Asymmetric "clip-Cycle" Synthesis of Pyrrolidines and Spiropyrrolidines

Article abstract of DOI:10.1021/acs.orglett.0c03090

The development of an asymmetric "clip-cycle"synthesis of 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines, which are increasingly important scaffolds in drug discovery programs, is reported. Cbz-protected bis-homoallylic amines were activate

Full text of DOI:10.1021/acs.orglett.0c03090

pubs.acs.org/OrgLett
Letter
Asymmetric “Clip-Cycle” Synthesis of Pyrrolidines and
Spiropyrrolidines
Christopher J. Maddocks, Kristaps Ermanis,* and Paul A. Clarke*
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ABSTRACT: The development of an asymmetric “clip-cycle” synthesis of 2,2- and 3,3-disubstituted pyrrolidines and
spiropyrrolidines, which are increasingly important scaffolds in drug discovery programs, is reported. Cbz-protected bis-homoallylic
amines were activated by “clipping” them to thioacrylate via an alkene metathesis reaction. Enantioselective intramolecular aza-
Michael cyclization onto the activated alkene, catalyzed by a chiral phosphoric acid, formed a pyrrolidine. The reaction
accommodated a range of substitutions to form 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines with high
enantioselectivities. The importance of the thioester activating group was demonstrated by comparison to ketone and oxoester-
containing substrates. DFT studies supported the aza-Michael cyclization as the rate- and stereochemistry-determining step and
correctly predicted the formation of the major enantiomer. The catalytic asymmetric syntheses of N-methylpyrrolidine alkaloids (R)-
irnidine and (R)-bgugaine, which possess DNA binding and antibacterial properties, were achieved using the “clip-cycle”
methodology.
natural products.4 However, despite this prevalence, the
yrrolidines appear in nearly 20% of FDA-approved drug
1
methods available to make them asymmetrically often have
Pmolecules which contain a saturated cyclic amine unit,
drawbacks. A common method is asymmetric lithiation of N-
Boc-pyrrolidine, followed by electrophilic quenching.5 The
drawbacks of cryogenic temperatures, pyrophoric reagents, and
the regular use of stoichiometric quantities of chiral diamine
are well documented.5 The alternative strategies of asymmetric
azomethine cycloaddition to olefins,6 organocatalytic ap-
proaches,7 and aza-Michael reactions,8 including the asym-
metric addition to nitroalkenes,9 tend to generate products
which need to undergo further reactions. An alternative
strategy is the intramolecular aza-Michael cyclization, and while
there are racemic reactions which generate pyrrolidines in
good yields,10 there are limited examples of asymmetric
versions of this reaction. Those which have been reported use
chiral auxiliaries on nitrogen11 or are limited to the formation
making them one of the most important structural features in
modern pharmaceuticals (Figure 1). Recently, spirocyclic
amines, including pyrrolidines, have become highly desirable
scaffolds2,3 as they are conformationally well-defined, which
allows them to be elaborated along specific vectors.
Pyrrolidines are also present in many biologically active
Received: September 15, 2020
Figure 1. Pyrrolidine-containing pharmaceuticals.
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of specific pyrrolidine substitution patterns.12 Interest in the
synthesis of substituted pyrrolidines and spiropyrrolidines has
increased over the past few years due to their recently
recognized value in drug discovery projects.2,3a,13 However,
while new methods to synthesize them have been developed,
few are general and asymmetric.14
To address these limitations, we envisaged the development
of the “clip-cycle” procedure. “Clip-cycle” is a strategy which
“clips” together a N-protected bis-homoallylic amine with a
thioacrylate to generate an activated alkene, with a pendent
nucleophile. The N-protected amine can then undergo aza-
Michael cyclization catalyzed by a chiral phosphoric acid
(CPA) to yield enantioenriched pyrrolidines (Scheme 1).
conversion (20% yield) to the pyrrolidine 6, which was formed
in 95:5 er. Gratifyingly, when p-tolyl thioacrylate 7 was used as
the metathesis partner α,β-unsaturated thioester 8a was
formed in 75% yield, which was cyclized to pyrrolidine 9a
using (R)-TRIP (20 mol %) in cyclohexane at 80 °C with
100% conversion (83% yield) and 98:2 er (Scheme 2). α,β-
Unsaturated thioesters were, therefore, chosen as the activating
group of choice due to their intermediate electrophilicity
compared to α,β-unsaturated aldehydes/ketones15 and ox-
oesters.16
The “clip-cycle” reaction was shown to be tolerant of a range
of substitutions at the 3-position of the pyrrolidine (Figure 2).
