Ruthenium-catalyzed regio- and enantioselective allylic substitution with water: Direct synthesis of chiral allylic alcohols

Article abstract of DOI:10.1002/anie.201101078

Less is more: A new route to access chiral allylic alcohols through the regio- and enantioselective substitution of monosubstituted allylic chlorides with water has been developed. The reaction is catalyzed effectively by planar-chiral cyclopentadienyl ruthenium complexes (see scheme). Copyright

Full text of DOI:10.1002/anie.201101078

DOI: 10.1002/anie.201101078
Asymmetric Hydroxylation
Ruthenium-Catalyzed Regio- and Enantioselective Allylic Substitution
with Water: Direct Synthesis of Chiral Allylic Alcohols**
Naoya Kanbayashi and Kiyotaka Onitsuka*
Enantioselective allylic substitution catalyzed by transition-
metal complexes is an important process in organic syn-
thesis.[1] For many years, mainly palladium complexes that
contain chiral ligands have been employed as efficient
catalysts in these reactions. Recent studies have demonstrated
that chiral catalysts based on other transition metals show
different regioselectivity in the synthesis of branched allylic
products via monosubstituted p-allyl intermediates.[2]
Although a variety of carbon and nitrogen nucleophiles can
be used in those reactions, applicable oxygen nucleophiles are
still limited to phenols and alcohols, which produce allylic
ethers.[3] Thus, enantioenriched branched allylic alcohols,
which serve as useful chiral building blocks, are often
synthesized by other processes, such as the hydrogenation of
a,b-unsaturated ketones,[4] the nucleophilic addition of vinyl-
metal reagents to aldehydes and ketones,[5] and the kinetic
resolution of racemic allylic alcohols.[6] Recently, new ways to
access these compounds have been developed, and they
involve allylic substitution by a two-step conversion involving
allylic esters and silyl ethers (Scheme 1; OPG = ester or silyl
and carbon nucleophiles catalyzed by planar-chiral cyclo-
pentadienyl ruthenium (Cp’Ru) complexes (1; see Table 1).[11]
This system was successfully extended to the regio- and
enantioselective allylic substitution of monosubstituted allylic
halides with oxygen and carbon nucleophiles.[12] From those
studies, we found that Cp’Ru catalysts showed characteristic
reactivity towards the less reactive nucleophiles. Thus, we
started an examination of the enantioselective allylic sub-
stitution with water using Cp’Ru catalysts.
Treatment of cinnamyl chloride (2a) with water in the
presence of 1 mol% of the Cp’Ru complex (S)-1a resulted in
the selective formation of the branched allylic alcohol (3a;
see equation in Table 1). After optimization of the reaction
conditions, we found that the reaction in a mixture of THF/
water (8:1) at 258C with sodium hydrogen carbonate
(1.2 equiv), produced 3a after 4 hours in 99% yield with
81% ee.[13] Notably, the linear allylic alcohol was not formed
at all. To improve the enantioselectivity, we examined the
effect of the aryl groups on the phosphine ligand of the Cp’Ru
catalyst (Table 1). Replacement of the phenyl groups with 3,5-
dimethylphenyl and 4-methoxy-3,5-dimethylphenyl groups
led to an increase in enantioselectivity to 88% ee and 90% ee,
respectively (Table 1, entries 2 and 3). Complexes 1d and 1e,
which have 3,5-difluorophenyl and 4-fluorophenyl groups,
quantitatively produced 3a in 88% ee and 87% ee, respec-
Table 1: Reaction of cinnamyl chloride (2a) with water.[a]
Scheme 1. Synthesis of chiral allylic alcohols by allylic substitution.
LG=leaving group.
ether).[7,8] In the reaction of allylic chlorides with boronic
acids in the presence of a ruthenium catalyst, the allylic
alcohols were synthesized but high regio- and enantioselec-
tivities were not achieved.[9] Herein, we describe the direct
synthesis of chiral allylic alcohols by the regio- and enantio-
selective allylic substitution using water as the nucleophile.[10]
Previously, we reported the enantioselective allylic sub-
stitution of 1,3-disubstituted allylic carbonates with amine
Entry
Cat.
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
(S)-1 f
99
99
99
99
99
97
81 (R)
88 (R)
90 (R)
88 (R)
87 (R)
81 (R)
[*] N. Kanbayashi, Prof. K. Onitsuka
Department of Macromolecular Science
Graduate School of Science, Osaka University
Machikaneyama 1-1, Toyonaka, Osaka 560-0043 (Japan)
Fax: (+81)6-6850-5474
E-mail: onitsuka@chem.sci.osaka-u.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology (Japan) and partly by the Sumitomo Foundation.
[a] Reaction conditions: 2a (1.0 mmol), cat. (10 mmol), NaHCO3
(1.2 mmol), THF (4 mL), and H2O (0.5 mL), 258C, 4 h. [b] Yields of
the isolated products. [c] Determined by HPLC analysis using a chiral
stationary phase. [d] Configuration is given in parentheses. THF=tetra-
hydrofuran.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101078.
Angew. Chem. Int. Ed. 2011, 50, 5197 –5199
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5197

