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Syntheses of Polycyclic Tetrahydrofurans by Cascade Reactions Consisting of Five-membered Ring Selective Prins Cyclization and Friedel-Crafts Cyclization Yuki Sakata, Eiko Yasui, Kazuhiko Takatori, Yuji Suzuki, Megumi Mizukami, and Shinji Nagumo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01195 • Publication Date (Web): 04 Jul 2018 Downloaded from http://pubs.acs.org on July 4, 2018

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The Journal of Organic Chemistry

Syntheses of Polycyclic Tetrahydrofurans by Cascade Reactions Consisting of Five-membered Ring Selective Prins Cyclization and Friedel-Crafts Cyclization

a Yuki Sakata, Eiko Yasui,a Kazuhiko Takatori,b Yuji Suzuki,a,c Megumi c a* Mizukami, and Shinji Nagumo

a) Department of Applied Chemistry, Kogakuin University, Nakano 2665-1, Hachioji, Tokyo 192-0015, Japan. b) Department of Synthetic Organic Chemistry, Meiji Pharmaceutical University, Noshio 2-522-1, Kiyose, Tokyo 204-8588, Japan. c) Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, Maeda 15-4-1, Teine, Sapporo, Hokkaido 006-8585, Japan. [email protected]

The First Cascade Reaction

The Second Cascade Reaction

MeO Ph MeO

CHO

N Ts

MeO HO

BF3 OEt2 0 oC

MeO

H

H O

O H

CHO

NTs

MeO BF3 OEt2 rt

H MeO

ABSTRACT: A novel cascade reaction consisting of a five-membered ring selective Prins cyclization and a subsequent Friedel-Crafts cyclization is reported. Treatment of homocinnamyl alcohols and aromatic aldehydes with BF3･OEt2 in CH2Cl2 afforded hydrocyclopentafurans. Also hydrocyclopentafurans underwent the same cascade reaction after its furan ring cleavage upon treatment with BF3･OEt2 at room temperature. Various combinations of hydropentafurans and aromatic aldehydes or indole aldehydes permitted divergent synthesis of diquinane-furans stuck in aromatic rings.

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INTRODUCTION A cascade reaction by which complex molecules are formed in a single operation from relatively simple substrates continues to be an attractive field of synthetic organic chemistry.1 Various types of reaction have been utilized as elements of cascade reactions. Prins cyclization, inter alia, is an important method for directly synthesizing oxygenated heterocycles from homoallylic alcohols and aldehydes.2 The reaction mechanism consists of three successive steps: (1) an acid-promoted condensation of a homoallylic alcohol and an aldehyde, (2) cyclization of the resultant oxocarbenium ion with an alkene, and (3) capture of the generated carbocation by some kind of nucleophile. In the second step, a 6-membered ring is generally favored over a 5-membered ring for cyclization to generate multisubstituted tetrahydropyrans with excellent regioselectivity. Possible nucleophiles in the third step include carboxylic acid,3 halogen ion,4 nitrile (i.e., Ritter reaction),5 and aromatic ring (i.e., Friedel-Crafts reaction).6 The combination of Prins cyclization with an intramolecular reaction constitutes a practical cascade reaction for generating complicated polycyclic frameworks in a single operation.7 Reddy and Yadav et al. reported a cascade reaction consisting of Prins cyclization and a subsequent intramolecular Friedel–Crafts cyclization that afforded tetrahydropyran fused with tetrahydronaphthalene.8 On the other hand, the presence of naturally occurring tetrahydrofurans with multiple substituents and/or fused with other ring systems has directed our attention to a 5-membered-selective Prins cyclization and its cascade cyclization. The unusual regioselectivity leading to tetrahydrofuran necessitates some kind of advantage that is superior to the stability of the chair form transition state in 6-membered ring closure. The number of substituents on alkene of a homoallylic alcohol affects the size selectivity of ring closure. Prins cyclization of mono- and


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(E)-di-substituted homoallylic alcohols show preferential formation of a 6-membered ring, whereas a (Z)-di-substituted homoallylic alcohol affords a mixture of tetrahydropyran and tetrahydrofuran.9 A chair form transition state for ring closure of tetrahydropyran from a (Z)-homoallylic alcohol and an aldehyde should be less stable than that from an (E)-homoallylic alcohol because the structure has an axial substituent. The regiochemistry is also affected by the stability of intermediary carbenium ions. Prins cyclization of a trisubstituted homoallylic alcohol favors a 5-exo cyclization over a 6-endo one because the 5-exo cyclization generates a more stable tertial carbenium ion (Scheme 1, eq. 1).10 Device of the neighboring group is also known to change the ring selectivity of an (E)-di-substituted homoallylic alcohol to 5-exo mode. Homoallylic alcohols fused with allylsilane (eq. 2),11 propargylsilane (eq. 3)12 and allenylsilane (eq. 4)13 react with aldehydes and ketones to give tetrahydrofuran derivatives, reactions that are frequently referred to as silyl-Prins reactions. The regioselectivity correlates with the formation of stabilized β-silylethyl and β-silylvinyl cation intermediates. However, these cations are immediately converted into the corresponding alkene and alkyne through the elimination of silyl groups and it is therefore difficult to apply them to a cascade reaction for affording tetrahydrofurans fused with other ring systems. As another neighboring group of a homoallylic alcohol directing ring selectivity to 5-exo, we have had a strong interest in a phenyl group. Namely, a homocinnamyl alcohol would undertake 5-ring-selective Prins cyclization with an aldehyde to generate a benzyl cation. Furthermore, if an aromatic aldehyde is selected as a coupling partner, the benzyl cation would give rise to further cyclization.14 We wish to report syntheses of various polycyclic tetrahydrofurans based on a novel cascade reaction consisting of 5-ring-selective Prins cyclization and intramolecular Friedel-Crafts cyclization.15



Scheme 1 5-Ring membered selective Prins cyclizations

RESULTS AND DISCUSSION We initially examined the reaction of trans-homocinnamyl alcohol 2A with several kinds of benzaldehydes 1A-G (Scheme 2). Treatment of 2A with 1A and/or 1C (1.3 equiv.) in the presence of BF3･OEt2 (3 equiv.) in CH2Cl2 at 0 °C (Method A) resulted in decomposition, whereas the reaction of 1B under the same conditions proceeded facilely to generate tetrahydroindenofuran 3BA-p (91%) and its regioisomer 3BA-o (6%) after 15 min. The relative configuration of 3BA-p was determined by NOE correlation as shown in Scheme 2. The reactive difference between 1B and 1C suggested that an electron releasing group at the meta position in benzaldehydes is crucial for this cascade reaction. We thus investigated the cascade cyclization of other aldehydes 1D-G having at least one meta-alkoxy group. As anticipated, aldehydes 1D-E bearing two meta-alkoxy groups reacted with 2A to give 3DA and 3EA in excellent yields after 15 min. Also, the reaction of 1F-G having a 4-alkoxy group afforded 3FA and 3GA in


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good yields, but it took a few hours to consume substrates. Furthermore, a slight amount of diquinane-furan 4FAF and 4GAG were simultaneously formed.



Scheme 2 Cascade reactions of 1 (1.3 eq.) and 2 (1 eq.) (Method A)

The number with symbols for each compound is systematically marked. The numbers represent types of compound: 1 is aromatic aldehyde, 2 is homocinnamyl alcohol, 3 is tetrahydroindenofuran, and 4 is diquinane-furan. The symbols represent substituent patterns on benzene rings of 1 and 2: A is non-substituted, B is 3-methoxy, C is 4-methoxy, D is 3,5-dimethoxy, E is 3,4,5-trimethoxy, F is 3,4-dimethoxy, and G is 3,4-diethoxy. For example, 3DA means that the compound is obtained by the coupling of 1D and 2A, and 4FAF means that the compound is obtained by further coupling of 3FA and 1F. Symbol “α” or “β” means the configuration of the branched aromatic ring, and “o” or “p” means the reacting site when using aldehyde 1B.

Scheme 3 shows the formation mechanism of 3FA and 4FAF as typical examples. The cascade reaction starts with 5-membered ring-selective Prins cyclization of the oxonium ion (I) derived from benzaldehyde 1F and homocinnamyl alcohol 2A. The cyclization might proceed non-stereoselectively to form both cis-benzyl cation (II) and trans-benzyl cation (III), which can be transformed to each other. However, only (II)


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should bring about the next 5-membered Friedel-Crafts cyclization to give 3FA because of the great ring strain of a trans-fused bicyclo[3.3.0] system. Compound 4FAF should be derived from 3FA by the second cascade cyclization, which is commenced with a BF3-promoted cleavage of the furan ring. The C-O bond cleavage necessitates the assistance of an electron-releasing group at the C6 position of hydroindenofuran. The resulting intermediate (IV-Ph) is converted to (V) by rearomatization concomitant with deprotonation. Intermediate (V) notably contains a homoallylic alcohol neighboring to the aryl group as well as 2A. Therefore, excess 1F couples with (V) to form oxonium ion (VI), which is further converted to 4FAF by the sequence of Prins cyclization and Friedel-Crafts cyclization.



Scheme 3 Formation mechanism of 3FA and 4FAF.


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Scheme 4 Cascade reaction of trans-homocinnamyl alcohols having a 3- or 4-methoxy group (Method A). OMe

OMe OMe HO

H

trans-2B

(1)

1D BF3 OEt2

MeO

H O -3DB (90%) OMe

trans-2B

MeO

H (2)

1F BF3 OEt2

MeO

H O -3FB (72%)

OMe OMe

OMe

HO

OMe H

trans-2C

H

+

1B BF3 OEt2

MeO

(3)

H O -3BC-p (72%)

H O -3BC-o (14%)

OMe

OMe H

trans-2C

(4)

1D BF3 OEt2

MeO

H O -3DC (93%)

OMe

OMe MeO MeO

H

trans-2C BF3 OEt2

MeO

MeO

+

1F H O -3FC (77%)

OH

H

MeO

H (5)

O 5FC (11%)

Next, we surveyed the scope limitation of this cascade reaction using various homocinnamyl alcohols bearing a methoxy group on the benzene ring. Scheme 4 summarizes the reactions of trans-2B and trans-2C having a 3- or 4-methoxy group.



Reactions of trans-2B with 1D and 1F proceeded stereoselectively to give β-3DB and β-3FB in 90% and 72% yields, respectively (eq. 1-2). The reaction of trans-2C with aldehyde 1B proceeded stereoselectively to afford regional isomers β-3BC-p (72%) and β-3BC-o (14%) (eq. 3). Likewise, trans-2C reacted with 1D to give β-3DC in an excellent yield (eq. 4). Interestingly, only the combination of trans-2C with 1F generated 5FC (11%) in addition to β-3FC (eq. 5). The structure was unambiguously determined by X-ray crystallographic analysis. As with the formation of diquinane-furan 4FAF and 4GAG (Scheme 2, eq. 4), the formation of 5FC should start with furan ring cleavage of β-3FC accelerated by the 6-methoxy group (Scheme 5). The resulting intermediate (IV-p-MeOPh) is converted to 5FC by coupling with alkene 2C, which is more reactive than 2A and 2B, concomitant with furan ring formation.

Scheme 5 Formation mechanism of 5FC.

Subsequently, we examined the reaction using cis-homocinnamyl alcohols (Scheme 6). Their stereochemical results were found to depend on the position of the methoxy group in homocinnamyl alcohols. Whereas trans-2B reacted with 1D to give only β-3DB (Scheme 4, eq. 1), the reaction of cis-2B with 1D gave α-3DB almost exclusively (α : β = 14 : 1) (Scheme 6, eq. 1). The reaction of 1F and cis-2B lost near


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stereospecificity to form β-3FB and α-3FB as a mixture with a ratio of 1 : 2 (eq. 2). On the other hand, the reaction of homocinnamyl alcohols having a 4-methoxy group generated β-isomers regardless of their alkene geometry (trans/cis). Namely, cis-2C reacted with aldehydes 1D and 1F to generate β-3DC and β-3FC as with the reaction of trans-2C (eq. 3-4). In the case of 1F, a trace amount of 5FC was also obtained.

Scheme 6 Cascade reaction by the use of cis-homocinnamyl alcohols (Method A).



The α/β-selectivity for the branched aryl group in hydroindenofurans seems to correlate with two factors in the intermediates (II-A) and (II-B) (Scheme 7): reactivity of the nucleophilic benzene ring and life time of a benzyl cation. These factors are affected by the respective ring substituent style. It should be noted that 3,5-dimethoxyphenyl (from 1D) is more nucleophilic than 3,4-dimethoxyphenyl (from 1F). On the other hand, the 4-methoxy group presented in trans- and cis-2c should stabilize the benzyl cation intermediates by the resonance effect to prolong their life time. Considering these factors, stereoselective formation of β-arylated hydroindenofurans in the cascade reaction using cis-2C can be explained as follows (Scheme 7 (a)). The life time of a benzyl cation derived from cis-2C is long enough to complete conformational change from (II-B), which would be initially formed after Prins cyclization, to a more stable form (II-A). On the other hand, the life time of a benzyl cation derived from cis-2B is not so long. In the cascade reaction of 1D and cis-2B, the second cyclization is completed prior to the conformational change to generate α-3DB selectively (Scheme 7 (b)). In the cascade reaction of 1F and cis-2B, the second cyclization proceeds from both (II-A) and (II-B) after partial conformational change, resulting in the formation of a mixture of α- and β-3FB (Scheme 7 (c)).


