Copper-Catalyzed Enantioselective Synthesis of β-Amino Alcohols Featuring Tetrasubstituted Tertiary Carbons

Article abstract of DOI:10.1002/adsc.201701613

Here we report a copper-catalyzed asymmetric propargylic substitution reaction to prepare tetrasubstituted β-amino-β-ethynyl alcohols in high yields and with enantiomeric ratio (er) up to 94:6. This transformation generates tetrasubstituted tertiary carbons by utilizing stable cyclic carbonates and amines as substrates, economical copper catalysts, and easily accessible ligands. (Figure presented.).

Full text of DOI:10.1002/adsc.201701613

Title: Copper-Catalyzed Enantioselective Synthesis of β-Amino
Alcohols Featuring Tetrasubstituted Tertiary Carbons
Authors: Lan Tian, Liang Gong, and Xia Zhang
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10.1002/adsc.201701613
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Catalyzed Enantioselective Synthesis of β-Amino
Alcohols Featuring Tetrasubstituted Tertiary Carbons
Lan Tian,a,† Liang Gong,a,† and Xia Zhanga,*
a
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative
Innovation Center for Biotherapy, Chengdu, PR China
These authors contribute equally.
†
Email: zhang-xia@scu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Here we report a copper-catalyzed asymmetric
propargylic substitution reaction to prepare tetrasubstituted
β-amino-β-ethynyl alcohols in high yields and with
enantiomeric ratio (er) up to 94:6. This transformation
generates tetrasubstituted tertiary carbons by utilizing
stable cyclic carbonates and amines as substrates,
economical copper catalysts, and easily accessible ligands.
Keywords: copper; catalysis; propargylation;
tetrasubstituted β-amino-β-ethynyl alcohols
Figure 1. Natural products and bioactive molecules
containing tetrasubstituted β-amino alcohols.
The
enantioselective
construction
of
tetrasubstituted tertiary carbons remains one of the
most challenging tasks in synthetic chemistry. One
difficulty lies in the steric congestion imposed by
four attached substituents.[1] In addition, the
stereoselective construction of tetrasubstituted
tertiary carbons requires bond-forming reactions that
yield the correct absolute configuration.[2] It is even
more challenging if the product molecules are acyclic
because of the rotational freedom associated with the
acyclic structures.[3] Tetrasubstituted chiral amino
alcohols contain such carbon centers and are
important scaffolds present in many natural products
and bioactive molecules (Figure 1). For example,
myriocin is a potent immunosuppressant (IC50 value
of 15 nM) and a widely used chemical probe in the
sphingolipid
research.[4]
Natural
products
salinosporamide A (IC50 = 11 ng/mL against HCT116
colon cancer cells)[5], omuralide[6], and lactacystin[7]
are potent proteasome inhibitors. Lycodoline shows
inhibitory activities against butyrylcholinesterase.[8]
Thus, the construction of tetrasubstituted chiral amino
alcohols is of high interest in the fields of organic
chemistry and medicinal chemistry. However, to
build such motifs from simple and readily available
starting materials remains daunting in synthetic
chemistry probably because of the difficulties
mentioned above, and only a limited number of
synthetic methodologies were reported.[9]
Scheme 1. The copper-catalyzed propargylic substitution
reactions to make tetrasubstituted chiral amino alcohols.
Nishibayashi and co-workers reported a copper-
catalyzed asymmetric synthesis of propargyl β-amino
alcohols using ethynyl epoxides as starting materials
(Scheme 1a).[9b] The Kleij group reported an
asymmetric approach of generating α,α-disubstituted
1
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10.1002/adsc.201701613
Advanced Synthesis & Catalysis
allylic β-amino alcohols based on a palladium-
catalyzed allylic amination.[9c] Our group decided to
construct tetrasubstituted chiral amino alcohols that
contain a linear shaped propargyl group. When
compared with other bulkier groups, the linear shaped
propargyl group may lead to less steric hindrance on
a tetrasubstituted tertiary carbon center. Moreover,
the terminal propargyl group is a versatile functional
group, allowing for a plethora of further chemical
transformations.[10] In this work, we developed an
asymmetric approach using stable cyclic carbonates
as substrates, economical copper catalysts, and easily
accessible ligands to enable practical synthesis of
tetrasubstituted β-amino-β-ethynyl alcohols. This
method provides access to complex tetrasubstituted
β-amino-β-ethynyl alcohols in high yields with
enantiomeric ratio (er) up to 94:6.
