Total Synthesis of (–)-HM-3 and (–)-HM-4 Utilizing a Palladium-Catalyzed Addition of an Arylboronic Acid to an Allenic Alcohol Followed by Eschenmoser–Claisen Rearrangement

Abstract

The first asymmetric total synthesis of (–)-HM-3 and (–)-HM-4, aromatic sesquiterpenes isolated from the phytopathogenic fungus Helicobasidium mompa, has been achieved. Highlight of the synthesis is an enantiospecific construction of the quaternary carbon stereocenter utilizing a palladium-catalyzed addition of arylboronic acid to the allenic alcohol followed by Eschenmoser–Claisen rearrangement.

(–)-HM-3 (1) and (–)-HM-4 (2) are aromatic sesquiterpenes that were isolated from the phytopathogenic fungus Helicobasidium mompa by Takahashi and Nohara in 1989.[1] The structure of (–)-HM-3 was originally proposed as 1′, which was revised to 1 based upon comparison with a synthetic compound by Srikrishna in 2006 (Figure [1]).[2] Because of the sterically congested structure of 1 and 2 which contain a quaternary carbon stereocenter at the benzylic position, considerable synthetic interest has been stimulated.

We have previously reported a palladium-catalyzed addition of arylboronic acids to allenic alcohols, in which aryl-substituted allylic alcohols having an E geometry were produced in regio- and stereoselective manner.[3] In addition, a quaternary carbon stereocenter can be created stereospecifically by the Claisen-type rearrangement of the resulting allylic alcohol (Scheme [1]).[4] Since this methodology is useful for the synthesis of natural products having a quaternary carbon stereocenter at the benzylic position,[5] we planned to apply it for the synthesis of (–)-HM-3 (1) and (–)-HM-4 (2). Herein, we report the first asymmetric total synthesis of 1 and 2, utilizing a palladium-catalyzed addition of an arylboronic acid to an allene followed by Eschenmoser–Claisen rearrangement.

Retrosynthetic analysis of (–)-HM-3 (1) and (–)-HM-4 (2) is shown in Scheme [2]. We expected that 1 and 2 could be synthesized from the cyclopentenone 3 via the functional transformation on the cyclopentane ring. Compound 3 would be produced by the construction of a five-membered ring from the amide 4, which may be obtained from the optically active allenic alcohol 5 and the arylboronic acid 6 by a sequential palladium-catalyzed addition–Eschenmoser–Claisen rearrangement.

The key sequence toward the intermediate 4 is outlined in Scheme [3]. When the optically active allenic alcohol 5 [5a] (96% ee) and the arylboronic acid 6 were treated with 5 mol% of [Pd₂(OH)₂(PPh₃)₄][BF₄]₂ [6] and five equivalents of Et₃N in dioxane–H₂O (20:1) at 80 ºC, the desired aryl-substituted allylic alcohol 7 was obtained together with an inseparable unidentified by-product. The resulting mixture of 7 was further subjected to the Eschenmoser–Claisen rearrangement to afford the corresponding amide 4 having a quaternary asymmetric center in 58% yield in two steps. The enantiomeric excess of 4 was determined as 95%, which indicates that a highly enantiospecific [3,3]-sigmatropic rearrangement via the cyclic transition state 8 had proceeded.[7]

The reaction of the amide 4 with MeLi afforded the methyl ketone 9 (81%), which was converted into the ketoaldehyde 10 by the oxidative cleavage of the double bond in 85% yield (Scheme [4]). Then construction of the cyclopentane ring by the intramolecular aldol condensation of 10 using K₂CO₃ was successfully accomplished to produce the cyclopentenone 3 in 96% yield. After α-dimethylation of 3 using NaH and MeI (65%), the resulting product 11 was hydrogenated to give the cyclopentanone 12 in 99% yield.

The final stage of the synthesis involves a reductive deoxygenation of the ketone moiety in 12 (Scheme [5]). In the synthesis of racemic HM-3 and HM-4 by Srikrishna, it was reported that the sequential thioacetalization–reductive desulfurization of 12 successfully proceeded. We initially examined the reactions according to the reported procedure, but this method did not give reproducible yield, unfortunately. After several attempts, it was found that Barton–McCombie radical deoxygenation protocol is more effective in our case. Thus, after the reduction of the ketone 12 with NaBH₄ (91% yield), the Barton–­McCombie deoxygenation for the resulting alcohol 13 afforded the desired product 14 in moderate yield. Cleavage of the methyl ether in 14 by the treatment with BBr₃ provided (–)-HM-4 (2) in 55% yield. Furthermore, (–)-HM-3 (1) was obtained in 81% yield by the regioselective acetylation of 2 using Ac₂O. Spectral data of synthetic (–)-HM-3 (1)[8] and (–)-HM-4 (2)[9] were in good agreement with those derived from the natural products.[10]

In conclusion, the first asymmetric total synthesis of (–)-HM-3 (1) and (–)-HM-4 (2) has been achieved. The key elements of the synthesis include the enantiospecific construction of the quaternary carbon stereocenter using a palladium-catalyzed addition of the arylboronic acid to the optically active allenic alcohol followed by ­Eschenmoser–Claisen rearrangement. Application of this process to the synthesis of other natural products is now in progress.

