Diastereoselective synthesis and spin-dependent photodecarbonylation of di(3-phenyl-2-pyrrolidinon-3-yl)ketones: Synthesis of nonadjacent and adjacent stereogenic quaternary centers

Article abstract of DOI:10.1039/b711786h

A diastereoselective procedure to obtain N-para-methoxybenzyl bis-α,α′-3-(3-phenyl-2-pyrrolidinone)yl substituted ketones with non-adjacent quaternary stereocenters, dl-2 and meso-3 was followed by a photoinduced, spin-dependent, and diastereoselective de

Full text of DOI:10.1039/b711786h

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COMMUNICATION
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Diastereoselective synthesis and spin-dependent photodecarbonylation
of di(3-phenyl-2-pyrrolidinon-3-yl)ketones: synthesis of nonadjacent
and adjacent stereogenic quaternary centers{
Marino J. E. Resendiz, Arunkumar Natarajan and Miguel A. Garcia-Garibay*
Received (in Bloomington, IN, USA) 2nd August 2007, Accepted 3rd November 2007
First published as an Advance Article on the web 12th November 2007
DOI: 10.1039/b711786h
efficiently as a result of the radical stabilizing abilities of their
a-phenyl and a-carbonyl substituents.3 Compound 1 also possesses
the aryl, carbonyl and nitrogen functionalities that are common to
many alkaloids, and should be valuable to determine the
applicability of the solid-state reaction for the synthesis of complex
natural products.6 In this communication, we report the stereo-
selective preparation of the DL- and meso-ketones 2 and 3 and
their unexpectedly selective solution photochemistry.
A diastereoselective procedure to obtain N-para-methoxybenzyl
bis-a,a9-3-(3-phenyl-2-pyrrolidinone)yl substituted ketones with
non-adjacent quaternary stereocenters, DL-2 and meso-3 was
followed by a photoinduced, spin-dependent, and diastereo-
selective decarbonylation to give compounds DL-4 and meso-5,
with adjacent all-carbon quaternary stereogenic centers.
Chemical structures with adjacent stereogenic quaternary carbon
centers are relatively common in biologically active substances,
including natural products and pharmaceuticals.1 However,
despite recent advances in synthetic methodology,2 there are no
satisfactory procedures for the preparation of this seemingly simple
structural motif. The primary challenge stems from the steric
impediments for six alkyl groups to converge with the precise
Compound 1 was prepared by para-methoxybenzyl (PMB)
protection of the free amide obtained by the method of Michael
et al. from diethyl 2-phenylmalonate.7 As indicated in Scheme 2,
formation of the lithium enolate of 1 with LiHMDS in THF at
278 uC followed by addition of 0.5 eq. of COCl2 and warming up
to ca. 240 uC gave the DL-pair 2 as the only detectable product in
75% isolated yield. Alternatively, reaction of the same enolate with
1,1-carbonyl diimidazolide (CDI) from 2110 to 260 uC provided
the meso-diastereomer 3 along with several unidentified bypro-
ducts. Reactions with COCl2 were monitored by TLC and allowed
to proceed until the starting material 1 was completely consumed,
typically within 2 h. Reactions with CDI were optimized for a yield
of 3 of ca. 45–50%, which gave some unreacted starting material
and several unidentified products. After establishing the isomeric
nature of 2 and 3 by mass spectrometry, 1H and 13C NMR, their
relative stereochemistry was assigned with help of single-crystal
X-ray diffraction analysis of 3,{ which turned out to be the meso-
diastereomer (Fig. 1). Notably, compound 3 adopts a non-
symmetric C1 conformation with the two phenyl substituents
adopting the two sides of the plane of the carbonyl group.
The results in Scheme 2 depend strongly on the conditions
indicated. Experiments carried out with NaH, NaHMDS and KH
did not give the desired ketones. Only starting material and
unidentified products were obtained. However, experiments with
NaHMDS and 10–20 eq. of LiCl yielded the desired products,
˚
orientation within a distance of 1.54 A, which is the bond distance
between the two adjacent carbons. To address this problem, our
group has been interested in the photodecarbonylation of
hexasubstituted ketones (Scheme 1).3 With quaternary carbon
˚
distances that are longer by 80% (ca. 2.8 A) and easier preparation,
hexasubstituted ketones are appealing synthetic intermediates.4
Notably, in addition to the stereocontrolled synthesis of hexasub-
stituted ketones, this strategy requires that the stereochemistry of
the intermediate radical pair be preserved and we have shown
excellent results when reactions are carried out in the crystalline
solid state.5
Interested in structures that occur in either meso- or DL- forms,
we decided to explore the two-step procedure illustrated in
Scheme 2, starting with 3-phenylpyrrolidine-2-one 1. We reasoned
that deprotonation followed by reaction with
a carbonyl
equivalent might form the desired hexasubstituted ketones in a
diastereoselective manner. We selected phenylpyrrolidinone 1 with
the expectation that the resulting ketones 2 and 3 would react
Scheme 1 Synthesis of all-carbon quaternary centers by photodecarbo-
nylation of hexasubstituted ketones.
Department of Chemistry and Biochemistry, University of California–
Los Angeles, 405 Hilgard Avenue, Los Angeles, California, 90095-1569,
USA. E-mail: mgg@chem.ucla.edu; Fax: 310-825-6707;
Tel: 310-825-3159
{ Electronic supplementary information (ESI) available: Experimental
data. See DOI: 10.1039/b711786h
Scheme 2 Reagents and conditions: (i) LiHMDS, then 0.5 eq. COCl2
(278 to 240 uC), THF; (ii) LiHMDS, then 0.5 eq. CDI (2110 to 260 uC),
THF.
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Chem. Commun., 2008, 193–195 | 193