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Scheme 7 Stereochemical insight of the cascade reaction using cis-homocinnamyl alcohol.



Since indole and pyrrole rings fused with cyclopentane are present in natural products such as bruceolline,16 paspaline,17 yuehchukene,18 and roseophilin19 and in pharmaceutical drugs such as laropiprant (MK-0524),20 we tried to apply the cascade reaction to the construction of these frameworks (Scheme 8).21,22 The trial began with the cascade reaction of pyrrole-2-carboxaldehyde 1H and indole-2-carboxaldehyde 1I, of which nitrogen was not protected. However, treatment of 1H by method A resulted in gradual decomposition and recovery of phenyl homoallylic alcohol. On the other hand, 1I did not react with 2A at all. Interestingly, a 1H NMR spectrum of an equimolar mixture of 1H and BF3·OEt2 in CD2Cl2 showed that the peak corresponding to aldehyde appeared to shift to a higher magnetic field than that of only 1H. This finding indicated that BF3 coordinated with aldehyde to form an enol structure. The structure was also confirmed by X-ray structural analysis. The facile enol formation should correlate with strong electron donation by nitrogen. In order to prevent electron donation, we carried out the cascade reaction of N-tosyl pyrrole 1J with 2A under the same conditions. As expected, pyrrole-fused hydrocyclopentafuran 3JA was obtained in 76% yield along with skeletal isomer 6JA, which would be generated by a furan ring transfer from 3JA via a C-O bond cleavage of the furan ring giving (VIII), two 1,2-hydride shifts giving (IX), and recyclization. The relative configuration of 3JA was determined by NOE experiments. The reaction of N-tosyl indole aldehyde 1K also proceeded well to produce 3KA (91%) and also 6KA (4%),23 the structure of which was confirmed by X-ray crystallography. Interestingly, when the cascade reaction of 1K was carried out at room temperature, formation of 6KA increased to yield of 31%.


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Scheme 8 Cascade reaction by the use of pyrrole aldehyde and 2-indole aldehyde (Method A).

Indole-3-carboxyaldehyde 1L coupled with 2A to give 3LA (70%), 6LA (9%), 3KA (2%) and 6KA (6%) (Scheme 9). The formation of 3KA in this reaction can be explained as follows. The intermediate (X) derived from 1L and 2A mainly causes 5-membered ring closure (route a) to afford 3LA as a major product. However, also 4-membered ring closure (route b) partially occurs to give a spiro intermediate (XI), which is converted into an oxonium ion (XII) by Grob type fragmentation.24 Finally, 5-membered ring closure of (XII) generates 3KA. Compounds 6KA and 6LA are generated by furan ring transfer of 3LA and 3KA, respectively.



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Scheme 9 Cascade reaction of 3-indole aldehyde.

Other positional isomers of indole aldehydes 1M-O were next subjected to the cascade reaction (Scheme 10). In the case of using indole-4-carboxyaldehyde 1M, annulations proceeded in two ways to give hydrobenzoindole 3MA-3 and cyclopentafuran

3MA-5

in

moderate

combined

yields.

The

reaction

of

indole-5-carboxyaldehyde 1N afforded two regional isomeric cyclopentafurans 3NA-4 and 3NA-6. Likewise, 1O coupled with 2A at two positions to give 3OA-5 and 3OA-7.


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Scheme 10 Cascade reaction by the use of various indole aldehydes. CHO

2A (1 eq.)

O

O

Ph

Ph

+ N Ts

BF3 OEt2 CH2Cl2 rt

N Ts

N Ts 3MA-5 (22%)

3MA-3 (33%)

1M (1.3 eq.)

2A (1 eq.)

OHC N Ts

O

Ph

O

+ BF3 OEt2 CH2Cl2 rt

1N (1.3 eq.)

Ph

N Ts

3NA-4 (30%)

N Ts

3NA-6 (19%)

Ph 2A (1 eq.) OHC

1O (1.3 eq.)

N Ts

+ BF3 OEt2 CH2Cl2 rt

O

N Ts

3OA-5 (28%)

O N Ts

Ph 3OA-7 (17%)

Unexpected formation of the diquinanes 4FAF and 4GAG observed in the reactions of 1F-G and 2A (Scheme 2) attracted our interest because complex and polycyclic compounds are obtained by a single operation. We thus improved the reaction conditions as follows. Treatment of a 3 : 1 molar mixture of 1F-G and 2A with BF3･ OEt2 (3 equiv.) in CH2Cl2 at room temperature afforded diquinanes 4FAF and 4GAG in excellent yields (method B, Table 1). Also 1E reacted with 2A under the conditions to give diquinane 4EAE in 26% yield along with 3EA (66%), but the reaction rate was slower than that of 1F-G. Compound 4EAE was obtained in 91% yield when the reaction was carried out in 1,2-dichloroethane at 50 oC. Interestingly, the reaction of 1D with 2A stopped at indenofuran 3DA and did not give 4DAD even by method B.



Table 1 Cascade reaction of 1 (3 eq.) and 2A (1 eq.) at room temperature (Method B)


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Scheme 11 Cascade reaction of pyrrole- and/or indole-fused cyclopentafuran

We next examined whether 3JA and 3KA reacted with another molecule of heterocyclic aldehydes (Scheme 11). Treatment of 3JA and 1J having a pyrrole ring with BF3·OEt2 in CH2Cl2 at room temperature showed many spots on TLC. Interestingly, the main product of them was 7JAJ rather than 4JAJ that we anticipated. Furthermore, cascade reaction of 3KA and aldehyde 1K resulted in a similar cyclization mode to generate 7KAK in high yield, the structure of which was unambiguously identified by X-ray crystallography. The formation of diquinanes 7JAJ and 7KAK seems to include the migration step of an alkene bond (from (XIV) to (XVII)) (Scheme 12). Complete migration might be correlated with strong steric repulsion between the tosyl group and the indole skeleton. If (XIV) proceeds on the regular pathway (i.e. Prins cyclization as it is), a spirocyclic intermediate (XVI) would be formed. However, it should be difficult for Friedel-Crafts cyclization of (XVI) to proceed due to the steric repulsion. Intermediate (XIV) is inevitably isomerized to (XVII), which then undergoes Prins cyclization with aldehyde 1K. Friedel-Crafts reaction of (XIX) has less steric repulsion and thus proceeds smoothly to produce 7KAK.



Scheme 12 Formation mechanism of 7KAK

With anticipation for preparing more divergent polycyclic frameworks, the coupling between hydrocyclopentafurans and aromatic aldehydes was applied to the combination of two substrates having different aromatic rings as shown in Table 2 (cross cascade reaction). Hydroindenofuran 3EA reacted with m-anisaldehyde 1B to generate polycyclic diquinanes 4EAB-p (66%) and 4EAB-o (9%) upon treatment with BF3·OEt2 in 1,2-dichloroethane at 50 oC. Similarly, 3EA reacted with 1F to give 4EAF in 76% yield. Also, 3FA coupled with 1B and 1E to afford 4FAB-p, 4FAB-o and 4FAE. We also examined the cross cascade reaction using indole aldehyde 1K or indole-fused cyclopentafuran 3KA. As we expected, coupling of 1K and 3FA afforded 4FAK in 90% yield. However, coupling of 1F and 3KA afforded 7KAF rather than 4KAF.


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Table 2 Cross cascade reactions of various cyclopentafurans and aromatic aldehydes

R6

R3 R2

R5

H

R1

H O 3EA (R1=R2=R3=OMe) 3FA (R1=R2=OMe, R3=H)

R4

CHO

1B (R4=OMe, R5=R6=H) 1E (R4=R5=R6=OMe) 1F (R4=R5=OMe, R6=H)

BF3 OEt2 4 or 7KAF rt, CH2Cl2 (Method B) or 50 oC, ClCH2CH2Cl (Method C)

Ph H N Ts O 1K

N Ts H O

H

3KA

MeO

MeO MeO MeO

O H

MeO

MeO MeO

H

O H H

MeO

O H

MeO

H

MeO OMe 4EAB-p (66% from 3EA + 1B) by Method C

MeO MeO

O H H

4EAB-o (9% from 3EA + 1B) by Method C

MeO MeO

O H H

OMe MeO 4EAF (76% from 3EA + 1F) by Method C

MeO

O H

MeO

H

OMe

MeO OMe 4FAB-p (79% from 3FA + 1B) by Method B Ph

4FAB-o (20% from 3FA + 1B) by Method B MeO

O

4FAE (98% from 3FA + 1E) by Method B Ph

OMe

O

H NTs

MeO

Ph

H MeO 4FAK (90% from 3FA + 1K) by Method B

OMe

MeO

O N Ts 7KAF (94% from 3KA + 1F) by Method B


N Ts OMe MeO 4KAF (not obtained)


CONCLUSION We have reported a novel cascade reaction of homoallylic alcohols linked to various aryl groups and aromatic aldehydes. Treatment of a homocinnamyl alcohol 2 and benzaldehydes, pyrrole aldehyde or indole aldehydes with BF3 generates cyclopentafurans 3 fused with various aromatic rings through 5-ring-selective Prins cyclization and subsequent Friedel-Crafts cyclization. In some cases, the resulting 3 was found to be further converted into diquinanes 4 stuck in two aromatic rings upon treatment with another molecule of aromatic aldehyde in the presence of BF3 at room temperature. The reaction mechanism of the second cascade reaction also consists of Prins cyclization and subsequent Friedel-Crafts cycliczation. These cascade reactions can be applied to the divergent synthesis of complex polycyclic compounds containing a diquinane skeleton in the central part.

EXPERIMENTAL SECTION General. Melting points were determined on a Yanagimoto MP-S3 micro melting point apparatus and were uncorrected. IR spectra were recorded on a JASCO FT/IR-4100. 1H and 13C NMR spectra were recorded on a JEOL JNN-ECX-400 spectrometer at 400 and 100 MHz, respectively. Chemical shifts were expressed in δ parts per million with tetramethylsilane as internal standard (δ = 0 ppm) for 1H NMR. Chemical shifts of carbon signals were referenced to CDCl3 (δC = 77.0 ppm), Benzene-d6 (δC = 128.0 ppm). The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. EI-mass spectra were recorded on a JEOL JMS-GCmate II. FAB-mass spectra were recorded on a JEOL JMS-700. Column chromatography was


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carried out on Merck’s Silica gel 60 (70-230 mesh ASTM). Dehydrated Dichloromethane (CH2Cl2) was purchased from Kanto Chemical and used without further purification. Synthesis of N-tosyl pyrrole aldehyde (1J). To a solution of 1H (0.208 g, 2.19 mmol) in CH2Cl2 (22 mL) was added TsCl (0.836 g, 4.38 mmol), Et3N (0.9 mL, 6.42 mmol), N,N-dimethyl-4-aminopyridine (53.5 mg, 0.438 mmol) at 0 oC under an argon atmosphere. After being stirred for 25 hours at room temperature, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with CH2Cl2. The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with hexane-AcOEt (3: 1) to give 1J (0.531 mg, 97%) as pale yellow crystal. The spectral data showed good agreement with the reported data.25 Typical synthetic procedure of N-tosyl indole aldehydes (1K-O). To a solution of indole aldehyde (1 eq.) in DMF was added NaH (1.5 eq.) and TsCl (2 eq.) at 0 oC under an argon atmosphere. After being stirred for 1.5-2.5 hours at room temperature, the reaction mixture was quenched with water and extracted with Et2O. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 1K-O as pale yellow crystal. 1-Tosyl-1H-indole-2-carbaldehyde (1K): 0.388 g, 88%; The spectral data showed good agreement with the reported data.26 1-Tosyl-1H-indole-3-carbaldehyde (1L): 0.215 g, 92%; The spectral data showed good agreement with the reported data.25 1-Tosyl-1H-indole-4-carbaldehyde (1M): 0.204 g, 96%; mp 143.7-144.5 oC; 1H NMR (CDCl3, 400 MHz) δ 10.17 (1H, s), 8.27 (1H, d, J = 8.4 Hz), 7.78-7.75 (3H, m),



