Parallel syntheses of (+)- and (-)-α-cuparenone by radical combination in crystalline solids

Article abstract of DOI:10.1002/anie.200700679

Photo[Organic]synthesis: Irradiation of well-designed crystalline ketones can result in the solvent-free generation of compounds having adjacent quaternary stereogenic centers, as illustrated for the enantiospecific synthesis of the natural products (+)-

Full text of DOI:10.1002/anie.200700679

Angewandte
Chemie
DOI: 10.1002/anie.200700679
Solvent-Free Synthesis
Parallel Syntheses of (+)- and (À)-a-Cuparenone by Radical
Combination in Crystalline Solids**
Arunkumar Natarajan, Danny Ng, Zhe Yang, and Miguel A. Garcia-Garibay*
Among the forces shaping the future of organic synthesis is
the drive for environmentally friendly processes in keeping
with the principles of green chemistry.[1] Strategies under
development include the engineering of microorganisms and
enzymes,[2] the application of efficient catalysts[1,3] and
environmentally friendly solvents,[4] and whenever possible,
Scheme 2. Retrosynthesis of (a)-cuparenone (1) by stereospecific
solid-state photodecarbonylation of diketone 2. The dotted line repre-
sents the reaction cavity; Ar=4-MeC6H4.
the use of chemical processes without solvents.[5,6a] It is also
expected that photochemical reactions will play an important
role in the synthesis of natural products and specialty
chemicals.[6,7] A promising reaction in this context is the
solvent-free photodecarbonylation of crystalline ketones
(Scheme 1).[6a,8] While the reaction is ideal for the synthesis
test novel methodologies, thus providing a good standard for
comparison.[14] As a starting point, we prepared racemic
cyclohexanedione (Æ )-2 in four simple steps in 59.7% overall
yield from methyl 2-tolyl-acetate (3) (Scheme 3). Clear
prisms of (Æ )-2 (m.p. 63.0–65.58C) obtained from hexane
were suitable for photochemical studies.
Scheme 1. Hexasubstituted acetones with radical-stabilizingsubstitu-
ents at both a carbons react photochemically in the crystalline state to
generate radical pairs that bond to form adjacent quaternary stereo-
genic centers in a highly stereospecific process.
of molecules with adjacent quaternary stereogenic centers,[9]
its application for the synthesis of enantiomerically pure
natural products has not been demonstrated.[10,11] With that in
mind, we report here a very efficient synthesis of the natural
product (a)-cuparenone (1), in which the two quaternary
centers are formed in the crystalline state with complete
stereocontrol (Scheme 2).
(a)-Cuparenone (1) is a crystalline compound and a
suitable candidate for a solid-to-solid photochemical reaction.
(S)-(+)-(a)-Cuparenone was first isolated from the wood of
the Mayur Pankhi in 1964[12] and (R)-(À)-(a)-cuparenone
from the liverwort Mannia fragrans in 1976.[13] With two
adjacent quaternary centers, one of which is stereogenic, (a)-
cuparenone has been one of the most sought-after targets to
Scheme 3. a) KH, MeI, THF, 08C, 92%; b) LDA, ethyl vinyl ketone,
THF, 08C, 81%;c) Na, MeOH, reflux, 99%; d) KH, MeI, DMF, 758C,
81%.
Irradiation of (Æ )-2 in degassed 0.1m benzene solutions
with a medium-pressure Hg Hanovia lamp using a Pyrex filter
(l > 290 nm) gave (Æ )-(a)-cuparenone in 34% yield along
with several other products after 100% percent conversion.[15]
In contrast, irradiation of (Æ )-2 in powder form (20 mg) at
À208C yielded (Æ )-(a)-cuparenone as the only product at
70% conversion. Larger samples (0.1 g) conveniently irradi-
ated at ambient temperature as nanocrystalline suspen-
sions[16–18] provided (Æ )-a-cuparenone in 85% yield.
[*] Dr. A. Natarajan, D. Ng, Z. Yang, Prof. Dr. M. A. Garcia-Garibay
Department of Chemistry and Biochemistry
University of California, Los Angeles
607 C.E. YoungDrive East, Los Angeles, CA 90095-1569 (USA)
Fax: (+1)310-825-3159
E-mail: mgg@chem.ucla.edu
[**] This work was supported by the National Science Foundation
through grant CHE0551938.
To prepare the enantiomerically pure natural products we
carried out a classical resolution of (Æ )-2 via the diastereo-
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
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meric difluorodioxaborinane complexes of b-keto-(S)-(a)-
(+)-(S,S)-7 and (À)-(S,R)-7, respectively. Circular dichroism
in CH2Cl2 displayed approximately opposite Cotton effects
with different intensities in the region of 220–350 nm (see the
Supporting Information).
methylbenzylamide (7) (Scheme 4)[19] b-Ketoester (Æ )-5 was
obtained in 92% yield by selective C-acylation of (Æ )-2 with
methyl cyanoformate, and subsequent treatment with
Removal of the chiral auxiliary from (+)-(S,S)-7
exposed one of the limitations of solid-state photo-
20
chemistry. Samples of (À)-(S)-2 ([a]D
(c = 1) =
À358)[21] failed to crystallize under a wide variety of
experimental conditions, and solid-state irradiation
could not be carried out. Solution irradiation of (À)-
(S)-2, as expected, gave low yields of the desired product
