( - )-Frontalin: Synthesis using the catalytic enantioselective addition of dimethylzinc to a ketone

Article abstract of DOI:10.1002/ejoc.200300261

The first enantioselective synthesis of (-)-frontalin involving an enantioselective nucleophilic 1,2-addition of dimethylzinc to a functionalized α,β-unsaturated ketone, in the presence of titanium tetraisopropoxide and a substoichiometric amount of the chiral ligand 1,2-trans-bis(hydroxycamphor-sulfonamido)cyclohexane (HOCSAC, 2) as the key step, is described. The enantiomeric excess is as high as 89%. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300261

SHORT COMMUNICATION
(؊)-Frontalin: Synthesis using the Catalytic Enantioselective Addition of
Dimethylzinc to a Ketone
[a]
[a]
[a]
´
Miguel Yus,* Diego J. Ramon, and Oscar Prieto
Keywords: Asymmetric catalysis / Enantioselectivity / C-C coupling / Lithium / Natural products
The first enantioselective synthesis of (−)-frontalin involving
an enantioselective nucleophilic 1,2-addition of dimethylzinc
to a functionalized α,β-unsaturated ketone, in the presence
sulfonamido)cyclohexane (HOCSAC, 2) as the key step, is
described. The enantiomeric excess is as high as 89%.
of titanium tetraisopropoxide and
a
substoichiometric
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
amount of the chiral ligand 1,2-trans-bis(hydroxycamphor- Germany, 2003)
Introduction
ation,[12] the only example of an enantioselective carbon-
carbon bond-forming approach being, to the best of our
knowledge, the allylation of benzyl pyruvate using an excess
of a chiral diisopropyl tartrate-allyl-tin complex.[13]
(1S,5R)-1,5-Dimethyl-6,8-dioxabicyclo[3.2.1]octane [(Ϫ)-
frontalin, 1] is one of the semiochemicals[1] (aggregation
pheromones) secreted from pine beetles of the Dendroctonus
family.[2] This compound has also been isolated from other
sources, such as the temporal gland of the male Asian el-
ephant during the condition of musth,[3] and the bark of
several angiosperm trees.[4] In the case of bark beetles, it
was supposed that (Ϫ)-frontalin, as well as other phero-
mone components, was obtained by simple modifications
of dietary precursors. However, according to different
radiolabeled acetate derivative experiments,[5] in the case of
male Dendroctonus jeffreyi it has been demonstrated that
compound 1 is de novo synthesized in the anterior mid-gut
tissue through the mevalonate pathway. Since these beetles
destroy large areas of pine forest, frontalin has been used
to control the progression of harmful insect infestations.[6]
Frontalin is a valuable simple target to test different
asymmetric synthetic methods. Thus, although it possesses
two stereocenters, the asymmetric key step is the construc-
tion of only one oxygen-substituted quaternary carbon ster-
eocenter,[7] the second one being dictated by the formation
of the bicyclic structure. All possible general strategies, such
as diastereoselective[8] and enantioselective protocols, have
been used in its preparation. Among the latter ones, it must
be pointed out that enzymatic,[9] as well as antibody,[10] res-
olutions of different substrates are well established method-
ologies. However, the chemical enantioselective approaches
have been restricted to those in which the construction of
the stereocenter is performed by the formation of a carbon-
oxygen bond, for example epoxidation[11] and dihydroxyl-
On the other hand, we have found that trans-1,2-bis(hyd-
roxycamphorsulfonamido)cyclohexane (HOCSAC, 2) is,
among other chiral sulfonamides, an extraordinary good li-
gand to perform enantioselective transformations. Thus,
compound 2 has been used in substoichiometric amounts
to carried out the enantioselective addition[14] of alkyl[15]
and aryl[16] organozinc reagents to aldehydes[17] and ke-
tones[18] in the presence of titanium tetraisopropoxide,[19]
achieving excellent levels of enantioselectivity. We now de-
scribe the first catalytic enantioselective synthesis of (Ϫ)-
frontalin which involves a carbon-carbon bond formation
process by a nucleophilic alkylation of the appropriate ke-
tone using HOCSAC (2) as the chiral promoter.
