Chiral pyrroline-based Ugi-three-component reactions are under kinetic control

Article abstract of DOI:10.1021/ol4012053

Although it is often assumed that the stereochemistry in Ugi multicomponent reactions is determined in the final Mumm rearrangement step, experimental and computational evidence that Ugi reactions on hydroxylated pyrrolines proceed under kinetic control is reported. The stereochemistry of the reaction is established with the addition of the isocyanide to the intermediate iminium ion, whose conformation is determined by its substitution pattern.

Full text of DOI:10.1021/ol4012053

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Chiral Pyrroline-Based
Ugi-Three-Component Reactions
Are under Kinetic Control
Erwin R. van Rijssel, Theodorus P. M. Goumans, Gerrit Lodder, Herman S. Overkleeft,
ꢀ
Gijsbert A. van der Marel,* and Jeroen D. C. Codee*
Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden,
The Netherlands
jcodee@chem.leidenuniv.nl; marel_g@chem.leidenuniv.nl
Received May 1, 2013
ABSTRACT
Although it is often assumed that the stereochemistry in Ugi multicomponent reactions is determined in the final Mumm rearrangement step,
experimental and computational evidence that Ugi reactions on hydroxylated pyrrolines proceed under kinetic control is reported. The
stereochemistry of the reaction is established with the addition of the isocyanide to the intermediate iminium ion, whose conformation is
determined by its substitution pattern.
The Ugi reaction is one of the most widely used multi-
component reactions and has found extensive application
in the generation of structural diversity in diverse com-
pound libraries.1 In the classic Ugi four-component reac-
tion, an aldehyde, an amine, a carboxylic acid, and an
isocyanide are combined to form a diamide motif. In this
event, the aldehyde is condensed with the amine to gen-
erate an imine (3, Scheme 1a). This species is protonated by
the carboxylic acid component to provide an iminium ion
(4), which is attacked by the isocyanide to generate a
nitrilium ion (5). This cation is intercepted by the carbox-
ylate to form an intermediate imidate (6). Mumm rearran-
gement of this imidate leads to the final Ugi product (7).2
In the closely related Ugi-three-component reaction, pre-
formed imines are made to react with an isocyanide and a
carboxylic acid. As a result of an Ugi multicomponent
reaction, a new chiral center is formed between the two
newly created amide functions and it is often assumed that
the stereoselectivity in the reaction is determined by the
irreversible Mumm rearrangement, which terminates the
series of preceding equilibria.1À3
In the past few years we explored the use of chiral,
carbohydrate-derived azidoaldehydes (exemplified by pentose-
derived 4-azido-aldehyde 8) to generate cyclic imines
as a starting point for an ensuing Ugi three-component
reaction process (see Scheme 1b).4,5 During the course
of these investigations we observed that some of these
reactions proceeded with excellent stereoselectivity while
(4) (a) Timmer, M. S. M.; Risseeuw, M. D. P.; Verdoes, M.; Filippov,
D. V.; Plaisier, J. R.; van der Marel, G. A.; Overkleeft, H. S.; van Boom,
J. H. Tetrahedron: Asymmetry 2005, 16, 177. (b) Bonger, K. M.;
Wennekes, T.; Filippov, D. V.; Lodder, G.; van der Marel, G. A.;
Overkleeft, H. S. Eur. J. Org. Chem. 2008, 3678. Wennekes, T.; Bonger,
K. M.; Vogel, K.; van den Berg, R. J. B. H. N.; Strijland, A.; Donker-
Koopman, W. E.; Aerts, J. M. F. G.; van der Marel, G. A.; Overkleeft,
H. S. Eur. J. Org. Chem. 2012, 6420.
(5) Bonger, K. M.; Wennekes, T.; de Lavoir, S. V. P.; Esposito, D.;
van den Berg, R. J. B. H. N.; Litjens, R. E. J. N.; van der Marel, G. A.
QSAR Comb. Sci. 2006, 25, 491.
(6) For related studies, see: (a) Chapman, T. M.; Davies, I. G.; Gu,
B.; Block, T. M.; Scopes, D. I. C.; Hay, P. A.; Courtney, S. M.; McNeill,
L. A.; Schofield, C. J.; Davis, B. G. J. Am. Chem. Soc. 2005, 127, 506. (b)
Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Tetrahedron Lett. 2004, 45,
6637. (c) Banfi, L.; Basso, A.; Guanti, G.; Merlo, S.; Repetto, C.; Riva,
R. Tetrahedron 2008, 64, 1114. (d) Cerulli, V.; Banfi, L.; Basso, A.;
Rocca, V.; Riva, R. Org. Biomol. Chem. 2012, 10, 1255. (e) Flanagan,
€
(1) (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169. (b)
€
Domling, A. Chem. Rev. 2006, 106, 17. (c) Ruijter, E.; Scheffelaar, R.;
Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234.