Acknowledgment

This study was supported in part by a Grant-in-Aid for Scientific Technique Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry from the Ministry of Agriculture, Forestry and Fisheries.

• References and Notes

• 1 Kajimoto T, Yamashita M, Imamura Y, Takahashi K, Nohara T, Shibata M. Chem. Lett. 1989; 18: 527
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• 2 Srikrishna A, Ravikumar PC. Tetrahedron 2006; 62: 9393
  Search in Google Scholar
• 3 Yoshida M, Matsuda K, Shoji Y, Gotou T, Ihara M, Shishido K. Org. Lett. 2008; 10: 5183
  CrossrefSearch in Google Scholar
• 4a Ziegler FE. Chem. Rev. 1988; 88: 1423
  CrossrefSearch in Google Scholar
• 4b Martín Castro AM. Chem. Rev. 2004; 104: 2939
  CrossrefSearch in Google Scholar
• 5a Yoshida M, Shoji Y, Shishido K. Org. Lett. 2009; 11: 1441
  CrossrefPubMedSearch in Google Scholar
• 5b Yoshida M, Shoji Y, Shishido K. Tetrahedron 2010; 66: 5053
  CrossrefSearch in Google Scholar
• 6 Bushnell GW, Dixon KR, Hunter RG, McFarland JJ. Can. J. Chem. 1972; 50: 3694
  CrossrefSearch in Google Scholar
• 7 To a stirred solution of allenic alcohol 5 (200 mg, 1.37 mmol) in dioxane–H₂O (20:1; 13.7 mL) were added arylboronic acid 6 (537 mg, 2.74 mmol), Et₃N (0.95 mL, 6.85 mmol), and [Pd₂(OH)₂(PPh₃)₄][BF₄]₂ (100.6 mg, 0.069 mmol) at r.t. After stirring was continued for 90 min at 80 °C, the reaction mixture was diluted with EtOAc and filtered through a pad of silica gel. The residue upon evaporation of the solvent was chromatographed on silica gel with hexane–EtOAc (95:5) as eluent to give allylic alcohol 7 as a mixture, which was used in the next reaction without further purification. To a stirred solution of allylic alcohol 7 (1.37 mmol) in p-xylene (29.1 mL) was added N,N-dimethyl-acetamide dimethylacetal (2.01 mL, 13.7 mmol) at r.t. After the stirring was continued under reflux conditions for 30 min, the solvent was removed in vacuo. The residue was chromatographed on silica gel with hexane–EtOAc (70:30) as eluent to give amide 4 (289.9 mg, 58% in 2 steps, 95% ee) as a yellow oil; [α]_D ³³ –9.6 (c = 1.00, CHCl₃). IR (KBr): 3023, 2936, 1643, 1492, 1458, 1401, 1275, 1052, 1021 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.69 (s, 3 H), 2.24 (s, 3 H), 2.85 (s, 3 H), 2.93 (s, 3 H), 3.04 (d, J = 14.8 Hz, 1 H), 3.10 (d, J = 14.8 Hz, 1 H), 3.75 (s, 3 H), 3.77 (s, 3 H), 6.25 (d, J = 16.4 Hz, 1 H), 6.82 (d, J = 16.4 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 7.17 (t, J = 7.6 Hz, 1 H), 7.28 (t, J = 7.6 Hz, 2 H), 7.36 (d, J = 7.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 15.6 (Me), 26.4 (Me), 35.4 (Me), 37.7 (Me), 42.4 (CH₂), 42.7 (Cq), 59.3 (Me), 60.0 (Me), 122.5 (CH), 124.7 (CH), 126.0 (CH), 126.0 (CH), 126.8 (CH), 128.4 (CH), 130.9 (Cq), 137.9 (Cq), 138.1 (Cq), 139.8 (CH), 151.6 (Cq), 151.7 (Cq), 171.3 (Cq). HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₃₀NO₃: 368.2226; found: 368.2226. Enantiomeric excess was determined by HPLC analysis [CHIRALCEL AS-H column, 10% isopropanol–hexane, flow rate = 0.3 mL/min, λ = 254 nm, t _R = 24.6 min (S), t _R = 26.6 min (R)].
• 8 Data for 1: mp 137.8–140.5 °C (recrystallized from EtOAc–hexane); [α]_D ²⁹ –33.3 (c = 0.44, CHCl₃). IR (KBr): 3339, 2924, 2361, 1736, 1421, 1373, 1281, 1239, 1191 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.74 (s, 3 H), 1.15 (s, 3 H), 1.40 (s, 3 H), 1.49–1.79 (m, 5 H), 2.11 (s, 3 H), 2.37 (s, 3 H), 2.53–2.61 (s, 1 H), 5.14 (s, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 7.08 (d, J = 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.0 (Me), 20.5 (CH₂), 20.6 (Me), 22.9 (Me), 25.5 (Me), 26.9 (Me), 39.4 (CH₂), 41.2 (CH₂), 44.9 (Cq), 51.3 (Cq), 121.1 (CH), 126.3 (CH), 128.2 (Cq), 133.0 (Cq), 138.0 (Cq), 146.5 (Cq), 168.5 (Cq). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₂₄O₃Na: 299.1623; found: 299.1618.
• 9 Data for 2: mp 104.5–106.9 °C (recrystallized from EtOAc–hexane); [α]_D ³³ –24.6 (c = 0.16, CHCl₃). IR (KBr): 2926, 1715, 1507, 1457, 1373, 1294 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.76 (s, 3 H), 1.18 (s, 3 H), 1.41 (s, 3 H), 1.51–1.80 (m, 5 H), 2.22 (s, 3 H), 2.55–2.64 (m, 1 H), 4.88 (s, 1 H), 5.55 (s, 1 H), 6.59 (d, J = 8.4 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 15.2 (Me), 20.2 (CH₂), 22.9 (Me), 25.3 (Me), 26.7 (Me), 39.2 (CH₂), 40.9 (CH₂), 44.9 (Cq), 51.0 (Cq), 120.6 (CH), 120.8 (CH), 121.1 (Cq), 131.2 (Cq), 142.1 (Cq), 143.1 (Cq). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₂₂O₂Na: 257.1517; found: 257.1516.
• 10 ¹H NMR and ¹³C NMR spectral data of 1 and 2 were in complete agreement with those reported for the natural and synthetic products (ref. 1 and 2). Although the reason is not clear, the optical rotations of our synthetic samples were different from the values reported for the natural products¹ [1: [α]_D −8.1 (CHCl₃); 2: [α]_D −57.4 (CHCl₃)].