Results and Discussion
The enantioselective synthesis of (Ϫ)-frontalin started
with the lithiation of chlorinated ketal 3, using lithium pow-
der and a substoichiometric amount of naphthalene,[20] to
lead to the lithium bis-homoenolate[21] 4 (Scheme 1). Reac-
tion of 4 with different cinnamoyl derivatives such as chlo-
ride, methyl ester or morpholine amide, yielded, after hy-
drolysis, the expected compound contaminated with by-
products arising from a double addition processes. To avoid
these by-products, the organolithium 4 was transmetal-
[a]
´
´
Departamento de Quımica Organica, Facultad de Ciencias,
Universidad de Alicante,
Apdo. 99, 03080-Alicante, Spain
Fax: (internat.) ϩ34-965/903-549
E-mail: yus@ua.es
Eur. J. Org. Chem. 2003, 2745Ϫ2748
DOI: 10.1002/ejoc.200300261
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2745

´
M. Yus, D. J. Ramon, O. Prieto
SHORT COMMUNICATION
lated[22] to give a less-reactive system, although it was first nally obtained frontalin with the already described com-
necessary to eliminate the excess of lithium by filtration, pound. The topicity of the addition is the same as that
since lithium is able to reduce different salts to their metallic found for simple ketones.
state, thus preventing the transmetallation process. To
Once the enantioselective key step had been successfully
achieve this, zinc and copper salts were successively added performed, it only remained to manipulate the structure to
to the above solution containing the organolithium inter- yield the desired product. Thus, ozonolysis[23] of the car-
mediate 4. The resulting functionalized organometallic de- bon-carbon double bond and reductive cleavage of the
rivative was successfully trapped by reaction with cinnamyl formed ozonide with sodium borohydride afforded the ex-
chloride, to afford ketone 5 in 72% overall yield. In this pected diol 7 with good yield (75%), with no loss of the
case, it must be pointed out that the only by-product de- enantiomeric excess, according to HPLC analysis. The final
tected was 2-methyl-2-propyl-1,3-dioxolane, which arises biphasic hydrolysis of the ketal functionality using hexane
from a proton abstraction of organolithium 4 from the reac- and hydrochloric acid yielded pure frontalin.[24] The abso-
tion medium.
lute configuration of the compound was assigned by com-
parison of the optical rotation with the previously reported
value and therefore the absolute configuration of com-
pounds 7 and 6 was assigned as S (see above).
Conclusion
The study presented here represents the first catalytic en-
antioselective synthesis of (Ϫ)-frontalin involving a carbon-
carbon bond formation process as the asymmetric key step
using a substoichiometric amount of chiral ligand. This
synthesis emphasises that the enantioselective addition of
organozinc reagents to ketones using HOCSAC might be
potentially used in other syntheses since the system keeps
its high enantioselectivity for different organozinc reagents
and even for functionalized ketones.
Scheme 1. (i) Li (excess), C10H8 (10% molar), THF, Ϫ78 °C,
30 min; (ii) filtration; (iii) ZnBr2, 0 °C, 15 min; (iv) CuCN·2LiCl,
30 min; (v) PhCHϭCHCOCl, 25 °C, 4 h; (vi) H2O (72% 3 to 5);
(vii) Me2Zn, Ti(OiPr)4, HOCSAC (2, 10% molar), PhMe, 25 °C,
24 h (81% yield, 89% ee); (viii) O3, CH2Cl2, Ϫ78 °C; (ix) NaBH4,
MeOH, 0 °C, 16 h (75% yield for two steps, 88% ee); (x) HCl (2
), C6H14 (80% yield, 85% ee)
Experimental Section
General Remarks: [α]D values were recorded at room temperature
(ca. 25 °C) on a DIP-1000 JASCO polarimeter (p.a. solvents, Pan-
reac). FT-IR spectra were obtained on a Nicolet Impact 400D spec-
trophotometer. NMR spectra were recorded on a Bruker AC-300
(300 MHz for 1H and 75 MHz for 13C) using CDCl3 as solvent and
The asymmetric key step is the addition of dimethylzinc
to the functionalized α,β-unsaturated ketone 5. Enantiose-
lective addition to ketones is much more difficult than that TMS as internal standard; chemical shifts are given in δ (ppm) and
coupling constants (J) in Hz. Mass spectra (EI) were obtained at
70 eV on a Shimazdu QP-5000 spectrometer, giving fragment ions
in m/z with relative intensities (%) in parentheses. High resolution
mass spectral analyses were performed by the Mass Spectrometry
Service at the University of Alicante. The purity of volatile prod-