3a in excellent yield and good enantioselectivity
(Table 1, entry 12). The reaction conditions are mild,
involving Et3N as the base, the reaction temperature
at -20 °C, 1 mol% of CuI, and 2 mol% of ligand L2.
The key factors that affected the yield and
enantioselectivity of this transformation are listed in
Table 1. The identity of copper salt is critical,
because the use of CuCl or Cu(OTf)2 dramatically
reduced the er of the products and slightly reduced
the reaction yield (entries 1-2). In the absence of a
ligand, (±)3a was produced in lower yield (entry 4).
If the base was omitted, the reaction did not proceed
(entry 13). Among the four ligands screened, L2
yielded the best results in terms of reaction yield and
enantioselectivity. Further screening of the reaction
Table 2. Scope of the propargyl carbonate substrates.a).
Inspired by the previously reported copper-
[11]
catalyzed propargylic substitution reactions,
we
investigated a model reaction between propargyl
carbonate 1a and 4-toluidine 2a (Table 1). We
identified conditions that yielded the target molecule
Table 1. Optimization of reaction conditions.a)
OH
1 mol% CuI
2 mol% (S,S)-L2
NH2
O
O
Ph
O
Et3N, toluene
Me
Ph NHTol
-20 o
C
2a
1a
3a
Me
O
O
PPh2
PPh2
N
N
N
N
N
PPh2
R
R
R = Me, (S,S)-L1
R = Bn, (S,S)-L2
S-(-)-L3
L4
Entry
[Cu]
Ligand
Base
Solvent
Yield[%] (er)b)
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
Cu(OTf)2
CuCl
CuI
1
2
3
4
5
6
L1
L1
toluene
toluene
toluene
toluene
toluene
toluene
84(60:40)
88(71:29)
92(85:15)
56(50:50)
96(92:08)
68(67:33)
L1
CuI
none
L2
CuI
CuI
L3
CuI
CuI
iPr2NEt
DBU
7
8
L4
L2
toluene
toluene
82(66:34)
88(85:15)
CuI
CuI
K2CO3
Et3N
9
L2
L2
toluene
toluene
66(57:43)
95(92:08)
10
11c)
12d)
13
CuI
Et3N
Et3N
L2
toluene
toluene
92(90:10)
CuI
none
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L2
L2
L2
L2
L2
L2
L2
L2
L2
98(94:06)
N.R.e)
toluene
THF
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
14
80(61:39)
78(56:44)
85(73:27)
75(60:40)
65(53:47)
70(90:10)
95(93:07)
MeOH
DCM
15
16
DMF
17
MeCN
18
19f)
20g)
toluene
toluene
Et3N
Et3N
a) Reaction conditions: All reactions of 1 (0.20 mmol) with
2a (0.24 mmol) were carried out in the presence of CuI
a) Reaction conditions: All reactions were run at 0.2 mmol
scale, under nitrogen, 1 mL solvent, and -20 °C for 2 h. b)
1
(0.002 mmol), (S,S)-L2 (0.004 mmol), and Et N (0.04
Yields were determined by H-NMR and er were
3
determined by HPLC. c) 5 mol% of base. d) 20 mol% of
base. e) No reaction. h) -78 °C for 10 h. g) One pot.
2
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10.1002/adsc.201701613
Advanced Synthesis & Catalysis
b)
c)
mmol) in toluene (1.0 mL) at -20 °C. Isolated yield.
Determined by HPLC.
with 2 (0.24 mmol) were carried out in the presence of CuI
(0.002 mmol), (S,S)-L2 (0.004 mmol), and Et3N (0.04
b)
c)
mmol) in toluene (1.0 mL) at -20 °C. Isolated yield.
Determined by HPLC. d) 0 °C, 4 h.
conditions revealed that toluene served as the best
solvent compared with THF, MeOH,
dichloromethane, DMF, or MeCN (entries 14-18).
Lowering the reaction temperature significantly
reduced the product yield (entry 19).
With the optimized conditions in hand, we
proceeded to explore the scope of this transformation.
