Synthesis of (−)‐Cubebol by Face‐Selective Platinum‐, Gold‐, or Copper‐Catalyzed Cycloisomerization: Evidence for Chirality Transfer

Abstract

Facing facts: Control of the configuration of the propargylic center in 1 is essential for the facial selectivity observed in the Pt-, Au-, or Cu-catalyzed enyne cycloisomerization. This route has been used for the stereoselective synthesis of the naturally occurring sesquiterpene (−)-cubebol (2). Herein we describe a direct, stereoselective synthesis of (−)-cubebol,1 based on Pt-,2, 3 Au-,4 and Cu-catalyzed5 enyne cycloisomerizations. (−)-Cubebol (1), 4-epicubebol (2), and α- and β-cubebenes 3 and 4, respectively, are naturally occurring sesquiterpenes, isolated from the berries of Piper cubeba (Scheme 1).1 Whereas 2 has a very bitter taste, the almost odorless (−)-cubebol (1) has a pronounced cooling effect and lends itself to diverse applications in the field of flavors.6 Shortly after the discovery of this new skeleton, a synthesis of the racemic cubebenes 3 and 4 was reported by Piers et al., and a synthesis of 1–4 was reported by Yoshikoshi and co-workers.7 Both syntheses are based on a cyclopropanation of diazoketone 5 (or the analogous isopropenyl compound, Scheme 2). Unfortunately, this route is not diastereoface-selective and affords the desired ketone 6 as the minor isomer in only moderate yield. We realized that a Pt-2, 3 or Au-catalyzed4 cycloisomerization of enynol esters8 would represent a direct and efficient access to cubebol. Constituants of Piper cubeba. Reported and planned synthesis of 6. The key precursors 8 a and 8 b (1:2 diastereomeric mixture) were readily prepared from (+)-(R,R)-tetrahydrocarvone (10) in an overall yield of 55 % (Scheme 3). A Wittig–Horner reaction and saponification afforded the acid 12. Whereas base-catalyzed deconjugation of the ester 11 proved to be unselective, and afforded (Z)-11 and substantial amounts of the isomeric ester with a tetrasubstituted double bond, deprotonation of 12 using excess Li-TMP, followed by protonation of the dianion with 5 % HCl, readily furnished 13. LiAlH4 reduction and Swern oxidation afforded the β,γ-unsaturated aldehyde 15. Addition of ethynyl-MgBr and esterification with pivaloyl chloride produced 8 a and 8 b as a 1:2 diastereomeric mixture. Reagents and conditions: a) trimethyl phosphonoacetate (1.2 equiv), NaH (1.1 equiv), THF, reflux, 15 h; b) KOH (1.7 equiv), EtOH, 60 °C, 24 h; c) BuLi (3.0 equiv), 2,2,6,6-tetramethylpiperidine (TMP, 3.15 equiv), THF, −5 °C, 30 min, then 11, −25 °C to RT, 16 h; then 5 % HCl; d) LiAlH4 (2 mol equiv), Et2O, reflux, 45 min; e) Swern oxidation; f) HCCMgBr (1.2 equiv), THF, 25–28 °C, 45 min; g) PivCl (1.1 equiv), NEt3 (1.2 equiv), DMAP (0.12 equiv), CH2Cl2 0 °C, 2 h. Piv=pivaloyl, DMAP=N,N-dimethylaminopyridine. Chromatographic purification of the alcohols 16 a, b and esterification of the fractions enriched in 16 a or 16 b gave access to the pivalates 8 a, b, enriched in 8 a and 