Highly Enantioselective Synthesis Using Prolinol as a Chiral Auxiliary: Silver-Mediated Synthesis of Axially Chiral Vinylallenes and Subsequent (Hetero)-Diels-Alder Reactions

Article abstract of DOI:10.1021/acs.orglett.9b02514

Using (S)-prolinol as a chiral auxiliary, axially chiral vinylallenes with excellent enantiopurity (up to >99% enantiomeric excess (ee)) were readily prepared from optically pure propargylamines in the presence of AgNO₃ under microwave irradiation. Subsequent (hetero)-Diels-Alder reaction of these axially chiral vinylallenes with azodicarboxylates or maleimides on water demonstrates excellent axial-to-point chirality transfer (up to 99% ee).

Full text of DOI:10.1021/acs.orglett.9b02514

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Highly Enantioselective Synthesis Using Prolinol as a Chiral
Auxiliary: Silver-Mediated Synthesis of Axially Chiral Vinylallenes
and Subsequent (Hetero)-Diels−Alder Reactions
,
†,‡
†,‡
†,‡
‡
Vanessa Kar-Yan Lo,*
Yu-Man Chan, Dongling Zhou, Patrick H. Toy,
,
†,‡
and Chi-Ming Che*
†State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, People’s Republic of
China
‡
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, People’s Republic of China
*
S Supporting Information
ABSTRACT: Using (S)-prolinol as a chiral auxiliary, axially chiral vinylallenes with excellent enantiopurity (up to >99%
enantiomeric excess (ee)) were readily prepared from optically pure propargylamines in the presence of AgNO under
3
microwave irradiation. Subsequent (hetero)-Diels−Alder reaction of these axially chiral vinylallenes with azodicarboxylates or
maleimides on water demonstrates excellent axial-to-point chirality transfer (up to 99% ee).
he pursuit of highly efficient and enantioselective
reactions for the construction of complex molecules
axially chiral vinylallenes (up to 94% yield with >99%
enantiomeric excess (ee)), using (S)-prolinol as the chiral
auxiliary, and their subsequent (hetero)-Diels−Alder reaction
with azodicarboxylates or maleimides on water to give the
corresponding cycloadducts in good to excellent yields (43%−
T
with point/axial chirality is everlasting in synthetic organic
1
chemistry. In the context of cost and time effectiveness, the
development of highly enantioselective reactions using
inexpensive metal reagents and readily available chiral
auxiliaries is beneficial for asymmetric synthesis of organic
molecules featuring diverse and complex structures with
practical applications.
98%) with excellent axial-to-point chirality transfer (up to
>
99% ee) under mild conditions.
Axially chiral vinylallenes, including those new in this work,
were prepared from optically active propargylamines in the
Axially chiral allenes are important structural motifs present
6
presence of 0.5 equiv of AgNO . The results are summarized
2
3
in natural products and are versatile chiral synthons attributed
in Table 1. Under microwave irradiation (50 W) for 20 min at
3
to axial-to-point chirality transfer. In particular, vinylallenes
70 °C, axially chiral vinylallenes 1a−1i bearing electron-
are flexible building blocks, because they can undergo various
donating or withdrawing aryl substituents were synthesized in
56%−94% isolated yields based on 52%−100% substrate
conversions with good to excellent enantioselectivity (between
4
cycloaddition reactions. However, the few preparation
4e−g,5
methods for this class of compounds
may limit the
advancement of their chemistry. Previously, we reported an
efficient protocol for easy access of axially chiral allenes from
79% ee and >99% ee), using (S)-prolinol as a chiral auxiliary.
The synthesis of 1j, bearing an iso-propenyl group required a
longer reaction time (1 h) for significant substrate conversion
optically pure propargylamines mediated by AgNO using (S)-
3
6
prolinol as a chiral auxiliary under microwave irradiation.
(
82%). Vinylallene 1a′, the enantiomer of 1a, was prepared
Extension of this protocol to the synthesis of vinylallenes was
found to be successful.
using (R)-prolinol as a chiral auxiliary in good yield (67%
In our endeavor to develop silver-catalyzed highly
enantioselective organic transformation reactions, we describe
7
Received: July 19, 2019
the silver(I)-mediated highly enantioselective synthesis of
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02514
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. AgNO -Mediated Preparation of Axially Chiral
of diethyl azodicarboxylate (DEAD; 1.1 equiv) in 1 mL of H O
2
3
Vinylallenes from Optically Active Propargylamines with
at room temperature (rt) for 0.5 h, giving cycloadduct 2a as a
single product in 96% isolated yield based on 97% conversion
of 1a with 98% ee (entry 1 in Table 2). Cycloadduct 2a′ (the
enantiomer of 2a) was obtained using 1a′ as the substrate with
comparable substrate conversion, isolated yield, and ee, as were
observed in the synthesis of 2a (entry 2 in Table 2).
