2015 Volume 63 Issue 8 Pages 565-572
This review summarizes the efforts to develop a radical-mediated three-component reaction and its application to a convergent approach to synthesize the 5/7/6-tricyclic framework (ABC-rings) of the densely functionalized dephnane diterpene, resiniferatoxin. The α-alkoxy bridgehead radical species, which was designed as the radical donor of the three-component reaction, was generated from O,Se- and O,Te-acetals under two different conditions. The generated α-alkoxy bridgehead radical effectively underwent the three-component reaction with α,β-unsaturated ketones and allyltributyltin/aldehyde under each of the conditions, giving rise to a wide variety of multiply functionalized 2,3-trans disubstituted cyclopentenone moieties. One of the established reactions was utilized as the key assembling reaction of the ABC-tricyclic framework of resiniferatoxin. The reaction of the bridgehead radical of the highly functionalized 6-membered C-ring, the 5-membered A-ring, and an allyltributyltin derivative effectively produced the C4-branched AC-rings. The last B-ring was constructed from the coupling adduct in two steps through the 7-endo cyclization, delivering the tricyclic framework possessing the correct C8 and 9-stereocenters of resiniferatoxin. The present methods demonstrate the power of the three-component reaction using an α-alkoxy bridgehead radical in a convergent approach to the complex architectures of daphnane diterpenes.
The plant families Euphorbiaceae and Thymelaeaceae are rich sources of bioactive diterpenes.1–3) Daphnane is a major class of diterpenes and has received considerable attention due to its important pharmacological activity.4–6) Resiniferatoxin (1, Fig. 1), a representative daphnane diterpene, is the irritant in the latex of Euphorbia resinifera.7,8) A detailed biological study revealed that 1 is a potent activator of the ion channel, transient receptor potential vanilloid 1, in the plasma membrane of sensory neurons.9,10) The strong analgesic property of 1 caused by desensitization of nociceptive neurons offers 1 as a potential therapeutic agent. Two other daphnanes, daphnetoxin11,12) and trigohownin A,13) have more highly oxidized carbon frameworks and a phenyl orthoester and display different bio-functions: daphnetoxin is a human immunodeficiency virus (HIV) inhibitor while trigohownin A exhibits cytotoxic activity. The broad spectrum of bioactivity exhibited by daphnanes is attributed to the diverse pattern of oxygen functional groups on the trans-fused 5/7/6-membered tricarbocycle (ABC-rings) and two types of orthoester (C9,13,14- or C9,12,14-orthoester) decorated with a variety of substituents.
The benefical pharmacological effects coupled with the intriguingly complex architectures of daphnanes have spurred intense interest in the chemical community.14,15) From a synthetic standpoint, the ABC-tricyclic system comprising a number of contiguous stereocenters and the extraordinary orthoesters8,16,17) are appealing for devising synthetic strategies. However, the successful total synthesis of daphnanes has been limited to reports from Wender’s group,18,19) despite extensive synthetic efforts by other research groups.20–36) We also have been inspired by the formidable structures of daphnanes to launch a synthetic study of 1 as the initial target. This review summarizes our effort to develop a key radical-mediated three-component reaction and its application to the convergent assembly of the tricyclic ABC-ring system of 1.
The over 120 species of daphnane diterpenes in nature provided us insights into employing a convergent strategy toward the total synthesis of resiniferatoxin (1). In general, a convergent approach to a target natural product is advantageous compared to a linear approach in the sense that the number of linear steps from a starting material to the natural product is minimized, and the diverse structures of the target natural product are accessible by coupling differently functionalized fragments.40) Accordingly, the incorporation of functionalized fragments into the ABC-tricyclic framework of 1 would be an expedient approach to the unified total synthesis of daphnanes. However, there are few C–C bond forming reactions that do not harm labile functional groups. From this perspective, development of a powerful and reliable methodology for fragment coupling was the initial challenge.
