The catalytic enantioselective, protecting group-free total synthesis of (+)-dichroanone

Article abstract of DOI:10.1021/ja061853f

Herein we report the first enantioselective total synthesis of (+)-dichroanone, confirming the absolute configuration of the natural product. This protecting group-free route features the first application of our enantioselective Tsuji allylation in the context of a natural product total synthesis. Additionally, this 11-step preparation of the molecule from commercial material features a novel Kumada-aromatization strategy and a rapid sequence for the conversion of a phenol to a hydroxy-p-benzoquinone. Copyright

Full text of DOI:10.1021/ja061853f

Published on Web 05/26/2006
The Catalytic Enantioselective, Protecting Group-Free Total Synthesis of
(+)-Dichroanone
Ryan M. McFadden and Brian M. Stoltz*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received March 17, 2006; E-mail: stoltz@caltech.edu
Scheme 1
(-)-Dichroanone (1) is a 4a-methyltetrahydrofluorene norditer-
penoid isolated from the flowering plant SalVia dichroantha STAPF,
found in Turkey.1 It belongs to a recently discovered yet growing
class of natural products that bear a [6-5-6] tricyclic core, including
dichroanal B (2),1 taiwaniaquinol B (3),2 standishinal (4),3 among
others (Figure 1).1,2,4,5 The biological activities of these compounds
are under investigation, and standishinal, which has been shown
to inhibit aromatase,6 could be used to develop agents targeting
estrogen-dependent carcinomas.5 Although the racemic total syn-
theses of dichroanone (1),7 dichroanal B (2),7,8 and taiwaniaquinol
B (3)9 have recently been completed, there have been no enantio-
selective syntheses of any member of this family. Our interest in
dichroanone (1) was piqued upon inspection of its interesting
structure, which includes a fully substituted quinone, the charac-
teristic [6-5-6] tricyclic core, and a benzylic all-carbon quaternary
stereocenter. Herein we report a concise, catalytic enantioselective
synthesis of (+)-dichroanone that does not employ protecting groups
and unambiguously confirms the absolute configuration of the
molecule.
Scheme 2
Figure 1. Dichroanone and related natural products (1-4).
%) in THF to produce quaternary allyl ketone 7 in 83% yield and
91% ee.14 Wacker oxidation15 of keto-olefin 7 was performed in a
Parr apparatus to afford complete conversion to diketone 10 in 77%
yield.16 Condensation of 10 using KOH in xylenes with azeotropic
water removal provided bicyclic enone 6 in excellent yield.17,18
Elaboration of enone 6 to more advanced intermediates was
challenging because of the propensity for most carbon electrophiles
to react at oxygen preferentially to C(5a) (Scheme 3). Fortunately,
Michael addition of the lithium enolate of 6 to methyl vinyl ketone
(MVK) at low temperature formed the desired C-C bond of keto-
enone 11 in good yield with high diastereoselectivity.19 Given the
success of this method, we pursued a Robinson annulation strategy
to form the final ring of dichroanone. Aldol condensation furnished
tricyclic enone 12 in 80% yield, albeit with partial epimerization
of the C(5a) stereocenter. This stereochemical loss was of little
consequence, as C(5a) is ultimately part of the quinone ring of 1.
Because attempts to oxidatively aromatize this newly formed ring
to a phenol were hampered by poor yields, we took the opportunity
to install the isopropyl group of the natural product, albeit as an
isopropenyl moiety, with the hope that the higher oxidation level
could be transposed into the ring. Hence, the kinetic enolate of
tricyclic enone 12 was trapped with N-phenyltriflimide to give enol-
triflate 13, which was immediately subjected to Kumada coupling
conditions with isopropenylmagnesium bromide. Interestingly, this
coupling led to a mixture of isomeric products, which converted
irreversibly to compound 5 upon exposure to acid. Gratifyingly,
Our laboratory recently developed a powerful method for the
enantioselective construction of quaternary centers by palladium-
catalyzed allylation,10 and we believed that this protocol could be
employed to stereoselectively install the quaternary center of
dichroanone (1). Specifically, our allylation method delivers cy-
clohexanones with stereogenicity R to the ketone. Prior to our work
in this area, many of these simple cyclohexanone building blocks
bearing all-carbon R-quaternary stereocenters centers were not
readily available in an enantioselective fashion or had never been
reported as single enantiomer substances.10,11 In addition to employ-
ing our catalytic asymmetric allylation reaction, we planned to
install the three oxygen atoms of dichroanone at a late synthetic
stage, eliminating the need to protect any phenols or quinones during
the synthesis (Scheme 1). Thus, dichroanone (1) could arise from
arene 5, which could be prepared via benzannulation of bicyclic
enone 6. Enone 6 could be prepared from allyl ketone 7 by
sequential Wacker oxidation and aldol condensation.10a Either
enantiomer of 7 is readily available from enol-carbonate 8 by
application of our enantioselective Tsuji allylation.10 Finally, 8 is
available from commercial 2,2,6-trimethylcyclohexanone (9).
We began our synthesis of (+)-dichroanone (1) by enolization
of 9 and trapping with allyl chloroformate, affording the enol
carbonate 8 in high yield with minimal C-acylation (Scheme 2).12,13
In the critical asymmetric Tsuji allylation, carbonate 8 was treated
with catalytic Pd2(dba)3 (2.5 mol %) and (S)-t-Bu-PHOX (6.25 mol
9
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10.1021/ja061853f CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Scheme 4
(+)-Dichroanone (1) was prepared in 4.0% overall yield over
11 steps without the use of protecting groups. The synthesis is
highlighted by the first use of our enantioselective Tsuji allylation
in the context of a natural product, a novel Kumada aromatization
of an enone, and a new method for generating a hydroxy-p-
benzoquinone from a phenol in a single reaction sequence. Efforts
directed toward the synthesis of other members of this interesting
family of natural products are underway.
Acknowledgment. We are grateful to Eli Lilly (graduate
fellowship to R.M.M.), Johnson & Johnson, Bristol-Myers Squibb,
Merck, Amgen, and the Dreyfus Foundation for generous funding.
Doug Behenna, J. T. Mohr, and Dr. Andrew Harned are acknowl-
edged for helpful discussions.
Supporting Information Available: Experimental details and
crystallographic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
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E.; Yesilada, E. Phytochemistry 1999, 50, 493-497.
(2) Lin, W.-H.; Fang, J.-M.; Cheng, Y.-S. Phytochemistry 1995, 40, 871-
when the crude reaction mixture was treated with aqueous HCl,
the major product isolated was aromatic hydrocarbon 5 in 65%
overall yield from enone 12.
873.
(3) Ohtsu, H.; Iwamoto, M,; Ohishi, H.; Matsunaga, S.; Tanaka, R. Tetra-
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(4) (a) Lin, W.-H.; Fang, J.-M.; Cheng, Y.-S. Phytochemistry 1996, 42, 1657-
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Despite having completed the synthesis of the carbon skeleton
of dichroanone, the oxidation of arene 5 to hydroxy-p-benzoquinone
1 was a significant hurdle. Toward this end, exposure of arene 5 to
TiCl4-mediated formylation conditions gave a 10:1 mixture of two
separable benzaldehydes. The structure of the major aldehyde (i.e.,
14) was confirmed by nOe experiments and the absence of hyperfine
coupling between the two remaining aryl protons. Baeyer-Villiger
oxidation furnished phenol 15 in 74% yield. After extensive
experimentation, the final oxidation sequence was carried out by
treatment of phenol 15 with IBX,20 followed by exposure to
pentafluorothiophenol, then NaOH/O2/MeOH, and finally 6 M HCl.
To our delight, this protocol furnished (+)-dichroanone (1) in 35%
yield. Synthetic (+)-dichroanone (1) proved spectroscopically
identical to nat-(-)-dichroanone with the exception of the sign of
rotation,1 confirming the absolute configuration of nat-(S)-(-)-
dichroanone.
(5) Chang, C.-I.; Chang, J.-Y.; Kuo, C.-C.; Pan, W.-Y.; Kuo, W.-Y. Planta
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(12) A minimal amount (3-5%) of C-acylation is observed. This material can
be processed along with 8 in the asymmetric allylation without event.10b
(13) Aboulhoda, S. J.; He´nin, F.; Muzart, J.; Thorey, C. Tetrahedron Lett. 1995,
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Our analysis for the conversion of phenol 15 to (+)-dichroanone
via the final sequence is as follows in Scheme 4. Oxidation of
phenol 15 with IBX produces unstable o-quinone 16, which was
(14) We arbitrarily chose to pursue the (S)-enantiomer of 7 by using (S)-t-Bu
PHOX as the ligand. In practice (R)-t-Bu PHOX is reasonably expensive.
(15) Smith, A. B., III; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett. 1998, 39,
8765-8768.
1
shown by H NMR analysis to be formed in 36% yield. Despite
(16) Without the use of a Parr apparatus, little or no oxidation was observed,
presumably due to problems with molecular oxygen uptake by the solvent.
(17) Thomas, A. F.; Ozainne, M.; Guntz-Dubini, R. Can. J. Chem. 1980, 58,
1810-1820.
extensive efforts to develop other oxidations, these conditions were
superior to any others tested and were the most direct for the
installation of the second oxygen atom. The crude o-quinone 16
was immediately treated with C6F5SH, which presumably undergoes
1,4-addition into the unsubstituted position, giving after tautomer-
ization a highly reactive catechol (17). Attempts to isolate this
catechol led to complex mixtures, including a second highly
unstable o-quinone (18). We found that complete oxidation of
catechol 17 to o-quinone 18 was cleanly promoted by molecular
oxygen in the presence of base. Although isolation of o-quinone
18 was problematic, we reasoned that it could be hydrolyzed to
dichroanone (1) in situ. Thus, base-mediated saponification of the
activated vinylogous thioester 18, followed by tautomerization,
completed the reaction. Dichroanone (1) is produced as the sole
isolable product through this novel sequence.
(18) The ee of enone 6 could be upgraded to 97% ee by preparation,
recrystallization, and hydrolysis of its semicarbazone derivative i. For the
experiment shown, a collection of multiple batches of 6 was used that
had a composite ee of 83%. See Supporting Information for further details.
(19) The relative stereochemistry was confirmed by X-ray crystallography. See
Supporting Information for details.
(20) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus, T. R. R.
Org. Lett. 2002, 4, 285-288.
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