a
(S)-Prolinol as a Chiral Auxiliary
This reaction showed high functional group tolerance
(
3
Table 2). Vinylallenes bearing halogens (1b and 1c; entries
and 4 in Table 2), Me (1d; entry 5 in Table 2), OMe (1e;
entry 6 in Table 2), COOMe (1f; entry 7 in Table 2), CHO
1g; entry 8 in Table 2), naphthalene (1h; entry 9 in Table 2)
(
and 1,3-benzodioxole (1i; entry 10 in Table 2) groups
underwent the reaction with DEAD on water at rt to give
the corresponding cycloadducts in good to excellent yields
(
76%−98% yield, based on 67%−98% substrate conversion)
with excellent axial-to-point chirality transfer within 0.5 h. The
effect of the alkyl group on the azodicarboxylate was also
examined (Table 2). While changing the −Et group of the
i
azodicarboxylate to − Pr did not exert significant steric
hindrance to the cycloaddition reaction, leading to 2k in
8
3% yield, based on complete substrate conversion with 98%
t
ee (entry 12, Table 2), the presence of a − Bu group led to a
reduction in both substrate conversion and isolated yield (66%
isolated yield, based on 85% conversion with 98% ee; entry 13
in Table 2). 1a could also underwent cycloaddition with 4-
phenyl-1,2,4-triazoline-3,5-dione (PTAD) smoothly to give 2m
in 91% yield with 97% ee (see Scheme 1).
The absolute configuration of 2a was determined by X-ray
crystallographic analysis. Crystal of 2a suitable for X-ray
crystallographic analysis was obtained by slow evaporation of
solvent from a solution of 2a in 10% isopropyl alcohol in
hexane at rt. As shown in Figure 1, the newly formed chiral
center (C1 in Figure 1) is determined as in R configuration,
supportive to the convention Diels−Alder reaction mechanism
that the azodicarboxylate approaches from the opposite side of
the aryl group of the vinylallene, which is less hindered.
The Diels−Alder reactions of vinylallenes with maleimides
was also studied (see Table 3). Compared to the reaction with
azodicarboxylates, the reactions with maleimides require a
higher reaction temperature (40 °C) and a longer reaction
time (4 h; see Table S2 in the Supporting Information for the
optimization details). Under the optimized condition, 0.10
mmol of vinylallene 1a (98% ee in R configuration, 1 equiv)
reacted with 0.11 mmol of N-methylmaleimide (1.1 equiv) in 1
a
Reaction conditions: propargylamines (0.4 mmol), AgNO3 (0.2
mmol, 0.5 equiv), CH CN (4 mL), microwave (50 W) at 70 °C for
2
3
b
1
0 min. Determined by H NMR analysis of the crude reaction
c
mixture. Isolated yield based on conversion of propargylamine.
d
e
Determined by HPLC, using a Chiralcel OD-3 column. Reaction
f
time = 1 h. (R)-Prolinol as a chiral auxiliary.
isolated yield based on 100% substrate conversion) with
comparable enantiopurity (99% ee). These findings further
support that the protocol allows for easy and efficient access to
axially chiral vinylallenes with high enantiopurity, and prolinol
serves as an inexpensive and efficient chiral auxiliary for point
chirality induction in propargylamines, which is, in turn,
transferred to the axial chirality in vinylallenes.
mL of H O at 40 °C for 4 h, giving cycloadduct 3a in 69%
2
The enantiomeric excess (ee) values of the vinylallenes was
found to be dependent to the electronic property of the
substituents on the aryl ring; ee was higher for vinylallenes
bearing electron-withdrawing groups such as −F (98% ee) or
isolated yield, based on 93% conversion with an endo:exo ratio
of 92:8 and 98% ee for the major diastereomer (entry 1 in
Table 3). The relative configuration of the three fused rings of
3a was determined by nuclear Overhauser effect spectroscopy
(NOESY) (see the Supporting Information).
