Spontaneous symmetry breaking during interrupted crystallization of an axially chiral amino acid derivative

Article abstract of DOI:10.1039/b922028c

High net enantiomeric excess was observed for crystal collections obtained by crystallization of the TFA salt of a configurationally stable yet racemic axially chiral amidoamine in EtOH solution with or without stirring (up to >99% ee at ≤15% crystallizat

Full text of DOI:10.1039/b922028c

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Spontaneous symmetry breaking during interrupted crystallization
of an axially chiral amino acid derivativew
Mark A. Sephton, Christopher R. Emerson, Lev N. Zakharov and Paul R. Blakemore*
Received (in Cambridge, UK) 21st October 2009, Accepted 4th February 2010
First published as an Advance Article onthe web 19th February 2010
DOI: 10.1039/b922028c
High net enantiomeric excess was observed for crystal collections
obtained by crystallization of the TFA salt of a configurationally
stable yet racemic axially chiral amidoamine in EtOH
solution with or without stirring (up to 499% ee at r15%
crystallization).
net optically active crystalline 1,10-binaphthyl deposited from
a supercooled melt at 150 1C.6 Liquid 1,10-binaphthyl is
configurationally labile at this elevated temperature; thus, the
Pincock process is a spontaneous resolution under racemizing
conditions and it is capable of yielding 450% of enantiopure
material. Later, Kondepudi et al. reproduced the Gaussian-
like distribution of ee (centered at 0% ee) found by Pincock
and Wilson and discovered that stirring of the 1,10-binaphthyl
melt resulted in a large net ee developing from almost every
crystallization.7 When stirring was employed, the distribution
of product ee was bimodal with mean absolute value of 70%
and a random occurrence of d- or l-isomer predominance. In
this communication, we document our findings concerning
the spontaneous resolution of a novel biaryl molecule from
solution and under conditions for which the compound possesses
complete configurational stability. Significantly, the molecular
system in question also manifests organocatalytic activity for
the aldol reaction.
A majority of racemic materials form crystals that belong to
centrosymmetric space groups and are correctly categorized as
true ‘‘racemic compounds’’ in which each single crystal is
composed of a 1 : 1 mixture of enantiomorphs in an ordered
arrangement.1 A second class of crystalline racemate, that of a
‘‘conglomerate,’’ is also possible in which individual crystals
are homochiral in their composition but such that the bulk
solid is a net racemate overall. Formation of conglomerates is
comparatively rare (occurring for less than 10% of crystalline
racemates),2 but when encountered this phenomenon allows
for direct resolution by a triage process involving: mechanical
separation of crystallites, identification of optical series for
each, then pooling together of all like individuals. Resolution
by crystal triage was most famously employed by Pasteur for
the separation of racemic sodium ammonium tartrate into its
d- and l-isomers.3 A more practical resolution technique that
also exploits conglomerate formation is effected by seeding of
a racemic mother liquor solution with a single enantiopure
crystal. This process, known as resolution by entrainment,1a
constitutes the most cost effective method for achieving
enantiomer separations on an industrial scale. Although often
described as such, it is debatable whether either of the resolution
processes described above are truly ‘‘spontaneous’’ given that
an extraneous source of chiral information is typically
required to obtain aggregated scalemic material in each case.
The generation of a meaningful enantiomeric excess in a
bulk phase from a racemic or achiral starting state, without the
intervention of a chiral entity (such as the human operator in
crystal triage, or the seed used for entrainment), constitutes a
spontaneous symmetry breaking event.4 Reports of resolution
purporting to come about by spontaneous symmetry breaking
are rare and present a challenge to orthodox theory.5 Pertinent
to the work detailed herein, Pincock and Wilson observed that
In search of new bifunctional templates for enantioselective
organocatalysis, we recognized that biaryls in which both a 21
amino moiety and a hydrogen-bond donor flank the chiral axis
would likely promote aldol processes.8 An efficient synthetic
entry to one such molecule presented itself when it was found
that deprotection and LiAlH4 reduction of bisamide 1 (derived
in three steps from m-anisic acid) generated an amidoamine 3
rather than the expected symmetrical bisamine (Scheme 1).
