Full text of DOI:10.1021/acs.orglett.8b02489

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Enantioselective Synthesis of Guvacine Derivatives
through [4 + 2] Annulations of Imines with α‑Methylallenoates
Qihai Xu,† Nathan J. Dupper,† Andrew J. Smaligo,† Yi Chiao Fan,† Lingchao Cai,† Zhiming Wang,†,§
Adam D. Langenbacher,‡ Jau-Nian Chen,‡ and Ohyun Kwon*,†
†Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
‡Department of Molecular Cellular and Developmental Biology, University of California, Los Angeles, California 90095, United
States
S
* Supporting Information
ABSTRACT: P-Chiral [2.2.1] bicyclic phosphines (HypPhos
catalysts) have been applied to reactions between α-
alkylallenoates and imines, producing guvacine derivatives.
These HypPhos catalysts were assembled from trans-4-
hydroxyproline, with the modular nature of the synthesis
allowing variations of the exocyclic P and N substituents.
Among them, exo-(p-anisyl)-HypPhos was most efficacious for
[4 + 2] annulations between ethyl α-methylallenoate and imines. Through this method, (R)-aplexone was identified as being
responsible for the decrease in the cellular levels of cholesterol.
unctionalized tetrahydropyridines and piperidines are
common structural motifs in many biologically active
substituted guvacines.9 Ramachandran’s group was the first
to report the preparation of C6-chiral guvacine derivatives.
They installed the C6-chiral center through the allylation of
imines using (−)-B-allyldiisopinocampheylborane in lengthy
syntheses (Scheme 1A).9a
Previously, we reported a general method for the synthesis
of functionalized tetrahydropyridines through phosphine-
catalyzed [4 + 2] annulation of imines with 2-alkyl-2,3-
butadienoates.10,11 A catalytic asymmetric version of this
transformation, using a chiral phosphine catalyst, was
F
natural products1 and synthetic pharmaceuticals.2 In fact,
piperidine is the most frequently encountered heterocycle in
the top-200 drug list.3 One particular piperidine structure, the
guvacine (1) moiety (Figure 1), has been identified as the
Scheme 1. Synthesis of Guvacine Derivatives
Figure 1. Guvacine and bioactive guvacine derivatives.
pharmacophore of the γ-aminobutyric acid (GABA) uptake
inhibitor.4−7 GABA is one of the major mammalian inhibitory
neurotransmitters, and a number of diseases, including
Parkinson’s, Huntington’s, epilepsy, and schizophrenia, have
been linked to the dysfunction of GABAergic synapses.5
Modification at the C6 position of guvacine (as in compound
2) can also result in good GABA uptake inhibition.4c,7 Our
recent collaboration with the Chen laboratory has revealed that
another guvacine derivative, aplexone (3), regulates arterio-
venous angiogenesis in zebrafish by acting on the HMG-CoA
reductase pathway.8 In the same zebrafish studies, we found
that aplexone lowered the levels of embryonic cholesterol to a
degree similar to that of atorvastatin (trade name: Lipitor).
Intrigued by the prevalence of 6-substituted tetrahydropyridine
motifs in both natural products and active pharmaceutical
ingredients (APIs), we wished to develop a simple process for
their synthesis.
A survey of the literature revealed a limited number of
general methods for the enantioselective synthesis of 6-
Received: August 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02489
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
presented by Fu; while high ee’s were obtained in the
syntheses of 2,6-disubstituted guvacines, 6-substituted guva-
cines were formed with only moderate enantioselectivities.12a
Zhao and colleagues also developed an enantioselective
synthesis of 2,6-disubstituted guvacines catalyzed by an
amino acid derived bifunctional phosphine; under their
conditions, however, the 6-phenylguvacine ester could not be
obtained (Scheme 1B).12b Furthermore, Guo and Sasai both
reported catalytic asymmetric [4 + 2] annulations of sulfamate-
derived cyclic imines with allenoates; again, they obtained high
ee’s only for 2,6- or 6,6-disubstituted guvacine derivatives,
respectively (Scheme 1C).12c,d Seeking to overcome the
limitations in preparing 6-substituted guvacine esters, we
examined a catalytic asymmetric [4 + 2] annulation of a simple
α-methylallenoate.
