Organocatalytic Enantioselective Conia-Ene-Type Carbocyclization of Ynamide Cyclohexanones: Regiodivergent Synthesis of Morphans and Normorphans

Article abstract of DOI:10.1002/anie.201908495

Described herein is an organocatalytic enantioselective desymmetrizing cycloisomerization of arylsulfonyl-protected ynamide cyclohexanones, representing the first metal-free asymmetric Conia-ene-type carbocyclization. This method allows the highly efficient and atom-economical construction of a range of valuable morphans with wide substrate scope and excellent enantioselectivity (up to 97 % ee). In addition, such a cycloisomerization of alkylsulfonyl-protected ynamide cyclohexanones can lead to the divergent synthesis of normorphans as the main products with high enantioselectivity (up to 90 % ee). Moreover, theoretical calculations are employed to elucidate the origins of regioselectivity and enantioselectivity.

Full text of DOI:10.1002/anie.201908495

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Organocatalytic Enantioselective Conia-Ene-Type
Carbocyclization of Ynamide-Cyclohexanones: Regiodivergent
Synthesis of Morphans and Normorphans
Authors: Longwu Ye, Yin Xu, Qing Sun, Tong-De Tan, Ming-Yang
Yang, Peng Yuan, Shao-Qi Wu, Xin Lu, and Xin Hong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201908495
Angew. Chem. 10.1002/ange.201908495
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http://dx.doi.org/10.1002/ange.201908495

10.1002/anie.201908495
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Asymmetric Catalysis
Organocatalytic Enantioselective Conia-Ene-Type Carbocyclization of
Ynamide-Cyclohexanones: Regiodivergent Synthesis of Morphans and
Normorphans
Yin Xu, Qing Sun, Tong-De Tan, Ming-Yang Yang, Peng Yuan, Shao-Qi Wu, Xin Lu,* Xin Hong, and
Long-Wu Ye*
Abstract: Catalytic carbocyclization of alkynyl carbonyls has attracted
considerable interest in organic synthesis because of its high bond-
forming efficiency and atom economy in the formation of
functionalized cyclic compounds. However, examples of such an
asymmetric version are quite scarce, and have so far been limited to
transition metal catalysts. Described herein is an organocatalytic
enantioselective desymmetrizing cycloisomerization of arylsulfonyl-
protected ynamide-cyclohexanones, which represents the first metal-
free asymmetric Conia-ene-type carbocyclization. This method allows
the highly efficient and atom-economical construction of a range of
valuable morphans with wide substrate scope and excellent
scarce,[3d,4c] and these methods often suffer from limited substrate
scope, inaccessible starting materials and low efficiency.
H
Me
N
N
R
N
H
N
H
O
O
H
O
H
H
(R = methyl, ethyl, allyl group)
nervous system agent
CO2Me
daphniyunnine A
anti-inflammatory
agent
kopsone
HO
Ph
Ph
N
HN
N
HN
enantioselectivity (up to 97% ee). In addition, such
a
O
O
O
O
HO
O
cycloisomerization of alkylsulfonyl-protected ynamide-
N
H
cyclohexanones can lead to the divergent synthesis of normorphans
as the main products with high enantioselectivity (up to 90% ee).
Moreover, theoretical calculations are employed to elucidate the
origins of regioselectivity and enantioselectivity.
antitumor agent
(+)-azaprophen
actinobolamine
peduncularine
Figure 1. Morphans and normorphans in bioactive molecules and natural
products.
