaldehyde 16 under aqueous NaOH conditions in EtOH, which provided chalcone 17 We initially combined 3-hydroxy-4-methoxyacetophenone 15 and 3-hydroxy-4-methoxybenzaldehyde methoxybenzaldehyde 16 under aqueous NaOH conditions in EtOH, which provided chalcone 17 methoxybenzaldehyde 16 under aqueous NaOH conditions in EtOH, provided chalcone in 46% yield (entry 1, Table 2). The use of cesium carbonate (Cs 2CO 3) as which the base in EtOH led to 17 17 1, 16 under aqueous conditions in of EtOH, which provided chalcone 17base in 46% yield led (entry in 46% yield (entryNaOH 1, Table 2). The use cesium carbonate (Cs2CO 3) as the in EtOH to 17 41% yield (entry Table2). 2). The However, synthesis 172CO was3)achieved SOCl2/EtOH inin 46% yield (entry 1,2,Table use of efficient cesium carbonate (Cs as the EtOH led(entry to 17 2, Table The use of 2, cesium (Cs CO the baseofin ledachieved to base 17using inin 41% 2efficient 3 ) as synthesis in 41%2).yield (entry Tablecarbonate 2). However, ofEtOH 17 was usingyield SOCl 2/EtOH as a catalyst system2,(acid catalysis) [23] to afford 17 in 83% yield (entry 3, Table 2). using SOCl2/EtOH in 41% yield (entry Table 2). However, efficient synthesis of 17 was achieved Table 2). However, synthesis[23] of 17 achieved using SOCl as a 2). catalyst system (acid 2 /EtOH as a catalyst systemefficient (acid catalysis) to was afford 17 in 83% yield (entry 3, Table as a catalyst system (acid catalysis) [23] to afford 17 in 83% yield (entry 3, Table 2). catalysis)Table [23] 2. toSynthesis afford 17 83% yield (entry 3,17 Table of in Claisen-Schmidt product under2). various catalysis conditions. a All reactions a All reactions Table 2. Synthesis Claisen-Schmidt product 17 under various catalysis conditions. were outof using ketone 15 (1 equiv.), aldehyde 16 various (1 equiv.), and catalyst in EtOH at 23 °C. a All Table 2.carried Synthesis of Claisen-Schmidt product 17 under catalysis conditions. reactions a All Table 2. Synthesis of Claisen-Schmidt product 17 under various catalysis conditions. reactions b were carried out using ketone 15 (1 equiv.), aldehyde 16 (1 equiv.), and catalyst in EtOH at 23 °C. NaOH (10% w/v). were carried out using ketone 15 (1 equiv.), aldehyde 16 (1 equiv.), and catalyst in EtOH at 23 °C.◦ were carried out using ketone 15 (1 equiv.), aldehyde 16 (1 equiv.), and catalyst in EtOH at 23 C. b NaOH (10% w/v). b NaOH (10% w/v). b NaOH (10% w/v).

Entry Catalyst Equivalent Time (h) Yield (%) a 1 NaOH b 2 16 46 Entry Catalyst Equivalent Time (h) Yield (%) a a Entry Catalyst Equivalent Time (h) Yield 2 Cs 2 CO 3 2 16 41 (%) Entry Catalyst Equivalent Time (h) Yield (%) a b 1 2 16 46 NaOH 3 SOCl 2bb 1 4 83 1 NaOH 2 16 46 1 NaOH 2 16 46 2 Cs32 CO3 16 41 Cs2CO 22 16 41 22 Cs 2 CO 3 2 16 3 SOCl217 in hand, 1 4 the conditions 83 41 With the Claisen-Schmidt product 3 SOCl 2 1 we employed 4 83 reported by Diver 3 SOCl 2 1 4 83 and co-workers with slight modification for its ethenolysis [24]. Exposing 17 to ethylene gas (60 psi pressure) with Hoveyda-Grubbs II 7 and 1,2-DCE (1,2-dichloroethane) as a solvent at by 40 °C With the Claisen-Schmidt product 17using in hand, we employed the conditions reported Diver With the Claisen-Schmidt product 17 in hand, we employed thearyl Claisen-Schmidt employed the conditions reported by Diver delivered ketone 9b in 71% yield (Scheme 5). and co-workers with slight modification for its ethenolysis [24]. Exposing 17 to ethylene gas (60 psi

