Scalable synthesis of vicinal quaternary stereocenters via the solid-state photodecarbonylation of a crystalline hexasubstituted ketone

Article abstract of DOI:10.1021/acs.orglett.0c03226

We report the synthesis and stereospecific solid-state photodecarbonylation of a hexasubstituted ketone featuring six distinct α-substituents. The photoproduct of the solid-state transformation features vicinal all-carbon quaternary stereocenters. While reactions carried out in bulk powders and aqueous crystalline suspensions were complicated by secondary photochemistry of the primary photoproduct, optimal conditions provided good yields and recyclable starting material. Subsequent transformations of the α-substituents having orthogonal chemical reactivity illustrate the potential of this transformation toward constructing complex architectures.

Full text of DOI:10.1021/acs.orglett.0c03226

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Letter
Scalable Synthesis of Vicinal Quaternary Stereocenters via the Solid-
State Photodecarbonylation of a Crystalline Hexasubstituted Ketone
Trevor Y. Chang, Jordan J. Dotson, and Miguel A. Garcia-Garibay*
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ABSTRACT: We report the synthesis and stereospecific solid-state photodecarbonylation of a hexasubstituted ketone featuring six
distinct α-substituents. The photoproduct of the solid-state transformation features vicinal all-carbon quaternary stereocenters. While
reactions carried out in bulk powders and aqueous crystalline suspensions were complicated by secondary photochemistry of the
primary photoproduct, optimal conditions provided good yields and recyclable starting material. Subsequent transformations of the
α-substituents having orthogonal chemical reactivity illustrate the potential of this transformation toward constructing complex
architectures.
Scheme 1
icinal, stereogenic, all-carbon quaternary centers
V(VSAQCs) embedded in the core of complex small
molecules and natural products constitute a compelling, yet
challenging to construct, motif in organic synthesis.1 The
inherent steric encumberment of the two quaternary carbons
hampers many conventional C−C bond-forming method-
ologies. While elegant solutions have been devised for the total
synthesis of several natural products and related scaffolds,2 a
general and efficient method that meets the ideals of green
chemistry3 remains a highly desirable addition to the synthetic
organic toolbox. To that end, while underexplored compared
to their solution-phase counterparts, photochemical reactions
in crystalline solids have been known to exhibit notable
advantages. Efforts in crystal engineering have spurred the
design of, among others, precise crystalline supramolecular
templates and photoswitchable moieties.4,5 These systems
exhibit photochemical reactivities and mechanical effects not
typically observed in solution and showcase promise in altering
the properties of APIs and engineering dynamic organic
materials.
Our group has previously shown examples where the solid-
state photodecarbonylation of crystalline ketones can be a
highly selective method to access VSAQCs-containing
molecules (Scheme 1a).6 In these transformations, hexasub-
stituted ketone 1 undergoes photochemical excitation and
subsequent decarbonylation to furnish radical pair 2. Restricted
motion of 2 within the crystalline lattice prevents radical
rotation prior to recombination to provide 3 with retention of
Received: September 25, 2020
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© XXXX American Chemical Society
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A

