Complementary stereochemical outcomes in proline-based self-regenerations of stereocenters

Article abstract of DOI:10.1021/ol403320d

Stereoselective alkylations of proline-based amino amides are described, where high levels of either a cis or trans configuration can be attained simply by the choice of the aminal group. Isobutryaldehyde-derived aminals provide the cis configuration, whi

Full text of DOI:10.1021/ol403320d

Letter
pubs.acs.org/OrgLett
Complementary Stereochemical Outcomes in Proline-Based Self-
Regenerations of Stereocenters
Brian J. Knight, Erin E. Stache, and Eric M. Ferreira*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
ABSTRACT: Stereoselective alkylations of proline-based
amino amides are described, where high levels of either a cis
or trans configuration can be attained simply by the choice of
the aminal group. Isobutryaldehyde-derived aminals provide
the cis configuration, while 1-naphthaldehyde-derived aminals
engender the complementary trans configuration.
bicyclic system. Further developments in this methodological
α-Quaternary proline-based amino acids and their derivatives
are important compounds owing to their applications as
synthetic building blocks and in peptide studies, among several
other areas.1−3 One of the most reliable processes for accessing
this structural motif in enantioenriched form is the self-
regeneration of stereocenters (SRS).4,5 This strategy entails
installing a temporary substituent and then using it to govern
diastereoselection in a subsequent alkylation process. Stereo-
selectivity has generally been attributed to a steric influence of
this substituent. We hypothesized that these reaction manifolds
may be dictated by specific characteristics of the temporary
group, and in turn this idea could lead to complementary
modes of selectivity. Herein, we illustrate this principle in the
context of α-quaternary amino amide synthesis, where we can
select for opposing alkylation stereoselectivities by simply
changing the nature of the imidazolidinone substituent.
approach have been reported,6 as well as wide exploitation in
several areas of study.2,3,6b An interesting reversal of stereo-
selectivity, based on structually similar amino amides, was
reported by Trauner in the combination of silyl enol ethers
with nitroolefins (Figure 1, 4 → 6).7 Considering this prior art
and given our interest in proline-based amino amides for the
design of ligands for palladium-catalyzed C−H bond
functionalizations,8 we appreciated the importance of confirm-
ing the stereochemical configuration that can arise from these
alkylation processes.9
To that end, we evaluated the reactivity of imidazolidinone 7
(Scheme 1), derived from the phenyl amide of proline and
Scheme 1. Alkylation of Isobutyraldehyde-Based
Imidazolidinone
In Seebach’s self-regeneration of stereocenters with proline,5
an N,O-acetal based on pivalaldehyde is generated, and
alkylation occurs from lithium enolate 2 to form acetal 3
(Figure 1). A 1,3-syn relationship between the tert-butyl and the
alkylating agent is observed, originating from the preference of
the bulky t-Bu group to be situated on the convex face of the
isobutyraldehyde.10 Alkylation using LDA and MeI produced
compound 8a, again as a single diastereomer. Cleavage of the
imidazolidinone8 afforded amino amide 9a with the absolute
configuration depicted (S).11 The stereochemistry of the
alkylation was therefore consistent with the facial selectivity
of Seebach’s work,5 in that the electrophile added in a syn
fashion relative to the isopropyl group.
We viewed this strategy as a general approach toward this α-
quaternary amino amide motif. A number of different alkylating
agents were evaluated (Table 1), and we consistently observed
formation of the 1,3-cis diastereomer. The nature of the amide
substituent was inconsequential to the diastereoselectivity, as
Received: November 16, 2013
Published: December 30, 2013
Figure 1. Proline-based self-regeneration of stereocenters.
© 2013 American Chemical Society
432
dx.doi.org/10.1021/ol403320d | Org. Lett. 2014, 16, 432−435