Introduction
Recently, catalytic carbocyclization of alkynyl carbonyls or
alkynyl silyl enol ethers has attracted considerable interest in
organic synthesis because of its high bond-forming efficiency and
atom economy in the formation of functionalized cyclic
compounds.[5-8] Despite these significant achievements, examples
of such an asymmetric version are quite scarce.[9-11] In 2005,
Toste et al. reported the first enantioselective intramolecular
Conia-ene reaction of alkynyl β-dicarbonyl compounds by
employing a Pd(II)/Yb(III) dual catalyst (Scheme 1a).[9a] On the
basis of this work, the relevant Conia-ene-type carbocyclizations
were further nicely explored by Shibasaki[9b] and Shibata,[9c]
respectively, via a similar bimetallic cooperative catalysis. In
The structurally diverse and interesting family of bridged N-
heterocycles, such as morphans and normorphans, are important
structural motifs that have been found in a number of bioactive
molecules and natural products (Figure 1).[1,2] Although many
impressive strategies have been established for their construction
in the past decades,[3,4] the practical synthesis of these
medicinally significant structures remains an intriguing objective
for the synthetic community, especially those with high
enantioselectivity. To date, successful examples of asymmetric
assembly of morphans and normorphans have been quite
addition,
the
enantioselective
metallo-organocatalyzed
[]
Y. Xu, T.-D. Tan, M.-Y. Yang, P. Yuan, Prof. Dr. L.-W. Ye
State Key Laboratory of Physical Chemistry of Solid Surfaces,
Key Laboratory for Chemical Biology of Fujian Province, and College
of Chemistry and Chemical Engineering, Xiamen University, Xiamen
361005, China
carbocyclization was realized by Michelet/ Ratovelomanana-Vidal
and Enders (Scheme 1b).[10] Very recently, Dixon et al.
demonstrated an elegant protocol for the chiral silver complex
and chiral amine co-catalyzed desymmetrization of 4-
propargylamino cyclohexanones that led to enantioenriched
morphans (Scheme 1c).[11] Although notable successes have
been achieved, these asymmetric carbocyclization reactions have
so far been limited to transition metal catalysts, especially the
chiral metal complexes, and such a metal-free protocol has not
been reported to date.
E-mail: longwuye@xmu.edu.cn
Q. Sun, Prof. Dr. X. Lu
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key
Laboratory for Theoretical and Computational Chemistry of Fujian
Province, and College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005, China
E-mail: xinlu@xmu.edu.cn
Ynamides are special alkynes bearing an electron-
withdrawing group on the nitrogen atom, and have proven to be
versatile building blocks in organic synthesis over the past
decade.[12] Importantly, the nitrogen atom is able to impose an
electronic bias, almost invariably rendering regioselective
nucleophilic α-addition by a diverse range of nucleophiles via
keteniminium intermediates under transition metal and Brønsted
acid catalysis. As a continuation of our work on developing
ynamide chemistry for heterocycle synthesis,[13] we herein report
S.-Q. Wu, Prof. Dr. X. Hong
Department of Chemistry, Zhejiang University, Hangzhou 310027,
China
Prof. Dr. L.-W. Ye
State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, Shanghai
200032, China
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
1
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10.1002/anie.201908495
Angewandte Chemie International Edition
the realization of an organocatalytic enantioselective
desymmetrizing cycloisomerization of arylsulfonyl-protected
ynamide-cyclohexanones, which represents the first example of a
whereas the use of only tertiary amine (without chiral secondary
amine) gave no conversion at all, indicating no involvement of a
racemic background reaction caused by the external base.[15] The
tertiary amine here most likely serves as a base to promote the
enamine formation via the reaction with 1a for the generation of
the enolate species and the protonated amine. Gratifyingly,
subsequent investigations on the reaction concentration and
solvent (Table 1, entries 7–10) demonstrated that 2a was
obtained in 95% yield with 95% ee by using PhCF3 (0.2 M) as
solvent (Table 1, entry 10). It should be specially mentioned that
the formation of normorphan 2a was detected in 35% yield in the
presence of tBuOH/H2O (1:1) as solvent (Table 1, entry 11) while
almost no 2a (<3%) was obtained in all of the other cases given
above (Table 1, entries 1–10).
completely
metal-free
asymmetric
Conia-ene-type
carbocyclization. In addition, a rare cyclization on the β-position of
the ynamide is also achieved.[14] This protocol allows the highly
efficient and atom-economical construction of various valuable
morphans with wide substrate scope and excellent
enantioselectivity
cycloisomerization
(Scheme
1d).