Scheme 1. Asymmetric “Clip-Cycle” Reaction
In this paper, we report the successful implementation of a
new two-step, programmable, catalytic approach for the
asymmetric synthesis of pyrrolidines and spiropyrrolidines in
high enantiopurity. The key features of this “clip-cycle” strategy
are that (i) it is modular, enabling a diverse range of
pyrrolidines to be assembled quickly and easily from readily
accessible N-protected amines and acrylates, (ii) it is catalytic
in both the “clip” and “cycle” steps, (iii) it is straightforward to
perform, (iv) it yields substituted pyrrolidine and spiropyrro-
lidine products directly in high enantiomeric excesses, and (v)
the thioester function provides a versatile handle for late stage
diversification.
Figure 2. Asymmetric “clip-cycle” synthesis of 3,3-disubstituted
pyrrolidines. Yields are reported over two steps. Enantiomeric ratios
were determined by chiral stationary-phase HPLC. In the case of 9f,
(ii) and (iii) relate to the use of (R)-TiPSY (20 mol %) as the catalyst
or the reaction being heated to 50 °C, respectively.
Three different activating groups were examined initially, a
ketone, an oxoester, and a thioester, in order to determine the
optimal electrophile for the asymmetric cyclization (Scheme
2). Hoveyda−Grubbs second-generation catalyst (HG-II) was
used to clip Cbz-protected bis-homoallylic amine 1a to each of
the electrophilic components. When 1a was treated with HG-II
in the presence of enone 2, cyclization to the pyrrolidine
occurred spontaneously. Coupling 1a with p-tolyl acrylate 4
generated oxoester 5 in 86% yield. Treatment of 5 with (R)-
TRIP (20 mol %) in cyclohexane at 80 °C resulted in only 24%
Replacing the methyl substitutents with cycloalkyl groups17
(9b−d, Figure 2) did not adversely affect the enantioselectivity
or yield of the “clip-cycle” reaction and generated spirocyclic
pyrrolidines. The more sterically congested gem-diphenyl
substitution (9e, Figure 2) was also tolerated in a slightly
lower yield and enantioselectivity. Unsubstituted amine (R =
H, 9f, Figure 2) was also tolerated, and the pyrrolidine 9f was
formed in 73% yield and 90:10 er. The enantioselectivity
increased to 94:6 er when an alternative CPA, (R)-TiPSY (20
mol %), was used. Reduction of the reaction temperature to 50
°C did not significantly affect the enantioselectivity of the
cyclization to 9f (Figure 2). The absolute sense of the
enantioselectivity in the clip-cycle reaction was determined as
(S) by the conversion of 9f into the known methyl
oxoester.17,18
Scheme 2. Effect of the Electrophile on the Asymmetric
“Clip-Cycle” Synthesis of Pyrrolidines
A similar variety of substituents were shown to be tolerated
at the 2-position of the pyrrolidine17 (Figure 3). 2,2-Dimethyl
substitution (11a, Figure 3) resulted in a pyrrolidine product
with a 96:4 er. Surprisingly, the use of (R)-TiPSY resulted in a
dramatic decrease in the enantioselectivity of the reaction and
the yield (20% yield, 76:24 er, 11a, Figure 3). Running the
reaction at 50 °C did not result in an increase in the
enantioselectivity, only in a reduced conversion (34% yield,
Figure 3). Changing the solvent to either DCE or toluene only
led to a reduction in yield of 11a (Figure 3).