(2) El Kaim, L.; Grimaud, L. Tetrahedron 2009, 65, 2153.
(3) Ugi, I.; Meyr, R. Chem. Ber. 1961, 94, 2229.
ꢀ
D. M.; Joullie, M. M. Synth. Commun. 1989, 19, 1. (f) Bowers, M. M.;
ꢀ
Carroll, P.; Joullie, M. M. J. Chem. Soc., Perkin Trans. 1 1989, 857.
r
10.1021/ol4012053
XXXX American Chemical Society

Table 1. Products of the Ugi Reaction on D-Pentose Derived
Pyrrolines 12À15a
Scheme 1. (a) Ugi Multicomponent Reaction; (b) Ugi Reaction
on a Preformed Pyrroline, Generated from a D-Pentose Derived
4-Azido Aldehyde, through a Staudinger-aza-Wittig Reaction
a Reaction conditions: (1) PMe3, MeOH, 0 °C; (2) pent-4-enoic acid,
RNC, MeOH, 0 °C.10
others provided diastereomeric products with little or no
selectivity.6,7 For example, the D-lyxo configured pyrroline
(12) gave after Ugi reaction with a variety of isocyanides
and carboxylates exclusively the all-cis substituted pyrro-
lidines, whereas the D-arabino configured pyrroline (13)
provided the 2,3-cis- and 2,3-trans-products in almost
equal amounts.5,8 The stereochemical course of these
reactions is obviously guided by the configuration of the
starting imine, but is not easily explained by considering
the Mumm rearrangement as the stereoselectivity deter-
mining step. Would this be true, then formation of the
thermodynamically more stable product would be ex-
pected. Here we describe experimental and computational
studies on the Ugi three-component reaction of all four
possible 4-deoxy-4-azido-D-pentose derived pyrrolines
12À15. Our results indicate that the stereoselectivity of
these Ugi multicomponent reactions is based on kinetic
control and is determined at the stage of attack of the
isocyanide at the iminium ion.
The four diastereomeric pentose-derived azidoaldehydes
used in this study, 8 (D-lyxo), 9 (D-arabino), 10 (D-xylo),
and 11 (D-ribo), and corresponding imines (12À15) are
depicted in Scheme 1b. Table 1 shows the results of the
Ugi reaction using these imines with either tert-butylisocya-
nide or cyclohexylisocyanide and pent-4-enoic acid.9 To
fully ascertain the stereochemistry of the newly formed
stereocenters in products 16À23, the pentenoyl groups,
which give rise to rotameric product mixtures, were re-
moved by iodine mediated hydrolysis (see Table S1, Sup-
porting Information). The structures of the resulting
products were unambiguously established with 1H and
13C NMR spectroscopy.9
The Ugi three-component reaction on lyxo-configured
imine 12 proceeded with excellent 2,3-cis-stereoselectivity
to provide the all-cis-linked pyrrolidines 16a and 17a, in
line with our previous observations. A similar stereochemical
outcome is observed for the ribo-configured imine 15,
with only the 2,3-cis pyrrolidines 22a and 23a formed.
In contrast, Ugi three-component reaction on the arabino-
and xylo-configured imines (13 and 14) proceeded with
virtually no stereoselectivity.
We argue that the stereochemical outcome of the Ugi
reaction cannot be rationalized through appreciation of
the steric interactions in the products 16À23. For example,
unfavorable 2,3-cis interactions would already be manifest
in the imidate intermediates (6), thereby eliminating the
Mumm rearrangement as the step governing the stereochem-
ical outcome of the reaction. Rather, we were drawn to the
parallels between the stereochemical course of C-allylation
reactions on furanosyl oxocarbenium ions as reported by
Woerpel and co-workers11 and the stereochemical outcome
of our Ugi three-component reactions. Woerpel and co-
workers proposed a model to account for the stereoselectivity
observed in C-allylation reactions of furanosides based
on the conformational preferences of the intermediate
oxocarbenium ions. They reasoned that the orientational
preferences of the ring substituents dictate the relative stabi-
lities of the possible oxocarbenium ion envelope conformers.
Alkoxy substituents at C-2 and C-3 (oxocarbenium ion
numbering) preferentially take up an equatorial and axial
position, respectively (as in 25b, see Scheme 2). The C-4 alkyl
(7) Chiral precursors have been shown to direct stereoselectivity: (a)
de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41, 3969.
(b) Basso, A.; Banfi, L.; Riva, R.; Guanti, G. Tetrahedron Lett. 2004, 45,
587.
(8) In this paper pyrrolidine numbering is used.
(10) Product ratios are determined by 1H NMR at 393 K to allow free
rotation around the newly formed tertiary amide bond.