We focused on a coupling method comprising the three-component reaction of an α-alkoxy bridgehead radical species, cyclic α,β-unsaturated ketone, and allyltributyltin/aldehyde. The advantage of a radical-mediated C–C bond formation for fragment coupling is the high reactivity of the radical species, enabling the formation of congested C–C bonds, and orthogonality to polar functional groups.41–43) In addition, an α-alkoxy bridgehead radical is spatially exposed and thus reactive, and the stereocenter is fixed by the cage structure throughout the reaction.44–52) We postulated that a three-component reaction using an α-alkoxy bridgehead radical species would allow convergent assembly of the multiply oxygenated polycyclic structure of 1.53,54)
Our study started with the synthesis of two precursors of the α-alkoxy bridgehead radical species and investigation of the reactivity of the radical using a simple orthoester model of resiniferatoxin (1, Chart 1). Condensation of carboxylic acid 2 with 2-mercaptopyridine N-oxide 3 using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) yielded Barton ester 4,55–57) which was in situ photo-irradiated with (PhSe)2 and (PhTe)2 to afford O,Se- and O,Te-acetals 5ab, respectively. Treatment of 5a with V-40 (0.4 eq) and n-Bu3SnH (6 eq) in refluxing toluene induced homolytic cleavage of the C–Se bond to generate α-alkoxy bridgehead radical 7. The radical 7 underwent coupling with cyclopentenone 6a (5 eq), producing adduct 8a in 77% yield. The C–Se bond of 5a was inert upon treatment with Et3B (3 eq)/O2 at 0°C,58,59) and 5a was quantitatively recovered. In contrast, the C–Te bond of 5b was effectively cleaved using the above Et3B/O2 system to generate bridgehead radical 7, which reacted with 6a (3 eq) at 0°C to afford 8a in 85% yield.60,61) It is noteworthy that two different methods generated the same α-alkoxy bridgehead radical species 7, which linked the two oxygenated 5 and 6-membered carbocycles under each of the conditions to furnish 8a.
The distinctive behavior between O,Se- and O,Te-acetals as radical donors led us to plan two types of three component reactions from orthoesters 5a and 5b (Chart 2A). Homolytic cleavage of the C–Se bond of 5a with stannyl radical (Y=n-Bu3Sn) would generate radical 7, which was to react with cyclic α,β-unsaturated ketone 6, resulting in the formation of 2,3-trans-disubstituted cyclic ketone 11 after introduction of the R1 group of 10 to 9. We anticipated that the nature of the radical species would define the multiple reaction process. Specifically, nucleophilic radical 7 assisted by the α-oxygen would preferentially react with the electron-deficient cyclic olefin of 6. The generated electrophilic radical at the α-position of ketone 9 would capture the electron-rich tin reagent to form three-component adduct 11 and release stannyl radical, which should cleave the C–Se bond. Alternatively, ethyl radical (Y=Et), which is derived from Et3B and O2, can cleave the C–Te bond of 5b to produce bridgehead radical 7. After the addition of the bridgehead radical 7 to 6, the resultant radical 9 was expected to be converted to anionic intermediate 12 in the presence of Et3B.62) The crossover mechanism would lead to the next aldol reaction of the boron enolate 12 with aldehyde 13 to deliver 2,3-trans-disubstituted cyclic ketone 14 with one more oxygen functional group than 11.63–65) By applying these methods, we anticipated that the two different coupling products 11 and 14, possessing AC-rings with the C9-tetra and C10-trisubstituted carbons of 1, would be accessible (Chart 2B).
