An efficient [3+2] annulation for the asymmetric synthesis of densely-functionalized pyrrolidinones and γ-butenolides

Article abstract of DOI:10.1039/d0cc05188h

Disclosed here is a new [3+2] annulation of siloxy alkynes that provides robust access to highly enantioenriched, densely-substituted pyrrolidinones and γ-butenolides, whose direct synthesis remains challenging. This process also represents a rare asymmetric synthesis of enantrioenriched molecules from siloxy alkynes.

Full text of DOI:10.1039/d0cc05188h

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Conformational control of nonplanar free base porphyrins:
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DOI: 10.1039/D0CC05188H
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An Efficient [3+2] Annulation for the Asymmetric Synthesis of
Densely-Functionalized Pyrrolidinones and γ-Butenolides†
Hui Qian,‡b Song Sun,‡a Wanxiang Zhao,b and Jianwei Sun*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Disclosed here is a new [3+2] annulation of siloxy alkynes that
provides robust access to highly enantioenriched, fully-substituted
pyrrolidinones and γ-butenolides, whose direct synthesis remains
challenging. This process also represents a rare asymmetric
synthesis of enantrioenriched molecules from siloxy alkynes.
O
O
CO2H
NHAc
O
O
OH
Me
NH
iPr
H
O
S
Cl
NH
HN
Me
Me
H
HO
HO
8
O
HO
OH
O
OH
O
(+)-lactacystin
Me
()-pramanicin
()-salinosporamide A
O
O
OH
Me
Ph
Pyrrolidinones (γ-lactams) and γ-butenolides are substructures
prevalent in numerous natural products and biologically active
molecules possessing diverse properties (Figure 1, e.g.,
Me
Et OH
Me
OMe
O
NH
O
O
O
Me Me Me
OH
pseurotin A
()-capensifuranone 1
antibacterial,
anticancer,
antiviral,
anti-inflammatory,
antifungal).1,2 They also serve as valuable intermediates in
organic synthesis.1,3-7 For example, pyrrolidinones are known
precursors to γ-aminobutyric acid (GABA) analogues, key
inhibitory neurotransmitters in the mammalian central
nervous system.3 After ring-opening, the chirality established
in these heterocycles could be easily imparted to the
functionalized chiral linear molecules, whose asymmetric
synthesis might not be so straightforward by direct
functionalization of the configurationally more flexible linear
framework. Consequently, asymmetric synthesis of
pyrrolidinones and γ-butenolides has been a subject of
intensive investigations over the past few decades. Although
various approaches have been developed, the majority
generate only one or two stereogenic centers.4-6 Indeed, it
remains as a formidable challenge to establish three
contiguous stereogenic centers in pyrrolidinones. Moreover,
direct access to the densely-substituted core of these two
heterocycles remains scarce (Figure 1). Here we report a new
approach to addressing these challenges by a [3+2] annulation
of siloxy alkynes.
Fig. 1 Useful molecules containing pyrrolidinones and γ-butenolide subunits.
Siloxy alkynes are versatile but less explored species in
organic synthesis.7 The polarized electron-rich C–C triple bond
has enabled them to participate in a range of annulation
processes.7,8 However, to the best of our knowledge, the
utilization of siloxy alkynes to create new stereogenic centers
in enantiospecific manner is essentially unknown. Siloxy
alkynes can participate in alkyne-carbonyl metathesis with
aldehydes to form α,β-unsaturated esters via stepwise [2+2]
cycloaddition followed by electrocyclic opening of the β-
lactone intermediate (Scheme 1a).9 We envisioned that this
process might be interrupted by using an α-amino ketone as
the reaction partner
a) Alkyne-carbonyl metathesis
R'
R
O
O-
R'
R
R
-
O
+
R'
OTIPS
+
+
O
R'
R
OTIPS
OTIPS
O
TIPS
b) Interrupted annulation with -aminocarbonyl (this work)

R2
R3
R3
O
HO
+
R2
-
R1
*
*
*
chirality transfer
*
+
R1
+
O
N
NHR'
TIPSO
-
R'
2
1
3
a. School of Petrochemical Engineering, and Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology, Changzhou University, Changzhou 213164, P.
R. China.
O
R2
R2
R3
OTIPS
IM2
R1
R3
HO
R1
b. Department of Chemistry, The Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong (Hong Kong). E-mail: sunjw@ust.hk
R'NH
N
chelation
control
O
R'
TIPS
IM1
†
Electronic
DOI: 10.1039/x0xx00000x
‡ These authors contributed equally to this work.
Supplementary
Information
(ESI)
available.
See
Scheme 1 Alkyne-carbonyl metathesis and its interrupted annulation.
