Enantioselective total synthesis of (+)-(2R,6R)-trans-γ-irone

Full text of DOI:10.1021/jo960392l

J . Org. Chem. 1996, 61, 6021-6023
6021
Sch em e 1a
En a n tioselective Tota l Syn th esis of
(+)-(2R,6R)-tr a n s-γ-Ir on e
Honore´ Monti,*,† Ge´rard Audran,†
J ean-Pierre Monti,‡ and Gilbert Leandri†
Laboratoire de Re´activite´ Organique Se´lective associe´
au CNRS, Faculte´ des Sciences de St-J e´roˆme,
Avenue Escadrille Normandie-Niemen,
13397 Marseille Cedex 20, France, and Laboratoire de
Biophysique, Faculte´ de Pharmacie, 80037 Amiens, France
Received February 27, 1996
The natural occurrence of trans-γ-irone (1) has recently
been demonstrated.1 Four synthetic routes to the race-
mate (()-1 can be found in the literature,2 but only one
route for (+)-(2R,6R)-1 and one for (-)-(2S,6S)-1 have
been reported.3,4 These two enantioselective syntheses
offer only a moderate enantiomeric excess and lack
complete stereo- and/or regioselectivity. In the first
synthetic approach, (+)-1 has to be isolated from its
Z-isomer (∼5:1) by chromatography, and, in the second,
(-)-1 is obtained as a 1:3 mixture containing a majority
of (+)-trans-R-irone-2.
a
Reagents: (a) Me2Cu(CN)Li2, Et2O, then ClPO(OEt)2/HMPA
(92%); (b) Me3SiCH2MgCl, Ni(acac)2, THF (85%); (c) butynone,
ZnI2, 4 Å molecular sieves, CH2Cl2 (83%); (d) catalytic TsH, CH3CN
(82%); (e) butynone, Me2AlCl, CH2Cl2 (93%); (f) TiCl4, CH2Cl2
(93%).
a
Numbering follows IUPAC rules for nomenclature of carotenoids.1
yl[(3,3,4-trimethylcyclohex-1-enyl)methyl]silane (+)-5 in
85% yield.9b
We use it only when referring to irones.
In a first attempt, based on analogy with the litera-
ture,4 the ZnI2-catalyzed H-ene reaction of (+)-5 with but-
3-yn-2-one was investigated. This reaction furnished a
mixture of two main products (6 + 7) and small amounts
(9:1) of isomeric derivatives, showing that, prior to the
H-ene reaction, a partial isomerization must have taken
place.10 To avoid the formation of these unwanted
isomers, we ran a new experiment in the presence of 4 Å
We report herein a straightforward enantioselective
synthesis of (+)-1 starting from (+)-(R)-3,4-dimethylcy-
clohex-2-en-1-one, (+)-3, based on the H-ene reaction of
butynone with a cyclohexenic allyltrimethylsilane5-7
(Scheme 1). The readily available8 enone (+)-3 was
converted into the cyclic diethyl enol phosphate (+)-4 in
92% yield by the 1,4-addition of dimethylcyanocuprate
Me2Cu(CN)Li2, followed by quenching with diethylchlo-
rophosphate in hexamethylphosphoric triamide.9 The
nickel acetylacetonate-catalyzed reaction of (+)-4 with
(trimethylsilyl)methylmagnesium chloride gave trimeth-
(8) Obtained in two steps from (+)-(2R,5R)-trans-dihydrocarvone,
conveniently separated by column chromatography from its minor cis
isomer starting from the commercial Aldrich mixture (hexane/ether
6:1).
† Faculte´ des Sciences de St-J e´roˆme.
‡ Faculte´ de Pharmacie.
(1) Rautenstrauch, V.; Willhalm, B.; Thommen, W.; Ohloff, G. Helv.
Chim. Acta 1984, 67, 325.
(2) (a) Garnero, J .; J oulain, D. Bull. Soc. Chim. Fr. 1979, 15. (b)
Kitahara, T.; Tanida, K.; Mori, K. Agric. Biol. Chem. 1983, 47, 581. (c)
Takazawa, O.; Kogami, K.; Hayashi, K. Bull. Chem. Soc. J pn 1985,
58, 389. (d) Leyendecker, F.; Comte, M.-T. Tetrahedron 1987, 43, 85.
