Personal Account DOI: 10.1002/tcr.201500005
THE CHEMICAL RECORD
Stereoselective Electrophilic Cyclization Akira Sakakura*[a] and Kazuaki Ishihara*[b] Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530 (Japan), E-mail: [email protected] [b] Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603 (Japan) and Japan Science and Technology Agency (JST), CREST, Furo-cho, Chikusa, Nagoya, 464-8603 (Japan)
[a]
Received: January 13, 2015 Published online: July 6, 2015
ABSTRACT: Electrophilic cyclizations of unactivated alkenes play highly important roles in the synthesis of useful building blocks. This account describes our contributions to the rational design of monofunctionalized chiral Lewis base catalysts for enantioselective iodo- and protocyclizations. For the stereoselective promotion of electrophilic bromocyclizations, nucleophilic phosphite–urea cooperative catalysts have been designed. Keywords: asymmetric synthesis, electrophilic cyclization, lactonization, Lewis bases, organocatalysis
1. Introduction A variety of bioactive polycyclic natural products that contain halogen atoms have been isolated from several marine organisms.[1] The biosynthesis of these halogenated cyclic natural products appears to be initiated by an electrophilic halogenation reaction at a carbon–carbon double bond.[2] Enzymes such as haloperoxidases generate an electrophilic halonium ion (or its equivalent), which enantioselectively reacts with the terminal carbon–carbon double bond of an isoprenoid to induce a diastereoselective cyclization reaction that produces a halogenated cyclic compound. Biomimetic electrophilic halocyclization of isoprenoids should be highly useful for the chemical synthesis of these halogenated cyclic natural products. Although several brominated cyclic terpenoids have been synthesized via a diastereoselective bromocyclization that uses stoichiometric amounts of a brominating reagent, most of the conventional methods are not efficient and give the desired products in poor to moderate yields.[3]
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In chemical organic synthesis, electrophilic cyclizations of unactivated alkenes are powerful tools for the enantio- or diastereoselective functionalization of alkenes. When an alkene substrate has a carbon nucleophile such as a carbon–carbon double bond or an aromatic ring, the reaction of the alkene with an electrophile is accompanied by carbon–carbon bond formation (Scheme 1).[4–6] On the other hand, the electrophilic cyclization of an alkene substrate bearing a heteroatom nucleophile such as a carboxy or hydroxy group is considered to be oxidation of the alkene. Although this type of reaction does not result in carbon–carbon bond formation, the oxidation of unactivated alkenes is a highly useful functional group transformation if the reaction can be conducted enantioselectively.[7–13] The current account presents our recent studies on selective electrophilic cyclizations, which include halonium-ioninduced and Brønsted acid catalyzed reactions.
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Scheme 1. Electrophilic cyclizations.
2. Enantioselective Iodocyclization To promote electrophilic halocyclizations, two methods can be used to activate the halogenating reagents by chiral catalysts (Scheme 2). In the conventional monofunctional Lewis acid approach (method A),[14] a Lewis acid electrophilically activates a halogenating reagent to generate an active species. Recent studies have shown that dual hydrogen-bond donors can also be used as acid catalysts for the activation of a halogenating reagent (method B).[8a,9e,13k] On the other hand, if a monofunctional Lewis base can nucleophilically activate a halogenating reagent, another type of ionic active species would be generated (method C). In 2005, we started our project on the design of monofunctional Lewis bases[15] for the selective promotion of electrophilic halocyclizations, since studies on Lewis base promoted halocyclizations were quite rare back then. This chapter summarizes our studies on enantioselective electrophilic iodocyclization promoted by chiral Lewis bases.
Akira Sakakura received his Ph.D. degree from Nagoya University in 2000 under the direction of Prof. Yoshihiro Hayakawa. After nine months of postdoctoral studies at Nagoya University, he joined Prof. Hideo Kigoshi’s group at the University of Tsukuba as an assistant professor in 2001. In 2003, he joined Prof. Kazuaki Ishihara’s group at the Graduate School of Engineering, Nagoya University, as an associate professor. In 2012, he was appointed to his current position as a full professor at the Graduate School of Natural Science and Technology, Okayama University.
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Scheme 2. Activation of halogenating reagents by chiral catalysts.
2.1. Enantioselective Iodocyclization of Homogeranylarenes[16] First, the activities of various achiral nucleophiles were examined in the electrophilic iodocyclization of 4-(homogeranyl)toluene (1) with N-iodosuccinimide (NIS). The reaction was catalytically conducted with 1.1 equivalent of NIS in the
Kazuaki Ishihara received his Ph.D. degree from Nagoya University in 1991 under the direction of Prof. Hisashi Yamamoto. He had the opportunity to work under the direction of Prof. Clayton H. Heathcock at the University of California, Berkeley, as a visiting graduate student in 1988. He was a JSPS Fellow under the Japanese Junior Scientists Program from 1989 to 1991. After completing his postdoctoral studies with Prof. E. J. Corey at Harvard University, he returned to Japan and joined Prof. H. Yamamoto’s group at Nagoya University as an assistant professor in 1992, and became an associate professor in 1997. In 2002, he was appointed to his current position as a full professor at Nagoya University.