The racemic samples of 3 (isolated as its crystalline TFA salt)
first prepared showed modest catalytic activity for the aldol
reaction, presumably via the usual enamine mechanism,9 and
we next sought to access this compound in scalemic form to
ascertain the level of enantioselectivity. Numerous potentially
viable methods to obtain enantiopure amidoamine 3 were
evaluated, including classical resolution approaches, but none
of the tactics initially surveyed met with a wholly satisfactory
outcome. During the course of these studies, X-ray diffraction
analyses were performed on single crystals of 3ꢀTFAz (Fig. 1)
and its uncharged precursor 1.y It was so revealed that both
compounds form conglomerate crystals, thus affording us an
opportunity to explore ‘‘spontaneous’’ resolution strategies.
Department of Chemistry, Oregon State University, Corvallis, Oregon
97331-4003, USA. E-mail: paul.blakemore@science.oregonstate.edu;
Fax: +1 541 737 2062; Tel: +1 541 737 6728
w Electronic supplementary information (ESI) available: All synthetic
procedures (including three step preparation of 1 from m-anisic acid)
and chracterization data for prepared compounds, details for crystalli-
zation of 3ꢀTFA, X-ray diffraction data (CIF) for 1 and 3ꢀTFA, NMR
spectra for all compounds, HPLC analysis methods. CCDC 748439
and 748440. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b922028c
Scheme 1 Conversion of bisamide 1 to amidoamine salt 3ꢀTFA.
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Fig. 1 ORTEP diagram for 3ꢀTFA conglomerate showing a bridging
trifluoroacetate anion between two homochiral biaryl cation units.
50% probability ellipsoids are plotted for non-hydrogen atoms.
The prospects for a practical crystal triage approach for the
direct resolution of amidoamine salt 3ꢀTFA were hampered by
the fact that only small needles low in mass (r1 mg) could be
grown from the EtOH mother liquor. By contrast, individual
crystals that were monolithic in outward appearance and of
over 100 mg in mass were easily grown from EtOAc solutions
of bisamide 1. Regrettably, a wide variation in the magnitude
of optical rotation was noted for crystals of 1 that were large
enough to be useful (e.g., Chart 1) suggesting that the isolated
crystallites were aggregates. Prismatic crystals with volumes in
the order of 1 cm3 were reliably obtained from dl-1 using an
historically noteworthy entrainment protocol,10 but optical
purity remained variable. The largest crystal of 1 obtained
by entrainment amounted to 1.26 g in mass and this prism
gave a polarimeter reading reflecting a net 70% ee when
Chart 2 Scattergraph of optical rotation data (in MeOH) recorded
from collections of crystals obtained by crystallization of dl-3ꢀTFA
from EtOH solution at rt. Mother liquor unstirred for experiments
1–10, and stirred at 400 rpm for experiments 11–20. Assay of crystal
collection #3 by derivatization/HPLC analysis indicated a 97% ee
(see ESIw).
evaluated with stirring of the mother liquor (Chart 2,
experiments 11–20). The appearance of a significant quantity
of solid now occurred rapidly (10–45 min vs. 3–24 h without
stirring) and individual crystals were minute and virtually
indistinguishable to the naked eye. Maximal ee values were
not encountered more frequently than before; however, a
significantly higher median ee was observed with stirring as
compared to without it (44% vs. 14%, respectively). The kind
of spontaneous resolution encountered herein is probably best
rationalized according to Kondepudi’s model,7a i.e., the result
of an atypical autocatalytic secondary nucleation process that
satisfies the classical Frank condition12 by suppressing further
primary nucleation.