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may not be involved. The formation of ketones 2 and 3 occurs by
intermediacy of an acyl chloride in the case of COCl2, and an acyl
imidazolide in the case of CDI. Two possible reaction trajectories
leading to the observed products with a lithium-chelated (S)-
enantiomer of the acyl chloride (A) and acyl imidazolide (B) and
approaching nucleophiles, respectively, are illustrated in Fig. 2.
Structure A has the lithium enolate approaching the acyl chloride
with the required si-face to form one of the enantiomers of the DL-
pair. Structure B accounts for the meso-diastereoselectivity when
the larger imidazolide ion is the leaving group. We speculate that
adverse steric interactions between phenyl and imidazolyl groups
and the preferred orientation of the enolate oxygen may cause the
enolate to flip and rotate to expose the re-face. Positioning the
phenyl group of the enolate in B close to the pyrrolidinone, which
would have been avoided in A, would account for longer reaction
times, more side products, and the lower yield of the meso
diastereomer 3.
After establishing the diastereoselective synthesis of 2 and 3 we
set out to investigate their photochemical reactivity in solution.
Experiments were carried out in deoxygenated 0.1 M benzene
solutions using a Hanovia medium pressure Hg lamp with l .
280 nm (Pyrex filter). Two major products obtained in 60–80%
were identified as the expected decarbonylation and radical–radical
combination products 4 and 5 (Scheme 3). Both have a molecular
ion M+ corresponding to the loss of CO from the starting ketones,
and their 1H and 13C NMR were consistent with the dynamically
averaged Cs and C2 symmetries of the meso- and DL-pair,
respectively. The stereochemical identities of 4 and 5 were
established with the help of single-crystal X-ray diffraction of
DL-4 (Fig. 1, bottom).{
Fig. 1 (Top) ORTEP diagram of ketone meso-3 (298 K) and (bottom)
decarbonylation product DL-4 (100 K). Compound 4 crystallizes in a
conformation with C2 symmetry and is viewed down the twofold axis
across the central C–C bond. Both structures are shown at the 30%
probability level.
Remarkably, while irradiation of ketone 2 gave compounds 4
and 5 in 40 and 20% isolated yields, respectively, the yields from
ketone 3 switched to 26 and 63%. Unexpectedly, they both display
a ca. 2 : 1 tendency to retain the stereochemistry of the reactant in
the product, requiring a mechanism with stereochemical memory.
While concerted CO extrusions have been considered in the
literature, there have been no conclusive examples reported.8 A
more likely mechanism involves a singlet state a-cleavage, loss of
CO, and rapid recombination of the singlet radical pair to preserve
the stereochemistry of the reactant. In fact, stereospecific reactions
of singlet radical pairs have been reported in the literature in the
photo-Claisen reaction9 and decarboxylative photocyclizations.10
In order to establish the stereochemical preferences of freely
Fig. 2 Possible reaction trajectories showing the preferred face attack
on the (S)-enantiomer of both acyl chloride and acyl imidazolide
intermediates.
suggesting that Li+ chelation is essential. There was no changes in
diastereoselectivity with a large excess of LiCl using LiHMDS,
suggesting that chelation of the 1,3-dicarbonyl is needed, but that
lithium-mediated aggregates of the electrophile and nucleophile
Scheme 3 Proposed reaction scheme to account for the spin-selective diastereoselectivity of ketone 3. A similar scheme applies to 2.
194 | Chem. Commun., 2008, 193–195
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investigated to determine their advantages and limitations as
compared to solution reactions.
This work was supported by NSF grant No. CHE0551938.
Notes and references
{ Crystal data for ketone 3 at 298(2) K: C37H36N2O5, M = 588.68,
monoclinic, space group P21/c, a = 15.4881(18), b = 10.8020(12), c =
Scheme 4 Reagents and conditions: (i) 5 eq. LiHMDS, 278 uC, 0.5 h,
THF; (ii) 5 eq. CuBr2, 2 h. 278 to rt.
3
23
˚
˚
19.017(2) A, b = 104.87(10)u, V = 3075.0(6) A , Z = 4, Dc = 1.263 Mg m
,
F(000) = 656, l = 0.71073 A, m(Mo-Ka) = 0.350 mm21, crystal size = 0.20
6 0.20 6 0.05 mm; of the 7275 reflections collected, 4340 (Rint = 0.0189)
were independent reflections; max./min. residual electron density 0.261/