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(Scheme 1b). With suitable Lewis acid activation, the initial C– ketones and siloxy alkynes participated smoothlyViienw tAhrtiicsle[O3n+li2ne]
DOI: 10.1039/D0CC05188H
C bond formation results in IM1. Instead of nucleophilic attack annulation. Ketones with different electronic properties were
from the resulting oxygen motif to form the strained four- all successful substrates. The corresponding diversely
membered oxetene, the nitrogen nucleophile is better substituted pyrrolidinone products were all generated with
positioned to cyclize with the silyl ketenium to form the five- high efficiency. The structure and stereochemistry of 3e were
membered ring IM2, which leads to pyrrolidinone 3 after confirmed unambiguously by X-ray crystallography. The mild
desilylation. Furthermore, the chirality in the α-amino ketone conditions tolerated various functional groups, including ether,
is expected to induce the two new stereogenic centers in the thioether, styrene, aryl halide, and silyl-protected alcohol.
product. In the first step, the diastereoselectivity is expected Heterocycles could also be incorporated into the products.
to be control by chelation. The final diasteroselective When the reaction was scaled up (1.8 mmol), the product yield
protonation step is expected to be thermodynamically remained excellent (92%, 3a). Notably, in all these examples,
controled.
the products were generated as a single diastereomer, and the
To test the above hypothesis, we employed the readily stereochemistry is consistent with chelation control in the
accessible enantiopure α-aminketone (R)-1a and alkyne 2a as intermolecular C–C bond forming step.
the model substrates (Table 1).10 The Brønsted acid HNTf2 was
R3
AgPF6
(10 mol%)
O
R3
OH
initially examined as a potential catalyst, as it has proven to be
superior in a range of reactions of siloxy alkynes.7,8,11
Unfortunately, no desired lactam 3a was observed (entry 1).
Next, various Lewis acids were tested. Sc(OTf)3 was catalytic
inactive either (entry 2). While the reaction could proceed in
the presence of BF3•OEt2, the desired product 3a was only
formed in 12% yield (entry 3). In contrast, silver salts with
weak counter anion were found to be much more active
(entries 4-6). Among them, AgPF6 showed the best
performance (entry 6). Next, different solvents were
compared, which identified MeCN to be the best choice.
Finally, increasing the loading of 2a combined with a higher
concentration could improve the yield to 85% (entry 11). It is
worth noting that the densely-substituted product 3a with
three contiguous stereogenic centers was formed as a single
diastereomer. More importantly, HPLC analysis confirmed that
the product was formed in the enantiopure form.
R2
R1
*
single
diastereomer
enantioenriched
R2
*
*
+
*
O
R1
NHTs
TIPSO
MeCN, rt
16 h
N
Ts
1
(R)- or (S)-
enantiopure
2
3
nBu
OH
nBu
O
nBu
O
nBu
OH
OH
Ph
OH
Ph
Ph
Ph
O
Me
Me
O
Ph
N
N
N
N
Ts
Ts
SMe
Ts
Ts
[a]
[a]
3a
3b
3c
3a
(+)- , 92%
, 83%
, 76%
()- , 86%
>99% ee
1.8-mmol scale
OMe
nBu
O
nBu
OH
Ph
OH
nBu
HO
Ph
O
Bn
N
N
O
Me
N
iPr
Ts
Ts
Ts
[a]
[a]
[a]
3d
, 73%
3e
3f
, 80%
, 76%
Cl
F
SMe
nBu
O
nBu
nBu
O
nBu
O
HO
HO
HO
HO
OMe
Me
[a]
O
Me
Me
Me
[a]
N
N
N
N
Ts
Ts
Ts
Ts
[a]
[a]
Table 1 Condition optimizationa
, 88%
, 74%
, 91%
, 94%
3g
3h
3i
3j
CF3
OMe
Me
nBu
Ph
nBu
HO
Me
nBu
O
O
HO
catalyst
nBu
O
HO
(10 mol%)
nBu
O
nBu
HO
HO
Me
Ph
CF3
+
O
OMe
Me
N
Me
N
NHTs
solvent, rt, 12 h
Me
Me
O
Me
Ts
3a
N
OTIPS
2a
N
N
Ts
Ts
Ts
Ts
single diastereomer
enantiopure
1a
(R)-
[a]
[a]
[a]
[a]
3k
3l
3m
3n
, 81%
, 67%
, 71%
, 67%
Entry
Catalyst
HNTf2
Sc(OTf)3
BF3•OEt2
AgOTf
AgNTf2
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
Solvent
Conv. (%)
Yield (%)
S
1
2
3b
4
5
6
7
8
9
10c
11d,e
DCM
DCM
DCM
DCM
DCM
< 5
< 5
54
55
50
65
74
77
93
96
100
-
-
nBu
nBu
tBu
OH
Me
OH
nBu
HO
HO
Ph
Me
O
Me
[a]
O
Me
O
Ph
O
12
31
36
46
26
38
57
75
85
N
N
N
N
Ts
Ts
Ts
Ts
[a]
3q
3r
, 70%
, 80%
3o
3p
, 90%
, 86%
DCM
TIPSO
OH
Ph
nOct
O
OH
Ph
OH
Ph
CHCl3
toluene
MeCN
MeCN
MeCN
Me
N
O
Me
O
Me
N
N
Ts
Ts
Ts
, 77%[b] (94%)[c]
3u
, 78%[b] (87%)[c]
3s
, 78%
3t
AgPF6
Scheme 2. Scope for the synthesis of pyrrolidinones. Reaction scale: 1 (0.3
mmol), 2 (0.6 mmol). Isolated yield. a(S)-1 was used. bRun at 50 oC for 48 h. cYield
in parentheses is based on recovered starting material.