(3) Miyashita, M.; Makino, N.; Singh, M.; Yoshikoshi, A. J . Chem.
Soc., Perkin Trans. 1 1982, 1303.
(4) Helmlinger, D.; Fra´ter, G. Helv. Chim. Acta 1989, 72, 1515.
(5) Audran, G.; Monti, H.; Le´andri, G.; Monti, J .-P. Tetrahedron Lett.
1993, 34, 3417.
(6) For ene reaction of butynone with alkenes, see: Snider, B. B.;
Brown, L. A.; Eichenconn, R. S.; Killinger, T. A. Tetrahedron Lett. 1977,
33, 2831. For closely related electron-deficient alkynes as enophiles,
see: (a) Mikami, K.; Loh, T.-P.; Nakai, T. J . Chem. Soc., Chem.
Commun. 1988, 1430. (b) Snider, B. B. In Comprehensive Organic
Synthesis Vol. 5; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New
York, 1991; pp 1-27 and references therein. (c) Dang, H.-S.; Davies,
A. G. J . Chem. Soc., Perkin Trans. 2 1991, 721. (d) Mikami, K.;
Shimizu, M. Chem. Rev. 1992, 92, 1021.
(a) Ozonolysis in methanol and then treatment with Cu(OAc)2/FeSO4
led to (+)-(R)-6-methylcyclohex-2-en-1-one (Solladie´, G.; Hutt, J . J . Org.
Chem. 1987, 52, 3560). (b) Treatment of this ketone with methyl-
lithium, followed by oxidation with pyridinium chlorochromate (PCC),
afforded (+)-3 (Iio, H.; Monden, M.; Okada, K.; Tokoroyama, T. J .
Chem. Soc., Chem. Commun. 1987, 358. See also: Dauben, W. G.;
Michno, D. M. J . Org. Chem. 1977, 42, 682).
(9) (a) Hayashi, T.; Fujiwa, T.; Okamoto, Y.; Katsuro, Y.; Kumada,
M. Synthesis 1981, 1001. (b) Danishefsky, S. J .; Mantlo, N. J . Am.
Chem. Soc. 1988, 110, 8129.
(10) In 1H NMR, these rearranged products, which we did not
investigate fully, were characterized by a multiplet (bis-allylic hydro-
gen) at 2.90 ppm.
(7) Thermal ene reactions with allylsilanes. For
a review, see:
Dubac, J .; Laporterie, A. Chem. Rev. 1987, 87, 319 and references
therein. See also: (a) Imazu, S.; Shimizu, N.; Tsuno, Y. Chem. Lett.
1990, 1845. (b) Cai, J .; Davies, A. G. J . Chem. Soc., Perkin Trans. 2
1992, 1743. Lewis acid-promoted ene reactions with allylsilanes: (a)
Mikami, K.; Matsukawa, S. Tetrahedron Lett. 1994, 35, 3133. (b) Aoki,
S.; Mikami, K.; Terada, M.; Nakai, T. Tetrahedron 1993, 49, 1783.
The same isomerization has been reported using ZnCl2 or ZnBr2 as
Lewis acid and starting from a substituted cyclohexene.4
S0022-3263(96)00392-1 CCC: $12.00 © 1996 American Chemical Society

6022 J . Org. Chem., Vol. 61, No. 17, 1996
Notes
Ch a r t 1
achieved by a short four-step procedure, giving an overall
yield of 68% starting from (+)-3 (Scheme 1, path b). In
addition, starting from (-)-3,16 this synthetic pathway
formally constituted synthesis of (-)-(2S,6S)-trans-γ-
irone.
Exp er im en ta l Section
For analytical thin-layer chromatography, Merck silica gel
F-254 on aluminum plates was used. Column chromatography
was performed with Silica gel 60 (70-230 mesh) using mixtures
of diethyl ether and pentane as eluant. Chiral HPLC analyses
were performed on Analprep EC 93 (column, Chiralcel OD-H
25 cm × 0.46 cm i.d.). GC analyses were carried out on a
Chrompack 9001 using a WCOT fused silica column (25 m ×
0.32 mm i.d.; CP-Wax-52 CB stationary phase). Microanalyses
were performed on a Technicon CHN analyzer at our University.
