Broad Spectrum Enolate Equivalent for Catalytic Chemo-, Diastereo-, and Enantioselective Addition to N-Boc Imines

Article abstract of DOI:10.1021/jacs.5b11248

Alkynyl ketones are attractive but challenging nucleophiles in enolate chemistry. Their susceptibility to other reactions such as Michael additions and the difficulty of controlling the enolate geometry make them difficult substrates. Mannich-type reactions, which previously have not been reported using N-carbamoyl-imines with simple ketone enolates, became our objective. In this report, we describe the first direct catalytic Mannich-type reaction between various ynones and N-Boc imines, whose stereocontrol presumably derives from catalyst control of enolate geometry. This method produces α-substituted β-amino ynones with excellent chemo-, diastereo-, and enantioselectivity. The products can be readily transformed into a broad range of molecular scaffolds upon further one-step transformations, demonstrating the utility of ynones as masked synthetic equivalents for a variety of unsymmetrically substituted acyclic ketones. In particular, alkynyl alkyl ketones resolve the long-standing problem of the inability to use the enolates of unsymmetrical dialkyl ketones lacking α-branching for regio- and stereoselective reactions.

Full text of DOI:10.1021/jacs.5b11248

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Article
Broad Spectrum Enolate Equivalent for Catalytic Chemo-,
Diastereo-, and Enantioselective Addition to N-Boc Imines
Barry M. Trost, and Chao-I (Joey) Hung
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11248 • Publication Date (Web): 02 Dec 2015
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Broad Spectrum Enolate Equivalent for Catalytic Chemo-, Diastereo-,
and Enantioselective Addition to N-Boc Imines
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Barry M. Trost* and Chao-I (Joey) Hung
Department of Chemistry, Stanford University, Stanford, California 94305-5580, United States
ABSTRACT: Alkynyl ketones are attractive but challenging nucleophiles in enolate chemistry. Their susceptibility to oth-
er reactions such as Michael additions and the difficulty of controlling the enolate geometry make them difficult sub-
strates. Mannich-type reactions, which previously have not been reported using N-carbamoyl-imines with simple ketone
enolates became our objective. In this report, we describe the first direct catalytic Mannich-type reaction between various
ynones and N-Boc imines, whose stereocontrol presumably derives from catalyst control of enolate geometry. This meth-
od produces -substituted -amino ynones with excellent chemo-, diastereo- and enantioselectivity. The products can be
readily transformed into a broad range of molecular scaffolds upon further one-step transformations, demonstrating the
utility of ynones as masked synthetic equivalents for a variety of unsymmetrically substituted acyclic ketones. In particu-
lar, alkynyl alkyl ketones resolve the longstanding problem of the inability to use the enolates of unsymmetrical dialkyl
ketones
lacking
-branching
for
regio-
and
stereoselective
reactions.
INTRODUCTION
geometric selectivity of the enolization process. Thus, in
attempting to develop the addition of such a ketone with
an electrophile under catalytic conditions, up to eight total
isomers are possible (eq. 2).
C-C bond formation through enolate chemistry is one of
the most fundamental and broadly utilized transfor-
mations in modern synthetic organic chemistry. Over the
past few decades, significant progress in this field has been
made not only in achieving high levels of control in addi-
tions to diverse electrophiles, but also with processes that
no longer require stoichiometric generation of the enolate
intermediates.1 Alkynyl ketones are valuable yet underex-
plored nucleophiles in this active area of research. Their
propensity to act as Michael acceptors and the difficulty of
controlling the enolate geometry due to lack of steric bulk
on the acetylene moiety render them challenging sub-
strates.2 Nonetheless, ynones are versatile building blocks
for structural proliferation into various synthetic targets.3
The high metallophilicity of the acetylene moiety can be
employed in chemoselective C-C bond formations such as
[2+2+2] cycloadditions,4 alkyne-alkyne or alkene-alkyne
coupling,5 and reductive coupling reactions.6 The adjacent
carbonyl group also allows rapid construction of various
heterocycles.7 The valuable ability of ynone enolates to act
as a broad spectrum enolate equivalent is significant, es-
pecially in a lead generation program in drug discovery,
where rapid access to a broad diversity of skeletal classes is
required.