aReaction scale: (R)-1a (0.05 mmol), 2a (0.1 mmol), solvent (0.5 mL). The
conversion, yield, and dr values are based on 1H NMR analysis of the crude
product using CH2Br2 as an internal standard. Run with 1.5 equiv of BF3•OEt2.
cRun with 1.5 equiv of 2a. dRun with 2.0 equiv of 2a. eConc. = 0.2 M.
b
The success in the synthesis of γ-lactams prompted us to
further explore its extension to the synthesis of γ-
butyrolactones from the corresponding α-hydroxy ketones.
With the above optimized conditions, we examined the
reaction scope (Scheme 2). A range of enantiopure α-amino
2 | J. Name., 2012, 00, 1-3
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O
BF3•OEt2
R3
R2
R3
Unfortunately, under the standard conditions, the reaction
between 4 and 2a resulted in no desired lactone formation.
Instead, ester 5 was formed, likely via initial silver activation of
the electron-rich alkyne followed by nucleophilic addition by
the hydroxy group and then desilylation.
View Article Online
R1
R2
+
(1.2 equiDv)OI: 10.1O039/D0CC05188H
R1
TIPSO
DCM (0.1 M), rt
12 h
O
OTMS
7
single diastereomer
enantioenriched
6
2
(0.2 mmol)
(0.3 mmol)
F
OMe
nBu
Me
O
AgPF6
nBu
O
Ph
O
nBu
(10 mol%)
Me
nBu
O
nBu
Me
OH
Ph
O
O
+
2a
(1)
Ph
Me
O
O
MeCN, rt
44%
nBu
O
Me
O
Ph
Me
Ph
O
Me
O
O
4
5
O
7a
7b
7c
7d
7e
, 77%
, 97%
, 80%
, 95%
, 84%
To minimize the interference of the free hydroxy group but
still retain its ability to participate in cyclization, we
hypothesized that suitable protection of the hydroxy with a
labile TMS group might solve the problem. Thus, substrate 6a
was evaluated for this process (Scheme 3). While silver salts
proved to be incapable of catalyzing the desired lactone
formation, considerable efforts were devoted to further
optimization. Finally, we were delighted to find that BF3•OEt2
could promote the formation of γ-butenolide 7a in 97% yield.
No obvious erosion in enantiopurity was observed in this
process (98% ee confirmed by HPLC). We also evaluated other
less labile silyl groups (e.g., TBS), but they were inferior. We
believe that the key role of the TMS group is to avoid the path
in eq. 1 in the first step, thereby permitting the desired C–C
bond formation to form IM3. Next, a silyl shift likely forms
IM4, which cyclizes to form IM5. Further desilylation and
elimination led to the observed product 7a.
nBu
O
Ph
OTIPS
nOct
O
Ph
Me
Ph
Ph
Me
Ph
Me
O
O
O
O
O
O
O
Me
Ph
O
7f
7g
7h
7i
7j
, 76%
, 92%
, 84%
, 64%
, 83%
Scheme 4 Scope for the synthesis of γ-butenolides.
The enantioenriched pyrrolidinone products are useful
synthetic precursors to other chiral molecules (Scheme 5). The
free hydroxyl group in 3a could be easily eliminated under
basic conditions to form α,β-unsaturated lactam 9.