Infrared spectra were recorded on a Perkin-Elmer 257 spec-
trometer. NMR spectra were recorded at 200 or 300 MHz for
1H and 50 or 75.5 MHz for 13C on a Bruker AM-200 or Bruker
AC-300 spectrometer with CDCl3 as solvent (Bruker AM-400 for
NOESY experiments). Chemical shifts (δ) are relative to tet-
ramethylsilane as internal standard. Optical rotations were
measured on a Perkin-Elmer 241 polarimeter. Unless otherwise
stated, solutions were dried with magnesium sulfate and
evaporated in a rotary evaporator under reduced pressure.
Dieth yl (+)-(4R)-(3,3,4-Tr im eth ylcycloh ex-1-en -1-yl)ph os-
p h or ic Tr iester ((+)-4). To a stirred suspension of copper(I)
cyanide (3.76 g, 42.0 mmol) in dry ether (100 mL) at -30 °C
was added dropwise MeLi (1.5 M in ether, 56.0 mL, 84.0 mmol)
under Ar atmosphere. The mixture was stirred for 1 h at -20
°C and cooled to -78 °C, and then (+)-3 (1.74 g, 14.0 mmol) in
ether (10 mL) was added dropwise. The reaction mixture was
slowly warmed to -30 °C and stirred at this temperature for 1
h, and then a mixture of ClPO(OEt)2 (6.1 mL, 42.0 mmol) and
HMPA (7.3 mL, 42.0 mmol) in THF (10 mL) was added dropwise.
The solution was allowed to rise to rt, stirred for 12 h and then
poured into a saturated aqueous NH4Cl/NH4OH solution (100
mL) and extracted with ether (3 × 60 mL). The organic layers
were combined, washed with 50 mL of brine, dried, and evap-
orated. The oily residue was subjected to column chromatog-
raphy on silica gel (pentane/ether 2:1) to afford 3.56 g (92%) of
molecular sieves (zeolite), which can serve as cation
exchangers.11 As expected, the reaction furnished cleanly
the inseparable mixture 6/7 (4:1) as the sole products in
83% yield. The regioselectivity of the H-ene reaction and
the trans relationship between the substituents could be
established by NMR spectroscopy. Recourse to NOESY
experiments established the absolute configuration and
conformation of 6 and 7. For the major allylsilane 6, the
NOESY plots were characterized by strong cross-peaks
between H4 and H5′ (Chart 1, A). Accordingly, this pair
of protons must reside in close proximity; this is uniquely
accommodated by A. The preference of molecules related
to 6 (or 7) to adopt a conformation with a pseudoaxial
side chain has been reported in the literature.2d,4,12 In
the same experiment, the NOE effect for vinylic H7′ and
equatorial H5′ (Chart 1, B) established the Z configura-
tion of the double bond in the minor vinylsilane 7. Fur-
ther, heating the mixture (6 + 7) in acetonitrile with a
catalytic amount of p-toluenesulfinic acid (TsH), accord-
ing to the procedure described in the literature for proto-
desilylation of vinylsilanes,13 provided (+)-trans-γ-irone
(1) as the only product in 82% yield (Scheme 1, path a).
Next, we envisaged that dimethylaluminum chloride
(Me2AlCl), which is a mild Lewis acid and a proton scav-
enger,14 would be an ideal catalyst for the H-ene reac-
tion. In agreement with our expectation, (+)-5 reacted
cleanly at low temperature (-30 °C) with but-3-yn-2-one,
furnishing the desired H-ene adduct as the single regio-
isomer (-)-6 in 93% yield. Isocyclic core allylsilanes
suffer ready protodesilylation with a Lewis acid like TiCl4
before all further reactions.15 Indeed, this generally
unwanted parasite reaction, applied to allylsilane (-)-6,
provided (+)-1 in 93% yield (Scheme 1, path b). Remark-
ably, this protodesilylation proceeded without any further
isomerization of the exocyclic double bond, and a single
diastereomer was detected by capillary GC. The high
optical purity of (+)-(2R,6R)-1 was verified by HPLC
(column, Chiralcel OD-H, 25 cm × 0.46 cm, i.d.), and
(+)-4. [R]25 +33.4 (c ) 1.8, CHCl3). IR (neat): ν 3060, 1690,
D
1280, 1040, 980, 810 cm-1
.