22
dissolved in MeOH: [a]D = ꢂ79.6 (c = 1.26). The
levorotatory scalemic material (l-1) was further converted as
before (Scheme 1), but the amidoamine obtained (l-3ꢀTFA)
exhibited low ee (o15%) indicating that partial racemization
had occurred during the two step sequence.11
With the possibility of converting scalemic bisamide 1 into
usefully enantioenriched samples of amidoamine 3 precluded,
focus returned to a direct resolution approach. Upon renewed
scrutiny, a rare symmetry breaking phenomenon was observed
to operate during crystallization of dl-3ꢀTFA from EtOH and
a truly spontaneous resolution was achievable if crystals were
harvested during the early phase of deposition. Interruption of
crystallization at r15% yield led to attainment of a significant
net ee from most experiments with a random predominance of
d- or l-isomers in up to a 499% ee. By way of illustration,
optical rotation data for crystal collections obtained from a
series of ten crystallization experiments conducted without
stirring of the mother liquor are given in Chart 2 (experiments
1–10). It is emphasized that crystal crops obtained from such
experiments consisted of many hundreds of tiny needles,
collected en masse by filtration and without any attempt to
effect an enantiomer differentiating mechanical triage. In an
effort to improve on the frequency with which superlative ee
would likely be realized, otherwise identical experiments were
With a useful and conceptually interesting solution to the
resolution problem thus identified, use of the enantioenriched
amidoamine 3 as an aldolization catalyst was investigated. As
its freebase, the amine was a comparatively poor promoter of
the aldol reaction between acetone and benzaldehydes (e.g.,
o10% yield with p-nitrobenzaldehyde). Superior results were
obtained by employing 3 in conjunction with modestly acidic
additives, particularly acetic acid (Table 1); however, salts of 3
formed from strong acids lacked all catalytic activity (e.g.,
3ꢀTFA and 3ꢀTfOH). Good conversion was noted for highly
electrophilic benzaldehydes, but non-activated and electron
rich substrates failed to react appreciably. Stereoinduction
from the catalyst was of limited efficacy as revealed by the
barely discernable level of enantioselectivity encountered.
In conclusion, the earlier work of Pincock and Wilson6 and
Kondepudi et al.7 had demonstrated that true spontaneous
resolution of
a biaryl compound was possible under
specialized conditions wherein the axially chiral substrate
was configurationally labile as it crystallized from a melt.
The observations documented herein establish that a symmetry
breaking resolution may also occur in the more general and
likely to be encountered scenario in which the biaryl maintains
stable enantiomeric atropisomers13 throughout crystallization
of its conglomerate from a solution phase. True spontaneous
Chart 1 Mass and optical rotation data (in MeOH) for 8 individual
crystals collected after non-seeded crystallization of dl-1 from EtOAc.
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Table 1 Catalysis of aldol reactions with amidoamine l-3 (of 82% ee)
1 (a) J. Jacques, A. Collet and S. H. Wilen, Enantiomers, Racemates,
and Resolutions, Wiley, New York, NY, 1981; (b) A. Collet,
M.-J. Brienne and J. Jacques, Chem. Rev., 1980, 80, 215.
2 (a) L. Perez-Garcıa and D. B. Amabilino, Chem. Soc. Rev., 2007,
36, 941; (b) L. Perez-Garcıa and D. B. Amabilino, Chem. Soc. Rev.,
2002, 31, 342.
3 For an authoritative historical perspective on Pasteur’s seminal
resolution work, see: G. B. Kauffman and R. D. Myers, J. Chem.
Educ., 1975, 52, 777.
Aldehyde 4 Product distribution (mol%)a Aldol adduct 5
4 D. K. Kondepudi and K. Asakura, Acc. Chem. Res., 2001, 34, 946.
5 (a) R. Plasson, D. K. Konepudi and K. Asakura, J. Phys. Chem. B,
2006, 110, 8481; (b) M. Avalos, R. Babiano, P. Cintas,
R. L. Jimenez and J. C. Palacios, Origins Life Evol. Biosphere,
2004, 34, 391.
6 (a) R. E. Pincock and K. R. Wilson, J. Am. Chem. Soc., 1971, 93,
1291; (b) K. R. Wilson and R. E. Pincock, J. Am. Chem. Soc., 1975,
97, 1474.
7 (a) D. K. Kondepudi, J. Laudadio and K. Asakura, J. Am. Chem.