As shown in Table 2, a variety of aryl propargyl
carbonates could be converted to the corresponding
product in excellent isolated yields and with moderate
enantioselectivities (3a-h). For example, propargyl
carbonates with both electron-rich (3b) and electron-
deficient (3d and 3g) aromatic rings were effective
reaction partners. Those containing halogenated
aromatic rings (3d, 3f, and 3g) were tolerated.
Propargyl carbonates bearing naphthyl group (3c) and
heterocyclic moieties (3h) underwent this reaction
smoothly and generated products in excellent
yields.[12] The absolute configuration of 3c was
determined by X-ray crystallography.[13]
The scope with respect to the amine reaction
partner was summarized in Table 3. Aryl amines
containing electron-donating (3i, and 3n-p) or
electron-withdrawing groups (3j-l) could engage in
this reaction. Those with para- (3i-l), meta- (3o) and
ortho- (3n-p) substitutions were tolerated. The use of
an alkyl amine yielded product 3q in moderate yield
and er.
Table 3. Scope of the amines.a)
a) Sonagashira reaction
MeO
O
NHTol
OMe
MeO
3b,
86:14 er
Pd(PPh3)2Cl2
CuI, TMG
NHTol
HO
OMe
O
THF, r.t. 8 h
HO
4, 50% yield, 86:14 er
I
b) Synthesis of indole
MeO
MeO
NHTol
N
NHTol
Pd(PPh3)2Cl2
CuI, TMG
I
Ts
DMF, 40 °C
TsHN
HO
HO
5, 65% yield
86:14 er
3b, 86:14 er
c) Hydrogenation
F3C
F3C
NHTol
NHTol
Pd/C, H2
MeOH
Me
r.t. 24 h
HO
3k, 85:15 er
HO
6, 90% yield, 85:15 er
d) Click reaction
Me
NHTol
OH
OH
Ph
N
N
O
N
3a, 94:6 er
CuSO4 5H2O
NaASc
HO
N
Me
NH
+
H
H2O:tBuOH=1:1
O
N
O
O
N
O
H
Me
7, 85% yield, 92:8 dr
N
O
Me
OH
Zidovudine
N3
Scheme 2. Product Derivatization.
To further demonstrate the utility of this method,
we performed some derivatization reactions on our
products. For example, Sonagashira coupling
installed an aryl group onto compound 3b, yielding
a)
Reaction conditions: All reactions of 1a (0.20 mmol)
3
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10.1002/adsc.201701613
Advanced Synthesis & Catalysis
compound 4.[14] The reaction of 3b with an ortho-
iodo aniline derivative resulted in the formation of
indole 5. The terminal alkyne group in 3h could also
be reduced to an ethyl (6) group smoothly. We then
made a Zidovudine derivative 7 (Scheme 2).[15]
Zidovudine is an FDA approved drug for preventing
and treating AIDS, which is also on the World Health
Organization’s List of Essential Medicines.[16] Taking
advantage of the click reaction,[10a] we obtained
compound 7 from 3a and Zidovudine in 85% yield.
Not surprisingly, the enantiopurity of the alkyne
starting materials was translated to the corresponding
products in all cases.
Langridge-Smith, H. B. Broughton, T. M. Dunn, J. H.
Naismith, D. J. Campopiano, J. Am. Chem. Soc. 2013,
135, 14276-14285.
[5] R. H. Feling, G. O. Buchanan, T. J. Mincer, C. A.
Kauffman, P. R. Jensen, W. Fenical, Angew. Chem.
Int. Ed. 2003, 42, 355-357.
[6] H. Tomoda, S. Omura, Yakugaku Zasshi 2000, 120,
935-949.
[7] G. Fenteany, R. F. Standaert, W. S. Lane, S. Choi, E.
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[9] a) W. S. Guo, A. J. Cai, J. N. Xie, A. W. Kleij,
Angew. Chem. Int. Ed. 2017, 56, 11797-11801; b) G.
Hattori, A. Yoshida, Y. Miyake, Y. Nishibayashi, J.
Org. Chem. 2009, 74, 7603-7607; c) A. J. Cai, W. S.
Guo, L. Martinez-Rodriguez, A. W. Kleij, J. Am.
Chem. Soc. 2016, 138, 14194-14197.
[10] a) H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew.
Chem. Int. Ed. 2001, 40, 2004-2021; b) X. W. Wu, B.
