Hypervalent Iodine(III)-Induced Domino Oxidative Cyclization for the

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Dec 21, 2016 - Cyclization for the Synthesis of Cyclopenta[b]furans ...... Mischne, M.P. An interrupted vinylogous iso-Nazarov reaction: Cycloisomerization of.
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Hypervalent Iodine(III)-Induced Domino Oxidative Cyclization for the Synthesis of Cyclopenta[b]furans Mei-Huey Lin *, Yu-Chun Chen, Shih-Hao Chiu, Yun-Fan Chen and Tsung-Hsun Chuang Department of Chemistry, National Changhua University of Education, Changhua 50007, Taiwan; [email protected] (Y.-C.C.); [email protected] (S.-H.C.); [email protected] (Y.-F.C.); [email protected] (T.-H.C.) * Correspondence: [email protected]; Tel.: +886-4-723-2105 (ext. 3543) Academic Editors: Wesley Moran and Arantxa Rodríguez Received: 17 November 2016; Accepted: 14 December 2016; Published: 21 December 2016

Abstract: A new strategy for cyclopenta[b]furan synthesis mediated by hypervalent iodine(III) has been described. The approach employs diacetoxyiodobenzene-induced initial dehydrogenation to a putative trienone intermediate and triggered sequential cycloisomerization to form the cyclo-penta[b]furan targets. Keywords: cyclopenta[b]furan; hypervalent iodine(III); domino oxidative cyclization; diacetoxyiodobenzene; cycloisomerization

1. Introduction Recent medicinal chemical studies have led to the identification of the cyclopenta[b]furan ring system as a potent inhibitor of CCR2, a chemokine receptor that plays an important role in inflammation-associated diseases [1,2]. Syntheses of the cyclopenta[b]furan core component have been achieved by employing palladium(0)-catalyzed intramolecular allylations (path a, Scheme 1), [3] and phosphine-catalyzed [3 + 2] cycloadditions of allenoates with β,γ-unsaturated α-ketoesters (path b, Scheme 1) [4]. In addition, the construction of tricyclic cyclopenta[b]furan derivatives was elaborated through ethylenediammonium diacetate (EDDA)-catalyzed tandem Knoevenagel-polycyclization reactions between 1,3-dicarbonyl compounds and α,β,γ,δ-unsaturated aldehydes (path c, Scheme 1) or Lewis acid-promoted cycloisomerization of conjugated trienones (path d, Scheme 1) [5,6]. On the other hand, hypervalent hypervalent iodine species possess similar chemical properties and reactivity as heavy metal reagents but lower toxicity and an environmentally benign nature. Therefore, the utilization of hypervalent iodine in organic synthesis has been drawing intensive attention [7–12]. Among its reactions, the reactions of 1,3-dicarbonyl compounds with hypervalent iodine(III) species such as diacetoxyiodobenzene generate β-diketo iodonium ylides which behave as a 1,3-dipole, with an electrophilic center next to a carbonyl group. For example, the synthetic application of hypervalent iodine(III) in forming heterocycles involves the addition of β-diketo iodonium ylides to olefins to form fused dihydrofurans (path e, Scheme 1) [13,14]. Recent progress in the use of hypervalent iodine(III) reagents in organic synthesis has shown that diacetoxyiodobenzene-mediated dehydrogenation reactions of α-alkyl-β-dicarbonyl compounds provide an alternative route to the Knoevenagel condensation [15,16]. Herein, we have devised a route for employing hypervalent iodine(III) in the synthesis of cyclopenta[b]furan derivatives 1 (Scheme 2).

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Molecules 2016, 21, 1713 (a) AcO

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AcO

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O

R1

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[4]

2

O

O

1

R

R

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R3 +

R2

R1

R3

R1 1

O

O

COOR2 O COOR4

COOR2

R1 O

R2

1

R O

[5](0.2 equiv) EDDA

H

R2 3 R 3

HO R

[5]

O EDDA = ethylenediammonium diacetate

(d) (d) O

EDDA = ethylenediammonium diacetate

O

R3 O

R2

R1

FeCl3(0.5 equiv)

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R2

R1

[6]

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O

(e) (e) O O

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O COOR4

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20 mol% PPh3

4 2 COOR COOR

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O

R

HH

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[3] Pd(PPh 3)4

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O O

PhI(OAc) PhI(OAc)22 [11-12] [11-12]

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Scheme 1. Routes for the synthesis of cyclopenta[b]furans.

Scheme 1. 1. Routes Routes for for the the synthesis synthesis of of cyclopenta[b]furans. cyclopenta[b]furans. Scheme

Scheme 2. Synthetic plans for the synthesis of cyclopenta[b]furan derivatives 1.

Scheme 2. Scheme 2. Synthetic Synthetic plans plans for for the the synthesis synthesis of of cyclopenta[b]furan cyclopenta[b]furan derivatives derivatives 1. 1. 2. Results and Discussions

In theDiscussions study described below, we have explored a method for the synthesis of cyclopenta[b] 2. 2. Results Results and and Discussions

furans containing a stereogenic, quaternary, aryl-substituted bridgehead carbon. For the preparation

In the study studydescribed describedbelow, below, explored a method forsynthesis the synthesis cyclopenta[b] of 2-aryl-1,4-dibromopenta-2,4-dienes 2have weexplored used a literature procedure developed ourofgroup [17]. In the wewe have a method for the ofincyclopenta[b]furans furans containing a stereogenic, quaternary, aryl-substituted bridgehead carbon. For the preparation The β-ketoesters linked with pentadiene tether 3 were prepared by C-alkylation of ethyl acetoacetate containing a stereogenic, quaternary, aryl-substituted bridgehead carbon. For the preparation of of 2-aryl-1,4-dibromopenta-2,4-dienes weused usedpurification literature procedure developed in enolate with 2; however, the chromatographic ofprocedure compoundsdeveloped 3 is difficultin inour mostgroup cases [17]. 2-aryl-1,4-dibromopenta-2,4-dienes 2 2we aaliterature our group [17]. (Table 1). In fact, only 3h can be isolated in pure form by recrystallization after chromatographic The β-ketoesters linked with pentadiene tether 3 were prepared by C-alkylation of ethyl acetoacetate The β-ketoesters linked with pentadiene tether 3 were prepared by C-alkylation of ethyl acetoacetate purification. Crude analogues 3a–g as obtained after silica-gel plug treatment were carried directly enolate enolate with with 2; 2; however, however, the the chromatographic chromatographic purification purification of of compounds compounds 33 is is difficult difficult in in most most cases cases into the next step, therefore, purity and exact yields of 3a–g are not given in Table 1. In order to evaluate (Table 1). In fact, only 3h can be isolated in pure form by recrystallization after chromatographic (Tablethe1).feasibility In fact,ofonly 3h can be isolated in pure form by recrystallization after chromatographic the new strategy for cyclopenta[b]furan synthesis, 3b serves as effective substrate in the purification. Crude analogues analogues3a–g 3a–gasasobtained obtained after silica-gel plug treatment were carried directly purification. plug treatment were carried reaction Crude with diacetoxyiodobenzene that takes after placesilica-gel by a one-pot, initial dehydrogenation todirectly give a into into the next step, therefore, purity and exact yields of 3a–g are not given in Table 1. In order to evaluate the next step,trienone therefore, purity andand exact yields of 3a–g are not given in Table In order to evaluate putative intermediate sequential cycloisomerization to form the 1. cyclopenta[b]furan the feasibility of the new strategy for cyclopenta[b]furan synthesis, 3b serves as effective substrate in the the feasibility of the newshow strategy forputative cyclopenta[b]furan synthesis, 3breactions serves as effective substrate in (Table 2). The results that the trienone produced in these is not isolable using reaction withwith diacetoxyiodobenzene that that takes place by abyone-pot, dehydrogenation to to give a chromatography, and at ambient temperature only the formation of theinitial trienone was observed (Table 2, give the reaction diacetoxyiodobenzene takes place a one-pot, initial dehydrogenation putative trienone intermediate and sequential cycloisomerization to form the cyclopenta[b]furan entriestrienone 1 and 8).intermediate At elevated temperature, the putative trienone underwent to a putative and sequential cycloisomerization to formcycloisomerization the cyclopenta[b]furan (Table 2). The results show that the putative trienone produced in these reactions is not isolable using (Table 2). The results show that the putative trienone produced in these reactions is not isolable chromatography, and at ambient temperature only the formation of the trienone was observed (Table 2, using chromatography, and at ambient temperature only the formation of the trienone was observed entries 1 and 8). At elevated temperature, the putative trienone underwent cycloisomerization to (Table 2, entries 1 and 8). At elevated temperature, the putative trienone underwent cycloisomerization

