Carboxy-directed asymmetric hydrogenation of α-alkyl-α-aryl terminal olefins: Highly enantioselective and chemoselective access to a chiral benzylmethyl center

Article abstract of DOI:10.1039/c4ob00018h

A carboxy-directed asymmetric hydrogenation of α-alkyl-α-aryl terminal olefins was developed by using a chiral spiro iridium catalyst, providing a highly efficient approach to the compounds with a chiral benzylmethyl center. The carboxy-directed hydrogenation prohibited the isomerization of the terminal olefins, and realized the chemoselective hydrogenation of various dienes. The concise enantioselective syntheses of (S)-curcudiol and (S)-curcumene were achieved by using this catalytic asymmetric hydrogenation as a key step.

Full text of DOI:10.1039/c4ob00018h

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Carboxy-directed asymmetric hydrogenation
of α-alkyl-α-aryl terminal olefins: highly
enantioselective and chemoselective access
to a chiral benzylmethyl center†
Cite this: Org. Biomol. Chem., 2014,
12, 2049
Received 3rd January 2014,
Accepted 29th January 2014
DOI: 10.1039/c4ob00018h
Shuang Yang,a,b Shou-Fei Zhu,a,b Na Guo,a,b Song Songa,b and Qi-Lin Zhou*a,b
www.rsc.org/obc
A carboxy-directed asymmetric hydrogenation of α-alkyl-α-aryl
terminal olefins was developed by using a chiral spiro iridium cata-
lyst, providing a highly efficient approach to the compounds with a
chiral benzylmethyl center. The carboxy-directed hydrogenation
prohibited the isomerization of the terminal olefins, and realized
the chemoselective hydrogenation of various dienes. The concise
enantioselective syntheses of (S)-curcudiol and (S)-curcumene
were achieved by using this catalytic asymmetric hydrogenation as
a key step.
The chiral benzylmethyl center is a ubiquitous subunit in
natural products and bioactive compounds (Scheme 1).1 Tran-
sition-metal-catalyzed asymmetric hydrogenation of α-alkyl-
α-aryl terminal olefins provides an ideal method for the
enantioselective construction of chiral benzylmethyl centers.
However, the asymmetric hydrogenation of α-alkyl-α-aryl termi-
nal olefins remains a challenge,2 although iridium-catalyzed
asymmetric hydrogenation of trisubstituted olefins, which
could also generate a chiral benzylmethyl center, has been well
established.3 The easily accessible α-alkyl-α-aryl terminal
olefins avoid the tedious separation of Z/E isomers in the syn-
thesis of trisubstituted olefins. Quite recently, several groups,
including us, developed highly enantioselective hydrogenation
reactions of α,α-diarylethenes by using –OH,4 –COOH,5 –OMe,6
Scheme 1 Selected natural products containing a chiral benzylmethyl
center.
hydrogen pressure in methanol using 0.25 mol% chiral spiro
iridium catalysts 18 (Table 1). With catalyst (Sa,S)-1a, 24% con-
version and 89% ee were obtained in 24 h (entry 1). The cata-
lyst (Sa,R)-1a exhibited lower enantioselectivity compared to its
diastereoisomer (Sa,S)-1a (entry 2). The catalyst (Sa)-1b having
no substituent on the oxazoline ring accomplished the hydro-
genation in 3.5 h with 99.1% ee (entry 3). The chiral spiro
iridium catalyst 1 bearing less bulky P-Ar, such as 3,5-
dimethylphenyl (1c) and phenyl (1d), showed slightly lower
enantioselectivity (entries 4 and 5). The basic additive is criti-
cal for obtaining a high reaction rate and full conversion. The
inorganic bases, including Cs2CO3 and Na2CO3, gave essen-
tially the same results as those obtained with NEt3; however,
the reaction became sluggish without the basic additive
(entries 6–8). The carboxy group is necessary for the hydrogen-
ation reaction, and the ester is fully inert under the identical
conditions (entry 9). The reaction could also be performed at
room temperature albeit a longer reaction time (24 h) was
required for full conversion (entry 10). The catalysts are less
active to the internal double bond. As an example, no hydro-
genation took place with 2-(but-2-en-2-yl)benzoic acid (E/Z =
4 : 1) under the standard reaction conditions for 24 h.