Scheme 1. Problems and Known Strategy to Selective-
ly Functionalize Unsymmetrical Dialkyl Ketones
One way to generate regio-defined acyclic dialkyl ketone
enolates involves the metal-catalyzed reductive coupling
of ,-unsaturated ketones via hydrogenation (eq. 3).8 In
such processes, the selected enone first undergoes 1,4-
addition by hydride to generate the reactive enolate inter-
mediate, which then is trapped by the desired electro-
phile.9,10 Although effective, this strategy is generally ap-
plied to ketones bearing a simple vinyl group. Since an
alkyne can function as a masked alkane, the use of ynones
also provides a potential route to direct regio-, diastereo-,
Our initial motivation derived from the fact that un-
symmetrical acyclic ketones lacking functionality in prox-
imity of the carbonyl group, such as 3-hexanone, do not
participate in reactions proceeding through enol or eno-
lates with high chemo-, regio-, diastereo-, and enantiose-
lectivity. As shown in eq. 1 (Scheme 1), the source of these
difficulties lies in the inability to control the regio- and
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and enantioselective modification on nonsymmetrical fore anticipated the possibility of ynones to overcome this
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2
3
4
5
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8
dialkyl ketones (Scheme 2). This particular strategy relies
on an acetylene moiety on one side of the ketone, prevent-
ing enolization on that side. After performing the enolate
chemistry, the acetylene moiety can be transformed into a
variety of compounds, including fully saturated unsym-
metrical ketones via hydrogenation.
observed limitation due to the unique steric and electron-
ic properties of the alkyne group. The excellent properties
of Boc as a nitrogen protecting group make the use of N-
Boc imines preferentially attractive. However, curiously,
according to a recent review, there are no examples of
simple ketone enolates serving as suitable donors for such
imines.14 To illustrate the difficulty of controlling the eno-
late geometry via traditional approaches even in the case
of alkynyl ketones, a control experiment using imine A
and ynone B was conducted under standard enolate con-
ditions (eq. 5). As expected, poor diastereoselectivity of
1.25 : 1 was obtained, suggesting the lack of steric differen-
tiation between the oxygen and the acetylene moiety. In
this respect, the catalyst must exercise control of the eno-
late geometry.
Scheme 2. Ynones as Advantageous Acyclic Donors in
Enolate Chemistry
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Scheme 3. Control Experiments
RESULTS AND DISCUSSION
Reports of direct catalytic enolization of ynones for en-
antioselective additions are rare.11 Previous examples in
the literature mainly focus on aldol reactions between
aldehydes and methyl ynones, and good diastereocontrol
was only observed in the presence of an α-hydroxy group.
More importantly, the use of ynones in Mannich-type
reactions is unknown. The lack of methods for diastereo-
and enantioselective Mannich-type reactions of ynones
and the valuable -substituted -amino ynone products
provided a fitting challenge and opportunity for the fur-
ther development of our metal-ProPhenol system.12 The
commercially available ProPhenol ligand is a member of
the aza-crown family that was mainly inspired by the
work of Cram on chiral crown compounds.13 When treat-
ed with an alkyl metal reagent such as Et2Zn or Bu2Mg,
this proline-derived ligand spontaneously assembles into
a chiral dinuclear metal complex via deprotonation of the
three hydroxyl groups. The resulting complex contains a
Lewis acidic site to activate an electrophile and a
Brønsted basic site to deprotonate a pronucleophile.
Despite previous success in an array of direct asymmet-
ric aldol and Mannich-type reactions using zinc-
ProPhenol catalysis, the scope of donors has been re-
stricted to methyl ketones (acetophenones,12a acetone,12e
methyl vinyl ketone,12f methyl ynones11a) or unsubstituted
α-hydroxy carbonyl compounds.12f-g To demonstrate the
difficulty of using higher alkyl ketones, a control experi-
ment using 3-hexanone and imine A was conducted. As
shown in eq. 4 (Scheme 3), no desired Mannich product
was observed using the Zn-ProPhenol catalyst. We there-
We initiated our studies with silyl-protected ynone 2a
as the model substrate since it is less likely to undergo
undesired Michael addition due to steric bulk (Table 1).
