Acyl Radical Addition onto Aza-Baylis–Hillman Adducts: A Stereocontrolled Access to 2,3,5-Trisubstituted Pyrrolidines

Article abstract of DOI:10.1002/adsc.201700362

Free-radical addition of acyl radicals to chiral aza-Baylis–Hillman adducts was shown to afford the corresponding 1,4-amino ketones in good yields and good 1,2-stereocontrol. These ketones were then elaborated further using conditions varying as a function of the nature of the N-protecting group. Robust N–Ts protection thus allowed the formation, under acidic conditions, of a cyclic iminium which was reduced using bulky (Me₃Si)₃SiH into the corresponding 2,3,5-pyrrolidine exhibiting a trans-trans relative configuration. In contrast, under these conditions, the N-Boc protecting group was removed, leading to the formation of stable dihydropyrroles, which were then hydrogenated with PtO₂, leading to 2,3,5-pyrrolidines having a trans-cis relative configuration. When additional ketone or ester groups were present on the pyrrolidine skeleton, further cyclization led to indolizidinones and pyrrolizidines in good overall yield in 4 steps and two-pot operations. (Figure presented.).

Full text of DOI:10.1002/adsc.201700362

Title: Acyl radical Addition onto Aza-Baylis-Hillman Adducts. A
Stereocontrolled access to 2,3,5-Trisubstituted Pyrrolidines
Authors: Yannick LANDAIS, Simon Grélaud, Jonathan Lusseau, and
Stéphane MASSIP
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10.1002/adsc.201700362
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Acyl Radical Addition onto Aza-Baylis-Hillman Adducts. A
Stereocontrolled Access to 2,3,5-Trisubstituted Pyrrolidines
Simon Grélaud,a Jonathan Lusseau,a Stéphane Massip,b and Yannick Landaisa*
a
Institute of Molecular Sciences, UMR-CNRS 5255, University of Bordeaux, 351 Cours de la libération, 33405 Talence
cedex, France
b
Institut Européen de Chimie et Biologie, 2, Rue Robert Escarpit, 33607 Pessac, France
Phone: (+33)-5 40 00 22 89; Fax : (+33)-5 40 00 62 86; e-mail: y.landais@ism.u-bordeaux1.fr
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Free-radical addition of acyl radicals to chiral aza- In contrast, under these conditions, the N-Boc protecting
Baylis-Hillman adducts was shown to afford the group was removed, leading to the formation of stable
corresponding 1,4-aminoketones in good yields and good dihydropyrroles, which were then hydrogenated with PtO2,
1,2-stereocontrol. These ketones were then elaborated further leading to 2,3,5-pyrrolidines having a trans-cis relative
using conditions varying as a function of the nature of the N- configuration. When additional ketone or ester groups were
protecting group. Robust N-Ts protection thus allowed the present on the pyrrolidine skeleton, further cyclization led
formation, under acidic conditions, of a cyclic iminium to indolizidinones and pyrrolizidines in good overall yield
which was reduced using bulky (Me3Si)3SiH into the in 4 steps and two-pot operations.
corresponding 2,3,5-pyrrolidine exhibiting a trans-trans
relative configuration.
Keywords: Radicals; Acyl; Aza-Baylis-Hillman reaction;
Indolizidines; pyrrolizidines
Introduction
Pyrrolidines, pyrrolizidines and indolizidines are
very common nitrogen heterocycles in nature,[1]
present in a large number of alkaloids isolated from
leguminous plants but also secretions of small
batrachians, ants or butterflies, which use these
nitrogenous poisons as chemical defence against
predators (Figure 1).[1a-b,1f] Polyhydroxyl analogues,
including castanospermine or swainsonine have
attracted much interest because of their glycosidase
inhibitory activities and their potential use in the
treatment against cancer and the HIV virus.[2] Since
these nitrogen cycles are ubiquitous in nature, a great
number of methodological studies has been devoted
to their synthesis.[3] Among the most effective
synthetic strategies, however, mention may be made
of stereocontrolled cycloadditions from nitrones,[3a-d]
intramolecular haloamidation reactions of olefins[3e-f]
or transition metal-catalyzed olefin amidation.[3h-i] In
this context, free-radical approaches have also been
reported and holds a special place, allowing the
efficient construction of complex nitrogen
heterocycles of various ring size, using for instance
cascade processes, under conditions which are
compatible with resident functional groups. [3l-p]
Figure 1. Naturally occurring pyrrolidines, pyrrolizidines
and indolizidines.