Organic Letters
Letter
Table 1. syn-Selective Alkylations of Isobutyraldehyde-Based
Imidazolidinones
Table 2. anti-Selective Alkylations of 1-Naphthaldehyde-
Based Imidazolidinones
a
b
Diastereomeric ratio measured by 1H NMR. LiCl (1.1 equiv) added.
a
b
Diastereomeric ratio measured by 1H NMR. LiCl (1.1 equiv) added.
both N-phenyl and N-n-butyl amides displayed high alkylation
selectivities.
chromatographically separable, and the trans products were
obtained in good overall yields.
At this stage, we posed the question whether an anti-selective
alkylation was possible. Under this premise, an energetically
favorable situation must override the aforementioned steric
biases that had dictated the syn-selective process. Promising
results were obtained with benzaldehyde-derived imidazolidi-
none 12 (Scheme 2). When treated with LDA and BnBr, a
Subsequent cleavage of the alkylated aminals would result in
a convenient route to enantioenriched α-quaternary amino
amide products. Although acid-mediated aminolysis with
aniline was effective in some cases (e.g., 8a → 9a, Scheme
1), increased steric hindrance rendered this process difficult for
others. We hypothesized that using hydroxylamine as the
nucleophile would be more successful, due to its enhanced
nucleophilicity14 for intercepting the presumed iminium and
the resulting stability of the oxime byproduct.15,16 Indeed, the
target products were accessed via aminolysis in generally
excellent yields (Table 3). These overall processes, therefore,
represent a divergent strategy toward accessing enantiomeric α-
Scheme 2. Alkylations of Aromatic Aldehyde-Based
Imidazolidinones
Table 3. Aminolysis of the Alkylated Imidazolidinones:
Stereodivergent α-Quaternary Amino Amide Synthesis
entry
imidazolidinone (R1,R2)
amide
9a
yield (%)
40:60 mixture of trans and cis diastereomers, respectively, was
produced. Following this lead, further investigations ultimately
revealed that the 1-naphthaldehyde group highly steered the
selectivity toward the trans diastereomer (92:8 trans/cis).12
Importantly, this outcome is in substantial contrast to the
isobutyraldehyde-derived imidazolidinone; to our knowledge
this example represents the first case of complementary
stereoselectivities in the family of SRS reactions based solely
on the “temporary” substituent.13
1
2
3
4
8a (Ph,Me)
>99
80
8b (Ph,Bn)
9b
8c (Ph,n-Bu)
11a (n-Bu,Me)
11b (n-Bu,Bn)
11c (n-Bu,n-Bu)
15a (Ph,Me)
15b (Ph,Bn)
15c (Ph,n-Bu)
17a (n-Bu,Me)
17b (n-Bu,Bn)
17c (n-Bu,n-Bu
9c
>99
>99
70
18a
a
5
a
18b
6
18c
88
7
ent-9a
ent-9b
ent-9c
ent-18a
ent-18b
ent-18c
>99
92
8
9
>99
98
We examined the scope of this alkylation and in general
obtained high selectivity for the trans diastereomer (Table 2).
Only in the case of MeI did we observe substantially
compromised diastereoselectivity, yet still favoring formation
of the trans product. In all cases, the diastereomers were
10
11
12
90
99
a
H2O/1,4-dioxane (3:2) solvent.
433
dx.doi.org/10.1021/ol403320d | Org. Lett. 2014, 16, 432−435