Vinylallenes 1b−1i bearing various electron-donating or
electron-withdrawing substituents underwent cyclization with
N-methylmaleimide smoothly to form the corresponding
cycloadducts 3b−3i in moderate to excellent yields (48%−
98%) with >90:10 endo:exo ratio and excellent axial-to-point
chirality transfer (entries 2−9 in Table 3). Vinylallene 1j
bearing iso-propenyl group also underwent the cycloaddition
reaction to give 3j in 69% isolated yield, based on 95%
substrate conversion with 96% ee (entry 10 in Table 3). It is
observed that the Diels−Alder reactions involving vinylallenes
1f and 1h bearing COOMe and naphthalene, respectively,
proceeded with low substrate conversion (26% for 1f, 35% for
−
COOMe (>99% ee), and the opposite was observed with
electron-donating groups such as −Me (95% ee) or −OMe
82% ee). This trend was also observed for gold-catalyzed
(
6
,8
preparation of axially chiral allenes, and is presumably due to
subsequent racemization via the coordination of the metal ion
to the allene moiety.
9
Further reaction of these axially chiral vinylallenes was then
explored. Hetero-Diels−Alder reactions of the vinylallene with
azodicarboxylates was selected as the first reactions to try, since
10
reports on such transformations are scarce. Under the
optimized condition (see Table S1 in the Supporting
Information for the optimization details), 0.10 mmol of 1a
(
98% ee in R configuration, 1 equiv) reacted with 0.11 mmol
B
DOI: 10.1021/acs.orglett.9b02514
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Organic Letters
Letter
a
Table 2. Substrate Scope of Hetero-Diels−Alder Reactions of 1 with Azodicarboxylates
a
b
1
Reaction conditions: 1 (0.10 mmol), azodicarboxylate (0.11 mmol), H O (1 mL). Determined by H NMR analysis of the crude reaction
2
c
d
e
mixture. Isolated yield based on conversion of 1. Determined by HPLC using a Chiralcel AD-3 or AD-H column. 2j does not contain any chiral
C center.
Scheme 1. Reaction of 1a with PTAD
1
h; entries 6 and 8 in Table 3). These results are likely due to
the fact that both of these vinylallenes and N-methylmaleimide
are all insoluble solids in water at rt.
Changing the dienophile to N-phenylmaleimide afforded 3k
in 80% isolated yield, based on 95% conversion, with excellent
endo:exo ratio (96:4) and ee (98%; entry 11 in Table 3).
Maleimide, with free N−H moiety, also underwent Diels−
Alder reaction with 1a, giving 3l in 43% isolated yield, based
Figure 1. ORTEP drawing of 2a. Non-hydrogen atoms are
represented by thermal ellipsoids drawn at the 30% probability level.
C
DOI: 10.1021/acs.orglett.9b02514
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Organic Letters
Letter
a
Table 3. Substrate Scope of Diels−Alder Reactions of 1 with Maleimides
a
b
1
Reaction conditions: 1 (0.10 mmol), maleimide (0.11 mmol), H O (1 mL). Determined by H NMR analysis of the crude reaction mixture.
2
c
d
e
Isolated yield based on conversion of 1. Determined by HPLC using a Chiralcel AD-H column. Only a single diastereomer was obtained for 3j.
on 53% substrate conversion and with 89:11 endo:exo ratio and
data_ request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
9
8% ee (entry 12 in Table 3).
To conclude, axially chiral vinylallenes with excellent
enantiopurity (up to >99%) can be efficiently prepared from
propargylamines mediated by AgNO , using (S)-prolinol as a
3
AUTHOR INFORMATION
chiral auxiliary. These axially chiral vinylallenes can undergo
highly enantioselective (hetero)-Diels−Alder reaction, leading
to cycloadducts in good to excellent yields (up to 98%) with
excellent axial-to-point chirality transfer (up to 99% ee).
■
*
*
Corresponding Authors
E-mail: cmche@hku.hk (C.-M. Che).
E-mail: vkylo@hku.hk (V. K.-Y. Lo).
ASSOCIATED CONTENT
Supporting Information
ORCID
■
*
S
Vanessa Kar-Yan Lo: 0000-0001-8000-5095
Patrick H. Toy: 0000-0001-6322-0121
Chi-Ming Che: 0000-0002-2554-7219
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02514.
Author Contributions
Detailed experimental procedure, spectral data (PDF)
The manuscript was written through contributions of all
Accession Codes
authors.
CCDC 1937998 contains 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
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b02514
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ACKNOWLEDGMENTS
■
We are thankful for the financial support from Innovation and
Technology Commission (HKSAR, China) to the State Key
Laboratory of Synthetic Chemistry and The University of
Hong Kong. We thank The University of Hong Kong’s
University Development Fund and the Dr. Hui Wai Haan
Fund for funding the Bruker D8 VENTURE X-ray
Diffractometer. We also thank Dr. K.-H. Low (HKU) for his
assistance in solving the X-ray crystal structure of 2a.
REFERENCES
■
(
1) (a) Asymmetric Synthesis−The Essentials; Christmann, M., Bras
̈
e,
S., Eds.; Wiley−VCH: Weinheim, Germany, 2008. (b) Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; John Wiley: Hoboken, NJ, 2010.