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form cyclopenta[b]furans (entry 1vs. vs.entry entry 7vs. vs.entry 8),reactions reactions which inorganic bases form cyclopenta[b]furans (entry 2,2,entry entry 8), ininwhich which inorganic bases to form cyclopenta[b]furans (entry 1 entry vs. entry 2, 77entry 7entry vs.8), entry 8), reactions ininorganic which inorganic form cyclopenta[b]furans (entry 111 vs. entry 2, entry reactions in bases form cyclopenta[b]furans (entry vs. entry 2, 2, entry 7 7vs. vs. entry 8), reactions in which inorganic bases gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the form cyclopenta[b]furans (entry 1 vs. entry entry vs. entry 8), reactions in which inorganic bases gave better yields than organic bases bases (entry(entry 4 vs. vs. entry entry 5, entry entry 8 vs. vs. entry 9). 9). In In addition, the bases gaveyields better than yieldsorganic than organic vs. entry 5, entry 8 vs. entry addition, the gave better yields than organic bases (entry 5, entry 9). In addition, the gave better bases (entry 44 vs. vs. 4entry entry 5, entry 88 vs. vs. entry 9). In addition, the gave better yields than organic bases (entry 4 5, entry 8 entry 9). In addition, the gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene oxidation-cycloisomerization process happened smoothly when[bis(trifluoroacetoxy)iodo]benzene [bis(trifluoroacetoxy)iodo]benzene oxidation-cycloisomerization process happened smoothly when oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene was employed. The ideal conditions for this process involve the use diacetoxyiodobenzeneand and was employed. The ideal conditions for this process involve the use ofof diacetoxyiodobenzene wasemployed. employed.The The ideal conditions for this process involve theuse useof ofdiacetoxyiodobenzene diacetoxyiodobenzene and was ideal conditions for this process involve the was employed. Thein ideal conditions for(Table this process involve the use of of diacetoxyiodobenzene diacetoxyiodobenzene and wascarbonate employed. The ideal conditions for this process involve the use andand sodium refluxing ethanol 2, entry 7). Next, a variety of aryl-substituted substrates sodium carbonate ininrefluxing refluxing ethanol (Table 2,2,entry entry 7). Next, aavariety variety ofofaryl-substituted aryl-substituted substrates sodium carbonate refluxing ethanol (Table entry 7). Next, variety aryl-substituted substrates sodium carbonate in ethanol (Table 2, 7). Next, a of substrates sodiumsodium carbonate in refluxing refluxing ethanol (Table 2, 2, entry 7). Next, aa variety variety ofaryl-substituted aryl-substituted substrates 3 carbonate in refluxing ethanol (Table entry7). 7).Next, Next,a variety of substrates sodium carbonate in ethanol (Table 2, entry of aryl-substituted substrates 3were wereexamined examined and Suzuki reactions were pursued in order to confirm the structural determination 3 and Suzuki reactions were pursued in order to confirm the structural determination examined andSuzuki Suzuki reactions were pursued in orderto toconfirm confirm the structural determination 33 were and reactions were pursued the structural determination 3examined were examined and Suzuki reactions were pursuedin inorder order to confirm the structural determination werethe examined and Suzuki reactions were pursued inof order to confirm the structural determination and relative stereochemistry at the ring junction thecyclopenta[b]furans cyclopenta[b]furans 1(Table (Table 1). and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1). and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1). and the relative stereochemistry at the ring junction of the 1 1). the relative stereochemistry at the ring junctionof thecyclopenta[b]furans cyclopenta[b]furans 1 1 1).1). and the theand relative stereochemistry at the the ring junction ofofthe the cyclopenta[b]furans 1(Table (Table 1). and relative stereochemistry at ring junction (Table Table cyclopenta[b]furans. Table 1.1. Synthesis ofof cyclopenta[b]furans. Table 1.Synthesis Synthesis cyclopenta[b]furans. Table 1. Synthesis of cyclopenta[b]furans. Table Table 1. Synthesis of cyclopenta[b]furans. Table 1. 1. Synthesis Synthesis of of cyclopenta[b]furans. cyclopenta[b]furans.

Entry Ar Ar Entry Entry Entry ArAr Entry Ar Entry Ar Entry 1 Ar 1 11 11 2 2 2 22 3 22 3 3 33 3

3 44 4 4 4 55 5 5 5 66 6 6 66 77 77 7 7

4 5 6 7

3, Yield (%)

3,Yield Yield (%) (%) 3,3,Yield Yield (%) 3, (%) 3, Yield--(%) (%) 3, Yield ----– --- -----– ---- -----–--------–--------- –-----– ---- --

-- 58 --3g, --– --

8

1, Yield (%) a

a

4, Yield (%) c

c

a 1, Yield 4,(%) Yield c c (%) Yield (%)aaa (%) Yield(%) 1,1,Yield Yield (%) 4,4,Yield Yield (%) ccc 1, (%) 4, a 1, Yield (%) 4, Yield (%) ba 1, Yield 4, Yield (%) 4a, Ar’ = Ar, 86 c 1a, 72; (%) (73) b b 4a,Ar’ Ar’= 4a, =Ar, Ar, 1a,72; 72; (73) Ar’ = Ar, 86 1a, 72;bbbb (73) 4a, 8686 1a, (73) 4a, == Ar, 86 1a, =Ar’ 4-PhC 6H86 4, 85 1b,72; 78;(73) (71)bb 4b, Ar’ 4a, Ar’ Ar, 1a, 72; (73) b b4b, Ar’=4b, =4-PhC 4-PhC H , 856 H4 , 85 1b,78; 78; (71) Ar’ 666=H 4b, Ar’ H64-PhC 44, 485 1b, (71) 1b, 78;bb (71) Ar’ === 4-PhC 1b, = Ar, 86 1c,78; 90;(71) (70) bbbb 4b, 4b, Ar’ 4-PhC 85 1b, 78; (71) 66H 4b, 4c, Ar’Ar’ 4-PhC H444,,, 85 85 1b, 78; (71) 4c,Ar’ Ar’= 4c, =Ar, Ar, 1c,90; 90; (70)bb b b 4c, 4c, Ar’ Ar, 8686 1c, 90; (70) Ar’ = Ar, 86 1c, 86 1c, (70) 1d, 7090;bbb (70) 4d, 4c, Ar’ Ar’====Ar, Ar,84 86 1c, 90; (70) 4c, Ar’ Ar, 86 1c, 90; (70) 1d,70 70 4d, Ar’ =Ar, Ar, 1d, 4d, Ar’ 8484 1e, 65 4e, Ar’ = =Ar, 82 1d, 70 4d, Ar’ = Ar, 84 1d, 4d, 1d, 70 70 4d, Ar’ Ar’ == Ar, Ar, 84 84 1e,6565 4e,Ar’ Ar’= 4e, =Ar, Ar, 1e, 4e, 8282 Ar’ 1e, 4e, Ar’ Ar, 82 1f,65 631e, 65 4f, 1e, 65 4e,Ar’ Ar’===Ar, Ar,81 82 = Ar, 82 Ar’= =Ar, Ar,8181 1f,1f,63 6363 4f,4f,Ar’ Ar’ 1f, 4f, === 4f, Ar, 81 Ar’ = Ar, 81 6H 4, 85 1g,63 871f, 63 4g, Ar’ =Ar’ 3-PhC 1f, 4f, Ar, 81 1f, 63 4f, Ar’ Ar, 81 485 , 85 1g,87 87 4g, Ar’ 6H H6H 1g, 87 4g, Ar’ = =3-PhC 3-PhC 1h, 64 4h, Ar’ =3-PhC Ar, 84 444,, 85 85 1g, 4g, Ar’ H3-PhC 1g, 87 4g, Ar’ 3-PhC 1g, 87 4g, Ar’ 6666=H 6 H4 , 85 44,, 85 1g, 87 Ar’ === 4g, 3-PhC

Reagents and Conditions: 3 (0.3 mmol), PhI(OAc)2 (0.6 mmol) and Na2CO3 (0.66 mmol) in EtOH (1.2 3g, 1h,64 64 4h,Ar’ Ar’=(1.5 =Ar, Ar, 8 3g, 5858 1h, 4h, 8484 mmol b8PhI(OCOCF 3)2 was employed instead . c 1h, 1 (0.5 Cs2Ar’ CO3 = mmol, mL). 3g, 58 1h, 4h, Ar, 84 8 8 64mmol), Ar’ Ar, 84 3g,3g, 5858 of PhI(OAc) 1h, 264 64 4h, Ar’ =4h, Ar, 84 =3.0 8 a mmol, 1.5 mmol for 4g), Pd(dppf)Cl 2 (0.05 mmol) in dioxane/water for 4b, 4g), PhB(OH)32 (0.75 a Reagents and Conditions: 3(0.3 (0.3mmol), mmol), PhI(OAc) 24b, (0.6 mmol) andNa Na 2CO 3 (0.66 mmol) EtOH(1.2 (1.2 and Conditions: PhI(OAc) 22 (0.6 mmol) and 22CO 33 (0.66 mmol) ininEtOH EtOH aa Reagents aa 2 2 3 Reagents and Conditions: 3 (0.3 mmol), PhI(OAc) 2 (0.6 mmol) and Na 2 CO 3 (0.66 mmol) in (1.2 a Reagents a Reagents and Conditions: 3 (0.3 PhI(OAc) 22 (0.6 (0.6 mmol) mmol) and Na 22CO(0.66 33 (0.66 mmol) in EtOH (1.2 b PhI(OCOCF c1 (5/1, 0.5and mL) 100 °C for 2 (0.3 h. mmol), Conditions: 3 mmol), PhI(OAc) and Na CO mmol) in EtOH (1.2 mL). b c 3 ) 2 was employed instead of PhI(OAc) 2 . (0.5 mmol), Cs 2 CO 3 (1.5 mmol, 3.0 mmol mL). 2 2 3 b c PhI(OCOCF3333))2222 was was employed employed instead instead of of PhI(OAc) PhI(OAc) 2. c 1 (0.5 mmol), Cs22CO33 (1.5 mmol, 3.0 mmol mL).b bbb PhI(OCOCF (0.5 mmol), mmol), Cs CO (1.53.0mmol, mmol, 3.0 mmol mL). c 2222.. cccmmol), 222CO 333 (1.5 PhI(OCOCF was employed instead of PhI(OAc) PhI(OAc) 11 (0.5 Cs 3.0 mmol mL). bPhI(OCOCF employed instead of PhI(OAc) Cs2 CO3 Cs (1.5 mmol, mmol 3.0 for 4b, 4g), PhI(OCOCF ))22 was employed instead of 2. 1 (0.5 mmol), 2CO 3 (1.5 mmol, mmol mL). 3 )2 33was 2 . 1 (0.5 2 (0.75 mmol, 1.5 mmol for 4b, 4g), Pd(dppf)Cl 2 (0.05 mmol) in dioxane/water for4b, 4b, 4g),PhB(OH) PhB(OH) 22 (0.75 mmol, 1.5 mmol for 4b, 4g), Pd(dppf)Cl 22 (0.05 mmol) in dioxane/water for 4g), PhB(OH) 1.5 mmol for1.5 4b, 4g),2.Pd(dppf)Cl mmol) ain dioxane/water 0.5 mL) 100 ◦ C 222 (0.75 mmol, mmol for 4b, 4g), Pd(dppf)Cl 222 (0.05 mmol) (5/1, in dioxane/water for 4b, 4g), PhB(OH) 2 (0.75 mmol, 2 (0.05 Table Reaction Optimizations . 2 (0.75 mmol, 1.5 mmol for 4b, 4g), Pd(dppf)Cl2 (0.05 mmol) in dioxane/water for(5/1, 4b,0.5 4g), PhB(OH) 100 for 2 h. h.mL) (5/1,for 0.52 mL) mL) 100 °C°C for h. (5/1, 0.5 100 °C for 22 h. a

(5/1, (5/1, 0.5 0.5 mL) mL) 100 100 °C °C for for 22 h. h.

a. a a Table Reaction Optimizations Table2.2. Table Reaction Optimizations aaa. . Table Table 2. 2. Reaction Reaction Optimizations Optimizations aa..