Soc., 1999, 121, 1448; (b) K. Asakura, Y. Nagasaka, M. Hidaka,
M. Hayashi, S. Osanai and D. K. Kondepudi, Chirality, 2004, 16, 131.
8 For a topologically distinct class of axially chiral 21 amines useful
for enantioselective organocatalysis, see: T. Kano and
K. Maruoka, Chem. Commun., 2008, 5465.
R
AL : DAL : AC : SM
Yieldb (%) eec (%)
#
1
2
3
4
5
6
7
8
4-NO2
4-CF3
4-Cl
3-Cl
2,6-Cl2
H
69 : 28 : 3 : 0
70 : 14 : 9 : 7
23 : 6 : 10 : 61
53 : 8 : 4 : 35
79 : 11 : 10 : 0
14 : 2 : 17 : 67
5 : 2 : 10 : 83
o1 : o1 : 2 : 97
34
41
13
24
58
6
3
1
1
o1
1
2
4-Me
4-MeO
2
0
nd
—
Determined by 1H NMR analysis of crude product mixture:
a
AL = aldol (8), DAL = a,a0-acetone double aldol, AC = aldol
condensation, SM = starting aldehyde. Isolated yield of purified
b
9 (a) S. Bertelsen and K. A. Jørgensen, Chem. Soc. Rev., 2009, 38,
2178; (b) D. W. C. MacMillan, Nature, 2008, 455, 304.
c
aldol adduct. By HPLC.
10 (a) M. E. Jungfleish, J. Pharm. Chim., 1882, 5, 346. For a recent
application and description: (b) M. K. Dowd, Chirality, 2003, 15, 486.
11 Loss of the stereochemical integrity most likely occurred during t-Bu
group deprotection in hot trifluoroacetic acid (TFA). Acid solvents
have been documented to reduce the configurational stability of 2,20-
dimethoxy-6,60-diphenamide, see: D. R. McKelvey, R. P. Kraig,
K. Zimmerman, A. Ault and R. Perfetti, J. Org. Chem., 1973, 38, 3610.
12 F. C. Frank, Biochim. Biophys. Acta, 1953, 11, 459.
13 The polarimeter reading for an optically active methanolic solution
of 3ꢀTFA remained unchanged after a period of 6.5 h at reflux.
14 For example, Co(III) complexes: (a) F. Guo, M. Casadesus,
E. Y. Cheung, M. P. Coogan and K. D. M. Harris, Chem.
Commun., 2006, 1854; (b) K. Asakura, D. K. Kondepudi and
R. Martin, Chirality, 1998, 10, 343. Ru(II) complexes:
(c) W. Huang and T. Ogawa, Polyhedron, 2006, 25, 1379. We
thank a referee for highlighting this work.
15 For notable recent examples, see: (a) W. L. Noorduin, T. Izumi,
A. Millemaggi, M. Leeman, H. Meekes, W. J. P. Van Enckevort,
R. M. Kellogg, B. Kaptein, E. Vlieg and D. G. Blackmond, J. Am.
Chem. Soc., 2008, 130, 1158; (b) S. B. Tsogoeva, S. Wei, M. Freund
and M. Mauksch, Angew. Chem., Int. Ed., 2009, 48, 590;
(c) R. J. Arthur, M. P. Coogan, M. Casadesus, R. Haigh,
D. A. Headspith, M. G. Franesconi and R. H. Laye, CrystEngComm,
2009, 11, 610.
16 See ref. 2 and for a recent example: (a) Q.-X. Yao, W.-M. Xuan,
H. Zhang, C.-Y. Tu and J. Zhang, Chem. Commun., 2009, 59. The
best known examples of symmetry breaking during crystallization
from an achiral liquid state concern inorganic salts, NaClO3 and
NaBrO3, see: (b) D. K. Kondepudi, K. L. Bullock, J. A. Digits,
J. K. Hall and J. M. Miller, J. Am. Chem. Soc., 1993, 115, 10211;
(c) C. Viedma, Phys. Rev. Lett., 2005, 94, 065504.
