Synthesis of (-)-cubebol by face-selective platinum-, gold-, or copper-catalyzed cycloisomerization: Evidence for chirality transfer

Article abstract of DOI:10.1002/anie.200504543

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 natura

Full text of DOI:10.1002/anie.200504543

Angewandte
Chemie
Scheme 1. Constituants of Piper cubeba.
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-
Scheme 2. Reported and planned synthesis of 6.
Synthetic Methods
selective and affords the desired ketone 6 as the minor isomer
in only moderate yield. We realized that a Pt-[2,3] or Au-
catalyzed[4] cycloisomerization of enynol esters[8] would
represent a direct and efficient access to cubebol.
The key precursors 8a and 8b (1:2 diastereomeric
mixture) were readily prepared from (+)-(R,R)-tetrahydro-
carvone (10) in an overall yield of 55% (Scheme 3). AWittig–
DOI: 10.1002/anie.200504543
Synthesis of (ꢀ)-Cubebol by Face-Selective
Platinum-, Gold-, or Copper-Catalyzed
Cycloisomerization: Evidence for Chirality
Transfer**
Charles Fehr* and JosØ Galindo
Herein we describe a direct, stereoselective synthesis of (ꢀ)-
cubebol,[1] based on Pt-,[2,3] Au-,[4] and Cu-catalyzed[5] enyne
cycloisomerizations.
(ꢀ)-Cubebol (1), 4-epicubebol (2), and a- and b-cube-
benes 3 and 4, respectively, are naturally occurring sesqui-
terpenes, 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]
[*] Dr. C. Fehr, J. Galindo
Scheme 3. Reagents and conditions: a)trimethyl phosphonoacetate
(1.2 equiv), NaH (1.1 equiv), THF, reflux, 15 h; b) KOH (1.7 equiv),
EtOH, 608C, 24 h; c)BuLi (3.0 equiv), 2,2,6,6-tetramethylpiperidine
(TMP, 3.15 equiv), THF, ꢀ58C, 30 min, then 11, ꢀ258C to RT, 16 h;
then 5% HCl; d)LiAlH 4 (2 mol equiv), Et2O, reflux, 45 min; e)Swern
oxidation; f)HCCMgBr (1.2 equiv), THF, 25–28 8C, 45 min; g)PivCl
(1.1 equiv), NEt3 (1.2 equiv), DMAP (0.12 equiv), CH2Cl2 08C, 2 h.
Piv=pivaloyl, DMAP=N,N-dimethylaminopyridine.
Firmenich SA
Corporate R&D Division
P.O. Box 239, CH-1211 Gen›ve 8 (Switzerland)
Fax: (+41)22-780-3334
E-mail: charles.fehr@firmenich.com
[**] We thank Dr. Jean-Yves de Saint Laumer, Firmenich SA, Geneva, for
the energy calculations.
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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 b,g-
unsaturated aldehyde 15. Addition of ethynyl-MgBr and
esterification with pivaloyl chloride produced 8a and 8b as a
1:2 diastereomeric mixture.
Chromatographic purification of the alcohols 16a,b and
esterification of the fractions enriched in 16a or 16b gave
access to the pivalates 8a,b, enriched in 8a and 8b,
respectively. These were then submitted separately to the
Pt- or Au-catalyzed cycloisomerization reaction (Table 1,
entries 1–3). When a mixture of 8a and 8b (1:9) was treated
with 2 mol% of PtCl2, the expected tricyclic enol pivalates 9a
and 9b 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 9a and 9b (entry 2). In contrast, the reaction
of a mixture of 8a and 8b (7:3) with PtCl2 afforded mainly the
desired 9a (9a/9b = 86:14; entry 3).
Scheme 4. 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), NEt 3 (1.1 equiv), DMAP
(0.12 equiv), 08C to RT, 15 h; c)K 2CO3 (1.2 equiv), [18]crown-6 (0.4 +
0.4 equiv), toluene, reflux, 19 h + 5 h; d)see Table 1; e)K 2CO3
(1.2 equiv), MeOH, RT, 90 min; f) CeCl3 (2.0 equiv), MeLi (2.0 equiv),
THF, ꢀ788C, 1 h; then 6,ꢀ788C to RT, 2 h.
(ꢀ)-cubebol in 95% yield, identical in all
respects with an authentic sample.[6]
Table 1: Cycloisomerization of 8a and 8b.
The different diastereoface selectivities
Entry
8a/8b
Conditions
9a/9b
Yield [%]
observed for the cycloisomerizations of 8a
and 8b prompted us to examine the chirality
transfer from the enantioenriched prop-
argyl 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
1
2
3
4
5
6
10:90
10:90
70:30
88:12
98:2
PtCl2 (2 mol%), DCE[a], 708C, 9 h
60:40
47:53
86:14
94:6
99:1
99:1
80
65
–
AgSbF6/Ph3PAuCl (2 mol%), CH2Cl2, 208C, 40 min
PtCl2 (2 mol%), DCE[a], 708C, 9 h
PtCl2 (2 mol%), DCE[a], 708C, 9 h
81
–
PtCl2 (2 mol%), DCE[a], 708C, 9 h
98:2
[Cu(CH3CN)4](BF4)(2 mol%), DCE [a], 608C, 9 h
77[b]
[a] DCE=1,2-dichloroethane. [b] 90% conversion.