Moreover,
a
similar
ynamide-
of
alkylsulfonyl-protected
cyclohexanones can lead to the divergent synthesis of
normorphans as the main products with high enantioselectivity.
Theoretical calculations are employed to elucidate the origins of
regioselectivity and enantioselectivity. In this paper, we wish to
report the results of our detailed investigations of this
organocatalytic enantioselective carbocyclization of ynamide-
cyclohexanones, including substrate scope, synthetic applications,
biological tests, and mechanistic studies.
Table 1. Optimization of reaction conditions.[a]
Yield [%][b] ee [%][c]
Entry
Catalyst
Reaction conditions
1
3a
3b
3c
3c
3d
3d
3d
3d
3d
3d
3d
50 (45)
<1 (90)
34 (60)
85 (<1)
10 (84)
20 (71)
35 (57)
72 (19)
83 (8)
<1
<1
86
85
96
96
95
95
87
95
93
toluene (0.05 M), 80 °C, 72 h
toluene (0.05 M), 80 °C, 72 h
toluene (0.05 M), 80 °C, 72 h
toluene (0.05 M), 80 °C, 48 h
toluene (0.05 M), 80 °C, 72 h
toluene (0.05 M), 80 °C, 72 h
toluene (0.10 M), 80 °C, 72 h
toluene (0.20 M), 80 °C, 72 h
PhCl (0.20 M), 80 °C, 72 h
2
3
4[d]
5[d]
6[e]
7[e]
8[e]
9[e]
10[e]
11[e,f]
95 (<1)
41 (<1)
PhCF3 (0.20 M), 80 °C, 36 h
tBuOH/H2O (1:1, 0.20 M), 80 °C, 64 h
[a] Reaction conditions: 1a (0.1 mmol), catalyst (20 mol %),
1
solvent (0.05-0.2 M), 80 °C, 36-72 h in vials. [b] Measured by H
NMR using diethyl phthalate as internal standard; unreacted
starting material in parenthesis. [c] Determined by HPLC analysis.
i
[d] 20 mol % of Pr2EtN was used as additive. [e] 20 mol % of
Et3N was used as additive. [f] 2a was formed in 35% NMR yield.
Scheme 1. Asymmetric catalytic carbocyclization of alkynyl carbonyls.
Ts = 4-toluenesulfonyl.
Results and Discussion
Cyclohexanone-tethered ynamide 1a was chosen as the
model substrate for our initial study, and selected results are
listed in Table 1.[15,16] To our delight, the desymmetrizing
cycloisomerization of 1a proceeded smoothly in the presence of
only proline 3a as catalyst, and importantly, the corresponding
morphan 2a was formed in 50% yield via an unusual addition on
the β-position of the ynamide (Table 1, entry 1). Of note, previous
silver-catalyzed carbocyclization of enol ether-tethered ynamides
occurred exclusively at the α-position of the ynamide.[8a] Although
the typically successful diarylprolinol silyl ether catalyst 3b was
inefficient in this reaction (Table 1, entry 2), the sterically less
demanding desilyloxy derivatives 3c-3d were found to be
effective chiral organocatalysts (Table 1, entries 3–6), and 96%
ee was obtained in the presence of 3d (Table 1, entries 5 and 6).