and co-workers with slight modification for its ethenolysis [24]. Exposing 17 to ethylene gas (60 psi pressure) with Hoveyda-Grubbs II 7 and using 1,2-DCE (1,2-dichloroethane) as a solvent at 40 °C◦ pressure) with Hoveyda-Grubbs II 7 and using 1,2-DCE (1,2-dichloroethane) as a solvent at 40 C using 40 °C delivered aryl ketone 9b in 71% yield and (Scheme 5).1,2-DCE (1,2-dichloroethane) delivered aryl ketone ketone 9b 9b in in 71% 71% yield yield (Scheme (Scheme 5). 5).

Scheme 5. Ethenolysis of chalcone 17 to deliver aryl ketone 9b.

Scheme 5. Ethenolysis of chalcone 17 to deliver aryl ketone 9b.

Scheme 5. 5. Ethenolysis of chalcone chalcone 17 17 to to deliver deliver aryl aryl ketone ketone 9b. 9b. Scheme Ethenolysis of

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To the best of our knowledge, this is the first time ethenolysis has been applied to cleave a chalcone compound such as 17). Importantly, no isomerization [25] the double is possible, To(i.e., the structure best of our knowledge, this is the first time ethenolysis hasofbeen appliedbond to cleave a givenchalcone the structure of chalcone 17, which any methylene groups adjacent to the double compound (i.e., structure such aslacks 17). Importantly, no isomerization [25] of the double bondbond. is possible, given the of of chalcone 17, which lacks any methylene we groups adjacentthe to one-pot, the Having accomplished thestructure synthesis aryl ketone 9a through ethenolysis, employed double bond. Having accomplished thepreviously synthesis of used aryl ketone 9a through ethenolysis, we employed two-step CM/hydrogenation protocol in ficuseptamine A synthesis. Gratifyingly, the one-pot, two-step protocol previously usedCM in ficuseptamine A synthesis. subjecting aryl ketone 9b CM/hydrogenation and terminal olefin 10 to our optimized conditions (Hoveyda-Grubbs Gratifyingly, subjecting aryl ketone 9b and terminal olefin 10 to our optimized CM conditions ◦ II 7 (10 mol %), CH2 Cl2 , 40 C) followed by one-pot hydrogenation delivered ficuseptamine B in 69% (Hoveyda-Grubbs II 7 (10 mol %), CH2Cl2, 40 °C) followed by one-pot hydrogenation delivered yield (Scheme 6). ficuseptamine B in 69% yield (Scheme 6).

Scheme 6. Synthesis of ficuseptamine B (1b) by one-pot CM/hydrogenation sequence.

Scheme 6. Synthesis of ficuseptamine B (1b) by one-pot CM/hydrogenation sequence.

The spectroscopic data of the synthetic ficuseptamines A and B were identical to those reported by

The spectroscopic data of A and B wereofidentical to those Shin-ya and co-workers [1].the Thesynthetic describedficuseptamines chemistry for the synthesis ficuseptamines A reported and B by through CM allows the generation of various analogues of these natural products a Shin-ya and co-workers [1]. The described chemistry for the synthesis of ficuseptamines A and Binthrough straightforward manner, could have other biological activities, such potential ligands manner, for CM allows the generation of which various analogues of these natural products inas a straightforward the 5-HT 7 receptor [26]. which could have other biological activities, such as potential ligands for the 5-HT7 receptor [26]. 3. Conclusions 3. Conclusions In summary, we have reported a highly efficient methodology for the first total synthesis of

In summary, we have reported a highly efficient methodology for the first total synthesis of ficuseptamines A and B through a CM strategy. A sequential one-pot, two-step CM/hydrogenation ficuseptamines A and B through a CM strategy. A sequential procedure was employed to expediently accomplish their total one-pot, synthesis.two-step CM/hydrogenation procedure was employed to expediently accomplish their total synthesis. 4. Materials and Methods