7.71 (1H, d, J = 6.8 Hz), 7.49-7.45 (2H, m), 7.23 (2H, d, J = 8.8 Hz), 2.33 (3H, s); 13C NMR (CDCl3, 100 MHz) δ 192.2 (CH), 145.5 (C), 135.5 (C), 135.1 (C), 130.1 (2C, CH), 129.5 (2C, CH), 129.0 (C), 128.9 (C), 126.9 (2C, CH), 124.3 (CH), 119.3 (CH), 108.5 (CH), 21.6 (CH3); IR (KBr) 3117, 2801, 2731, 1697, 1581, 1366, 1180, 1142, 1119, 1088, 671 cm-1; HRMS (EI, double-focusing) calcd for C16H13NO3S [M]+ 299.0616, found 299.0590. 1-Tosyl-1H-indole-5-carbaldehyde (1N): 0.248 g, 93%; mp 134.6-135.4 oC; 1H NMR (CDCl3, 400 MHz) δ 10.03 (1H, s), 8.11 (1H, d, J = 8.8 Hz), 8.06 (1H, d, J = 0.8 Hz), 7.85 (1H, dd, J = 8.8 1.2 Hz), 7.79 (2H, d, J = 8.4 Hz), 7.67 (1H, d, J = 3.6 Hz), 7.25 (2H, d, J = 8.4 Hz), 6.77 (1H, d, J = 3.2 Hz), 2.34 (3H, s); 13C NMR (CDCl3, 100 MHz) δ 191.8 (CH), 145.6 (C), 138.1 (C), 135.0 (C), 132.3 (C), 130.9 (C), 130.1 (2C, CH), 128.1 (CH), 126.9 (2C, CH), 125.3 (CH), 124.8 (CH), 114.0 (CH), 109.4 (CH), 21.6 (CH3); IR (KBr) 3132, 3109, 2816, 1690, 1597, 1366, 1273, 1165, 1150, 1111, 1088 cm-1; HRMS (EI, double-focusing) calcd for C16H13NO3S [M]+ 299.0616, found 299.0625. 1-Tosyl-1H-indole-6-carbaldehyde (1O): 0.208 g, 95%; mp 155.4-157.1 oC; 1H NMR (CDCl3, 400 MHz) δ 10.08 (1H, s), 8.49 (1H, s), 7.80 (2H, d, J = 8.4 Hz), 7.78-7.76 (2H, m), 7.25 (2H, d, J = 8.8 Hz), 6.73 (1H, d, J = 3.6 Hz), 2.34 (3H, s); 13C NMR (CDCl3, 100 MHz) δ 191.9 (CH), 145.6 (C), 135.7 (C), 135.0 (C), 134.6 (C), 130.3 (C), 130.2 (3C, CH), 126.9 (2C, CH), 123.8 (CH), 122.0 (CH), 116.4 (CH), 109.0 (CH), 21.6 (CH3); IR (KBr) 3132, 3109, 2816, 2731, 1690, 1597, 1427, 1366, 1273, 1173, 1126, 1088, 1003 cm-1; HRMS (EI, double-focusing) calcd for C16H13NO3S [M]+ 299.0616, found 299.0601. Typical procedure of the cascade reaction (Method A). To a solution of 1 (1.3


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eq.) and 2 (1 eq.) in CH2Cl2 was added borontrifluoride diethylether complex (3 eq.) at 0 oC or room temperature under an argon atmosphere. After being stirred for minutes or hours, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3. If polarities of product and aromatic aldehyde 1 are close, the crude was subjected to column chromatography on silica gel after treatment with NaBH4 in MeOH. Typical procedure of the cascade reaction (Method B). To a solution of 2 (or 3) and three equivalents of 1 in CH2Cl2 was added borontrifluoride diethylether complex (3 eq.) at room temperature under an argon atmosphere. After being stirred for hours, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4 or 7. Typical procedure of the cascade reaction (Method C). To a solution of 2 (or 3) and three equivalents of 1 in 1,2-dichloroethane was added borontrifluoride diethylether complex (3 eq.) at room temperature under an argon atmosphere. After being stirred for hours at 50 oC, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4. (3aS,4R,8bS)-rel-7-Methoxy-4-phenyl-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]f uran (3BA-p): 0.246 g, 91%; 1H NMR (CDCl3, 400 MHz) δ 7.29 (2H, m), 7.21 (1H, m),



Page 26 of 49

7.08 (2H, m), 7.00 (1H, d, J = 2.0 Hz), 6.88 (1H, d, J = 8.0 Hz), 6.83 (1H, dd, J = 8.0, 2.0 Hz), 5.57 (1H, d, J = 6.8 Hz), 4.16 (1H, d, J = 3.6 Hz), 3.94 (1H, m), 3.82 (3H, s), 3.78 (1H, dt, J = 8.0, 6.4 Hz), 3.08 (1H, m), 2.24 (1H, m), 1.94 (1H, m);

13

C NMR

(CDCl3, 100 MHz) δ 159.6 (C), 145.9 (C), 143.4 (C), 138.1 (C), 128.5 (2C, CH), 127.5 (2C, CH), 126.3 (CH), 126.0 (CH), 116.5 (CH), 109.0 (CH), 86.6 (CH), 67.6 (CH2), 56.7 (CH), 55.3 (CH3), 53.5 (CH), 33.8 (CH2); IR (film) 2941, 2864, 1609, 1491, 1254 cm-1; HRMS (EI, double-focusing) calcd for C18H18O2 [M]+ 266.1307, found 266.1287. (3aS,4R,8bS)-rel-5-Methoxy-4-phenyl-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]f uran (3BA-o): 16.7 mg, 6%; mp 128.3-129.0 oC; 1H NMR (CDCl3, 400 MHz) δ 7.31 (1H, t, J = 7.6 Hz), 7.24 (2H, t, J = 7.6 Hz), 7.20-7.13 (1H, m), 7.09 (1H, d, J = 7.2 Hz), 7.07-7.01 (2H, m), 6.75 (1H, d, J = 8.0 Hz), 5.70 (1H, d, J = 7.6 Hz), 4.33 (1H, d, J = 2.0 Hz), 3.84 (1H, ddd, J = 8.0, 6.8, 5.2 Hz), 3.69-3.63 (4H, m), 3.01-2.95 (1H, m), 2.32-2.23 (1H, m), 1.88-1.80 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 156.2 (C), 145.4 (C), 144.3 (C), 132.8 (C), 129.7 (CH), 128.2 (2C, CH), 127.1 (2C, CH), 125.9 (CH), 117.4 (CH), 110.3 (CH), 86.8 (CH), 67.2 (CH2), 55.2 (CH3), 54.5 (CH), 52.5 (CH), 34.3 (CH2); IR (KBr) 2965, 2938, 2891, 2855, 1591, 1481, 1269, 1055, 760 cm-1; HRMS (EI, +

double-focusing) calcd for C18H18O2 [M] 266.1307, found 266.1305.

(3aS,4R,8bS)-rel-5,7-Dimethoxy-4-phenyl-3,3a,4,8b-tetrahydro-2H-indeno[1,2 -b]furan (3DA): 0.163 g, 92%; mp 167.0-167.5 oC; 1H NMR (CDCl3, 400 MHz) δ 7.24 (2H, m), 7.16 (1H, m), 7.03 (2H, m), 6.60 (1H, d, J = 2.0 Hz), 6.34 (1H, d, J = 2.4 Hz), 5.64 (1H, d, J = 7.2 Hz), 4.25 (1H, d, J = 2.0 Hz), 3.84 (1H, m), 3.83 (3H, s), 3.68 (1H, m), 3.60 (3H, s), 2.96 (1H, m), 2.27 (1H, m), 1.85 (1H, m);

13

C NMR (CDCl3, 100

MHz) δ 161.6 (C), 156.8 (C), 145.7 (C), 144.8 (C), 128.2 (2C, CH), 127.0 (2C, CH), 125.8 (CH), 125.2 (C), 99.6 (CH), 99.4 (CH), 86.8 (CH), 67.3 (CH2), 55.4 (CH3), 55.1


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(CH3), 53.9 (CH), 52.8 (CH), 34.2 (CH2); IR (KBr) 2938, 2886, 1459, 1340, 1117 cm-1; HRMS (EI, double-focusing) calcd for C19H20O3 [M]+ 296.1412, found 296.1424. (3aS,4R,8bS)-rel-5,6,7-Trimethoxy-4-phenyl-3,3a,4,8b-tetrahydro-2H-indeno[1 ,2-b]furan (3EA): 0.176g, 90%; 1H NMR (CDCl3, 400 MHz) δ 7.27 (2H, m), 7.18 (1H, m), 7.07 (2H, m), 6.79 (1H, s), 5.64 (1H, d, J = 6.8 Hz), 4.27 (1H, d, J = 2.4 Hz), 3.89 (3H, s), 3.86 (1H, m), 3.80 (3H, s), 3.72 (1H, m), 3.32 (3H, s), 3.00 (1H, m), 2.25 (1H, m), 1.88 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 154.4 (C), 149.6 (C), 146.1 (C), 142.7 (C), 137.7 (C), 131.0 (C), 128.3 (2C, CH), 127.2 (2C, CH), 126.1 (CH), 103.1 (CH), 87.1 (CH), 67.3 (CH2), 60.6 (CH3), 59.9 (CH3), 55.9 (CH3), 55.1 (CH), 52.9 (CH), 34.3 (CH2); IR (film) 2972, 2938, 1458, 1215 cm-1; HRMS (EI, double-focusing) calcd for C20H22O4 [M]+ 326.1518, found 326.1488. (3aS,4R,8bS)-rel-6,7-Dimethoxy-4-phenyl-3,3a,4,8b-tetrahydro-2H-indeno[1,2 -b]furan (3FA): 0.146 g, 82%; mp 91.0-92.5 oC; 1H NMR (CDCl3, 400 MHz) δ 7.29 (2H, m), 7.22 (1H, m), 7.09 (2H, m), 6.98 (1H, s), 6.44 (1H, s), 5.57 (1H, d, J = 6.8 Hz), 4.16 (1H, d, J = 3.6 Hz), 3.91 (1H, m), 3.91 (3H, s), 3.91 (1H, m), 3.74 (3H, s), 3.73 (1H, m), 3.04 (1H, m), 2.21 (1H, m), 1.94 (1H, m);

13

C NMR (CDCl3, 100 MHz) δ

150.3 (C); 149.2 (C), 145.9 (C), 138.0 (C), 133.9 (C), 128.6 (2C, CH), 127.5 (2C, CH), 126.4 (CH), 107.2 (2C, CH), 86.8 (CH), 67.3 (CH2), 57.6 (CH), 55.8 (2C, CH3), 53.6 (CH), 33.9 (CH2); IR (KBr) 2961, 2851, 1655 cm-1; HRMS (EI, double-focusing) calcd for C19H20O3 [M]+ 296.1412, found 296.1427. (3aS,4R,8bS)-rel-6,7-Diethoxy-4-phenyl-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b ]furan (3GA): 0.160 g, 82%; 1H NMR (CDCl3, 400 MHz) δ 7.29 (2H, m), 7.21 (1H, m), 7.07 (2H, m), 6.97 (1H, s), 6.44 (1H, s), 5.53 (1H, d, J = 6.8 Hz), 4.12 (3H, m), 3.93 (2H, q, J = 6.8 Hz), 3.91 (1H, m), 3.75 (1H, dt, J = 8.8, 6.0 Hz), 3.02 (1H, m), 2.19 (1H,



m), 1.94 (1H, m), 1.46 (3H, t, J = 6.8 Hz), 1.36 (3H, t, J = 6.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 150.0 (C), 148.9 (C), 145.9 (C), 138.1 (C), 134.0 (C), 128.5 (2C, CH), 127.5 (2C, CH), 126.3 (CH), 109.4 (CH), 109.2 (CH), 86.8 (CH), 67.3 (CH2), 64.4 (2C, CH2), 57.5 (CH), 53.7 (CH), 33.8 (CH2), 14.8 (CH3), 14.6 (CH3); IR (film) 2976, 2932, 2870, 1740, 1605, 1506 cm-1; HRMS (EI, double-focusing) calcd for C21H24O3 [M]+ 324.1725, found 324.1706. (3aS,4R,8bS)-rel-5,7-Dimethoxy-4-(3-methoxyphenyl)-3,3a,4,8b-tetrahydro-2H -indeno[1,2-b]furan (β-3DB): 30.4 mg, 90%; mp 94.8-95.3 oC; 1H NMR (CDCl3, 400 MHz) δ 7.16 (1H, t, J = 8.4 Hz), 6.70 (1H, dd, J = 8.4, 2.4 Hz), 6.63 (1H, d, J = 8.0 Hz), 6.60-6.58 (2H, m), 6.34 (1H, d, J = 2.4 Hz), 5.63 (1H, d, J = 7.2 Hz), 4.23 (1H, d, J = 1.6 Hz), 3.86-3.81 (4H, m), 3.76 (3H, s), 3.67 (1H, q, J = 7.6 Hz), 3.62 (3H, s), 2.98-2.92 (1H, m), 2.31-2.22 (1H, m), 1.87-1.79 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 161.6 (C), 159.5 (C), 156.8 (C), 147.5 (C), 144.8 (C), 129.1 (CH), 125.0 (C), 119.4 (CH), 113.1 (CH), 110.7 (CH), 99.7 (CH), 99.4 (CH), 86.8 (CH), 67.3 (CH2), 55.4 (CH3), 55.2 (CH3), 55.0 (CH3), 53.9 (CH), 52.7 (CH), 34.2 (CH2); IR (KBr) 2961, 2897, 2845, 1608, 1487, 1261, 1204, 1139, 1051 cm-1; HRMS (EI, double-focusing) calcd for C20H22O4 [M]+ 326.1518, found 326.1503. (3aS,4R,8bS)-rel-6,7-Dimethoxy-4-(3-methoxyphenyl)-3,3a,4,8b-tetrahydro-2H -indeno[1,2-b]furan (β-3FB): 73.9 mg, 72%; 1H NMR (CDCl3, 400 MHz) δ 7.22 (1H, t, J = 8.0 Hz), 6.97 (1H, s), 6.77 (1H, dd, J = 8.4, 0.8 Hz), 6.68 (1H, d, J = 7.6 Hz), 6.62 (1H, dd, J = 2.4, 2.0 Hz), 6.46 (1H, s), 5.57 (1H, d, J = 6.8 Hz), 4.13 (1H, d, J = 4.0 Hz), 3.94-3.89 (4H, m), 3.77 (3H, s), 3.76-3.70 (4H, m), 3.07-3.01 (1H, m), 2.26-2.16 (1H, m), 1.96-1.89 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 159.7 (C), 150.2 (C), 149.1 (C), 147.5 (C), 137.7 (C), 133.8 (C), 129.5 (CH), 119.9 (CH), 113.5 (CH), 111.2 (CH), 107.2