Table 1. Asymmetric Allenoate−Imine [4 + 2] Annulations
a
b
cd
,
entry
6
4
additive
ratio
yield (%) ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
6a
6a
6a
6a
6c
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
6e
6f
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
4g
4c
4c
4c
4c
4c
4c
none
1:0.03
1:0.03
1:0.03
1:0.03
1:0.22
1:0.02
>1:0.01
1:0.08
1:0.03
>1:0.01
1:0.01
1:0.01
1:0.04
1:0.05
1:0.14
1:0.02
1:0.05
36
42
54
89
78
71
89
54
81
84
82
70
50
56
67
46
29
80
77
75
79
89
77
77
79
81
73
−48
95
97
98
91
94
97
MgSO4
Na2CO3
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
Recently, we developed a class of trans-hydroxy-L-proline
(Hyp) derived chiral phosphines, which we have named
“HypPhos” ligands (Figure 2).13a These catalysts are readily
e
e
e
e
e
Figure 2. HypPhos catalysts 4.
e
a
1
Regioisomeric ratio of γ:β′ adducts, determined from the H NMR
synthesized on a decagram scale and are also commercially
available through Sigma-Aldrich.14,15 We drew on these unique
P-chiral phosphines previously to develop an asymmetric
version of Lu’s [3 + 2] annulation.16 Herein, we disclose the
asymmetric synthesis of 6-substituted guvacines through the [4
+ 2] annulation of imines with ethyl α-methylallenoate
(Scheme 1D).
spectrum of the crude reaction product.17 Isolated yield after column
chromatography. Determined through supercritical fluid chromatog-
raphy (SFC) using an AS or OJ-H column. The ee of the major
product. AcOH (10 mol %) was added.
b
c
d
e
4c as the catalyst for the enantioselective production of 6-
substituted guvacines.
We began our investigation by treating the N-(p-nitro-
benzenesulfonyl) (p-Ns) imine 6a with ethyl α-methylalle-
noate (5) in the presence of the HypPhos catalyst 4a (Table 1,
entry 1). Although we obtained 80% ee, the yield was low
despite complete consumption of the imine. One of the
byproducts was p-nitrobenzenesulfonamide, formed from
hydrolysis of the imine. We suspected that beneficial effects
would arise if we could inhibit imine hydrolysis using water- or
acid-sequestering additives. After testing many inorganic salts,
drying agents, and other additives (entries 2−4), we obtained
the best results (89% yield, 79% ee; entry 4) after addition of 4
Å molecular sieves (MS) at 100 mg/mmol. After vetting
several solvents, we found that CH2Cl2, the solvent employed
in the original 2003 report,10a was most amenable for this
annulation.18 While a p-Ns group on the imino nitrogen atom
resulted in higher selectivity for the γ-adduct, under these
conditions a p-toluenesulfonyl (p-Ts) group provided a similar
yield and higher ee (entry 5). The modular synthesis of the
HypPhos catalysts 4 allowed straightforward variation of the
exocyclic substituents on both the P and N atoms (entries 6−
11).13a With the exception of 4d, the exo-HypPhos catalysts
4a−f all afforded good yields and enantioselectivities. When
the catalysts 4c or 4f were used, one regioisomer was obtained
almost exclusively (entries 7 and 10). The endo-phenyl-
HypPhos 4g, with the opposite configuration at the P center,
rendered the opposite enantioselectivity (as it did also in the
allenoate−imine [3 + 2] annulation),13 but the enantiose-
lectivity was lower (entry 11). Considering the combination of
regioselectivity, yield, and ee, we chose exo-(p-anisyl)-HypPhos
The enantioselectivity decreased slightly in the presence of
additives, particularly base (cf. entries 1 and 3). We
hypothesized that the higher enantioselectivity in the absence
of additives might have been caused by the presence of acidic
p-nitrobenzenesulfonamide, a byproduct of the hydrolysis of
the imine. Bifunctional chiral phosphines containing hydrogen
bond donors are ubiquitous in asymmetric phosphine
organocatalysis.19 We have also documented that the presence
of a Brϕnsted acid enhanced the reaction rate and
enantioselectivity of the allene−imine [3 + 2] annulation
employed in our total synthesis of (−)-actinophyllic acid.16a
From an examination of more than a dozen Brϕnsted acid
additives, we found that acetic acid (10 mol %) produced the
best enantioselectivity, with a slight decrease in product yield
(entry 12).18 We also tested the effects of other protecting
groups on the imino nitrogen atom (entries 13−17).
Reasonable yields of the guvacine products were obtained
from the imines 6b−d in the presence of both 4 Å MS and
acetic acid (entries 13−15). The p-bromobenzenesulfonyl
imine 6e and the o-nitrobenzenesulfonyl imine 6f proved to be
too labile under these conditions, providing their annulation
products in lower yields (entries 16 and 17). Based on the
combination of regioselectivity, product yield, enantioselectiv-
ity, and ease of removal,20 we chose the p-Ns protecting group
for further application.