Replacing the p-tolyl thioester with a mesityl thioester also
resulted in 92:8 er (11b, Figure 3). A range of cycloalkyl
B
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an s-cis or s-trans conformation in TS-13A. Investigation of all
four combinations was necessary to identify the lowest energy
pathway. Both steps could be catalyzed by the CPA. An
alternative pathway proceeding via an iminol and correspond-
ing cyclization transition state TS-13B was also briefly
considered, but early model studies found that this pathway
is much higher in energy and was not investigated in more
detail.
Conformational searches were done on the starting material,
intermediates, products, and transition-state-like structures.
Selected conformers were then reoptimized at DFT level, and
free energies calculated (B3LYP19/6-31G**20/SMD-
(cyclohexane)21//M06-2X22/def2-TZVP23/ SMD-
(cyclohexane); see the SI for further details). Computational
results (Figure 4) show that the Brønsted acid acts as a proton
Figure 3. Asymmetric “clip-cycle” synthesis of 2,2-disubstituted
pyrrolidines. Yields are reported over two steps. Enantiomeric ratios
were determined by chiral stationary phase HPLC. In the case of 11a
(ii), (R)-TiPSY (20 mol %) was used as the catalyst. In (iii)−(v), the
reaction was heated to 50 °C. In the case of 11h the reaction was run
for 48 h.
substituents could be introduced with no detrimental effect on
the enantioselectivity of the pyrrolidine product (11c−f,
Figure 3). However, when 4-N-Cbz-piperidyl or 2,2-diphenyl
substitution was present the yields and enantioselectivity of the
reaction were lower (11g−h, Figure 3). This could be due to
the increased steric bulk of the diphenyl groups or the
additional N-Cbz-group interacting with CPA catalyst. Thus,
(R)-TRIP was still the optimal CPA for the “clip-cycle”
reaction, although the reaction is slightly less tolerant of 2,2-
disubstitution than of 3,3-disubstitution.
Figure 4. Results from the computational study of CPA-catalyzed
enantioselective aza-Michael reaction.
Intrigued by the high levels of enantioselectivity, the “clip-
cycle” reaction was investigated computationally. Our working
mechanistic hypothesis (Scheme 3) was that the carbamate
nitrogen in 12a directly cyclizes on to the α,β-unsaturated
thioester, forming the aminoenol 14, which then tautomerizes
to give the pyrrolidine product 11a. The aminoenol can have
either an S or R stereogenic center configuration, and either E
or Z enol geometry depending on whether the thioester adopts
shuttle and catalyzes both the cyclization to give the aminoenol
14 and its subsequent tautomerization to the thioester 11a.
The cyclization is the rate-limiting and stereochemical-
determining step. Computations indicate that the S,E pathway
is the most favorable, and the next lowest energy competing
pathway is the enantiomeric R,Z pathway. The main difference
between these competing transition states is the orientation of
the thioester α-proton: in the S,E TS it is pointing away from
the catalyst pocket, while in the R,Z TS it is pointing inward to
allow amide to approach from the other side. This steric clash
is presumably the main reason for the difference in the
energies. The free energies of the remaining S,Z and the R,E
cyclization transition states were 27.9 and 29.4 kcal/mol,
respectively, which is much higher than in the S,E and the R,Z
pathways. Our computational study predicted formation of the
(S)-product 11a with 93:7 er, which fits well the
experimentally observed value of 96:4 er.
Scheme 3. Mechanistic Hypothesis for Enantioselective
CPA-Catalyzed Aza-Michael Cyclization
N-Methylpyrrolidine-containing alkaloids such as (R)-
irnidine24a 16 and (R)-bgugaine24b 17 have been shown to
have a strong binding affinity for DNA25 and possess antibiotic
properties against Gram-positive bacteria;24b (R)-bgugaine is
also a potent hepatotoxin.26 To date there have been three
racemic total syntheses27 and five total syntheses of single
enantiomers of these alkaloids,28 where the stereochemistry
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was either set from the chiral pool or via the use of a chiral
auxiliary. One report utilized a Sharpless asymmetric
dihydroxylation reaction to install the required stereochemis-
try.28f Clip-cycle pyrrolidine formation enabled the short,
catalytic enantioselective total syntheses of these alkaloids
(Scheme 4).
racemic substrates are ongoing and will be reported in due
course.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03090.