Recently, our laboratory has developed a novel free-
radical approach toward the oxygenated analogs, i.e.
tetrahydrofurans such as 3, based on a sequence
featuring: (1) a stereocontrolled addition of an acyl
radical, generated from the corresponding selenoester
2a, to Baylis-Hillman adduct 1, followed by (2) a
one-pot desilylation/acetalization and (3) a reduction
of the oxonium generated in situ under acid
conditions (Scheme 1).[4] The three steps, which can
be carried out in a single pot, proceed with excellent
1,2- and 1,3-diastereocontrol in the presence of
(Me3Si)3SiH (TTMSH),[5] reacting as a radical then
ionic hydrogen transfer agent. This strategy opened
up a straightforward and efficient access to 2,3,5-
trisubstituted tetrahydrofurans from readily accessible
1
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10.1002/adsc.201700362
Advanced Synthesis & Catalysis
precursors. Based on this work, we describe here an such as 4b and selenoester 2b, under similar
extension of the methodology to the synthesis of conditions, which produced the desired N-
trisubstituted pyrrolidines, showing that the simple tosylpyrrolidines 5b-c in generally good yields, albeit
modification of the nature of the protecting group on with modest diastereoselectivities as compared to 5a.
nitrogen (Ts, Boc, Cbz) offers additional
opportunities to access various nitrogen heterocycles,
including pyrrolidines IIIa of complementary
stereochemistry, dihydropyrroles IIIb, but also
bicyclic pyrrolizidines IIIc or indolizidines IIId. For
instance, it was discovered that a Cbz-protecting
group allowed the formation of the pyrrolidine IIIa
having a trans-trans relative configuration, while
under similar conditions, the N-Boc-analogue led to
the trans-dihydropyrrole IIIb in excellent yield.
Scheme 2. Addition of acyl radical onto aza-Baylis-
Hillman adducts 4a-b.
Scheme 1. Synthesis of substituted tetrahydrofurans and
pyrrolidines from Baylis-Hillman adducts and selenoesters.
1,2-stereocontrol during reduction of the enoyl radical,
resulting from the addition of the acyl radical onto the
enoate, may be rationalized invoking hydrogen-
Results and Discussion
bonding between the ester C=O group and the
tosylamide N-H in transition state (TS) A, as
Preliminary experiments were carried out using N-
proposed earlier by Kündig et al..[10] The bulky
tosyl-protected aza-Baylis-Hillman adduct 4a,
silicon hydride would then approach anti relative to
prepared from the corresponding p-tosylimine and
the largest R2 group to install the C2-C3-syn relative
configuration (Figure 2). The lower diastereocontrol
observed with the furyl substituent in 5c is presently
not clear, but might result from the occurrence of two
energetically close TS A and A’. In the latter, a
putative hydrogen bonding between the furyl oxygen
and the tosylamide N-H, would lead the hydrogen to
eclipse the enoyl system as in A1,3 models, the two
diastereotopic faces being weakly differentiated.[11-13]
1,3-Stereocontrol may be explained as proposed
earlier in the tetrahydrofuran series.[4a] Reduction of
the iminium likely proceeds through an envelope
conformation such as B (Figure 2), with the ester
group in pseudo-axial position as to maximize
electrostatic effects with the iminium ions.[14] Inside
approach of TTMSH on the lower energy conformer
B thus occurs anti to the R2 group to generate the 2,5-
cis configuration.
ethyl acrylate.[6] Treatment of 4a in the presence of
selenoester 2a,[4,7] as an acyl radical precursor, with
TTMSH in benzene[8] and t-BuON=NOt-Bu
(DTBHN) as an initiator, led to the addition product,
which was not isolated, but directly submitted to an
acidic treatment to trigger the cyclization into the
desired iminium intermediate (Scheme 2). Addition of
BF3-OEt2 was shown to provide the putative iminium,
which was then reduced in situ using TTMSH as an
hydride donor.[9] N-p-tosylpyrrolidine 5a was thus
obtained in good overall yield and satisfying
diastereocontrol. Interestingly, the diastereomeric
1
ratio estimated through H NMR after the first step
was the same at that measured on 5a, indicating that
the reduction of the iminium intermediate and
generation of C2 and C5 chiral centers occurred with
complete 1,3-stereocontrol, while TTMSH reduction
in the first step and formation of C2 and C3 centers
occurred with a 8:1 diastereocontrol. X-ray diffraction
studies showed that, in good agreement with previous
work in the tetrahydrofuran series,[4] 5a possessed a
2,3,5-trans-trans relative configuration. The study
was then extended to other N-Ts protected allylamine
2
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10.1002/adsc.201700362
Advanced Synthesis & Catalysis
Table 1. Addition of acyl radical onto N-Cbz-protected
aza-Baylis-Hillman adducts 7a-c.
Figure 2. Rationalization of the 1,2- and 1,3-stereocontrol.
Entry
8
d.r.a) Yieldb)
9
d.r.a)
Yield b)
63c)
34d)
84e)
58c)
66
-
In order to improve the level of diastereocontrol
during the reduction of radical intermediate A, the
addition of 2a onto 4a was also attempted using
Et2BOMe to chelate the nitrogen atom and the
carbonyl group (Scheme 3).[15] However, and in
contrast with recent studies in the tetrahydrofuran
series, the addition product 6 was obtained in good
yield but with a lower stereocontrol than above
(Scheme 2).
1
2
3
4
5
6
7
8
-
-
5:1
40:34:26
60:22:18
2:1
100:0
-
-
-
8a
8b
8c
8d
8e
8f
9a
9b
9c
9d
9e
-
4:1
3:1
-
72
70
-
6:1
5:1
5:1
4:1
77
89
75
60
-
-
8g
8h
-
-
a) estimated from the 1H NMR of the crude reaction mixture.
b) Isolated yield after chromatography. c) Isolated yield over
2 steps (of the mixture of diastereomers). d) Isolated yield of
the major diastereomer 9b (stereochemistry shown above).
e)
Isolated yield of the inseparable mixture of the 3
diastereomers.
Using the conditions optimized in the N-Ts series, the
overall sequence provided the desired N-Cbz
protected pyrrolidines 9a-e in generally good yields
with moderate to excellent diastereocontrol (Table
1).[18] In certain cases, the diastereomeric acyl
addition products 8 could not be separated and were
directly subjected to the reduction step (Table 1,
entries 1 and 4) to provide the corresponding
pyrrolidines 9. Contrasting results were however
observed, depending on the nature of the R2
substituent in 7a-c. Reduction of the iminium was
totally diastereoselective for R2 = Ph, the d.r. of the
final pyrrolidines 9a and 9d illustrating the
stereoselectivity of the acyl radical addition (Table 1,
entries 1, 4 and 5). With other R2 groups, we observed
a slightly lower diastereocontrol in both steps, as
indicated by the formation of a mixture of 3
diastereomers, showing that the reduction of one
iminium diastereomer was not totally stereoselective
Scheme 3. Addition of acyl radical onto allylamine 4a in
the presence of Et2BOMe as an additive.
Although this approach provided the desired
pyrrolidines in good yields and satisfying sterocontrol,
it was anticipated that the rather harsh N-Ts group
deprotection conditions might hamper further
transformation of more functionalized substrates.[16]
The addition of acyl radicals was thus extended to
aza-Baylis-Hillman adducts protected with the more
labile, but yet stable benzyloxycarbonyl (Cbz) N-
protecting group. Aza-Baylis-Hillman adducts were
prepared using reported procedures[17] (see supporting
information), then subjected to the radical acyl
addition process, starting from various selenoesters
2a-e (Table 1).
(Table 1, entries 2-3).
A
trans-trans 2,3,5-
stereochemistry was proposed for the major
diastereomer of 9b-c, by analogy with that of
pyrrolidine 9a. With selenoesters 2d-e bearing a
3
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10.1002/adsc.201700362
Advanced Synthesis & Catalysis
ketone functional group, the acyl addition provided
the expected amino-ketones 8f-g in excellent yield
and satisfying diastereocontrol (Table 1, entries 6-7).
However, all our attempts to cyclize 8f-g, using BF3-
OEt2 and TTMSH, failed to afford the corresponding
pyrrolidines and led to starting material
decomposition, in contrast with recent studies.[18]
Better results were obtained through metal-catalyzed
reduction (Scheme 4).[19] Hydrogenation of 8f with 5
mol% of Pd-C thus led to dihydropyrrole 10 and
pyrrolizidine 11. The former results from the Cbz
deprotection, followed by a 5-exo reductive amination.
Further hydrogenation of the imine 10 then led to the
corresponding pyrrolidine, which was not observed
but directly converted, through a second reductive
amination into 11 as a mixture of three separable
diastereomers, the stereochemistry of the major one
1
being assigned through 2D H NMR (supporting
information).[20] It is worth mentioning that reduction
of the imine 10 through metal-catalyzed
hydrogenation affords the complementary 2,5-trans
configuration (in 11) as compared to the 2,5-cis
generated through TTMSH reduction (vide infra). In
contrast with the TTMSH reduction of iminiums
above (Figure 2), electrostatic effects are less
important in imine metal-catalyzed hydrogenation.