Entry Base Solvent, Temp Yield (%) a 1 NaHCO3 CH3CN, r.t. 0 2 NaHCO3 CH3CN, reflux 48 3 Na2CO3 Solvent, CH3CN, reflux 60 (%)aa a Entry Base Temp Yield Yield Entry Base Solvent, Temp Yield (%) aa Yield (%) a Entry Base Solvent, Temp (%) Entry Temp Entry Base Solvent, Temp Yield (%) a 4 Base K2CO3 Solvent, CH3Solvent, CN,Temp reflux 53(%) Entry Base Yield 1 NaHCO NaHCO CH 3CN, r.t. 0 1 33 3 CH 33CN, r.t. 0 1 NaHCO 3 CH 3 CN, r.t. 0 DBU CH33CN, CN, 12 1 CHreflux CN, r.t. 0 1 2 5NaHCO NaHCO CH 0 3 33 3r.t. NaHCO 3 CH CH 3CN, reflux 2 6NaHCO NaHCO CN, reflux 4848 2 NaHCO 333 3 CH CH 333CN, CN, reflux 48 2 CH CN, reflux 48 Na 2CO PhCH 33 , reflux 26 2 NaHCO 3 3 reflux 48 3 2 3 NaHCO 3 CH 3CN, reflux 4860 Na 2CO CH 3CH CN, reflux Na 2CO 3 3 CH 3CN, reflux 60 b 3 CN, reflux 78 (71) 60 reflux 2 CO 32CO 3reflux 333 7NaNa 222Na CO 33 3 CHEtOH, 333CN, 60 Na 2CO33 CH 3CN, reflux 6053 4 8 K2KCO K 23CO 3 CH 3CH CN, reflux 4 CN, reflux 53 4 22CO 3 CH 3 CN, reflux 53 3reflux Na233CO3 CH33CN, EtOH, r.t. 0 44 K 53 K222CO CO 33 CH 33CN, reflux 5312 5 DBU CH CN, reflux 12 3 5 DBU CH 3 CN, reflux 5 9 DBU DBU CH333CN, CN, reflux reflux 12 DMAP CH reflux 31 12 DBU CHEtOH, CN, reflux 12 6 CO3 PhCH , reflux 26 555 6 Na2DBU CH 33CN, reflux 12 3 a Reagents and Conditions: Na 2CO PhCH 3reflux , reflux (0.3 23 mmol) and base (1.2 Na 2mmol), CO 33 3 PhI(OAc) PhCH ,(0.6 2626(0.66 mmol) in solvent 66 3bNa Na 222CO PhCH 333, reflux 26 7 EtOH, reflux 78 (71) b 2 CO 3 333 Na 2CO PhCH 3, reflux 26(71) b b PhI(OCOCF 3 ) (0.6 mmol) and Na 2 CO 3 (0.66 mmol) in EtOH (1.2 mL) reflux. mL). b 3b (0.3 mmol), 6 7 Na 2 CO 3 EtOH, reflux 78 b 7 Na CO 3 EtOH, EtOH, reflux r.t. 78 78 (71) (71) Na 222CO CO EtOH, reflux 8 0 2 CO 3 3333 Na EtOH, reflux 78 (71) (71) bbb 777 8 NaNa 22CO EtOH, reflux 78 Na 2CO EtOH, r.t. 0 8 Na 22CO 33 3 EtOH, r.t. 0 9 DMAP EtOH, reflux 31 8 Na2CO3 EtOH, r.t. 0

aa aa aa

88

Na22CO CO33 Na

EtOH, r.t. r.t. EtOH,

00

DMAPPhI(OAc) EtOH, reflux 9 93b (0.3DMAP DMAP EtOH, reflux 3131 Reagents and Conditions:9 mmol), mmol) and base (0.66 mmol) in solvent (1.2 mL). 2 (0.6 EtOH, reflux 31 9 3b3 )(0.3 DMAP EtOH, reflux 31 b 3b (0.3 mmol), PhI(OCOCF a Reagents (0.6 mmol) and Na CO (0.66 mmol) in EtOH (1.2 mL) reflux.inin 2 2 3 and Conditions: mmol), PhI(OAc) 2 (0.6 mmol) and base (0.66 mmol) solvent(1.2 (1.2 Reagents and Conditions: 3b (0.3 mmol), PhI(OAc)2 (0.6 mmol) and base (0.66 mmol) solvent a

Reagents and and Conditions: Conditions: 3b 3b (0.3 (0.3 mmol), mmol), PhI(OAc) PhI(OAc)222 (0.6 (0.6 mmol) mmol) and and base base (0.66 (0.66 mmol) mmol) in in solvent solvent (1.2 (1.2 Reagents Reagents Conditions: 3b PhI(OAc) mmol) and base mmol) in solvent (1.2 22 (0.6 Reagents and Conditions: 3b (0.3 (0.3 mmol), mmol), PhI(OAc) (0.6 mmol) andmmol) base (0.66 (0.66 mmol) inmL) solvent (1.2 b 3band b (0.3 mmol), PhI(OCOCF 2 (0.6 mmol) and Na 2CO 3 (0.66 in EtOH (1.2 reflux. mL). b 3b (0.3 mmol), PhI(OCOCF 33)223)(0.6 mmol) and Na 22CO 33 (0.66 mmol) in EtOH (1.2 mL) reflux. mL). b b 3 2 2 3 mL). 3b (0.3 (0.3 mmol), mmol), PhI(OCOCF PhI(OCOCF333))222 (0.6 (0.6 mmol) mmol) and and Na Na222CO CO333 (0.66 (0.66 mmol) mmol) in in EtOH EtOH (1.2 (1.2 mL) mL) reflux. reflux. mL). bb 3b

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The stereochemistry stereochemistry of of the the fused-bicyclic fused-bicyclic ring ring system system in in 4b 4b was was shown shown to to be be cis cis using using X-ray X-ray The The stereochemistry of the 1fused-bicyclic ring system in 4b[18]. was shown to be cis using X-ray crystallographic analysis(Figure (Figure 1and andSupplementary Supplementary Material) [18]. crystallographic analysis Material) crystallographic analysis (Figure 1 and Supplementary Material) [18].

Figure 1. ORTEP plot of X-ray crystallographic data for 4b. Figure 1. ORTEP plot of X-ray crystallographic data for 4b. Figure 1. ORTEP plot of X-ray crystallographic data for 4b.

A proposed plausible mechanism is shown in Scheme 3. First, the formation of putative trienone A proposed plausible mechanism in Scheme mechanism is is shown shown Scheme 3. First, the formation putative trienone A through diacetoxyiodobenzene-mediated dehydrogenation reaction gave theof newly formed C–C A through diacetoxyiodobenzene-mediated dehydrogenation the newly formed through diacetoxyiodobenzene-mediated dehydrogenation reaction gave double bond as E/Z-form mixtures or ones where the Z-isomer predominated [15]. However, C–C only double bond E/Z-form ororones the Z-isomer predominated However, onlyonly the double bondas aspossesses E/Z-form mixtures mixtures oneswhere where the Z-isomer predominated [15]. However, the E-isomer the proper steric alignment to form the target [15]. cyclopenta[b]furans 1. E-isomer possesses the proper steric alignment to form the target cyclopenta[b]furans 1. Therefore, the E-isomer possesses the proper steric alignment to form the target cyclopenta[b]furans 1. Therefore, a simple thermal cycloisomerization of the trienone to a cyclopenta[b]furan is not likely in aTherefore, simple thermal cycloisomerization of the trienone todehydrogenation atrienone cyclopenta[b]furan is not likely in a simple thermal cycloisomerization of the to a cyclopenta[b]furan isthis not scenario. likely in this scenario. In the diacetoxyiodobenzene-mediated process at elevated temperature, In the diacetoxyiodobenzene-mediated dehydrogenation process at elevated temperature, acetic this scenario. In the diacetoxyiodobenzene-mediated dehydrogenation process atrole elevated temperature, acetic acid produced during the reaction presumably plays an important in promoting the acid produced during the reaction presumably plays an important role in promoting the sequential acetic acid produced during the reaction presumably plays an important role in promoting the sequential cycloisomerization from a cationic dienyl structure B to form the cyclopenta[b]furans. cycloisomerization from a cationic structure to form the cyclopenta[b]furans. sequential cycloisomerization fromdienyl a cationic dienylBstructure B to form the cyclopenta[b]furans.