ucts and the chromatographic analyses (GLC) were determined
with a Hewlett Packard HP-5890 instrument equipped with a flame
ionization detector and 12 m HP-1 capillary column (0.2 mm
diam., 0.33 mm film thickness, OV-1 stationary phase), using nitro-
gen (2 mL/min) as carrier gas, Tinjector ϭ 275 °C, Tdetector ϭ 300
to the corresponding aldehydes for both steric and elec-
tronic reasons. However, chiral ligand HOCSAC (2) is the
only one to overcome these problems, and it is able to pro-
mote the enantioselective addition of different organozinc
reagents to ketones. Moreover, in other related methodolog-
ies using different chiral ligands there is a great dependence
of the enantioselectivity upon the substrate structure, with
modest levels of enantioselectivity for the functionalized
compounds. This addition reaction merits a special com-
ment, since it permits not only the use of simple ketones °C, Tcolumn ϭ 60 °C (3 min) and 60Ϫ270 °C (15 °C/min), P ϭ
40 kPa; tR values are given in min under these conditions. The
enantiomeric excesses (ee) were determined with a Hewlett Packard
HP-1100 HPLC instrument equipped with a 25 cm OD-H or AD
Chiralcel column (0.46 cm diameter); tR(R) and tR(S) values are
given in min under these conditions. Thin layer chromatography
(TLC) was carried out on Schleicher & Schuell F1400/LS 254 plates
coated with a 0.2 mm layer of silica gel; detection by UV254 light,
staining with phosphomolybdic acid (25 g phosphomolybdic acid,
10 g Ce(SO4)2·4H2O, 60 mL concentrated H2SO4 and 940 mL H2O)
or with I2; Rf values are given under these conditions. Column
but also functionalized ones with a negligible decrease in
the enantioselectivity. Thus, the reaction was carried out
using an excess of dimethylzinc (1:2.4 molar ratio) and ti-
tanium tetraisopropoxide (1:1.3 molar ratio), and a substo-
ichiometric amount of HOCSAC (10%). After one day, the
starting ketone had been consumed and the expected ter-
tiary alcohol 6 was isolated in 81% yield (Scheme 1). The
enantiomeric excess (89%) was determined by HPLC using
a racemic mixture of alcohol 6 as standard, the absolute
configuration (S) being deduced by correlation of the fi- chromatography was performed using silica gel 60 of 35Ϫ70 mesh.
2746  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2003, 2745Ϫ2748

Synthesis of (Ϫ)-Frontalin
SHORT COMMUNICATION
Chiral HOCSAC (2) was prepared from the corresponding cyclo-
hexyldiamine and camphorsulfonyl chloride,[15] other reagents are
commercially available (Acros, Aldrich, Strem) and were used as
received. Solvents were dried by standard procedures.
1 h, until the blue color of ozone was noticeable. MeOH (15 mL)
and NaBH4 (0.38 g, 10 mmol) were added at 0 °C to the above
solution, and the temperature was allowed to rise to 25 °C over-
night. The reaction was then quenched by addition of water
(10 mL) and the resulting mixture was extracted with CH2Cl2 (5 ϫ
20 mL), the combined organic layers were dried over anhydrous
MgSO4 and the solvents evaporated (15 Torr) to give a residue,
which was purified by column chromatography, affording the pure
title compounds 7[9d] as a colorless oil (0.17 g, 75%). tR ϭ 11.05,
Rf ϭ 0.46 (hexane/ethyl acetate, 1:1). [α]D ϭ Ϫ2.1 (c ϭ 1.0, Et2O),
ee ϭ 88% {ref.:[9d] [α]D ϭ Ϫ1.8 (c ϭ 1.2, Et2O), 90%}. tR(S) ϭ 3.25
and tR(R) ϭ 4.00 (OD-H, UV 200 nm, hexane/2-propanol 97:3,
flow 1 mL/min). IR (film): ν˜ ϭ 3383, 3410 (OH), 1152, 1055 cmϪ1
(CO). 1H NMR: δ ϭ 1.08, 1.32 (2 s, 3 H each, 2 ϫ CH3), 1.30Ϫ1.75
[m, 6 H, (CH2)3], 2.45Ϫ2.65 (m, 2 H, 2 ϫ OH), 3.28, 3.34 (2 d,
J ϭ 11.0 Hz, 1 H each, CH2OH), 3.85Ϫ4.00 (m, 4 H, 2 ϫ CH2O)
ppm. 13C NMR: δ ϭ 18.6, 23.4, 24.0, 39.1, 40.2, 64.6 (2 C), 70.0,
72.7, 110.2 ppm. MS: m/z (%) ϭ 189 [Mϩ Ϫ Me] (Ͻ1), 87 (34), 72
(12), 71 (14), 43 (100).
2-Methyl-2-(4-oxo-6-phenylhex-5-en-1-yl)-1,3-dioxolane (5): A solu-
tion of the chlorodioxolane 3 (2.26 mL, 15 mmol) in THF (10 mL)
was added to a green suspension of lithium powder (0.80 g,
1.12 mmol) and naphthalene (0.11 g, 0.32 mmol) in THF (20 mL)
at Ϫ78 °C. After 30 min, the unreacted lithium was filtered off with
a cannula, and a solution of ZnBr2 (4.38 g, 19.5 mmol) in THF
(15 mL) was added. The resulting solution was allowed to warm to
0 °C and after 15 min another solution of CuCN (1.175 g,
19.5 mmol) and LiCl (1.65 g, 39 mmol) in THF (10 mL) was added.