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Table 1. Iodocyclization of 1 promoted by achiral and chiral nucleophiles.
Entry
Nucleophile (mol %)
Solvent
Yield [%][c]
ee [%][d]
1[a] None CH2Cl2 0 — .......................................................................................................... 2[a] PBu3 (30) CH2Cl2 99 — 3[a] PPh3 (30) CH2Cl2 67 — 4[a] PPh3 (30) toluene 0 — 5[a] P(OPh)3 (30) CH2Cl2 51 — .......................................................................................................... 6[b] 4 (30) CH2Cl2 95 0 7[b] 4 (100) toluene 11 0 8[b] 5 (100) CH2Cl2 95 0 9[b] 5 (100) toluene 57 95 (3S) [a]
Unless otherwise noted, the reaction of 1 (0.1 mmol) and NIS (1.1 equiv) was conducted in solvent (1 mL) in the presence of a nucleophile at 2788C for 24 h and then at 2408C for 6 h. [b]The reaction was conducted at 2408C for 24 h. [c]The yield of 2 was evaluated by 1H NMR analysis after treatment with ClSO3H (50 lL) in iPrNO2 (2 mL) at 2788C for 4 h. [d]The enantiomeric excess of 2 was determined by chiral HPLC analysis.
presence of a nucleophile (30 mol %) in CH2Cl2 (Table 1). The reaction gave the desired trans-fused AB-ring product 2a, together with endo- and exo-isomeric A-ring products 3a (2a:3a 5 ca. 7:3). The trans-substituted A-ring products and cis-fused AB-ring product were not obtained. Since treatment of the mixture of 2a and 3a with ClSO3H gave 2a as a single trans-fused diastereomer,[5f ] the yield of 2a was evaluated after the subsequent diastereoselective cyclization. As a result, trivalent phosphorus compounds such as PBu3, PPh3 and P(OPh)3 showed good catalytic activity. In contrast, nucleophilic amines such as DABCO and DMAP were completely inert (data not shown). Based on these results, we next designed chiral nucleophiles to promote the enantioselective iodocyclization of 1 with NIS (Table 1). Commercially available chiral phosphora-
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midite 4 showed high activity in CH2Cl2, although the obtained 2a was racemic (entry 6). The use of toluene as solvent decreased the yield of 2a (11%) with no enantioselectivity (entry 7). Intensive study toward the design of a chiral nucleophile revealed that the introduction of a triphenylsilyl group at the 3- and 30 -positions of the chiral phosphoramidite and the use of toluene as solvent resulted in extremely high enantioselectivity (95% ee, 3S enantiomer), although the yield of 2a was moderate (57%) (entry 9). The absolute configuration of the obtained 2a was determined to be (3S,5R,10S) by chiral HPLC analysis after conversion to the known deiodinated compound[5b] by treatment with Bu3SnH (2 equiv) and AIBN (1 mol %) in toluene at 908C. The efficient chiral environment would be created by the bulky 3,30 -triphenylsilyl groups around the nucleophilic phosphorus atom. Although chiral nucleophile 5 could, in principle, catalytically promote the enantioselective iodocyclization of 1, a stoichiometric amount of 5 was required for the efficient promotion of iodocyclization. We propose here a mechanism for the enantioselective iodocyclization of 1 (Scheme 3). The catalytic cycle would involve the reaction of 5 with NIS to give iodophosphonium salt 6 as an active species. Electrophilic iodination of the terminal double bond of 1 followed by cyclization gives the desired product 2a and succinimide. The solvent effect in the iodocyclization might be ascribed to the nature of the iodophosphonium salt generated from 5 and NIS (Scheme 3). In CH2Cl2, the iodophosphonium salt would be a loose ionic species (more active species 6a) and the highly ionic nature might result in the high activity of 5. Free rotation of the P–N bond might lead to a flexible conformation of the 1-phenethylamino moiety in 6a, which would result in no enantioselectivity in CH2Cl2. On the other hand, in the less polar toluene, the iodophosphonium salt would be a tight ion pair (less active species 6b). The succinimide anion might form a hydrogen bond with the proton of the NH group in active species 6b to fix the conformational flexibility of the 1-phenethylamino moiety. The less ionic nature might result in the low activity of 5 and the fixed conformation might lead to high enantioselectivity in toluene. When the 5-promoted iodocyclization of 1 with NIS was conducted in toluene in the presence of one equivalent of DMF or 1-ethyl-3methylimidazolium triflate, the enantioselectivity was significantly decreased, although the yield of 2a was improved (82% yield, 7% ee and 84% yield, 0% ee, respectively). These additives should act as polar solvents to make the active species highly ionic, which would result in the high reactivity and poor enantioselectivity in toluene. The following mechanism is proposed to explain the absolute stereopreference in the 5-promoted iodocyclization of 1 (Figure 1). Structure A is the Newman projection of the tight ion-pair species 6b viewed along the I–P bond. Compound 1
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Scheme 3. Proposed mechanism for enantioselective iodocyclization.