Alternatively, it could also be protected to form silyl ether 10,
which then underwent ring-opening to form Weinreb amide
11. It is worth noting that 11 can be regarded as an important
precursor to the densely-functionalized γ-amino acids, a family
of valuable molecules in medicinal chemistry.3 In retrospect,
comparing with the starting material L-alanine 12, the
formation of 11 is a formal insertion of a two-carbon unit with
defined stereochemistry between carbonyl and the α-carbon
in 12 without touching the chirality of the amino group. Partial
reduction with DIBAL at –78 oC resulted in formation of
hemiaminal 13, which could serve as an attractive
intermediate toward pyrrolidines substituted at all positions
upon reacting with different nucleophiles. For example, in the
presence of BF3•OEt2, allylation could proceed quantitatively
to form 14, which has four consecutively stereogenic centers.
It is worth mentioning that pyrrolidine is another important
unit widely present in natural alkaloids.12 Notably, in all these
transformations, the products were all formed as a single
diastereomer.
O
Ph
Me
7a
nBu
BF3•OEt2
(1.2 equiv)
Me
Ph
OTMS
2a
+
O
O
DCM, rt, 12 h
97%
(98% ee)
6a
(R)-
TMSO Ph
Me
nBu
OTIPS
TMS
O
Ph
TMSO
O
Ph
O
nBu
nBu
O
Me
Me
O
O
TIPS
IM3
IM4
IM5
TIPS
Scheme 3 Synthesis of γ-butenolides.
Next we examined the scope using the optimized protocol
(Scheme 4). Various enantioenriched α-siloxy ketones,
including those with electron-withdrawing and electron-
donating substituents, were subjected to the annulation with
siloxy alkynes. The corresponding enantioenriched densely-
substituted γ-butenolides were all obtained with high
efficiency.
TMSO
Me nBu
Me
nBu
O
(b)
Ph
Me
(c)
2
1
N
MeO
NHTs
88%
87%
N
Ph OTMS
O
Ts
10
11
inserted
unit
nBu
O
OH
Ph
formal insertion
between C1 and C2
The result in eq. 1 prompted us to examine whether amide 8
could serve as a viable intermediate toward the cyclization
product 3f by intramolecular aldol-type cyclization (eq. 2). In
fact, treating 8 with AgPF6 in MeCN did not form lactam 3f,
which ruled out this possibility.
nBu
O
Ph
Me
(a)
Me
Me
N
N
2
98%
HO
1
Ts
3a
NH2
Ts
()-
O
9
12
nBu
HO
nBu
HO
HO
Ph
Ph
Me
(d)
73%
OMe
O
(e)
Me
AgPF6
N
nBu
HO
Me
N
(10 mol%)
quant.
Ts
(2)
Ts
X
TsN
O
MeCN, rt
MeO
O
Me
13
14
N
nBu
Ts
Scheme 5 Product transformations. (a) MeONa, MeOH; (b) TMSOTf, 2,6-lutidine,
8
3f
, not observed
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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DCM; (c) MeO(Me)NH•HCl, iPrMgCl, THF; (d) DIBAL, DCM, –78 oC; (e)
allyltrimethylsilane, BF3•OEt2, MeCN.
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In conclusion, we have developed a new [3+2] annulation for
the robust asymmetric synthesis of chiral pyrrolidinones,
which complements their conventional synthetic strategies,
particularly in view of the establishment of three consecutive
stereogenic centers. This process also represents a rare
demonstration of using siloxy alkynes to access
enantioenriched molecules. With suitable design, the use of α-
aminoketones successfully interrupted the bond-forming
sequence in the alkyne-carbonyl metathesis to furnish a more
favored five-membered ring structure. With the superior
catalyst AgPF6, the chirality in the α-aminoketones induced the
two newly established stereogenic centers in the
pyrrolidinones with excellent stereospecificity. This protocol
was also successfully extended to the efficient synthesis of
chiral γ-butenolides with slight modification of the α-hydroxy
ketones as well as the Lewis acid activator. The heterocyclic
products are not only valuable themselves in medicinal
chemistry but also useful synthetic precursors to other
important chiral molecules, such as GABA and pyrrolidine
derivatives.
6
Reviews (a-c) and selected examples (d-h) for the
asymmetric synthesis γ-butenolides: a) M. Seitz and O.
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Kitson, A. Millemaggi, and R. J. K. Taylor, Angew. Chem. Int.
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Financial support was provided by NSFC (91956114), Jiangsu
specially appointed professors program, and Hong Kong RGC
(GRF16302719, 16302617). We thank Herman H. Y. Sung for
help in structure elucidation by X-ray crystallography.
7
8
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Conflicts of interest
There are no conflicts to declare.
Notes and references
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three simple steps from L-alanine:
(1) N-protection
(2) Weinreb amide formation
O
HOOC
Me
Me
Ph
NH2
(3) Grignard reagent
84% yield (3 steps)
NHTs
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