From the results shown in entries 1 and 3 it was
remained unaltered throughout the course of the reaction, as
shown by measurements taken after 50% conversion.
Surprisingly, Pt-catalyzed cycloisomerization of 25
(69% ee) afforded, in addition to the expected rearranged
enol pivalate 26 (10–20% ee, unknown absolute configura-
tion), 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 cyclo-
propanation of the achiral transient vinyl carbene C (path-
way (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 cycloisomeriza-
tion with [1,2]-acyl shift (pathway (c)). Intramolecular addi-
tion of the ester carbonyl to the metal-complexed acetylene A
anticipated that 8a would afford 9a with an excellent facial
selectivity. We therefore addressed the question of a dia-
stereoselective synthesis of 8a, 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 18a and 18b and
base-catalyzed cleavage of the carbinol fragment of 19a and
19b, 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 8a and 8b
(88:12) was used for the cycloisomerization step.
Indeed, PtCl2-catalyzed cycloisomerization of a mixture
of 8a and 8b (88:12) afforded 9a with a 94:6 selectivity
(Table 1, entry 4), and chromatographically enriched 8a (8a/
8b 98:2) afforded 9a 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 (708C) favored the formation of
by-products.
Hydrolysis of 9a afforded the known ketone 6, and
diastereoselective (97:3) addition of MeLi/CeCl3 furnished
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and poured into saturated aqueous NaHCO3. Extraction
(Et2O), washing (H2O, then saturated aqueous NaCl),
drying (Na2SO4), concentration, and bulb-to-bulb dis-
tillation (100–1208C/0.01 mbar) afforded 1.60 g of 9a
and 9b (9a/9b = 94:6; 81%). A solution of 9a and 9b
(9a/9b = 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 (100–1258C/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 ꢀ788Cafforded 680 mg of pure 6. M.p. 60–
60.58C(lit. 58.5–59.5 8C[7b]),[a]D20 (CHCl3; c = 1.30) ꢀ20.1
(lit. [a]2D0 = ꢀ23.9 (isooctane)[7b]); 1H NMR (400 MHz,
CDCl3): d = 0.59 (m, 1H), 0.90–1.00 (m, 1H), 0.91 (d, J =
7.0 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.99 (d, J = 6.0 Hz,
3H), 1.19 (m, 1H), 1.27 (t, J = 2.5 Hz, 1H), 1.45–1.52 (m,
2H), 1.58–1.70 (m, 2H), 1.78–1.90 (m, 2H), 1.98–
2.21 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d =
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).
Scheme 5. Reagents and conditions: a)–c) see Scheme 3a)–c); [A] DCE, 708C, 8 h;
[B] toluene, 508C, 9 h, 73% conversion; [C] toluene, 508C, 4 h, 50% conversion;
[D] DCE, 708C, 90 min; GC yields.
23: [a]2D0 (CHCl3; c = 0.56) + 24.8 (61% ee by chiral GC[18] (major
1
enantiomer: first peak)); H NMR (400 MHz, CDCl3): d = 0.92–1.02
(m, 1H); 0.96 (s, 3H), 1.09 (s, 3H), 1.20–1.30 (m, 2H), 1.35–1.55 (m,
2H), 1.51 (d, J = 2.5 Hz, 1H), 1.59 (ddd, J = 8.0, 2.5, 2.1 Hz, 1H),
1.80–1.90 (m, 1H), 1.95–2.12 ppm (m, 4H); 13CNMR (100 MHz,
CDCl3): d = 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 GC[18] (major enantiomer: first peak);
1H NMR (400 MHz, CDCl3): d = 0.90 (s, 3H), 0.99 (s, 3H), 1.00 (s,
3H), 1.07–1.30 (m, 4H), 1.34–1.48 (m, 1H), 1.60–1.70 (m, 2H), 2.15
(d, J = 19.5 Hz, 1H), 2.24 (d, J = 19.5 Hz, 1H), 2.51 (d, J = 19.5 Hz,
1H), 2.52 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d = 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 GC[18] (major enantiomer: first peak);
1H NMR (400 MHz, CDCl3): d = 0.95 (s, 3H), 1.05–1.10 (m, 1H), 1.06
(s, 3H), 1.15–1.25 (m, 2H), 1.19 (s, 3H), 1.42 (m, 1H), 1.65 (s, 1H),
1.65–1.87 (m, 3H), 1.96–2.04 (m, 1H), 2.15–2.28 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d = 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).
