Preorganization of achiral molecules for asymmetric synthesis through crystallization-induced immobilization in homochiral conformations

Article abstract of DOI:10.1002/anie.200351609

Enantioselective photochemistry: By forming salts with optically pure amines, achiral carboxylic acids can be induced to crystallize in chiral conformations that are preorganized for enantioselective photochemical reactions. Irradiation of crystals of the

Full text of DOI:10.1002/anie.200351609

Angewandte
Chemie
Photochemical Asymmetric Synthesis
Preorganization of Achiral Molecules for
Asymmetric Synthesis through Crystallization-
Induced Immobilization in Homochiral
Conformations**
Brian O. Patrick, John R. Scheffer,* and Carl Scott
The work described in this article represents the latest
installment from our laboratory in a long-term program
aimed at developing new methods of asymmetric synthesis in
organic photochemistry,[1] a relatively unexplored field that
has recently attracted widespread attention and interest.[2] By
way of introduction, consider the common situation of a
conformationally mobile molecule that is achiral in solution
as a result of rapid equilibration between enantiomeric
conformers. If such conformers could be immobilized and
caused to react in enantiomerically pure form, this could be
used to great advantage in asymmetric synthesis. The
prevention of conformational equilibration is relatively
straightforward and can be achieved through crystallization.
Selective crystallization in an enantiomerically pure form,
however, is more problematic, as the great majority of achiral,
conformationally mobile molecules crystallize as racemic
compounds containing equal amounts of both conformational
enantiomers.[3]
Our approach to this problem has been to introduce a
second element of chirality to the system in the form of an
easily removed, enantiomerically pure chiral auxiliary. In this
situation the conformers become diastereomers rather than
enantiomers, and one diastereomer will generally crystallize
out in a process known as a “crystallization-induced asym-
metric transformation.”[3,4] The crystals are then subjected to
a chemical reaction that fixes the evanescent conformational
chirality in the form of permanent molecular chirality;
removal of the temporary chiral auxiliary completes the
process, leaving the reaction product in enantiomerically
enriched form.
Scheme 1. Photochemical conversion of 7-benzoylnorbornane deriva-
tives into the corresponding cyclobutanols.
bonus was the finding that one of the reactions was a single
crystal-to-single crystal process.[6] This allowed crystal struc-
tures to be obtained at the beginning, mid-point and end of
the reaction and absolute configuration correlations to be
established between reactant and product.[7]
The key starting material, 7-methyl-7-benzoylnorbor-
nane-p-carboxylic acid (1a) was synthesized in a straightfor-
ward fashion from 7-methyl-7-carboxynorbornane[8] by
a) acid chloride formation ((COCl)2, CH2Cl2, catalyst
DMF), b) nucleophilic acyl substitution (p-FPhMgBr, THF,
08, 43% overall for steps a and b), c) nucleophilic aromatic
~
substitution (KCN, DMSO, , 93%) and d) hydrolysis of the
nitrile (KOH, aq. EtOH, 98%).
Prior to the asymmetric induction studies, the photo-
chemistry of methyl ester 1b was investigated in solution and
the solid state. In both instances the reaction was remarkably
clean, affording racemic cyclobutanol 2b as the exclusive
product; according to GC, no other photoproducts were
formed in amounts greater than 0.5%. The structure and
relative stereochemistry of cyclobutanol 2b were established
by detailed spectroscopic analysis and confirmed by an X-ray
crystal structure of one of the corresponding ammonium salts,
2c (see below).
For the asymmetric induction studies, chiral auxiliaries
were introduced by the treatment of carboxylic acid 1a with a
series of optically pure amines to form the corresponding 1:1
ammonium salts (1c); Table 1 lists the amines used. Poly-
crystalline samples of the salts (1–2 mg) were sandwiched
between pyrex microscope slides and irradiated to varying
degrees of conversion under nitrogen. The chiral auxiliaries
Specifically, we consider here enantio- and diastereose-
lection in the photochemical conversion of 7-benzoylnorbor-
nane derivatives initiated by hydrogen atom abstraction (1,
Scheme 1) into the corresponding cyclobutanols (2), a new
example of the well known Yang photocyclization reaction.[5]
The application of the conformational preorganization tech-
nique described above leads to near-quantitative de and ee
values in the crystalline state, even at very high conversions. A
Table 1: Asymmetric induction in the solid state photochemistry of salts
1c.[a]
Entry Amine
Conversion ee values of [a][b]
[%]
2b [%]
1
2
3
(R)-(+)-1-phenylethylamine
100
100
94
98
97
96
(À)
(+)
(+)
[*] Prof. Dr. J. R. Scheffer, Dr. B. O. Patrick, C. Scott
Department of Chemistry
(S)-(À)-1-phenylethylamine
(1S,2R)-(À)-1-amino-2-
indanol
(1S,2S)-(+)-2-amino-3-
methoxy-1-phenyl-1-propanol
(R)-(À)-2-amino-1-butanol
University of British Columbia
2036 Main Mall, Vancouver, B.C. V6T 1Z1 (Canada)
Fax: (+1)604-822-3496
4
5
88
95
84
(À)
(À)
E-mail: scheffer@chem.ubc.ca
100
[**] We thank the Natural Sciences and Engineering Research Council of
Canada for financial support.
[a] All photolyses were conducted at room temperature. Irradiation of the
salts in solution invariably led to racemic 2b. [b] Sign of rotation of
predominant enantiomer of 2b at the sodium D line.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 3775 –3777
DOI: 10.1002/anie.200351609
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3775