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(CH), 107.1 (CH), 86.7 (CH), 67.2 (CH2), 57.6 (CH), 55.8 (2C, CH3), 55.0 (CH3), 53.4 (CH), 33.9 (CH2); IR (film) 3001, 2955, 2864, 2833, 1607, 1584, 1504, 1265, 1225, 1103, 1049, 756 cm-1; HRMS (EI, double-focusing) calcd for C20H22O4 [M]+ 326.1518, found 326.1522. (3aS,4R,8bS)-rel-7-Methoxy-4-(4-methoxyphenyl)-3,3a,4,8b-tetrahydro-2H-ind eno[1,2-b]furan (β-3BC-p): 72.2 mg, 72%; 1H NMR (CDCl3, 400 MHz) δ 7.02-6.99 (3H, m), 6.88-6.81 (4H, m), 5.55 (1H, d, J = 6.8 Hz), 4.11 (1H, d, J = 4.4 Hz), 3.93 (1H, ddd, J = 8.0, 7.2, 4.0 Hz), 3.82 (3H, s), 3.80-3.74 (4H, m), 3.06-3.01 (1H, m), 2.26-2.17 (1H, m), 1.96-1.89 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 159.5 (C), 158.1 (C), 143.3 (C), 138.5 (C), 138.0 (C), 128.4 (2C, CH), 126.0 (CH), 116.5 (CH), 113.9 (2C, CH), 109.0 (CH), 86.6 (CH), 67.7 (CH2), 55.9 (CH), 55.3 (CH3), 55.2 (CH3), 53.7 (CH), 33.7 (CH2); IR (film) 2999, 2953, 2864, 2835, 1609, 1510, 1493, 1252, 1178, 1034, 824, 756 cm-1; HRMS (EI, double-focusing) calcd for C19H20O3 [M]+ 296.1413, found 296.1411. (3aS,4R,8bS)-rel-5-Methoxy-4-(4-methoxyphenyl)-3,3a,4,8b-tetrahydro-2H-ind eno[1,2-b]furan (β-3BC-o): 13.8 mg, 14%; 1H NMR (CDCl3, 400 MHz) δ 7.30 (1H, t, J = 7.6 Hz), 7.08 (1H, d, J = 8.0 Hz), 6.98-6.94 (2H, m), 6.80-6.74 (2H, m), 6.75 (1H, d, J = 8.4 Hz), 5.69 (1H, d, J = 7.6 Hz), 4.29 (1H, d, J = 1.2 Hz), 3.86-3.81 (1H, m), 3.77 (3H, s), 3.68-3.62 (4H, m), 2.97-2.91 (1H, m), 2.31-2.22 (1H, m), 1.86-1.78 (1H, m); 13

C NMR (CDCl3, 100 MHz) δ 157.7 (C), 156.2 (C), 144.2 (C), 137.6 (C), 133.1 (C),

129.6 (CH), 128.0 (2C, CH), 117.3 (CH), 113.5 (2C, CH), 110.3 (CH), 86.7 (CH), 67.3 (CH2), 55.2 (CH3), 55.1 (CH3), 53.6 (CH), 52.7 (CH), 34.2 (CH2); IR (film) 3005, 2938, 2864, 2835, 1593, 1510, 1479, 1265, 1252, 1057, 1038, 758 cm-1; HRMS (EI, +


(3aS,4R,8bS)-rel-5,7-Dimethoxy-4-(4-methoxyphenyl)-3,3a,4,8b-tetrahydro-2H



-indeno[1,2-b]furan (β-3DC): 88.6 mg, 93%; mp 108.9-109.6 oC; 1H NMR (CDCl3, 400 MHz) δ 6.97-6.93 (2H, m), 6.80-6.76 (2H, m), 6.59 (1H, d, J = 2.4 Hz), 6.34 (1H, d, J = 2.0 Hz), 5.63 (1H, d, J = 7.6 Hz), 4.21 (1H, d, J = 1.2 Hz), 3.86-3.81 (4H, m), 3.77 (3H, s), 3.67 (1H, q, J = 6.8 Hz), 3.61 (3H, s), 2.95-2.89 (1H, m), 2.31-2.22 (1H, m), 1.86-1.78 (1H, m);

13

C NMR (CDCl3, 100 MHz) δ 161.5 (C), 157.6 (C), 156.8 (C),

144.6 (C), 137.9 (C), 127.8 (2C, CH), 125.4 (C), 113.5 (2C, CH), 99.6 (CH), 99.4 (CH), 86.8 (CH), 67.2 (CH2), 55.4 (CH3), 55.2 (CH3), 55.1 (CH3), 53.0 (CH), 52.9 (CH), 34.1 (CH2); IR (KBr) 3001, 2936, 2878, 1599, 1512, 1252, 1207, 1140, 1053 cm-1; HRMS (EI, double-focusing) calcd for C20H22O4 [M]+ 326.1518, found 326.1522. (3aS,4R,8bS)-rel-6,7-Dimethoxy-4-(4-methoxyphenyl)-3,3a,4,8b-tetrahydro-2H -indeno[1,2-b]furan (β-3FC): 26.0 mg, 77%; 1H NMR (CDCl3, 400 MHz) δ 7.02-6.98 (2H, m), 6.97 (1H, s), 6.86-6.82 (2H, m), 6.43 (1H, s), 5.55 (1H, d, J = 7.6 Hz), 4.11 (1H, d, J = 3.6 Hz), 3.95-3.89 (4H, m), 3.79 (3H, s), 3.77-3.71 (4H, m), 3.03-2.97 (1H, m), 2.24-2.15 (1H, m), 1.95-1.89 (1H, m);

13

C NMR (CDCl3, 100 MHz) δ 158.1 (C),

150.3 (C), 149.1 (C), 138.3 (C), 137.9 (C), 133.7 (C), 128.4 (2C, CH), 113.9 (2C, CH), 107.1 (2C, CH), 86.7 (CH), 67.3 (CH2), 56.8 (CH), 55.8 (2C, CH3), 55.2 (CH3), 53.8 (CH), 33.8 (CH2); IR (film) 3007, 2957, 2864, 2835, 1608, 1508, 1249, 1221, 1099, 1038, 754 cm-1; HRMS (EI, double-focusing) calcd for C20H22O4 [M]+ 326.1518, found 326.1528. 2-((1R*,2R*,3R*)-5,6-Dimethoxy-1-(4-methoxyphenyl)-3-((2R*,3S*)-2-(4-meth oxyphenyl)tetrahydrofuran-3-yl)-2,3-dihydro-1H-inden-2-yl)ethan-1-ol (5FC): 2.8 mg, 11%; mp 126.0-127.0 oC; 1H NMR (Benzene-d6, 400 MHz) δ 7.56 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.4 Hz), 7.07 (1H, s), 6.93 (2H, d, J = 9.2 Hz), 6.86 (2H, d, J = 8.8 Hz), 6.53 (1H, s), 4.97 (1H, d, J = 9.6 Hz), 3.99 (1H, q, J = 7.6 Hz), 3.87 (1H, d, J = 6.8 Hz),


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3.71 (1H, td, J = 9.2, 3.6 Hz), 3.57 (3H, s), 3.35 (3H, s), 3.34 (3H, s), 3.31 (1H, dd, J = 7.6, 2.4 Hz), 3.27 (3H, s), 3.19-3.10 (1H, brm), 3.09-3.00 (1H, brm), 2.54-2.44 (2H, m), 1.85-1.77 (1H, m), 1.69-1.64 (2H, m), 1.43-1.33 (1H, m);

13

C NMR (Benzene-d6, 100

MHz) δ 159.8 (C), 159.1 (C), 150.2 (C), 149.1 (C), 140.7 C), 136.4 (C), 135.6 (C), 134.2 (C), 130.1 (2C, CH), 128.6 (2C, CH), 114.4 (2C, CH), 114.2 (2C, CH), 110.4 (CH), 109.0 (CH), 83.8 (CH), 67.7 (CH2), 61.6 (CH2), 59.2 (CH3), 56.1 (CH), 55.4 (CH3), 54.7 (2C, CH3), 52.4 (CH), 48.5 (CH), 43.8 (CH), 32.1 (CH2), 28.2 (CH2); IR (KBr) 3443, 2936, 2910, 2891, 1613, 1517, 1504, 1248, 1050, 1034, 829 cm-1; HRMS (EI, double-focusing) calcd for C31H36O6 [M]+ 504.2512, found 504.2511. (3aS,4S,8bS)-rel-5,7-Dimethoxy-4-(3-methoxyphenyl)-3,3a,4,8b-tetrahydro-2H -indeno[1,2-b]furan (α-3DB): 30.0 mg, 86%, β-3DB : α-3DB = 1 : 14; 1H NMR for α-3DB (CDCl3, 400 MHz) δ 7.16 (1H, t, J = 8.0 Hz), 6.73 (1H, dd, J = 8.4, 2.8 Hz), 6.64 (1H, d, J = 1.6 Hz), 6.62 (1H, d, J = 8.0 Hz), 6.59 (1H, s), 6.39 (1H, d, J = 2.4 Hz), 5.37 (1H, d, J = 7.6 Hz), 4.54 (1H, d, J = 9.2 Hz), 3.84 (3H, s), 3.75-3.68 (4H, m), 3.57 (3H, s), 3.48 (1H, q, J = 7.2 Hz), 3.42-3.36 (1H, m), 1.65-1.56 (1H, m), 1.37-1.30 (1H, m);

13

C NMR for α-3DB (CDCl3, 100 MHz) δ 161.4 (C), 159.2 (C), 157.0 (C), 145.2

(C), 143.5 (C), 128.6 (CH), 124.3 (C), 121.0 (CH), 114.2 (CH), 111.1 (CH), 100.0 (CH), 99.6 (CH), 86.9 (CH), 68.5 (CH2), 55.4 (CH3), 55.1 (CH3), 55.0 (CH3), 49.3 (CH), 47.3 (CH), 29.3 (CH2); IR (film) 3001, 2943, 2866, 2837, 1601, 1489, 1456, 1207, 1144, 1051, 756 cm-1; HRMS (EI, double-focusing) calcd for C20H22O4 [M]+ 326.1518, found 326.1494. (3aS,4S,8bS)-rel-6,7-Dimethoxy-4-(3-methoxyphenyl)-3,3a,4,8b-tetrahydro-2H -indeno[1,2-b]furan (α-3FB) : 12.6 mg, 38%, β-3FB : α-3FB = 1 : 2; 1H NMR for α-3FB (CDCl3, 400 MHz) δ 7.26 (1H, t, J = 8.0 Hz), 6.99 (1H, s), 6.81 (1H, dd, J = 8.0,



Page 32 of 49

2.4 Hz), 6.77 (1H, d, J = 7.6 Hz), 6.73 (1H, dd, J = 2.4, 1.6 Hz), 6.60 (1H, s), 5.48 (1H, d, J = 7.6 Hz), 4.57 (1H, d, J = 8.8 Hz), 3.92 (3H, s), 3.78-3.71 (7H, m), 3.52 (1H, q, J = 8.0 Hz), 3.42-3.35 (1H, m), 1.61-1.52 (1H, m), 1.42-1.34 (1H, m); 13C NMR for α-3FB (CDCl3, 100 MHz) δ 159.6 (C), 149.9 (C), 149.2 (C), 143.4 (C), 135.8 (C), 134.9 (C), 129.3 (CH), 121.6 (CH), 114.9 (CH), 111.7 (CH), 107.7 (CH), 107.2 (2C, CH), 86.3 (CH), 67.8 (CH2), 56.0 (CH3), 55.9 (CH3), 55.1 (CH3), 51.5 (CH), 47.8 (CH), 29.2 (CH2); IR (film) 3001, 2938, 2862, 2833, 1607, 1584, 1504, 1464, 1263, 1225, 1093, 1049, 754 cm-1; HRMS (EI, double-focusing) calcd for C20H22O4 [M]+ 326.1518, found 326.1511. (3aS,4R,7bS)-rel-4-Phenyl-7-tosyl-2,3,3a,4,7,7b-hexahydrofuro[3',2':4,5]cyclo penta[1,2-b]pyrrole (3JA): 50.1 mg, 76%; mp 150.0-151.1 oC; 1H NMR (CDCl3, 400 MHz) δ 7.99 (2H, d, J = 8.4 Hz), 7.31-7.27 (3H, m), 7.23-7.18 (1H, m), 7.14 (1H, d, J = 3.2 Hz), 7.07-7.05 (2H, m), 5.92 (1H, d, J = 3.2 Hz), 5.65 (1H, d, J = 6.4 Hz), 3.92 (1H, ddd, J = 8.8, 6.8, 3.2 Hz), 3.87 (1H, d, J = 2.4 Hz), 3.59 (1H, td, J = 9.2, 5.2 Hz), 3.33-3.27 (1H, m), 2.42 (3H, s), 2.16-2.07 (1H, m), 2.00-1.94 (1H, m);

13

C NMR

(CDCl3, 100 MHz) δ 144.74 (C), 144.70 (C), 136.8 (C), 136.3 (C), 136.2 (C), 129.6 (2C, CH), 128.6 (2C, CH), 127.6 (2C, CH), 126.9 (2C, CH), 126.6 (CH), 126.5 (CH), 108.5 (CH), 79.5 (CH), 66.8 (CH2), 59.6 (CH), 51.3 (CH), 33.9 (CH2), 21.6 (CH3); IR (KBr) 2932, 2870, 1597, 1373, 1180, 1134, 671 cm-1; HRMS (EI, double-focusing) calcd for C22H21O3NS [M]+ 379.1242, found 379.1220. (3bS,6aS)-rel-3b-Phenyl-1-tosyl-1,3b,5,6,6a,7-hexahydrofuro[2',3':3,4]cyclope nta[1,2-b]pyrrole (6JA): 3.9 mg, 6%; mp 125.2-127.1 oC; 1H NMR (CDCl3, 400 MHz) δ 7.74 (2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.29-7.18 (5H, m), 7.14 (1H, d, J = 3.2 Hz), 6.06 (1H, d, J = 3.2 Hz), 3.92 (1H, ddd, J = 8.8, 6.4, 3.6 Hz), 3.71 (1H, td, J =


Page 33 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


9.2, 5.2 Hz), 3.29-3.20 (2H, m), 2.74 (1H, d, J = 14.0 Hz), 2.44 (3H, s), 2.29-2.20 (1H, m), 1.78-1.71 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 145.0 (2C, C), 137.9 (C), 136.08 (C), 133.2 (C), 130.0 (2C, CH), 128.0 (2C, CH), 126.8 (CH), 126.7 (2C, CH), 125.6 (CH), 125.2 (2C, CH), 108.3 (CH), 92.1 (C), 67.7 (CH2), 56.8 (CH), 34.9 (CH2), 32.9 (CH2), 21.6 (CH3); IR (KBr) 2947, 2870, 1597, 1366, 1173, 1126, 671 cm-1; HRMS (EI, double-focusing) calcd for C22H21O3NS [M]+ 379.1242, found 379.1269.