Therefore, an approach of H2/Pd inside a lower
energy envelope conformation such as B’ (Scheme 4),
in which both substituents at C2 and C3 are in
equatorial position, is likely preferred, leading to the
observed 2,5-trans configuration.[14d] When the
reaction was repeated with PtO2 as a catalyst,[21] only
traces of 11 were observed. Finally, a combination of
Pd-C and PtO2 provided 11 in good yield again as a
mixture of 3 stereoisomers, but with a satisfying
diastereocontrol. Pd-C thus proved efficient to
remove the N-Cbz group, while PtO2 led to good
results for the imine hydrogenation. As an illustration,
pyrrolidine 9a was converted quantitatively in only 1h
into the free pyrrolidine 12 using 5 mol% of Pd-C.
Similarly, treatment of pyrrolidine 9e under the same
conditions led to the indolizidinone 13 after
cyclization with Et3N. X-ray diffraction studies on 13
confirmed the 2,5-cis configuration obtained upon
BF3-Et2O/TTMSH reduction. Treatment of N-Cbz
pyrrolidine 9d under the same conditions than for 9e
surprisingly did not afford the corresponding
pyrrolizidinone, although Cbz-deprotection was
observed on the crude reaction mixture.
Scheme 4. Cbz removal and further functionalization of
pyrrolidines 9.
Another set of experiments was performed using N-
Boc protected allylamines 14a-b and selenoesters 2a-
e. It was anticipated that the lability of the Boc group
under acidic conditions would allow an easy
formation of the iminium intermediate after acyl
radical additions and N-Boc deprotection with
Brønsted or Lewis acids.[22] Reduction in situ of the
so-formed iminium with TTMSH would thus provide
the deprotected pyrrolidines in a two steps one-pot
process.
Table 2. Addition of acyl radical onto N-Boc-protected
allylamines 14a-b.
4
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10.1002/adsc.201700362
Advanced Synthesis & Catalysis
modest diastereocontrol.[19,21] Comparison between 1H
NMR of the crude mixture of both reactions, revealed
that the major diastereomer in 19a was the minor
isomer (6%) in 12.
Entry 15 d.r.a) Yieldb) Imine d.r.a) Yield b)
1
2
3
4
5
6
7
10:1
-
-
10:1
-
68c)
-
-
84
-
-
10:1
3:1
10:1
10:1
3.5:1
6:1
70
56
66
69
61
15a
15b
15c
15d
15e
15f
17a
17b
17c
17d
17e
10
-
6:1
60
79
6:1
75d)
15g
17f
a) estimated from the 1H NMR of the crude reaction mixture.
b)
c)
Isolated yield after chromatography.
14% of
d)
hemiaminal 16 was also isolated. 56% overall yield over
2 steps from 15g.
Preliminary experiments with aza-Baylis-Hillman
adduct 14a and selenoester 2a led, as expected, to the
addition product 15a with a good diastereocontrol,
along with the corresponding hemiaminal 16 (Table 2,
entry 1). Direct treatment of the crude reaction
mixture containing 15a with BF3-OEt2 and TTMSH
led to the N-Boc deprotection and formation of the
imine 17a with a 10:1 diastereomeric ratio, indicating
that 16 had the same relative configuration and was
issued from the cyclization of 15a. The formation of
17a as a unique product also showed that the silane
was unable to reduce the imine under these Lewis-
acid conditions. Treatment of 15a with BF3-OEt2
alone effectively led to 17a in 70% yield and 10:1 d.r.
(Table 1, entry 1). When the two-steps reaction was
repeated with allylamine 14b, bearing an alkyl
substituent in allylic position, imine 17b was obtained
with a lower diastereocontrol (entry 2), in good
agreement with previous observations made with N-
Ts and N-Cbz analogues (see for instance 8c, Table 1).
This general trend was followed, whatever the nature
of the selenoester 2, as shown by the diastereocontrol
observed during the formation of imines 10 and 17c-f
(Table 1, compare entries 3-4 and 6-7 with entry 5).
The failure during reduction of imine 17a with
TTMSH in the presence of BF3-OEt2 was attributed to
the presence of CH3CN as a solvent, which
coordinates to the Lewis acid, thus preventing the
formation of the iminium intermediate. When the
reaction was performed in CH2Cl2 instead, the
iminium generated in situ from 2a and 14a was
effectively reduced by TTMSH, affording 12
(Scheme 5), in modest yield but satisfying
diastereocontrol, with spectroscopic data matching
those of the pyrrolidine prepared from 9a (Scheme 4).
Better diastereocontrol was observed when carrying
out the reduction of 15d in DCE at low temperature.
Scheme 5. Reduction of imines with TTMSH and H2-PtO2.
Imines 17d and 17e were also hydrogenated using
PtO2 as a catalyst, affording indolizidinones 20a-b
having the complementary stereochemistry to that of
13 above (Scheme 6). This procedure was also
extended to imines 17g and 10 having an additional
ketone functional group. Under these conditions, 17g
led to the corresponding indolizidine 21 as a mixture
of 4 stereoisomers in a 60% combined yield. Finally,
more encouraging results were obtained with imine
10, which under similar conditions, led to
pyrrolizidine 11 identical to that prepared from 8f and
with
a
satisfying stereocontrol (Scheme 4).
Compounds such as 11, having 4 stereocenters, may
thus be prepared in good yield and reasonable
diastereocontrol in only 4 steps and two-pot from
simple starting materials.
Pyrrolidine
18
was
obtained
with
high
diastereocontrol, although with modest conversion
(30% of imine 17d was also isolated), and slowly
cyclized into indolizidinone 13, identical to that
prepared from N-Cbz pyrrolidine 9e (Scheme 4).
Interestingly, when imines 17a-b were hydrogenated
using PtO2 as a catalyst, pyrrolidines 19a-b having
the
complementary
2,3,5-trans-cis
relative
configuration were formed in good yield, albeit with
5
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10.1002/adsc.201700362
Advanced Synthesis & Catalysis
M). TTMSH (3 eq.) was added followed by BF3-OEt2
(1.5 eq.). The reaction mixture was stirred at 25°C for
12h and quenched by addition of a saturated aqueous
solution of NaHCO3. The aqueous layer was extracted
twice with EtOAc and combined organic layers were
dried over Na2SO4, concentrated under reduced
pressure and purified by chromatography.
General procedure for the synthesis of
dihydropyrroles 17: To a mixture of phenyl
selenoester (1.2 eq.), N-Boc aza- Baylis-Hillman
adduct (1 eq.) and TTMSH (1.5 eq.) in benzene (0.1
M) was added DTBHN (0.1 eq.). The reaction
mixture was heated at 45°C and stirred for 4h.
DTBHN was added (0.1 eq.) and the reaction mixture
was stirred for an additional 12h at this temperature.
The reaction mixture was concentrated under reduced
pressure and the crude was dissolved in MeCN (0.1
M). BF3.OEt2 (2 eq.) was added and the reaction
mixture was stirred at 25°C for 12h and quenched by
addition of a saturated solution of NaHCO3. The
aqueous layer was extracted twice with EtOAc and
combined organic layers were dried over Na2SO4,
concentrated under reduced pressure and purified by
chromatography.
Scheme 6. Formation of pyrrolizidines and indolizidines
from imines 17d-g and 10.
Conclusion
In summary, we reported here the stereocontrolled
access to N-protected and unprotected pyrrolidines
having stereocenters at 2-, 3- and 5-positions in good
Experimental Details
overall yields and high diastereocontrol. The level of Crystal Structures CCDC1531874 (5a), CCDC 1531876
(13) contain the supplementary crystallographic data for
stereocontrol was shown to be highly dependent on
the nature of the substituent on the stereocenter of the
starting aza-Baylis-Hillman adducts. Varying the
nature of the protecting group on nitrogen also
allowed further transformations. For instance, acyl
addition products having N-Cbz groups could be
cyclized stereoselectively into the Cbz-protected
this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www .ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
pyrrolidines. In contrast, the analogous N-Boc SG thanks the Ministère de l’Enseignement Supérieur et de la
Recherche for a PhD fellowship. The Agence Nationale de la
adducts were unprotected under Lewis-acidic
conditions, leading after cyclization to the
corresponding stable dihydropyrroles. Pt-catalyzed
hydrogenation of the latter gave access to pyrrolidines
having a relative configuration, complementary to
that of pyrrolidines obtained through the BF3-
Recherche (ANR) (Spirosyn, N° 11-BS07-006-02) and CNRS are
gratefully acknowledged for financial support.
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7
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1
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8
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Advanced Synthesis & Catalysis
FULL PAPER
Acyl radical Addition onto aza-Baylis-Hillman
Adducts. A Stereocontrolled access to 2,3,5-
Trisubstituted Pyrrolidines
Adv. Synth. Catal. 2017, Volume, Page – Page
Simon Grélaud, Jonathan Lusseau, Stéphane
Massip, and Yannick Landais*
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