(11) (a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.;
Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 10879. (b) Smith, D. M.;
Tran, M. B.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 14149.
(9) See Supporting Information for the synthesis of the starting
azidoaldehydes, the full experimental details on the reaction conditions,
analytical data, energy diagrams, and optimized structures of the
calculations.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3 (top) shows the reaction pathway energy
diagram of the D-lyxo configured imine 12 starting at the
protonatedimine(27). Thepathway shows twoexothermic
steps, one, the formation of the imidate (28) from the
nitrilium ion (27) and, the other, the Mumm rearrange-
ment, proceeding through a cyclic intermediate14 (30) that
is higher in energy than the preceding imidate.15 The large
drop in energy in going from the nitrilium ion to the
imidate indicates that the addition of the carboxylate to
the nitrilium ion is essentially nonreversible. Therefore the
stereochemistry of the Ugi reaction is determined before
this event. The calculations provide support for the two-
conformer hypothesis, described above. Thus, two low
energy conformations were found for the D-lyxo iminium
ion (27a and 27b), of which the 4E-envelope ion (27a) is the
one lower inenergy. This conformer places the C-3 and C-4
substituents in favorable positions while steric interactions
between the C-3 and C-5 substituent are minimal in this
structure. Notably, the difference in energies between the
conformers is larger in the two transition states (28a and
28b) in which the isocyanide attacks the iminium ions than
in the starting envelope conformers 27a and 27b. This
contrasts the perception that steric interactions between
the axially oriented C-4 substituent and the incoming
nucleophile make transition state 28a less favorable. A
close inspection of transition state 28a for the attack on the
methyl isocyanide on the 4E iminium ion reveals that the
C-4 substituent actually approaches the incoming nucleo-
phile. A possible explanation for this approach is the
electrostatic stabilization of the positive charge that devel-
ops on the isocyanide carbon atom by the C-4 oxygen
substituent while the addition progresses.16 Scheme 3
(bottom) depicts the course of the addition and shows the
4E f 4T3 f E3 reaction trajectory in which the stabilizing
interaction of the C-4-substituent and the incoming nucleo-
phile becomes clear. The calculated difference in energy
Scheme 2. D-Ribose Oxocarbenium Conformers 25a and 25b
Attacked by Allyltrimethylsilane and D-Lyxo Configured Imi-
nium Ion Conformers 27a and 27b Attacked by an Isocyanide
substituent (oxocarbenium ion numbering) does not have a
strong preference for either orientation but can play an
important role in combination with the other ring substitu-
ents through mutual steric interactions. Nucleophiles would
then approach the intermediate envelope oxocarbenium ions
preferentially from the “inside” (the side of the envelope syn
to the carbon atom which lies out of the envelope plane) to
avoid developing eclipsing interactions with the neighboring
ring substituent. A final contributing factor they identified
was the steric interaction between the substituents and the
incoming nucleophile. When these conformational prefer-
ences are translated to the iminium ions at hand it becomes
clear that the D-lyxo iminium ion preferentially adopts an
4E-conformation (27a Scheme 2, iminium ion numbering),
allowing the C-3 and C-4 substituents to take up a preferred
orientation. Inside attack on this iminium ion leads to the all-
cis-product. In the same vein, the D-ribo iminium ion prefers
the E4-envelope and inside attack on this conformer accounts
for the formation of the 2,3-cis products. For the D-arabino
and the D-xylo iminium ions the substituent preferences are
conflicting, resulting in a mixture of iminium ion conformers
of comparable stability and thereby leading to a mixture of
diastereomeric products.
To gain more insight into the course of the Ugi reactions
on pentose derived pyrrolines, we performed a quantum-
mechanical DFT study12,9 in which we calculated the
relative energies of the intermediates through which the
reaction passes for all four diastereomeric imines, starting
from either envelope conformer. The calculations were
performed at the B3LYP/6-31G* level with inclusion of
the solvent (methanol) through a Polarized Continuum
Model and employed methyl substituted imines, methyl
isocyanide, and acetic acid as reaction partners.13 Energies
ofthe individual reactants were added tothe energies ofthe
protonated imines and the nitrilium species in order to
compare relative energies. In addition, transition states
were calculated for the attack of the isocyanide on the
protonated imines.9
between the two transition states (ΔΔE‡ = 2.5 kcal molÀ1
;
2,3-cis/2,3-trans, 28a/28b = 98:2) corroborates the observed
stereoselectivity in the Ugi reaction of imine 12 (experimental
2,3-cis/2,3-trans = >98:2).