should approach the iodine of A with the terminal dimethyl group away from the triphenylsilyl group, avoiding their steric hindrance. As shown in structure B, the Si face of the terminal isobutenyl group of 1 would preferentially react with 6b, while the reaction at the Re face would be disfavored because of steric hindrance between the dimethyl group and the N-(1-phenethyl)amino group (structure C). The present method could also be applied to 3-(homogeranyl)toluene, 4-(homogeranyl)anisole and 4-(homofarnesyl)toluene (Scheme 4). The reactions of 3-(homogeranyl)toluene and 4-(homogeranyl)anisole gave the corresponding products as single diastereomers with high enantioselectivities (91% ee). The reaction of 4-(homofarnesyl)toluene gave the desired iodinated tetracyclic compound as a major product along with a byproduct (dr 94:6) with almost complete enantioselectivity (99% ee). Enantioselective bromo- and chlorocyclizations are highly valuable since many marine natural products contain bromo and/or chloro substituents. Unfortunately, however, bromocyclization of 1 with NBS gave poor enantioselectivity, and chlorocyclization with NCS did not give any chlorinated prod-
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ucts. For the chemical synthesis of brominated and chlorinated products with high enantioselectivity, the transhalogenation of 2a was quite effective (Scheme 5). Lithiation of 2a followed by bromination with BrCF2CF2Br gave the corresponding brominated compound 2b in 85% yield. The use of ClCF2CF2Cl as a chlorination reagent gave the chlorinated compound 2c in 70% yield. 2.2. Enantioselective Iodolactonization of 4-Substituted Pent-4-enoic Acids[17] Enantioselective halolactonization is one of the most useful methods for the asymmetric functionalization of alkenes. Various chiral organocatalysts have been reported for enantioselective halolactonizations since 2010. Therefore, we also investigated the enantioselective iodolactonization of unsaturated carboxylic acids based on our study of asymmetric iodocyclization promoted by monofunctional Lewis bases. Our initial investigation of the catalytic activities of various achiral Lewis bases gave fundamental information on
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Fig. 1. Proposed explanation for the absolute stereopreference.
nucleophilic base catalysis in the iodolactonization of unsaturated carboxylic acids. When the reaction of 4-benzylpent-4enoic acid was conducted with NIS (1.1 equiv), phosphorus(III) compounds (30 mol %) such as triphenyl phosphite, tri(isopropyl) phosphite and triphenylphosphine showed good
catalytic activities (Table 2, entries 1–3). In sharp contrast, pentavalent triphenyl phosphate and thiophosphate were almost inert under the same conditions (entries 4 and 5). Very
Scheme 5. Transhalogenation of 2a.
Table 2. Catalytic activities of achiral bases in the iodolactonization of 4-benzylpent-4-enoic acid.[a]
Entry
Yield [%][b]
Catalyst I1 5
NIS[c]
I2[d]
NIS 1 I2[e]
1 P(OPh)3 60 0 81 2 P(OiPr)3 55 — 85 63 — 80 3 PPh3 4 O 5 P(OPh)3 0 18 100 5 S 5 P(OPh)3 3 — 100 .......................................................................................................... 6 none 1 0 37 [a]
Scheme 4. Enantioselective iodocyclization of 3-(homogeranyl)toluene, 4(homogeranyl)anisole and 4-(homofarnesyl)toluene.
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The reaction of 4-benzylpent-4-enoic acid (0.1 mmol) was conducted in the presence of a catalyst (30 mol %) in toluene (1 mL) at 2408C for 4 h. [b]Determined by 1H NMR analysis. [c]Yield when the reaction was conducted with NIS (1.1 equiv) for 4 h. [d]Yield when the reaction was conducted with I2 (1.1 equiv) for 4 h. [e]Yield when the reaction was conducted with NIS (1.1 equiv) and I2 (1.1 equiv) for 1 h.
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surprisingly, the catalytic activities of triphenyl phosphate and thiophosphate,[18] which are less nucleophilic than trivalent phosphorus compounds, remarkably increased when NIS and I2 (1.1 equiv each) were used together as iodinating reagents.[8a,d,f ] A complex of NIS and I2 might be generated from NIS and I2 as a highly active iodinating reagent, since the combined use of NIS and I2 in the absence of any catalyst gave the corresponding iodolactone in 37% yield (entry 6). Based on these results, we next designed chiral phosphate catalysts for enantioselective iodolactonization. As a result, we found that chiral phosphate 7 showed high catalytic activity and high enantioselectivity for the reaction of 4-benzylpent-4enoic acid (Scheme 6). When N-chlorophthalimide (NCP) was used as the activator of I2, instead of NIS, the enantioselectivity was improved (92% ee).[19] Very interestingly, in the presence of 1.5 equivalents of NCP, only 0.5 equivalents of I2 sufficiently promoted the reaction to give the corresponding
Scheme 6. Chiral phosphate-catalyzed iodolactonization of 4-benzylpent-4enoic acid.