Interestingly, the use of tertiary amines as additives significantly
accelerated the reaction efficiency (Table 1, entries 3–6),[9f,17]
With the optimal reaction conditions in hand (Table 1, entry
10), we then assessed the scope of this enantioselective
organocatalytic desymmetrizing reaction for the synthesis of
morphans 2 (Table 2). Besides the Ts-protected ynamide, the
reaction also proceeded smoothly with MBS-, SO2Ph- and 2-
Naph-protected ynamides, affording the desired morphans 2b
(68%, 91% ee), 2c (96%, 94% ee) and 2d (90%, 92% ee),
respectively. In addition, various aryl-substituted ynamides
bearing either electron-withdrawing or -donating groups were
good substrates to afford products 2e–2m in 82−97% yields and
88−97% ee, and especially ynamides with ortho-substituted aryl
motifs were also tolerated. The reaction was also extended to the
naphthyl-substituted ynamide to produce the corresponding 2n in
2
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10.1002/anie.201908495
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Interestingly, when Ms-protected ynamide 4a was employed
under the above optimized reaction conditions, the corresponding
normorphan 5a was obtained as a major product with only E
configuration of the double bond [eq. (1)],[19] which is distinctively
different from the related silver-catalyzed protocol by Miesch
where a Z configured exo double bond was formed through the
favorable conformation of the keteneiminium intermediate.[8a]
Further studies revealed that a higher ratio of 5a/5a was obtained
95% yield and 91% ee. Then, various alkyl-substituted ynamides
were screened and the desired morphans 2o–2u were obtained
in 84−92% yields and 87−95% ee. Notably, a range of functional
groups were perfectly tolerated, including phenyl, alkenyl, and
protected hydroxy. Moreover, this chemistry was also compatible
with an alkenyl-substituted ynamide and even terminal ynamide
to deliver the desired products 2v and 2w in good yields, albeit
with a significantly reduced enantiocontrol in the latter case. Our
attempts to extend the reaction to cyclobutanone-ynamide 1x,
acyclic ketone-ynamide 1y and aldehyde-ynamide 1z have been
unsuccessful as yet,[18] and attempts to prepare the heterocycle-
substituted ynamides failed.[15] Finally, the use of ent-3d as chiral
organocatalyst also led to the efficient formation of the desired
ent-2a with the opposite enantioselectivity (93% ee). Importantly,
an unusual cyclization on the β-carbon of the ynamide was
achieved in all these cases (attack on the α-carbon: <3%). Thus,
this protocol provides a highly efficient and practical route for the
synthesis of valuable enantioenriched morphans.
t
in the presence of pyrrolidine as catalyst and BuOH as solvent
while chiral normorphan 5a was formed in 58% NMR yield with
90% ee by employing 3d as chiral catalyst under the optimized
reaction conditions.[15]
Table 2. Reaction scope for the formation of chiral morphans 2.[a]
Inspired by these results, we also examined the scope of this