Communications
tively (Table 1, entries 4 and 5). These results indicate that the
methoxyphenyl)propanone with a ruthenium catalyst,[16] no
isomerization was observed in the present system (Table 2,
entry 2). Moreover, because the reaction conditions are very
mild, methoxycarbonyl and formyl groups are well tolerated
in this reaction (Table 2, entries 4 and 5). The reactions of
naphthyl and dienyl derivatives 2g–2i produced the corre-
sponding allylic alcohols (Table 2, entries 6–8). The present
reaction also proceeded with alkyl-substituted allylic chlor-
ides 2j–2m to give 3j–3m, respectively (Table 2, entries 9–
12). Although the yields of 3k and 3l were not very high, the
substrates were completely consumed and no by-products
were formed. Technical difficulties in the isolation of 3k and
3l resulted from their relatively low boiling points, thus
resulting in lower yields. Meanwhile, the reaction of m-
bis(chloropropenyl)benzene (4) gave allylic diol (5) in 90%
yield with 99% ee and 82% de [Eq. (2)]. This result indicates
that the configuration in the first allylic hydroxylation does
not affect the enantioselectivity of the second reaction. In all
the reactions described above, regioselectivity was high
because the formation of linear products was not observed.
enantioselectivity is not affected by the electronic properties
of the aryl group but is affected by the steric properties of the
aryl group. Complex 1 f (Table 1, entry 6) showed the same
enantioselectivity as 1a, thus indicating the catalyst contain-
ing the large 3,5-diisopropylphenyl groups (1 f) was not
suitable for this reaction.
Gais and co-workers reported the palladium-catalyzed
deracemization of 1,3-disubstituted allylic carbonates to give
chiral allylic alcohols.[14] On the basis of some control
experiments, they concluded that the reaction proceeded
through the nucleophilic attack of the hydrogen carbonate
ion, and subsequent decarboxylation. In contrast, in our
reaction water actually functions as a hydroxide source. The
reaction using sodium formate instead of sodium hydrogen
carbonate also produced 3a in 64% yield with 80% ee.[13]
Critical evidence was obtained in the isotope labeling experi-
ment. The reaction using H218O led to the selective formation
of [18O]-3a instead of 3a [Eq. (1)], and this result was
unequivocally confirmed by mass spectrometry.[15] To the best
of our knowledge, this is a rare example of an allylic
substitution that uses water as the nucleophile to give the
chiral allylic alcohol in good yield and high enantioselectiv-
ity.[10]
Similar to other asymmetric allylic substitutions using 1,[12]
the reaction proceeds via the p-allyl intermediates (S)-6 that
are generated by the oxidative addition of allylic chloride with
high diastereoselectivity (Scheme 2). Indeed, treatment of
The scope of the present allylic hydroxylation is summa-
rized in Table 2. The reactions of cinnamyl chloride deriva-
tives, which possess various substituents, selectively produced
the corresponding branched allylic alcohols 3 in good yields
with high enantioselectivities (Table 2, entries 1–5), although
substrates with electron-withdrawing groups required longer
reaction times for complete conversion. Although Bruneau
and co-workers reported that 3c easily isomerizes into 1-(4-
Table 2: Reaction of allylic chlorides (2) with water.[a]
Entry Substrate
Cat.
t [h] Yield [%][b] ee [%][c,d]
1
2
3
4
5
6
7
8
2b (R=4-MeC6H4)
(S)-1d
(S)-1b
(S)-1c 12
(S)-1c 12
(S)-1c 12
(S)-1c
(S)-1c
(S)-1b
(S)-1d 12
(S)-1d 18
(S)-1b 18
4
4
99
99
99
99
93
99
95
96
99
78
87
99
90 (R)
76 (R)
94 (R)
93 (R)
93 (R)
90 (R)
89 (R)
