Selective deoxygenation of allylic alcohol: Stereocontrolled synthesis of lavandulol

Article abstract of DOI:10.1021/ol200779y

Selective deoxygenation of allylic alcohol can be successfully carried out by the formation of alkoxyalkyl ether (EE or MOM), followed by Pd(dppe)Cl ₂-catalyzed reduction with LiBHEt₃. (+)-S-Lavandulol has been efficiently synthesized by the application of this protocol to the diol derived from the Pb(OAc)₄-promoted oxidative ring-opening of (-)-R-carvone. This deoxygenation method is general and selective for allylic alcohols.

Full text of DOI:10.1021/ol200779y

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2682–2685
Selective Deoxygenation of Allylic
Alcohol: Stereocontrolled Synthesis
of Lavandulol
Hee Jin Kim, Liang Su, Heejung Jung, and Sangho Koo*
Department of Chemistry, Department of Nano Science and Engineering,
Myong Ji University, Yongin, Kyunggi-Do, 449-728, Korea
sangkoo@mju.ac.kr
Received March 24, 2011
ABSTRACT
Selective deoxygenation of allylic alcohol can be successfully carried out by the formation of alkoxyalkyl ether (EE or MOM), followed by
Pd(dppe)Cl2-catalyzed reduction with LiBHEt3. (þ)-S-Lavandulol has been efficiently synthesized by the application of this protocol to the diol
derived from the Pb(OAc)4-promoted oxidative ring-opening of (ꢀ)-R-carvone. This deoxygenation method is general and selective for allylic
alcohols.
Lavandulol, the key ingredient of lavender oil and the
sex pheromone of the vine mealybug,1 has an interesting
structural feature that arises from the unusual tail-to-tail
coupling of dimethylallyl pyrophosphate.2 Racemic synthe-
sis of this monoterpene species mainly relied on the
regiocontrolled coupling of properly substituted allylic
compounds with formaldehyde toproduce the homoallylic
alcohol, which was mediated by sulfone,3 Ti(IV) or
Ce(III),4 and Sn(IV),5 even though some rearrangement
reactions such as Claisen and Prins have found their rare
uses.6 Stereoselective synthesis of lavandulol further re-
quires establishing the isopropenyl chiral center, which has
drawn much attention from the synthetic organic commu-
nity. Asymmetric allylation or protonation of senecioic
acid derivatives using a chiral auxiliary has been the main
repertoire in the enantiomerically pure lavandulol
synthesis.7 Stereocontrolled synthesis of lavandulol with
use of a cyclic template must be the most efficient method
since the cheap monoterpenoid, chiral carvone is readily
available. Grob-type fragmentation of the 1,3-diol deriva-
tive from (ꢀ)-R-carvone has been applied to the synthesis
of (þ)-S-lavandulyl acetate. However, the above strategy
suffered from nonselective BayerꢀVilliger oxidation in
producing the homoallylic alcohol, which instead gave rise
to the epoxidation of the electron-rich alkenes.8 It was
(1) Hinkens, D. M.; McElfresh, J. S.; Millar, J. G. Tetrahedron Lett.
2001, 42, 1619–1621.
(2) Takano, S.; Tanaka, M.; Seo, K.; Hirama, M.; Ogasawara, K.
J. Org. Chem. 1985, 50, 931–936.
(3) Inomata, K.; Igarashi, S.; Mohri, M.; Yamamoto, T.; Kinoshita,
H.; Kotake, H. Chem. Lett. 1987, 707–710.
(4) McCullough, D. W.; Bhupathy, M.; Piccolino, E.; Cohen, T.
Tetrahedron 1991, 47, 9727–9736.
(5) Ueno, Y.; Aoki, S.; Okawara, M. J. Chem. Soc., Chem. Commun.
1980, 683–684.
(6) (a) Matsui, M.; Stalla-Bourdillon, B. Agric. Biol. Chem. 1968, 32,
1246–1249. (b) Cookson, R. C.; Mirza, N. S. Synth. Commun. 1981, 11,
299–301.
(7) (a) Cardillo, G.; D’Amico, A.; Orena, M.; Sandri, S. J. Org.
Chem. 1988, 53, 2354–2356. (b) Piva, O. J. Org. Chem. 1995, 60, 7879–
7883. (c) Faure, S.; Piva, O. Synlett 1998, 1414–1416.
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2004, 60, 5013–5017.
r
10.1021/ol200779y
Published on Web 04/21/2011
2011 American Chemical Society