enantioselective organocatalytic desymmetrizing reaction for the
synthesis of normorphans 5. As depicted in Table 3, the reaction
occurred well with a variety of aryl-substituted ynamides 4,
including isopropylsulfonyl-protected ynamide 4i, leading to the
formation of the corresponding functionalized normorphans 5a–5i
in moderate to excellent yields with 76−90% ee. Instead, when
the alkyl-substituted ynamide 4 (R = alkyl) was employed, the
formation of the corresponding morphan 5′ as main product was
observed.[15] In addition, excellent E/Z ratios (>50:1) of the newly
generated olefin moieties were observed in all cases. Of note, all
the regioisomers were readily isolated by column chromatography,
and higher 5/5′ ratios could be obtained in case of aryl-substituted
ynamides with electron-withdrawing groups. The absolute
configuration of 5h was established by X-ray diffraction analysis
(Figure 2).[20]
Ph
O
R
PG
2e, R = 4-Cl, 86%, 88% ee
2f
N
, R = 4-Br, 87%, 91% ee
Ts
2g, R = 3-F, 91%, 89% ee
2h, R = 4-Me, 94%, 97% ee
2i, R = 4-OMe, 91%, 94% ee
2j, R = 3-Me, 97%, 95% ee
2k, R = 3-OTBS, 87%, 88% ee
2l, R = 2-F, 86%, 95% ee
2m, R = 2-Cl, 82%, 90% ee
N
2a, PG = Ts, 91%, 95% ee
2b, PG = MBS, 68%, 91% ee
2c, PG = SO2Ph, 96%, 94% ee
O
2d, PG = SO2(2-Naph), 90%, 92% ee
Ts
Ts
N
N
5
Ts
N
O
O
Table 3. Reaction scope for the formation of chiral normorphans 5.[a]
O
2n, 95%, 91% ee[b]
2o, R = 87%, 93% ee[b,c]
2p, 84%, 87% ee[b,c]
Ph
Ts
Ts
Ts
RO
N
3
N
N
3
O
O
O
2s, R = Ac, 89%, 93% ee[c]
2t, R = Boc, 90%, 91% ee[c]
2u, R = TBS, 92%, 90% ee[c]
[c]
[c]
2q
, 87%, 95% ee
2r
, 88%, 92% ee
O
O
5b, R = Cl, 65%, 83% ee (5b:5b' = 2.4:1)
5c, R = Br, 73%, 81% ee (5c:5c' = 2.9:1)
5d, R = Ac, 92%, 76% ee (5d:5d' > 20:1)
Ph
Ts
Ts
R
N
N
N
N
Ts
Ph
N
Ms
Ms
H
H
5a, 53%, 90% ee
(5a:5a' = 1.6:1)
O
2w, 70%, 61% ee[b,c]
O
O
O
2v, 74%, 90% ee[b,c]
ent-2a, 90%, 93% ee[d]
O
[a] Reaction conditions: 1 (0.2 mmol), 3d (0.04 mmol), Et3N (0.04
mmol), PhCF3 (1 mL), 80 °C, 36 h, in vials; isolated yields are
reported; ees are determined by HPLC analysis. [b] Time = 64 h.
[c] [1] = 0.40 M. [d] Ent-3d was used. PG = protecting group,
MBS = 4-methoxybenzenesulfonyl, Naph = naphthyl, TBS =
tbutyldimethylsilyl, Ac = acetyl, Boc = tbutoxycarbonyl.
5e, R = F, 76%, 83% ee (5e:5e' = 5.3:1)
5f, R = Cl, 80%, 82% ee (5f:5f' = 5.5:1)
5g, R = Br, 81%, 82% ee (5g:5g' = 5.3:1)
5h, R = Me, 53%, 88% ee (5h:5h' = 1.3:1)
R
N
Ph
iPrO2S
H
N
5i, 51%, 87% ee
(5i:5i' = 1.5:1)
Ms
H
[a] Reaction conditions:
tBuOH/H2O (1/1; 1 mL), 80 °C, 64 h, in vials; isolated yields are
4
(0.2 mmol), 3d (0.04 mmol),
reported; ees are determined by HPLC analysis. Ms
methanesulfonyl.
=
3
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10.1002/anie.201908495
Angewandte Chemie International Edition
a)
Ts
1a (3.2 mmol, 1.18 g)
Ph
Ts
N
N
standard
conditions
HO
vi)
i)
Ph
N
H
H
2aa, 92%, 93% ee
2af, 96%, 92% ee
2a
dr > 20:1
dr > 20:1
(1.06 g, 90%, 95% ee)
v)
ii)
iv) iii)
Ph
Ts
Ph
Ts
N
N
HO
OMe
X
O
Ph
O
Ts
Me
Figure 2. Structure of compound 5h in its crystal.