(
c) Koskinen, A. M. P. Asymmetric Synthesis of Natural Products;
Wiley: Hoboken, NJ, 2012.
2) For reviews, see: (a) The Chemistry of Allenes; Landor, S. R., Ed.;
(
Academic Press: London, 1982. (b) Modern Allene Chemistry; Krause,
N., Hashmi, A. S. K., Eds.; Wiley−VCH: Weinheim, Germany, 2004.
(
1
c) Hoffmann-Roder, A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43,
̈
196. (d) Huang, X.; Ma, S. Acc. Chem. Res. 2019, 52, 1301.
3) For reviews, see: (a) Hashmi, A. S. K. Angew. Chem., Int. Ed.
000, 39, 3590. (b) Bates, R. W.; Satcharoen, V. Chem. Soc. Rev. 2002,
1, 12. (c) Ma, S. Chem. Rev. 2005, 105, 2829. (d) Ma, S. Pure Appl.
(
2
3
Chem. 2006, 78, 197. (e) Yu, S.; Ma, S. Angew. Chem., Int. Ed. 2012,
5
2
(
1, 3074. (f) Lop
904.
4) For selected examples, see: (a) Reich, H. J.; Eisenhart, E. K.;
Whipple, W. L.; Kelly, M. J. J. Am. Chem. Soc. 1988, 110, 6432.
b) Murakami, M.; Itami, K.; Ito, Y. J. Am. Chem. Soc. 1997, 119,
́
ez, F.; Mascarenas, J. L. Chem. Soc. Rev. 2014, 43,
̃
(
7
5
163. (c) Spino, C.; Thibault, C.; Gingras, S. J. Org. Chem. 1998, 63,
283. (d) Murakami, M.; Minamida, R.; Itami, K.; Sawamura, M.; Ito,
Y. Chem. Commun. 2000, 2293. (e) Sasaki, M.; Kondo, Y.; Kawahata,
M.; Yamaguchi, K.; Takeda, K. Angew. Chem., Int. Ed. 2011, 50, 6375.
(
2
f) Yang, M.; Yokokawa, N.; Ohmiya, H.; Sawamura, M. Org. Lett.
012, 14, 816. (g) Han, Y.; Qin, A.; Ma, S. Chin. J. Chem. 2019, 37,
4
86.
(
5) For reviews, see: (a) Hoffmann-Ro
Chem., Int. Ed. 2002, 41, 2933. (b) Yu, S.; Ma, S. Chem. Commun.
011, 47, 5384. (c) Chu, W.-D.; Zhang, Y.; Wang, J. Catal. Sci.
̈
der, A.; Krause, N. Angew.
2
Technol. 2017, 7, 4570. For selected examples, see: (d) Krause, N.;
Purpura, M. Angew. Chem., Int. Ed. 2000, 39, 4355. (e) Ogasawara,
M.; Fan, L.; Ge, Y.; Takahashi, T. Org. Lett. 2006, 8, 5409. (f) Wei,
X.-F.; Wakaki, T.; Itoh, T.; Li, H.-L.; Yoshimura, T.; Miyazaki, A.;
Oisaki, K.; Hatanaka, M.; Shimizu, Y.; Kanai, M. Chem. 2019, 5, 585.
(
6) Lo, V. K.-Y.; Zhou, C.-Y.; Wong, M.-K.; Che, C.-M. Chem.
Commun. 2010, 46, 213.
7) (a) Chen, G.-Q.; Xu, Z.-J.; Chan, S. L.-F.; Zhou, C.-Y.; Che, C.-
(
M. Synlett 2011, 2011, 2713. (b) Gu, X.; Xu, Z.-J.; Lo, V. K.-Y.; Che,
C.-M. Synthesis 2012, 44, 3307.
(
(
8) Lo, V. K.-Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2008, 10, 517.
9) Deutsch, C.; Gockel, B.; Hoffmann-Roder, A.; Krause, N. Synlett
̈
2
(
007, 2007, 1790.
10) (a) Wang, X.; Donovalova, J.; Hollis, A.; Johnson, D.;
Rodriguez, A.; Kennedy, G. D.; Krishnan, G.; Banks, H. J. Heterocycl.
Chem. 1994, 31, 871. (b) Regas, D.; Ruiz, J. M.; Afonso, M. M.;
́
Palenzuela, J. A. J. Org. Chem. 2006, 71, 9153. (c) Sasaki, M.; Kondo,
Y.; Moto-ishi, T.-i.; Kawahata, M.; Yamaguchi, K.; Takeda, K. Org.
Lett. 2015, 17, 1280.
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