(3aS,4R,9bS)-rel-4-Phenyl-9-tosyl-2,3,3a,4,9,9b-hexahydrofuro[3',2':4,5]cyclo penta[1,2-b]indole (3KA): 42.8 mg, 91%; mp 201.0-201.3 oC; 1H NMR (CDCl3, 400 MHz) δ 8.06 (2H, d, J = 8.4 Hz), 8.01 (1H, d, J = 8.4 Hz), 7.29-7.20 (6H, m), 7.12-7.09 (2H, m), 7.06 (1H, d, J = 7.6 Hz), 7.00 (1H, d, J = 7.2 Hz), 5.92 (1H, dd, J = 6.8, 1.2 Hz), 4.10 (1H, dd, J = 3.6, 2.0 Hz), 4.06 (1H, ddd, J = 8.4, 6.8, 2.4 Hz), 3.71 (1H, td, J = 9.6, 4.4 Hz), 3.45-3.40 (1H, m), 2.35 (3H, s), 2.25-2.16 (1H, m), 2.11-2.06 (1H, m); 13

C NMR (CDCl3, 100 MHz) δ 144.6 (C), 143.5 (C), 141.6 (C), 140.4 (C), 135.5 (C),

130.3 (C), 129.5 (2C, CH), 128.7 (2C, CH), 127.5 (2C, CH), 127.0 (2C, CH), 126.7 (CH), 125.3 (C), 124.6 (CH), 123.2 (CH), 120.1 (CH), 114.5 (CH), 80.7 (CH), 66.9 (CH2), 58.9 (CH), 50.7 (CH), 34.0 (CH2), 21.5 (CH3); IR (KBr) 2963, 2839, 1605, 1358, 1173, 1126, 756, 671, 579 cm-1; HRMS (EI, double-focusing) calcd for C26H23O3NS [M]+ 429.1399, found 429.1385. (3aS,9cS)-rel-9c-Phenyl-5-tosyl-2,3,3a,4,5,9c-hexahydrofuro[2',3':3,4]cyclope nta[1,2-b]indole (6KA): 1.9 mg, 4%; mp 156.5-157.4 oC; 1H NMR (CDCl3, 400 MHz) δ 8.01 (1H, d, J = 8.0 Hz), 7.74 (2H, d, J = 8.4 Hz), 7.31-7.19 (8H, m), 7.14-7.07 (2H, m), 7.06 (1H, d, J = 7.6 Hz), 4.15 (1H, ddd, J = 8.8, 7.2, 3.2 Hz), 3.72 (1H, td, J = 9.2, 5.2 Hz), 3.59 (1H, dd, J = 17.2, 8.0 Hz), 3.32 (1H, tt, J = 8.8, 2.8 Hz), 3.07 (1H, dd, J = 17.6, 2.8 Hz), 2.37-2.29 (4H, m), 1.88-1.82 (1H, m);

13




145.0 (C), 144.3 (C), 144.0 (C), 140.7 (C), 135.5 (C), 129.9 (2C, CH), 128.2 (2C, CH), 127.0 (CH), 126.9 (C), 126.5 (2C, CH), 125.3 (C), 125.2 (2C, CH), 123.9 (CH), 123.7 (CH), 119.5 (CH), 114.3 (CH), 92.1 (C), 67.8 (CH2), 56.1 (CH), 35.0 (CH2), 34.8 (CH2), 21.5 (CH3); IR (KBr) 3057, 2947, 2843, 1615, 1597, 1445, 1371, 1178, 1007 cm-1; HRMS (EI, double-focusing) calcd for C26H23O3NS [M]+ 429.1399, found 429.1411. Scheme 8 : A crude was purified by column chromatography on silica gel eluted with hexane-AcOEt (9 : 1) to give 3LA with a slight amount of 3KA (96.6 mg) and the mixture of 6LA and 6KA (20.5 mg). 3LA : 3KA = 35 : 1; 3LA = 93.9 mg, 70% (Calculated from 1H-NMR spectrum). The mixture of 6LA and 6KA was purified by column chromatography on silica gel eluted with Benzene to give 6LA (12.3 mg, 9%) and 6KA (8.2 mg, 6%). (3aS,4R,9cS)-rel-4-Phenyl-5-tosyl-2,3,3a,4,5,9c-hexahydrofuro[2',3':3,4]cyclo penta[1,2-b]indole (3LA): mp 184.6-185.9 oC; 1H NMR (CDCl3, 400 MHz) δ 7.97-7.90 (1H, m), 7.66-7.62 (1H, m), 7.29-7.20 (6H, m), 7.32-7.23 (5H, m), 7.10-7.04 (4H, m), 6.94 (2H, d, J = 8.4 Hz), 5.78 (1H, dd, J = 6.8, 1.2 Hz), 4.59 (1H, s), 3.86 (1H, ddd, J = 8.8, 6.8, 5.2 Hz), 3.65 (1H, q, J = 8.4 Hz), 3.31-3.26 (1H, m), 2.33-2.23 (4H, m), 2.00-1.93 (1H, m);

13


140.5 (C), 135.2 (C), 129.4 (2C, CH), 128.7 (2C, CH), 127.8 (2C, CH), 126.8 (2C, CH), 126.7 (CH), 125.8 (C), 125.3 (C), 124.2 (CH), 123.5 (CH), 119.7 (CH), 114.4 (CH), 79.8 (CH), 66.8 (CH2), 58.3 (CH), 53.5 (CH), 34.2 (CH2), 21.4 (CH3); IR (KBr) 2940, 2847, 1597, 1443, 1366, 1173, 1049, 1003, 756, 671 cm-1; HRMS (EI, double-focusing) calcd for C26H23O3NS [M]+ 429.1399, found 429.1398. (3aR,9bR)-rel-9b-Phenyl-9-tosyl-2,3,3a,4,9,9b-hexahydrofuro[3',2':4,5]cyclope nta[1,2-b]indole (6LA): mp 188.0-189.0 oC; 1H NMR (CDCl3, 400 MHz) δ 8.11 (1H, d,


Page 34 of 49

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J = 8.4 Hz), 7.68 (2H, d, J = 8.0 Hz), 7.44 (1H, d, J = 7.6 Hz), 7.35-7.22 (7H, m), 7.08 (2H, d, J = 8.4 Hz), 4.22 (1H, dt, J = 8.8, 6.0 Hz), 3.88 (1H, td, J = 8.0, 5.6 Hz), 3.33-3.27 (1H, m), 3.16 (1H, dd, J = 16.0, 8.4 Hz), 2.64 (1H, dd, J = 16.0, 2.4 Hz), 2.40-2.31 (1H, m), 2.29 (3H, s), 1.85-1.78 (1H, m);

13


144.9 (C), 144.1 (C), 142.4 (C), 140.8 (C), 135.6 (C), 129.3 (C), 129.2 (2C, CH), 128.1 (2C, CH), 127.4 (2C, CH), 126.6 (CH), 125.9 (C), 124.9 (2C, CH), 124.8 (CH), 123.2 (CH), 119.7 (CH), 115.1 (CH), 93.3 (C), 68.5 (CH2), 58.6 (CH), 35.2 (CH2), 29.3 (CH2), 21.4 (CH3); IR (KBr) 2968, 2920, 2853, 1595, 1449, 1373, 1175, 964 cm-1; HRMS (EI, +

double-focusing) calcd for C26H23O3NS [M] 429.1399, found 429.1403.

(6R,6aS,9aS)-rel-6-Phenyl-4-tosyl-4,6,6a,7,8,9a-hexahydrobenzofuro[5,6,7-cd] indole

(3MA-3)

&

(6R,6aS,9aS)-rel-6-Phenyl-3-tosyl-3,6,6a,7,8,9a-hexahydrofuro[3',2':4,5]cyclopenta[1,2 -e]indole (3MA-5): A crude was repeatedly subjected to column chromatography on silica gel eluted with hexane-AcOEt (9 : 1) to give 3MA-3 (51.6 mg, 33%) and 3MA-5 (34.4 mg, 22%). 3MA-3 : 1H NMR (CDCl3, 400 MHz) δ 7.88 (1H, dd, J = 8.0, 1.6 Hz), 7.70 (2H, d, J = 8.4 Hz), 7.40-7.30 (5H, m), 7.24-7.22 (2H, m), 7.19 (2H, d, J = 8.4 Hz), 6.92 (1H, d, J = 1.6 Hz), 4.90 (1H, d, J = 4.4 Hz), 4.10 (1H, q, J = 8.0 Hz), 4.02 (1H, td, J = 9.6, 4.4 Hz), 3.82 (1H, dd, J = 9.6, 2.0 Hz), 2.67-2.61 (1H, m), 2.34 (3H, s), 2.17-2.08 (1H, m), 1.99-1.81 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 144.7 (C), 142.3 (C), 135.3 (C), 133.5 (C), 129.7 (2C, CH), 129.4 (C), 128.7 (4C, CH), 128.0 (C), 127.1 (CH), 126.7 (2C, CH), 125.7 (CH), 123.3 (C), 122.6 (CH), 121.6 (CH), 113.5 (CH), 76.6 (CH), 66.6 (CH2), 46.4 (CH), 40.9 (CH), 29.8 (CH2), 21.5 (CH3); IR (film) 3024, 2932, 2878, 1597, 1443, 1366, 1180, 1111, 1034, 756, 671 cm-1; HRMS (EI, double-focusing) calcd



Page 36 of 49

for C26H23O3NS [M]+ 429.1399, found 429.1392. 3MA-5 : mp 192.7-193.4 oC; 1H NMR (CDCl3, 400 MHz) δ 7.89 (1H, d, J = 8.8 Hz), 7.77 (2H, d, J = 8.4 Hz), 7.63 (1H, brs), 7.29-7.19 (5H, m), 7.05 (2H, d, J = 7.6 Hz), 6.90 (1H, d, J = 8.8 Hz), 6.84 (1H, brs), 5.83 (1H, d, J = 7.6 Hz), 4.26 (1H, brs), 3.91 (1H, q, J = 7.2 Hz), 3.72 (1H, q, J = 7.2 Hz), 3.18-3.11 (1H, brm), 2.35 (3H, s), 2.29-2.19 (1H, m), 1.95-1.91 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 145.8 (C), 144.9 (C), 141.2 (C), 135.4 (C), 134.6 (C), 134.1 (C), 129.9 (2C, CH), 128.6 (2C, CH), 127.66 (C), 127.65 (2C, CH), 127.0 (CH), 126.9 (2C, CH), 126.4 (CH), 121.5 (CH), 114.6 (CH), 106.9 (CH), 85.8 (CH), 67.8 (CH2), 57.7 (CH), 53.5 (CH), 33.9 (CH2), 21.5 (CH3); IR (KBr) 2947, 2862, 1597, 1366, 1180, 1134, 664 cm-1; HRMS (EI, +

double-focusing) calcd for C26H23O3NS [M] 429.1399, found 429.1394.