N
2ae, 80%, 93% ee
2ab, 83%, 93% ee
2ad, X = F
2ac, X = Br
dr > 20:1
dr > 20:1
66%, 92% ee
79%, 93% ee
dr > 20:1
dr > 20:1
Further synthetic transformations of the as-synthesized chiral
morphans and normorphans were then explored (Scheme 2). For
example, chiral morphan 2a, prepared on a gram scale in 90%
yield with 95% ee, could be readily converted into the desired
products 2aa (92%, 93% ee) and 2ab (83%, 93% ee),
respectively, by treatment with NaBH4 and MeMgBr. Interestingly,
the use of NBS and Selectfluor led to the selective
difunctionalization of the double bond from the less hindered face
to produce the corresponding 2ac and 2ad with three contiguous
stereocenters in good yields. In addition, facile hydrogenation of
the double bond afforded the desired 2ae in 80% yield with 93%
ee. Moreover, the synthesis of indole-fused morphan 2af was
achieved in 96% yield upon exposure to PhNHNH2 and TsOH
(Scheme 2a). The absolute configurations of 2ad and 2ae were
confirmed by X-ray diffraction analysis (Figures 3 and 4),[20] which
also determined the absolute configuration of morphans 2. The
synthesis of anti-inflammatory agent 2wb[1c] was also achieved
starting from morphan 2w through reduction of the alkenyl and
carbonyl groups, followed by oxidation of the methylene group
adjacent to the nitrogen and deprotection of the Ts group
(Scheme 2b). Finally, the reduction and oxidation of the double
bond of normorphan 5a afforded the corresponding 5aa (75%,
89% ee) and 5ab[2a,21] (58%, 90% ee), respectively; the latter
could be further transformed into the corresponding 5ac (29%, 2
steps, 91% ee) and 5ad (90%; Scheme 2c). Importantly, the
enantioselectivities were well maintained and excellent
diastereoselectivities (dr > 20:1) were achieved in all these
transformations.
b)
1) (CH2SH)2 (1.2 equiv)
BF3 Et2O (1.2 equiv), DCM
2) Et3SiH (3 equiv)
1) RuCl3 (20 mol %)
NaIO4 (3 equiv)
O
NTs
NH
BF3 Et2O (3 equiv), DCM
MeCN/CCl4/H2O
2w
3) Raney Ni (< 50 m)
EtOH, 80 °C
2) H2SO4 (conc.)
2wa, 53%
(3 steps)
2wb, 72% (2 steps)
anti-inflammatory agent
c)
O
O
O
RuCl3 (5 mol %)
NaIO4 (3 equiv)
10% Pd/C
2 (1 M Pa)
EtOH, RT, 6 h
N
N
N
MeCN/CH3CO2H/H2O
RT, 1 h
H
Ph
O
Bn
Ms
Ms
Ms
H
5ab, 58%
90% ee
5aa, 75%
89% ee, dr > 20:1
5a, 90% ee
1) (CH2SH)2 (1.2 equiv)
BF3 Et2O (1.2 equiv), DCM
B2H6 THF (4 equiv)
THF, reflux
N
N
2) Raney Ni (< 50 m)
EtOH, 80 °C
O
Ms
Ms
5ac, 29% (2 steps)
5ad, 90%
91% ee
Scheme 2. Gram scale reaction and synthetic applications. Reagents and
conditions: i) NaBH4 (1.2 equiv), MeOH, 0 °C, 0.5 h; ii) MeMgBr (2 equiv), THF,
0 °C, 4 h; iii) NBS (2 equiv), DCM/MeOH (1:1), RT, 5 min; iv) Selectfluor (2
equiv), MeCN/MeOH (2:1), -40 °C, 11 h; v) 10 % Pd/C, H2 (2 M Pa), EtOAc, RT,
24 h; vi) PhNHNH2 (2 equiv), TsOH (2 equiv), toluene, 80 °C, 6 h.
Moreover, we also tested the newly synthesized morphans
and normorphans for their bioactivity as antitumor agents. The
cytotoxic effects of these compounds were evaluated against a
panel of cancer cells, including breast cancer cells MDA-MB-231
and MCF-7, melanoma cells A375, and esophageal cancer cells
SK-GT-4 and KYSE-450, based on cell viability assays.[15] Our
preliminary studies revealed that almost half of these morphans
exhibited significant cytotoxic effects on MDA-MB-231 and A375,
and a few morphans exhibited cytotoxic effects on SK-GT-4 and
KYSE-450, whereas the normorphan derivatives displayed weak
antitumor activity against these five cell lines.
