Cp*Ru(PN) complex-catalyzed isomerization of allylic alcohols and its application to the asymmetric synthesis of muscone

Article abstract of DOI:10.1021/ja050770g

Highly efficient isomerization of allylic alcohols into saturated carbonyls is accomplished using the catalyst system of Cp*RuCl[Ph₂P(CH₂)₂NH₂-κ²-P,N]-KOt-Bu (Cp* = η⁵-C₅(CH₃)₅) under mild conditions. Mechanistic consideration based on isotope-labeling experiments indicated the present reaction is applicable to the asymmetric isomerization of racemic sec-allylic alcohols with a prochiral olefin via dynamic kinetic resolution. A concise asymmetric synthesis of muscone has been achieved, where the asymmetric isomerization using an optically active ligand is a key reaction. Copyright

Full text of DOI:10.1021/ja050770g

Published on Web 04/12/2005
Cp*Ru(PN) Complex-Catalyzed Isomerization of Allylic Alcohols and Its
Application to the Asymmetric Synthesis of Muscone
Masato Ito, Sachiko Kitahara, and Takao Ikariya*
Department of Applied Chemistry, Graduate School of Science and Engineering and Frontier CollaboratiVe
Research Center, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan
Received February 5, 2005; E-mail: tikariya@apc.titech.ac.jp
Scheme 2. Cp*Ru(PN)-Catalyzed Isomerization of 3
Catalytic selective transformation of allylic alcohols to saturated
carbonyls (isomerization of allylic alcohols) is a potentially useful
process due to its high atom-economy. Hence, considerable effort
has been devoted in the past few decades, developing highly
efficient, transition metal, catalyst systems for this reaction.1a,b
A
number of metal hydride catalysts have been known to promote
the reaction, in which reversible transposition of the olefinic moiety
in the substrate via the metal hydride addition-elimination mech-
anism leads to the formation of an intermediate enol that tautomer-
izes to a saturated carbonyl irreversibly. However, the metal
hydrides are, in principle, active against most olefinic moieties in
a nonselective manner. Hence, they show only poor chemoselec-
tivity in the isomerization of allylic alcohols bearing other olefinic
units.1c,d Therefore, recent attention has been focused on different
mechanisms involving the reaction of the Ru hydride species with
the enone ligand derived from Ru allyloxide, leading to high
chemoselectivity.1e-h
We have recently developed highly efficient half-sandwich Ru
catalysts having a metal/NH bifunctionality for hydrogen transfer
between alcohols and carbonyls.2,3 Coordinatively unsaturated Ru
amide complexes derived from RuCl(N-sulfonyl-1,2-diamine) (η6-
arene)2 or Cp*RuCl[Ph2P(CH2)2NH2-κ2-P,N] (1a)3 (Cp* ) η5-
pentamethylcyclopentadienyl) effectively dehydrogenate alcohols
possibly through a pericyclic transition state, leading to coordina-
tively saturated Ru hydride complexes with concomitant formation
of carbonyls. In particular, a series of Cp*Ru catalysts bearing
tertiary phosphine-primary amine (PN) ligands effect very rapid
racemization of chiral nonracemic sec-alcohols via intramolecular
hydrogen transfer3b (Scheme 1). We have expanded the scope of
the intramolecular hydrogen transfer and found that Cp*Ru(PN)
catalysts efficiently promote chemo- and stereoselective isomer-
ization of allylic alcohols to give functionalized carbonyls in high
yields. Again, the metal/NH bifunctional property of this catalyst
plays a crucial role in the excellent catalyst performance.
and 94% yield, respectively), whereas the rate of the reaction
seriously decreased with increasing methyl substitution at the
nitrogen (63% yield for Ph2P(CH2)2NHMe and 18% yield for
Ph2P(CH2)2NMe2), indicating the crucial importance of the protic
amino group in the ligand for determining catalyst performance.
Neither a combination of monodentate phosphine or amine ligands
nor bidentate diphosphine ligands gave satisfactory results.
Since a binary catalyst system of the preformed complex 1a with
KOt-Bu exhibited better catalyst performance4 than that attained
by the ternary system, the binary system was used to examine the
scope and limitation of the isomerization.
Table 1. Isomerization of Various Allylic Alcoholsa
entry
3
R1
R2
R3
R4
yield, %
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
2-furyl
3-furyl
2-thienyl
3-thienyl
3-pyridyl
H
Me
H
H
Me
H
H
Me
H
Me
H
H
H
Me
H
H
H
Me
Me
H
>99
>99
>99
67
>99
>99
>99
37
>99
>99
>99
>99
>99
>99
>99
-(CH2)3-
-(CH2)4-
Me
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
10b
11
12
13
14
15
3j
3m
3n
3o
3p
3q
H
H
H
H
H
Scheme 1. Racemization Catalyzed by Cp*Ru(PN) Complexes
a [3] ) 0.5 M in toluene, 3:1a:KOt-Bu )100:1:1, 30 °C, 1 h. b In C6D6.
As listed in Table 1, allylic alcohols with varying substitution
pattern on the CdC bond (3) are cleanly convertible in the presence
of 1a and KOt-Bu to the corresponding ketones 4 within 1 h at 30
°C. The present isomerization is characterized by broad tolerance
to multiple substitution on the CdC bond and to a variety of
functional groups including an isolated CdC bond. Notably, even
allylic alcohols with a trisubstituted CdC bond can be smoothly
transformed into their corresponding ketones (entries 5-9). In
addition, isolated CdC bonds in 3k and 3l or heteroaromatic groups