(5bS,8aS,9R)-rel-9-Phenyl-3-tosyl-3,5b,7,8,8a,9-hexahydrofuro[2',3':3,4]cyclo penta[1,2-e]indole

(3NA-4)

&

(4bS,7aS,8R)-rel-8-Phenyl-1-tosyl-1,4b,6,7,7a,8-hexahydrofuro[3',2':4,5]cyclopenta[1,2 -f]indole (3NA-6): A crude was repeatedly subjected to column chromatography on silica gel eluted with hexane-AcOEt (9 : 1) to give 3NA-4 (42.5 mg, 30%) and 3NA-6 (26.5 mg, 19%). 3NA-4 : mp 199.0-201.4 oC; 1H NMR (CDCl3, 400 MHz) δ 7.95 (1H, d, J = 8.8 Hz), 7.75 (2H, d, J = 8.8 Hz), 7.43-7.41 (2H, m), 7.28-7.18 (5H, m), 7.06-7.04 (2H, m), 6.07 (1H, dd, J = 3.6, 0.8 Hz), 5.67 (1H, d, J = 6.8 Hz), 4.35 (1H, d, J = 3.6 Hz), 3.90 (1H, ddd, J = 8.8, 7.2, 4.8 Hz), 3.71 (1H, td, J = 8.8, 6.0 Hz), 3.14-3.08 (1H, m), 2.35 (3H, s), 2.28-2.19 (1H, m), 1.98-1.91 (1H, m);

13


144.9 (C), 144.7 (C), 138.4 (C), 137.1 (C), 135.6 (C), 135.3 (C), 129.9 (2C, CH), 128.7 (2C, CH), 127.6 (2C, CH), 127.2 (C), 126.9 (2C, CH), 126.6 (CH), 126.4 (CH), 121.6


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(CH), 113.4 (CH), 106.9 (CH), 87.0 (CH), 67.5 (CH2), 57.1 (CH), 53.9 (CH), 33.9 (CH2), 21.5 (CH3); IR (KBr) 2947, 2862, 1597, 1373, 1173, 1134, 1049, 756, 679 cm-1; HRMS (EI, double-focusing) calcd for C26H23O3NS [M]+ 429.1399, found 429.1391. 3NA-6 : 1H NMR (CDCl3, 400 MHz) δ 7.58-7.55 (4H, m), 7.50 (1H, d, J = 3.6 Hz), 7.33-7.26 (3H, m), 7.10 (1H, d, J = 8.4 Hz), 7.06 (1H, d, J = 8.4 Hz), 6.63 (1H, d, J = 4.4 Hz), 5.56 (1H, d, J = 6.8 Hz), 4.32 (1H, d, J = 4.4 Hz), 3.94 (1H, td, J = 8.0, 4.8 Hz), 3.81 (1H, q, J = 8.4 Hz), 3.15-3.09 (1H, m), 2.32 (3H, s), 2.29-2.19 (1H, m), 2.02-1.95 (1H, m);

13


138.1 (C), 136.0 (C), 134.8 (C), 131.2 (C), 129.6 (2C, CH), 128.6 (2C, CH), 127.7 (2C, CH), 126.8 (3C, CH), 126.5 (CH), 118.0 (CH), 110.4 (CH), 109.3 (CH), 86.0 (CH), 67.9 (CH2), 57.1 (CH), 54.0 (CH), 33.6 (CH2), 21.5 (CH3); IR (film) 3017, 2932, 2862, 1597, 1450, 1373, 1219, 1173, 756, 671 cm-1; HRMS (EI, double-focusing) calcd for C26H23O3NS [M]+ 429.1399, found 429.1381. (3aS,4R,9bS)-rel-4-Phenyl-8-tosyl-2,3,3a,4,8,9b-hexahydrofuro[2',3':3,4]cyclo penta[1,2-f]indole

(3OA-5)

&

(5bS,8aS,9R)-rel-9-Phenyl-1-tosyl-1,5b,7,8,8a,9-hexahydrofuro[3',2':4,5]cyclopenta[1,2 -g]indole (3OA-7): A crude was repeatedly subjected to column chromatography on silica gel eluted with hexane-AcOEt (9 : 1) to give 3OA-5 (37.5 mg, 28%) and 3OA-7 (23.5 mg, 17%). 3OA-5 : 1H NMR (CDCl3, 400 MHz) δ 8.08 (1H, s), 7.81 (2H, d, J = 8.0 Hz), 7.53 (1H, d, J = 3.6 Hz), 7.30-7.18 (5H, m), 7.10-7.05 (3H, m), 6.50 (1H, d, J = 4.0 Hz), 5.64 (1H, d, J = 6.8 Hz), 4.22 (1H, d, J = 4.8 Hz), 3.96 (1H, ddd, J = 8.8, 8.0, 4.8 Hz), 3.80 (1H, td, J = 8.8, 6.4 Hz), 3.17-3.11 (1H, m), 2.35 (3H, s), 2.28-2.19 (1H, m), 1.98-1.92 (1H, m);

13




139.5 (C), 135.3 (C), 134.8 (C), 132.3 (C), 129.9 (2C, CH), 128.6 (2C, CH), 127.7 (2C, CH), 127.0 (CH), 126.9 (2C, CH), 126.5 (CH), 117.5 (CH), 110.5 (CH), 108.7 (CH), 86.4 (CH), 67.9 (CH2), 56.7 (CH), 54.0 (CH), 33.3 (CH2), 21.5 (CH3); IR (film) 2970, 2932, 2862, 1597, 1443, 1373, 1173, 756 cm-1; HRMS (EI, double-focusing) calcd for C26H23O3NS [M]+ 429.1399, found 429.1402. 3OA-7 : 1H NMR (CDCl3, 400 MHz) δ 7.57-7.55 (2H, m), 7.42 (1H, d, J = 8.0 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.10-7.08 (3H, m), 6.95 (2H, d, J = 8.4 Hz), 6.77-6.74 (2H, m), 6.71 (1H, d, J = 4.0 Hz), 5.62 (1H, d, J = 6.8 Hz), 5.32 (1H, s), 3.80 (1H, dt, J = 8.0, 7.2 Hz), 3.51 (1H, q, J = 7.6 Hz), 2.89 (1H, dt, J = 9.6, 7.2 Hz), 2.35-2.27 (4H, m), 1.77-1.69 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 146.0 (C), 144.0 (C), 142.1 (C), 135.7 (C), 133.3 (C), 132.6 (C), 129.5 (2C, CH + C), 129.4 (CH), 128.2 (2C, CH), 127.2 (2C, CH), 126.1 (2C, CH), 125.7 (CH), 121.9 (CH), 121.5 (CH), 110.0 (CH), 85.5 (CH), 67.1 (CH2), 55.6 (CH), 52.9 (CH), 33.6 (CH2), 21.4 (CH3); IR (film) 3017, 2932, 2862, 1597, 1450, 1373, 1219, 1173, 756, 671 cm-1; HRMS (EI, double-focusing) calcd for C26H23O3NS [M]+ 429.1399, found 429.1402. (3aR,7bS,12S,12aR)-rel-4,5,6,9,10,11-Hexamethoxy-12-phenyl-1,2,3a,7b-tetra hydro-12H-indeno[2',1':2,3]indeno[1,2-b]furan (4EAE): 0.187 g, 91%; mp 169.1-169.8 o

C; 1H NMR (CDCl3, 400 MHz) δ 7.28 (2H, m), 7.19 (1H, m), 7.08 (2H, brs), 6.94 (1H,

s), 6.66 (1H, s), 5.28 (1H, s), 4.82 (1H, s), 4.58 (1H, s), 4.11 (3H, s), 3.89 (3H, s), 3.86 (1H, m), 3.84 (3H, s), 3.82 (3H, s), 3.74 (3H, s), 3.63 (1H, q, J = 6.8 Hz), 3.31 (3H, s), 1.69 (2H, t, J = 6.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 154.1 (C), 154.0 (C), 149.5 (C), 149.3 (C), 143.5 (C), 141.9 (C), 141.4 (C), 140.5 (C), 137.7 (C), 130.5 (C), 129.0 (C), 128.3 (3C, CH), 126.4 (2C, CH), 103.4 (CH), 103.2 (CH), 95.0 (CH), 68.3 (C), 67.3 (CH2), 60.9 (CH3), 60.8 (CH3), 60.6 (CH3), 60.0 (CH3), 57.4 (CH), 56.0 (CH3), 55.8


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(CH3), 55.7 (CH), 34.5 (CH2); IR (KBr) 2967, 2870, 1602, 1142, 1055 cm-1; HRMS (EI, double-focusing) calcd for C30H32O7 [M]+ 504.2148, found 504.2133.

(3aR,7bS,12R,12aS)-rel-5,6,9,10-Tetramethoxy-12-phenyl-1,2,3a,7b-tetrahydro -12H-indeno[2',1':2,3]indeno[1,2-b]furan (4FAF): 0.229 g, 86%; mp 167.5-169.5 oC; 1

H NMR (CDCl3, 400 MHz) δ 7.33 (2H, m), 7.26 (1H, m), 7.09 (2H, brm), 6.94 (1H, s),

6.91 (1H, s), 6.87 (1H, s), 6.51 (1H, s), 5.31 (1H, s), 4.55 (1H, s), 4.51 (1H, s), 3.95 (3H, s), 3.90 (3H, s), 3.87 (3H, s), 3.87 (1H, m), 3.72 (3H, s), 3.66 (1H, dt, J = 8.4, 6.4 Hz), 1.72 (1H, ddd, J = 12.8, 6.4, 4.4 Hz), 1.58 (1H, m);

13


150.2 (C), 149.3 (C), 149.1 (C), 148.9 (C), 142.9 (C), 136.8 (C), 136.6 (C), 136.1 (C), 133.3 (C), 128.9 (CH), 128.5 (2C, CH), 126.7 (2C, CH), 108.3 (CH), 108.0 (CH), 106.6 (CH), 106.5 (CH), 93.8 (CH), 68.6 (C), 68.2 (CH2), 60.5 (CH), 58.0 (CH), 56.1 (CH3), 56.0 (CH3), 55.9 (2C, CH3), 35.0 (CH2); IR (KBr) 2932, 2882, 2832, 1501 cm-1; HRMS (EI, double-focusing) calcd for C28H28O5 [M]+ 444.1937, found 444.1927. (3aR,7bS,12R,12aS)-rel-5,6,9,10-Tetraethoxy-12-phenyl-1,2,3a,7b-tetrahydro-1 2H-indeno[2',1':2,3]indeno[1,2-b]furan (4GAG): 0.252 g, 84%; mp 106.0-108.5 oC; 1H NMR (CDCl3, 400 MHz) δ 7.31 (2H, m), 7.24 (1H, m), 7.07 (2H, brd, J = 6.8 Hz), 6.92 (1H, s), 6.89 (1H, s), 6.87 (1h, s), 6.50 (1H, s), 5.28 (1H, s), 4.49 (1H, s), 4.48 (1H, s), 4.17-4.00 (6H, m), 3.90 (2H, dq, J = 6.8, 2.4 Hz), 3.84 (1H, ddd, J = 12.0, 7.2, 4.4 Hz), 3.65 (1H, dt, J = 8.4, 6.4 Hz), 1.70 (1H, m), 1.54 (1H, m), 1.47 (3H, t, J = 6.8 Hz), 1.45 (3H, t, J = 6.8 Hz), 1.44 (3H, t, J = 6.8 Hz), 1.33 (3H, t, J = 6.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 149.8 (C), 149.1 (C), 148.9 (C), 148.6 (C), 143.0 (C), 137.0 (2C, C), 136.3 (C), 133.5 (C), 129.0 (CH), 128.4 (2C, CH), 126.6 (2C, CH), 110.6 (CH), 110.0 (CH), 109.2 (CH), 109.1 (CH), 93.7 (CH), 68.6 (C), 68.2 (CH2), 65.0 (CH2), 64.9 (CH2), 64.5 (CH2), 64.4 (CH2), 60.5 (CH), 57.9 (CH), 35.1 (CH2), 14.90 (CH3), 14.86 (CH3), 14.84



(CH3), 14.7 (CH3); IR (KBr) 2978, 2936, 1508 cm-1; HRMS (EI, double-focusing) calcd for C32H36O5 [M]+ 500.2563, found 500.2561. (3aR,6bS,10aR)-rel-6b-Phenyl-4,9-ditosyl-1,2,3a,6b,9,10-hexahydro-4H-furo[2 ',3':3,3a]pentaleno[2,1-b:5,6-b']dipyrrole (7JAJ): 40.0 mg, 32%; mp 228.1-228.6 oC; 1

H NMR (CDCl3, 400 MHz) δ 7.97 (2H, d, J = 8.4 Hz), 7.74 (2H, d, J = 8.4 Hz), 7.35

(2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.24-7.19 (3H, m), 7.15 (1H, d, J = 3.2 Hz), 7.09 (1H, d, J = 3.2 Hz), 6.88 (2H, dd, J = 8.0, 2.0 Hz), 6.08 (1H, d, J = 3.2 Hz), 5.89 (1H, d, J = 3.6 Hz), 5.24 (1H, s), 3.72 (1H, ddd, J = 8.8, 7.2, 4.0 Hz), 3.40 (1H, d, J = 16.4 Hz), 3.18 (1H, td, J = 9.2, 6.0 Hz), 3.10 (1H, d, J = 16.8 Hz), 2.45 (3H, s), 2.43 (3H, s), 1.62-1.47 (2H, m); 13C NMR (CDCl3, 100 MHz) δ 145.2 (C), 144.7 (C), 142.4 (C), 138.1 (C), 137.1 (C), 136.1 (C), 135.8 (C), 134.7 (C), 133.6 (C), 130.2 (2C, CH), 129.6 (2C, CH), 128.2 (2C, CH), 127.8 (2C, CH), 127.7 (2C, CH), 126.9 (CH), 126.7 (2C, CH), 126.6 (CH), 124.9 (CH), 108.0 (CH), 107.8 (CH), 87.8 (CH), 79.0 (C), 67.3 (CH2), 59.9 (C), 39.6 (CH2), 37.6 (CH2), 21.68 (CH3), 21.65 (CH3); IR (KBr) 3132, 3063, 2940, 2862, 1597, 1373, 1180, 1134, 671 cm-1; HRMS (EI, double-focusing) calcd for C34H30N2O5S2 [M]+ 610.1596, found 610.1604. (3aR,8cS,14aR)-rel-8c-Phenyl-4,13-ditosyl-1,2,3a,8c,13,14-hexahydro-4H-furo [2',3':3,3a]pentaleno[2,1-b:5,6-b']diindole (7KAK): 37.5 mg, 77%; mp 251.9-253.7 oC; 1