Benzyldimethylsilyl group was chosen due to the poten-
tial subsequent functionalization via Hiyama cross-
coupling.15 Moreover, Boc-protected aldimine 1a was se-
lected for initial optimization process due to its stability
and ease of handling. Astonishingly, the first experiment
using 2 equivalents of 2a and aldimine 1a in the presence
of 20 mol% of Zn-ProPhenol catalyst produced a near
perfect result (entry 1), in which the desired Mannich ad-
duct 3a was obtained as a single diastereomer in 99%
yield and 97% ee. This result suggested that our catalyst
system did generate one enolate isomer preferentially
over the other. Decreasing the catalyst loading to 10 mol%
did not show any detrimental effect. Although excellent
selectivity was retained by further decreasing the catalyst
loading to 5 mol%, the reaction never proceeded to full
conversion even at room temperature (entry 3). Subse-
quent optimization showed that ynone 2a can be reduced
to 1.2 equivalents to give 3a in 99% yield and excellent
diastereo- and enantioselectivity (entry 5). To our delight,
reactions with alkyl-substituted ynone 2g, which is more
prone to undergo undesired Michael additions, gave
comparable results despite minor erosion of the diastere-
oselectivity (entry 7), and further adjustment of the reac-
tion temperature did not give significant improvement
(entry 8 & 9). Eventually, by reducing the catalyst loading
to 5 mol%, 3h was obtained as a single diastereomer in
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91% yield with excellent ee (entry 10). The high conver-
sion of 2g with only 5 mol% of catalyst in contrast to 2a
Table 2. Scope of the Reaction with Aromatic Iminesa
1
2
3
4
5
6
7
8
might potentially be due to the absence of the bulky silyl-
protecting group directly attached to the acetylene moie-
ty. Finally, it should be noted that the ligand can be easily
recovered and recycled via chromatography (80% recov-
ery), hence enhancing the effective turnover number.
entry
1
3
Structure
yieldb
99%
dr/ee
>20 : 1,
99%
a
Table 1. Optimization of the reaction conditionsa
9
>20 : 1,
91%
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2
b
95%
>20 : 1,
99%
3
c
88%
86%
>20 : 1,
98%
4
d
>20 : 1,
99%
entry
3
x
equiv. of yieldb
2, T (°C)
drc
eed
5
e
f
75%
95%
>20 : 1,
92%
1
2
3e
3a
3a
3a
3a
3a
3a
3h
3h
3h
3h
20
10
5
2, 4
2, 4
99%
95%
78%
96%
99%
85%
93%
70%
95%
91%
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
15 : 1
97%
99%
98%
97%
99%
99%
99%
99%
95%
99%
6
2, rt
9.5 : 1,
99%
4
10
10
10
10
10
10
5
1.5, 4
1.2, 4
1.0, 4
1.2, 4
1.2, -10
1.2, rt
1.2, 4
7
g
89%
91%
5
>20 : 1,
99%
6
8b
h
7
8
16 : 1
13 : 1,
92%
9
10e
15 : 1
9b
i
j
81%
>20 : 1
17 : 1,
96%
10b
85%
aReaction conditions: : 0.24 mmol 1, x mol% L1, 2x mol%
Et2Zn (1.0 M in hexanes), 4 Å molecular sieves (10 mg), in
THF (0.3 M) at the indicated temperature and concentration.
16 : 1,
99%
bIsolated yield. Determined by 1H-NMR analysis. dDeter-
c
e
mined by HPLC on a chiral stationary phase. Reaction was
done in 0.6 M THF.
11b
k
91%
NA,
With the optimized conditions in hand, we then evalu-
ated the generality of this catalytic process (Table 2). On
the acceptor side, a variety of aromatic N-Boc aldimines
was successfully reacted with ynone donors. Both elec-
tron-withdrawing and electron-donating groups were
tolerated in ortho, meta, and para positions. Heteroaro-
matic imines also gave the product in high yields and se-
lectivities without poisoning the Zn catalyst. On the do-
nor side, a variety of functional groups, including alkenes,
unprotected terminal acetylenes, esters, protected alco-
hols, arenes, and bulky alkyl chains were tolerated with-
out significant perturbation of the reactivity and selectivi-
ties, demonstrating the high chemoselectivity of this cata-
lytic process. Moreover, as described in the optimization
table, reactions with alkyl-substituted ynones were per-
formed using 5 mol% loading of catalyst (3h-3k).
12c
13c
l
85%
85%
97%
NA,
m
94%
NA,
92%
14c
15c
n
o
83%
80%
NA,
95%
aReaction conditions: 0.24 mmol 1, 0.29 mmol 2, 10 mol% L1,
20 mol% Et2Zn, 4 Å molecular sieves (10 mg), in THF (0.3 M)
at 4 °C for 16 h. bReaction run with 5 mol% catalyst in THF
(0.6 M). cReaction run at -10 °C for 48 h.