1H-NMR (200 MHz, CDCl3): δ 0.84
(s, 3H), 0.87 (d, J ) 6.4 Hz, 3H), 0.99 (s, 3H), 1.30 (td, J ) 7.1,
1.0 Hz, 6H), 1.37-1.69 (m, 3H), 2.02-2.33 (m, 2H), 4.10 (dq, J
) 7.9, 7.1 Hz, 4H), 5.20 (br s, 1H). 13C-NMR (50 MHz, CDCl3):
δ 14.8, 15.5 (d, J ) 6.1 Hz), 22.5, 27.0, 28.7, 34.1, 37.1, 63.5 (d,
J ) -5.8 Hz), 121.3 (d, J ) 4.9 Hz), 145.9 (d, J ) -9.1 Hz).
Anal. Calcd for C13H25O4P: C, 56.51; H, 9.12. Found: C, 56.62;
H, 9.15.
(+)-(4R)-Tr im eth yl[(3,3,4-tr im eth ylcycloh ex-1-en -1-yl)-
m eth yl]sila n e ((+)-5). To a stirred mixture of enol phosphate
(+)-4 (2.76 g, 10 mmol) and Ni(acac)2 (257 mg, 1.0 mmol) in THF
(50 mL) was added 0.25 equiv of a 1 M ethereal solution of
(trimethylsilyl)methylmagnesium chloride (2.5 mL, 2.5 mmol)
at rt. This addition process was repeated every 1 h for a total
of 11 h of reaction time and 2.5 equiv of Grignard reagent (25
mL, 25 mmol). The reaction was quenched with 50 mL of a 20%
aqueous NH4Cl solution and stirred for 45 min. After extractive
workup with ether (3 × 50 mL), the organic layers were
combined, washed with 50 mL of brine, dried, and evaporated.
Purification by chromatography on silica gel (pentane) afforded
the [R]25 +59.4 (c ) 1.2, CH2Cl2) is in good agreement
D
with the literature value,4 which is [R]25D -43.3 (c ) 0.8,
CH2Cl2) for (-)-1 with a reported 70% ee.
In conclusion, the first complete enantioselective total
synthesis of (+)-(2R,6R)-trans-γ-irone ((+)-1) has been
1.79 g (85%) of (+)-5. [R]25 +52.3 (c ) 2.0, CHCl3). IR (neat):
D
(11) (a) Thomas, J . M.; Theocaris, C. R. In Modern Synthetic
Methods; Scheffold, R., Ed.; Springer Verlag: Berlin, 1989; p 249. (b)
Dyer, A. In An Introduction to Zeolite Molecular Sieves; Wiley:
Chichester, 1988. (c) Temme, O.; Laschat, S. J . Chem. Soc., Perkin
Trans. 1 1995, 125.
(12) Torii, S.; Uneyama, K.; Matsunami, S. J . Org. Chem. 1980, 45,
16.
(13) Buchi, G.; Wuest, H. Tetrahedron Lett. 1977, 4305.
(14) (a) Snider B. B. Acc. Chem. Res. 1980, 13, 426. (b) Snider, B.
B.; Rodini, D. J .; Karras, M.; Kirk, T. C.; Deutsch, E. A.; Cordova, R.;
Price, R. T. Tetrahedron 1981, 37, 3927. (c) Snider, B. B.; Rodini, D.
J .; Kirk, T. C.; Cordova, R. J . Am. Chem. Soc. 1982, 104, 555. (d)
Cartaya-Marin, C. P.; J ackson, A. C.; Snider, B. B. J . Org. Chem. 1984,
49, 2443. (e) Snider, B. B. In Selectivities in Lewis Acid Promoted
Reactions; Schinzer, D., Ed.; Kluwer Academic Publishers: London,
1989; p 147.