Organic Letters
Letter
quaternary amino amides and amino acids17 from the
inexpensive, naturally occurring enantiomer of proline.18
This stereochemical dichotomy in these alkylations is
certainly curious. We believe the isopropyl-based alkylations
(Table 1) are aligned with the prior alkylative transformations
involving proline-derived N,O-acetals;5,19 diastereoselectivity
arises primarily from the steric influence of the isopropyl group
(Figure 2). In enolate 12, the all-staggered orientation of the
diastereoselectivity. The naphthyl species, in contrast, offers an
electronic biasing, which in turn results in anti stereoselection.
Further investigations into this unique observation of
complementary stereoselectivities are ongoing and will be
reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectra, and crystallographic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
Figure 2. Rationalization for syn-selective alkylations.
*E-mail: emferr@mail.colostate.edu.
Notes
substituents across the N−C−N bonds positions the
pyrrolidine ring above the enolate plane.20 As the alkylating
agent approaches from underneath, the sp2-hybridized enolate
carbon begins to pyramidalize toward forming a cis-fused 5,5-
ring system. In this reaction trajectory, the i-Pr group also
moves toward being situated on the convex face of the forming
bicycle, avoiding the steric congestion of the concave side.
The effect of the 1-naphthyl group is much more difficult to
rationalize. The magnitude and direction of stereoselectivity
were relatively consistent for both the N-phenyl and N-butyl
amides, suggesting that arene−arene π interactions are not
primary contributors to selection. Figure 3 illustrates our
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Colorado State University and the Donors of the American
Chemical Society Petroleum Research Fund are acknowledged
for support of this research. Curtis Seizert, Tyler Miller, and
Angella Greenawalt are acknowledged for experimental
contributions. The Kennan and Rovis groups are acknowledged
for sharing HPLC equipment.
REFERENCES
■
(1) Calaza, M. I.; Cativiela, C. Eur. J. Org. Chem. 2008, 3427−3448.
(2) For select recent examples in synthesis and catalysis, see:
(a) Frebault, F.; Simpkins, N. S.; Fenwick, A. J. Am. Chem. Soc. 2009,
131, 4214−4215. (b) Crick, P. J.; Simpkins, N. S.; Highton, A. Org.
Lett. 2011, 13, 6472−6475. (c) Su, B.; Cai, C.; Wang, Q. J. Org. Chem.
2012, 77, 7981−7987. (d) Tong, S.-T.; Harris, P. W. R.; Barker, D.;
Brimble, M. A. Eur. J. Org. Chem. 2008, 164−170.
(3) For select examples in peptidomimetics, see: (a) Genin, M. J.;
Johnson, R. L. J. Am. Chem. Soc. 1992, 114, 8778−8783. (b) Hoffmann,
T.; Lanig, H.; Waibel, R.; Gmeiner, P. Angew. Chem., Int. Ed. 2001, 40,
3361−3364. (c) Vartak, A. P.; Johnson, R. L. Org. Lett. 2006, 8, 983−
986. (d) Bittermann, H.; Bockler, F.; Einsiedel, J.; Gmeiner, P.
̈
Figure 3. Rationalization for anti-selective alkylations.
Chem.Eur. J. 2006, 12, 6315−6322.
(4) For a review on SRS, see: Seebach, D.; Sting, A. R.; Hoffmann,
M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708−2748.
(5) For accessing α-quaternary proline-based amino amides using
SRS, see: (a) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am.
Chem. Soc. 1983, 105, 5390−5398. (b) Beck, A. K.; Blank, S.; Job, K.;
Seebach, D.; Sommerfeld, T. Org. Synth. 1995, 72, 62−73.
(6) (a) Wang, H.; Germanas, J. P. Synlett 1999, 33−36. (b) Artman,
G. D., III; Grubbs, A. W.; Williams, R. M. J. Am. Chem. Soc. 2007, 129,
6336−6342.
current hypothesis. Enolization presumably occurs in the same
fashion as in the isopropyl system. The anti diastereoselectivity
suggests that the immediate intermediate enolate must have an
inverted central nitrogen atom (i.e., structure 21). In this
orientation, the nitrogen lone pair is located to somewhat
delocalize into the C−C σ* of the aminal-naphthyl bond.
Although this positions the naphthyl group on the concave face
of the bicyclic enolate, its planarity coupled with its electron-
withdrawing nature may sterically and electronically permit this
orientation to occur in measurable amounts, in contrast to the
isopropyl group.21,22 This overall rationalization is quite
speculative at this stage; both computational and experimental
studies are underway to more definitively elucidate the subtle
effects of this transformation.
In summary, we have described a remarkable difference in
stereoselection in the SRS reaction class. Proline-based aminals
can be alkylated with excellent diastereoselectively to form
either the cis or trans diastereomers of α-quaternary analogues,
and these products can be subsequently aminolyzed to produce
the enantiomeric α-quaternary amino amides. An isopropyl
substituent provides a sufficient steric component to lead to syn
(7) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41,
4556−4559.
(8) Stache, E. E.; Seizert, C. A.; Ferreira, E. M. Chem. Sci. 2012, 3,
1623−1628.
(9) The stereochemical courses of amide enolate alkylations can
often be subject to subtle effects. See: Groaning, M. D.; Meyers, A. I.
Tetrahedron 2000, 56, 9843−9873.
(10) We selected isobutyraldehyde over the traditional pivalaldehyde
because of cost and its similar behavior in SRS with amino amides. For
a recent example, see: Wang, X.; Xu, Y.; Zhang, L.; Krishnamurthy, D.;
Wirth, T.; Nicola, T.; Senanayake, C. H. Org. Lett. 2010, 12, 4412−
4415.
(11) Absolute configuration determined by comparison with an
independent synthesis. See the Supporting Information for details.
(12) In these studies we changed the solvent system to a PhCH3/
THF/hexanes mixture. We generally observed higher magnitudes of
434
dx.doi.org/10.1021/ol403320d | Org. Lett. 2014, 16, 432−435

