Enantioselective Three-Step Synthesis of Homo-β-proline: A Donor-Acceptor Cyclopropane as Key Intermediate

Article abstract of DOI:10.1021/acs.orglett.7b01111

An enantioselective three-step synthesis of the GABA uptake inhibitor (S)-(+)-homo-β-proline was developed. The basis for the synthesis was the enantioselective Cu^I-catalyzed cyclopropanation of N-Boc-pyrrole, a substrate that persistently has proved to be challenging in such transformations. The cyclopropanation can be performed on a 150 mmol scale, and the two subsequent steps (i.e., hydrogenation and in situ cyclopropane-opening/double-deprotection) toward the target molecule proceed smoothly in quantitative yield without loss of enantiopurity.

Full text of DOI:10.1021/acs.orglett.7b01111

Letter
pubs.acs.org/OrgLett
Enantioselective Three-Step Synthesis of Homo-β-proline: A Donor−
Acceptor Cyclopropane as Key Intermediate
Ludwig K. A. Pilsl,† Thomas Ertl,‡ and Oliver Reiser*
Institut fur Organische Chemie, Universitat Regensburg, Universitatsstr. 31, 93053 Regensburg, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: An enantioselective three-step synthesis of the GABA uptake inhibitor (S)-(+)-homo-β-proline was developed.
The basis for the synthesis was the enantioselective CuI-catalyzed cyclopropanation of N-Boc-pyrrole, a substrate that persistently
has proved to be challenging in such transformations. The cyclopropanation can be performed on a 150 mmol scale, and the two
subsequent steps (i.e., hydrogenation and in situ cyclopropane-opening/double-deprotection) toward the target molecule
proceed smoothly in quantitative yield without loss of enantiopurity.
Scheme 1. Retrosynthesis of homo-β-proline (1) from N-
Boc-pyrrole (3)
omo-β-proline (3-pyrrolidineacetic acid, 1) is a structural
analogue of the nonproteinogenic γ-amino acid and
H
neurotransmitter γ-aminobutyric acid (GABA) and was first
mentioned in the late 1950s in a series of Japanese patents.1
Studies on its biological potential appeared around 20 years
later, when a group of Danish scientists discovered that 1 is an
inhibitor of GABA uptake.2 Further studies on N-substituted
derivatives of 1 emphasized its potential as a modulator of
neuronal and glial GABA’ergic function.3 Besides its biological
activity, the core structure of 1 is a common structural element
in many classes of natural products4 and is also used as an
integral building block and/or pharmacophore in drug
development, as illustrated by the large body of literature
making use of this particular scaffold.5
Racemic homo-β-proline ( -1) is commercially available
from a handful of suppliers ranging approximately 20−200
USD/mmol. Commercial sources for the enantiopure material
are scarce with higher costs. This may be due to the limited
number of reported syntheses for either racemic or enantiopure
1. To date, there are a total of ten synthetic protocols reported
in the literature that aim for the synthesis of 1 (see Supporting
Information (SI)),6 and only two of these are of enantiose-
lective nature.7,8 Given the highly interesting properties
combined with the restricted accessibility, we envisioned the
synthesis of enantiomerically pure 1 from a monocyclopropa-
nated pyrrole derivative 2-R (Scheme 1), utilizing the unique
properties of donor−acceptor cyclopropanes9 that allow the
ring opening of the weakest bond in the three-membered ring.
While the asymmetric cyclopropanation reactions of furans can
be carried out with ethyl diazoacetate in high enantioselectiv-
ities (>90% ee) using copper(I) bis(oxazoline) complexes,10,11
the analogous transformation of N-protected pyrrole such as 3
led only to unsatisfactory results (<50% ee).12 Bulkier
aryldiazoacetates derived from arylglycines in combination
with chiral Rh(II)-catalysts were reported to achieve the
cyclopropanation of 3 in 79% ee;13 however, with the parent
diazoacetates derived from glycine all our attempts to utilize
Rh(II)-catalysts only led to aromatic substitution rather than
cyclopropanation of 3. Beyond the projected synthesis of
homo-β-proline (1), monocyclopropanated pyrrol 2-Me has
already been proven for the synthesis of β-aminocyclopropane-
carboxylic acids 414 or of pyrrolidinones 5,15 being valuable as
building blocks for biologically active peptidomimetics and
foldamers or for natural products and drugs.
Consequently, we decided to screen a series of chiral
copper(I) complexes generated from Cu(OTf)2 by in situ
reduction with phenylhydrazine to give rise to the active CuI
Received: April 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01111
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Organic Letters
Letter
species in the presence of various aza-bis(oxazoline) (azabox,
Table 1) ligands.16 The latter are closely related in their steric
N-Boc-pyrrole, Table 1, entry 11), yielding 2-tBu in 44% (59%
brsm) yield and 87% ee. After recrystallization from hexanes
enantiomerically pure 2-tBu (>99% ee) was isolated in
multigram quantity.
The absolute stereochemistry of 2-tBu was determined by a
combination of optical rotation, chiral HPLC, and X-ray
analysis and follows the Pfaltz model for asymmetric induction
in cyclopropanation of alkenes catalyzed by copper(I)-bis-
(oxazoline) complexes (Figure 1 and SI). It is interesting to
Table 1. Enantioselective Cyclopropanation of N-Boc-
a
pyrrole with CuI-aza-bis(oxazoline) Complexes
yield
yield
6 (%)
ee
6 (%)
b
c
b
c
entry
R
ligand t (°C) 2 (%)
ee 2 (%)
1
2
tBu
tBu
tBu
Me
tBu
tBu
Me
tBu
tBu
tBu
tBu
tBu
7
−10
−10
−15
20
24
29
19
54
33
26
61
23
30
37
37
33
52
55
81
64
52
83
90
93
2
n.d.
0
Figure 1. Transition state model 13 for the asymmetric cyclo-
propanation of 3 and single crystal X-ray structure of 2-tBu (Color
code: C = gray, H = white, N = blue, O = red).
8
10
3
9
−
−
n.d.
4
10
10
10
11
11
11
11
11
12
n.d.
24
2
5
0
18
note that the double cyclopropanation adduct 6-tBu, which was
also characterized by X-ray analysis (SI), is formed with low
enantioselectivity. This suggests that the minor enantiomer
(ent)-2-tBu efficiently undergoes the second cyclopropanation
as well, indicating substrate rather than catalyst control in this
step.
6
−20
20
n.d.
n.d.
27
7
n.d.
31
17
−
8
20
9
−10
−20
−15
0
n.d.
−
40
10
d
e
f
11
44 (59)
87 (>99)
12
Having succeeded in the enantioselective preparation of 2-
tBu, we focused on the downstream steps toward homo-β-
proline (1). Upon treatment of cyclopropane 2-tBu with TFA/
Et3SiH aiming at double bond hydrogenation, ring opening,
and protecting group removal in a one-pot reaction, indeed 1
was detected in trace amounts, but the conversion was
somewhat sluggish with diverse side products being formed.
Hence, it was decided to hydrogenate first the enamine 2-tBu
under neutral conditions in order to prevent its activation as an
imine electrophile by protonation. Initially, Pd/C at ambient
pressure of hydrogen was employed, giving rise to the desired
product 14 in 85% yield after chromatographic purification.
Optimization of the hydrogenation step was carried out by
changing the catalyst or the pressure of hydrogen gas.
Quantitative yields of 14 without the necessity for a
chromatographic workup were achieved using either Rh/C (5
wt %, 0.14 mol % Rh, 8 h at 1 atm H2) or Pd/C (10 wt %, 2.4
mol % Pd, 4 h at 20 atm H2) (Scheme 2).
Next, various conditions for the opening of the cyclopropane
ring of 14 with concurrent deprotection of the N-Boc group
and the tert-butyl ester were tested. It became apparent that the
desired transformation to 1 can be achieved with various
Brønsted or oxophilic Lewis acids; however, epimerization
during the ring-opening/deprotection cascade was the major
obstacle. For example, employing Sc(OTf)3/Et3SiH under
reflux conditions resulted in a complete conversion of 14;
however, 1 could only be obtained in racemic form (see SI).
Application of TFA/Et3SiH under milder conditions
confirmed that the temperature for the cyclopropane ring-
opening step is crucial for the enantiopurity of the product
(>99% ee at 0 °C vs 73% ee at ambient temp); however, long
reaction times became necessary for complete conversion.
When BF3·OEt2 was applied under the same conditions, the
reaction time could be decreased dramatically to 2 days along
g
f
h
12
17
57 (99)
19
26
a
Reaction conditions: 3.0 mmol (0.5 g) of 3, 1 mol % Cu(OTf)2, 2.2
mol % ligand, 1 mol % PhNHNH2, 4.5 mmol of diazoacetate, 3 mL of
DCM. Isolated yield. Determined by chiral HPLC. 150.6 mmol
(25.2 g) 3. brsm. After recrystallization from hexanes. (ent)-2.