Under the optimized conditions, a range of imines could be
employed as substrates in the catalytic syntheses of guvacine
derivatives, with excellent enantioselectivities (Table 2).21
B
DOI: 10.1021/acs.orglett.8b02489
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Substrate Scope for Asymmetric [4 + 2]
Annulations
a
b
c
entry
6 (Ar)
product
ratio
yield (%) ee (%)
1
2
3
4
5
6
7
8
6a, Ph
7a
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
1:0.01
>1:0.01
1:0.01
1:0.04
1:0.01
>1:0.01
>1:0.01
1:0.01
1:0.01
1:0.02
>1:0.01
>1:0.01
>1:0.01
>1:0.01
1:0.45
70
81
66
63
64
29
50
53
51
64
51
52
63
59
73
95
95
97
96
98
74
94
97
97
96
90
96
93
96
59
Figure 3. Proposed transition state for the [4 + 2] annulation of 5 and
6a.
6g, o-MeOC6H4
6h, m-MeOC6H4
6i, p-MeOC6H4
6j, p-MeC6H4
6k, o-ClC6H4
6l, m-ClC6H4
6m, p-ClC6H4
6n, p-BrC6H4
6o, p-FC6H4
6p, p-NCC6H4
6q, p-O2NC6H4
6r, 2-furyl
6s, 2-thienyl
6t, 2-N-methylpyrrolyl
dienolate in place, and the latter allows for a controlled Re-face
attack of the imine to give the (R)-annulation product.
The products of these [4 + 2] reactions can be further
transformed into a variety of derivatives. For example,
compound 7a undergoes denosylation20 to produce ethyl 6-
phenylguvacine 8 with no loss of optical purity (Scheme 2A).23
9
10
11
12
13
14
15
Scheme 2. Transformations of 7a and 7c
a
Regioisomeric ratio of γ:β′ adducts determined from 1H NMR
spectrum of crude reaction product.17 Isolated yield after column
chromatography. Determined through SFC using an AS or OJ-H
b
c
column.
Imines derived from benzaldehydes presenting electron-
donating substituents reacted with higher yields and stereo-
selectivities (entries 2−5), while benzaldimines featuring
electron-withdrawing substituents produced slightly lower
yields and enantioselectivities (entries 6−12). These trends
became more prominent for ortho-substituted benzaldimines
(cf. entries 2 and 6). While the imine 6g provided the guvacine
product 7g in 81% yield and 95% ee, the imine 6k, derived
from o-chlorobenzaldehyde, generated its product 7k in 29%
yield and 74% ee.
On the basis of X-ray diffraction of 7n, we assigned the
absolute configuration of the 6-substituted guvacine esters
unambiguously as the R-configuration. Strikingly, the C6
phenyl substituent adopts the axial position of the half-chair
conformer of the guvacine ester ring, presumably to minimize
any steric clash with the adjacent p-nitrobenzenesulfonyl
group. Heteroaryl imines were also suitable substrates for
this annulation (entries 13 and 14). 2-Furyl and 2-thienyl
substituents produced their guvacines in 93 and 96% ee,
respectively. The 2-N-methylpyrrole-imine 6t produced the
corresponding guvacine product 7t in good yield, albeit with
moderate ee (entry 15), presumably because of the proximal
N-methyl group, similar to the steric effect observed for the
reaction of o-chlorobenzaldimine in entry 6.
Based on modeling of the transition state of the allene−
imine [3 + 2] annulation, we propose the transition-state
model shown in Figure 3 for the [4 + 2] reaction between the
allenoate 5 and the imine 6a. Two key favorable interactions
present in the stereochemistry-determining transition state are
a Coulombic interaction between the allenoate CO oxygen
atom and the phosphorus atom of the phosphonium enolate,
and hydrogen bonds between the imine N-sulfonyl oxygen
atom and hydrogen atoms on the carbon atom α to the
phosphonium center.22 The former locks the phosphonium
In this manner, it should be possible to synthesize a variety of
optically pure guvacine derivatives.24 We suspected that we
could use this annulation to synthesize other biologically
important compounds in an asymmetric fashion. The
asymmetric synthesis of APIs has gained considerable attention
in recent years.25 In this vein, we wished to identify the
eutomer of aplexone (3) in hopes of employing it in future
biological studies. Applying the HypPhos catalysts 4c and ent-
4c, we obtained both enantiomers of the annulation product
7c in 56% yield and 98% ee. We then accessed aplexone (3)
through a high-yielding Tebbe olefination/hydrolysis sequence
(Scheme 2B).