in 3m-q (entries 11-15) do not interfere with the reaction giving
The ternary catalyst system of Cp*RuCl(cod) (cod ) 1,5-
cyclooctadiene), PN ligand 2a, and KOt-Bu has proven to smoothly
promote isomerization of R-vinylbenzyl alcohol (3a) (3a:Ru:2a:
KOt-Bu ) 100:1:1:1) at 30 °C in toluene ([3a] ) 0.5 M in toluene)
to give propiophenone (4a) quantitatively after 1 h (Scheme 2).
The catalyst performance was highly influenced by the structures
of the PN ligands employed. Structurally analogous PN ligands
with an NH2 group (2b-d) also accelerate the reaction (78, 70,
9
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10.1021/ja050770g CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Asymmetric Synthesis of Musconea
Scheme 3. Isotope-Labeling Experiments
a Reaction conditions: (a) 1g + KOt-Bu (5 mol %), toluene, 30 °C. (b)
Grubbs 2nd Generation Catalyst (10 mol %), ClCH2CH2Cl, 65 °C, 68%.
(c) Pd/C, H2 (1 atm), EtOH, 30 °C, 90%.
respectively. These products were subjected to ring-closing olefin
metathesis (RCM) using Grubbs 2nd Generation Catalyst and,
subsequently, to hydrogenation using a Pd/C catalyst to afford good
yields of both antipodes of muscone without any loss of optical
purity. Design of better chiral PN ligands for the present asymmetric
isomerization is now actively underway.
the corresponding ketones 4k-q in quantitative yields within 1 h,
suggesting a distinct mechanistic feature associated with metal/
NH bifunctionality.
Isomerization of isotope-labeled allylic alcohols using 1a with
KOt-Bu provided valuable information on the mechanism. PhCD-
(OH)CHdCH2 (3a-d1, >99% D) was catalytically isomerized into
PhCOCH2CH2D (4a-d1, >99% D) exclusively, and no deuterium
was incorporated into the R-carbon of the carbonyl group in the
product. Therefore, the present catalyst system may distinguish
between the hydrogen on the OH group and that on the OH-bearing
carbon in 3a and relocate them onto the R- and â-carbons in 4a,
respectively. As previously reported,3 the in situ generated Ru amido
complex Cp*Ru[Ph2P(CH2)2NH-κ2-P,N] (5a) should dehydrogenate
3a-d1 via a pericyclic transition state to give Cp*RuD[Ph2P(CH2)2-
NH2-κ2-P,N] (6a-d1) and PhCOCHdCH2 (PVK)5 (Scheme 3). Then,
6a-d1 presumably transfers its deuterium and one of the hydrogens
on the N to form Câ-D and CR-H bonds in 4a-d1 regiospecifically
due to the latent polarity of the PVK.6 In sharp contrast, no
regiospecificity was observed in the isomerization of CH3CD(OH)-
CHdC(CH3)(CH2)2CHdC(CH3)2 (3l-d1, E:Z ) 7:3, >99% D)
bearing two alkyl substituents at the distal sp2 carbon of the allylic
alcohol unit. In fact, the deuterium in 3l-d1 was distributed almost
equally (42:57) at the R- and â-carbons in 4l, suggesting that H-D
scrambling3b in 6a-d1 should precede the reduction of the intermedi-
ary trisubstituted enone, possibly due to its low reactivity for the
steric reasons. It is consistent with the fact that enantiomerically
enriched (-)-(E)-3l (50% ee) was isomerized in the presence of
1a and KOt-Bu to give completely racemic 4l and that the recovered
(E)-3l at an early stage of the reaction was found to be partially
racemized.
Encouraged by the highly efficient and unique isomerization with
Cp*Ru(PN) catalysts, we have next examined asymmetric isomer-
ization of racemic sec-allylic alcohols via dynamic kinetic resolu-
tion7 with a well-defined chiral catalyst Cp*RuCl[(S)-Ph2PCH2-
CHR5NHR6-κ2-P,N] (R5, R6 ) -(CH2)3-) (1g) prepared using a
chiral PN ligand derived from L-proline.8 The reaction of (()-(Z)-
3l or (()-(E)-3l in toluene containing 1g and KOt-Bu (3l:1g:KOt-
Bu ) 20:1:1, [3l] ) 0.5 M) proceeded smoothly at 30 °C to give
the corresponding optically active ketone 4l with 62% (S) and 66%
(R) ee, respectively, in good yields. It should be noted that the
enantioface differentiation is reversed by the geometry of the
olefinic unit in 3l and that enantiomeric excess values of 4l remain
constant throughout the reaction as a result of dynamic kinetic
resolution.
Acknowledgment. Support of this research was provided by
Ministry of Education, Culture, Sports, Science, and Technology
of Japan (Nos. 16750073 and 14078101), by Taisho Pharmaceutical
Co. Ltd. (M.I), and by the 21 COE Program “Creation of Molecular
Diversity and Development of Functionalities” (S.K.). We are
grateful to Takasago International Corporation for a gift of a sample
of neral.
Supporting Information Available: Full experimental details
including spectral data and determination of enantiomeric excesses. This
material is available free of charge via the Internet at http://pubs.acs.org.
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This new type of asymmetric isomerization of racemic sec-allylic
alcohols was applicable to the asymmetric synthesis of muscone.9
As outlined in Scheme 4, the starting allylic alcohols, (()-(Z)- or
(()-(E)-3r, which were readily prepared by the addition of
9-decenyllithium to neral and geranial, respectively, were isomerized
in toluene containing 1g and KOt-Bu as a catalyst to give the
corresponding (R)-4r with 64% ee and (S)-4r with 74% ee,
JA050770G
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