iodolactone in high yield and with high enantioselectivity (95%, 93% ee). These experimental results indicated that NCP acted as not only the activator but also the oxidant of I2. The fact that NCP was consumed during the reaction to generate phthalimide also supported this notion. The absolute configuration of the obtained iodolactone was determined to be R by comparison of the specific rotation after conversion to known 5-benzyl-5-(hydroxymethyl)dihydrofuran-2(3H)-one ((i) KOH, THF–H2O; (ii) 1 M aq. HCl).[20] A proposed mechanism for the 7-catalyzed iodolactonization is shown in Scheme 7. Lewis acidic NCP might activate I2 through halogen-bonding interactions to form the active iodinating reagent 8. The generation of 8 is supported by Raman spectra of a mixture of NCP and I2 in toluene (observed at 114 cm21). The reaction of chiral phosphate 7 with 8 would give chiral iodoxyphosphonium salt 9 as an active species for iodolactonization. This step generates ICl, a highly active iodinating reagent. This is why the use of 0.5 equivalents of I2 was sufficient to complete the iodolactonization. Enantioselective electrophilic iodination of the double bond of 4-benzylpent-4enoic acid with 9 followed by lactonization gave the desired (R)-iodolactone. The present method could be applied to various 4-(arylmethyl)pent-4-enoic acids to give the corresponding iodolactones with high enantioselectivity within a short reaction time (Scheme 8). In addition, 4-(cyclohexylmethyl)- and 4isobutyl-substituted substrates were successfully converted to the corresponding iodolactones with high enantioselectivity. However, the introduction of a 2-fluoro substituent to the benzyl group significantly decreased the enantioselectivity. The reactions of phenyl- and n-octyl-substituted substrates also
Scheme 7. Proposed mechanism of iodolactonization.
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Scheme 8. Enantioselective iodolactonization of 4-substituted 4-pentenoic acids.
fact, based on our preliminary experiments, when the reaction of 4-(homogeranyl)toluene (1) with BDSB (1.0 equiv) was conducted at 2258C, the corresponding bromocyclization product 2b was obtained in 68% yield. As described above, we have developed a chiral monofunctional Lewis base promoted iodocyclization of homogeranyl- and homofarnesylarenes and an iodolactonization of 4substituted 4-pentenoic acids.[16,17] For example, P(OPh)3 (30 mol %) successfully catalyzed the reaction of 1 with NIS (1.1 equiv) to give a mixture of 2a and 3a (X 5 I) in 80% yield, along with less than 1% yield of byproducts (Scheme 9). On the other hand, bromocyclization with NBS under the same reaction conditions gave only 10% yield of 2b and 3b (X 5 Br), along with significant amounts of dibromide 10b (X 5 Br, 13% yield) and an unknown byproduct (ca. 2% yield). The design of new catalysts is needed for selective promotion of bromocyclization of homogeranylarenes. This chapter summarizes our studies on the design of Lewis base–Brønsted acid cooperative catalysts for regio- and diastereoselective bromocyclizations. 3.1. Design of an Acid–Base Combination Catalyst for the Bromocyclization of Homogeranylarenes[22]
Scheme 9. P(OPh)3-catalyzed halocyclization of 4-homogeranyltoluene (1).
showed poor enantioselectivity, although the reactivity was good.
3. Selective Bromocyclization While many marine natural compounds contain bromine atoms,[1] iodine-containing natural compounds are rare. The development of a regio- and diastereoselective bromoniuminduced polyene cyclization is very important for the synthesis of these bromine-containing cyclic natural compounds. In 2009, Snyder and colleagues reported bromodiethylsulfonium bromopentachloroantimonate (Et2SBrSbCl5Br, BDSB) as a highly active electrophilic bromination reagent.[21] The use of BDSB gives the bromocyclization products in high yields. In
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A proposed mechanism for the triaryl phosphite catalyzed bromocyclization of 1 and the generation of undesired dibromide 10b is shown in Scheme 10. Nucleophilic activation of NBS by the triaryl phosphite catalyst gives bromophosphonium salt 11 as an active species. Regioselective bromination of the terminal double bond of 1 with 11 followed by cyclization gives the desired AB-ring product 2b and the isomeric mixture of Aring products 3b. In another pathway, phosphonium bromide 12 might be generated[23] through the nucleophilic attack of succinimide anion on the bromophosphonium cation in 11. The bromide anion of 12 may be responsible for the generation of dibromide 10b. For successful promotion of the bromocyclization of 1, it is critical to suppress the generation of phosphonium bromide 12 via the design of new Lewis base catalysts. An investigation of the catalytic activities of various phosphorus(III) compounds for the bromocyclization of 1 with NBS showed that the use of triaryl phosphites bearing electron-withdrawing substituents such as P(OC6H4-4-F)3 and P(OC6H4-4-CF3)3 gave moderate yields of 2b and 3b, although the generation of dibromide 10b could not be suppressed (Table 3, entries 1 and 2). It is conceivable that the electron-withdrawing groups on these phosphites increased the reactivity of the corresponding bromophosphonium salt 11 to promote the reaction with 1. Further investigation of the catalytic activities of various triaryl phosphites revealed that the introduction of a urea group at the para position of the catalyst (14a and 14b in Table
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Scheme 10. Proposed mechanism for the bromocyclization of 1 and the generation of dibromide 10b.