8 b, respectively. These were then submitted separately to the Pt- or Au-catalyzed cycloisomerization reaction (Table 1, entries 1–3). When a mixture of 8 a and 8 b (1:9) was treated with 2 mol % of PtCl2, the expected tricyclic enol pivalates 9 a and 9 b were formed in a ratio of 3:2 in 80 % yield (entry 1), and the Au-catalyzed reaction gave, in a less clean reaction, a 47:53 mixture of 9 a and 9 b (entry 2). In contrast, the reaction of a mixture of 8 a and 8 b (7:3) with PtCl2 afforded mainly the desired 9 a (9 a/9 b=86:14; entry 3). Entry 8 a/8 b Conditions 9 a/9 b Yield [%] 1 10:90 PtCl2 (2 mol %), DCE[a], 70 °C, 9 h 60:40 80 2 10:90 AgSbF6/Ph3PAuCl (2 mol %), CH2Cl2, 20 °C, 40 min 47:53 65 3 70:30 PtCl2 (2 mol %), DCE[a], 70 °C, 9 h 86:14 – 4 88:12 PtCl2 (2 mol %), DCE[a], 70 °C, 9 h 94:6 81 5 98:2 PtCl2 (2 mol %), DCE[a], 70 °C, 9 h 99:1 – 6 98:2 [Cu(CH3CN)4](BF4) (2 mol %), DCE[a], 60 °C, 9 h 99:1 77[b] From the results shown in entries 1 and 3 it was anticipated that 8 a would afford 9 a with an excellent facial selectivity. We therefore addressed the question of a diastereoselective synthesis of 8 a, which was accomplished by a reagent-controlled diastereoselective addition (88:12) of 2-methyl-3-butyn-2-ol to aldehyde 15 using the Zn reagent obtained from (−)-N-methylephedrine (17) and Zn(OTf)2, followed by esterification of a mixture of 18 a and 18 b and base-catalyzed cleavage of the carbinol fragment of 19 a and 19 b, according to the procedure of Carreira and co-workers (Scheme 4).9, 10 The S configuration of the newly formed stereogenic center is in accord with the above-cited work of Carreira and co-workers. A mixture of pivalates 8 a and 8 b (88:12) was used for the cycloisomerization step. Reagents and conditions: a) Zn(OTf)2 (2.0 equiv), 17 (2.1 equiv), NEt3, toluene, RT, 2 h; then 2-methyl-3-butyn-2-ol (2.1 equiv), RT, 15 min; then slow addition of 15 in toluene at RT (15 h + 9 h after introduction); b) PivCl (2.2 equiv), NEt3 (1.1 equiv), DMAP (0.12 equiv), 0 °C to RT, 15 h; c) K2CO3 (1.2 equiv), [18]crown-6 (0.4 + 0.4 equiv), toluene, reflux, 19 h + 5 h; d) see Table 1; e) K2CO3 (1.2 equiv), MeOH, RT, 90 min; f) CeCl3 (2.0 equiv), MeLi (2.0 equiv), THF, −78 °C, 1 h; then 6,−78 °C to RT, 2 h. Indeed, PtCl2-catalyzed cycloisomerization of a mixture of 8 a and 8 b (88:12) afforded 9 a with a 94:6 selectivity (Table 1, entry 4), and chromatographically enriched 8 a (8 a/8 b 98:2) afforded 9 a with excellent facial selectivity (99:1; entry 5). Interestingly, inexpensive [Cu(CH3CN)4](BF4) (2 mol %) also efficiently catalyzed the cycloisomerization (99:1; 77 % yield after 90 % conversion).5 Prolonged reaction times or higher temperatures (70 °C) favored the formation of by-products. Hydrolysis of 9 a afforded the known ketone 6, and diastereoselective (97:3) addition of MeLi/CeCl3 furnished (−)-cubebol in 95 % yield, identical in all respects with an authentic sample.6 The different diastereoface selectivities