96 (R)
85 (S)
83 (S)
97 (R)
90 (R)
Scheme 2. Proposed reaction pathway for asymmetric allylic hydroxyl-
ation.
2c (R=4-MeOC6H4)
2d (R=4-CF3C6H4)
2e (R=4-MeO2CC6H4)
2 f (R=4-OHCC6H4)
2g (R=1-naphthyl)
2h (R=2-naphthyl)
(S)-6a (Ar= R = Ph) with H2O and sodium hydrogen car-
bonate in CH3CN resulted in the quantitative formation of 3a
(R = Ph) with 93% ee. The absolute configuration of 3 is in
agreement with the reaction mechanism involving an attack
of the coordinated hydroxy group at the substituted allylic
carbon atom of the p-allyl group in complex (S)-7, which is
the key to the high regio- and enantioselectivities.
4
7
4
=
2i (R=(E)-PhCH CH)
9
2j (R=PhCH2CH2)
2k (R=n-C5H11)
2l (R=c-C6H11)
10
11
12
2m (R=tBuPh2SiOCH2) (S)-1c 12
This reaction was successfully applied to the synthesis of a
known intermediate enroute to the 12-membered macrolide
(+)-chloriolide (Scheme 3). Kirsh and Haug prepared the
chiral allylic alcohol (S)-10 from the readily available
[a] Reaction conditions:
2 (1.0 mmol), cat. (10 mmol), NaHCO3
(1.2 mmol), THF (4 mL), and H2O (0.5 mL), 258C, 4 h. [b] Yields of
the isolated products. [c] Determined by HPLC analysis using a chiral
stationary phase. [d] Configuration is given in parentheses.
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Scheme 3. Enantioselective formal synthesis of (+)-chloriolide. a) 8,
NBS, AIBN, PhCl; b) NaHCO3 aq., acetone, 48% (2 steps); c) NCS,
DMS, CH2Cl2, 90%; d) (R)-1b (1 mol%), NaHCO3, THF, 258C, 12 h
(see the Supporting Information for details). AIBN=2,2’-azoisobutyro-
nitrile, DMS=dimethylsulfide, NBS=N-bromosuccinimide, NCS=N-
chlorosuccinimide.
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trichloroacetimidate in seven steps, which included the Over-
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steps through the corresponding allylic bromide and alcohol,
in 43% yield. The reaction of 9 using (R)-1b gave the target
allylic alcohol (S)-10 in 93% yield with 91% ee, and this can
be converted into (+)-chloriolide in nine steps.
In conclusion, we have developed a synthetic route to
chiral allylic alcohols that involves allylic substitution with
water. Complete regioselectivity and high enantioselectivity
were achieved by using the planar-chiral Cp’Ru catalysts. The
simplicity and availability of the nucleophile, the mild
reaction conditions, and the broad scope of the allylic
chlorides are the attributes of the present system. Further
studies to extend the reaction to other nucleophiles are
ongoing.
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Experimental Section
General procedure: NaHCO3 (101 mg, 1.2 mmol) and Cp’Ru catalyst
1 (10 mmol, 1 mol%) were added to a solution of allylic chloride 2
(1.0 mmol) in THF (4.0 mL) and water (0.5 mL), and the reaction
mixture was stirred for 4 h at 258C. After dilution with diethyl ether,
the reaction mixture was filtered through Celite, and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate, 10:1) to
give a colorless oil.
Received: February 12, 2011
[13] See the Supporting Information.
Published online: April 21, 2011
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2904.
Keywords: allylation · asymmetric synthesis · hydroxylation ·
[15] MS (EI): 3a: m/z 134 (59) [M+], 133 (100) [(MÀH)+], 117 (66)
.
ruthenium · water
[(MÀOH)+]; [18O]-3a: m/z 136 (55) [M+], 135 (100) [(MÀH)+],
18
117 (98) [(MÀ OH)+].
[16] M. Helou, J.-L. Renaud, B. Demerseman, F. Carreaux, C.
Bruneau, New J. Chem. 2008, 32, 929.
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Angew. Chem. Int. Ed. 2011, 50, 5197 –5199
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5199