Asymmetric Multicomponent Reactions for Efficient Construction of Homopropargyl Amine Carboxylic Esters

Article abstract of DOI:10.1021/acs.orglett.9b02139

Developing an efficient and highly enantioselective protocol to access homopropargyl amines is of high interest to the synthetic community and also remains a formidable challenge for organic chemists. Here, we present integrated Rh₂(OAc)₄- and BINOL-derived chiral phosphoric acid cooperatively catalyzed three-component reactions of alkynyldiazoacetates, imines with various nucleophiles including alcohols, indoles, and N,N-disubstituted anilines, affording the corresponding homopropargyl amines containing two vicinal chiral centers in satisfactory yields with high to excellent diastereo- and enantioselectivities.

Full text of DOI:10.1021/acs.orglett.9b02139

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Asymmetric Multicomponent Reactions for Efficient Construction of
Homopropargyl Amine Carboxylic Esters
Sifan Yu, Ruyu Hua, Xiang Fu, Gengxin Liu, Dan Zhang, Shikun Jia, Huang Qiu,* and Wenhao Hu*
Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University,
Guangzhou 510006, China
*
S Supporting Information
ABSTRACT: Developing an efficient and highly enantioselective protocol
to access homopropargyl amines is of high interest to the synthetic
community and also remains a formidable challenge for organic chemists.
Here, we present integrated Rh (OAc) - and BINOL-derived chiral
2
4
phosphoric acid cooperatively catalyzed three-component reactions of
alkynyldiazoacetates, imines with various nucleophiles including alcohols,
indoles, and N,N-disubstituted anilines, affording the corresponding
homopropargyl amines containing two vicinal chiral centers in satisfactory
yields with high to excellent diastereo- and enantioselectivities.
nantiomerically pure homopropargyl amines are versatile
building blocks for the synthesis of many bioactive
been few alternative strategies to access chiral β-branched
homopropargyl amines (Scheme 1b), demand for developing
novel complementary strategies for the enantioselective syn-
thesis of homopropargyl amines is expected to remain strong in
this field.
6
E
1
,2
compounds and natural products,
such as indolizidine
2
a
2c,d
2
09B and hederacine A.
As such, developing enantiose-
lective synthetic methods for these compounds is of great
3
interest to the synthetic community. A traditionally synthetic
Asymmetric multicomponent reactions (AMCRs) represent a
powerful and efficient method for construction of enantiomeri-
cally pure organic compounds with complexity as well as skeletal
approach toward α-branched homopropargyl amines is
enantioselective propargylation of Schiff bases with various
4
7
propargyl or allenyl metal reagents (Scheme 1a), and
diversity. As intermediates of high interest, ylide or zwitterionic
intermediates that were generated in situ by metal-associated
carbenes derived from diazo compounds and an array of
nucleophiles have been recognized as key intermediates in
Scheme 1. Efficient Construction of HPACEs
8
−11
several novel AMCRs.
The reactivity profile of ylide or
zwitterionic intermediates, which are heavily dependent on the
structure of the substituents adjacent to the diazo carbon, have
significant influence on the selectivity and efficiency of the
12,13
AMCRs.
α-Aryldiazoacetates are among the most widely
used substrates in AMCRs, and there are also limited elegant
9f,13b
examples with α-alkyldiazoacetates
and α-alkenyldiazoace-
10a
14
tates. In contrast, the AMCRs with alkynyldiazoacetates
remain unexplored according to our current best knowledge in
this area. Herein, we present highly enantioselective three-
component reactions of alkynyldiazoacetates, imines with three
kinds of nucleophiles including alcohols, indoles, and N,N-
disubstituted anilines, which provide an efficient access to α,β-
disubstituted homopropargyl amine carboxylic esters (HPA-
CEs) bearing a quaternary stereogenic center (Scheme 1c).
The initial proof-of-concept experiment was performed under
a dinitrogen atmosphere with methyl 2-diazo-4-(trimethylsilyl)-
but-3-ynoate 2a added to a solution of 4-bromobenzyl alcohol
considerable efforts have been made to develop catalytically
1
a and imine 3a in the presence of Rh (OAc) (2.0 mol %) and
2 4
asymmetric methods, relying on developing novel chiral metal
5
BINOL-derived chiral phosphoric acid (CPA) 4a (10.0 mol %)
complexes. However, these propargylation reactions that
involve the use of stoichiometrically synthesized or pregenerated
propargyl or allenyl metals would strongly limit the chemical and
functional diversity of the final products. Although there have
Received: June 20, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02139
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
via a syringe pump for 15.0 min at 0 °C. The desired product 5a
was obtained in 90% yield with dr 5:1 and 12% ee. Then various
BINOL-derived CPAs 4 were screened. The substituents on the
BINOL-derived CPAs had a significant impact on the diastereo-
and enantioselectivity, albeit a negligible impact on the yield of
the three-component product 5a. Gratifyingly, the BINOL-
derived CPAs 4h with a bulky triphenylsilyl group (SiPh3)
afforded the three-component product 5a in 91% yield with dr
Table 1. Substrate Scope of Three-component Reactions of 1
and 2 with 3
a
9
:1 and 94% ee; replacement of dirhodium tetraacetate with
several dirhodium catalysts including Rh (TFA) , Rh (esp) ,
2
4
2
2
and Rh (Oct) did not give any enhanced results. Other Rh(I),
2
4
Pd(0), Pd(II), Cu(I), Cu(II), Au(I), and Ag(I) catalysts, have
been proven to be unsuitable in our current system. We then
explored different solvents in the three-component reaction.