observed for the cycloisomerizations of 8 a and 8 b prompted us to examine the chirality transfer from the enantioenriched propargyl pivalates 21 and 25, which are readily accessible from the aldehydes 20 and 24.11 Pt- or Cu-catalyzed rearrangement of 21 (95 % ee) afforded 22, which gave, after hydrolysis, ketone 23 with 57–61 % ee (Scheme 5).12 The ee value of 21 and 22 remained unaltered throughout the course of the reaction, as shown by measurements taken after 50 % conversion. Reagents and conditions: a)–c) see Scheme 3 a)–c); [A] DCE, 70 °C, 8 h; [B] toluene, 50 °C, 9 h, 73 % conversion; [C] toluene, 50 °C, 4 h, 50 % conversion; [D] DCE, 70 °C, 90 min; GC yields. Surprisingly, Pt-catalyzed cycloisomerization of 25 (69 % ee) afforded, in addition to the expected rearranged enol pivalate 26 (10–20 % ee, unknown absolute configuration), the isomeric non-rearranged enol pivalate 27 (60–67 % ee, unknown absolute configuration), as evidenced by conversion of 26 and 27 into the ketones 28 and 29, respectively. The Pt- or Au-catalyzed cycloisomerizations of secondary enynol esters are believed to proceed by an initial [1,2] O shift of the metal-complexed acetylene A and subsequent cyclopropanation of the achiral transient vinyl carbene C (pathway (a); Scheme 6).2 On the basis of the chirality transfer we observed, pathway (a) can be dismissed.13 Alternatively, cyclopropanation of the electron-rich olefin with the metal-complexed acetylene A, followed by [1,2]-O-migration of E (pathway (b)),14 the presumed reaction course for the formation of the non-rearranged enol pivalate 27 by a [1,2] H shift of E or F,15 is also not operative for 26, as the rearranged and non-rearranged cycloisomerization products 26 and 27 exhibit different enantiomeric excess values. This leads us to propose a new mechanism for the cycloisomerization with [1,2]-acyl shift (pathway (c)). Intramolecular addition of the ester carbonyl to the metal-complexed acetylene A leads to the vinyl metal species B, followed by nucleophilic attack of the CC double bond to the oxy-allyl system and cyclopropane ring closure in G.16, 17 Proposed mechanism for the cycloisomerizations. In conclusion, we have succeeded in a direct, stereoselective synthesis of (−)-cubebol, based on a Pt-, Au-, or Cu-catalyzed cycloisomerization in which control of the configuration of the propargylic center is essential for the facial selectivity. In addition, complementary cycloisomerization studies of enantioenriched propargyl pivalates suggests that the cyclization occurs on a “half-rearranged” species B (Scheme 6). (−)-6: A solution of 8 a and 8 b (8 a/8 b=88:12; 1.98 g; 6.80 mmol) in 1,2-dichloroethane (30 mL) was treated with PtCl2 (36 mg; 0.136 mmol) and heated for 9 h at 70 °C. The solution was cooled and poured into saturated aqueous NaHCO3. Extraction (Et2O), washing (H2O, then saturated aqueous NaCl), drying (Na2SO4), concentration, and bulb-to-bulb distillation (100–120 °C/0.01 mbar) afforded 