ν 3030, 1660, 1255, 850 cm-1
.
1H-NMR (200 MHz, CDCl3): δ
0.04 (s, 9H), 0.83 (s, 3H), 0.91 (d, J ) 6.1 Hz, 3H), 0.99 (s, 3H),
1.41 (s, 2H), 1.37-1.59 (m, 3H), 1.75-2.05 (m, 2H), 4.95 (br s,
1H). 13C-NMR (50 MHz, CDCl3): δ -1.4, 15.9, 23.2, 27.3, 28.2,
29.6, 31.1, 34.7, 38.1, 131.4, 132.2. Anal. Calcd for C13H26Si:
C, 74.20; H, 12.45. Found: C, 74.32; H, 12.41.
(1′R,5′R,3E)-4-(5′,6′,6′-Tr im eth yl-2′-[(tr im eth ylsilyl)m eth -
yl]cycloh ex-2′-en -1′-yl)bu t-3-en -2-on e a n d (1′R,3′R,3E)-4-
(2′,2′,3′-Tr im et h yl-(Z)-6′-[(t r im et h ylsilyl)m et h ylid en e]cy-
cloh ex-1′-yl)bu t-3-en -2-on e (6 + 7). A suspension of allylsilane
(+)-5 (421 mg, 2.0 mmol), anhydrous ZnI2 (958 mg, 3.0 mmol),
(16) Prepared like (+)-3 starting from (-)-(2S,5S)-trans-dihydro-
carvone (Hua, D. H.; Venkataraman, S. J . Org. Chem. 1988, 53, 1095).
(15) Monti, H.; Feraud, M. Synth. Commun., in press.

Notes
J . Org. Chem., Vol. 61, No. 17, 1996 6023
powdered 4 Å molecular sieves (0.6 g), and butynone (204 mg,
3.0 mmol) in anhydrous CH2Cl2 (10 mL) was stirred at rt for 12
h under Ar atmosphere. After filtration and removal of the
solvent, the residue was chromatographed on silica gel (pentane/
ether 20:1) to afford 462 mg (83%) of a ∼4:1 inseparable mixture
of 6 and 7 (based on capillary GC and integration of 1H NMR
peaks). Anal. Calcd for C17H30OSi (6 + 7): C, 73.31; H, 10.86.
Found: C, 73.46; H, 10.90.
(+)-(1′R,3′R,3E)-4-(2′,2′,3′-Tr im et h yl-6′-m et h ylid en ecy-
cloh ex-1′-yl)bu t-3-en -2-on e [(+)-(2R,6R)-tr a n s-γ-Ir on e, (+)-
1]. (i) Usin g p-Tolu en esu lfin ic Acid . To a solution of 6 + 7
(278 mg, 1.0 mmol) and p-toluenesulfinic acid (31 mg, 0.2 mmol)
in 10 mL of CH2Cl2 was added one drop of water, and the
mixture was refluxed for 3 h. After cooling to rt, the reaction
mixture was quenched with H2O (15 mL) and extracted with
CH2Cl2 (2 × 20 mL). The organic layers were combined, dried,
and evaporated. The residue was chromatographed (pentane/
ether 15:1) to afford 170 mg (82%) of pure (+)-1.
6. 1H-NMR (300 MHz, CDCl3): δ -0.08 (s, 9H), 0.72 (d, J )
6.5 Hz, 3H), 0.76 (s, 3H), 0.77 (s, 3H), 1.15 and 1.37 (AB, J )
-17.0 Hz, 2H), 1.52-1.72 (m, 2H), 1.91-2.15 (m, 1H), 2.18 (s,
3H), 2.19 (d, J ) 9.3 Hz, 1H), 5.20-5.25 (m, 1H), 5.92 (d, J )
15.8 Hz, 1H), 6.58 (dd, J ) 15.8, 9.3 Hz, 1H). 13C-NMR (75.5
MHz, CDCl3): δ -1.1, 14.9, 20.9, 25.6 , 26.5, 26.6, 31.6, 32.3,
35.4, 56.5, 120.9, 132.5, 133.4, 148.9, 198.2.