Br Br

Br Br

3 3

CO 2Et CO 2EtO PhI(OAc) 2 O PhI(OAc) Na 2CO32 Ar Na 2CO3 Ar

COMe COMeOEt OEt O Ar O B Ar B

Ph COMe AcO Ph I COMeOEt AcO I OEt O Br Ar O Br Ar

Br Br

COMe COMeOEt OEt O Ar O A Ar

HOAc HOAc

A

Br Br

COMe H COMeOEt H OEt O Ar O Ar

Br Br

CO2 Et H CO2 Et H OH Ar OH Ar

- H+ - H + Br Br

H CO 2Et H CO 2Et O Ar O 1Ar 1

Scheme 3. Plausible Mechanism. Scheme 3. Plausible Plausible Mechanism. Mechanism. Scheme 3.

3. Materials and Methods 3. Materials Methods 3. Materials and and Methods 3.1. General Information 3.1. General 3.1. General Information Information All commercially available chemicals were used without further purification. TLC analyses were All commercially available chemicals were used without further purification. TLC analyses chemicals without further purification. TLC analyses were run All on commercially a TLC glass available plate (silica gel 60were F254,used EMD Millipore, Darmstadt, Germany) and were were run on a TLC glass plate (silica gel 60 F254, EMD Millipore, Darmstadt, Germany) and were run on a TLC glassUV plate gel 60 of F254, EMD Millipore, acid Darmstadt, Germany) and visualized visualized using and(silica a solution phosphomolybdic in ethanol (5 wt %) orwere p-anisaldehyde visualized using UV andof a solution of phosphomolybdic acid ethanol (5EMD wt %)Millipore). or p-anisaldehyde 1H-NMR using and a solution phosphomolybdic acid in ethanol (5inwt %) or p-anisaldehyde stain. Flash stain. UV Flash chromatography was performed using silica gel (70–230 mesh, 1 1 stain. Flash was performed using silicamesh, gelAV-300, (70–230 mesh, BioSpin EMDH-NMR Millipore). H-NMR chromatography was performed using silica gel (70–230 EMD Bruker Millipore). spectra were spectra werechromatography recorded on a 300 MHz spectrometer (Bruker GmbH, Karlsruhe, spectra were recorded on a 300 MHz spectrometer (Bruker AV-300, Bruker BioSpin GmbH, Karlsruhe, 13 recorded on aC-NMR 300 MHz spectrometer (Bruker BioSpin GmbH, Karlsruhe, Germany). Germany). spectra were recorded at AV-300, 75 MHz Bruker on the same instrument with complete proton 13C-NMR spectra were recorded at 75 MHz on the same instrument with complete proton 13 Germany). C-NMR spectra were recorded at 75 MHz Chemical on the same instrument with relative completetoproton decoupling (see Supplementary Material). shifts are reported CHCl3decoupling [δH 7.24, δC decoupling (see77.0]. Supplementary Material). Chemical shifts relative aremass reported relative to CHCl 3 [δH 7.24, δC (see Supplementary Material). Chemical shifts are reported tospectra CHCl δC (central (central line) Mass spectra and high-resolution were recorded on line) the 3 [δ H 7.24, (central line) 77.0]. Mass spectra and high-resolution mass spectra were recorded on the Thermo/Finnigan Quest MAT Mass Spectrometer (Thermo Finnigan LLC, San Jose, CA, USA). Thermo/Finnigan Quest MAT Mass Spectrometer (Thermo Finnigan LLC, San Jose, CA, USA).

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77.0]. Mass spectra and high-resolution mass spectra were recorded on the Thermo/Finnigan Quest MAT Mass Spectrometer (Thermo Finnigan LLC, San Jose, CA, USA). 3.2. Synthesis 3.2.1. General Procedure for the Synthesis of Cyclopenta[b]furans 1 A mixture of bromodiene 2 (0.3 mmol), ethyl acetoacetate (0.3 mmol, 39 mg), and NaOEt (0.4 mmol, 27 mg) in EtOH (2 mL) was stirred at reflux overnight. The mixture was cooled to ambient temperature (25–28 ◦ C) and transferred to a separatory funnel, followed by addition of Et2 O (5 mL) and water (10 mL). The aqueous layer was back extracted with Et2 O (2 mL × 2). The combined organic layers were washed with brine (5 mL), dried over MgSO4 , and concentrated in a rotary evaporator. The residue was purified by a silica gel plug using Et2 O/hexanes (10/1, 10 mL) as the eluent, followed by concentration to give the bromoester 3. To a solution of bromoester 3 (0.3 mmol, based on bromo-diene 2) in EtOH (1.2 mL) was added Na2 CO3 (0.6 mmol, 64 mg) and PhI(OAc)2 (0.6 mmol, 193 mg) at ambient temperature. The resulting mixture was heated to reflux under N2 for 3 h. The reaction was then cooled room temperature and H2 O (2 mL) was added. Et2 O (5 mL) was added and the mixture was transferred to a separatory funnel. The aqueous layer was back extracted with Et2 O (5 mL × 2). The combined organic layers were washed with 2 N HCl (2 mL), dried over Na2 SO4 , filtered, and concentrated in a rotary evaporator. The residue was purified by silica gel chromatography using Et2 O/hexanes (1/10) as eluent to give the title products as yellow oils. Using this general procedure, the following title compounds were obtained: Ethyl 5-bromo-2-methyl-6a-phenyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (1a). Yield 55 mg (72%). TLC (Et2 O/hexanes (1:10)) Rf = 0.44; 1 H-NMR (CDCl3 ) δ 1.25 (t, J = 7.2 Hz, 3H), 2.28 (d, J = 1.5 Hz, 3H), 2.83 (dt, J = 17.4, 2.1 Hz, 1H), 3.15 (ddd, J = 17.4, 7.8, 2.1 Hz, 1H), 3.74 (dt, J = 7.8, 1.5 Hz, 1H), 4.09–4.20 (m, 2H), 5.98 (t, J = 2.1 Hz, 1H), 7.25–7.35 (m, 5H); 13 C-NMR (CDCl3 ) δ 14.3 (CH3 ), 14.4 (CH3 ), 46.9 (CH2 ), 53.9 (CH), 59.6 (CH2 ), 100.8 (C) 105.8 (C), 124.5 (CH × 2), 128.0 (CH), 128.6 (CH × 2), 129.1 (C), 131.9 (CH), 142.0 (C), 165.5 (C), 167.0 (C); IR (neat) 2977, 1698, 1644 cm−1 ; EI-MS m/z (rel intensity) 350 ([M + 2]+ , 10), 348 ([M]+ , 10), 302 (29), 223 (100); HRMS [M]+ calcd. for C17 H17 BrO3 : 348.0361, found 348.0366. Ethyl 5-bromo-6a-(4-bromophenyl)-2-methyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (1b). Yield 100 mg (78%). TLC (Et2 O/hexanes (1:10)) Rf = 0.43; 1 H-NMR (CDCl3 ) δ 1.26 (t, J = 7.2 Hz, 3H), 2.28 (d, J = 1.5 Hz, 3H), 2.80 (dt, J = 17.4, 1.8 Hz, 1H), 3.14 (ddd, J = 17.4, 7.8, 1.8 Hz, 1H), 3.69 (dt, J = 7.8, 1.5 Hz, 1H), 4.06–4.28 (m, 2H), 5.93 (t, J = 1.5 Hz, 1H), 7.15 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H); 13 C-NMR (CDCl ) δ 14.2 (CH ), 14.4 (CH ), 46.8 (CH ), 53.9 (CH), 59.7 (CH ), 100.3 (C) 105.9 (C), 122.0 3 3 3 2 2 (C), 126.3 (CH × 2), 129.6 (C), 131.5 (CH), 131.7 (CH × 2), 141.1 (C), 165.4 (C), 166.8 (C); IR (neat) 2976, 1703, 1488 cm−1 ; EI-MS m/z (rel intensity) 428 ([M + 2]+ , 19), 426 ([M]+ , 10), 382 (59), 301 (100); HRMS [M]+ calcd. for C17 H16 Br2 O3 : 425.9466, found 425.9462. Ethyl 5-bromo-6a-(4-chlorophenyl)-2-methyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (1c). Yield 104 mg (90%). TLC (Et2 O/hexanes (1:10)) Rf = 0.43; 1 H-NMR (CDCl3 ) δ 1.25 (t, J = 7.2 Hz, 3H), 2.28 (d, J = 1.5 Hz, 3H), 2.83 (dt, J = 17.4, 2.1 Hz, 1H), 3.13 (ddd, J = 17.4, 7.8, 2.1 Hz, 1H), 3.68 (dt, J = 7.8, 1.5 Hz, 1H), 4.09–4.20 (m, 2H), 5.93 (t, J = 2.1 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H); 13 C-NMR (CDCl ) δ 14.2 (CH ), 14.3 (CH ), 46.8 (CH ), 53.9 (CH), 59.6 (CH ), 100.2 (C) 105.9 (C), 125.9 3 3 3 2 2 (CH × 2), 128.7 (CH × 2), 129.5 (C), 131.5 (CH), 133.8 (C), 140.5 (C), 165.3 (C), 166.7 (C); IR (neat) 2977, 1700, 1646 cm−1 ; EI-MS m/z (rel intensity) 384 ([M + 2]+ , 15), 382 ([M]+ , 12), 338 (44), 257 (100); HRMS [M]+ calcd. for C17 H16 BrClO3 : 381.9971, found 381.9978.