7
and –NH2 as directing groups. In this communication, we
report a highly enantioselective (up to 99.8% ee) and highly
chemoselective carboxy-directed hydrogenation of α-alkyl-
α-aryl terminal olefins catalyzed by iridium complexes of chiral
spiro phosphine-oxazolines ligands (1), providing an efficient
method for the construction of chiral benzylmethyl centers.
In the initial study, the asymmetric hydrogenation of
2-(hex-1-en-2-yl)benzoic acid (2a) was performed at 6 atm
aState Key Laboratory and Institute of Elemento-organic Chemistry,
Nankai University, Tianjin 300071, China
bCollaborative Innovation Center of Chemical Science and Engineering (Tianjin),
China. E-mail: qlzhou@nankai.edu.cn
Under the optimal reaction conditions, various α-alkyl-
α-aryl terminal olefins (2a–2m)9 were hydrogenated in the
presence of the catalyst (Sa)-1b at 6 atm hydrogen pressure
†Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, HPLC and SFC spectra for the products. See DOI:
10.1039/c4ob00018h
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side chain has a negligible influence on the reaction rate and
enantioselectivity (entries 1–3). The substrates 2d and 2e
having a bulkier R2 group required longer reaction time for
full conversion (entries 4 and 5). The functional groups such
as –OMe (2g and 2l), –Br (2i and 2j), and –Cl (2k) on the
phenyl rings or at side chains of substrates could be tolerated
in this hydrogenation reaction, which facilitates further trans-
formations of the hydrogenation products.
Table 1 Iridium-catalyzed asymmetric hydrogenation of 2-(hex-1-en-
2-yl)benzoic acida
We then investigated the challenging substrates (2n–2q)
having an additional carbon–carbon double bond at the side
chain (Scheme 2). It is delightful that the internal double bonds
in the diene substrates (2n–2p) remain unreacted in the hydro-
genation reaction. When the substrate contains an additional
terminal carbon–carbon double bond (2q), the reaction still
showed a chemoselectivity in the hydrogenation of α-alkyl-α-aryl
disubstituted double bond, producing 3q in 83% yield.
Iridium-catalyzed asymmetric hydrogenation of 8-methy-
lene-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (2r) with
an exo-terminal olefin was also investigated (Scheme 3). With
catalyst (Sa)-1b, hydrogenation of 2r was accomplished within
18 h with 91% ee, showing that the carboxy-directed asym-
metric hydrogenation is an efficient strategy for constructing a
chiral cyclic benzylmethyl center.10
Entry
Catalyst
Base
Time (h)
Conv.b (%)
eec (%)
1
2
3
4
(Sa,S)-1a
(Sa,R)-1a
(Sa)-1b
(Sa)-1c
(Sa)-1d
(Sa)-1b
(Sa)-1b
(Sa)-1b
(Sa)-1b
(Sa)-1b
NEt3
NEt3
NEt3
NEt3
24
24
3.5
5
24
28
89
79
99.1
97
98
97
97
95
—
100
100
100
100
100
32
5
NEt3
5
6d
7d
8
Cs2CO3
Na2CO3
None
NEt3
3.5
3.5
24
24
24
9e
10f
0
100
NEt3
99.2
a Reaction conditions: 1/2a/base = 0.00125 : 0.5 : 0.5 (mmol), in 2 mL
methanol at 45 °C. b Determined by 1H NMR. c Determined by SFC
using
a
Chiralpak AD-H column. d 0.5 Equiv. base was used.
A deuterium-labeling study was performed to investigate
whether there was olefin migration in the hydrogenation
(Scheme 4). The absence of deuterium at the 3-position of the
side chain of the hydrogenation product d-3a clearly demon-
e Hydrogenation of methyl 2-(hex-1-en-2-yl)benzoate, the ester form of
2a. f Performed at 25 °C.