Communications
were removed by treatment of the photolysis mixtures with
ethereal diazomethane, and the resulting methyl esters were
analyzed to obtain the ee values by chiral HPLC and for the
extent of conversion by GC. As before, cyclobutanol 2b was
the sole GC-detectable photoproduct. The results are sum-
marized in Table 1.
The data in Table 1 reveal that the ee values obtained for
photoproduct 2b in the solid state were excellent (84–98%),
even at very high conversions. As expected for a well-behaved
system, the use of (R)-(+)- and (S)-(À)-1-phenylethylamine
as chiral auxiliaries (entries 1 and 2) led to the optical
antipodes of cyclobutanol 2b in equal ee. In contrast to the
results in the solid state, photolysis of the salts in solution led
to racemic 2b, a result that highlights the critical role played
by the reaction medium in controlling enantioselectivity.
To gain a greater understanding of the solid-state photo-
chemistry, X-ray crystal-structure studies were undertaken.
To date only the 1-phenylethylamine salt has given crystals
suitable for X-ray analysis, but fortuitously, the solid state
photoreaction in this case proved to be of the rare single
crystal-to-single crystal variety,[6] which permitted the struc-
ture of both reactant and product to be obtained at various
stages of reaction. Figure 1a shows the crystal structure of the
(S)-(À)-1-phenylethylamine salt prior to photolysis, and
Figure 1b and 1c depict the structure of the mixed crystal
following 70% and 93% conversion to the corresponding
cyclobutanol. The final ORTEP drawing (Figure 1d) shows
the structure of the cyclobutanol photoproduct following its
recrystallization from methanol.
The crystal structures reveal the source of the high
enantio- and diastereoselectivity. Under the influence of the
ionic chiral auxiliary, the reactant crystallizes in a homochiral
conformation in which the carbonyl oxygen (red) is much
closer to g-hydrogen atom HX (green, 2.70 Š) than to g-
hydrogen HY (purple, 3.43 Š). As a result, only HX is
abstracted,[9] leading to a 1,4-hydroxybiradical that undergoes
least motion closure with “retention of configuration” at the
carbonyl carbon. Closure of the biradical with inversion
would require rotation of the aryl and hydroxyl groups about
the C7-carbonyl carbon bond, a large amplitude motion that
is topochemically forbidden in the crystalline state.[10] Enan-
tioselectivity and diastereoselectivity are thus a direct con-
sequence of conformational preorganization of the reactant in
a rigid matrix that severely limits the range of motions
available along the reaction coordinate.[11]
Figure 1b and 1c prove that HX is, in fact, the hydrogen
abstracted. Because the absolute configuration of the ionic
chiral auxiliary is known, the absolute configuration of both
reactant and product is established, which in turn allows us to
state with certainty that abstraction of HX leads to the
experimentally observed photoproduct. We note that the
reactant and product have nearly identical geometries, except
for an upward movement of the g-carbon to allow for
cyclobutane ring formation and a change in orientation of
Figure 1. ORTEP representations of a) (S)-(À)-1-phenylethylamine salt
1c; b) mixed crystal containing 70% 2c and 30% 1c; c) mixed crystal
containing 93% 2c and 7% 1c; d) salt 2c after recrystallization from
methanol. The oxygen atoms are red, nitrogen blue, g-HX (most
favored for abstraction) green and g-HY purple. In (b) and (c) portions
of salt 1c are represented by dashed bonds and gray atoms. Ellipsoids
are set at the 50% probability level.
An interesting question associated with single crystal-to-
single-crystal transformations is whether the crystal structure
of the “as formed” product is the same as that of the
recrystallized material. Figure 1d shows that, in the present
instance, it is not. Recrystallization has brought about not
only a substantial change in molecular conformation (reor-
ientation of the aromatic ring and its associated ionic