First, O,Se-acetal 5a was subjected to the two-component reaction with cyclic α,β-unsaturated ketones to form linkages between two carbocyclic structures (Table 1). In the reactions, a syringe pump was used to slowly add n-Bu3SnH (10a, 6 eq) and V-40 (0.4 eq) to the refluxing toluene solution and suppress the reduction of bridgehead radical 7 with excess n-Bu3SnH. As with cyclopentenone 6a in Chart 1, cyclohexenone 6b, cycloheptenone 6c, and cyclooctenone 6d were attached to the bridgehead position to afford 8b, c, and d in 56%, 26%, and 45% yields, respectively (entries 1–3). The reaction of 5a with cyclopentenone 6e possessing a tert-butyldimethylsilyl (TBS)-oxy group produced 8e as a single diastereoisomer by addition from the opposite face of the functional group (entry 4).
 | |||
|---|---|---|---|
| Entry | Radical acceptor | Product | Yield |
| 1 |  |  | 56% |
| 2 |  |  | 26% |
| 3 |  |  | 45% |
| 4 |  |  | 65%b) |
a) Reaction conditions: 5a (1 eq), 6 (5 eq), 10a (6 eq), V-40 (0.4 eq), toluene (0.02 M), 110°C. 10a and V-40 (0.2 eq) were added by syringe pump over 3 h, and the reaction mixture was stirred for an additional 1 h. b) Compound 8e was obtained as a single diastereoisomer.
The two-component radical reaction was extended to the three-component reaction (Table 2). Treatment of 5a with cyclopentenone 6a/cyclohexenone 6b, allyltributyltin 10b, and V-40 in toluene at 110°C produced 2,3-trans-disubstituted cycloalkanone 11a/11b as the single diastereomer (entries 1/2). In the coupling using 6e as the radical acceptor, 2,3-trans-3,4-trans-trisubstituted cyclopentanone 11c was exclusively produced in 77% yield (entry 3).
 | ||||
|---|---|---|---|---|
| Entry | Radical acceptor | Allyltributyltin | Product | Yieldb) |
| 1 |  |  |  | 75% |
| 2 |  | |  | 32%c) |
| 3 |  | |  | 77% |
a) Reaction conditions: 5a (1 eq), 6 (5 eq), 10b (6 eq), V-40 (0.4 eq), toluene (0.2 M), 110°C, 8 h. b) Product was obtained as a single diastereoisomer. c) Compoud 5a was recovered in 15% yield.
The success of the three-component reaction using O,Se-acetal 5a led us to turn to the other challenge of using O,Te-acetal 5b (Table 3). The three-component reaction of O,Te-acetal 5b, cyclopentenone 6a, and aldehyde 13a/b/c was initiated using the Et3B/O2 system at 0°C, producing 14a/b/c as the sole stereoisomer (entries 1/2/3). Bulky aliphatic aldehydes 13d and e were applicable to the coupling as trapping reagents for the boron enolate to afford 14d and e, respectively (entries 4, 5). Although α,β-unsaturated aldehydes 13f and g could potentially serve as acceptors of the bridgehead radical, the compounds were found to react as electrophiles with the boron enolate (entries 6, 7). Specifically, bridgehead radical 7 underwent the first radical addition to α,β-unsaturated ketone 6a in the presence of 13f/g, and the second aldol reaction occurred between the resultant boron enolate and the aldehyde, leading to the formation of 14f/g. The scope of the coupling method was expanded to synthesize 2,3-trans-disubstituted cyclopentenones with a higher oxidation level. Specifically, cyclopentenones 6e and f were utilized as the acceptors of bridgehead radical 7, producing 14h and i, respectively, after the aldol reaction with benzealdehyde 13a (entries 8, 9). Importantly, all of the aldol reactions stereoselectively generated the configurations of the secondary hydroxy groups in 14. The chair-like transition state 12′ can explain the stereoselective approach of the aldehydes to the enolates by avoiding the interaction with the bulky trioxaadamantane orthoester66–70) (Fig. 2).