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configuration. The rigid reaction cavity also limits the number
of products as compared to those observed in solution because
it avoids alternative reactions arising from the dissociation of
radical pair 2 to form free radicals. In this study, we address a
more complex substrate featuring multiple orthogonal func-
tional groups that may be viewed analogously to synthons for
more complex structures.
To assess the ability of the solid-state photodecarbonylation
reaction as an entry to construct complex molecules with six
different functional groups, we prepared hexasubstituted
ketone 4 and tested its photochemical reactivity in the
crystalline solid-state (Scheme 1b). This substrate represents
one of the most complex crystalline ketones studied to date,
and the synthetic versatility of photoproduct 5 can be explored
by the selective transformations of the orthogonal functional
handles. We suggest that the opportunity to readily prepare
drug-like VSAQCs-containing compounds with low molecular
weight and complex three-dimensional functionality may open
new avenues for the medicinal chemistry community.7−9
Our synthetic approach to ketone 4 is depicted in Scheme 2.
The synthesis commenced by cyanomethylation of malonic
unit cell having the two enantiomers related by a crystallo-
graphic inversion center. The molecule adopts a conformation
where the α-cyano and α’-cyanomethyl groups are linked by
bonds that are approximately aligned with the plane of the
carbonyl group, the two aromatic groups directed toward one
side of the plane, and the methyl and allyl groups directed
toward the opposite direction. The dihedral angles formed by
the plane of the aromatic rings and the sigma bonds
undergoing α-cleavage are 74° (m-MeOCOPh−) and 50°
(Ph−), which are stereoelectronically suited to exert sufficient
benzylic stabilization of the incipient carbon-centered radicals
(Figure 1).11 The crystal structure also revealed the relative
configuration of the two stereocenters to be (R,S)/(S,R)
(Figure S3).
Scheme 2
Figure 1. X-ray molecular structure of hexasubstituted ketone 4. Left:
Triclinic unit cell as viewed down the reciprocal cell axis a*. Right:
Dihedral angles of stabilizing interactions between adjacent π-systems
and breaking σ-bonds (blue).
With crystalline 4 in hand, we set out to explore the
photodecarbonylation of 4. Table 1 summarizes the results in
dilute solutions and in crystalline solids in the form of bulk dry
powders or aqueous suspensions. Reactions carried out in
dilute benzene solutions of 4 (Table 1, entry 1) resulted in full
Table 1. Conversion and Recombination Product Ratio
upon Irradiation of Ketone 4 in Various Reaction Media
a
ester 6 under basic conditions to give the symmetric bis(allyl)
ester 7 in 92% yield. This fully substituted ester was then
subjected to a palladium-catalyzed Tsuji−Trost allylation to
give allyl ester 8 in 90% yield, furnishing one of the requisite
quaternary stereocenters present in 4. This was followed by a
two-step saponification, dehydrochlorination sequence to
provide 9, which was carried forward without further
purification due to its hydrolytic lability. Acid chloride 9 was
then coupled with the lithium carbanion of 10 to afford ketone
4 as a viscous oil in yields of 45−60% and a diastereomeric
ratio (dr) of 1.8:1. Diastereomeric resolution of 4 was achieved
through fractional recrystallization (see SI p S7). After
subjecting the solids to three recrystallization cycles, a dr
greater than 30:1 was achieved. The minor diastereomer of
ketone 4 remained a viscous oil despite exhaustive attempts to
nucleate crystallization and was therefore not a suitable
candidate for a solid-state photodecarbonylation analysis.10
Single crystals of 4 obtained by slow solvent evaporation were
suitable for X-ray diffraction structural elucidation. The
b
entry
medium
time (h) conversion of 4 (yield of 5) dr (5)
c
d
1
2
3
4
5
6
7
8
9
solution
2
1
2
4
6
100% (16%)
1.8:1
8.0:1
8.6:1
8.6:1
8.7:1
e
bulk solid
bulk solid
bulk solid
bulk solid
suspension
suspension
suspension
suspension
suspension
37 (−)
e
56 (−)
79 (−)
e
e
85 (−)
1
4
5
8
<5 (trace)
40 (65)
f
8.0:1
8.2:1
8.2:1
8.6:1
f
53 (58)
f
81 (32)
f
10
16
91 (30)
a
All reactions carried out using a 450 W medium-pressure Hanovia
Hg arc lamp equipped with a Pyrex filter (cutoff λ > 290 nm). dr
determined by H NMR integration of α-methyl substituents in 5.
0.05 mmol in deuterated benzene (C6D6) sparged with Argon.
Isolated yield. Analytical scale; yields omitted. Yields based on
recovered starting material.
b
1
c
d
e
f
̅
structure was solved in the triclinic space group P1 with a
B
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conversion within 2 h of irradiation, yielding very complex
product mixtures. The recombination photoproduct 5 was
isolated in a yield of 16% and dr of 1.8:1.12 New vinyl group
resonances between 6.5 and 6.0 ppm in the 1H NMR spectrum
of the crude material suggested that some of the side products
arise from disproportionation reactions. Both the low chemical
yield and the poor stereospecificity of 5 in solution are
consistent with a mechanism that involves free radical
products.
After optimizing the solid-state photodecarbonylation
reaction, we set out to explore the synthetic versatility of
photoproduct 5. Scheme 3 shows optimized reaction
Scheme 3
Solid-state photochemical experiments were carried out on
bulk powders prepared by grinding small crystals between two
microscope slides prior to irradiation (Table 1, entries 2−5).
Conversion under these conditions was less efficient as
compared to the solution phase. This is consistent with
previous reports from our group showing that accumulated
product can act as a filter, preventing additional reaction
progress along the depth of the crystals and sometimes leading
to the formation of secondary photoproducts. However, these
reactions were highly selective, yielding the desired compound
5 with consistently higher retention of configuration as
indicated by the dr = 8.0−8.6:1.13 While bulk-solid irradiation
of 4 improved the reaction yield and stereospecificity,
diminished reaction velocities with increasingly larger sample
loading (>10 mg per slide) limited material throughput.14
Therefore, we decided to explore suspending the crystalline
solids in water via a modified reprecipitation method as a
means to scale up the photochemical reactions. We have