auxiliary), but also a complete change in packing arrange-
À
the C O bond accompanying the change in hybridization at
the carbonyl carbon from sp2 to sp3. Presumably it is this close
resemblance in size and shape between reactant and product
that makes the single crystal-to-single crystal transformation
possible.
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Angewandte
Chemie
Olovsson, J. R. Scheffer, J. Trotter, Pure Appl. Chem. 1997, 69,
815.
ment (from orthorhombic to monoclinic). Based on a very
limited number of examples, such changes appear to be the
rule rather than the exception when the products of single
crystal-to-single crystal reactions are recrystallized.[12]
In summary, the use of ionic chiral auxiliaries to preor-
ganize achiral organic molecules for asymmetric synthesis
through crystallization-induced immobilization in homochiral
conformations works well for the Yang photocyclization of 7-
methyl-7-benzoylnorbornane derivatives. Related studies
from our research group have shown the technique to give
high ee values in a wide variety of excited state processes,[1]
and it is clear that this approach represents one of the most
powerful methods of asymmetric synthesis available in the
field of organic photochemistry. Finally we point out that
optically pure photoproducts, such as those formed in the
present study, have potential as chiral synthons, and current
efforts in our laboratory are directed along these lines. In
addition, we are currently working toward extending the
solid-state ionic chiral-auxiliary method to ground state as
well as excited state processes.
[8] S. Beckmann, H. Geiger, Chem. Ber. 1961, 94, 48.
[9] There is now a large body of crystallographic evidence indicating
that g-hydrogen atom abstraction in the solid state occurs
preferentially over distances near the sum of the van der Waals
radii of oxygen and hydrogen (2.72 Š). See H. Ihmels, J. R.
Scheffer, Tetrahedron 1999, 55, 885.
[10] 1,4-Hydroxybiradical ring closure involving retention of config-
uration at the hydroxyl-bearing carbon has been noted previ-
ously and appears to be a general feature of Yang photo-
cyclization reactions conducted in the crystalline state. See for
example A. D. Gudmundsdottir, T. J. Lewis, L. H. Randall, S. J.
Rettig, J. R. Scheffer, J. Trotter, C.-H. Wu, J. Am. Chem. Soc.
1996, 118, 6167; M. Leibovitch, G. Olovsson, J. R. Scheffer, J.
Trotter, J. Am. Chem. Soc. 1998, 120, 12755.
[11] Interestingly, the diastereoselectivity of the solution phase
photoreaction is identical to that observed in the crystalline
state. One explanation of this result is that, even in solution,
rotation about the C7-carbonyl carbon bond in the initially
formed biradical is slow relative to closure owing to unfavorable
steric interactions developed between the aryl and methyl
groups. In addition, the biradical (a triplet) may be formed in
a conformation in which intersystem crossing to the singlet and
closure is faster than rotation. For examples in which geometry-
dependent intersystem crossing is thought to control the stereo-
chemistry of 1,4-biradical closure, see A. G. Griesbeck, H.
Heckroth, J. Am. Chem. Soc. 2002, 124, 396, and references
therein.
Experimental Section
See the Supporting Information for the cell constants and related
crystallographic data as well as the details of the synthesis of keto-acid
1a, its conversion into an ionic chiral auxiliary-containing salt, the
photolysis of the salt in the crystalline state, the diazomethane
workup procedure and the characterization of cyclobutanol photo-
product 2b.
[12] See for example, V. Buchholz, V. Enkelmann, Mol. Cryst. Liq.
Cryst. 1998, 313, 309; K. Novak, V. Enkelmann, G. Wegner, K. B.
Wagnener, Angew. Chem. 1993, 105, 1678; Angew. Chem. Int.
Ed. Engl. 1993, 32, 1614. For a counter example, see K. Honda,
Bull. Chem. Soc. Jpn. 2002, 75, 2383.
Received: April 8, 2003 [Z51609]
Keywords: asymmetric synthesis · crystal engineering ·
.
photochemistry · solid-state reactions · topochemistry
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