Enantioselective synthesis of chiral β-aryloxy alcohols by asymmetric hydrogenation of a-aryloxy aldehydes via dynamic kinetic resolution

Article abstract of DOI:10.1002/adsc.200800634

A catalytic enantioselective hydrogenation of racemic α-aryloxy aldehydes via dynamic kinetic resolution has been developed by using (diamine)(spirodiphosphine)ruthenium(II) chloride [RuCl ₂(SDPs)(diamine)] catalysts. Employing this new reactio

Full text of DOI:10.1002/adsc.200800634

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DOI: 10.1002/adsc.200800634
Enantioselective Synthesis of Chiral b-Aryloxy Alcohols by
Asymmetric Hydrogenation of a-Aryloxy Aldehydes via
Dynamic Kinetic Resolution
Zhang-Tao Zhou,a Jian-Hua Xie,a and Qi-Lin Zhoua,*
a
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic
of China
Fax : (+86)-22-2350-6177; e-mail: qlzhou@nankai.edu.cn
Received: October 15, 2008; Published online: January 13, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800634.
Abstract: A catalytic enantioselective hydrogena-
tion of racemic a-aryloxy aldehydes via dynamic ki-
netic resolution has been developed by using
thesis of chiral b-aryloxy alcohols by asymmetric hy-
drogenation of a-aryloxy aldehydes via DKR.
The enantiomerically enriched b-aryloxy primary
alcohols are a very important class of building blocks
for the synthesis of a wide variety of biologically
active compounds. For example, enantiomerically
pure 2-aryloxy-1-propanols are starting materials for
the synthesis of sorbinil homologues,[6] juvenile hor-
mones[7] and glucokinase activating agents.[8] Howev-
er, the methods for the preparation of optically active
b-aryloxy primary alcohols are limited to the ring-
opening of chiral epoxides with phenol and its deriva-
tives,[9] the resolution of racemic a-aryloxy alcohols
with lipase-catalyzed enantioselective acylation,[10]
and the conversions of lactic acid derivates.[11] Encour-
aged by the high activities and enantioselectivities of
ACHTUNGTRENNUNG
C
ACHTUNGTRENNUNG
new reaction system a variety of optically active b-
aryloxy primary alcohols were synthesized in high
yields and moderate to good enantioselectivities.
Keywords: aldehydes; b-aryloxy primary alcohols;
asymmetric catalysis; dynamic kinetic resolution;
ruthenium
The catalytic asymmetric hydrogenation of prochiral the RuCl2ACTHNUTRGENNGU(SDPs)ACHUTNGTREN(NUGN diamine) catalysts in the hydrogena-
ketones appears to be the most attractive route to tion of a-aryl aldehydes, we investigated the asym-
produce enantiomerically enriched secondary alco- metric hydrogenation of a-aryloxy aldehydes cata-
hols.[1] One of the most efficient catalysts for this lyzed by RuCl
CHUTGTNREN(UNG SDPs)CAHTUNGTRNE(NUGN diamine) via DKR, targeting
2A
transformation is the chiral RuCl2(diphosphine)- on the development of a new strategy for the prepara-
(diamine) complexes initially reported by Noyori and tion of enantiomerically enriched b-aryloxy primary
co-workers.[2] In the presence of base in 2-propanol, a alcohols (Scheme 2).
wide range of simple ketones can be hydrogenated by The asymmetric hydrogenation of 3-methyl-2-phen-
chiral RuCl2(diphosphine)(diamine) catalysts to the oxybutanal (1a) was chosen as a standard reaction to
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
corresponding secondary alcohols in high enantiomer- optimize the reaction conditions. The reaction was
ic excess at a very low catalyst loading.[3] However, carried out in i-PrOH containing the catalyst
due to the hydrogenation of the carbonyl group in al- {RuCl2[(S)-SDP]ACTHUNGTRENNUNG
dehydes the latter cannot provide chiral alcohols, and BuOK
people rarely consider to use an asymmetric hydroge-
nation of aldehydes to synthesize optically active
compounds containing a primary alcohol function.[4]
Recently, we reported the first example of the asym-
metric hydrogenation of racemic a-aryl aldehydes via
dynamic kinetic resolution (DKR) catalyzed by ruthe-
nium complexes of chiral spirodiphosphines (SDPs)
(Scheme 1).[5] As a continuing effort in this significant
Scheme 1. Asymmetric hydrogenation of racemic a-aryl al-
reaction, we herein disclose an enantioselective syn- dehydes.
Adv. Synth. Catal. 2009, 351, 363 – 366
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363