3)[24] successfully suppressed the generation of dibromide 10b (
THE CHEMICAL RECORD
Stereoselective Electrophilic Cyclization Akira Sakakura*[a] and Kazuaki Ishihara*[b] Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530 (Japan), E-mail: [email protected] [b] Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603 (Japan) and Japan Science and Technology Agency (JST), CREST, Furo-cho, Chikusa, Nagoya, 464-8603 (Japan)
[a]
Received: January 13, 2015 Published online: July 6, 2015
ABSTRACT: Electrophilic cyclizations of unactivated alkenes play highly important roles in the synthesis of useful building blocks. This account describes our contributions to the rational design of monofunctionalized chiral Lewis base catalysts for enantioselective iodo- and protocyclizations. For the stereoselective promotion of electrophilic bromocyclizations, nucleophilic phosphite–urea cooperative catalysts have been designed. Keywords: asymmetric synthesis, electrophilic cyclization, lactonization, Lewis bases, organocatalysis
1. Introduction A variety of bioactive polycyclic natural products that contain halogen atoms have been isolated from several marine organisms.[1] The biosynthesis of these halogenated cyclic natural products appears to be initiated by an electrophilic halogenation reaction at a carbon–carbon double bond.[2] Enzymes such as haloperoxidases generate an electrophilic halonium ion (or its equivalent), which enantioselectively reacts with the terminal carbon–carbon double bond of an isoprenoid to induce a diastereoselective cyclization reaction that produces a halogenated cyclic compound. Biomimetic electrophilic halocyclization of isoprenoids should be highly useful for the chemical synthesis of these halogenated cyclic natural products. Although several brominated cyclic terpenoids have been synthesized via a diastereoselective bromocyclization that uses stoichiometric amounts of a brominating reagent, most of the conventional methods are not efficient and give the desired products in poor to moderate yields.[3]
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In chemical organic synthesis, electrophilic cyclizations of unactivated alkenes are powerful tools for the enantio- or diastereoselective functionalization of alkenes. When an alkene substrate has a carbon nucleophile such as a carbon–carbon double bond or an aromatic ring, the reaction of the alkene with an electrophile is accompanied by carbon–carbon bond formation (Scheme 1).[4–6] On the other hand, the electrophilic cyclization of an alkene substrate bearing a heteroatom nucleophile such as a carboxy or hydroxy group is considered to be oxidation of the alkene. Although this type of reaction does not result in carbon–carbon bond formation, the oxidation of unactivated alkenes is a highly useful functional group transformation if the reaction can be conducted enantioselectively.[7–13] The current account presents our recent studies on selective electrophilic cyclizations, which include halonium-ioninduced and Brønsted acid catalyzed reactions.
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Scheme 1. Electrophilic cyclizations.
2. Enantioselective Iodocyclization To promote electrophilic halocyclizations, two methods can be used to activate the halogenating reagents by chiral catalysts (Scheme 2). In the conventional monofunctional Lewis acid approach (method A),[14] a Lewis acid electrophilically activates a halogenating reagent to generate an active species. Recent studies have shown that dual hydrogen-bond donors can also be used as acid catalysts for the activation of a halogenating reagent (method B).[8a,9e,13k] On the other hand, if a monofunctional Lewis base can nucleophilically activate a halogenating reagent, another type of ionic active species would be generated (method C). In 2005, we started our project on the design of monofunctional Lewis bases[15] for the selective promotion of electrophilic halocyclizations, since studies on Lewis base promoted halocyclizations were quite rare back then. This chapter summarizes our studies on enantioselective electrophilic iodocyclization promoted by chiral Lewis bases.
Akira Sakakura received his Ph.D. degree from Nagoya University in 2000 under the direction of Prof. Yoshihiro Hayakawa. After nine months of postdoctoral studies at Nagoya University, he joined Prof. Hideo Kigoshi’s group at the University of Tsukuba as an assistant professor in 2001. In 2003, he joined Prof. Kazuaki Ishihara’s group at the Graduate School of Engineering, Nagoya University, as an associate professor. In 2012, he was appointed to his current position as a full professor at the Graduate School of Natural Science and Technology, Okayama University.
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Scheme 2. Activation of halogenating reagents by chiral catalysts.
2.1. Enantioselective Iodocyclization of Homogeranylarenes[16] First, the activities of various achiral nucleophiles were examined in the electrophilic iodocyclization of 4-(homogeranyl)toluene (1) with N-iodosuccinimide (NIS). The reaction was catalytically conducted with 1.1 equivalent of NIS in the
Kazuaki Ishihara received his Ph.D. degree from Nagoya University in 1991 under the direction of Prof. Hisashi Yamamoto. He had the opportunity to work under the direction of Prof. Clayton H. Heathcock at the University of California, Berkeley, as a visiting graduate student in 1988. He was a JSPS Fellow under the Japanese Junior Scientists Program from 1989 to 1991. After completing his postdoctoral studies with Prof. E. J. Corey at Harvard University, he returned to Japan and joined Prof. H. Yamamoto’s group at Nagoya University as an assistant professor in 1992, and became an associate professor in 1997. In 2002, he was appointed to his current position as a full professor at Nagoya University.
