Thermal and photochemical transformation of conformational chirality into configurational chirality in the crystalline state

Article abstract of DOI:10.1021/ja029182i

Because they crystallize in chiral conformations in which abstraction of only one of two diastereotopic γ-hydrogen atoms is possible, salts formed between achiral keto-acids possessing the tricyclo[4.4.1.0]undecane ring system and optically pure amines un

Full text of DOI:10.1021/ja029182i

Published on Web 03/14/2003
Thermal and Photochemical Transformation of Conformational Chirality into
Configurational Chirality in the Crystalline State
Kenneth C. W. Chong and John R. Scheffer*
Department of Chemistry, UniVersity of British Columbia, VancouVer, B.C. V6T 1Z1, Canada
Received November 1, 2002; E-mail: scheffer@chem.ubc.ca
Table 1. Solid-State Photolysis and Thermolysis of Chiral Salts of
Keto-acid 1a
In recent years, the chiral crystalline environment has been
employed to carry out a variety of photochemical asymmetric
syntheses and has given very encouraging results.1 Because such
reactions occur in a confining chiral crystal lattice medium,
molecular motions are severely restricted, and high enantioselec-
tivities can be achieved. In principle, this concept can be applied
to ground-state as well as excited-state reactions. However, it is
usually difficult to preserve crystallinity during reactions at elevated
temperatures, and as a result, examples of solid-state thermal
asymmetric syntheses are usually limited to ambient temperature
processes.2 It occurred to us that this problem could be overcome
by using high-melting ionic crystals. In this communication, we
report the successful utilization of ionic chiral auxiliaries3 in the
crystalline state to synthesize an optically active olefin via a thermal
as well as a photochemical process. As far as we are aware, these
results represent the first example of asymmetric induction in the
Norrish type II cleavage reaction as well as the first report of an
enantioselective thermal pericyclic reaction in the crystalline state.
The compounds chosen for study were ketones possessing the
achiral tricyclo[4.4.1.0]undecane ring system 1 (Scheme 1).4 Such
compounds are photochemically as well as thermally labile.
Irradiation causes efficient Norrish type II cleavage to give chiral
olefins of general structure 3,5 and the same products are formed
thermally via a 1,5-sigmatropic shift process known as the enolene
rearrangement.6 Salts 1c-h were prepared by reacting achiral
carboxylic acid 1a with optically pure amines. The ammonium ions
act as chiral auxiliaries, causing the salts to crystallize in homochiral
space groups.1b When the salts are irradiated or thermolyzed in the
solid state, the diastereomeric transition states leading to 3 or ent-3
are differentiated by the chiral reaction medium, thereby leading
to asymmetric induction. This study is the first to allow a direct
comparison of ee in a thermal and photochemical solid-state
asymmetric synthesis.
photochemicala
thermal
salt convb (%) ee (%) Rc
temp (°C)
time (h) conv (%) ee (%) Rc
1c
>98
95
+
52-56
70-74
90-95
45-50
90-95
90-95
45-50
90-95
85-90
110-120
110-120
90-95
48
15
10
48
0.5
10
96
10
12
15
15
4
>98
94
>98
42
52
>98
32
>98
28
>98
>98
>98d
36
27
20
56
48
40
58
30
16
10
12
<5
+
1d
>98
91
-
-
1e
1f
75
>98
>98
73
69
65
-
-
-
-
1g
1h
>98
>98
63
70
+
-
+
-
a Samples were irradiated at -25 °C through Pyrex using a 450-W
Hanovia medium-pressure mecury lamp. b Conversion % based on NMR.
c Sign of rotation of 3b at the sodium D-line. d Sample melted.
Scheme 1
We turn first to the photochemical study. Irradiation of an
acetonitrile solution of keto-ester 1b produces 3b, which undergoes
a second Norrish type II cleavage upon prolonged photolysis to
give a mixture of hexahydronaphthalenes 4 and methyl 4-acetyl-
benzoate (5b). When compound 1b was photolyzed in the crystal-
line state, only traces of secondary photoproducts were formed.