Scheme 6. Proposed mechanism for the cycloisomerizations.
leads to the vinyl metal species B, followed by nucleophilic
ꢀ
attack of the C Cdouble bond to the oxy-allyl system and
cyclopropane ring closure in G.[16,17]
In conclusion, we have succeeded in a direct, stereoselec-
tive synthesis of (ꢀ)-cubebol, based on a Pt-, Au-, or Cu-
catalyzed cycloisomerization in which control of the config-
uration 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).
Received: December 21, 2005
Published online: March 23, 2006
Keywords: cycloisomerization · cyclopropanes ·
.
diastereoselectivity · homogeneous catalysis · natural products
[1] F. Vanasek, V. Herout, F. Sorm, Collect. Czech. Chem. Commun.
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Experimental Section
(ꢀ)-6: A solution of 8a and 8b (8a/8b = 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 708C. The solution was cooled
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Communications
M. Malacria, J. Am. Chem. Soc. 2004, 126, 8656; C. Blaszykow-
actions. Placing the side chain above the cyclohexene ring orients
the dioxolane and PtCl2 (in (Z)-B, Scheme 6) away from the
cyclohexene and the isopropyl groups. A preliminary calculation
of the two possible reactive conformers (with OAc instead of
OPiv) with an imposed distance of 3 Š shows that B1 is more
stable than B2 by ca. 2.9 kcalmolꢀ1. Calculations were per-
formed at the DFT level (B3LYP/LACVP**), using Jaguar 5.5;
Schrꢀdinger, Inc., Portland, OR, 1991 – 2005. Most probably the
same diastereoface selectivity is observed in the cyclization 21!
22. The lower selectivity is certainly caused by the missing
ski, Y. Harrak, M.-H. Gonçalves, J.-M. Cloarec, A.-L. Dhimane,
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[5] [Cu(CH3CN)4](BF4) efficiently catalyzes the cycloisomerization
of certain unsaturated tertiary propargylic alcohols: C. Fehr, I.
Farris, H. Sommer.
[6] M. I. Velazco, L. Wuensche, P. Deladoey (Firmenich SA),
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isopropyl group. Surprisingly, the cycloisomerization 25!26 is
much less selective. This may be due to steric interactions
between the methyl group and the metal. The cyclization 25!27
is highly selective. Probably the reaction conformer
A
(Scheme 6) in which the acetylene group is above the cyclo-
hexene ring minimizes the steric interactions between the
pivalate and the cyclohexene ring.
[18] Chiral capillary column: CP-Chirasil-DEX CB (25 m ꢁ 0.25 mm)
(Chrompack).
[9] D. Boyall, F. Lopez, H. Sasaki, D. Frantz, E. M. Carreira, Org.
Lett. 2000, 2, 4233; J. W. Bode, E. M. Carreira, J. Org. Chem.
2001, 66, 6410.
[10] Despite the slow addition of 15, it accumulates during the
reaction. Diminishing the amount of reagents leads to a slower
reaction and to the formation of by-products.
[11] Synthesis of 20: a) 2,2-dimethylcyclohexanone, triethyl phos-
phonoacetate (1.2 equiv), NaOEt (1.1 equiv), pentane, reflux,
24 h (100%); b) lithium diisopropylamide (LDA, 1.05 equiv),
THF, ꢀ258Cto RT, 30 min (80%); c) LiAlH (1.50 molequiv),
4
Et2O, reflux, 45 min (93%); d) Swern oxidation (92%); for the
synthesis of 21, see: O. Isler, M. Montavon, R. Rüegg, P. Zeller,
Helv. Chim. Acta 1956, 39, 259; G. L. Olson, H.-C. Cheung, K. D.
Morgan, R. Borer, G. Saucy, Helv. Chim. Acta 1976, 59, 567.
[12] The indicated absolute configuration of 23 is based on the
stereoselectivity observed in the cycloisomerization of 8a
(cubebol synthesis).
[13] The lower ee values of the rearrangement products when
compared to the substrates reflect an imperfect stereocontrol
and not a racemization, as the ee values of 21 and 22 remained
constant during the reaction.
[14] This mechanism has recently been proposed on the basis of a
DFT computational study: see Ref. [3].
[15] For the related cycloisomerization of propargylic alcohols or
ethers, see E. Soriano, P. Ballesteros, J. Marco-Contelles,
Organometallics 2005, 24, 3172 and Refs. [2a, 2c, 3b, 4, and 5].
[16] Incidentally, this mechanism is closely related to the mechanism
proposed for the Rautenstrauch rearrangement: X. Shi, D. J.
Gorin, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 5802; we cannot
exclude that, depending on the substrate, the reaction path-
ways (a) or (b) compete with pathway (c).
[17] A referee pointed out that the vinyl metal species B would most
likely possess the E configuration. However, the formation of
the Z isomer by anchimeric assistance[3b] is also plausible and
would allow the cyclization B!G to occur with minimal steric
interactions. The stereoselectivity of the cycloisomerization
8a!9a can be rationalized by invoking minimal steric inter-
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