 | ||||
|---|---|---|---|---|
| Entry | Radical acceptor | Electrophile | Product | Yieldb) |
 |  |  | ||
| 1 | 6a | 13a: R2=Ph | 14a: R2=Ph | 89%c) |
| 2d) | 6a | 13b: R2=Me | 14b: R2=Me | 86% |
| 3 | 6a | 13c: R2=n-C6H13 | 14c: R2=C6H13 | 77% |
| 4 | 6a | 13d: R2=cyclohexyl | 14d: R2=cyclohexyl | 99% |
| 5e) | 6a | 13e: R2=t-Bu | 14e: R2=t-Bu | 74% |
| 6f) | 6a | 13f: R2=(E)-CH=CHMe | 14f: R2=(E)-CH=CHMe | 41% |
| 7g) | 6a | 13g: R2=CH=CMe2 | 14g: R2=CH=CMe2 | 76% |
 |  |  | ||
| 8 | 6e: X=OTBS | 13a | 14h: X=OTBS | 86% |
| Y=H | Y=H | |||
| 9e) | 6f: X=H | 13a | 14i: X=H | 87% |
| Y=OAc | Y=OAc | |||
a) Reaction conditions: 5b (1 eq), 6 (3 eq), 13 (3 eq), Et3B (3 eq), CH2Cl2 (0.1 M), 0°C, 15 min. b) Product was obtained as a single isomer. c) 14a was obtained as the major isomer (dr=9 : 1). d) Ten equivalents of 13b was used. e) Conditions: 5b (1 eq), 6a (2 eq), 13e (5 eq), Et3B (3 eq), CH2Cl2 (0.1 M), rt, 60 min. f) Two equivalents of 6a was used. g) Conditions: 5b (1 eq), 6a (2 eq), 13g (5 eq), Et3B (3 eq), CH2Cl2 (0.1 M), 0°C, 15 min.
We demonstrated that the radical-mediated three-component reactions effectively incorporated the two carbocycles and a carbon chain into the multiply functionalized compounds. Thus, we planned to integrate the three-component reaction as a key assembling reaction of the A- and C-rings of resiniferatoxin (1). In planning the route to the ABC-tricyclic framework from the three-component adduct, we adopted the other radical reaction as the B-ring cyclization process. The convergent approach to 1 was planned on the basis of the two radical reactions (Chart 3). Tricarbocycle 15 was designed as the advance intermediate toward 1 before adjusting the C10-stereochemistry and installing the C4-hydroxy, orthoester, and vanillyl ester groups. In turn, retrosynthetic disconnection of the C7–8 bond of 15 provided the AC-ring 16 possessing the C8-xanthate. The C8-xanthate was to be utilized as a precursor of the C8-radical, which would undergo B-ring formation by 7-endo cyclization. The C4-substituted AC-ring 17 could be accessible by application of the key three-component reaction: the reaction of α-alkoxy bridgehead radical derived from 18, 5-membered A-ring 6e, and branched allyltributyltin 10c should assemble the requisite carbon structure for the ABC-tricyclic framework. In this reaction, the pre-installed C9-stereocenter as O,Se-acetal was to be transferred onto the C9-tetrasubstituted carbon of 1 in a stereospecific manner, while the C10-configuration would be transferred from that of the TBS-oxy group in A-ring 6e. The C-ring 18, the precursor of the key α-alkoxy bridgehead radical species, possessed the complex cyclohexane structure decorated with the five contiguous stereocenters (C8, 9, 11, 13, 14), along with the bridgehead O,Se-acetal and the caged orthoester structures. Toward the synthesis of C-ring 18, we selected lactol 1972,73) as the starting material from which a series of stereoselective transformations and optimization of the order of functionalization would be implemented.