Table 2 Iridium-catalyzed asymmetric hydrogenation of 2-alkylvinyl strated that olefin migration did not occur in the reaction. The
benzoic acidsa
presence of deuterium at the 6′-position on the phenyl ring
Time
Product (h)
Yieldb
(%)
ee
(%)
Entry R1; R2
1
2
3
4
5
H; nBu (2a)
3a
3b
3c
3d
3e
3.5
3
5
12
48
98
99
98
98
98
99.1
98
99.1
99.5
99.6
H; Et (2b)
H; nPent (2c)
H; iPr (2d)
H; Cy (2e)
6
7
3f
2.5
98
98
99.1
99.2
3g
2.5
10
9
10
10
13
11
8
9
10
11
12
13
2-Naphthyl; nBu (2h)
5-Br; nBu (2i)
3h
3i
3j
3k
3l
3m
98
98
98
98
98
99
99.4
98
99
99.8
99.3
99.1
4-Br; nBu (2j)
Scheme 2 Carboxy-directed enantioselective and chemoselective
hydrogenation of dienes.
4,5-Cl2; nBu (2k)
5-OMe; Et (2l)
5-Me; Et (2m)
a Reaction conditions and analyses of products were the same as those
of Table 1, entry 3. Full conversions were obtained for all reactions.
b Isolated yield.
(Table 2). All the tested substrates could be hydrogenated to
the corresponding chiral 2-alkyl benzoic acids with excellent
Scheme 3 Iridium-catalyzed asymmetric hydrogenation of 8-methy-
yields and enantioselectivities (98–99.8% ee). The length of the lene-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid.
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hydrogenation of α-alkyl-α-aryl terminal olefins in organic syn-
thesis (Scheme 5).
Conclusions
In summary, we have developed a highly efficient iridium-cata-
lyzed asymmetric hydrogenation of α-alkyl-α-aryl terminal
olefins, which provides an efficient approach to the chiral
benzylmethyl centers. The use of a carboxy group as the
directing group prohibited the isomerization of the terminal
olefins in the reaction, and realized the chemoselective hydro-
genation of various dienes. Concise enantioselective syntheses
of (S)-curcudiol and (S)-curcumene were achieved by using
this highly efficient catalytic asymmetric hydrogenation as a
key step.
Scheme 4 Deuterium-labeling study.
could be attributed to the carboxy-directed C–H activation by
the iridium catalyst.11
To demonstrate the synthetic potential of the carboxy-
directed asymmetric hydrogenation of α-alkyl-α-aryl terminal
olefins further, we conducted the total synthesis of (S)-curcu-
diol,12 an inhibitor of gastric H, K-ATPase isolated from the
marine sponge Epipolasis sp.13 First, 2-bromo-6-methylhepta-
1,5-diene (6) was prepared by copper-catalyzed coupling of 2,3-
dibromoprop-1-ene 4 and Grignard reagent 5.14 The Suzuki
coupling of the bromide 6 and boronic acid 7, followed by a
hydrolysis, gave compound 9. The hydrogenation of 9 was per-
formed in the presence of 0.02 mol% catalyst (Ra)-1b (S/C =
5000) to produce the acid (S)-10 in 98% yield with 96% ee. The
reduction of the carboxy group of (S)-10, followed by a Dess–
Martin oxidation, produced the aldehyde 11 in 86% yield. The
aldehyde 11 was converted to (S)-curcudiol by Baeyer–Villiger
oxidation and a reduction in 81% yield. Thus, the synthesis of
(S)-curcudiol was accomplished in 51% overall yield. Moreover,
another natural product, (S)-curcumene, was also prepared in
89% yield by means of decarboxylation of the hydrogenation
product (S)-10 with copper powder.15 The easily available start-
ing materials, economical steps, and high yields of (S)-curcu-
diol and (S)-curcumene showed the high potential for wide
applications of Ir-catalyzed asymmetric carboxy-directed
Acknowledgements
We thank the National Natural Science Foundation of China,
the National Basic Research Program of China (973 Program)
(2012CB821600), and the “111” project (B06005) of the
Ministry of Education of China for financial support.
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Scheme 5 Total syntheses of (S)-curcudiol and (S)-curcumene.
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