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This reaction can also be performed using simple me- as in L4 also showed a decrease in ee as well as yield (en-
1
2
3
4
5
6
7
8
thyl ynones as donors (3l-3o) to give high yields and ex-
cellent selectivity at -10 °C. To show the scalability and
practicality of the method, several examples (3h, 3k, 3m)
were performed at 2.4 mmol scale, giving comparable
results to the small-scale reactions. In contrast to the re-
sult from the control experiment (Scheme 3), our new
approach can allow the formation of ynone 3j in 85%
yield with excellent ee and dr. In addition, N-Dpp pro-
tected imines were also examined. However, low conver-
sions and selectivities were observed (See SI Table S5).
try 6). ProPhenol L6, which has shown to improve the
enantioselectivity of aldol reaction of glycinate benzo-
phenone imines, did not result in any beneficial effect.11i
Initial examination using aliphatic imine 1k, on the
other hand, led to complete isomerization to the corre-
sponding enecarbamate under typical reaction conditions
(entry 1, Table 4). This observation suggested the -
proton of imine 2k is comparably or even more acidic
than the -protons of ynone 2a under the reaction condi-
tions. Fortunately, we were able to overcome this unde-
sirable process via slow addition of the imine. Subsequent
adjustments of the addition rate as well as the equiva-
lence of imine gave 84% yield and 85% ee as a single dia-
stereomer (entry 5). Finally, further ligand optimization
showed that the same non-C2-symmetric ligand L2 was
optimal for the enantioselectivity (entry 6).
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Table 3. Optimization with α,β-unsaturated imine 1j a
Table 4. Optimization with aliphatic imine 1ka
entry
L
equiv.
of 1k
slow
add. (h)
yieldc
drd
eee
entry
L
x
T (°C)
yieldb
88%
68%
60%
96%
75%
85%
63%
80%
drc
9 : 1
9 : 1
10 : 1
9 : 1
7 : 1
8 : 1
8 : 1
9 : 1
eed
1
L1
L1
L1
L2
L3
10
10
5
4
-10
4
75%
77%
74%
88%
77%
82%
65%
70%
1b
2
3
L1
L1
L1
L1
L1
L2
L3
L4
1.0
2.0
2.0
2.0
1.5
0
3
n.p.
32%
55%
88%
84%
89%
75%
86%
NA
NA
2
3
4
5
6
7
8
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
82%
80%
85%
85%
95%
80%
88%
6
10
10
4
4
5
12
12
12
12
12
4
L4 10
L5 10
L6 10
4
6
7
8
1.5
4
1.5
4
1.5
aReaction conditions: : 0.24 mmol 1, x mol% L, 2x mol%
Et2Zn (1.0 M in hexanes), 4 Å molecular sieves (10 mg), in
THF (0.3 M) at the indicated temperature for 8 h. bIsolated
aReaction conditions: : 0.24 mmol 2a, x mol% L, 2x mol%
Et2Zn (1.0 M in hexanes), 4 Å molecular sieves (10 mg), in
THF (0.3 M) at rt and stirred for 12 h after imine addition.
bNo desired product. cIsolated yield. dDetermined by 1H-NMR
analysis. eDetermined by HPLC on a chiral stationary phase.
c
yield. Determined by 1H-NMR analysis. dDetermined by
HPLC on a chiral stationary phase.