The fate of enol intermediate 2 in the solid state was followed by
FT-IR. When a KBr pellet of compound 1b was irradiated, the
ketone stretch at 1666 cm-1 disappeared, and a new peak was
observed at ∼3400 cm-1, which corresponds to the OH stretch of
enol 2. There was no significant change in the IR spectrum over a
period of days at room temperature under nitrogen, but upon
heating, the enol OH stretch diminished, and a new absorption at
∼1680 cm-1 corresponding to compound 3b was observed. These
experiments explain the absence of secondary photochemistry in
the crystalline state.
at -25 °C. The reaction mixtures were then converted to methyl
ester 3b by treatment with ethereal diazomethane and analyzed by
chiral HPLC. Enantiomeric excesses obtained for photoproduct 3b
in the solid state ranged from fair (63%) to excellent (95%) (Table
1). In contrast, photolysis of the optically active salts in solution
led only to racemic 3b, a result that highlights the critical role played
by the chiral crystal lattice in controlling enantioselectivity.
The high ee’s observed in the solid state can be explained by a
Crystals of salts 1c-h were crushed between Pyrex microscope
slides, sealed in polyethylene bags under nitrogen, and irradiated
9
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J. AM. CHEM. SOC. 2003, 125, 4040-4041
10.1021/ja029182i CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
In line with this is the finding that enol 2 could also be detected in
the thermal rearrangement.10 The lower ee’s obtained in the thermal
reaction can be attributed to an increase in conformational flexibility
accompanying softening of the crystal lattice at elevated temper-
atures.11
In summary, the present study demonstrates that both excited-
and ground-state asymmetric induction can be achieved in the
crystalline state by using the ionic chiral auxiliary approach. For
the photochemical process, near quantitative ee’s can be achieved
at >98% conversion, a result that highlights the synthetic potential
of the method for the synthesis of optically active olefins. For the
thermal process, the optical yields are not outstanding. Nevertheless,
this is the first example of the application of ionic chiral auxiliaries
in a solid-state thermal reaction. In the future, we hope to modify
the procedure and apply it to a wide variety of ground-state
reactions.
Figure 1. Molecular mechanics calculation of the most stable conformation
of compound 1a. Ha and Hb are the two abstractable γ-hydrogen atoms; O
is the oxygen atom of CdO.
conformational effect. Molecular mechanics calculations indicate
that the minimum-energy conformation of ketones of general
structure 1 is a chiral one in which γ-hydrogens Ha and Hb become
diastereotopic rather than enantiotopic (Figure 1).7 In this conforma-
tion the carbonyl oxygen is much closer to Ha (2.5 Å) than to Hb
(3.3 Å), and if, as seems likely, salts 1c-h adopt a similar
conformation in the solid state the asymmetric induction can be
explained by preferential abstraction of the more favorably located
γ-hydrogen in the initial step of the photoreaction.8 The role of the
ionic chiral auxiliary in this process is thus a relatively passive
one. It is not directly involved in the transition state and serves
simply to preorganize the counterions in a homochiral conformation
favorable for the formation of a single enantiomer of the product,
thereby transforming conformational chirality into configurational
chirality.
We turn now to the thermal reactions of salts 1c-h. Heating
these compounds at various temperatures (Table 1) under an
atmosphere of nitrogen followed by diazomethane workup led to
clean formation of ketone 3b; melting was observed only in the
case of salt 1h. The challenge of carrying out thermal asymmetric
induction in the crystalline state is that reaction should occur prior
to crystal melting. The thermal behavior of salts 1c-h was analyzed
by differential scanning calorimetry, which showed two distinct
patterns of behavior. The first, characteristic of salts 1c-g, consists
of an exothermic process (enolene rearrangement plus crystallization
of the products) followed by an endothermic event (melting of
products). The second type, shown by salt 1h, is one in which
melting of the reactant precedes or is concomitant with rearrange-
ment and is followed by a crystallization event and a second
endotherm due to the melting of the product. As summarized in
Table 1, reactions of the first type (compounds 1c-g) gave low to
moderate ee’s, whereas the second type of reaction (compound 1h)
led to racemic 3b.