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Table 1. Iodocyclization of 1 promoted by achiral and chiral nucleophiles.
Entry
Nucleophile (mol %)
Solvent
Yield [%][c]
ee [%][d]
1[a] None CH2Cl2 0 — .......................................................................................................... 2[a] PBu3 (30) CH2Cl2 99 — 3[a] PPh3 (30) CH2Cl2 67 — 4[a] PPh3 (30) toluene 0 — 5[a] P(OPh)3 (30) CH2Cl2 51 — .......................................................................................................... 6[b] 4 (30) CH2Cl2 95 0 7[b] 4 (100) toluene 11 0 8[b] 5 (100) CH2Cl2 95 0 9[b] 5 (100) toluene 57 95 (3S) [a]
Unless otherwise noted, the reaction of 1 (0.1 mmol) and NIS (1.1 equiv) was conducted in solvent (1 mL) in the presence of a nucleophile at 2788C for 24 h and then at 2408C for 6 h. [b]The reaction was conducted at 2408C for 24 h. [c]The yield of 2 was evaluated by 1H NMR analysis after treatment with ClSO3H (50 lL) in iPrNO2 (2 mL) at 2788C for 4 h. [d]The enantiomeric excess of 2 was determined by chiral HPLC analysis.
presence of a nucleophile (30 mol %) in CH2Cl2 (Table 1). The reaction gave the desired trans-fused AB-ring product 2a, together with endo- and exo-isomeric A-ring products 3a (2a:3a 5 ca. 7:3). The trans-substituted A-ring products and cis-fused AB-ring product were not obtained. Since treatment of the mixture of 2a and 3a with ClSO3H gave 2a as a single trans-fused diastereomer,[5f ] the yield of 2a was evaluated after the subsequent diastereoselective cyclization. As a result, trivalent phosphorus compounds such as PBu3, PPh3 and P(OPh)3 showed good catalytic activity. In contrast, nucleophilic amines such as DABCO and DMAP were completely inert (data not shown). Based on these results, we next designed chiral nucleophiles to promote the enantioselective iodocyclization of 1 with NIS (Table 1). Commercially available chiral phosphora-
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midite 4 showed high activity in CH2Cl2, although the obtained 2a was racemic (entry 6). The use of toluene as solvent decreased the yield of 2a (11%) with no enantioselectivity (entry 7). Intensive study toward the design of a chiral nucleophile revealed that the introduction of a triphenylsilyl group at the 3- and 30 -positions of the chiral phosphoramidite and the use of toluene as solvent resulted in extremely high enantioselectivity (95% ee, 3S enantiomer), although the yield of 2a was moderate (57%) (entry 9). The absolute configuration of the obtained 2a was determined to be (3S,5R,10S) by chiral HPLC analysis after conversion to the known deiodinated compound[5b] by treatment with Bu3SnH (2 equiv) and AIBN (1 mol %) in toluene at 908C. The efficient chiral environment would be created by the bulky 3,30 -triphenylsilyl groups around the nucleophilic phosphorus atom. Although chiral nucleophile 5 could, in principle, catalytically promote the enantioselective iodocyclization of 1, a stoichiometric amount of 5 was required for the efficient promotion of iodocyclization. We propose here a mechanism for the enantioselective iodocyclization of 1 (Scheme 3). The catalytic cycle would involve the reaction of 5 with NIS to give iodophosphonium salt 6 as an active species. Electrophilic iodination of the terminal double bond of 1 followed by cyclization gives the desired product 2a and succinimide. The solvent effect in the iodocyclization might be ascribed to the nature of the iodophosphonium salt generated from 5 and NIS (Scheme 3). In CH2Cl2, the iodophosphonium salt would be a loose ionic species (more active species 6a) and the highly ionic nature might result in the high activity of 5. Free rotation of the P–N bond might lead to a flexible conformation of the 1-phenethylamino moiety in 6a, which would result in no enantioselectivity in CH2Cl2. On the other hand, in the less polar toluene, the iodophosphonium salt would be a tight ion pair (less active species 6b). The succinimide anion might form a hydrogen bond with the proton of the NH group in active species 6b to fix the conformational flexibility of the 1-phenethylamino moiety. The less ionic nature might result in the low activity of 5 and the fixed conformation might lead to high enantioselectivity in toluene. When the 5-promoted iodocyclization of 1 with NIS was conducted in toluene in the presence of one equivalent of DMF or 1-ethyl-3methylimidazolium triflate, the enantioselectivity was significantly decreased, although the yield of 2a was improved (82% yield, 7% ee and 84% yield, 0% ee, respectively). These additives should act as polar solvents to make the active species highly ionic, which would result in the high reactivity and poor enantioselectivity in toluene. The following mechanism is proposed to explain the absolute stereopreference in the 5-promoted iodocyclization of 1 (Figure 1). Structure A is the Newman projection of the tight ion-pair species 6b viewed along the I–P bond. Compound 1
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Scheme 3. Proposed mechanism for enantioselective iodocyclization.
