Enantiospecific synthesis of vicinal stereogenic tertiary and quaternary centers by combination of configurationally-trapped radical pairs in crystalline solids

Article abstract of DOI:10.1021/ol0347803

(Matrix presented) Photochemical irradiation of crystalline (2R,4S)-2-carbomethoxy-4-cyano-2,4-diphenyl-3-butanone 1 led to highly efficient decarbonylation reactions. Experiments with optically pure and racemic crystals showed that the intermediate radic

Full text of DOI:10.1021/ol0347803

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2531-2534
Enantiospecific Synthesis of Vicinal
Stereogenic Tertiary and Quaternary
Centers by Combination of
Configurationally-Trapped Radical Pairs
in Crystalline Solids
Martha E. Ellison, Danny Ng, Hung Dang, and Miguel A. Garcia-Garibay*
Department of Chemistry and Biochemistry, UniVersity of California-Los Angeles,
Los Angeles, California 90095-1569
mgg@chem.ucla.edu
Received May 7, 2003
ABSTRACT
Photochemical irradiation of crystalline (2R,4S)-2-carbomethoxy-4-cyano-2,4-diphenyl-3-butanone 1 led to highly efficient decarbonylation reactions.
Experiments with optically pure and racemic crystals showed that the intermediate radical pairs undergo a highly diastereo- and enantiospecific
radical−radical combination that leads to the formation of two adjacent stereogenic centers in good chemical yield and with high chemical
control. Reactions with chiral crystals occurred with quantitative enantiomeric yields and >95% diastereomeric yields.
We have recently shown that crystalline ketones with radical
stabilizing substituents in the two R-positions can photode-
carbonylate to form radical pairs in a relatively efficient and
reliable manner. We have reported examples involving
ketones with alkyl, phenyl,1 carbonyl,2 and alkoxy substit-
uents.3 In addition, we have observed that radical pairs
formed in crystals tend to form C-C bonds in a highly
chemoselectiVe and stereospecific manner.4 In this com-
munication, we report an application of this reaction in a
remarkably simple and promising method for the construction
of compounds with adjacent tertiary and quaternary stereo-
genic centers. Our motivation for this study comes from the
well-documented occurrence of natural products possessing
such a structural feature and from the difficulties involved
in their preparation by conventional synthetic methods.5 In
addition, we believe that challenging, solvent-free reactions
may contribute to the development of the rapidly expanding
field of environmentally benign chemistry.6
To determine the feasibility of the solid-state method, we
prepared optically pure and racemic samples of (2R,4S)-2-
carbomethoxy-4-cyano-2,4-diphenyl-3-butanone 1 (Scheme
1) and analyzed their photochemistry in solution and its two
(1) (a) Choi, T.; Peterfy, K.; Khan, S. I.; Garcia-Garibay, M. A. J. Am.
Chem. Soc. 1996, 118, 12477-12478. (b) Peterfy, K.; Garcia-Garibay, M.
A. J. Am. Chem. Soc. 1998, 120, 4540-4541.
(2) (a) Yang, Z.; Ng, D.; Garcia-Garibay, M. A. J. Org. Chem. 2001,
66, 4468-4475. (b) Campos, L. M.; Ng, D.; Yang, Z.; Dang, H.; Martinez,
H. L.; Garcia-Garibay, M. A. J. Org. Chem. 2002, 67, 3749-3754.
(3) Ng, D.; Yang, Z.; Garcia-Garibay, M. A. Tetrahedron Lett. 2002,
43, 7063-7066.
(4) Formation of radical pairs and their reactivity in crystalline solids
have been previously analyzed within a primarily mechanistic context: (a)
Hollingsworth, M. D.; McBride, J. M. AdV. Photochem. 1990, 15, 279-
379. (b) Baretz, B.; Turro, N. J. J. Am. Chem. Soc. 1983, 105, 1309-1316.
(5) (a) Overman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem. Soc.
1999, 121, 7702-7703. (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem.,
Int. Ed. 1998, 37, 388-401. (b) Fuji, K. Chem. ReV. 1993, 93, 2037-
2066.
(6) (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, 1998. (b) Poliakoff, M.;
Fitzpatrick, J. M.; Farren, T. R. A., P. T. Science 2002, 297, 807-810.
10.1021/ol0347803 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/12/2003