On the basis of the previous results[8-11] and density
functional theory (DFT) computations,[15] plausible mechanisms
for regiodivergent synthesis of morphans and normorphans are
illustrated in Scheme 3. Initially, an amine-ketone condensation
between pyrrolidine 3d and the ynamide-tethered cyclohexanone
via intermediate A gives the enamine intermediate B. The
nucleophilic carbon site of its enamine group can attack either the
β or α position of the ynamide group to form vinyl anion
intermediates C or C', respectively.[22] As Ts is more electron-
withdrawing than Ms, the β and α carbon of the Ts-containing
ynamide are both positively charged and the nucleophilic attack
favors the β site to form a sterically less strained 6-membered-
ring intermediate C that leads eventually to morphan 2a. In the
case of PG=Ms, the β carbon is negatively charged, and the
Figure 3. Structure of compound 2ad in its crystal.
Figure 4. Structure of compound 2ae in its crystal.
4
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10.1002/anie.201908495
Angewandte Chemie International Edition
nucleophilic addition thus favors the positively charged α carbon
generation of major enantiomer. In short, the observed
enantioselectivity is dominated by steric effects.
site to form
a sterically more strained five-membered-ring
intermediate C', precursor of normorphan 5a. The observed
protecting-group-dependent regiodivergence can be attributed to
the stronger electron-withdrawing capability of Ts than Ms in the
ynamide substrate. Furthermore, more detailed DFT
computations showed that the regioselectivity of cyclization is
much more sensitive on the polarity of solvent in the case of
PG=Ts than in the case of PG=Ms.[15]
Figure 5. Optimized structures (key bond lengths in Å) and relative free
energies (∆G, kcal/mol) of the C−C bond formation transition states leading to
2a and its enantiomer from 1a catalyzed by 3d.
Conclusions
In summary, we have developed an organocatalytic
enantioselective
desymmetrizing
cycloisomerization
of
arylsulfonyl-protected ynamide-cyclohexanones, allowing the
highly efficient and atom-economical construction of a range of
valuable morphans with wide substrate scope and excellent
enantioselectivity (up to 97% ee). To our best knowledge, this
protocol not only represents the first metal-free asymmetric
Conia-ene-type carbocyclization, but also constitutes the first
ynamide reaction catalyzed only by amine, which is transition
metal- and Brønsted acid-free. In addition, a rare cyclization on
the β-position of the ynamide is achieved. Moreover, such a
Scheme 3. Plausible reaction mechanism. Relative free energies (∆G, kcal/mol)
of key intermediates and transition states are computed at the SMD-M06-2X/6-
311+G(d,p)//SMD-M06-2X/6-31G(d) level for reactions in solvent (PhCF3 for the
case of PG=Ts and tBuOH/H2O (1:1) for the case of PG=Ms) at 298 K. Data for
the case of PG=Ms are given in parentheses. The structures of key
intermediates B as well as Mulliken charges (q) on selected atoms are also
shown.
cycloisomerization
of
alkylsulfonyl-protected
ynamide-
cyclohexanones can lead to the divergent synthesis of various
normorphans as main products with high enantioselectivity (up to
90% ee). Further transformations and biological tests of these
bridged N-heterocycles have been conducted, highlighting the
potential utility of this chemistry. DFT studies are employed to
elucidate the origins of regioselectivity and enantioselectivity, and
it is revealed that both protecting group of the substrate and
reaction solvent are the key factors governing regiocontrol. The
present protocol offers new opportunities for the development of
novel reactions of ynamides, especially those based on
asymmetric catalysis.[23]
To understand the origin of enantioselectivity, the C−C bond
formation transition states (Figure 5) leading to the final product
morphan 2a and its enantiomer were carefully explored. Among
them, the transition states TSC and TSC2 having the bulky
bis(aryl)methyl group and ynamide phenyl moiety located at the
opposite side of the enamine plane are lower in free energy than
TSC1 and TSC3 that have the bis(aryl)methyl group and ynamide
phenyl moiety located at the same side of the enamine plane.