Using the approach reported previously, we examined the
development of the caudal vein plexus in zebrafish embryos.8
These initial phenotypic assays revealed that (R)-aplexone is
the active enantiomer, while (S)-aplexone did not affect plexus
development at the concentrations tested. Specifically,
( )-aplexone produced a “no plexus” phenotype at a
concentration of 10 μM, while (R)-aplexone was more potent,
producing a “no plexus” phenotype at a concentration of only 5
μM.26 (S)-Aplexone, on the other hand, did not disrupt plexus
formation, even at 20 μM. Next, we tested the abilities of (R)-
and (S)-aplexone to decrease the cellular levels of cholesterol
in zebrafish embryos (Figure 4). ( )-Aplexone lowered the
cholesterol levels to an extent similar to that of atorvastatin
(AT). We concluded that (R)-aplexone is the active
enantiomer: it decreased the cholesterol levels to a greater
extent than AT; (S)-aplexone had no such activity.
In summary, we have demonstrated, for the first time, highly
enantioselective [4 + 2] annulations of ethyl α-methylallenoate
and imines for the construction of chiral guvacine derivatives.
Using HypPhos catalysts, the methodology disclosed herein
C
DOI: 10.1021/acs.orglett.8b02489
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
thank Dr. Saeed Khan (UCLA) for the crystallographic
analyses. Q.X. and N.J.D. thank Prof. Neil K. Garg, Ben W.
Boal, and Lucas Morrill (UCLA) for sharing their SFC
instrument.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02489.
■
S
Representative experimental procedures and spectral
data for all new compounds (PDF)
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Accession Codes
CCDC 903385 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
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.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ohyun@chem.ucla.edu.
ORCID
́
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Mascarenas, J. L. Chem. Soc. Rev. 2014, 43, 2904. (c) Wang, Z.; Xu,
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Zhiming Wang: 0000-0002-6583-3826
Ohyun Kwon: 0000-0002-5405-3971
Present Address
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(b) Xiao, H.; Chai, Z.; Wang, H.-F.; Wang, X.-W.; Cao, D.-D.; Liu,
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§(Z.W.) College of Pharmaceutical Science, Zhejiang Chinese
Medical University, Hangzhou, Zhejiang 311400, P. R. China.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported by the NIH (R01GM071779) and
the NSF (equipment grant CHE-1048804). We are grateful to
Boehringer Ingelheim for the generous donation of (2R,4S)-
hydroxyproline and the Scientific Advancement Grant. We
(14) See the Supporting Information for the synthetic procedures
and characterization data of the HypPhos catalysts 4b−f and ent-4a.
D
DOI: 10.1021/acs.orglett.8b02489
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) For the Kwon Group Sigma−Aldrich Professor Portal, visit:
http://www.sigmaaldrich.com/technical-documents/articles/
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September 10, 2018).
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(18) See the Supporting Information for more details.
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(21) tert-Butyl α-methylallenoate was coupled with the imine 6a to
give the annulation product 7u in 85% yield and 74% ee. Ethyl α-(p-
tolylmethyl)allenoate was coupled with the imine 6a to give the
annulation product 7v in 67% yield and 77% ee.
(22) The P−O distance was measured at 2.59 Å; the natural bond
orbital (NBO) interaction energy (ENBO) was 6.04 kcal/mol in the [3
+ 2] annulation.13 Measured distances and NBO interaction energies
(ENBO) of these contacts were 2.33 Å (ENBO = 1.88 kcal/mol) and
2.50 Å (ENBO = 1.46 kcal/mol) in the [3 + 2] annulation.
(23) Interestingly, the enantiomer of ethyl 6-phenylguvacine (8)
with 88% ee was reported to have a value of [α]D20 of +68 (CHCl3, c
= 0.1). See ref 9c for details.
(24) Attempts to make alkyl-substituted guvacine derivatives akin to
the GABA uptake inhibitor 2 led only to hydrolysis of the imine.
Withholding the catalytic AcOH did not inhibit hydrolysis of the alkyl
imine.
(25) Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. Chem. Rev.
2006, 106, 2734.
(26) See the Supporting Information for images of the zebrafish
embryo development.
E
DOI: 10.1021/acs.orglett.8b02489
Org. Lett. XXXX, XXX, XXX−XXX