envisioned, based on our ring-expansion and ring-contrac-
tion studies,9 that an oxidative ring-opening reaction of the
1,2-diol derived from chiral carvone would perfectly fit
into the enantiomeric synthesis of lavandulol utilizing a
cyclic template (Scheme 1). The main obstacle in this route
seemed to be the selective deoxygenation of allylic alcohol
in the presence of homoallylic alcohol. We report herein
our efforts to the stereocontrolled synthesis of lavandulol
from chiral carvone with the main emphasis on the selec-
tive deoxygenation of allylic alcohol.
5 was then reduced to diol 6 by LiAlH4 in 93% yield. Now,
the selective deoxygenation at the allylic alcohol from diol
6 would complete the enantiomeric synthesis of (þ)-S-
lavandulol (1e), which was far more challenging than what
we initially imagined.
Table 1. Protection of the Hydroxyl Groups in Diol 6
protecting
group
yield
(%)
entry
reagent (equiv)
product
1
2
Ac
Bz
Bz
Ms
Ms
Ts
AcCl (2.5), Et3N (6)
BzCl (2.5), Et3N (6)
BzCl (1), Et3N (2.5)
MsCl (1), Et3N (3)
MsCl (10), Et3N (6)
TsCl (10), pyridine (6)
9a
9b
7b/9b
8c
93
88
Scheme 1. Stereocontrolled Synthesis of (þ)-S-Lavandulol (1e)
from (ꢀ)-R-Carvone (2)
3
40/30
39
4
5
8c
64
6
8d
8e
38
7
TBDMS TBDMSCl (1), Et3N (2.5)
TBDMS TBDMSCl (3), Et3N (6)
EEa
26
8
9e
81
9
EVEb (6), PPTSc (0.5)
9f
83
10
MOM
CH2(OMe)2 (30), P2O5 (3)
9g
69
a 1-Ethoxyethyl. b Ethyl vinyl ether. c Pyridinium p-toluenesulfonate.
We sought two possibilities for the selective deoxygena-
tion of the allylic alcohol in 6: first, protection of both
hydroxyl groups as acetates and Pd-catalyzed selective
reduction of the allylic acetate; second, selective protection
of the allylic alcohol as a sulfonate and reduction of the
sulfonate. In searching for a selective protection method
of the allylic alcohol in the presence of the homoallylic
alcohol in diol 6, various conditions have been tested
(Table 1). Protection of both alcohols in 6 with excessive
reagents proceeded uneventfully for acetates, benzoates,
TBDMS ethers, 1-ethoxyethyl (EE) ethers, and methox-
ymethyl (MOM) ethers (entries 1ꢀ2 and 8ꢀ10). Selective
protection as a sulfonate was possible only for the homo-
allylic alcohol, contrary to our hope, even with excessive
Table 2. Reaction Conditions and Results for the Selective
Deoxygenation of the Protected Diols 9
The cheaper and more abundant (ꢀ)-R-carvone (2) was
selected as a starting material for the synthesis of (þ)-S-
lavandulol (1e). Direct R0-acetoxylation of (ꢀ)-R-carvone
by Pb(OAc)4 did not proceed presumably due to the steric
effect of the isopropenyl group.10 Monoperphthalic acid
oxidation (ureaꢀH2O2, phthalic anhydride) of the TMS
enol ether from 2 produced the desired R0-hydroxyketone 3
in 92% yield as a separable 2:1 (β:R-hydroxy) mixture after
hydrolytic workup (Scheme 1). Reduction of 3 as a stereo-
isomeric mixture by NaBH4 produced 1,2-diol in 93%
yield. The mixture of the four stereisomers of 4 (see the
Supporting Information for the 1H NMR analysis of each
isomer)11 was subjected to the oxidative ring-opening
reaction by Pb(OAc)4 to give dial 5 in 98% yield. We
demonstrated the importance of the acidic workup (HCl
solution) to produce the dial with E-alkenyl configuration,
which was isomerized from the initially formed dial with
Z-alkene.9b In fact, oxidative ring-opening of 4 by NaIO4
without acidic workup exclusively produced the dial with
Z-alkene (see the Supporting Information for details). Dial
entry compd
reagent (equiv)
condition
product (%)
1
2
3
4
5
6
7
8
9
9a
9a
9a
9b
9a
9a
9a
9f
HCO2H/Et3N (4),
Pd(dppe)2Cl2 (0.5)
NaBH3CN (4),
60 °C, 21 h
in THF
rt, 5.5 h
in THF
rt, 3 h
1a (22)/
10a (27)
1a (38)/
10a (7)
8a (7)/
Pd(dppe)2Cl2 (0.5)
LiBHEt3 (3),
Pd(dppe)2Cl2 (0.3)
NaBH3CN (4),
in THF
rt, 10 h
in THF
6 (29)
1b (19)
Pd(dppe)2Cl2 (0.5)
Li-naphthalide (10) 0 °C, 0.5 h
6 (42)
in THF
Na/Hg (20),
0 °C, 4.5 h
in MeOH
6 (68)
Na2HPO4 (4)
Li (10), EtNH2 (156) ꢀ78 °C, 0.1 h
1e (56)
1c (68)
1d (64)
in THF
LiBHEt3 (3),
80 °C, 10 h
in dioxane
80 °C, 9 h
in dioxane
Pd(dppe)2Cl2 (0.2)
LiBHEt3 (3),
9g
Pd(dppe)2Cl2 (0.2)
Org. Lett., Vol. 13, No. 10, 2011
2683