shown that crystalline suspensions react in a more homoge-
neous manner, increasing the reaction velocity and con-
version.15−19 Thus, aqueous suspensions of 4 were prepared by
dissolving the ketone in a minimal amount of acetone, which
was added dropwise to rapidly stirring water with submicellar
surfactant concentrations. The reprecipitated solids were
collected via filtration and confirmed to be crystalline and of
the same polymorphic phase as the bulk powders (Figure S2).
Treatment of the reaction vessel glass surface with a silanizing
agent (Sigmacote) rendered the surface hydrophobic and
helped avoid material build-up on the reactor walls. It was also
found that sonication of the suspensions for 5 min after every
hour of irradiation limited the adherence of reaction material
to the glass surface.
Similar to the bulk powder reactions, irradiation of aqueous
crystalline suspensions of 4 (Table 1, entries 6−10) exhibited
higher chemoselectivity, with 5 being the only product isolated
in 30−65% yields based on recovered starting material (brsm).
The diastereoselectivity observed in these cases was similar to
that seen for reactions carried out on small amounts of bulk
powder (dr = 8.0−8.7:1). We found that stopping the reaction
after 4 h (Table 1, entry 7) led to the highest yields of 5
(brsm), and the recovered ketone could be readily crystallized
and subjected to irradiation.
Notably, greater conversion of 4 as suspended crystals
resulted in yields of 5 that were unexpectedly low (Table 1,
entries 8−10).20 We hypothesized that the observed loss of
chemical yield at high conversion was indicative of secondary
photochemical decomposition of 5. To test this hypothesis, we
conducted a control experiment (not shown) in which pure 5
was irradiated. As expected, an unidentifiable yellow material
was observed after 2 h, suggesting 5 may decompose during
irradiation. Despite the limitations of this particular substrate,
photodecarbonylation reactions in crystalline suspensions
could be carried out on scales as large as 300 mg.
conditions first carried out on model compounds and
subsequently applied to 5. Treating 5 with LiBH4 at 55 °C
proved to be selective for methyl benzoate reduction,
providing alcohol 11 in 52% yield (brsm). The use of other
reducing agents such as LiAlH4 or DIBAL-H resulted in
complex product mixtures and significant decomposition.
Epoxidation with m-CPBA gave 12 as a mixture of
diastereomers with a dr ≈ 1.7:1 after 18 h at 35 °C.
Hydrogenation of the terminal alkene using palladium on
activated carbon gave 13 in 98% yield, and saponification
afforded the corresponding acid 14, though cold temperature
was necessary to avoid decomposition. Single-crystal X-ray
diffraction unambiguously determined the structure and
relative stereochemistry of 13 (Figure S4). Interestingly,
when 5 was treated with nitrile-selective reducing conditions,
neither 15 nor any other identifiable reduced products were
observed, and only starting material was recovered from the
reaction mixture. This reactivity contrasts with the efficient
reduction of model nitrile 10 to furnish the primary amine 16
(Scheme 3b).21 While these transformations demonstrate
some of the versatility of 5, we note that some of the
challenges faced (i.e., the failed conversion to 15) were likely
due to the dense steric encumberment of the VSAQCs motif.
In conclusion, we illustrate the relatively simple preparation
of compounds containing vicinal, all-carbon substituted
quaternary stereocenters by taking advantage of the solid-
C
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state photodecarbonylation of a diastereomerically pure
crystalline ketone with six different α-substituents. We have
shown that photochemical reactions in crystals proceed with
highly improved chemo- and stereoselectivity and can be easily
carried out on synthetically useful scales by taking advantage of
aqueous crystalline suspensions. Transformations of the
orthogonal functional groups in the photoproduct demonstrate
some of the challenges and potential for the synthetic
elaboration of three-dimensionally complex structures. While
the yield and stereoretention for the photodecarbonylation of
this particular crystalline starting material were modest,22 this
report showcases the continued development of a promising
green methodology for the stereospecific construction of
vicinal quaternary carbons.
̈
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03226.
Synthesis and spectroscopic characterization of com-
pounds 4−14 and 16−19 and select crystal parameters
of compounds 4 and 13 (PDF)
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Green Chemistry: Science and Politics of Change. Science 2002, 297,
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CCDC 2033983−2033984 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Miguel A. Garcia-Garibay − Department of Chemistry and
Biochemistry, University of California, Los Angeles, California
90095-1569, United States; orcid.org/0000-0002-6268-
1943; Email: mgg@chem.ucla.edu
̌
̌
́
(e) Macgillivray, L. R.; Papaefstathiou, G. S.; Friscic, T.; Hamilton,
̌
T. D.; Bucar, D. K.; Chu, Q.; Varshney, D. B.; Georgiev, I. G.
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Templates to Ladderanes to Metal-Organic Frameworks. Acc. Chem.
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cycloaddition. Chem. Rev. 2016, 116, 9914−9993.
Authors
Trevor Y. Chang − Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095-1569,
United States
Jordan J. Dotson − Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095-1569,
United States
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03226
Notes
(6) Dotson, J. J.; Perez-Estrada, S.; Garcia-Garibay, M. A. Taming
Radical Pairs in Nanocrystalline Ketones: Photochemical Synthesis of
Compounds with Vicinal Stereogenic All-Carbon Quaternary Centers.
J. Am. Chem. Soc. 2018, 140, 8359−8371.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the National Science Foundation (CHE-
1855342) for financial support.
■
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Increasing Saturation as an Approach to Improving Clinical Success. J.
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as primary photoproduct 5 is expected from the photodecarbonyla-
tion of 4 following the “least-motion” descriptor proposed by Schmidt
and co-workers (ref 4a and references within).
E
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