should approach the iodine of A with the terminal dimethyl group away from the triphenylsilyl group, avoiding their steric hindrance. As shown in structure B, the Si face of the terminal isobutenyl group of 1 would preferentially react with 6b, while the reaction at the Re face would be disfavored because of steric hindrance between the dimethyl group and the N-(1-phenethyl)amino group (structure C). The present method could also be applied to 3-(homogeranyl)toluene, 4-(homogeranyl)anisole and 4-(homofarnesyl)toluene (Scheme 4). The reactions of 3-(homogeranyl)toluene and 4-(homogeranyl)anisole gave the corresponding products as single diastereomers with high enantioselectivities (91% ee). The reaction of 4-(homofarnesyl)toluene gave the desired iodinated tetracyclic compound as a major product along with a byproduct (dr 94:6) with almost complete enantioselectivity (99% ee). Enantioselective bromo- and chlorocyclizations are highly valuable since many marine natural products contain bromo and/or chloro substituents. Unfortunately, however, bromocyclization of 1 with NBS gave poor enantioselectivity, and chlorocyclization with NCS did not give any chlorinated prod-
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ucts. For the chemical synthesis of brominated and chlorinated products with high enantioselectivity, the transhalogenation of 2a was quite effective (Scheme 5). Lithiation of 2a followed by bromination with BrCF2CF2Br gave the corresponding brominated compound 2b in 85% yield. The use of ClCF2CF2Cl as a chlorination reagent gave the chlorinated compound 2c in 70% yield. 2.2. Enantioselective Iodolactonization of 4-Substituted Pent-4-enoic Acids[17] Enantioselective halolactonization is one of the most useful methods for the asymmetric functionalization of alkenes. Various chiral organocatalysts have been reported for enantioselective halolactonizations since 2010. Therefore, we also investigated the enantioselective iodolactonization of unsaturated carboxylic acids based on our study of asymmetric iodocyclization promoted by monofunctional Lewis bases. Our initial investigation of the catalytic activities of various achiral Lewis bases gave fundamental information on
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Fig. 1. Proposed explanation for the absolute stereopreference.
nucleophilic base catalysis in the iodolactonization of unsaturated carboxylic acids. When the reaction of 4-benzylpent-4enoic acid was conducted with NIS (1.1 equiv), phosphorus(III) compounds (30 mol %) such as triphenyl phosphite, tri(isopropyl) phosphite and triphenylphosphine showed good
catalytic activities (Table 2, entries 1–3). In sharp contrast, pentavalent triphenyl phosphate and thiophosphate were almost inert under the same conditions (entries 4 and 5). Very
Scheme 5. Transhalogenation of 2a.
Table 2. Catalytic activities of achiral bases in the iodolactonization of 4-benzylpent-4-enoic acid.[a]
Entry
Yield [%][b]
Catalyst I1 5
NIS[c]
I2[d]
NIS 1 I2[e]
1 P(OPh)3 60 0 81 2 P(OiPr)3 55 — 85 63 — 80 3 PPh3 4 O 5 P(OPh)3 0 18 100 5 S 5 P(OPh)3 3 — 100 .......................................................................................................... 6 none 1 0 37 [a]
Scheme 4. Enantioselective iodocyclization of 3-(homogeranyl)toluene, 4(homogeranyl)anisole and 4-(homofarnesyl)toluene.
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The reaction of 4-benzylpent-4-enoic acid (0.1 mmol) was conducted in the presence of a catalyst (30 mol %) in toluene (1 mL) at 2408C for 4 h. [b]Determined by 1H NMR analysis. [c]Yield when the reaction was conducted with NIS (1.1 equiv) for 4 h. [d]Yield when the reaction was conducted with I2 (1.1 equiv) for 4 h. [e]Yield when the reaction was conducted with NIS (1.1 equiv) and I2 (1.1 equiv) for 1 h.
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surprisingly, the catalytic activities of triphenyl phosphate and thiophosphate,[18] which are less nucleophilic than trivalent phosphorus compounds, remarkably increased when NIS and I2 (1.1 equiv each) were used together as iodinating reagents.[8a,d,f ] A complex of NIS and I2 might be generated from NIS and I2 as a highly active iodinating reagent, since the combined use of NIS and I2 in the absence of any catalyst gave the corresponding iodolactone in 37% yield (entry 6). Based on these results, we next designed chiral phosphate catalysts for enantioselective iodolactonization. As a result, we found that chiral phosphate 7 showed high catalytic activity and high enantioselectivity for the reaction of 4-benzylpent-4enoic acid (Scheme 6). When N-chlorophthalimide (NCP) was used as the activator of I2, instead of NIS, the enantioselectivity was improved (92% ee).[19] Very interestingly, in the presence of 1.5 equivalents of NCP, only 0.5 equivalents of I2 sufficiently promoted the reaction to give the corresponding
Scheme 6. Chiral phosphate-catalyzed iodolactonization of 4-benzylpent-4enoic acid.