Zhang-Tao Zhou et al.
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vealed that the ligand (S)-DMM-SDP bearing 4-me-
thoxy-3,5-dimethylphenyls gave the highest enantiose-
lectivity (74% ee, entry 5). Different diamines were
then examined and the combination of diphosphine
(S)-DMM-SDP and diamine (R,R)-DACH, (S,R,R)-
3h showed to be the best catalyst, affording the hy-
drogenation product 2a in 98% yield with 79% ee
(entry 8). The commercially available Xyl-BINAP
was also evaluated and the corresponding catalyst
(R,R,R)-4 gave a comparable result with Xyl-SDP cat-
alyst (S,R,R)-3i (entry 10).
A strong base is essential for the quick racemiza-
tion of the aldehyde substrate before hydrogenation.
Although the base can promote a side reaction of al-
dehydes, no by-product was observed in the reactions
with 0.02 (S/B=10) and 0.04 mmolmLÀ1 (S/B=5) of
t-BuOK. When the concentration of t-BuOK was in-
creased to 0.06 mmolmLÀ1 (S/B=3.3) a trace amount
of by-product was detected by TLC, while the yield
and ee value of hydrogenation product have not been
influenced (entry 12).
Scheme 2. Asymmetric hydrogenation of racemic a-aryloxy
aldehydes via DKR.
The substrate scope of the reaction was examined
by using catalyst (S,R,R)-3h. A series of racemic a-ar-
0.04 mmolmLÀ1, S/C=1000) under 50 atm of H2 at yloxy aldehydes can be hydrogenated to the corre-
room temperature. After reacting for 8 h, the hydro- sponding primary alcohols in full conversions. As
genation product, 3-methyl-2-phenoxybutanol (2a), shown in Table 2, the hydrogenation of a-aryloxy al-
was isolated in 98% yield with 62% ee (Table 1, dehydes having a bulky alkyl substituent such as i-Pr,
entry 1). Comparison of spirodiphosphine ligands re- c-Pent, c-Hex and t-Bu at the a-position gave higher
Table 1. Asymmetric hydrogenation of aldehyde 1a, optimizing the reaction conditions.[a]
Entry
Catalyst
Diphosphine
Diamine
Yield [%][b]
ee [%][c]
1
2
3
4
N
(S)-SDP
(S)-Tol-SDP
(S)-An-SDP
G
98
96
94
95
98
54
27
98
93
95
96
95
62
66
70
72
74
9
(S)-Xyl-SDP
(S)-DMM-SDP
(S)-DMM-SDP
(R)-DMM-SDP
(S)-DMM-SDP
(S)-Xyl-SDP
(R)-Xyl-BINAP
(S)-DMM-SDP
(S)-DMM-SDP
5
6[d]
7[e]
8
0
79
77
77
78
77
9
10
11[f]
12[g]
[a]
Reaction conditions: S/C=1000, [1a]=0.2 mmolmLÀ1, [t-BuOK]=0.04 mmolmLÀ1, i-PrOH, room temperature (20–
258C), 50 atm of H2, 8 h, 100% conversion.
Isolated yield from chromatography on silica gel.
[b]
[c]
[d]
[e]
[f]
Determined by HPLC with a Chiralcel OD-H column.
56% conversion. The product 2a has a same optical rotation with the product obtained by catalyst (S,R,R)-3a.
32% conversion.
[t-BuOK]=0.02 mmolmLÀ1.
[g]
[t-BuOK]=0.06 mmolmLÀ1.
364
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Adv. Synth. Catal. 2009, 351, 363 – 366

Enantioselective Synthesis of Chiral b-Aryloxy Alcohols by Asymmetric Hydrogenation
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Table 2. Asymmetric hydrogenation of racemic a-aryloxy al-
Experimental Section
dehydes 1 catalyzed by (S,R,R)-3h.[a]
General Procedure for Asymmetric Hydrogenation of
Racemic a-Aryloxy Aldehydes
The catalyst (0.002 mmol) was placed in a 30-mL hydroge-
nation vessel. Anhydrous i-PrOH (8.0 mL) was introduced
with a syringe and the vessel was purged with hydrogen and
pressurized to 40 atm for 5 min. After releasing the pressure,
the a-aryloxy aldehyde (2 mmol) and a solution of t-BuOK
in i-PrOH (0.2 mmolmLÀ1, 2.0 mL, 0.4 mmol) were added.
The vessel was purged with hydrogen and pressurized to 50
atm. After stirring at room temperature for 8 h, the reaction
was stopped. The solvent was vaporized and the residue was
subjected to chromatography on a silica gel column, the
pure alcohol was weighed to determine the yield. The enan-
tioselectivity was determined by HPLC using a Chiralpak
OD-H column or Chiralpak AD-H column.
Entry Substrate
R
X
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
i-Pr
Me
Et
H
H
H
H
H
H
H
4-Me
4-MeO 93
4-Cl
4-t-Bu
3-Me
3-MeO 96
3-Br
2-Me
2-MeO 98
1-Naph 93
98
94
93
95
96
97
94
95
79
40 (R)
53
41
71
71
74
78
Bn
c-Pent
c-Hex
t-Bu
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
9
81
10
12
13
14
15
16
17
18
1j
1k
1l
1m
1n
1o
1p
1q
93
96
93
71
78
76
Acknowledgements
79
92
93
78
78
We thank the National Natural Science Foundation of China
(Grant Nos. 20532010, 20572049, 20721062), the Major Basic
Research Development Program (Grant No. 2006CB806106),
the “111” project (B06005) of the Ministry of Education of
China, and Merck Research Laboratories for financial sup-
port.
81
74
[a]
Reaction
conditions:
S/C=1000,
[substrate]=
0.2 mmolmLÀ1, [t-BuOK]=0.04 mmolmLÀ1, i-PrOH,
room temperature (20–258C), 50 atm of H2, 8~10 h,
100% conversion.
The yield was obtained by chromatography on silica gel.
The ee values were determined by chiral HPLC using
chiral OD-H or AD-H column.
[b]
[c]
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