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Ethyl 5-bromo-2-methyl-6a-(p-tolyl)-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (1d). Yield 76 mg (70%). TLC (Et2 O/hexanes (1:10)) Rf = 0.51; 1 H-NMR (CDCl3 ) δ 1.25 (t, J = 7.2 Hz, 3H), 2.28 (d, J = 1.5 Hz, 3H), 2.32 (s, 3H), 2.82 (dt, J = 17.4, 1.8 Hz, 1H), 3.13 (ddd, J = 17.4, 7.8, 1.8 Hz, 1H), 3.72 (dt, J = 7.8, 1.5 Hz, 1H), 4.09–4.20 (m, 2H), 5.97 (t, J = 1.8 Hz, 1H), 7.15 (s, 4H); 13 C-NMR (CDCl3 ) δ 14.3 (CH3 ), 14.4 (CH3 ), 21.0 (CH3 ), 46.8 (CH2 ), 53.8 (CH), 59.5 (CH2 ), 100.7 (C) 105.8 (C), 124.4 (CH × 2), 128.9 (C), 129.2 (CH × 2), 131.9 (CH), 137.8 (C), 139.0 (C), 165.6 (C), 167.0 (C); IR (neat) 2979, 1702, 1644 cm−1 ; EI-MS m/z (rel intensity) 364 ([M + 2]+ , 5), 362 ([M]+ , 6), 316 (19), 237 (100); HRMS [M]+ calcd. for C18 H19 BrO3 : 362.0518, found 362.0515. Ethyl 5-bromo-6a-(4-methoxyphenyl)-2-methyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (1e). Yield 74 mg (65%). TLC (Et2 O/hexanes (1:10)) Rf = 0.48; 1 H-NMR (CDCl3 ) δ 1.25 (t, J = 7.2 Hz, 3H), 2.27 (d, J = 1.5 Hz, 3H), 2.81 (dt, J = 17.4, 1.8 Hz, 1H), 3.12 (ddd, J = 17.4, 7.8, 1.8 Hz, 1H), 3.71 (dt, J = 7.8, 1.5 Hz, 1H), 3.78 (s, 3H), 4.06–4.22 (m, 2H), 5.97 (t, J = 1.8 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H); 13 C-NMR (CDCl3 ) δ 14.3 (CH3 ), 14.4 (CH3 ), 46.8 (CH2 ), 53.7 (CH), 55.3 (CH3 ), 59.5 (CH2 ), 100.6 (C), 105.8 (C), 113.9 (CH × 2), 125.8 (CH × 2), 128.8 (C), 131.9 (CH), 134.1 (C), 159.3 (C), 165.6 (C), 166.9 (C); IR (neat) 2981, 1698, 1643 cm−1 ; EI-MS m/z (rel intensity) 380 ([M + 2]+ , 6), 378 ([M]+ , 6), 332 (20), 253 (100); HRMS [M]+ calcd. for C18 H19 BrO4 : 378.0467, found 378.0458. Ethyl 5-bromo-6a-(3-methoxyphenyl)-2-methyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (1f). Yield 72 mg (63%). TLC (Et2 O/hexanes (1:10)) Rf = 0.45; 1 H-NMR (CDCl3 ) δ 1.24 (t, J = 7.2 Hz, 3H), 2.28 (d, J = 1.5 Hz, 3H), 2.82 (dt, J = 17.4, 1.8 Hz, 1H), 3.14 (ddd, J = 17.4, 7.8, 1.8 Hz, 1H), 3.73 (dt, J = 7.8, 1.8 Hz, 1H), 3.79 (s, 3H), 4.03–4.24 (m, 2H), 5.95 (t, J = 1.8 Hz, 1H), 6.79–6.86 (m, 3H), 7.24–7.29 (m, 1H); 13 C-NMR (CDCl ) δ 14.2 (CH ), 14.3 (CH ), 46.8 (CH ), 53.8 (CH), 55.2 (CH ), 59.5 (CH ), 100.6 (C) 3 3 3 2 3 2 105.8 (C), 110.7 (CH), 112.7 (CH), 116.7 (CH), 129.0 (C), 129.7 (CH), 131.8 (CH), 143.6 (C), 159.7 (C), 165.5 (C), 166.9 (C); IR (neat) 2981, 1702, 1644 cm−1 ; EI-MS m/z (rel intensity) 380 ([M + 2]+ , 10), 378 ([M]+ , 10), 332 (21), 253 (100); HRMS [M]+ calcd. for C18 H19 BrO4 : 378.0467, found 378.0461. Ethyl 5-bromo-6a-(3-bromophenyl)-2-methyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (1g). Yield 112 mg (87%). TLC (Et2 O/hexanes (1:10)) Rf = 0.53; 1 H-NMR (CDCl3 ) δ 1.24 (t, J = 7.2 Hz, 3H), 2.28 (d, J = 1.5 Hz, 3H), 2.83 (dt, J = 17.7, 2.1 Hz, 1H), 3.15 (ddd, J = 17.7, 7.8, 2.1 Hz, 1H), 3.70 (dt, J = 7.8, 2.1 Hz, 1H), 4.06–4.21 (m, 2H), 5.95 (t, J = 2.1 Hz, 1H), 7.15–7.20 (m, 2H), 7.37–7.41 (m, 2H); 13 C-NMR (CDCl3 ) δ 14.2 (CH3 ), 14.3 (CH3 ), 46.7 (CH2 ), 53.9 (CH), 59.6 (CH2 ), 99.9 (C) 105.8 (C), 122.7 (C), 123.7 (CH), 127.6 (CH), 129.6 (CH), 130.1 (CH), 131.0 (CH), 131.3 (CH), 144.2 (C), 165.2 (C), 166.6 (C); IR (neat) 2979, 1704, 1643 cm−1 ; EI-MS m/z (rel intensity) 428 ([M + 2]+ , 19), 426 ([M]+ , 10), 382 (59), 301 (100); HRMS [M]+ calcd. for C17 H16 Br2 O3 : 425.9466, found 425.9460. Ethyl 5-bromo-2-methyl-6a-(naphthalen-2-yl)-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (1h). Yield 77 mg (64%). TLC (Et2 O/hexanes (1:10)) Rf = 0.48; 1 H-NMR (CDCl3 ) δ 1.26 (t, J = 7.2 Hz, 3H), 2.35 (d, J = 1.5 Hz, 3H), 2.90 (dt, J = 17.4, 1.8 Hz, 1H), 3.22 (ddd, J = 17.4, 7.8, 1.8 Hz, 1H), 3.84 (dt, J = 7.8, 1.8 Hz, 1H), 4.11–4.23 (m, 2H), 6.09 (t, J = 1.8 Hz, 1H), 7.35 (dd, J = 8.4, 1.8 Hz, 1H), 7.44–7.51 (m, 2H), 7.74 (s, 1H), 7.80–7.85 (m, 3H); 13 C-NMR (CDCl3 ) δ 14.3 (CH3 ), 14.4 (CH3 ), 46.9 (CH2 ), 53.7 (CH), 59.6 (CH2 ), 100.9 (C) 105.9 (C), 112.6 (CH), 123.1 (CH), 126.2 (CH), 126.4 (CH), 127.6 (CH), 128.1 (CH), 128.7 (CH), 129.3 (C), 131.8 (CH), 132.8 (C), 132.9 (C), 139.0 (C), 165.5 (C), 167.0 (C); IR (neat) 3058, 1700, 1637 cm−1 ; EI-MS m/z (rel intensity) 400 ([M + 2]+ , 11), 398 ([M]+ , 11), 273 (99), 202 (100); HRMS [M]+ calcd. for C21 H19 BrO3 : 398.0518, found 398.0516. 3.2.2. General Procedure for the Suzuki Reactions of Cyclopenta[b]furans 1 To a solution of cyclopenta[b]furan 1 (0.5 mmol) in dioxane/H2 O (5 mL/1 mL) was added Cs2 CO3 (1.5 mmol, 489 mg), PhB(OH)2 (0.75 mmol, 91 mg), and Pd(dppf)Cl2 (0.05 mmol, 37 mg) at ambient temperature. The resulting mixture was vacuumed and purged with N2 for 3 times. The reaction was heated to 100 ◦ C under N2 for 2 h. The reaction was then cooled room temperature and concentrated in a rotary evaporator. EtOAc (5 mL) and H2 O (1 mL) were added and the mixture was transferred to