Scheme 1
enantiomorphous crystal forms.7 A stereochemical correlation
based on single-crystal X-ray diffraction analyses confirmed
that the solid state reaction occurs by retention of configu-
ration at the two configurationally trapped radical centers.
Compound 1 was obtained in enantiomerically pure and
racemic forms from 2-methyl-2-phenyl malonic acid mono-
methyl ester 3b (Scheme 2). Samples of (+)-(R)-3b were
Figure 1. Gas chromatograph obtained after ca. 40% conversion
upon photolysis of (()-(2RS,4SR)-1 in benzene solutions (bottom)
and in crystals (top). Results of experiments carried out with (+)-
(2R,4S)-1 were essentially identical.
50 mg) irradiated under similar conditions resulted in a very
clean reaction with formation of a major photoproduct in
40-60% conversion and >95% selectivity (Figure 1, top).
The product was later shown to be (+)-(2R,3R)-2 and
(()-(2RS,3RS)-2 from the optically pure and racemic crystals,
respectively.
Scheme 2
The relative configurations of (+)-(2R,4S)-1 and
(()-(2RS,4SR)-1 were established by single-crystal X-ray
diffraction analyses (Figure 2). Enantiomerically pure
prepared from the meso diester 3a8 by enzymatic desym-
metrization with pig liver esterase (90% ee)9 or by resolution
of acid (()-3b with (-)-1-(1-naphthyl)ethylamine.10 Acid
(+)-3b was converted into the corresponding acyl chloride,
which was reacted with the anion of benzyl cyanide to give
ketone (2R,4S)-1 and its diastereomer (2R,4R)-1a (not shown)
in 85% isolated yield in a 4:1 ratio. Pure samples of
(+)-(2R,4S)-1 {[R]D ) 120° (c 0.73, CHCl3)} were obtained
by crystallization from hexane and diethyl ether (4:1 v/v).
Thin needles of the optically pure ketone had a melting point
of 66-68 °C. An identical procedure starting with racemic
(()-3b led to racemic crystals of (()-(2RS,4SR)-1,11 which
have a melting point of 97-100 °C.
Photochemical experiments with oxygen-free 0.1 M ben-
zene solutions of (+)-(2R,4S)-1 and (()-(2RS,4SR)-1 using
a Hanovia lamp with a Pyrex filter (λ > 300 nm) at 298 K
led to complex product mixtures (Figure 1, bottom). In
contrast, crystals of (+)-(2R,4S)-1 and (()-(2RS,4SR)-1 (ca.
(7) For an excellent monograph describing the crystallization of chiral
molecules, please see: Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers,
Racemates and Resolutions; John Wiley & Sons: New York, 1981.
(8) Canet, J. L.; Louis, F. A.; Salaun, J. J. Org. Chem. 1992, 57, 3463-
73.
(9) Toone, E. J.; Jones, B. Tetrahedron: Asymmetry 1991, 2, 1041-
1052.
(10) Optically enriched samples of (+)-3b were obtained by crystalliza-
tion of (()-3b with (-)-1-(1-naphthyl)ethylamine in Et2O (50% ee). These
crystallized as optically pure (+)-(2R,4S)-1 after the reaction sequence in
Scheme 2.
Figure 2. ORTEP diagrams of (top) (+)-(2R,4S)-1 and its solid-
state product (+)-(2R,3R)-2 and (bottom) ORTEP diagrams of (()-
(2RS,4SR)-1 and the racemic solid-state photoproduct (()-(2RS,3RS)-
2. The X-ray structures of (+)- and (()-2 were obtained after
dissolving crystals of reacted 1. From the racemic crystals, only
the (2R,4S)-1 and (2R,3R)-2 enantiomers are illustrated.
(11) Optically pure and racemic forms of diastereomers are named as
recommended by: Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; John Wiley & Sons: New York, 1994; Chapter 5, pp 117-
124.
(+)-(2R,4S)-1 crystallizes in the hexagonal space group
P65 with six ketones and one disordered hexane molecule
2532
Org. Lett., Vol. 5, No. 14, 2003