4. Materials and Methods

4.1. General Chemistry Experimental

4.1. General Chemistry Experimental

Chemical reactions were performed in over-dried glassware under nitrogen and anhydrous

Chemical were performed in over-dried glassware under nitrogen and anhydrous conditions, reactions unless otherwise stated. Reactions were magnetically stirred using a Teflon-coated stir bar andunless monitored by pre-coated gel aluminum plates (0.25 mm thickness) with a fluorescent stir conditions, otherwise stated.silica Reactions were magnetically stirred using a Teflon-coated indicator (254 nm), using UV light as the oxidative with staining using bar and monitored by pre-coated silica gel visualizing aluminumagent. platesAlternatively, (0.25 mm thickness) a fluorescent an aqueous basic solution of KMnO 4 and heat was carried out for visualization. Silica gel (60 Å, indicator (254 nm), using UV light as the visualizing agent. Alternatively, oxidative staining using 200–425 mesh) was used for flash column chromatography. Nuclear magnetic resonance (NMR) an aqueous basic solution of KMnO4 and heat was carried out for visualization. Silica gel (60 Å, spectra were recorded on a Bruker 400 MHz spectrometer (Bruker, Billerica, MA, USA) in acetone200–425 mesh) was used for flash column chromatography. Nuclear magnetic resonance (NMR) d6, CDCl3, or DMSO-d6 as the solvent. Chemical shifts are reported in parts per million (ppm) with spectra were recorded on a Bruker 400 MHz spectrometer (Bruker, Billerica, MA, USA) in acetone-d6 , reference to the hydrogenated residues of the deuterated solvent as the internal standard. Coupling CDClconstants , the solvent. Chemical are reported inexpressed parts perasmillion 3 or DMSO-d 6 asare (J values) recorded in Hertz (Hz), shifts and signal patterns are follows:(ppm) singlet with reference to the hydrogenated residues of the deuterated solvent as the internal standard. Coupling (s), doublet (d), dd (doublet of doublets), triplet (t), quintet (quint), and multiplet (m). Elemental constants (J values) are recorded Hertz (Hz),Elmer and signal are(PerkinElmer, expressed as Inc., follows: singlet (s), analyses were performed on ain2400 Perkin Seriespatterns II analyzer Waltham, doublet (d), dd (doublet of doublets), triplet (t), quintet (quint), and multiplet (m). Elemental analyses were performed on a 2400 Perkin Elmer Series II analyzer (PerkinElmer, Inc., Waltham, MA, USA).