DCE and PhMe were capable of this transformation, albeit in
lower yield and decreased diastereo- and enantioselectivity of
the product 5a, whereas THF dramatically diminished the yield.
Moreover, a decrease or increase in temperature failed to
improve the enantioselectivity of this transformation (see the
Supporting Information for details).
With the optimized reaction conditions in hand, we then
investigated the substrate scope of imines for this trans-
formation. As shown in Table 1, a variety of imines with
electron-withdrawing groups such as Br, F, CF , Ac, CO Me,
3
2
and NO , some functional groups that are problematic in
2
traditionally synthetic approaches, were well tolerated in the
three-component reaction (products 5b−g), furnishing the
corresponding three-component products in good to excellent
yields (70−85%), with good to excellent dr (9:1 to >20:1) and
excellent ee (90−94%). The methyl-substituted imines was also
suitable for this reaction, affording the product 5h in the highest
yield (92%), but with lowest ee (68%) and average dr (10:1). To
our delight, imines with meta- and ortho-substituents success-
fully afforded the corresponding products 5i and 5j in acceptable
yield (60−85%) with good dr (10:1) and excellent ee (92−
a
Reaction conditions: 1a/2a/3a/4/ Rh (OAc) = 0.36/0.36/0.30/
.03/0.006 mmol and 2a in 1.0 mL of solvent was added into a
9
6%). Furthermore, the aldimine containing sulfur-substituted
2
4
0
heterocyclic rings, (E)-N-4-Br-phenyl-1-(thiophene-2-yl)-
methanimine, was proven to be compatible with this reaction
solution of 1a, 3a, 4, Rh (OAc) , and 100 mg 4 Å MS in 1.0 mL of
solvent via a syringe pump under a dinitrogen atmosphere for 15.0
min, and the resulting mixture was stirred for another 1.0 h.
2
4
(
product 5k). Next, the scope of this transformation with
respect to the alcohol component was investigated. For different
types of alcohols, this asymmetric three-component reaction
proceeded smoothly to provide the corresponding three-
component products in a satisfactory manner (products 5l−
o). To test the steric tolerance of the reaction, we chose the very
bulky fluorenol as the alcohol component, and an array of
alkynyldiazoacetates were investigated. A variety of methyl/
ethyl alkynyldiazoacetates containing silyl groups including
TMS, TES, TBS, and TIPS were well tolerated in this
transformation (products 5p, 5q, 5r, 5u, and 5v). Interestingly,
alkynyldiazoacetates containing a chloro functional group and a
long alkyl chain successfully gave the corresponding products 5s
and 5t in satisfactory yields (64−80%) with excellent dr (15:1−
Scheme 2. Synthesis of Gram-Scale Transformations of 5q
>
20:1) and ee (92−95%).
As shown in Scheme 2, to illustrate the synthetic utility of this
transformation, a gram-scale experiment with fluorenol, diazo
compound 2c, and imine 3a was carried out in the presence of
Rh (OAc) and 4h at 0 °C in DCM for 2 h, affording 1.03 g of 5q
2
4
in 72% yield without diminishing the dr (10:1) and ee (92%).
Furthermore, treatment of 5q with lithium borohydride
yield. Compound 11 could be efficiently transformed into
triazole compound 12 in 89% yield via a copper(I)-catalyzed
azide−alkyne cycloaddition (CuAAC). The structure and
absolute stereochemistry of 5q and 11 were confirmed by X-ray
crystallographic analysis of 12 (Figure 1a, CDCC 1902392).
(
LiBH ) gave 10 in 88% yield with the same diastereo- or
4
16
enantioselectivity. In addition, the TIPS group of 5q could be
efficiently removed by treatment with tetrabutylammonium
15
fluoride (TBAF) in THF at 0 °C, furnishing 9 in moderate
B
DOI: 10.1021/acs.orglett.9b02139
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Organic Letters
Letter
good yields (products 8a−d). Meanwhile, various imines and
alkynyldiazoacetates were suitable for this asymmetric three-
component reaction with N-benzylindole (products 8e−g). The
absolute configuration of 8a was determined to be (1S,2S) by X-
ray crystal diffraction analysis (Figure 1b, CDCC 1892221).