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a separatory funnel. The aqueous layer was back extracted with EtOAc (5 mL × 2). The combined organic layers were dried over Na2 SO4 , filtered, and concentrated in a rotary evaporator. The residue was purified by silica gel chromatography to give the title product. The following compounds were prepared using this method: Ethyl 2-methyl-5,6a-diphenyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (4a). Yield 149 mg (86%). A yellow oil; TLC (EtOAc/hexanes (1:10)) Rf = 0.50; 1 H-NMR (CDCl3 ) δ 1.29 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 3.02 (dt, J = 17.1, 2.1 Hz, 1H), 3.29 (ddd, J = 17.1, 7.8, 2.1 Hz, 1H), 3.88 (dt, J = 7.8, 1.5 Hz, 1H), 4.11–4.26 (m, 2H), 6.23 (t, J = 2.1 Hz, 1H), 7.26–7.39 (m, 8H), 7.54 (d, J = 7.8 Hz, 2H); 13 C-NMR (CDCl3 ) δ 14.4, 40.2, 52.8, 59.3, 102.3, 106.4, 124.6, 125.5, 126.4, 127.5, 128.4, 128.5, 134.7, 143.1, 146.5, 165.9, 166.6; IR (neat) 2977, 1698, 1644 cm−1 ; EI-MS m/z (rel intensity) 346 ([M]+ , 12), 300 (100), 257 (30), 229 (47); HRMS [M]+ calcd. for C23 H22 O3 : 346.1569, found 346.1561. Ethyl 6a-([1,10 -biphenyl]-4-yl)-2-methyl-5-phenyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (4b). Yield 180 mg (85%). A colorless solid, m.p. 118–120 ◦ C; TLC (EtOAc/hexanes (1:10)) Rf = 0.35; 1 H-NMR (CDCl3 ) δ 1.28 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 3.02 (dt, J = 17.1, 1.8 Hz, 1H), 3.31 (ddd, J = 17.1, 6.0, 2.1 Hz, 1H), 3.91 (dt, J = 6.0, 1.8 Hz, 1H), 4.10–4.25 (m, 2H), 6.25 (t, J = 1.8 Hz, 1H), 7.30–7.45 (m, 8H), 7.53–7.55 (m, 6H); 13 C-NMR (CDCl3 ) δ 14.3, 40.1, 52.8, 59.3, 102.2, 106.4, 125.0, 125.4, 126.3, 126.9, 127.1, 127.2, 128.3, 128.4, 128.6, 134.6, 140.4, 140.5, 142.1, 146.5, 165.8, 166.5; IR (neat) 3031, 1700, 1637 cm−1 ; EI-MS m/z (rel intensity) 422 ([M]+ , 10), 376 (100), 333 (13), 305 (23); HRMS [M]+ calcd. for C29 H26 O3 : 422.1882, found 422.1878. Ethyl 6a-(4-chlorophenyl)-2-methyl-5-phenyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (4c). Yield 164 mg (86%). A yellow oil; TLC (EtOAc/hexanes (1:10)) Rf = 0.43; 1 H-NMR (CDCl3 ) δ 1.31 (t, J = 7.2 Hz, 3H), 2.32 (s, 3H), 3.04 (dt, J = 17.1, 2.1 Hz, 1H), 3.30 (ddd, J = 17.1, 7.8, 2.1 Hz, 1H), 3.84 (dt, J = 7.8, 1.8 Hz, 1H), 4.13–4.29 (m, 2H), 6.19 (t, J = 1.8 Hz, 1H), 7.27–7.40 (m, 7H), 7.54 (d, J = 7.8 Hz, 2H); 13 C-NMR (CDCl ) δ 14.4, 40.1, 52.9, 59.4, 101.8, 106.4, 124.6, 125.0, 126.1, 128.4, 128.5, 128.6, 133.3, 134.5, 3 141.7, 146.9, 165.7, 166.4; IR (neat) 2979, 1698, 1643 cm−1 ; EI-MS m/z (rel intensity) 382 ([M + 2]+ , 4), 380 ([M]+ , 10), 334 (100), 228 (36); HRMS [M]+ calcd. for C23 H21 ClO3 : 380.1179, found 380.1184. Ethyl 2-methyl-5-phenyl-6a-(p-tolyl)-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (4d). Yield 151 mg (84%). A yellow oil; TLC (EtOAc/hexanes (1:10)) Rf = 0.60; 1 H-NMR (CDCl3 ) δ 1.31 (t, J = 7.2 Hz, 3H), 2.32 (s, 3H), 2.36 (s, 3H), 3.03 (dt, J = 17.1, 2.1 Hz, 1H), 3.30 (ddd, J = 17.1, 7.8, 2.1 Hz, 1H), 3.88 (dt, J = 7.8, 1.8 Hz, 1H), 4.17–4.25 (m, 2H), 6.24 (t, J = 1.8 Hz, 1H), 7.18 (d, J = 8.1 Hz, 2H), 7.25–7.40 (m, 5H), 7.56 (d, J = 8.1 Hz, 2H); 13 C-NMR (CDCl3 ) δ 14.4, 14.5, 21.0, 40.2, 52.8, 59.3, 102.4, 106.4, 124.6, 125.6, 126.4, 128.4, 128.5, 129.1, 134.8, 137.3, 140.2, 146.3, 166.0, 166.6; IR (neat) 2977, 2923, 1693 cm−1 ; EI-MS m/z (rel intensity) 360 ([M]+ , 11), 314 (100), 243 (27), 228 (20); HRMS [M]+ calcd. for C24 H24 O3 : 360.1725, found 360.1721. Ethyl 6a-(4-methoxyphenyl)-2-methyl-5-phenyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (4e). Yield 154 mg (82%). A red oil; TLC (EtOAc/hexanes (1:10)) Rf = 0.50; 1 H-NMR (CDCl3 ) δ 1.29 (t, J = 7.2 Hz, 3H), 2.29 (s, 3H), 2.99 (dt, J = 17.1, 1.8 Hz, 1H), 3.26 (ddd, J = 17.1, 6.6, 2.1 Hz, 1H), 3.79 (s, 3H), 3.83 (dt, J = 6.6, 1.8 Hz, 1H), 4.13–4.24 (m, 2H), 6.22 (t, J = 1.8 Hz, 1H), 6.88 (d, J = 6.6 Hz, 2H), 7.25–7.38 (m, 5H), 7.53 (d, J = 7.8 Hz, 2H); 13 C-NMR (CDCl3 ) δ 14.4, 14.5, 40.1, 52.7, 55.2, 59.4, 102.2, 106.4, 113.7, 125.5, 125.9, 126.4, 128.4, 128.5, 134.8, 135.3, 146.3, 159.0, 166.0, 166.6; IR (neat) 2931, 1696, 1644 cm−1 ; EI-MS m/z (rel intensity) 376 ([M]+ , 18), 330 (100), 287 (19), 259 (33); HRMS [M]+ calcd. for C24 H24 O4 : 376.1675, found 376.1672.

