Rhodium-catalyzed asymmetric tandem cyclization for efficient and rapid access to underexplored heterocyclic tertiary allylic alcohols containing a tetrasubstituted olefin

Article abstract of DOI:10.1021/ol500993h

The first Rh-catalyzed asymmetric tandem cyclization of nitrogen- or oxygen-bridged 5-alkynones with arylboronic acids was achieved. The simple catalytic system involving a rhodium(I) complex with readily available chiral BINAP ligand promotes the reaction to proceed in a highly stereocontrolled manner. This protocol provides a very reliable and practical access to a variety of chiral heterocyclic tertiary allylic alcohols possessing a tetrasubstituted carbon stereocenter and an all-carbon tetrasubstituted olefin functionality in good yields with great enantioselectivities up to 99% ee.

Full text of DOI:10.1021/ol500993h

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed Asymmetric Tandem Cyclization for Efficient and
Rapid Access to Underexplored Heterocyclic Tertiary Allylic Alcohols
Containing a Tetrasubstituted Olefin
Yi Li and Ming-Hua Xu*
State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China
S
* Supporting Information
ABSTRACT: The first Rh-catalyzed asymmetric tandem cycliza-
tion of nitrogen- or oxygen-bridged 5-alkynones with arylboronic
acids was achieved. The simple catalytic system involving a
rhodium(I) complex with readily available chiral BINAP ligand
promotes the reaction to proceed in a highly stereocontrolled
manner. This protocol provides a very reliable and practical
access to a variety of chiral heterocyclic tertiary allylic alcohols possessing a tetrasubstituted carbon stereocenter and an all-carbon
tetrasubstituted olefin functionality in good yields with great enantioselectivities up to 99% ee.
he transition-metal-catalyzed tandem cyclization reactions
complementing that obtained by using hydrogen as reducing
Tof 5-alkyne-1-carbonyl derivatives provide a powerful, agent (Scheme 1a).7c,d
As for enantioselective cyclization employing nitrogen- or
straightforward, and atom-economical approach to diverse five-
membered cyclic allyl alcohols with an exocyclic olefin, which
are employed widely in organic and medicinal chemistry.1
Among them, nitrogen- or oxygen-linked 5-alkyne-1-carbonyl
compounds are particularly important starting materials for the
construction of corresponding heterocyclic building blocks,
such as tetrahydrofuran or tetrahydropyrrole derivatives.
Despite the great progress made in developing efficient
transition-metal catalysts including nickel,2 rhodium,3 palla-
dium,4 titanium,5 or ruthenium6 complexes, surprisingly, related
asymmetric processes to give more valuable enantiomerically
enriched products remain an understudied and elusive topic in
the literature.7−9 Rhodium-catalyzed asymmetric hydrogenation
of heteroatom-linked acetylenic aldehydes disclosed by Krische
in 2006 represents the first successful example of enantiose-
lective cyclization (Scheme 1a).7a,b Furthermore, there are two
reports of rhodium-catalyzed asymmetric reductive cyclization
of similar 5-alkynals with the chelating heteroatom-substituted
acetaldehydes or acyl phosphonates by Tanaka, nicely
oxygen-linked 5-alkynyl ketones to afford chiral cyclic tertiary
allylic alcohols, it is less explored mainly due to the decreased
carbonyl electrophilicity and difficulty of stereocontrol (regio-
and enantiocontrol). To our knowledge, only a single example
of using trimethylsilyl-substituted NTs-tethered 5-alkynone as
substrate was reported under palladium catalysis, giving
moderate enantiocontrol (82% ee).7e,8 Alternatively, Hayashi
and Murakami have demonstrated that rhodium-catalyzed
asymmetric arylative cyclization of 5-alkyne-1-carbonyls (X =
C(CH2OBn)2, C(CO2Me)2 for substrate in Scheme 1a) with
stable, commercially available arylboronic acids is an attractive
route to carbocyclic allylic alcohols.9 However, these processes
are not equally applicable to nitrogen- or oxygen-linked
substrates,10 and it was assumed that the malonate tether
contributes to the high regioselectivity of initial 1,2-addition
across alkyne. Therefore, the development of an efficient
catalytic system is desirable. We describe herein a highly
enantioselective synthesis of heterocyclic tertiary allylic alcohols
with an all-carbon tetrasubstituted olefin11 functionality via
arylative cyclization promoted by a Rh(I)/BINAP complex
(Scheme 1b).