(ii) P r otod esilyla tion w ith TiCl4. To a stirred, cooled (-70
°C) solution of (-)-6 (278 mg, 1.0 mmol) in anhydrous CH2Cl2
(10 mL) was added dropwise TiCl4 (1 M solution in CH2Cl2, 3.0
mL, 3.0 mmol). TLC monitoring showed the total disappearance
of (-)-6 after 1 h. The reaction mixture was then poured into a
saturated aqueous NaHCO3 solution (20 mL) and extracted with
CH2Cl2 (2 × 30 mL). The organic layers were combined, dried,
and evaporated to afford a residue, from which (+)-1 (192 mg,
93%) was obtained pure after chromatography (pentane/ether
7. 1H-NMR (300 MHz, CDCl3): δ 0.02 (s, 9H), 0.70 (d, J )
6.6 Hz, 3H), 0.71 (s, 3H), 0.85 (s, 3H), 2.07-2.15 (m, 1H), 2.17
(s, 3H), 2.38 (tdd, J ) 12.4, 5.0, 2.0 Hz, 1H), 2.84 (d, J ) 7.6 Hz,
1H), 5.23-5.28 (m, 1H), 6.01 (dd, J ) 15.8, 1.1 Hz, 1H), 7.00
(dd, J ) 15.8, 7.6 Hz, 1H). 13C-NMR (75.5 MHz, CDCl3): δ 0.5,
15.5, 20.6, 27.1, 27.6, 31.9, 35.9, 36.5, 38.2, 58.0, 125.9, 132.0,
147.0, 156.2, 197.9.
15:1). [R]25 +59.4 (c ) 1.2, CH2Cl2). IR (neat): ν 3060, 1680,
D
1650, 1620, 990, 895 cm-1 1H-NMR (200 MHz, CDCl3): δ 0.80
.
(s, 3H), 0.85 (d, J ) 6.6 Hz, 3H), 0.88 (s, 3H), 1.20-1.40 (m,
1H), 1.50-1.75 (m, 2H), 2.15-2.25 (m, 2H), 2.24 (s, 3H), 2.61
(d, J ) 8.9 Hz, 1H), 4.66 (br s, 1H), 4.71 (br s, 1H), 6.06 (d, J )
15.8 Hz, 1H), 7.05 (dd, J ) 15.8, 8.9 Hz, 1H). 13C-NMR (50 MHz,
CDCl3): δ 15.4, 21.3, 26.9, 27.2, 31.3, 36.2, 37.6, 59.4, 110.3,
131.8, 147.3, 147.8, 198.3. Anal. Calcd for C14H22O: C, 81.50;
H, 10.75. Found: C, 81.55; H, 10.72.
(-)-(1′R,5′R,3E)-4-(5′,6′,6′-Tr im eth yl-2′-[(tr im eth ylsilyl)-
m et h yl]cycloh ex-2′-en -1′-yl)b u t -3-en -2-on e ((-)-6). To a
stirred, cooled (-30 °C) solution of allylsilane (+)-5 (421 mg, 2.0
mmol) and butynone (150 mg, 2.2 mmol) in anhydrous CH2Cl2
(10 mL) was added dropwise Me2AlCl (1 M solution in CH2Cl2,
2.4 mL, 2.4 mmol) under Ar atmosphere. After 20 min at this
temperature, the reaction mixture was poured into a saturated
aqueous NaHCO3 solution (20 mL) and extracted with CH2Cl2
(3 × 30 mL). The organic layers were combined, washed with
brine (30 mL), dried, and evaporated. The residue was puri-
fied by chromatography (pentane/ether 20:1), which gave 518
Ack n ow led gm en t. The authors acknowledge Dr. R.
Faure for running NOESY experiments and Dr. G. Gil
for running chiral HPLC analyses.
mg (93%) of pure (-)-6. [R]25 -170.3 (c ) 1.9, CHCl3). IR
D
(neat): ν 3040, 1690, 1680, 1630, 1250, 850 cm-1. Anal. Calcd
for C17H30OSi: C, 73.31; H, 10.86. Found: C, 73.43; H, 10.89.
(For 1H- and 13C-NMR, see above).
J O960392L