The catalytic process was also applicable to nonaro-
matic imines. Using the standard conditions with L1, α,β-
unsaturated imine 1j gave high product yields and dia-
stereoselectivity (entry 1, Table 3). To enhance the enan-
tioselectivity of this process, several ligands were exam-
ined, especially the recently developed non-C2-symmetric
ProPhenol ligands, which have shown to improve the
enantioselectivity substantially in the vinylation reaction
previously described.12h To our delight, the combination
of p-trifluoromethylphenyl and phenyl in the prolinol
backbone L2 was found to be optimal without perturbing
the conversion and diastereoselectivity (entry 4). Interest-
ingly, when switching to the more electron-rich ligand L3
(entry 5), the enantioselectivity was similar to the parent
ProPhenol ligand L1. The differential enantioinduction of
L2 was further demonstrated by performing the reaction
with the C2-symmetric analogous L5, in which significant
decreases in yield and enantioselectivity were observed
(entry 7). Curiously, using a donor-acceptor substituted
With the optimized conditions, different nonaromatic
N-Boc imines were examined (Table 5). In general, good
to excellent selectivities were observed. More important-
ly, imines bearing two enolizable -protons were also
compatible substrates in this process (entry 6 & 7), giving
the corresponding ynones in excellent yields and selectiv-
ities. The incorporation of these highly enolizable imines
not only considerably enhances the scope of this reaction,
but also serves as a rare occasion where simple ketones
are used as successful donors.14
Table 5. Reaction with Nonaromatic Imines
entry
3
Structure
yieldb
dr/ee
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We then further elaborated the obtained products 3 to
9 : 1,
88%
1
2
3
4
5
6
7
8
demonstrate their synthetic utility, especially with respect
to library design in which each Mannich adduct can be
converted into a wide diversity of scaffolds via a single
step (Scheme 4). These transformations also validate the
utility of ynones as a masked synthetic equivalent for a
variety of unsymmetrically substituted acyclic ketones.
Ketones with different degrees of unsaturation can be
readily prepared. Pd-C catalyzed hydrogenation gave the
fully saturated ketone 3ha in 95% yield, demonstrating an
efficient route to products equivalent to direct functional-
ization of unsymmetrical dialkyl ketones via two effective
atom-economic catalytic addition processes. Our previ-
ously developed Ru-catalyzed hydrosilylation and subse-
quent same-pot desilylation with CsF gave (E)-enones
3hb and 3ma in good yields,16 whereas (Z)-enone 3ja was
generated upon partial hydrogenation using Lindlar’s
catalyst with quinoline. Heterocycles, including pyrazole
3ka, pyrimidine 3na, and triazole 3hc, were obtained in
excellent yields using literature single-step processes.7a-c
Upon NaBH4 reduction, chiral propargyl alcohol 3da was
prepared in high yield with 8 : 1 dr, and the relative con-
figuration was determined by NOESY after cyclization to
the cyclic carbamate 3db using NaH. The benzyldime-
thylsilyl group was removed during the reaction as well
due to in situ-generated tert-butoxide.
1a
p
q
86%
90%
9 : 1,
91%
2a
>20 : 1,
99%
3a
r
s
86%
89%
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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>20 : 1,
95%
4b
>20 : 1,
94%
5b
6b
t
85%
95%
>20 : 1,
98%
u
>20 : 1,
97%
7b
v
95%
aReaction conditions: 0.24 mmol 1, 0.29 mmol 2, 10 mol% L2,
20 mol% Et2Zn (1.0 M in hexanes), 4 Å molecular sieves (10
mg), in THF (0.3 M) at 4 °C for 8 h. bReaction run with drop-
wise addition of imines (1.5 equiv) over 12 h at rt.
A 6-endo-dig cyclization catalyzed by in situ-generated
PPh3AuSbF6 gave pyridinone 3mb in 96% yield,17 which is
Scheme 4 Exemplified One-Step Structural Diversification of -Amino Ynones
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an important intermediate for a later total synthesis
(Scheme 5). -Substituted ynones, which have never been
employed in this type of transformation, reacted sluggish-
ly with significant epimerization at the -position using
the same catalyst, but changing to a more -donating
NHC ligand gave 3hd and 3jb in high yields without any
side reaction. The relative configurations of the -
substituted -amino ynones were unambiguously deter-
compounds from the Lythraceae alkaloid family,24 one
1
2
3
4
5
6
7
8
noticeable example being (-)-decinine 7, which can be
readily synthesized from 6.25 The total synthesis of 6 fur-
ther demonstrated the exceptional synthetic utility of our
methodology incorporating ynones, in which cyclic ter-
tiary alkaloids can be readily constructed from the com-
mon backbone 3.