Scheme 1. Tandem Cyclization Protocol To Access Chiral
Heterocyclic Allylic Alcohols
Our initial survey commenced with evaluation of representa-
tive chiral phosphoramidite ligand L1 and phosphine ligands
L2−L3 in arylative cyclization of ether-linked 5-alkynone 1a
with (4-methoxyphenyl)boronic acid 2a in the presence of 2.5
mol % of [Rh(COE)2Cl]2 and KOH (30 mol %) in toluene/
H2O (10:1) at 60 °C. Intriguingly, the reactions proceeded
smoothly to afford the expected cyclized product 3a (Table 1,
entries 1−3). Of these examined, the commercially available
Received: April 4, 2014
Published: April 28, 2014
© 2014 American Chemical Society
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Letter
With the optimal reaction conditions in hand, we sought to
evaluate the scope and generality of the reaction. As
summarized in Table 2, a wide variety of ether-linked 5-
Table 1. Optimization of Reaction Conditions for Rhodium-
Catalyzed Asymmetric Arylative Cyclization of 1a with 2a
a
Table 2. Rh/(R)-BINAP-Catalyzed Asymmetric Arylative
a
Cyclization of 1
b
c
entry
1
1
Ar2
3
yield (%)
ee (%)
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
4-OMeC6H4
4-MeC6H4
4-tBuC6H4
C6H5
3a
3b
3c
3d
3e
3f
87
73
70
75
72
76
78
88
78
70
82
70
80
79
85
83
80
78
72
72
84
77
68
49
97
92
97
91
94
96
94
96
90
91
96
94
99
97
97
97
98
98
98
98
70
65
96
94
d
2
3
d
4
b
c
5
6
7
8
4-ClC6H4
4-FC6H4
entry
L
base
temp (°C)
solvent
yield (%) ee (%)
1
L1
L2
L3
L4
L5
L6
L7
L8
L3
L3
L3
L3
L3
L3
L3
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
K2CO3
KF
60
60
60
60
60
60
60
60
40
RT
40
40
40
40
40
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
CH2Cl2
MeOH
toluene
toluene
83
70
86
75
74
61
41
<5
87
78
37
77
60
74
77
58
51
94
92
93
88
11
4-BrC6H4
2-naphthyl
3-MeC6H4
3-FC6H4
3g
3h
3i
2
3
d
9
4
d
10
3j
5
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-OMeC6H4
4-FC6H4
3k
3l
6
7
4-OMeC6H4
4-FC6H4
3m
3n
3o
3p
3q
3r
8
9
97
97
88
91
64
97
96
4-OMeC6H4
4-FC6H4
10
11
12
13
14
15
4-OMeC6H4
4-FC6H4
4-OMeC6H4
4-FC6H4
3s
3t
1f
1g
1h
1i
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
4-FC6H4
3u
3v
3w
3x
a
The reaction was performed with 1a (0.1 mmol), 2a (0.3 mmol),
[Rh(COE)2Cl]2 (2.5 mol %), L (10 mol %), and base (30 mol %) in 2
b
mL of solvent/H2O (10:1). COE = cyclooctene. Isolated yields.
c
1i
Determined by HPLC analysis using a chiral stationary phase.
a
The reaction was performed with 1 (0.1 mmol), 2 (0.3 mmol),
[Rh(COE)2Cl]2 (2.5 mol %), (R)-BINAP (L3, 10 mol %), and KOH
b
(30 mol %) in 2 mL of toluene/H2O (10:1) at 40 °C. Isolated yields.
(R)-BINAP L3 (10 mol %) exhibited the greatest preference
both in terms of catalytic activity and enantiocontrol (86% yield
and 94% ee) (entry 3). To attain higher reactivity and
enantioselectivity, a series of biaryl-type bisphosphine ligands
L4−L8 that contain different chiral backbones or sterically
hindered aromatic substituents on the phosphorus were
subsequently tested (entries 4−8). Unfortunately, no superior
results were obtained. In all cases, the bisphosphine ligands
were either less effective or altogether inactive. Following up on
the encouraging results obtained with (R)-BINAP, effects
related to the reaction temperature, solvent, and base were
carefully examined. As revealed, it was found that lowering the
reaction temperature to 40 °C was beneficial for the
improvement of enantioselectivity (97% ee) without loss of
reactivity (entry 9). However, at room temperature, a small
erosion of yield was observed (entry 10). In addition, the
investigation of various solvents including dioxane, CH2Cl2, and
MeOH suggested that the use of toluene was the best choice
(entries 9 and 11−13). Further efforts to improve the reaction
yield and ee by tuning the effect of base turned out to be
unhelpful (entries 14 and 15).