H NMR (CDCl3, 400 MHz) δ 8.05-8.01 (3H, m), 7.99 (1H, d, J = 8.8 Hz), 7.75 (2H, d,

J = 8.4 Hz), 7.39 (1H, d, J = 7.6 Hz), 7.30-7.17 (10H, m), 7.12 (1H, d, J = 8.0 Hz), 7.01 (1H, t, J = 7.6 Hz), 6.93 (2H, brd, J = 6.4 Hz), 5.63 (1H, s), 3.94 (1H, dt, J = 8.4, 4.8 Hz), 3.84 (1H, d, J = 17.2 Hz), 3.48-3.42 (2H, m), 2.35 (6H, s), 1.79-1.75 (2H, m); 13C NMR (CDCl3, 100 MHz) δ 145.3 (C), 144.7 (C), 141.1 (C), 140.3 (C), 140.2 (C), 140.1 (C), 139.6 (C), 135.6 (C), 135.2 (C), 131.1 (C), 130.4 (C), 130.1 (2C, CH), 129.5 (2C,


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CH), 128.5 (2C, CH), 127.9 (2C, CH), 127.5 (2C, CH), 127.3 (CH), 126.4 (2C, CH), 125.5 (C), 125.1 (C), 124.6 (CH), 123.8 (CH), 123.4 (CH), 123.2 (CH), 120.7 (CH), 119.8 (CH), 114.6 (CH), 114.5 (CH), 88.8 (CH), 77.3 (C), 67.7 (CH2), 59.8 (C), 40.5 (CH2), 37.2 (CH2), 21.5 (2C, CH3); IR (KBr) 3055, 2970, 2924, 2855, 1597, 1373, 1173, 571 cm-1; HRMS (EI, double-focusing) calcd for C42H34N2O5S2 [M]+ 710.1909, found 710.1936. (3aR,7bR,12S,12aR)-rel-5,9,10,11-Tetramethoxy-12-phenyl-1,2,3a,7b-tetrahydr o-12H-indeno[2',1':2,3]indeno[1,2-b]furan

(4EAB-p)

&

(3aR,7bR,12S,12aS)-rel-7,9,10,11-Tetramethoxy-12-phenyl-1,2,3a,7b-tetrahydro-12H-in deno[2',1':2,3]indeno[1,2-b]furan (4EAB-o): 0.229 g, 75%, 4EAB-p : 4EAB-o = 7 : 1; 1

H NMR for 4EAB-p (CDCl3, 400 MHz) δ 7.40 (1H, d, J = 9.2 Hz), 7.28 (2H, t, J = 7.2

Hz), 7.19 (1H, t, J = 7.2 Hz), 7.08 (2H, brs), 6.92-6.90 (2H, m), 6.59 (1H, s), 5.32 (1H, s), 4.62 (1H, s), 4.60 (1H, s), 3.88 (1H, q, J = 7.6 Hz), 3.84 (3H, s), 3.79 (3H, s), 3.73 (3H, s), 3.61 (1H, q, J = 7.6 Hz), 3.32 (3H, s), 1.69 (2H, t, J = 6.8 Hz); 13C NMR for 4EAB-p (CDCl3, 100 MHz) δ 159.8 (C), 154.0 (C), 149.8 (C), 143.5 (2C, C), 141.5 (C), 140.0 (C), 136.4 (C), 130.6 (C), 128.3 (4C, CH), 126.4 (CH), 124.6 (CH), 116.1 (CH), 109.3 (CH), 102.5 (CH), 94.7 (CH), 68.2 (CH2), 67.8 (C), 60.6 (CH3), 59.9 (CH), 59.5 (CH3), 56.0 (CH3), 55.8 (CH), 55.3 (CH3), 34.5 (CH2); IR (film) 3009, 2940, 1736, 1597, 1481, 1335, 1211, 1119, 1065, 756 cm-1; HRMS (EI, double-focusing) calcd for C28H28O5 [M]+ 444.1937, found 444.1946. (3aR,7bR,12S,12aR)-rel-5,6,9,10,11-Pentamethoxy-12-phenyl-1,2,3a,7b-tetrah ydro-12H-indeno[2',1':2,3]indeno[1,2-b]furan (4EAF): 0.230 g, 76%; mp 161.9-162.5 o

C; 1H NMR (CDCl3, 400 MHz) δ 7.28 (2H, t, J = 7.2 Hz), 7.19 (1H, t, J = 7.2 Hz), 7.08

(2H, brs), 6.99 (1H, s), 6.88 (1H, s), 6.60 (1H, s), 5.33 (1H, s), 4.61 (1H, s), 4.60 (1H, s),



Page 42 of 49

3.96 (3H, s), 3.89-3.84 (7H, m), 3.74 (3H, s), 3.58 (1H, q, J = 6.8 Hz), 3.32 (3H, s), 1.69 (2H, t, J = 6.8 Hz);

13


149.4 (C), 143.5 (C), 141.6 (C), 139.9 (C), 136.4 (C), 133.7 (C), 130.8 (C), 128.3 (4C, CH), 126.4 (CH), 107.7 (CH), 106.7 (CH), 102.4 (CH), 95.0 (CH), 67.9 (CH2), 67.8 (C), 60.6 (CH3), 60.4 (CH), 59.9 (CH3), 56.3 (CH3), 56.0 (CH3), 55.92 (CH), 55.90 (CH3), 35.0 (CH2); IR (KBr) 2932, 2832, 1605, 1458, 1335, 1227, 1111 cm-1; HRMS (EI, +


(3aR,7bS,12R,12aS)-rel-5,9,10-Trimethoxy-12-phenyl-1,2,3a,7b-tetrahydro-12 H-indeno[2',1':2,3]indeno[1,2-b]furan

(4FAB-p)

&

(3aR,7bR,12R,12aS)-rel-7,9,10-Trimethoxy-12-phenyl-1,2,3a,7b-tetrahydro-12H-indeno [2',1':2,3]indeno[1,2-b]furan (4FAB-o): 0.345 g, 99%, 4FAB-p : 4FAB-o = 4 : 1; mp 168.0-168.5 oC; 1H NMR for 4FAB-p (CDCl3, 400 MHz) δ 7.37 (1H, d, J = 9.2 Hz), 7.31 (2H, t, J = 7.2 Hz), 7.24 (1H, t, J = 7.2 Hz), 7.07 (2H, brs), 6.92-6.90 (2H, m), 6.84 (1H, s), 6.51 (1H, s), 5.31 (1H, s), 4.56 (1H, s), 4.50 (1H, s), 3.90-3.86 (4H, m), 3.78 (3H, s), 3.71-3.64 (4H, m), 1.72 (1H, dt, J = 11.6, 6.4 Hz), 1.59 (1H, dt, J = 12.8, 7.6 Hz); 13C NMR for 4FAB-p (CDCl3, 100 MHz) δ 159.7 (C), 149.0 (C), 143.1 (C), 143.0 (C), 136.7 (C), 136.4 (C), 136.2 (C), 128.8 (2C, CH), 128.4 (2C, CH), 126.7 (CH), 124.6 (CH), 116.2 (CH), 109.7 (CH), 108.2 (CH), 106.6 (CH), 93.7 (CH), 68.5 (CH2), 68.4 (C), 59.5 (CH), 58.0 (CH), 55.9 (CH3), 55.8 (CH3), 55.3 (CH3), 34.6 (CH2); IR (KBr) 2932, 2832, 1605, 1497, 1296, 1219, 1096 cm-1; HRMS (EI, double-focusing) calcd for C27H26O4 [M]+ 414.1831, found 414.1829. (3aR,7bS,12R,12aS)-rel-4,5,6,9,10-Pentamethoxy-12-phenyl-1,2,3a,7b-tetrahy dro-12H-indeno[2',1':2,3]indeno[1,2-b]furan (4FAE): 0.423 g, 98%; mp 149.9-150.5 o

C; 1H NMR (CDCl3, 400 MHz) δ 7.31 (2H, t, J = 7.2 Hz), 7.23 (1H, t, J = 7.2 Hz), 7.15


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(1H, s), 7.07 (2H, brs), 6.67 (1H, s), 6.50 (1H, s), 5.28 (1H, s), 4.77 (1H, s), 4.48 (1H, s), 4.08 (3H, s), 3.88-3.84 (10H, m), 3.71 (3H, s), 3.68 (1H, q, J = 6.8 Hz), 1.71 (1H, dt, J = 12.8, 6.8 Hz), 1.62 (1H, dt, J = 12.8, 6.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 154.1 (C), 149.4 (C), 149.0 (C), 148.9 (C), 143.4 (C), 142.1 (C), 137.5 (C), 136.7 (C), 136.4 (C), 129.3 (C), 128.7 (2C, CH), 128.4 (2C, CH), 126.6 (CH), 107.9 (CH), 107.8 (CH), 103.5 (CH), 94.5 (CH), 68.3 (CH2), 67.9 (C), 60.9 (CH3), 60.8 (CH3), 58.4 (CH), 57.6 (CH), 56.0 (CH3), 55.9 (CH3), 55.8 (CH3), 34.7 (CH2); IR (KBr) 2932, 2855, 1605, 1466, 1342, 1219, 1119, 1034 cm-1; HRMS (EI, double-focusing) calcd for C29H30O6 [M]+ 474.2042, found 474.2021. (3aS,4R,8bS,13bR)-rel-6,7-Dimethoxy-4-phenyl-13-tosyl-2,3,4,8b,13,13b-hexa hydrobenzo[5,6]furo[2',3':3,3a]pentaleno[2,1-b]indole (4FAK): 51.2 mg, 90%;

1

H

NMR (CDCl3, 400 MHz) δ 8.05-8.01 (3H, m), 7.65 (1H, d, J = 8.8 Hz), 7.39-7.25 (5H, m), 7.22 (2H, d, J = 8.4 Hz), 7.16 (2H, brs), 7.04 (1H, s), 6.45 (1H, s), 5.75 (1H, d, J = 0.8 Hz), 4.74 (1H, s), 4.59 (1H, s), 3.95-3.91 (4H, m), 3.71 (3H, s), 3.65 (1H, ddd, J = 10.4, 9.2, 5.2 Hz), 2.34 (3H, s), 1.75 (1H, ddd, J = 12.8, 4.4, 2.4 Hz), 1.50 (1H, ddd, J = 12.8, 10.4, 7.2 Hz);

13


142.0 (C), 140.2 (C), 139.8 (C), 136.3 (C), 135.5 (C), 134.2 (C), 129.8 (C), 129.5 (2C, CH), 129.3 (2C, CH), 128.5 (2C, CH), 127.5 (2C, CH), 126.9 (CH), 125.4 (C), 124.6 (CH), 123.3 (CH), 119.6 (CH), 114.7 (CH), 108.5 (CH), 107.2 (CH), 87.3 (CH), 73.4 (C), 67.9 (CH2), 57.8 (CH), 56.1 (CH3), 56.0 (CH3), 55.9 (CH), 36.2 (CH2), 21.5 (CH3); IR (film) 3021, 2938, 2862, 1599, 1506, 1371, 1215, 1174, 1098, 754 cm-1; HRMS (EI, double-focusing) calcd for C35H31NO5S [M]+ 577.1923, found 577.1910.

(3aR,7bR,13aR)-rel-5,6-Dimethoxy-7b-phenyl-12-tosyl-1,2,3a,7b,12,13-hexahy drobenzo[5,6]furo[3',2':3a,4]pentaleno[2,1-b]indole (7KAF): 54.4 mg, 94%; 1H NMR



Page 44 of 49

(CDCl3, 400 MHz) δ 8.05 (1H, d, J = 8.4 Hz), 7.76 (2H, d, J = 8.8 Hz), 7.25-7.19 (7H, m), 7.09 (1H, t, J = 7.6 Hz), 6.92-6.88 (3H, m), 6.86 (1H, s), 5.22 (1H, s), 3.91 (1H, ddd, J = 8.8, 6.8, 4.8 Hz), 3.86 (3H, s), 3.83 (3H, s), 3.73 (1H, d, J = 18.0 Hz), 3.57 (1H, td, J = 8.4, 6.4 Hz), 3.33 (1H, d, J = 17.2 Hz), 2.37 (3H, s), 1.76-1.63 (2H, m);

13

C NMR

(CDCl3, 100 MHz) δ 150.0 (C), 149.4 (C), 145.0 (C), 141.6 (C), 140.0 (C), 139.8 (C), 137.8 (C), 135.4 (C), 134.2 (C), 130.5 (C), 130.0 (2C, CH), 128.3 (2C, CH), 128.2 (2C, CH), 126.9 (CH), 126.5 (2C, CH), 125.6 (C), 123.7 (CH), 123.4 (CH), 119.1 (CH), 114.6 (CH), 107.7 (CH), 107.2 (CH), 94.6 (CH), 71.9 (C), 67.8 (CH2), 65.4 (C), 56.1 (CH3), 55.8 (CH3), 40.6 (CH2), 36.7 (CH2), 21.5 (CH3); IR (film) 3021, 2936, 2859, 1599, 1504, 1445, 1369, 1283, 1217, 1188, 1175, 1103, 758 cm-1; HRMS (EI, +

double-focusing) calcd for C35H31NO5S [M] 577.1923, found 577.1928.


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ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Synthetic procedure of homocinnamyl alcohols (2B-C). ORTEP drawings as shown by X-ray crystallographiy for 5FC, BF3-coordinated structure of 1H, 6KA, 3LA, 6LA, 7KAK and copies of the 1

H/13C NMR of all new products.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS We thunk a Grant-in-Aid for Scientific Research (C) (No. 16K05782) and the Strategic Research Foundation Grant-aided Project for Private Universities from the Ministry of Education, Culture, Sport, Science, and Technology, Japan (MEXT), 2014-2018 (S1411005).

(1)

REFERENCES Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Cascade Reactions in Total

(2)

Synthesis. Angew. Chem., Int. Ed. 2006, 45, 7134. Review on Prins cyclization, see: Olier, C.; Kaafarani, M.; Gastaldi, S.; Bertrand, M. P. Synthesis of tetrahydropyrans and related heterocycles via prins

(3)

cyclization; extension to aza-prins cyclization. Tetrahedron 2010, 66, 413. Barry, C. St. J.; Crosby, S. R.; Harding, J. R.; Hughes, R. A.; King, C. D.; Parker, G. D.; Willis, C. L. Stereoselective Synthesis of

(4)

4-Hydroxy-2,3,6-trisubstituted Tetrahydropyrans. Org. Lett. 2003, 5, 2429. For example, (a) Miranda, L. S. M.; Vasconcellos, M. L. A. A. Chemoselective RuO4 Oxidation of Phenyl or p-Methoxyphenyl Groups to Carboxylic Acid



Functions in the Presence of a Tetrahydropyran Ring. Synthesis 2004, 1767; (b) Chan, K.-P.; Ling, Y. H.; Loh, T.-P. Formal synthesis of (+)-SCH 351448: the Prins cyclization approach. Chem. Commun. 2007, 939; (c) Kishi, Y.; Nagura, H.; Inagi, S.; Fuchigami, T. Facile and highly efficient synthesis of fluorinated heterocycles via Prins cyclization in ionic liquid hydrogen fluoride salts. Chem. (5)

Commun. 2008, 3876. For example, (a) Albizati, K. F.; Perron, F. J. Synthesis of 4-hetero-substituted pyranosides via dioxenium cation-olefin cyclization. J. Org. Chem. 1987, 52, 4128; (b) Al-Mutairi, E. H.; Crosby, S. R.; Darzi, J.; Harding, J. R.; Hughes, R. A.; King, C. D.; Simpson, T. J.; Smith, R. W.; Willis, C. L. Stereocontrolled synthesis of 2,4,5-trisubstituted tetrahydropyrans. Chem. Commun. 2001, 835; (c) Yadav, J. S.; Subba Reddy, B. V.; Narayama Kumar, G. G. K. S.; Reddy, G. M. CeCl3·7H2O/AcCl-catalyzed Prins–Ritter reaction sequence: a novel

(6)

synthesis of 4-amido tetrahydropyran derivatives. Tetrahedron Lett. 2007, 48, 4903. (a) Tian, X.; Jaber, J. J.; Rychnovsky, S. D. Synthesis and Structure Revision of Calyxin Natural Products. J. Org. Chem. 2006, 71, 3176; (b) Reddy, U. C.; Bondalapati, S.; Saikia, A. K. Stereoselective Synthesis of 2,6-Disubstituted-4-Aryltetrahydropyrans Using Sakurai-Hosomi-PrinsFriedel-Crafts Reaction. Eur. J. Org. Chem. 2009, 1625; (c) Reddy, U. C.; Bondalapati, S.; Saikia, A. K. Stereoselective One-Pot, Three-Component Synthesis of 4-Aryltetrahydropyran via Prins−Friedel−Crafts Reaction. J. Org.

(7)

Chem. 2009, 74, 2605. Yadav, J. S.; Chakravarthy, P. P.; Borkar, P.; Reddy, B. V. S.; Sarma, A. V. S. Intramolecular-Prins-cyclization: a novel synthesis of

(8)

hexahydro-2H-furo[3,2-c]pyran derivatives. Tetrahedron Lett. 2009, 50, 5998. (a) Yang, X.-F.; Wang, M.; Zhang, Y.; Li, C.-J. 2,4-Diaryltetrahydropyran Formation by the Prins Cyclization and Its Application towards the Synthesis of Epicalyxin F and Calyxin I. Synlett 2005, 1912; (b) Reddy, B. V. S.; Borkar, P.; Yadav, J. S.; Sridhar, B.; Gree, R. J. Tandem Prins/Friedel-Crafts Cyclization for Stereoselective Synthesis of Heterotricyclic Systems. Org.

(9)

Chem. 2011, 76, 7677. Yang, X.-F.; Mague, J. T.; Li, C.-J. Diastereoselective Synthesis of Polysubstituted Tetrahydropyrans and Thiacyclohexanes via Indium Trichloride

(10)

Mediated Cyclizations. J. Org. Chem. 2001, 66, 739. (a) Lolkema, L. D.; Hiemstra, H.; Semeyn, C.; Sprckamp, W.N. π-Cyclizations


Page 46 of 49

Page 47 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


of α-methoxycarbonyl oxycarbenium ions; synthesis of oxacyclic carboxylic esters. Tetrahedron 1994, 50, 7115; (b) Lolkema, L. D.; Semeyn, C.; Ashek, L.; Hiemstra, H.; Speckamp, W. N. Studies on the role of the 2-oxonia Cope rearrangement in π-cyclizations of α-methoxycarbonyl oxycarbenium ions. Tetrahedron 1994, 50, 7129; (c) Loh, T.-P.; Hu, Q.-Y.; Tan, K.-T.; Cheng, H.-S. Diverse Cyclization Catalyzed by In(OTf)3 for the Convergent Assembly of (11)

Substituted Tetrahydrofurans and Tetrahydropyrans. Org. Lett. 2001, 3, 2669. (a) Chen, C.; Mariano, P. S. An Oxidative Prins Cyclization Methodology. J. Org. Chem. 2000, 65, 3252; (b) Peng, F.; Hall, D. G. Simple, Stable, and Versatile Double-Allylation Reagents for the Stereoselective Preparation of

(12)

Skeletally Diverse Compounds. J. Am. Chem. Soc. 2007, 129, 3070. Shin, C.; Oh, Y.; Cha, J. H.; Pae, A. N.; Choo, H.; Cho, Y. S. Synthesis of sterically congested bicyclic tetrahydrofurans via Pd-catalyzed cyclization.

(13)

Tetrahedron 2007, 63, 2182. Okada, T.; Shimoda, A.; Shinada, T.; Sakaguchi, K. Ohfune, Y. Regioselective Prins Cyclization of Allenylsilanes. Stereoselective Formation of

(14)

Multisubstituted Heterocyclic Compounds. Org. Lett. 2012, 14, 6130. Spivey et al. reported a cascade reaction involving 5-membered ring selective Prins reaction utilizing homocinnamyl alcohol and applied it to a concise synthesis of (+)-Lophirone, See, (a) Spivey, A. C.; Laraia, L.; Bayly, A. R.; Rzepa, H. S.; White, A. J. P. Stereoselective Synthesis of cis- and trans-2,3-Disubstituted Tetrahydrofurans via Oxonium−Prins Cyclization: Access to the Cordigol Ring System. Org. Lett. 2010, 12, 900; (b) Abas, H.; Linsdall, S. M.; Mamboury, M.; Rzepa, H. S.; Spivey, A. C. Total Synthesis of (+)-Lophirone H and Its Pentamethyl Ether Utilizing an Oxonium–Prins

(15)

Cyclization. Org. Lett. 2017, 19, 2486. A part of this work was reported as a preliminary communication. Suzuki, Y.; Niwa, T.; Yasui, E.; Mizukami, M.; Miyashita, M.; Nagumo, S. Tandem five membered-ring selective Prins reaction and Friedel-Crafts reaction. Tetrahedron

(16)

Lett. 2012, 53, 1337. (a) Chen, H.; Bai, J.; Fang, Z.-F.; Yu, S.-S.; Ma, S.-G.; Xu, S.; Li, Y.; Qu, J.; Ren, J.-H.; Li, L.; Si, Y.-K.; Chen, X.-G. Indole Alkaloids and Quassinoids from the Stems of Brucea mollis. J. Nat. Prod. 2011, 74, 2438; (b) Lopchuk, J. M.; Green, I. L.; Badenock, J. C.; Gribble, G. W. A Short, Protecting Group-Free Total

(17)

Synthesis of Bruceollines D, E, and J. Org. Lett. 2013, 15, 4485. (a) Springer, J. P.; Clardy, J. Paspaline and paspalicine, two indole-mevalonate



metabolites from claviceps paspali. Tetrahedron Lett. 1980, 21, 231; (b) Smith III, A. B.; Mewshaw, R. Total synthesis of (-)-paspaline. J. Am. Chem. Soc. (18)

1985, 107, 1769. Kong, Y.-C.; Cheng, K.-F.; Cambie, R. C.; Waterman, P. G. Yuehchukene: a novel indole alkaloid with anti-implantation activity. J. Chem. Soc., Chem.

(19) (20)

Commun. 1985, 47. Hayakawa, Y.; Kawakami, K.; Seto, H.; Furihata, K. Structure of a new antibiotic, roseophilin. Tetrahedron Lett. 1992, 33, 2701. Sturino, C. F.; O’Neill, G.; Lachance, N.; Boyd, M.; Berthelette, C.; Labelle, M.; Li, L.; Roy, B.; Scheigetz, J.; Tsou, N.; Aubin, Y.; Bateman, K. P.; Chauret, N.; Day, S. H.; Lévesque, J.-F.; Seto, C.; Silva, J. H.; Trimble, L. A.; Carriere, M.-C.; Denis, D.; Greig, G.; Kargman, S.; Lamontagne, S.; Mathieu, M.-C.; Sawyer, N.; Slipetz, D.; Abraham, W. M.; Jones, T.; McAuliffe, M.; Piechuta, H.; Nicoll-Griffith, D. A.; Wang, Z.; Zamboni, R.; Young, R. N.; Metters, K. M. Discovery of a Potent and Selective Prostaglandin D2 Receptor Antagonist, [(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]

(21)

-acetic Acid (MK-0524). J. Med. Chem. 2007, 50, 794. For some examples of the synthesis of functionalized cyclopenta[b]indoles, see: (a) Churruca, F.; Fousteris, M.; Ishikawa, Y.; von Wantoch Rekowski, M.; Hounsou, C.; Surrey, T.; Giannis, A. A Novel Approach to Indoloditerpenes by Nazarov Photocyclization: Synthesis and Biological Investigations of Terpendole E Analogues. Org. Lett. 2010, 12, 2096; (b) Saito, K.; Sogou, H.; Suga, T.; Kusama, H.; Iwasawa, N. Platinum(II)-Catalyzed Generation and [3+2] Cycloaddition Reaction of α,β-Unsaturated Carbene Complex Intermediates for the Preparation of Polycyclic Compounds. J. Am. Chem. Soc. 2011, 133, 689; (c) Xu, B.; Guo, Z.-L.; Jin, W.-Y.; Wang, Z.-P.; Peng, Y.-G.; Guo, Q.-X. Multistep One-Pot Synthesis of Enantioenriched Polysubstituted

(22)

Cyclopenta[b]indoles. Angew. Chem. Int. Ed. 2012, 51, 1059. For some examples of the synthesis of functionalized cyclopenta[b]pyrroles, see: (a) Bachu, P.; Akiyama, T. Brønsted acid-catalyzed Nazarov cyclization of pyrrole derivatives accelerated by microwave irradiation. Bioorg. Med. Chem. Lett. 2009, 19, 3764; (b) Meiling, H.; Hui, L.; Li, S.; Feifei, J.; Yuanyuan, L.; Qingwei, J.; Chuanjun, S.; Junbiao, C. Synthesis of an Advanced Intermediate

(23)

of the Macrotricyclic Core of Roseophilin. Synlett 2011, 2995. Hamada et al. reported synthesis of phenyl-hydrocyclopentaindole by a cascade


Page 48 of 49

Page 49 of 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


reaction including a similar Friedel-Crafts cyclization of benzyl cation. See, Yokosaka, T.; Nakayama, T.; Nemoto, T.; Hamada, Y. Acid-promoted Cascade

(24)

Cyclization to Produce Fused-polycyclic Indole Derivatives. Org. Lett. 2013, 15, 2978. Grob, C. A. Mechanisms and Stereochemistry of Heterolytic Fragmentation.

(25)

Angew. Chem., Int. Ed. Engl. 1969, 8, 535. Je´roˆme W.; Boris G.; Hisanori N.; Erick M. C. Hydrazines and Azides via the Metal-Catalyzed Hydrohydrazination and Hydroazidation of Olefins. J. Am.

(26)

Chem. Soc. 2006, 128, 11693. Prasath, K.; Srinivasa, R. M.; Sharon, S. M. T.; Philip. W. H. C. Gold-Catalyzed Cycloisomerizations of 1-(2-(Tosylamino)phenyl)prop-2-yn-1-ols to 1H-Indole-2-carbaldehydes and (E)-2-(Iodomethylene)indolin-3-ols. J. Org. Chem. 2011, 76, 7633.


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