The absolute configuration of the C-N bond of 3 was
further confirmed using O-methylmandelic amides26
9
1
mined by comparing the vicinal homonuclear H-1H cou-
9
and 9’ derived from 3da after Boc removal using TFA and
the subsequent same-pot EDC coupling (Scheme 6). Sub-
stantial anisotropic magnetic effects were observed on H1
and H2 of 9 due to the proximal phenyl ring on the O-
methylmandelic acid moiety in the most stable confor-
mation. Similar shielding effect was also observed on the
3,4-dimethoxyphenyl group of 9’ when the opposite enan-
tiomer of O-methylmandelic acid was applied.
pling constants upon Au-catalyzed 6-endo-dig cycliza-
tions, which are consistent with other results reported in
the literature.18 Using our reported Pd-catalyzed alkyne-
alkyne coupling conditions, heavily functionalized enyne
3pa was obtained in 82% yield with excellent stereo- and
chemoselectivity.5c Finally, Ru-catalyzed [2+2+2] cycload-
dition19 with 1-hexyne gave -amino indanone 3kb, a
member of a class of molecule that can modify muscarinic
receptor activity for treating or alleviating diseases,20 in
93% yield as a single regioisomer.
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Scheme 6. Determination of Absolute Stereochemis-
try using O-Methylmandelic Acid
Scheme 5. Total Synthesis of (-)-Lasubine II
The proposed catalytic cycle is depicted in Scheme 7.
After the formation of the dinuclear Zn-ProPhenol com-
plex 10, deprotonation of ynone 2 occurs and places the
nucleophile in a chiral environment (11 and 11’), in which
the enolate can adopt either the (E)- or (Z)-geometry with
reversible interconversion. N-Boc imine 1 then enters the
reaction cycle, and binds preferentially to the catalyst
system bearing the (Z)-enolate via a bidentate coordina-
tion to both zinc atoms (12). This explains the high dia-
stereoselectivity of the reaction even when the electro-
philes were introduced in slow addition as shown in the
case of aliphatic imines. The particular arrangement of 12
minimizes the steric interactions of notably R and R1 of
both substrates and the corresponding prolinol diphenyl
ligand substituents. The enolate then attacks the electro-
phile to give intermediate 13 with the observed stereo-
Pyridinone 3mb was readily converted into (-)-lasubine
II 6 (Scheme 5), which was originally isolated from the
leaves of Lagerstroemia subcostata koehne by Fuji et al.21
The quinolizidine moiety is widely encountered in drug-
like compounds and natural products of potential biolog-
ical activities.22 After Pd-C catalyzed hydrogenation,
ZnBr2-mediated Boc deprotection followed by a same-pot
intramolecular SN2 displacement under basic condition
furnished quinolizidine 5 in 85% yield. Other typical Boc
removal conditions, including TFA, TMSOTf, HCl in or-
ganic solvents, thermolysis, and other metallic Lewis ac-
ids, generally resulted in ring-opening via elimination of
the C-N bond due to the adjacent electron-rich aromatic
group. Subsequent reduction using L-selectride gave (-)-
lasubine II 6 in 93% yield as a single diastereomer.23 Alka-
loid 6 is also an essential fragment in many bioactive
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Experiment details, compound characterization data, and
spectra. This material is available free of charge via the In-
ternet at http://pubs.acs.org.
chemistry. Finally, deprotonation of ynone 2 liberates the
Mannich-adduct 3, and turnovers the catalytic cycle.
1
2
3
4
5
6
Scheme 7. Proposed Catalytic Cycle
Experimental procedures and compound characterization
description (PDF)
Compound spectra (PDF)
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8
AUTHOR INFORMATION
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Corresponding Author
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bmtrost@stanford.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Institutes of Health (GM-033049) and
the National Science Foundation (CHE-1360634) for their
generous support of our program. We also thank Dr. Stephen
R. Lynch (Stanford University) for conducting NOE experi-
ments.
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CONCLUSION
The present study provides a highly chemo-, diastereo-,
and enantioselective Mannich-type reaction using ynones
as the donors catalyzed by the Zn-ProPhenol complex.
This method tolerates a variety of functional groups on
the donors and acceptors, allowing rapid construction of
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Mannich products in a catalytic fully selective manner.
More importantly, the products offer rapid access to a
broad spectrum of chiral-amine-containing skeletal types
utilizing the synthetic versatility of the ynone moiety, and
also provide an effective route to selectively functionalize
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proach can facilitate lead discovery in medicinal chemis-
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complex natural products. Considering the broad scope
and functional group compatibility of this methodology
along with the high diastereo- and enantioselectivity, we
anticipate that this process can be expanded to other
electrophiles, such as aldehydes, ketones, or ketimines,
offering new classes of chiral ynones ready for structural
diversification.
ASSOCIATED CONTENT
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