(ent)-6.
b
c
d
e
f
g
h
demand to bis(oxazoline)17 ligands but bear the possibility of
electronic variation through alkylation on the central nitrogen,
thus acting as an anionic or neutral ligand. Moreover, aza-
bis(oxazolines) can be readily immobilized18 on various
supports through functionalization of the central nitrogen,
which facilitates catalyst recovery being relevant for possible
large-scale applications.
The monocyclopropanated adduct 2-R could be obtained
from 3 in moderate yields along with varying amounts of
biscyclopropanated adduct 6-R19 (Table 1). The cyclo-
propanations occur with complete diastereoselectivity; i.e., the
ester groups orient on the convex face of the bicycle in 2-R and
6-R. Steric bulk in both the ligand and the diazoacetate is key to
achieving high enantioselectivities. Thus, tert-butyl diazoacetate
was far superior compared to the corresponding methyl ester
(entries 7, 8), and likewise, tert-butyl substitution in the chiral
ligand is required compared to isopropyl, benzyl, or indanyl
derived aza-bis(oxazolines) (entries 1, 2, 12). Notably,
nonalkylated aza-bis(oxazoline) ligands generally gave better
results than alkylated ones (entries 3, 6, 10) or bis(oxazoline)
ligands.12 Optimal conditions were found by using an in situ
generated catalyst from Cu(OTf)2/PhNHNH2/11 and tert-
butyldiazoacetate as the cyclopropanation reagent at −10 to
−20 °C (entries 9, 10) to yield 2-tBu in 90−93% ee.
The robustness of this cyclopropanation step was demon-
strated by performing the reaction on a 150 mmol scale (25 g
B
DOI: 10.1021/acs.orglett.7b01111
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Letter
Scheme 2. Ring Opening of Cyclopropane Ring and Possible
Epimerization
Scheme 4. Synthesis of Homo-β-proline (1) from N-Boc-
pyrrole (3)
Scheme 5. Transesterification of 2-tBu toward β-ACC 4
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01111.
■
with only a slight erosion of enantiopurity (97% ee, Scheme 3).
For analytical purposes, 15 was isolated and characterized;
however, the crude could be directly converted to 1 in overall
quantitative yield starting from 14.
S
Scheme 3. Ring-Opening/Deprotection Cascade toward
Homo-β-proline (1)
Experimental details, optimization of reaction conditions,
crystallographic data for 2-tBu, 6-tBu, and 15; and
summary of literature syntheses of 1 (PDF)
Crystallographic data for 2-tBu (CIF)
Crystallographic data for 6-tBu (CIF)
Crystallographic data for 15 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Oliver.Reiser@chemie.uni-regensburg.de.
ORCID
The scalability of the newly developed synthetic route was
demonstrated by starting from 3.6 mmol (1.00 g) of 2-tBu,
resulting in 457 mg of 1 ([α]2D0 +9.5 (c 1, H2O))20 in an overall
yield of >99% without the necessity to isolate either 14 or 15
(Scheme 4).
The β-aminocyclopropanecarboxylic acid (β-ACC) derivative
4 can be incorporated into peptides using established coupling
strategies, which has led to biologically active peptidomimetics
and foldamers with interesting properties.14 This compound
has not been accessible via an enantioselective route until now,
but required the enzymatic resolution or chiral separation of
racemic 2-Me.21 Transesterification of 2-tBu to 2-Me was
smoothly achieved without erosion of enantiopurity (Scheme
5), which can be further converted to 4 following our
previously reported protocol.21b
Oliver Reiser: 0000-0003-1430-573X
Present Address
†Patheon Regensburg GmbH, Donaustauferstrasse 378, 93055
Regensburg, Germany.
Author Contributions
‡L.K.A.P. and T.E. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by DFG (Graduiertenkolleg Medizinische
Chemie GRK 1910 and RE948/9-1) is gratefully acknowl-
edged. Evonik Degussa GmbH is acknowledged for a generous
donation of L-tert-leucine. Dr. Martin Glos, Dr. Markus Hager,
Dr. Klaus Harrar, and Dr. Peter Kreitmeier (all University of
Regensburg) are acknowledged for technical assistance and
fruitful discussions.
In summary, we have developed the enantioselective
cyclopropanation of N-Boc-pyrrole (3) on gram scale, which
can be converted in quantitative yield and without the need for
chromatographic purification of intermediates to enantiomeri-
cally pure homo-β-proline 1.
C
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D
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