Organic Letters
Letter
anti-selectivity with this solvent mixture compared to THF/hexanes,
but the directionality was the same in both systems.
(13) There is a lone report of a syn-selective alkylation reported
based on mandelic acid derivatives: Liu, Y.-Q.; Liu, H.; Zhong, B.;
Deng, Y.-L.; Liu, K. Synth. Commun. 2005, 35, 1403−1412. In this
case, the benzaldehyde acetal is illustrated to give the opposite
stereochemical outcome than established anti-selective results with
pivalaldehyde-based acetals.4 We believe, however, that the config-
uration of this acetal stereocenter is illustrated incorrectly, and this
process is in fact also an anti-selective alkylation. Our notion is
corroborated by a second report from the same authors, where anti-
selective alkylations of the benzaldehyde-derived mandelic acid
derivative are performed: Han, X.-Y.; Liu, H.; Liu, C.-H.; Wu, B.;
Zhong, B.-H.; Liu, K.-L. J. Chem. Res. 2004, 816−817.
(14) For references discussing the α-effect, see: (a) Fina, N. J.;
Edwards, J. O. Int. J. Chem. Kinet. 1973, 5, 1−26. (b) Buncel, E.; Um,
I.-K. Tetrahedron 2004, 60, 7801−7825.
(15) (a) Kalia, J.; Raines, R. T. Angew. Chem., Int. Ed. 2008, 47,
7523−7526. (b) Wiberg, K. B.; Glaser, R. J. Am. Chem. Soc. 1992, 114,
841−850.
(16) For a related example of imidazolidinone aminolysis with
H2NOH·HCl, see: Feenstra, R. W.; Stokkingreef, E. H. M.; Reichwein,
A. M.; Lousberg, W. B. H.; Ottenheijm, H. C. J.; Kamphuis, J.;
Boesten, W. H. J.; Schoemaker, H. E.; Meijer, E. M. Tetrahedron 1990,
46, 1745−1756.
(17) Related imidazolidinone hydrolysis to amino acid: Seebach, D.;
Dziadulewicz, E.; Behrendt, L.; Cantoreggi, S.; Fitzi, R. Liebigs Ann.
Chem. 1989, 1215−1232.
(18) In the naphthyl systems, we have eliminated the possibility of an
endo-selective condensation with subsequent syn-selective alkylation
and aminolysis. See the Supporting Information for details.
(19) No “memory effect” was observed in the process, evaluated by
alkylation of a formaldehyde-derived imidazolidinone. See Supporting
Information.
(20) Pyramidalization of both nitrogens of the imidazolidinone
should occur upon enolization. This orientation is aligned with a
proposed transition state in the alkylations of imidazolidinones based
on glycine derivatives. See: Seebach, D.; Juaristi, E.; Miller, D. D.;
Schickli, C.; Weber, T. Helv. Chim. Acta 1987, 70, 237−261.
(21) The hypothesis is also consistent with the 1-naphthyl group
being more electron-withdrawing than a phenyl ring, aligned with the
stereoselectivity trend in Scheme 2.
(22) Interestingly, the 1-naphthyl group behaves similarly to the tert-
butyl group in mandelic acid derivative alkylations. See: Misaki, T.;
Ureshino, S.; Nagase, R.; Oguni, Y.; Tanabe, Y. Org. Process Res. Dev.
2006, 10, 500−504.
435
dx.doi.org/10.1021/ol403320d | Org. Lett. 2014, 16, 432−435