1.60 g of 9 a and 9 b (9 a/9 b=94:6; 81 %). A solution of 9 a and 9 b (9 a/9 b=94:6; 1.50 g; 5.17 mmol) in MeOH (25 mL) was treated with K2CO3 (861 mg; 6.24 mmol) and stirred for 90 min at RT. After partial concentration, the product was extracted (Et2O/H2O), washed (H2O, then saturated aqueous NaCl), dried (Na2SO4), concentrated, and bulb-to-bulb distilled (100–125 °C/0.01 mbar) to afford 1.13 g of 6 (86 % pure, 91 %). Purification by chromatography on SiO2 (150 g) with an eluent of cyclohexane/AcOEt (7:3), followed by crystallization in pentane at −78 °C afforded 680 mg of pure 6. M.p. 60–60.5 °C (lit. 58.5–59.5 °C7b),[α] (CHCl3; c=1.30) −20.1 (lit. [α]=−23.9 (isooctane)7b); 1H NMR (400 MHz, CDCl3): δ=0.59 (m, 1 H), 0.90–1.00 (m, 1 H), 0.91 (d, J=7.0 Hz, 3 H), 0.95 (d, J=6.5 Hz, 3 H), 0.99 (d, J=6.0 Hz, 3 H), 1.19 (m, 1 H), 1.27 (t, J=2.5 Hz, 1 H), 1.45–1.52 (m, 2 H), 1.58–1.70 (m, 2 H), 1.78–1.90 (m, 2 H), 1.98–2.21 ppm (m, 3 H); 13C NMR (100 MHz, CDCl3): δ=214.6 (s), 43.4 (d), 40.3 (s), 39.7 (d), 33.3 (t), 33.2 (d), 32.5 (d), 31.3 (d), 30.8 (t), 26.6 (t), 26.0 (t), 19.9 (q), 19.4 (q), 18.9 ppm (q); MS: m/z (%): 206 [M+] (65), 191 (24), 164 (88), 149 (45), 135 (35), 122 (100), 107 (55), 93 (64), 91 (65), 79 (75), 69 (40), 55 (41), 41 (46). 23: [α] (CHCl3; c=0.56) +24.8 (61 % ee by chiral GC18 (major enantiomer: first peak)); 1H NMR (400 MHz, CDCl3): δ=0.92–1.02 (m, 1 H); 0.96 (s, 3 H), 1.09 (s, 3 H), 1.20–1.30 (m, 2 H), 1.35–1.55 (m, 2 H), 1.51 (d, J=2.5 Hz, 1 H), 1.59 (ddd, J=8.0, 2.5, 2.1 Hz, 1 H), 1.80–1.90 (m, 1 H), 1.95–2.12 ppm (m, 4 H); 13C NMR (100 MHz, CDCl3): δ=214.8 (s), 43.2 (s), 41.1 (d), 37.3 (t), 33.2 (t), 29.9 (s), 28.4 (d), 27.9 (q), 24.9 (q), 24.6 (t), 23.3 (t), 18.0 ppm (t); MS: m/z (%): 178 [M+] (26), 163 (9), 136 (16), 135 (16), 121 (30), 110 (100), 107 (25), 93 (28), 91 (22), 79 (33), 69 (40). 28: 12 % ee by chiral GC18 (major enantiomer: first peak); 1H NMR (400 MHz, CDCl3): δ=0.90 (s, 3 H), 0.99 (s, 3 H), 1.00 (s, 3 H), 1.07–1.30 (m, 4 H), 1.34–1.48 (m, 1 H), 1.60–1.70 (m, 2 H), 2.15 (d, J=19.5 Hz, 1 H), 2.24 (d, J=19.5 Hz, 1 H), 2.51 (d, J=19.5 Hz, 1 H), 2.52 ppm (m, 1 H); 13C NMR (100 MHz, CDCl3): δ=220.2 (s), 40.5 (t), 39.5 (t), 37.5 (t), 36.8 (s), 33.8 (t), 30.2 (s), 27.6 (2q), 25.6 (d), 24.4 (s), 18.1 (t); 17.1 ppm (q); MS: m/z (%): 192 [M+] (51), 177 (57), 149 (63), 136 (64), 107 (73), 93 (100), 79 (97), 69 (71), 67 (38), 55 (39), 41 (48). 29: 60 % ee by chiral GC18 (major enantiomer: first peak); 1H NMR (400 MHz, CDCl3): δ=0.95 (s, 3 H), 1.05–1.10 (m, 1 H), 1.06 (s, 3 H), 1.15–1.25 (m, 2 H), 1.19 (s, 3 H), 1.42 (m, 1 H), 1.65 (s, 1 H), 1.65–1.87 (m, 3 H), 1.96–2.04 (m, 1 H), 2.15–2.28 ppm (m, 2 H); 13C NMR (100 MHz, CDCl3): δ=215.9 (s), 49.3 (s), 44.5 (d), 37.8 (2t), 34.2 (t), 31.8 (s), 30.9 (s), 27.6 (q), 26.2 (q), 21.9 (t), 18.8 (q); 18.0 ppm (t); MS: m/z (%): 192 [M+] (43), 177 (27), 150 (58), 136 (71), 135 (100), 123 (60), 121 (55), 107 (64), 93 (59), 79 (57), 69 (38), 55 (30), 41 (38).