per unit cell.12 The racemic compound crystallizes in the
space group P21/c with four molecules per unit cell and no
solvent of crystallization.13 The absolute configuration of
(+)-(2R,4S)-1 was assigned from the known configuration
of (+)-(R)-3b, which is determined by the enantioselectivity
of the enzymatic hydrolysis.9
As illustrated in Figure 2, the structure of ketone (2R,4S)-1
is very similar in the two enantiomorphous (i.e., enantio-
merically pure and racemic) crystal forms.7 It is characterized
by a conformation where the 2-methyl and 4-cyano substit-
uents are approximately eclipsed with the ketone carbonyl
and the phenyl groups adopt a staggered orientation. The
main difference between the two molecular structures is the
orientation of the carboxylate ester groups. The ester carbonyl
points toward the cyano substituent in the racemic crystals
and in the opposite direction in the optically pure modifica-
tion.14
Assuming that double inversion in the crystal lattice is
extremely unlikely, the optical purity of (+)-(2R,3R)-2 is
determined by the optical purity of crystalline (+)-(2R,4S)-
1, which is expected to be 100% in its enantiomorphous
phase. An [R]D ) 128° (c 1, EtOAc) determined for
(+)-(2R,3R)-2 is of the same sign as those of the ketone
precursor (+)-(2R,4S)-1 and the acid ester (+)-3b. A >95%
de determined by GLC for optically active and racemic
samples (Figure 1, top trace) indicates a very small amount
of inversion at either one of the two stereogenic centers. A
small stereochemical loss may be due to reaction occurring
at the crystal surface or at defect sites. X-ray structural
elucidation of (+)-(2R,3R)-2 (mp ) 78-79 °C)15 and
(()-(2RS,3RS)-2 (mp ) 99-101 °C)16 confirmed the ex-
pected stereospecificity of the bond-forming reaction. The
simple visualization of the reaction illustrated in Scheme 1
is borne out from the X-ray structures shown in Figure 2.
The spatial orientation of the substituents at C2 and C4 in
ketone 1 is maintained at stereocenters C2 and C3 in product
2. Notably, the orientation of the ester group in crystals of
(+)-(2R,4S)-1 is different than that observed in crystals of
(+)-(2R,3R)-2 (Figure 2, top). However, for reactions in
crystals, it is well-known that changes in size and shape must
be relatively small.17 Therefore, it is likely that (+)-(2R,3R)-2
is originally formed with the ester carbonyl in a conformation
similar to that of the starting material and that it only changes
after the reacted sample is dissolved and recrystallized. Very
small conformational differences can be appreciated for the
structure of compound 2 in its two crystal forms.
Regarding the reaction mechanism, it is well-known18 that
decarbonylation proceeds in a stepwise manner by sequential
R-cleavage and decarbonylation.2 With experimental1,2a,3 and
computational2b evidence gathered in our group, we have
suggested some general guidelines to “engineer reactions in
crystals”.1-3 Our observations indicate that photodecarbo-
nylation in the solid state is enabled by substituents that lower
the bond dissociation energy of the two R-bonds by more
than ca. 12 kcal/mol as compared to that of acetone (BDE-
[Me-COMe] ) 81.1 kcal/mol).19 This suggestion arises from
a known relation between reaction efficiencies and heats of
reaction first proposed by Fisher and Paul.20 R-Cleavage and
decarbonylation in ketone 1 are enabled by phenyl, car-
bomethoxy, and cyano groups. On the basis of extensive
literature data,19 one may expect that phenyl, ester, and
methyl groups at C2 will lower the R-bond dissociation
energy by ca. 25 kcal/mol with respect to that of acetone.
Similarly, phenyl and cyano substituents at C4 are expected
to weaken the other R-bond by ca. 23 kcal/mol, which is
also well in excess of the suggested value. Not surprisingly,
compound 1 reacts in crystals with apparent efficiencies that
compete with those observed in solution reactions.
Knowing that accumulation of the product depresses the
melting point of the pure starting material, it is advantageous
to document the nature of the (ideally) two-component
system so that a suitable photolysis temperature is selected.21
Differential scanning calorimetric (DSC) analyses of
(()-(2RS,4SR)-1 before reaction and after ca. 45% conver-
sion indicate that a solid phase is preserved below ca. 30-
40 °C and that reaction proceeds by a phase separation
mechanism (Figure 3).21 The melting transition of pure
(()-(2RS,4SR)-1 at 97 °C broadens and shifts to lower
temperatures as the product accumulates in crystals of the
reactant phase. That phase separation occurs in this reaction
is deduced by the observation of a broad peak at about 60
°C, which corresponds to the formation of a eutectic mixture.
This result suggests that high reaction yields with maintained
selectivity may be attained by controlling the temperature
(12) (+)-(2R,4S)-1: C19H17NO3, MW ) 307.34, space group P65, a )
19.154(3) Å, Å, b ) 19.154(3) Å, c ) 8.393(2) Å, R ) â ) 90°, γ )
120°, V ) 2666.5(9) Å3, Z ) 6, Fcalcd ) 1.156 Mg/m3, F(000) ) 978, λ )
0.71073 Å, µ(Mo KR) ) 0.080 mm-1, T ) 100(2) K, crystal size ) 0.60
× 0.10 × 0.10 mm3. Of the 15 993 reflections collected (2.72° e θ e
28.29°), 4062 [R(int) ) 0.0297] were independent reflections; max/min
residual electron density 357 and -176 e nm-3, R1 ) 0.0369 [I > 2σ(I)]
and wR2 ) 0.0874 (all data).
(13) (()-(2R,4S)-1: C19H17NO3, MW ) 307.34, space group P21/c, a
) 12.238(3) Å, b ) 9.468(2) Å, c ) 13.810(4) Å, â ) 97.769(5)°, V )
1585.6(7) Å3, Z ) 4, Fcalcd ) 1.287 Mg/m3, F(000) ) 648, λ ) 0.71073
Å, µ(Mo KR) ) 0.087 mm-1, T ) 100(2) K, crystal size ) 0.4 × 0.3 ×
0.3 mm3. Of the 9819 reflections collected (1.68° e θ e 28.26°), 3760
[R(int) ) 0.0298] were independent reflections; max/min residual electron
density 327 and -189 e nm-3, R1 ) 0.0371 [I > 2σ(I)] and wR2 ) 0.1030
(all data).
(14) Calculated (AM1) dipole moments are 5.92 and 3.53 D for structures
in racemic and optically active crystals, respectively. However, only the
chiral crystals are macroscopically polar.
(15) (+)-(2R,4S)-2: C18H17NO2, MW ) 279.33, space group P21, a )
8.4096(6) Å, b ) 9.4818(7) Å, c ) 9.3272(6) Å, â ) 96.9610(10)°, V )
738.25(9) Å3, Z ) 2, Fcalcd ) 1.257 Mg/m3, F(000) ) 296, λ ) 0.71073 Å,
µ(Mo KR) ) 0.082 mm-1, T ) 100(2) K, crystal size ) 0.50 × 0.40 ×
0.33 mm3. Of the 6629 reflections collected (2.20° e θ e 28.27°), 3454
[R(int) ) 0.0132] were independent reflections; max/min residual electron
density 272 and -150 e nm-3, R1 ) 0.0284 [I > 2σ(I)] and wR2 ) 0.0680
(all data).
(16) (()-(2RS,3RS)-2: C18H17NO2, MW ) 279.33, space group P21/n,
a ) 11.1764(16) Å, b ) 9.0080(13) Å, c ) 15.168(2) Å, â ) 98.844(2),
V ) 1508.9(4) Å3, Z ) 4, Fcalcd ) 1.230 Mg/m3, F(000) ) 592, λ ) 0.71073
Å, µ(Mo KR) ) 0.080 mm-1, T ) 100(2) K, crystal size ) 0.40 × 0.35 ×
0.25 mm3. Of the 9649 reflections collected (2.12° e θ e 28.30°), 3568
[R(int) ) 0.0170] were independent reflections; max/min residual electron
density 360 and -190 e nm-3, R1 ) 0.0345 [I > 2σ(I)] and wR2 ) 0.0875
(all data).
(17) Cohen, M. D. Angew. Chem., Int. Ed. Engl. 1975, 14, 386-393.
(18) Weiss, D. Org. Photochem; Padwa, A., Ed.; Marcel Deker: New
York, 1981; Vol. 5, pp 347-420.
(19) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic
Compounds; CRC Press: Boca Raton, FL, 2003.
(20) Fisher, H.; Paul, H. Acc. Chem. Res. 1987, 20, 200-206.
(21) Keating, A. E.; Garcia-Garibay, M. A. Molecular and Supramo-
lecular Photochemistry; Ramamurthy, V., Schanze, K., Eds.; Marcel
Dekker: New York, 1998; Vol. 2, pp 195-248.
Org. Lett., Vol. 5, No. 14, 2003
2533