with complete racemization. Nonetheless, the syntheses
of (+)- and (À)-(a)-cuparenone were completed by
taking advantage of the high melting points of the
ketoamide complexes 7. Parallel UV/Vis irradiation of
suspended nanocrystals of (+)-(S,S)-7 and (À)-(S,R)-7
(100 mg) in aqueous cetyltrimethylammonium bromide
(CTAB) solutions led to the clean formation of the (a)-
cuparenone ketoamide derivatives (+)-(S,S)-8 and (À)-
(S,R)-8 with 100% stereoselectivity in 80% yield
(Scheme 5).[22] Removal of the BF2 unit with NaOAc
in ethanol followed by amide hydrolysis and decarbox-
ylation gave the the two natural products each in 90%
yield. The optical rotation of the two final products
matched the values reported in the literature[23,24] and
Scheme 4. a) LiHMDS, MeO(CO)CN, 92%; b) BF3OEt2, toluene, 100%;
c) (S)-(a)-methylbenzylamine, MeCN, 80%; d) silica gel chromatography
(EtOAc/hexane 2:8). LiHMDS=lithium hexamethyldisilylazide.
BF3OEt2 gave difluorodioxaborinane (Æ )-6 in > 98% yield.
Reaction of (Æ )-6 with (À)-(S)-(a)-methylbenzylamine in
acetonitrile yielded 80% of diastereomers 7. Separation by
column chromatography (EtOAc/hexane 2:8) led to pure 7A
and 7B, with Rf values of 0.4and 0.3, respectively. Crystal-
lization from ether gave 7A and 7B as colorless X-ray-quality
needles (224–2278C) and platelike crystals (192–1988C),
respectively.
Since we knew that the absolute configuration of the (a)-
methylbenzylamine enantiomer used is S, we could determine
by single-crystal X-ray diffraction analysis[20] that the quater-
nary carbon of 7A also has the S configuration (Figure 1).
With the (S,S)-7 configuration assigned to the less polar
diastereomer A, the configuration of the more polar isomer
was assigned as (S,R)-7. Optical rotation measurements
Scheme 5. a) hn, suspension of nanocrystals in aq. CTAB solution,
80%; b) MeCO2Na, EtOH, 708C, >98%; c) 6.0m HCl, 1008C, 90%.
CTAB=cetyltrimethylammonium bromide; MBA=methyl benzyl
amine.
23
revealed [a]D (c = 0.25) values of + 608 and À2378, for
the CD spectra display a perfect mirror-image relation with
maxima at 300 nm (see the Supporting Information).
Previous syntheses of (a)-cuparenone range from 3 to 15
steps for racemic samples and from 7 to 20 steps for the
enantiomerically enriched natural product (see the Support-
ing Information). The highest overall yields are 56% for the
racemic sample and 29% (96.5% ee) for (À)-(a)-cupare-
none.[14] Using a photochemical solid-to-solid reaction as the
key step, we report here the total synthesis of (Æ )-(a)-
cuparenone in four steps and 60% overall yield. For the
parallel synthesis of the two enantiomerically pure natural
products, five reactions and one diastereomeric separation
starting from (Æ )-2 led to (S)-(+)-1 and (R)-(À)-1 in 100% ee
and 52% total yield (26% of each pure enantiomer).
Figure 1. X-ray structure of the less polar diastereomer, 7A, shown to
have the absolute configuration (S,S)-7; ellipsoids at the 30% proba-
bility level.
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[11] M. E. Ellison, D. Ng, H. Dang, M.A. Garcia-Garibay, Org. Lett.
In conclusion, the photoinduced decarbonylation of
crystalline hexasubstituted ketones offers a very simple
approach for the stereospecific synthesis of natural products
with adjacent stereogenic quaternary centers. With higher
yields, fewer steps, ideal selectivities, and easy scaleup, solid-
to-solid reactions may have a strong impact on natural
product synthesis and green chemistry.
2003, 5, 2531 – 2534.
[12] G. L. Chetty, S. Dev, Tetrahedron Lett. 1964, 5, 73 – 77.
[13] V. Benesova, Collect. Czech. Chem. Commun. 1976, 41, 3812 –
3814.
[14] Roughly 20 racemic and 17 asymmetric syntheses have been
reported. For number of steps, yields, and references, please
consult the Supporting Information.
[15] Identifiable byproducts include 12% 2-tolyl-6-methyl-5-oxo-1-
heptene and 4% 2-methyl-6-tolyl-3-xo-1-heptene formed by
radical disproportionation.
Received: February 13, 2007
Published online: July 26, 2007
[16] Stable suspensions were prepared by the reprecipitation method
(Ref. [17]), by addition of a saturated solution of (Æ )-2 in
acetone into a vigorously stirred aqueous CTAB solution five
times below its critical micelle concentration of 1.6 ” 10À4 m (L.
Sepulveda, J. Cortes, J. Phys. Chem. 1985, 89, 5322 – 5324).
[17] H. Kasai, H. S. Nalwal, H. Oikawa, S. Okada, H. Matsuda, N.
Minami, A. Kakutal, K. Ono, A. Mukohl, H. Nakanishi, Jpn. J.
Appl. Phys. Part 2 1992, 31, L1132 – L1134.
[18] For recent examples of solid-state reactions using crystalline
suspensions, see: a) M. Veerman, M. J. E. Resendiz, M. A.
Garcia-Garibay, Org. Lett. 2006, 8, 2615 – 2617; b) S. Takahashi,
H. Miura, H. Kasai, S. Okada, H. Oikawa, H. Nakanishi, J. Am.
Chem. Soc. 2002, 124, 10944; c) D.-K. Bucar, L. R. MacGillivray,
J. Am. Chem. Soc. 2007, 129, 32 – 33.
Keywords: enantioselectivity · photodecarbonylation ·
solid-state reactions · solid-state structures ·
sustainable chemistry
.
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