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High-resolution mass spectrometry was conducted using a Micromass Q-ToF mass spectrometer (Waters Corporation, Milford, MA, USA). 4.2. Experimental Procedures for Chemical Synthesis and Characterization Data of Compounds 4.2.1. Synthesis of 1-(4-Hydroxy-3-methoxyphenyl)prop-2-en-1-one (9a) A round-bottom flask equipped with a magnetic stir bar was charged with 3-hydroxy-1-(4hydroxy-3-methoxyphenyl)propan-1-one 11 (2.52 g, 12.8 mmol) and conc. HBr (30 mL) was then added. The reaction mixture was then stirred at 95 ◦ C for 2 h. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered, washed with ice-cold H2 O, and dried to afford 3-bromo-1-(4-hydroxy-3-methoxyphenyl)propan-1-one 12 (quantitative yield, 3.09 g, 93%) as a white solid, which was judged to be of good purity by TLC analysis and mass spectrometry, and carried forward in crude form to the next step. To a stirred solution of 3-bromo-1-(4-hydroxy-3-methoxyphenyl)propan-1-one 12 (3 g, 11.6 mmol) in dry benzene (50 mL), was added, dropwise, a solution of DBU (2.08 mL, 13.9 mmol) in dry benzene (5 mL). A condenser was attached, and the reaction mixture was stirred at 70 ◦ C for 3 h. The solvent was removed in vacuo, and the crude product was extracted with EtOAc (three times). The combined organic layers were washed with H2 O, brine, dried over MgSO4 , filtered, and concentrated in vacuo. The crude product was then purified by silica gel column chromatography to afford 9a (1.42 g, 69%) as a white solid. 1 H-NMR (400 MHz, acetone-d6 ): δ 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 17.0, 10.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.36 (dd, J = 17.0, 2.0 Hz, 1H), 5.86 (dd, J = 10.4, 2.0 Hz, 1H), 3.93 (s, 3H); HRMS calcd. for C10 H11 O3 [M + H]+ 179.0708, found 179.0713. Anal. calcd. for C10 H10 O3 : C, 67.41; H, 5.66. Found: C, 67.31; H, 5.55. 4.2.2. Synthesis of Ficuseptamine A by a One-Pot Cross Metathesis/Hydrogenation Procedure (1a) To a stirred solution of aryl ketone 9a (315 mg, 1.77 mmol) and N,N-dimethyl-4- pentene-1-amine 10 (100 mg, 0.885 mmol) in dry and degassed CH2 Cl2 (5 mL), was added Hoveyda-Grubbs second generation catalyst 7 (55 mg, 0.0885 mmol, 10 mol %). The reaction mixture was then deoxygentated by performing vacuum/N2 cycles four times and stirred at 40 ◦ C for 10 h. After the completion of the reaction, Pd/C (10 wt %) was added, and the N2 atmosphere was substituted with H2 by performing vacuum/H2 cycles four times. The reaction mixture was then stirred under a double layer H2 balloon at 23 ◦ C for 16 h. The Pd/C catalyst was removed by filtration through a pad of Celite® , followed by washing of the filter cake with CH2 Cl2 (10 mL), and the filtrate was evaporated in vacuo. The crude product was purified directly by silica gel column chromatography to afford ficuseptamine A (1a) as a white solid (153 mg, 65%). Spectroscopic data for synthetic ficuseptamine A matched literature data of natural ficuseptamine A [1]. 1 H-NMR (400 MHz, acetone-d6 ): δ 7.57 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.93 (t, J = 7.2 Hz, 2H), 2.21 (t, J = 7.2 Hz, 2H), 2.13 (s, 2 × 3H), 1.68 (quint, J = 7.2 Hz, 2H), 1.47 (quint, J = 7.2 Hz, 2H), 1.37 (quint, J = 7.2 Hz, 2H); 13 C-NMR (100 MHz, acetone-d6 ) δ: 198.6, 152.1, 148.3, 130.6, 123.8, 115.3, 111.5, 60.2, 56.2, 45.6, 38.4, 28.3, 27.8, 25.3; HRMS calcd. for C15 H24 NO3 [M + H]+ 266.1756, found 266.1767. Anal. calcd. for C15 H23 NO3 : C, 67.90; H, 8.74; N, 5.18. Found: C, 67.76; H, 8.70; N, 5.07. 4.2.3. Synthesis of (2E)-1,3-Bis(3-Hydroxy-4-methoxyphenyl)prop-2-en-1-one (17) Compound 17 was synthesized using a previously reported method, except that it required purification [23]. To a stirred solution of 3-hydroxy-4-methoxyacetophenone 15 (1.20 g, 7.89 mmol) and 3-hydroxy-4-methoxybenzaldehyde 16 (1.31 g, 7.89 mmol) in absolute EtOH (5 mL), was added thionyl chloride (0.58 mL, 7.89 mmol) dropwise and the reaction mixture was stirred at 23 ◦ C for 4 h. The reaction mixture was precipitated by the addition of H2 O (~5 mL), and the resulting precipitate was filtered, washed with ice-cold H2 O, and ice-cold EtOH. After the crude product was allowed to air dry, purification by recrystallization from EtOH afforded 17 (1.97 g, 83%) as a yellow solid. Analytical