c
Determined by HPLC analysis using a chiral stationary phase; see the
Supporting Information for details. The reaction was performed at 60
d
°C.
alkynones 1 bearing different substituents on the aromatic ring
attached to carbonyl group and/or at the alkyne terminus were
successfully reacted with various arylboronic acids 2, providing
the corresponding chiral tertiary allylic alcohols containing a tri-
or tetrasubstituted olefin and tetrahydrofuran skeleton 3a−x
mostly in good to high yields and excellent enantioselectivities
(up to 99% ee). In general, with respect to para-substituted and
meta-substituted arylboronic acids, the electronic properties of
the phenyl ring of boronic acids did not appear to affect the
reaction yield and enantiomeric excess values (entries 1−10).
However, with the more hindered 2-methylphenylboronic acid
or 1-naphthylboronic acid, almost no reaction occurred (data
not shown). Moreover, ether-linked 5-alkynones 1b−f with
either electron-donating or electron-withdrawing groups on the
aromatic ring attached to carbonyl group were found to be
suitable substrates, as they exhibited high reactivity (70−85%
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yield) and led to the formation of highly optically active
products 3k−t (94−99% ee) (entries 11−20). In the cases of 5-
alkynones 1g−h bearing sterically demanding ethyl or n-hexyl,
respectively, at the alkyne terminus, a distinct decrease in
enantioselectivity was observed (entries 21 and 22). When R =
Ph, unfortunately, no cyclized product was obtained. Notably,
when more challenging 5-alkynone 1i, possessing acidic
hydrogen at the alkyne terminus, was used as the substrate,
the tandem reactions proceeded equally smoothly and
generated cyclized products with an exocyclic trisubstituted
olefin in very high levels of stereocontrol (94−96% ee) (entries
23 and 24).
Considering that glycidol containing a tetrahydrofuran
skeleton is a unique motif existing in some biologically active
compounds, such as peribysin B12 and milbemycin deriva-
tives,13 epoxidation of the above obtained chiral tertiary allylic
alcohol was attempted. As illustrated in Scheme 2, treatment of
Scheme 2. Synthesis of the Spirocyclic Compound 6
Fortunately, the structure of the product 3r was confirmed
unambiguously by single-crystal X-ray analysis, and the newly
formed chiral center was determined to have the S
configuration (Figure 1). Assuming an analogous reaction
mechanism, the same absolute configurations of the obtained
cyclic tertiary allylic alcohol derivatives were assigned.
3a with m-CPBA in CH2Cl2 at 0 °C for 12 h led to efficient
access to the desired product 6 in 74% yield with >20:1
diastereomeric ratio while maintaining high enantioselectivity.
The molecular structure as well as the absolute configuration of
the oxirine stereocenters were confirmed by single-crystal X-ray
crystallography. Thus, a particularly interesting spirocyclic
architecture bearing three consecutive quarternary stereo-
centers that is otherwise difficult-to-access was established in
a highly stereoselective fashion.
Figure 1. X-ray crystal structure of (S)-3r.
On the basis of the reaction stereochemical outcome, a
plausible catalytic cycle and enantio-differentiation models are
proposed in Figure 2. Initiation of the reaction through the
transmetalation of hydroxyrhodium(I) A with arylboronic acid
2 generates the arylrhodium(I) B, which subsequently
Given the remarkable performance of the present catalyst
system in asymmetric arylative cyclization of ether-linked 5-
alkynones 1 with arylboronic acids 2, its further applicability
was also examined with tosylamide-linked 5-alkynones 4 (Table
3, entries 1−4). To our delight, under the same reaction
conditions, reaction involving tosylamide-linked 5-alkynones
4a,b with several electronically different para-substituted
arylboronic acids were all found to be successful to afford the
corresponding chiral tertiary allylic alcohols 5a−d containing
tetrahydropyrrole skeleton in up to 71% yield with outstanding
enantioselectivity (96−99% ee).