Scheme 4. Total Syntheses of (R)-Irnidine and (R)-
Bgugaine
Full experimental procedures and analysis data for all
new compounds, overview of the computational
methods and results (PDF)
a
AUTHOR INFORMATION
Corresponding Authors
■
Kristaps Ermanis − Centre for Molecular Informatics,
Department of Chemistry, University of Cambridge, Cambridge,
U.K. CB2 1EW; orcid.org/0000-0001-9703-8758;
Email: ke291@cam.ac.uk
Paul A. Clarke − Department of Chemistry, University of York,
York, U.K. YO10 5DD; orcid.org/0000-0003-3952-359X;
Email: paul.clarke@york.ac.uk
Author
Christopher J. Maddocks − Department of Chemistry,
University of York, York, U.K. YO10 5DD
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03090
a
Reagents and conditions: (a) Hoveyda−Grubbs II (10 mol %), CuI,
DCE, 50 °C, 14 h, 88%; (b) (R)-TIPSY (20 mol %), cyclohexane, 80
°C, 81%; (c) 18 or 19, CuTC, Pd(Ph3P)4 (5 mol %), Cs2CO3, THF,
55 °C, 20 h, 73% (20) 77% (21); (d) TsNHNH2, AcOH (cat.),
MeOH, 24 h 88% (20), 90% (21); (e) NaBH3CN, ZnCl2, MeOH,
reflux, 16 h, 40% (22), 81% (23); (f) LiAlH4, THF, 15 h, 88% (16),
68% (17). HG-II = Hoveyda−Grubbs second-generation catalyst,
CuTC = copper(I) thiophene-2-carboxylate.
Notes
The authors declare no competing financial interest.
Full set of DFT output files with optimized structures,
frequencies and high-level single-point energies can be found
at 10.17863/CAM.50976. Additional reference spectroscopic
and reaction data can be found at DOI: 10.15124/a01fe9be-
9b9e-43ac-8a21-20a9075784c5.
The total syntheses of both (R)-irnidine and (R)-bgugaine
were achieved from a common β-homoproline intermediate 9f.
β-Homoproline thioester 9f was synthesized in 94:6 er and
71% isolated yield over two steps by the “clip-cycle” reaction
using (R)-TiPSY. A Liebeskind−Srogl coupling of 9f with the
appropriate alkylborane (18 or 19) yielded 20 or 21 in 73%
and 77% yields, respectively. Wolf−Kischner reduction of 20
and 21 via formation of the tosyl hydrazone (88% and 90%
yields for the hydrazone formation from 20 and 21
respectively) was followed by reduction with NaBH3CN and
ZnCl2 to give 22 in 40% yield and 23 in 81% yield over two
steps. Finally, LiAlH4 reduction of the Cbz groups of 22 and
23 delivered the natural products (R)-irnidine 16 and (R)-
bgugaine 17 in 88% and 68% yields in six steps from 1f.
In conclusion, we have developed a modular and
enantioselective Brønsted acid-catalyzed “clip-cycle” synthesis
of 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines,
which are key units in drug discovery programs, and we have
used this in the catalytic enantioselective synthesis of (R)-
irnidine and (R)-bgugaine in 18% and 33% overall yields,
respectively. This method compares favorably with other
methods for the synthesis of pyrrolidine natural products,
including those which utilize aza-Michael reactions as it avoids
the need for cryogenic temperatures29 and yields the natural
products in only six steps. Investigation into substrates with
additional double-bond substitution and kinetic resolution of
ACKNOWLEDGMENTS
■
We thank the Department of Chemistry, University of York
(C.J.M.) and the Leverhulme Trust and Isaac Newton Trust
(K.E.) for financial support. The computational work has been
performed using resources provided by the Cambridge Tier-2
system operated by the University of Cambridge Research
Computing Service (http://www.hpc.cam.ac.uk) funded by
EPSRC Tier-2 capital grant EP/P020259/1.
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