reagents (entries 4ꢀ6). The possibility of the selective
deoxygenation of the allylic alcohol via sulfonate thus
seemed implausible. It is worth mentioning that benzoate
protection shows certain preference to the allylic alcohol
(entry 3), while TBDMS ether protection still favors the
homoallylic alcohol (entry 7) when a stoichiometric re-
agent is used.
Conditions for the selective deoxygenation at the allylic
site of the protected diols 9 were investigated, and the
results are summarized in Table 2. Selective reduction of
the palladium complex from allylic acetate with a soft hydride
nucleophile such as ammonium formate (HCO2H/Et3N)
or NaBH3CN was deteriorated by the formation of the
inseparable regioisomeric homoallylic acetate 10a together
with the desired lavandulyl acetate 1a (entries 1ꢀ2).12
Utilizing a stronger hydride nucleophile (LiBHEt3) facili-
tated hydrolysis of the acetate groups (entry 3). The
π-allyl reduction from dibenzoate 9b with NaBH3CN pro-
duced only the desired lavandulyl benzoate 1b, but in a fairly
low yield (entry 4). Radical reduction of diacetate 9a with
Li-naphthalide or Na(Hg) produced diol 6 by the hydrolysis
of both acetates (entries 5ꢀ6). The condition with Li in
EtNH2 was successful in producing the desired (þ)-S-lavan-
dulol (56% yield) by selective deoxygenation of allylic
Table 3. Selective Deoxygenation of Allylic Alcohols by the Formation of 1-Ethoxyethyl Ethersa and Palladium-Catalyzed LiBHEt3
Reactionb
a The formation of 1-ethoxyethyl (EE) ether was carried out by the reaction of the corresponding alcohol (1 equiv) with ethyl vinyl ether (3 equiv/
ꢀOH) in CH2Cl2 in the presence of pyridinium p-toluenesulfonate (0.25 equiv/ꢀOH) at 0 °C to room temperature. b The mixture of the EE-protected
alcohol (1 equiv), Pd(dppe)Cl2 (0.05 equiv), and LiBHEt3 (3 equiv) in 1,4-dioxane was heated at 70ꢀ80 °C for 3ꢀ4 h. c A ∼1:1 mixture of regioisomers
was obtained. d The crude reduction product was treated with p-TsOH (0.01 equiv) in MeOH at room temperature for 2 h for deprotection of EE. e
A
∼3:1 mixture of stereoisomers was obtained. f The overall yield of the coupling between allylic sulfone and unsaturated aldehyde, and the protection of
the resulting allylic alcohol. g The reduction was carried out at room temperature for 6 h. h The reductionwas carried out at room temperature for 4 h, and
then 70ꢀ80 °C for 6 h.
2684
Org. Lett., Vol. 13, No. 10, 2011