With the designed C-ring 18 in hand, we began the assembly of the 5/7/6-tricyclic framework with the three-component reaction of the three fragments (18, 6e, and 10c, Chart 5). Under reflux in chlorobenzene in the presence of V-40 (0.5 eq), the bridgehead radical 38, which was generated from 18, stereoselectively reacted with the double bond of 6ea (5 eq) from the opposite side of the C1-TBS-oxy group. The resultant α-carbonyl radical then captured branched allyltributyltin 10c (5 eq), giving rise to adduct 17a with the correct C9 and C10-stereocenters of resiniferatoxin (1). Saponification of the acetate of 17a concomitantly eliminated TBSOH to afford 39a in 27% yield over 2 steps. Although the three-component reaction resulted in a low yield of the desired product, the efficiency of the coupling was improved by using the other C1-isomer of the A-ring 6eb that served as the more effective acceptor of the bridgehead radical 38. Specifically, subjection of three fragments, 18, 6eb and 10c, to the above conditions gave rise to 17b in higher yield. The thus obtained 17b was saponified, giving rise to 39b in 56% overall yield from 18. Importantly, the present three-component reaction realized the attachment of the C4-substituted 5-membered A-ring to the highly oxygenated C-ring and the stereospecific construction of the C9-tetrasubstituted carbon, without touching any of the acid- and base-sensitive functional groups.
The 7-membered B-ring was constructed in 2 steps from 39b. First, the C8 hydroxy group of 39b was converted into xanthate 16.76,77) The obtained xanthate 16 was treated with n-Bu3SnH and V-40 in xylene at 180°C under microwave irradiation to trigger the generation of the C8-radical 40. The subsequent addition of the radical to the C6–7 olefin in the 7-endo manner led to the formation of the tricyclic compound 41 as the single product. Of note, the other two double bonds (C1–2 and C15–16) in 40 did not participate in the radical reaction. Furthermore, the radical cyclization installed the correct C8-configuration of 1. This outcome would arise from the selective approach of the C6–7 double bond to the C8 radical from the α-face outside of the cyclohexane to avoid steric interaction with H11/H12. Overall, 5-step transformation from C-ring 18 constructed the 5/7/6-tricarbocyclic structure with establishment of the correct C8 and C9-stereocenters of 1. Finally, the tert-butyldiphenylsilyl (TBDPS) group was removed with HF∙pyridine, giving rise to 15 as a potential intermediate of resiniferatoxin (1).
Radical-mediated three-component reactions and a convergent approach to the ABC-tricyclic framework of resiniferatoxin (1) were developed. An α-alkoxy bridgehead radical species was designed as the radical donor and was generated from O,Se- or O,Te-acetals by two different protocols. Stannyl radical was utilized to generate the α-alkoxy bridgehead radical from O,Se-acetal 5a, which underwent coupling with cyclic α,β-unsaturated ketones 6 and allyltributyltin 10b via two radical reactions. Three-component reaction by the radical/polar crossover mechanism was pursued by using O,Te-acetal 5b, cyclic α,β-unsaturated ketones 6, and aldehyde 13 employing the Et3B/O2 system. In both methods, the multiple reaction process and the stereoselectivity were effectively controlled, leading to the formation of functionalized 2,3-trans-disubstituted cyclopentenones 11 and 14. One of the established methods was applied to the convergent assembly of the ABC-tricyclic framework of resiniferatoxin (1). The three-component reaction of the bridgehead radical of the highly functionalized C-ring, 5-membered A-ring 6eb, and allyltributyltin 10c produced the C4-branched AC-ring structure as the single product. The 7-membered B-ring was constructed by the radical reaction: the 7-endo cyclization of xanthate 16 constructed the tricyclic framework possessing the correct C8 and C9-stereocenters of 1. The present study demonstrated the power of the three-component reaction using an α-alkoxy bridgehead radical in constructing the fused carbocycles of the complex diterpenes. Further study towards the total synthesis of resiniferatoxin (1) from the synthesized 15 is underway in our laboratory.
I express my profound gratitude to Prof. Masayuki Inoue at the University of Tokyo for his direction, continuous support, and encouragement. I sincerely thank my highly talented co-workers whose names appear in the reference section of this review. The work described in this review was financially supported by a Grant-in-Aid for Start-up, Young Scientists (B) and Scientific Research (C) from the JSPS, and a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.
The author declares no conflict of interest.