Interestingly, improved results were obtained when we chose
N,N-dibenzylaniline as the nucleophile component (products
9
a−d). Remarkably, excellent diastereo- and enantioselectivities
were observed in all cases.
To gain more mechanistic insights of these novel three-
component reactions, further control experiments and kinetic
isotope effect (KIE) studies were performed. First, we prepared
the O−H insertion product 13 form 1b and 2a with Rh (OAc)
2
4
as the catalyst (C−H insertion product 14 and 15, see the
Supporting Information for details). However, upon addition of
imine 3a, three-component product 5o was not detected under
standard reaction conditions (similar results were obtained with
N-benzylindole a or N,N-dibenzylaniline 7a; see the Supporting
Information for details). In the novel three-component
reactions, the aziridine 16 was also a possible intermediate
that underwent a ring-opening process to form the observed
three-component reaction products. To clarify this issue, we
performed the reaction of 2e and 3a under standard reaction
conditions, and only a trace of aziridine 16 was observed by LC−
MS; further addition of 1b (6a or 7a) did not give any detectable
three-component reaction products 5s (8a or 9a). These control
reactions exclude the possibility that the three-component
products (5o/5s and 8a, 9a) were formed from the addition of
the O−H/C−H insertion products to 3a or the aziridine ring-
opening reactions with respective nucleophiles by a stepwise
pathway (Scheme 3a). Additionally, a KIE experiment was
performed with N,N-dibenzylaniline 7a and its deuterated
Figure 1. X-ray single crystal structures of 12 and 8a.
Very recently, our research group reported several AMCRs via
trapping of active zwitterionic intermediates generated by metal
carbenes with carbon-centered nucleophiles such as indoles and
10a,13c
N,N-disubstituted anilines.
We further envisioned that this
three-component strategy would enable highly efficient
syntheses of enantiomerically rich α,β-disubstituted homopro-
pargyl amines bearing an all-carbon quaternary stereogenic
center, which is a particularly challenging task in modern organic
synthesis. As shown in Table 2, we were very pleased to find that
indoles and N,N-dibenzylanilines were suitable for this trans-
formation under the above optimized reaction conditions.
Various substituted N-benzylindoles underwent this trans-
formation smoothly to give the corresponding products in
Scheme 3. Mechanism Studies of the Three-Component
Reactions
Table 2. Substrate Scope of Three-Component Reactions of
a
6
/7 and 2 with 3
a
Reaction conditions: the same as Table 2.
C
DOI: 10.1021/acs.orglett.9b02139
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
analogue [D]-7a. A KIE value of 1.0 suggested that the C−H
bond cleavage of 7a was not related to the rate-limiting step
scope. Further investigations toward the biological activities of
these polyfunctionalized HPACEs are ongoing in our
laboratory.
(Scheme 3b). Overall, these observations were consistent with
our previously proposed mechanism via a trapping reaction
reactive intermediate pathway (Scheme 3c).
8a
ASSOCIATED CONTENT
Supporting Information
■
The stereoselective outcome of the three-component reaction
with alkynyldiazoacetates is in agreement with our previous
observation on three-component reactions with aryl diazoes-
S
*
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02139.
1
0a
ters. As shown in Scheme 4, with the interaction model
Experimental procedure and spectroscopic data for all
new compounds (PDF)
Scheme 4. Proposed Transition State for the Three-
Component Reactions
Accession Codes
CCDC 1892221 and 1902392 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: qiuhuang@mail.sysu.edu.cn.
E-mail: huwh9@mail.sysu.edu.cn.
ORCID
Dan Zhang: 0000-0003-0200-8527
Wenhao Hu: 0000-0002-1461-3671
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the Guangdong
Innovative and Entrepreneurial Research Team Program (No.
2016ZT06Y337), National Natural Science Foundation of
China (21801255), National Science & Technology Major
Project (2018ZX09711002-006), and Natural Science Founda-
tion of Guangdong Province (2018A030310141).
17
proposed by Simon and Goodman, the stereochemistry for
́
these three-component reactions catalyzed by BINOL-derived
CPA 4h can be well rationalized (TS I). For example, the
energetically favorable E-imine 3a, activated by 4h through
hydrogen bonding between 4h proton and the nitrogen of 3a, is
used to trap the zwitterionic intermediates generated in situ by
metal-associated carbenes derived from alkynyldiazoacetates
and N-benzylindole. Meanwhile, the direction of the 3a N-
phenyl group is proposed to be toward the empty side of the
catalyst pocket; then the acidic C−H proton of the newly
formed zwitterionic intermediates coordinates the Lewis basic
phosphoryl oxygen atom via a weak hydrogen bond; further
nucleophilic carbon attacks the imine and the following proton
transfer occurs through the BINOL-derived CPA 4h to give the
product (1S,2S)-8a with the observed stereochemistry. Using
the same model, the observed stereochemistry for the three-
component reaction with alcohols can also be rationalized by a
similar transition state (TS II) to give (2R,3S)-5a.
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