Acknowledgment. We thank the Natural Sciences and Engi-
neering Research Council of Canada for financial support.
Supporting Information Available: Synthesis of starting materials,
photochemical procedures and analytical techniques used in asymmetric
induction studies, infrared and differential scanning calorimetry traces
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Vaida, M.; Popvitz-Biro, R.; Leiserowitz, L.; Lahav, M. In Photo-
chemistry in Organized and Constrained Media; Ramamurthy, V., Ed.;
VCH: New York, 1991; pp 247-302. (b) Scheffer, J. R. Can. J. Chem.
2001, 79, 349 and references therein. (c) Tanaka, K.; Miyamoto, H.; Toda,
F. In Molecular and Supramolecular Photochemistry; Ramamurthy, V.,
Schanze, K. S., Eds.; Marcel Dekker: New York, 2001; Vol. 8, pp 385-
425. (d) Sakamoto, M. Chem. Eur. J. 1997, 3, 684.
(2) Tanaka, K.; Toda, F. Chem. ReV. 2000, 100, 1025 and references therein.
(3) For an introduction to the use of ionic auxiliaries in solid-state organic
photochemistry, see: Gamlin, J. N.; Jones, R.; Leibovitch, M.; Patrick,
B.; Scheffer, J. R.; Trotter, J. Acc. Chem. Res. 1996, 29, 203.
(4) For the synthesis of compound 1a, see Supporting Information.
(5) Owing to the relief of cyclopropane ring strain, Norrish type II cleavage
is favored over Yang cyclization in the case of compounds of general
structure 1. For a discussion of the Norrish type II chemistry of cyclopropyl
ketones, see: Dauben W. G.; Schutte, L.; Wolf, R. E. J. Org. Chem. 1969,
34, 6273; For a review of the Norrish/Yang type II reaction, see: Wagner,
P. J.; Park, B.-S. In Organic Photochemistry; Padwa, A., Ed.; Marcel
Dekker: New York, 1991; Vol. 11, Chapter 4.
(6) Roberts, R. M.; Landolt, R. G.; Greene, R. N.; Heyer, E. W. J. Am. Chem.
Soc. 1967, 89, 1404.
(7) To date, all attempts to determine the X-ray crystal structures of salts
1c-1h have not met with success. Because most compounds crystallize
in or near their minimum-energy conformations, the analysis in this case
is based on the calculated structure shown in Figure 1.
(8) For a similar situation in which the enantioselectivity of Yang photocy-
clization in the crystalline state is governed by preferential abstraction of
the geometrically favored γ-hydrogen atom, see: Leibovitch, M.; Olov-
vson, G.; Scheffer, J. R.; Trotter, J. J. Am. Chem. Soc. 1998, 120, 12755.
The preference for abstraction of Ha over Hb in the case of ketones of
general structure 1 is in accord with previous work from our laboratory
on the geometric requirements for type II hydrogen transfer. See: Ihmels,
H.; Scheffer, J. R. Tetrahedron 1999, 55, 885.
Table 1 shows that, in every case, the ee for the photochemical
Norrish type II cleavage reaction is greater than that observed in
the thermal enolene rearrangement.9 The enolene rearrangement is
likely to be governed by conformational factors similar to those
discussed for the photochemical reaction, since the process involves
a concerted 1,5-shift of one of the two diastereotopic γ-hydrogen
atoms.6 The fact that the enantiomerically enriched products
obtained thermally and photochemically have the same sign of
optical rotation suggests that the two pathways are quite similar.
(9) Because the photochemical ee’s were necessarily determined under
conditions where the thermal reaction was immeasurably slow, direct
comparison of the thermal and photochemical ee’s at the same temperature
and conversion was not possible.
(10) The enol could be detected in this case by dissolving the salt in methanol-
d4 and immediately recording the 1H NMR spectrum.
(11) In agreement with this picture, the ee obtained by heating salt 1c to >98%
conversion at 52-56 °C (36%) was nearly twice that obtained at 90-95
°C (20%). For a discussion of crystalline state thermal reactions, see: Paul,
I. C.; Curtin, D. Y. Acc. Chem. Res. 1973, 6, 217.
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