• References and Notes

• 1 Kajimoto T, Yamashita M, Imamura Y, Takahashi K, Nohara T, Shibata M. Chem. Lett. 1989; 18: 527
  Search in Google Scholar
• 2 Srikrishna A, Ravikumar PC. Tetrahedron 2006; 62: 9393
  Search in Google Scholar
• 3 Yoshida M, Matsuda K, Shoji Y, Gotou T, Ihara M, Shishido K. Org. Lett. 2008; 10: 5183
  CrossrefSearch in Google Scholar
• 4a Ziegler FE. Chem. Rev. 1988; 88: 1423
  CrossrefSearch in Google Scholar
• 4b Martín Castro AM. Chem. Rev. 2004; 104: 2939
  CrossrefSearch in Google Scholar
• 5a Yoshida M, Shoji Y, Shishido K. Org. Lett. 2009; 11: 1441
  CrossrefPubMedSearch in Google Scholar
• 5b Yoshida M, Shoji Y, Shishido K. Tetrahedron 2010; 66: 5053
  CrossrefSearch in Google Scholar
• 6 Bushnell GW, Dixon KR, Hunter RG, McFarland JJ. Can. J. Chem. 1972; 50: 3694
  CrossrefSearch in Google Scholar
• 7 To a stirred solution of allenic alcohol 5 (200 mg, 1.37 mmol) in dioxane–H₂O (20:1; 13.7 mL) were added arylboronic acid 6 (537 mg, 2.74 mmol), Et₃N (0.95 mL, 6.85 mmol), and [Pd₂(OH)₂(PPh₃)₄][BF₄]₂ (100.6 mg, 0.069 mmol) at r.t. After stirring was continued for 90 min at 80 °C, the reaction mixture was diluted with EtOAc and filtered through a pad of silica gel. The residue upon evaporation of the solvent was chromatographed on silica gel with hexane–EtOAc (95:5) as eluent to give allylic alcohol 7 as a mixture, which was used in the next reaction without further purification. To a stirred solution of allylic alcohol 7 (1.37 mmol) in p-xylene (29.1 mL) was added N,N-dimethyl-acetamide dimethylacetal (2.01 mL, 13.7 mmol) at r.t. After the stirring was continued under reflux conditions for 30 min, the solvent was removed in vacuo. The residue was chromatographed on silica gel with hexane–EtOAc (70:30) as eluent to give amide 4 (289.9 mg, 58% in 2 steps, 95% ee) as a yellow oil; [α]_D ³³ –9.6 (c = 1.00, CHCl₃). IR (KBr): 3023, 2936, 1643, 1492, 1458, 1401, 1275, 1052, 1021 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.69 (s, 3 H), 2.24 (s, 3 H), 2.85 (s, 3 H), 2.93 (s, 3 H), 3.04 (d, J = 14.8 Hz, 1 H), 3.10 (d, J = 14.8 Hz, 1 H), 3.75 (s, 3 H), 3.77 (s, 3 H), 6.25 (d, J = 16.4 Hz, 1 H), 6.82 (d, J = 16.4 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 7.17 (t, J = 7.6 Hz, 1 H), 7.28 (t, J = 7.6 Hz, 2 H), 7.36 (d, J = 7.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 15.6 (Me), 26.4 (Me), 35.4 (Me), 37.7 (Me), 42.4 (CH₂), 42.7 (Cq), 59.3 (Me), 60.0 (Me), 122.5 (CH), 124.7 (CH), 126.0 (CH), 126.0 (CH), 126.8 (CH), 128.4 (CH), 130.9 (Cq), 137.9 (Cq), 138.1 (Cq), 139.8 (CH), 151.6 (Cq), 151.7 (Cq), 171.3 (Cq). HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₃₀NO₃: 368.2226; found: 368.2226. Enantiomeric excess was determined by HPLC analysis [CHIRALCEL AS-H column, 10% isopropanol–hexane, flow rate = 0.3 mL/min, λ = 254 nm, t _R = 24.6 min (S), t _R = 26.6 min (R)].
• 8 Data for 1: mp 137.8–140.5 °C (recrystallized from EtOAc–hexane); [α]_D ²⁹ –33.3 (c = 0.44, CHCl₃). IR (KBr): 3339, 2924, 2361, 1736, 1421, 1373, 1281, 1239, 1191 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.74 (s, 3 H), 1.15 (s, 3 H), 1.40 (s, 3 H), 1.49–1.79 (m, 5 H), 2.11 (s, 3 H), 2.37 (s, 3 H), 2.53–2.61 (s, 1 H), 5.14 (s, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 7.08 (d, J = 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.0 (Me), 20.5 (CH₂), 20.6 (Me), 22.9 (Me), 25.5 (Me), 26.9 (Me), 39.4 (CH₂), 41.2 (CH₂), 44.9 (Cq), 51.3 (Cq), 121.1 (CH), 126.3 (CH), 128.2 (Cq), 133.0 (Cq), 138.0 (Cq), 146.5 (Cq), 168.5 (Cq). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₂₄O₃Na: 299.1623; found: 299.1618.
• 9 Data for 2: mp 104.5–106.9 °C (recrystallized from EtOAc–hexane); [α]_D ³³ –24.6 (c = 0.16, CHCl₃). IR (KBr): 2926, 1715, 1507, 1457, 1373, 1294 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.76 (s, 3 H), 1.18 (s, 3 H), 1.41 (s, 3 H), 1.51–1.80 (m, 5 H), 2.22 (s, 3 H), 2.55–2.64 (m, 1 H), 4.88 (s, 1 H), 5.55 (s, 1 H), 6.59 (d, J = 8.4 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 15.2 (Me), 20.2 (CH₂), 22.9 (Me), 25.3 (Me), 26.7 (Me), 39.2 (CH₂), 40.9 (CH₂), 44.9 (Cq), 51.0 (Cq), 120.6 (CH), 120.8 (CH), 121.1 (Cq), 131.2 (Cq), 142.1 (Cq), 143.1 (Cq). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₂₂O₂Na: 257.1517; found: 257.1516.
• 10 ¹H NMR and ¹³C NMR spectral data of 1 and 2 were in complete agreement with those reported for the natural and synthetic products (ref. 1 and 2). Although the reason is not clear, the optical rotations of our synthetic samples were different from the values reported for the natural products¹ [1: [α]_D −8.1 (CHCl₃); 2: [α]_D −57.4 (CHCl₃)].

• Supplementary Material