In conclusion, we have shown that photodecarbonylation
of crystalline ketones with radical-stabilizing R-substituents
provides a promising strategy for the diastereo- and enan-
tiospecific construction of adjacent stereogenic quaternary
and tertiary centers. The method used for the synthesis of 1
can be easily modified to prepare a large number of
analogues, which may be used to obtain building blocks for
the synthesis of more complex molecules. The generality of
this procedure and applications in total synthesis will be
reported in forthcoming publications.
Acknowledgment. Support by NSF Grants CHE-0073431,
CHE0242270, and CHE9871332 (X-ray) is gratefully ac-
knowledged.
Figure 3. Differential scanning calorimetric (DSC) analysis of (()-
(2RS,4SR)-1 before photolysis (top) and after 45% conversion
(bottom). The eutectic transition is marked with an asterisk (*) in
the bottom thermogram.
Supporting Information Available: X-ray diffraction
data for racemic and optically pure crystals of compounds 1
and 2 (CIF files) and experimental procedures for the
preparation of 3a, 1, 3b, and 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
of the reaction well below the eutectic point. While the
presence of solvent in crystals of (+)-(2R,4S)-1 makes the
phase diagram more complex and high conversions difficult,
suitable crystals may be obtained from other solvents or from
the melt, by hydrolysis of the ester to form the carboxylic
acid, or by forming higher-melting carboxylate salts,22
alternatives that will be investigated.
OL0347803
(22) Gamlin, J. N.; Jones, R.; Leibovitch, M.; Patrick, B.; Scheffer, J.
R.; Trotter, J. Acc. Chem. Res. 1996, 29, 203-209.
2534
Org. Lett., Vol. 5, No. 14, 2003