iodolactone in high yield and with high enantioselectivity (95%, 93% ee). These experimental results indicated that NCP acted as not only the activator but also the oxidant of I2. The fact that NCP was consumed during the reaction to generate phthalimide also supported this notion. The absolute configuration of the obtained iodolactone was determined to be R by comparison of the specific rotation after conversion to known 5-benzyl-5-(hydroxymethyl)dihydrofuran-2(3H)-one ((i) KOH, THF–H2O; (ii) 1 M aq. HCl).[20] A proposed mechanism for the 7-catalyzed iodolactonization is shown in Scheme 7. Lewis acidic NCP might activate I2 through halogen-bonding interactions to form the active iodinating reagent 8. The generation of 8 is supported by Raman spectra of a mixture of NCP and I2 in toluene (observed at 114 cm21). The reaction of chiral phosphate 7 with 8 would give chiral iodoxyphosphonium salt 9 as an active species for iodolactonization. This step generates ICl, a highly active iodinating reagent. This is why the use of 0.5 equivalents of I2 was sufficient to complete the iodolactonization. Enantioselective electrophilic iodination of the double bond of 4-benzylpent-4enoic acid with 9 followed by lactonization gave the desired (R)-iodolactone. The present method could be applied to various 4-(arylmethyl)pent-4-enoic acids to give the corresponding iodolactones with high enantioselectivity within a short reaction time (Scheme 8). In addition, 4-(cyclohexylmethyl)- and 4isobutyl-substituted substrates were successfully converted to the corresponding iodolactones with high enantioselectivity. However, the introduction of a 2-fluoro substituent to the benzyl group significantly decreased the enantioselectivity. The reactions of phenyl- and n-octyl-substituted substrates also
Scheme 7. Proposed mechanism of iodolactonization.
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Scheme 8. Enantioselective iodolactonization of 4-substituted 4-pentenoic acids.
fact, based on our preliminary experiments, when the reaction of 4-(homogeranyl)toluene (1) with BDSB (1.0 equiv) was conducted at 2258C, the corresponding bromocyclization product 2b was obtained in 68% yield. As described above, we have developed a chiral monofunctional Lewis base promoted iodocyclization of homogeranyl- and homofarnesylarenes and an iodolactonization of 4substituted 4-pentenoic acids.[16,17] For example, P(OPh)3 (30 mol %) successfully catalyzed the reaction of 1 with NIS (1.1 equiv) to give a mixture of 2a and 3a (X 5 I) in 80% yield, along with less than 1% yield of byproducts (Scheme 9). On the other hand, bromocyclization with NBS under the same reaction conditions gave only 10% yield of 2b and 3b (X 5 Br), along with significant amounts of dibromide 10b (X 5 Br, 13% yield) and an unknown byproduct (ca. 2% yield). The design of new catalysts is needed for selective promotion of bromocyclization of homogeranylarenes. This chapter summarizes our studies on the design of Lewis base–Brønsted acid cooperative catalysts for regio- and diastereoselective bromocyclizations. 3.1. Design of an Acid–Base Combination Catalyst for the Bromocyclization of Homogeranylarenes[22]
Scheme 9. P(OPh)3-catalyzed halocyclization of 4-homogeranyltoluene (1).
showed poor enantioselectivity, although the reactivity was good.
3. Selective Bromocyclization While many marine natural compounds contain bromine atoms,[1] iodine-containing natural compounds are rare. The development of a regio- and diastereoselective bromoniuminduced polyene cyclization is very important for the synthesis of these bromine-containing cyclic natural compounds. In 2009, Snyder and colleagues reported bromodiethylsulfonium bromopentachloroantimonate (Et2SBrSbCl5Br, BDSB) as a highly active electrophilic bromination reagent.[21] The use of BDSB gives the bromocyclization products in high yields. In
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A proposed mechanism for the triaryl phosphite catalyzed bromocyclization of 1 and the generation of undesired dibromide 10b is shown in Scheme 10. Nucleophilic activation of NBS by the triaryl phosphite catalyst gives bromophosphonium salt 11 as an active species. Regioselective bromination of the terminal double bond of 1 with 11 followed by cyclization gives the desired AB-ring product 2b and the isomeric mixture of Aring products 3b. In another pathway, phosphonium bromide 12 might be generated[23] through the nucleophilic attack of succinimide anion on the bromophosphonium cation in 11. The bromide anion of 12 may be responsible for the generation of dibromide 10b. For successful promotion of the bromocyclization of 1, it is critical to suppress the generation of phosphonium bromide 12 via the design of new Lewis base catalysts. An investigation of the catalytic activities of various phosphorus(III) compounds for the bromocyclization of 1 with NBS showed that the use of triaryl phosphites bearing electron-withdrawing substituents such as P(OC6H4-4-F)3 and P(OC6H4-4-CF3)3 gave moderate yields of 2b and 3b, although the generation of dibromide 10b could not be suppressed (Table 3, entries 1 and 2). It is conceivable that the electron-withdrawing groups on these phosphites increased the reactivity of the corresponding bromophosphonium salt 11 to promote the reaction with 1. Further investigation of the catalytic activities of various triaryl phosphites revealed that the introduction of a urea group at the para position of the catalyst (14a and 14b in Table
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Scheme 10. Proposed mechanism for the bromocyclization of 1 and the generation of dibromide 10b.
3)[24] successfully suppressed the generation of dibromide 10b (