More delicately, TSC2 has a shorter C-HH-C distance than TSC
does (1.98 vs 2.11 Å), hinting the former having stronger C-HH-
C steric repulsion. As such, TSC is the lowest in free energy,
giving rise to a 2.8 kcal/mol (TSC vs TSC2) preference for the
Acknowledgements
5
This article is protected by copyright. All rights reserved.

10.1002/anie.201908495
Angewandte Chemie International Edition
Kusawa, H. Yamabe, Y. Onizawa, T. Hoshino, N. Iwasawa, Angew. Chem.
Int. Ed. 2005, 44, 468.
We are grateful for financial support from the National Natural
Science Foundation of China (21622204, 91545105 and
21772161), the President Research Funds from Xiamen
University (20720180036), NFFTBS (No. J1310024), PCSIRT,
and Science & Technology Cooperation Program of Xiamen
(3502Z20183015). We thank Professor Xianming Deng from
Xiamen University (School of Life Sciences) for assistance with
biological tests and Mr Zanbin Wei from Xiamen University
(College of Chemistry and Chemical Engineering) for assistance
with X-ray crystallographic analysis. We also thank the
anonymous reviewers for insightful readings and constructive
suggestions.
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Conflict of interest
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The authors declare no conflict of interest.
Keywords: asymmetric catalysis · cyclizations · heterocycles ·
desymmetrization · organocatalysis
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[19] We speculate that the E configuration of the double bond should be
attributed to thermodynamic factors as the alkenyl anion intermediate C' is
presumably involved, as shown in Scheme 3.
[20] CCDC 1919345 (5h), 1919346 (2ad) and 1919347 (2ae) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre.
6
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10.1002/anie.201908495
Angewandte Chemie International Edition
[21] Attempts to remove the Ms protecting group of compounds 5ab and 5ad to
synthesize the bioactive molecules in second row of Figure 1 have been
unsuccessful as yet.
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Int. Ed. 2014, 53, 8333.
[23] This protocol represents an extremely rare example of organocatalytic
enantioselective reaction of ynamides. Ynamides are still scarcely used in
catalytic asymmetric reactions; see representative examples: a) M.
Moskowitz, C. Wolf, Angew. Chem. Int. Ed. 2019, 58, 3402; b) R. N.
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Chem. Soc. 2006, 128, 4586.
7
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10.1002/anie.201908495
Angewandte Chemie International Edition
Asymmetric Catalysis
Yin Xu, Qing Sun, Tong-De Tan, Ming-Yang
Yang, Peng Yuan, Shao-Qi Wu, Xin Lu,* Xin
Hong, and Long-Wu Ye* Page – Page
Organocatalytic Enantioselective Conia-
Ene-Type Carbocyclization of Ynamide-
Cyclohexanones:
Regiodivergent
Synthesis of Morphans and Normorphans
An organocatalytic enantioselective desymmetrizing cycloisomerization of
arylsulfonyl-protected ynamide-cyclohexanones is disclosed for practical and atom-
economical assembly of morphans with excellent enantioselectivity, which represents
the first metal-free asymmetric Conia-ene-type carbocyclization. In addition, such a
cycloisomerization of alkylsulfonyl-protected ynamide-cyclohexanones can lead to the
divergent synthesis of normorphans as the main products with high enantioselectivity.
Moreover, theoretical calculations are employed to elucidate the origins of
regioselectivity and enantioselectivity.
8
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