˚
diffusing 3-phenylpyrrolidinone-3-yl radicals, we explored the
triplet-sensitized photoreactivity of 2 and 3 using acetone as the
solvent and sensitizer.11 In parallel experiments, after each reactant
was consumed, the DL-compound 4 was obtained as the major
product (ca. 50%) with only small amounts of the meso isomer
(,5%).12 Experiments carried out with 3 dissolved in isoprene, a
well-known triplet quencher,13 were completely stereospecific,
providing 5 as the only product. A kinetic scheme that accounts
for the proposed spin-selective reactivity is illustrated in Scheme 3
with meso-3 as the reactant.
20.209 e A23, R1 = 0.0447 (I . 2s(I)) and wR2 = 0.0901. Crystal data for
˚
compound 5 at 100 K: C36H36N2O4, M = 560.67, monoclinic, space group
˚
C3/c, a = 18.277(6), b = 10.860(6), c = 16.533(8) A, b = 116.358(7)u, V =
3
23
˚
˚
2940(2) A , Z = 4, Dc = 1.266 Mg m , F(000) = 656, l = 0.71073 A,
m(Mo-Ka) = 0.350 mm21, crystal size = 0.20 6 0.10 6 0.10 mm; of the
3301 reflections collected, 2034 (Rint = 0.0189) were independent reflections;
max/min residual electron density 0.261/20.209 e A23, R1 = 0.0447 (I .
˚
2s(I)) and wR2 = 0.0901. CCDC 656274 and 656275. For crystallographic
data in CIF or other electronic format see DOI: 10.1039/b711786h
1 (a) J-P. Pete and N. Hoffman, Diastereodifferentiating Photoreactions,
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Sci., 2006, 5, 449–451.
As illustrated in Scheme 3, the singlet radical pair 1RP-1
preferentially formed upon direct irradiation must lose CO before
rotation within the solvent cage so that 1RP-2 may form the new s
bond without losing the stereochemistry of the reactant. Given
that the decarbonylation of substituted phenylacetyl radicals is
1
1
exothermic, the reversible formation of RP-1 from caged RP-2
and CO is very unlikely.14 When acetone is used as the triplet
sensitizer, a-cleavage from 33 produces the triplet radical pair 3RP-
1, which loses CO and diffuses apart to form free radicals.
Although the extent of stereoselectivity often decreases in the
triplet manifold,15 free radicals formed from either ketone
diastereomer experience a high double induction and a tendency
to form DL-4. Additional evidence for the proposed mechanism
comes from the effect of isoprene, which quenches the triplet
ketone, prevents the formation of free radicals, and renders the
reaction of 3 almost completely stereospecific to 5. Furthermore,
quantum yield measurements at l = 300 nm with 0.02 M solutions
in deoxygenated benzene using valerophenone actinometry16 gave
values of W2A4 # 0.05 and W3A5 # 0.005, which are suggestive of
a very large fraction of 1RP-1 returning to the starting ketone. The
differences in efficiency between the two diastereomers suggest that
recombination to the starting ketone is about 10 times less likely
for the DL-RP-1 as compared to meso-RP-1, which is consistent
with the high selectivity shown by free radicals which form DL-4 in
preference of meso-5. Further evidence was obtained by investigat-
ing the coupling of the free radicals produced by oxidation of the
enolate of 1,17 which yielded the DL-isomer 4 with a 10 : 3
preference over the meso-isomer 5 (Scheme 4).
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J. Ramnauth and E. Lee-Ruf, Can. J. Chem., 1997, 75, 518.
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In conclusion, with phenylpyrrolidinone as a starting material
this study expands on a new method to obtain structures with non-
adjacent (2 and 3) and adjacent (4 and 5) quaternary stereogenic
centers in a highly diastereoselective manner. To the best of our
knowledge, this is the first case involving photodecarbonylations
via the Norrish type I mechanism with a high diastereoselectivity
that can be controlled by accessing different spin multiplicities of
the excited state. Experimental and theoretical studies are in
progress to establish the source of the diastereoselectivity of ketone
formation. Photochemical studies in crystals are also being
14 For kinetic data for the decarbonylation of acyl radicals, please see: (a)
C. Chatgilialoglu, D. Crich, M. Komatsu and I. Ryu, Chem. Rev., 1999,
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17 T. Langer, M. Illich and G. Helmchen, Tetrahedron Lett., 1995, 36,
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