After 15 min at the same temperature, a solution of cinnamoyl
chloride (2.67 g, 16.05 mmol) in THF (5 mL) was added. The reac-
tion mixture was stirred for 4 h, allowing the temperature to rise
to 25 °C. Then, the mixture was quenched with a saturated solution
of NH4Cl (25 mL). The resulting mixture was extracted with di-
ethyl ether (3 ϫ 30 mL), the combined organic layers were dried
over anhydrous MgSO4 and the solvents evaporated (15 Torr) to
give a residue, which was purified by column chromatography, af-
fording the pure title compounds 5 as yellow oil (2.81 g, 72%). tRϭ
14.8, Rf ϭ 0.26 (hexane/ethyl acetate, 4:1). IR (film): ν˜ ϭ 3045,
1612, 1449 (CHϭC), 1714, 1661 (CϭO), 1173 cmϪ1 (CO). 1H
NMR: δ ϭ 1.33 (s, 3 H, CH3), 1.65Ϫ1.85, 3.15Ϫ3.25 [2 m, 4 H
and 2 H, respectively, (CH2)3], 3.90Ϫ4.00 (m, 4 H, 2 ϫ CH2O),
6.74, 7.55 (2 d, J ϭ 16 Hz, 1 H each, CHϭCHCO), 7.35Ϫ7.45,
7.50Ϫ7.55 (2 m, 2 H and 3 H, respectively, ArH) ppm. 13C NMR:
δ ϭ 18.65, 23.65, 38.25, 40.6, 64.5 (2 C), 109.7, 126.05, 128.1 (2
C), 128.8 (2 C), 129.2, 130.25, 142.25 ppm. MS: m/z (%) ϭ 260
[Mϩ] (Ͻ1), 131 (25), 103 (19), 99 (15), 87 (100), 77 (11). HRMS
calcd. for C16H20O3: 260.1412; found 260.1419.
1,5-Dimethyl-6,8-dioxabicyclo[3.2.1]octane (1): HCl (1 mL, 2 ) was
added at 25 °C to a solution of the dioxolane 7 (0.50 g, 0.24 mmol)
in hexane (2 mL). After 1 h, the organic layer was decanted, dried
over anhydrous MgSO4 and the solvents evaporated (15 Torr) to
give pure frontalin (1)[24] as a colorless oil (0.29 g, 85%). [α]D
ϭ
Ϫ51.6 (c ϭ 0.4, Et2O), ee ϭ 85% {ref.:[9d] [α]D ϭ Ϫ52.1 (c ϭ 0.5,
Et2O), 90%}. tR(S) ϭ 3.30 and tR(R) ϭ 4.40 (OD-H, UV 200 nm,
hexane/2-propanol 99:1, flow 1 mL/min).
Acknowledgments
This work was supported by DGI (Project BQU2001-0538) from
´
the Spanish Ministerio de Educacion, Cultura y Deporte and the
2-(4-Hydroxy-4-methyl-6-phenylhex-5-en-1-yl)-2-methyl-1,3-dioxo-
lane (6): Ti(OiPr)4 (1.65 mL, 5.6 mmol) and Me2Zn (5.2 mL, 2 
in toluene, 10.3 mmol) were added at 0 °C under argon to a solu-
tion of HOCSAC (2, 0.235 g, 0.43 mmol) in toluene (5 mL). After
10 min, the resulting pale green solution was warmed up to 25 °C
and then ketone 5 (1.12 g, 4.3 mmol) was added as a solution in
toluene (2 mL). After 24 h, the solution was quenched by successive
addition of MeOH (3 mL) and a saturated solution of NH4Cl
(5 mL). The resulting mixture was extracted with diethyl ether (3
ϫ 20 mL), the combined organic layers were dried over anhydrous
MgSO4 and the solvents evaporated (15 Torr) to give a residue,
which was purified by column chromatography, affording the pure
title compounds 6 as a colorless oil (0.96 g, 81%). tR ϭ 14.2, Rf ϭ
0.14 (hexane/ethyl acetate, 4:1). [α]D ϭ ϩ6.9 (c ϭ 4.26, CHCl3),
ee ϭ 89%. tR(S) ϭ 29.4 and tR(R) ϭ 39.1 (AD, UV 220 nm, hexane/
2-propanol 97:3, flow 1 mL/min). IR (film): ν˜ ϭ 3080, 1494 (CHϭ
Generalitat Valenciana (CTIDIB/2002/318). O. Prieto thanks the
Universidad de Alicante for financial suppor.
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Received April 29, 2003
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Eur. J. Org. Chem. 2003, 2745Ϫ2748