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data were in accordance with literature data [27]. 1 H-NMR (400 MHz, CDCl3 ): δ 7.72 (d, J = 16.2 Hz, 1H), 7.63-7.60 (m, 2H), 7.40 (d, J = 16.2 Hz, 1H), 7.28-7.27 (m, 1H), 7.12 (dd, J = 10.4, 2.0 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H); 13 C NMR (100 MHz, DMSO-d6 ): δ 188.5, 152.7, 150.7, 147.0, 146.9, 144.3, 131.3, 128.1, 122.8, 122.4, 119.8, 115.2, 114.8, 112.5, 111.8, 56.3, 56.2; HRMS calcd. for C17 H17 O5 [M + H]+ 301.1076, found 301.1065. Anal. calcd. for C17 H16 O5 : C, 67.99; H, 5.37. Found: C, 67.80; H, 5.41. 4.2.4. Synthesis of 1-(3-Hydroxy-4-methoxyphenyl)prop-2-en-1-one (9b) Compound 9b was synthesized using the slightly modified reaction conditions of Diver et al. [24]. To an inert and oven-dried high-pressure flask, was added compound 17 (800 mg, 2.67 mmol), dry and degassed 1,2-dichloroethane (35 mL), and Hoveyda-Grubbs second generation catalyst 7 (42 mg, 0.067 mmol). The flask was purged with ethylene for 5 min, pressurized to 60 psi, and stirred at 40 ◦ C for 12 h, after which time TLC analysis indicated consumption of the internal alkene 17. The pressure was then slowly vented, and the solvent was evaporated in vacuo. The crude product was then purified directly by silica gel column chromatography, to afford 9b (337 mg, 71%) as a white solid. 1 H-NMR (400 MHz, acetone-d6 ): δ 7.59 (dd, J = 8.4, 2.0 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 17.0, 10.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.33 (dd, J = 17.0, 2.0 Hz, 1H), 5.84 (dd, J = 10.4, 2.0 Hz, 1H), 3.94 (s, 3H); 13 C NMR (100 MHz, acetone-d ): δ 188.9, 153.0, 147.7, 133.2, 131.8 128.9, 122.8, 115.7, 111.8, 56.5; HRMS 6 calcd. for C10 H11 O3 [M + H]+ 179.0708, found 179.0719. Anal. calcd. for C10 H10 O3 : C, 67.41; H, 5.66. Found: C, 67.35; H, 5.59. 4.2.5. Synthesis of Ficuseptamine B by a One-Pot Cross Metathesis/Hydrogenation Procedure (1b) The experimental procedure for the synthesis of ficuseptamine A (1a) was followed, except that aryl ketone 9b was used as the cross metathesis partner with N,N-dimethyl-4-pentene-1-amine 10 to afford ficuspetamine B (1b) (162 mg, 69%) as a white solid. Spectroscopic data for synthetic ficuseptamine B matched literature data of natural ficuseptamine B [1]. 1 H-NMR (400 MHz, acetone-d6 ): δ 7.52 (dd, J = 8.5, 2.0 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H), 2.90 (t, J = 7.2 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H), 2.15 (s, 2 × 3H), 1.66 (quint, J = 7.2 Hz, 2H), 1.48 (quint, J = 7.2 Hz, 2H), 1.37 (quint, J = 7.2 Hz, 2H); 13 C-NMR (100 MHz, acetone-d6 ): δ 198.9, 152.4, 147.3, 131.7, 121.7, 115.2, 111.5, 60.1, 56.3, 45.5, 38.5, 28.1, 27.7, 25.2; HRMS calcd. for C15 H24 NO3 [M + H]+ 266.1756, found 266.1741. Anal. calcd. for C15 H23 NO3 : C, 67.90; H, 8.74; N, 5.28. Found: C, 67.78; H, 8.66; N, 5.19. Author Contributions: Conceived of and designed the experiments: H.M.A.H. Performed the experiments: H.M.A.H. Analyzed the data: H.M.A.H. Wrote the paper: H.M.A.H. Acknowledgments: This work was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, under grant number G-1436-141-202. The author, therefore, would like to thank DSR for financial support. Conflicts of Interest: The author declares no conflict of interest.

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Sample Availability: Samples of the compounds are not available from the author. © 2018 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).