acetate and simultaneous hydrolysis of the homoallylic
acetate, as was reported in a related system (entry 7).12
Allylic tetrahydropyranyl (THP) ethers are commonly
used as a protecting group under basic conditions, but can
be regarded as a leaving group in the cross-coupling
reaction with organocopper reagents.13 The leaving group
ability of acetal protecting groups was also demonstrated
for 1-ethoxyethyl (EE) ethers in the Cu(I)-mediated cou-
pling reaction with Grignard reagents.14 We were very
happy to find that acetal protecting groups might also be
regarded as a good leaving group in the Pd-catalyzed
deoxygenation with Super hydride (LiBHEt3), and that it
was selective only for allylicalcohols. Diacetals9f(EE) and
9g (MOM) respectively produced the corresponding
monoacetal 1c (68% yield) and 1d (64% yield) by the
Pd-catalyzed deoxygenation with LiBHEt3 (entries 8ꢀ9).
Acetals from the homoallylic alcohols survived the above
deoxygenation condition. (þ)-S-Lavandulol (1e) was ob-
tained quantitatively after deprotection of monoacetal 1c
under catalytic p-TsOH in MeOH.
The generality and selectivity of this unprecedented
deoxygenation method for allylic alcohol was demon-
strated for various compounds (Table 3). The deoxygena-
tion proceeds at the EE-protected allylic alcohol through
the π-allyl palladium complex, in which hydride is deliv-
ered to the less-hindered site. The reduction is highly
regioselective if there is steric bias in the substituents of
the π-allyl complex. Either retention (entries 1ꢀ2, 6, and
9ꢀ11) or complete migration (5 and 7) of the car-
bonꢀcarbon double bond has occurred. A ∼1:1 mixture
of regioisomers was obtained when the size of the sub-
stituents was comparable (entries 4 and 8). The deoxygena-
tion is selective only for the EE ethers from allylic alcohols,
and those from benzylic alcohol and simple alcohol survive
the reaction condition (entries 5 and 8) as was demon-
strated in the lavandulol synthesis.
We were curious about any selectivity for desulfonation
over deoxygenation in the Pd-catalyzed reduction with
LiBHEt3, since the same reagents under milder condition
(25 °C instead of 70ꢀ80 °C) have been applied to the
desulfonation reaction in the sulfone-mediated chain-ex-
tension of terpenoids.15 Compound 27 was prepared by
EE-protection of the coupling product between geranyl
sulfone and (E)-3,7-dimethylocta-2,6-dienal, and was sub-
jected to the desulfonation condition (room temperature
for 6 h). Allylic alcohol 28 was exclusively obtained in 69%
yield after deprotection of the acetal group, which impli-
cated that sulfone is a better leaving group than EE-ether
(entry 9). Both desulfonation and deoxygenation are also
possible by sequential elimination at room temperature
and then at 70ꢀ80 °C (entry 10). Squalene (31) can be
prepared in 77% yield by this protocol from the EE ether
30 generated by the coupling between (2E,6E)-farnesyl
sulfone and (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienal
(entry 11).
In summary, the stereocontrolled total synthesis of (þ)-
S-lavandulol has been completed in seven steps, 44%
overall yield from a readily available (ꢀ)-R-carvone. This
method highlights the oxidative ring-opening of the 1,2-
diol derived from the cyclic template and the deoxygena-
tion of the acetal-protected allylic alcohol, which is quite
general and selective even in the presence of benzylic or
other simple alcohols.
Acknowledgment. This work was supported by the
Korea Research Foundation (Grant KRF-2006-312-
C00580) and by Priority Research Centers Program (No.
2010-0028300) through the NRF of Korea funded by the
MEST. Special thanks go to Dr. Carsten Blettner at BASF
for generous donation of high-quality LiBHEt3 reagent.
(9) (a) Yeo, J. E.; Yang, X.; Kim, H. J.; Koo, S. Chem. Commun.
2004, 236–237. (b) Do, Y.-S.; Sun, R.; Kim, H. J.; Yeo, J. E.; Bae, S.-H.;
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Salakhutdinov, N. F. Helv. Chim. Acta 2007, 90, 353–368.
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751–754.
Supporting Information Available. Experimental proce-
dures, characterization data, and 1H NMR and 13C NMR
spectra for all the new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
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