resolution of configurationally stable metal coordination
complexes is quite well known;14 however, examples of related
symmetry breaking resolution phenomena concerning purely
organic molecules, such as that discovered for amidoamine
salt 3ꢀTFA, are dominated by systems which either lack
configurational stability15 or else are achiral16 in the liquid
state. The unanticipated behavior of 3ꢀTFA is likely linked to
its ionic character and the ability of bridging achiral trifluoro-
acetate anions to communicate spatially pervasive non-
covalent interactions.2,17 Finally, of further significance is
the fact that amidoamine 3 exhibits some catalytic activity
for the direct acetone aldol reaction. While enantioselectivity
in this particular process is low, the observation is supportive
of one plausible mechanism by which homochirality could
arise in a given prebiotic environment; i.e., spontaneous
resolution of an active catalyst component thence propagation
of this chiral information via enantioselective transformation
of some other prochiral substance.18,19
The generous financial support of Oregon State University
is gratefully acknowledged. The National Science Foundation
(CHE-0722319) and the Murdock Charitable Trust (2005265)
are also thanked for their support of the OSU NMR facility.
17 Conglomerate formation has also been reported for an organic salt
formed from an axially chiral acid (1,10-binaphthyl-2,20-dicarboxylic
acid) in the presence of an achiral basic unit (3,5-dimethylpyrazole).
Crystals exhibited hemihedrism and resolution was conducted by a
mechanical triage. It is speculated that interrupted crystallization in
this system might also result in symmetry breaking resolution, see:
O. Hager, A. L. Llamas-Saiz, C. Foces-Foces, R. M. Claramunt,
C. Lopez and J. Elguero, Helv. Chim. Acta, 1999, 82, 2213.
18 For discourse and leading references on current theories relating to
the origin of biological homochirality, see: D. G. Blackmond,
Angew. Chem., Int. Ed., 2009, 48, 2648.
Notes and references
z Crystal data for 3ꢀCF3CO2H: C20H23F3N2O5, Mr
T = 173(2) K, l = 0.71073 A (MoKa), 0.35 ꢃ 0.15 ꢃ 0.10 mm,
orthorhombic, P212121, 8.5061(6), 12.7978(9),
c = 19.4743(14) A, V = 2120.0(3) A3, Z = 4, Dc = 1.342 g cmꢂ3
m = 0.113 mmꢂ1, F(000) = 896, 2ymax = 50.01, 20 323 reflections,
3731 unique (Rint 0.0269), 349 parameters, R1 0.0468,
= 428.40,
a
=
b
=
,
=
=
wR2 = 0.1273 [I 4 2s(I)], GOF = 1.055, max/min residual electron
density +0.684/ꢂ0.446 e Aꢂ3. CCDC 748440.
y Crystal data for 1: C26H36N2O4, Mr = 440.57, T = 173(2) K,
l = 0.71073 A (MoKa), 0.35 ꢃ 0.24 ꢃ 0.17 mm, monoclinic, P21,
a = 10.5558(7), b = 10.4979(7), c = 11.4257(8) A, b = 103.691(1)1,
19 For two recent reports of crystallization based absolute asym-
metric synthesis, see: (a) A. Lennartson, S. Olsson, J. Sundberg and
M. Hankansson, Angew. Chem., Int. Ed., 2009, 48, 3137;
(b) A. Kuhn and P. Fischer, Angew. Chem., Int. Ed., 2009, 48,
V = 1230.15(14) A3, Z = 2, Dc = 1.189 g cmꢂ3, m = 0.080 mmꢂ1
,
F(000) = 476, 2ymax = 55.01, 8028 reflections, 5304 unique (Rint
=
0.0121), 433 parameters, R1 0.0329, wR2 0.0844
6857. For a non-crystallization based absolute asymmetric
=
=
synthetic method, see: (c) T. Kawasaki, M. Sato, S. Ishiguro,
T. Saito, Y. Morishita, I. Sato, H. Nishino, Y. Inoue and
K. Soai, J. Am. Chem. Soc., 2005, 127, 3274.
[I 4 2s(I)], GOF = 1.017, max/min residual electron density
+0.217/ꢂ0.151 e Aꢂ3. CCDC 748439.
ꢁc
This journal is The Royal Society of Chemistry 2010
2096 | Chem. Commun., 2010, 46, 2094–2096