Wang, Y. Zhou, H. Liu, Org. Lett. 2017, 19, 1294-
1297; c) K. Sonogashira, Y. Tohda, N. Hagihara,
Tetrahedron Lett. 1975, 4467-4470; d) R. Z. Li, H.
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Zhang, Z. Y. Fu, J. Liu, S. Y. Yang, D. Jia, D. W.
Niu, Chem 2017, 3, 834-845.
In summary, we report an efficient copper-
catalyzed
asymmetric
approach
to
form
tetrasubstituted β-amino-β-ethynyl alcohols in high
yields and with er up to 94:6. This procedure utilizes
stable cyclic carbonates and amines as substrates,
economical copper catalysts, and easily accessible
ligands. This method is amenable for the preparation
of various tetrasubstituted β-amino-β-ethynyl
alcohols, including those with ortho-substitutions and
heterocycles. The utility of these products was further
demonstrated by their straightforward derivatization
reactions.
Experimental Section
[11] a) R. J. Detz, M. M. E. Delville, H. Hiemstra, J. H.
van Maarseveen, Angew. Chem. Int. Ed. 2008, 47,
3777-3780; b) G. Hattori, H. Matsuzawa, Y. Miyake,
Y. Nishibayashi, Angew. Chem. Int. Ed. 2008, 47,
3781-3783; c) G. Hattori, K. Sakata, H. Matsuzawa,
Y. Tanabe, Y. Miyake, Y. Nishibayashi, J. Am. Chem.
Soc. 2010, 132, 10592-10608; d) A. Yoshida, G.
Hattori, Y. Miyake, Y. Nishibayashi, Org. Lett. 2011,
13, 2460-2463; e) R. J. Detz, Z. Abiri, R. le Griel, H.
Hiemstra, J. H. van Maarseveen, Chem. Eur. J. 2011,
17, 5921-5930; f) C. Zhang, Y. H. Wang, X. H. Hu,
Z. Zheng, J. Xu, X. P. Hu, Adv. Synth. Catal. 2012,
354, 2854-2858; g) M. Shibata, K. Nakajima, Y.
Nishibayashi, Chem. Commun. 2014, 50, 7874-7877;
h) K. Tsuchida, Y. Senda, K. Nakajima, Y.
Nishibayashi, Angew. Chem. Int. Ed. 2016, 55, 9728-
9732.
Synthesis of (R)-2-phenyl-2-(p-tolylamino)but-3-yn-
1-ol (3a): in a nitrogen-filled glove-box, CuI (0.002 mmol,
1 mol%) and (S,S)-L2 (0.004 mmol, 2 mol%) were
dissolved in anhydrous toluene (0.5 mL). The resulting
solution was capped with a septum, taken out of the glove-
box, and heated at 60 °C for 1 h. The reaction flask was
then cooled to -20 °C. To this flask was sequentially added
a solution of 4-acetenyl-4-phenyl-1,3-dioxolan-2-one (1a,
0.2 mmol, 1.0 equiv.) in toluene, and a solution of p-
toluidine (0.24 mmol，1.2 equiv.) and triethylamine (0.04
mmol) in toluene by a gas-tight syringe. The reaction flask
was kept at -20 °C for 2 h. The solvent was concentrated
under reduce pressure and the residue was purified by
column chromatography (SiO2) using petroleum ether and
ethyl acetate (30:1 to 10:1) as eluents to give 3a as a white
solid (50 mg, 0.199 mmol, 98%).
Acknowledgements
We acknowledge gratefully the funding from State Key
Laboratory of Biotherapy and Cancer Center, West China
Hospital, Sichuan University.
[12] We tried a propargyl carbonate with a cyclohexyl
group. However, no reaction occured under standard
conditions.
[13] CCDC-1584495 contains the supplementary
crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge
Crystallographic Data Centre via
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10.1002/adsc.201701613
Advanced Synthesis & Catalysis
Elkins, J. Moye, P. Stratton, J. Balsley, New Engl. J.
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5
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10.1002/adsc.201701613
Advanced Synthesis & Catalysis
UPDATE
Copper-Catalyzed Enantioselective Synthesis of β-
Amino Alcohols Featuring Tetrasubstituted
Tertiary Carbons
Adv. Synth. Catal. Year, Volume, Page – Page
Lan Tian, Liang Gong, and Xia Zhang*
6
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