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Ethyl 6a-(3-methoxyphenyl)-2-methyl-5-phenyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (4f). Yield 152 mg (81%). A yellow oil; TLC (EtOAc/hexanes (1:10)) Rf = 0.44; 1 H-NMR (CDCl3 ) δ 1.30 (t, J = 7.2 Hz, 3H), 2.32 (s, 3H), 3.02 (dt, J = 17.1, 2.1 Hz, 1H), 3.30 (ddd, J = 17.1, 7.8, 2.1 Hz, 1H), 3.80 (s, 3H), 3.88 (dt, J = 7.8, 1.8 Hz, 1H), 4.16–4.24 (m, 2H), 6.22 (t, J = 1.8 Hz, 1H), 6.80–6.84 (m, 1H), 6.92–6.95 (m, 2H), 7.25–7.39 (m, 4H), 7.55 (d, J = 8.1 Hz, 2H); 13 C-NMR (CDCl3 ) δ 14.4, 40.2, 52.8, 55.2, 59.4, 102.2, 106.5, 110.7, 112.4, 116.9, 125.4, 126.4, 128.4, 128.5, 129.5, 134.7, 144.8, 146.5, 159.7, 165.9, 166.5; IR (neat) 3056, 2979, 1693 cm−1 ; EI-MS m/z (rel intensity) 376 ([M]+ , 18), 330 (100), 287 (48), 259 (41); HRMS [M]+ calcd. for C24 H24 O4 : 376.1675, found 376.1680. Ethyl 6a-([1,10 -biphenyl]-3-yl)-2-methyl-5-phenyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (4g). Yield 180 mg (85%). A red oil; TLC (EtOAc/hexanes (1:10)) Rf = 0.53; 1 H-NMR (CDCl3 ) δ 1.33 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H), 3.10 (dt, J = 17.1, 1.8 Hz, 1H), 3.38 (ddd, J = 17.1, 6.0, 2.1 Hz, 1H), 3.99 (dt, J = 6.0, 1.8 Hz, 1H), 4.20–4.28 (m, 2H), 6.32 (t, J = 1.8 Hz, 1H), 7.34–7.49 (m, 8H), 7.53–7.63 (m, 6H); 13 C-NMR (CDCl ) δ 14.4, 14.5, 40.3, 52.9, 59.4, 102.4, 106.5, 123.4, 123.6, 125.5, 126.4, 126.5, 127.2, 127.3, 3 128.4, 128.5, 128.7, 128.9, 134.7, 141.0, 141.5, 143.7, 146.6, 165.9, 166.6; IR (neat) 3060, 2981, 1706 cm−1 ; EI-MS m/z (rel intensity) 422 ([M]+ , 13), 376 (100), 333 (23), 305 (27); HRMS [M]+ calcd. for C29 H26 O3 : 422.1882, found 422.1884. Ethyl 2-methyl-6a-(naphthalen-2-yl)-5-phenyl-4,6a-dihydro-3aH-cyclopenta[b]furan-3-carboxylate (4h). Yield 167 mg (84%). A yellow oil; TLC (EtOAc/hexanes (1:10)) Rf = 0.38; 1 H-NMR (MHz, CDCl3 ) δ 1.31 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H), 3.09 (dt, J = 17.1, 1.8 Hz, 1H), 3.37 (ddd, J = 17.1, 7.8, 1.8 Hz, 1H), 3.98 (d, J = 7.8 Hz, 1H), 4.14–4.29 (m, 2H), 6.34 (t, J = 1.8 Hz, 1H), 7.33–7.49 (m, 6H), 7.58–7.61 (m, 2H), 7.75–7.85 (m, 4H); 13 C-NMR (CDCl3 ) δ 14.5, 14.6, 40.4, 52.9, 59.5, 102.6, 106.7, 123.2, 125.5, 126.1, 126.3, 126.5, 127.6, 128.2, 128.5, 128.6, 132.8, 133.1, 134.8, 140.4, 146.9, 166.1, 166.8; IR (neat) 3056, 2977, 1698 cm−1 ; EI-MS m/z (rel intensity) 396 ([M]+ , 22), 350 (100), 307 (23), 279 (53); HRMS [M]+ calcd. for C27 H24 O3 : 396.1725, found 396.1733. 4. Conclusions In summary, the synthetic application of hypervalent iodine(III) in the formation of cyclopenta[b]furans is described. This method provides an alternative route to access the target for those cases where the corresponding diene-aldehyde precursor is not readily available or its use limited by intrinsic potential instability. Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/ 12/1713/s1. Acknowledgments: Financial support from the Ministry of Science and Technology of the Republic of China, Taiwan (MOST 105-2113-M-018-004) is gratefully acknowledged. We also thank the assistance from Chang-Chih Hsieh for the X-ray structure determination. Author Contributions: M.-H.L. conceived and designed the experiments; Y.-C.C. and S.-H.C. performed the experiments. Y.-F.C. performed the X-ray analysis. T.-H.C. gave insight suggestions. Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 1a–h, 4a–h are available from the authors. © 2016 by the authors; 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/).