Table 3. Rh/(R)-BINAP-Catalyzed Asymmetric Arylative
a
Cyclization of 4
b
c
entry
Ar1
C6H5
Ar2
5
yield (%)
ee (%)
1
2
3
4
4-OMeC6H4
4-FC6H4
5a
5b
5c
5d
61
71
62
70
96
98
99
97
C6H5
4-ClC6H4
4-ClC6H4
4-OMeC6H4
4-FC6H4
a
The reaction was performed with 4 (0.1 mmol), 2 (0.3 mmol),
[Rh(COE)2Cl]2 (2.5 mol %), (R)-BINAP (L3, 10 mol %), and KOH
b
(30 mol %) in 2 mL of toluene/H2O (10:1) at 40 °C. Isolated yields.
c
Determined by HPLC analysis using a chiral stationary phase; see the
Figure 2. Proposed catalytic cycle and models for reaction
Supporting Information for details.
enantioselectivity.
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Organic Letters
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Soc. 2006, 128, 1406. (c) Wang, H.; Han, X.; Lu, X. Tetrahedron 2010,
66, 9129.
(5) Ti-catalyzed reaction: Crowe, W. E.; Rachita, M. J. J. Am. Chem.
undergoes regioselective syn addition to the carbon−carbon
triple bond in 1 to afford the vinylrhodium(I) intermediate C.
The observed high regioselectivity of addition across alkyne
might be attributed to chelation control14 through the
coordination of rhodium to the carbonyl group.3b,9b The
resulting vinylrhodium(I) intermediate C undergoes intra-
molecular enantioselective nucleophilic addition to the carbonyl
group in a 5-exo mode, forming the rhodium(I) alkoxide
intermediate D, which is readily hydrolyzed under protic
conditions to regenerate A with liberation of product 3. In the
cyclization process, the enantiodifferentiating carborhodation15
takes place preferentially from the si face of the ketone carbonyl
through C II to avoid the steric congestion with bisphosphine
ligand, thereby affording the S product.
In summary, we have developed a highly efficient rhodium-
catalyzed asymmetric tandem arylation/cyclization of nitrogen-
or oxygen-bridged 5-alkynones with arylboronic acids by using
a structurally simple, commercially available chiral BINAP as
ligand. The reaction showed remarkably broad substrate scope
and excellent enantiocontrol (up to 99% ee). Importantly, this
method offers a reliable and practical access to a variety of
highly enantioenriched tertiary allylic alcohols containing a
heterocyclic skeleton, such as tetrahydrofuran or tetrahydro-
pyrrole, which are important units that have been found in
numerous natural products and pharmaceutical compounds.
Further applications of the methodology are currently under-
way in our laboratory.
Soc. 1995, 117, 6787.
(6) Ru-catalyzed reaction: Patman, R. L.; Chaulagain, M. R.;
Williams, V. M.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2066.
(7) For asymmetric reductive cyclization, see: (a) Rhee, J. U.;
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(d) Masuda, K.; Sakiyama, N.; Tanaka, R.; Noguchi, K.; Tanaka, K.
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(8) For a report of cationic Pd(II)-catalyzed asymmetric cyclization
of aroylmethyl 2-alkynoates bearing an electron-deficient alkyne to
produce optically active hydroxy lactone, see: Song, J.; Shen, Q.; Xu,
F.; Lu, X. Org. Lett. 2007, 9, 2947.
(9) (a) Shitani, R.; Okamoto, K.; Otomaru, Y.; Ueyama, K.; Hayashi,
T. J. Am. Chem. Soc. 2005, 127, 54. (b) Miura, T.; Shimada, M.;
Murakami, M. Synlett 2005, 4, 667.
(10) A single example of O-tethered 5-alkynone cyclization was
reported, giving the corresponding racemic tetrahydrofuran product in
only 21% yield due to the poor regioselectivity control; see ref 9b.
(11) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698.
(12) Yamada, T.; Iritani, M.; Minoura, K.; Kawai, K.; Numata, A. Org.
Biomol. Chem. 2004, 2, 2131.
(13) Naito, S.; Saito, A.; Furukawa, Y.; Hata, T.; Nakada, Y.;
Muramatsu, S.; Ide, J. J. Antibiot. 1994, 47, 812.
(14) For examples of the chelation-conrolled regioselective syn
addition of arylrhodium(I) to the carbon−carbon triple bond, see:
(a) Lautens, M.; Yoshida, M. Org. Lett. 2002, 4, 123 and references
cited therein. (b) Lautens, M.; Yoshida, M. J. Org. Chem. 2003, 68, 762
and references cited therein.
ASSOCIATED CONTENT
* Supporting Information
■
S
(15) (a) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169.
(b) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2894.
Experimental methods and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xumh@simm.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21325209) and the State key Laboratory of Drug Research for
financial support.
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