The other three imine stereoisomers show similar energy
diagrams,9 indicating thatthereactionpathways of the Ugi
reactions of these imines are comparable to the one
described for the D-lyxo imine.17 The relative energies of
the iminium ion envelope conformers, the transition states
of the corresponding isocyanide additions, and the result-
ing nitrilium ions are listed in Table 2. Although the overall
(14) Several bicyclic intermediates can be formed in this reaction step,
differing in the stereochemistry of the newly formed hemiaminal linkage
and the stereochemistry of the double bond (see Supporting Infor-
mation). The lowest energy intermediate is shown in the figure.
(15) Although the addition of the isocyanide to the imine can also be
envisioned to proceed via an SN2-like pathway in which the incoming
isocyanide displaces an anomeric (covalent) acetate, we deem this path-
way to be less likely given the stabilities of the intermediate iminium ions
and the polarity of the solvent.
(12) Forsimilar theoretical approaches, see: (a)Maeda, S.; Komagawa,
S.; Uchiyama, M.; Morokuma, K. Angew. Chem., Int. Ed. 2011, 50, 644.
(16) Chao, C. S.; Lin, C. Y.; Mulani, S.; Hung, W. C.; Mong, K. K. T.
Chem.;Eur. J. 2011, 17, 12193.
ꢀ
(b) Cheron, N.; Ramozzi, R.; El Kaım, L.; Grimaud, L.; Fleurat-Lessard,
¨
(17) When all iminium ions are compared it becomes clear that the 4E
Ara is the most stable conformer of the four isomers (4E Lyxo = 1.00
kcal molÀ1, 4E Ara = 0.00 kcal molÀ1, E4 Xylo = 0.96 kcal molÀ1, E4
Ribo = 0.99 kcal molÀ1).
P. J. Org. Chem. 2012, 77, 1361.
(13) The stereoselectivity of the Ugi reaction of the per-O-methylated
xylo derived imine was similar to that for the Ugi reaction of its per-
O-benzylated counterpart (see Supporting Information).
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Relative Energies of Iminium Ion Conformers, Tran-
sition States, Nitrilium Ions, and Theoretical Product Ratios
Scheme 3. (Top) Energy Diagram of the Ugi Reaction on the
D-Lyxo Configured Imine Starting at the Iminium Ion;a (Bottom)
Optimized Structures of the D-Lyxo 4E Iminium Ion (27a), the
Transition State (28a) of the Attack of the Isocyanide on This Ion,
and the Resulting Nitrilium Ion (26a)
In conclusion, our experimental results supported by the
calculational data reported here show that the diastereos-
electivity of the Ugi three-component reaction using pen-
tose derived pyrrolines is determined in the transition state
of the isocyanide addition step to the iminium ion and that
these reactions therefore proceed under kinetic control.
This stands in contrast to the classic mechanistic view that
the Ugi reaction proceeds through a series of equilibrium
reactions before ending with the irreversible Mumm re-
arrangement in the thermodynamically favored product.
For the pyrrolines studied here, the conformation of the
iminium ion intermediates, in combination with the stabi-
lizing effect of an axially positioned C-4 ether on the
developing positive charge in the incoming nucleophile, is
the deciding factor in the stereochemical course of the
isocyanide addition reaction. It might well be that the
kinetic scenario described here is not only valid for the
pyrrolines used in this study but also of importance for
many other Ugi reactions and other multicomponent
reaction featuring isocyanides. Our results therefore may
help in the development of predictive models for diastereo-
selective Ugi-type multicomponent reactions, which would
have considerable impact in library design for drug discovery
and development.
a Energies are given relative to the combined energy of the 4E iminium
ion 27a and its reaction partners.
reaction pathways are similar there are important differ-
ences to note. For both the D-arabino and D-xylo config-
ured iminium ions, the energy difference between the
transition states of the isocyanide additions is smaller than
the difference in energy between the starting envelope
conformers. Also here the stabilizing interaction of the
axially oriented C4-substituent with the nucleophile be-
comes apparent. For example, while the D-xylo configured
4
E4 iminium ion is favored over its E counterpart by
1 kcal molÀ1, the transition state originating from the
latter ion is slightly lower in energy than the transition
state derived from the former. The D-ribo Ugi reaction
energy profile parallels that of its D-lyxo congener.
The difference in energy between the two isocyanide
addition transition states is larger than the energy
difference between the parent iminium ion envelopes
leading to the selective formation of the 2,3-cis-nitri-
lium ion and subsequently the 2,3-cis-Ugi product. The
calculated energy differences between the transition
states nicely match the experimental stereoselectivities
for the four diastereomeric imines as summarized in
Table 2. Finally, the calculations confirm that the
relative stabilities of the Ugi products cannot account
for the observed selectivities.9
Acknowledgment. This work was financially supported
by The Netherlands Organization for Scientific Research.
Supporting Information Available. Experimental details,
calculational and analytical data. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX