Enantioselective syntheses of candenatenins B and C using a chiral anthracene auxiliary

Article abstract of DOI:10.1016/j.tetlet.2009.12.108

The asymmetric syntheses of two anticancer natural products, candenatenins B and C, are described, leading to a revision of the originally assigned stereochemistries. The syntheses follow a Diels-Alder/retro-Diels Alder strategy using a chiral anthracene auxiliary to access both targets with 90% ee. The inherent structural qualities of the auxiliary allow for both regio- and diastereoselective transformations.

Full text of DOI:10.1016/j.tetlet.2009.12.108

Tetrahedron Letters 51 (2010) 1091–1094
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective syntheses of candenatenins B and C using a chiral
anthracene auxiliary
*
Amanda L. Jones, Xiang Liu, John K. Snyder
Center for Chemical Methodology and Library Development and the Department of Chemistry, Boston University, 590 Commonwealth Ave., Boston, MA 02215, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric syntheses of two anticancer natural products, candenatenins B and C, are described,
leading to a revision of the originally assigned stereochemistries. The syntheses follow a Diels–Alder/
retro-Diels Alder strategy using a chiral anthracene auxiliary to access both targets with 90% ee. The
inherent structural qualities of the auxiliary allow for both regio- and diastereoselective transformations.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 2 December 2009
Revised 17 December 2009
Accepted 17 December 2009
Available online 24 December 2009
Keywords:
Asymmetric synthesis
Diels–Alder reaction
Candenatenin
Chiral anthracene
Chiral 4-substituted cyclohexenones
The use of chiral anthracene derivatives as stereocontrolling aux-
iliaries in Diels–Alder/retro Diels–Alder (DA/rDA) sequences has the
potential to become a useful tool for asymmetric synthesis.1–3 By
tailoring the auxiliary so that one hemisphere contains a stereogenic
center adjacent to the anthracene core while the other remains
unobstructed, one can control not only the diastereoselectivity of
the initial cycloaddition, but also the selectivities of subsequent
transformations of functional groups originating from the dieno-
phile. Our group,2 as well as that of Jones,3 have reported the use
of chiral 9-substituted anthracenes 1–3 (Fig. 1) in highly diastereo-
selective Diels–Alder cycloadditions with maleimide and related
dienophiles. Further transformations, including carbonyl reductions
(Scheme 1, Eq. 1)2a and Grignard additions (Scheme 1, Eq. 2)2b were
achieved with complete regioselectivity at the carbonyl remote to
the anthracene-derived stereogenic center, with a diastereoselec-
tive approach of the Grignard reagents occurring solely from the
more accessible top face of the cycloadduct. Release of the trans-
formed dienophile could then be achieved by a retro Diels–Alder
(rDA) reaction,2b–f,3a,c,4,5 to give enantioenriched heterocycles such
as 9 (Scheme 1, Eq. 3).2d
Figure 1. 9-Substituted chiral anthracene auxiliaries.
successfully function as a stereocontrolling element in the DA/
rDA sequence with p-benzoquinone dienophiles in the syntheses
of enantioenriched, chiral 4-substituted cyclohexenones (Scheme
2). In this strategy, a cycloaddition between 2 and 10, with
subsequent regioselective carbonyl transformation of cycloadduct
11 followed by a cycloreversion would allow access to the target
4-substituted cyclohexenones 13 in highly enantioenriched form.
Several examples of this structural motif are found in the recently
discovered candenatenins B–D 14–16 (assigned structures, Fig. 2).7
These compounds were isolated from the heartwood of Dalbergia
candenatensis and both 14 and 15 showed modest levels of activity
against an HT-29 colon cancer cell line (17.8 and 19.7
tively), though this anticancer activity was also shown to be a
consequence of the promiscuous ,b-unsaturated carbonyl func-
lM, respec-
Based on these results, we considered the application of other
dienophiles in this DA/rDA methodology, specifically p-benzoqui-
none. Knapp has previously applied a DA/rDA strategy with an
achiral anthracene template as an alkene protecting group with
p-benzoquinone as the dienophile in his synthesis of rac-conduri-
tol.6 Thus, we felt that a homochiral anthracene template should
a
tionality. The single remote stereogenic centers of 14–16 are
tertiary alcohols, which we have previously shown are accessible
via regioselective Grignard addition to dicarbonyl-containing
cycloadducts of chiral anthracenes, making these natural products
ideal targets for our ongoing studies in the use of chiral anthracene
auxiliaries. Another important goal in this work was to find a
procedure which accomplished the cycloreversion without the
* Corresponding author. Tel.: +1 617 353 2621; fax: +1 617 353 2466.
E-mail address: jsnyder@bu.edu (J.K. Snyder).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.108

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A. L. Jones et al. / Tetrahedron Letters 51 (2010) 1091–1094
Figure 3. Transition state models to explain diastereoselectivity.8
need to resort to flash vacuum pyrolysis, a methodology which
severely restricts application of the DA/rDA strategy.
The highly diastereoselective cycloaddition of ent-2 with 10 has
been reported by Jones and co-workers,8 and we had also observed
similar diastereoselectivity with 2.4 In Jones’ work, optimized con-
ditions produced the desired cycloadduct in 67% yield and a diaste-
reomeric ratio (dr) of 96:4. The proposed basis for this selectivity
was suggested to be the unfavorable electrostatic repulsion be-
tween the lone pairs on the carbonyl and methoxy oxygen atoms
in the unfavored transition state (Fig. 3).8 Recent theoretical
studies by Aviyente and co-workers9 have supported this basis of
stereoselectivity in the cycloadditions of 2 with maleic anhydride.
Our synthesis began with the diastereoselective cycloaddition
of 2 (97.5% ee)10 and 10, yielding 17 (77% yield, 19:1 dr,11 Scheme
3). Hydrogenation with 10% Pd/C using an H-CubeÒ reactor on a
100 mg scale gave 18 in 88% isolated yield. Regioselective Grignard
addition to 18 with allylmagnesium chloride 19 should then estab-
lish the single stereocenter present in the natural products. While
this reaction did proceed in 91% yield at low temperature, an 11:1
mixture of inseparable regioisomers was isolated, in contrast to the
production of a single isomer in the analogous allyl Grignard addi-
tion to maleimide cycloadducts 44 and 6.2b The major product was
determined to be 20,12 as expected. The minor product, which
could not be purified in sufficient amounts for independent struc-
ture assignment, was assumed to be regioisomer 21, resulting
from addition to the carbonyl closer to the original anthracene
Scheme 1. Transformations of chiral anthracene cycloadducts.
Scheme 2. Synthetic plan to access homochiral 4-substituted cyclohexenones.
Figure 2. Structures of candenatenins B–D 14–16.
Scheme 3. Synthesis of cycloadduct 20.

A. L. Jones et al. / Tetrahedron Letters 51 (2010) 1091–1094
1093
135 °C, minimal conversion (630%) was observed under both
microwave irradiation (entries 1–3) and conventional oil bath
heating conditions (entry 7). Addition of stoichiometric amounts
of a Lewis acid (Sc(OTf)3) gave higher conversion at 135 °C (60%),
but some decomposition products were also noticed (entry 4). By
changing the solvent to 1,2-dichlorobenzene (entries 5 and 8) or
DMSO (entry 6) without Lewis acid catalysis,4,14 at higher temper-
atures, higher conversions were achieved. Based upon this study,
the conditions chosen for cycloreversion were microwave irradia-
tion at 180 °C using 1,2-dichlorobenzene as solvent, which can be
easily removed from the crude reaction mixture during chromato-
graphy.
Enantioenriched cycloadducts 25 and 27 were then subjected to
the optimized cycloreversion conditions, yielding the enantiomers
of the natural products, ent-14 and ent-15, both in 78% yield
(Scheme 5), along with 85% recovery of the chiral anthracene (a
small amount of anthrone was also detected by TLC from oxidation
of the chiral anthracene under the high temperature conditions).
Chiral HPLC analysis of ent-14 indicated 90% ee, in accordance
with the 97.5% ee of the original chiral anthracene 2, and the small
quantities of the inseparable minor regioisomer from the allyl
Grignard addition yielding the opposite enantiomer upon cyclore-
version. The synthetic compounds had 1H and 13C NMR spectro-
scopic data identical to the literature report.7 However, the sense
of optical rotation was the same as that reported in the literature,15
although the synthesized compounds have the opposite configura-
tion based on the chiral anthracene used and the outcome of the
ensuing regio- and diastereoselective transformations. Therefore,
the synthetic compounds share the same configuration as the nat-
ural products and the original stereochemical assignment of cand-
enatenins B and C should be revised to (S). The original assignment
of the absolute stereochemistry of candenatenin B 14 was based on
a CD comparison with that of the natural product piperkadsin A
(Inset).16 Such a comparison for absolute stereochemical assign-
ment is not valid since the chromophores of piperkadsin A are sig-
nificantly different from that of 14.
Scheme 4. Heck coupling of allyl cycloadduct 20.
stereogenic center, rather than diastereomer 22 (Scheme 3, inset),
which would result from allyl Grignard addition to the bottom face
of the same carbonyl as in the production of 20, as this is a very
unfavorable mode of addition for steric reasons.
A Heck coupling13 was then performed to install the aryl rings
found in the natural products (Scheme 4). These reactions pro-
ceeded readily with no detection of the (Z)-alkene. However, sepa-
ration of the minor regioisomer from the previous Grignard
addition step was still not achieved, so the combined material
was carried through to the final step.
With cycloadducts 25 and 27 in hand, the retro Diels–Alder
(rDA) cycloreversion was investigated. Previously, flash vacuum
pyrolysis at 400 °C was required to achieve good yields of product
and fully recover the chiral anthracene auxiliary.2b–f,3a,4 While
effective, this methodology is not attractive due to the special
nature of the apparatus needed as well as the extremely high tem-
perature. Refluxing in high boiling solvents has also been em-
ployed for rDA reactions from anthracene diene systems.2b–d,4,5b
However, recent reports have shown that microwave irradiation
in DMSO for 5 min has also been effective at promoting rDA reac-
tions.4,14 Using racemic cycloadduct 25 as a test substrate, several
conditions were screened to determine the optimal parameters for
cycloreversion (Table 1). At temperatures less than or equal to
Table 1
Condition screening for the cycloreversion
In conclusion, the syntheses of two anticancer natural products,
candenatenins B and C, have been achieved using a DA/rDA strat-
egy with a chiral anthracene auxiliary. The synthetic compounds
were produced in 90% ee and good yields over a 5-step linear se-
quence (42% and 33% overall yields for B and C, respectively).
Entry
Conditions
Solvent
% Conv.a
1
2
3
4
5
6
7
8
l
l
l
l
l
l
W, 75 °C, 300 W, 10 min
W, 85 °C, 300 W, 10 minb
W, 135 °C, 300 W, 20 min
W, 135 °C, 300 W, 20 minb
W, 180 °C, 200 W, 20 min
W, 230 °C, 150 W, 5 min
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
1,2-Dichlorobenzene
DMSO
0
10
20
60c
100
100
30
135 °C, 18 h
180 °C, 2.5 h
Chlorobenzene
1,2-Dichlorobenzene
80c
a
b
c
Based upon TLC and/or crude NMR analysis.
With 1.0 equiv Sc(OTf)3 additive.
Decomposition products also detected.
Scheme 5. Cycloreversion of cycloadducts 25 and 27.

1094
A. L. Jones et al. / Tetrahedron Letters 51 (2010) 1091–1094
A.; Snyder, J. K. Tetrahedron Lett. 2003, 44, 931; (f) Sanyal, A.; Snyder, J. K. Org.
Lett. 2000, 2, 2527.
3. For work from the Jones group: (a) Jones, S.; Valette, D. Org. Lett. 2009, 11,
5358; (b) Adams, H.; Bawa, R. A.; McMillan, K. G.; Jones, S. Tetrahedron:
Asymmetry 2007, 18, 1003; (c) Atherton, J. C. C.; Jones, S. Tetrahedron Lett. 2002,
43, 9097.
4. Liu, X. PhD Dissertation, Boston University, 2009.
5. (a) Rickborn, B. Org. React. 1998, 52, 1; (b) Chung, Y. S.; Duerr, B. F.; Nanjappan,
P.; Czarnik, A. W. J. Org. Chem. 1988, 53, 1334.
6. Knapp, S.; Ornaf, R. M.; Rodriques, K. E. J. Am. Chem. Soc. 1983, 105, 5494.
7. Cheenpracha, S.; Karalai, C.; Ponglimanont, C.; Kanjana-Opas, A. J. Nat. Prod.
2009, 72, 1395.
8. Adams, H.; Jones, S.; Ojea-Jiminez, I. Org. Biomol. Chem. 2006, 4, 2296.
9. Celebi-Olcum, N.; Sanyal, A.; Aviyente, V. J. Org. Chem. 2009, 74, 2328.
The sense of optical rotation of the synthesized compounds led to a
revision of the originally assigned stereochemistry of the natural
products. The high-yielding and highly selective nature of the
DA/rDA strategy employing chiral anthracene templates as stereo-
controlling elements make this an attractive methodology for
asymmetric synthesis. In this example, a facile synthesis of chiral
4-substituted cyclohexenones, which historically have proven
challenging to obtain in highly enantioenriched form,17 has been
achieved. Future plans are aimed at applying this methodology to
more complex natural products and natural product-based scaf-
folds, in particular focusing on cyclohexenones with stereogenic
centers at C4.
10. Determined by chiral HPLC using a chiralpak AD column (150 ꢀ 4.6 mm, 5
l
particle size), 0.5% isopropyl alcohol/99.5% hexanes as eluent at a flowrate of
1.0 mL/min, detection wavelength 214 nm. Retention times are as follows:
major enantiomer: 4.317 min; minor enantiomer: 4.730 min.
Acknowledgments
11. All isomeric ratios determined by crude NMR and/or UPLC.
12. Determined by 2D NMR spectroscopy in CDCl3: key HMBC correlations
between bridge proton H-3 (d 2.41) and allylic carbon C-7 (d 45.2) as well as
H-7 (d 2.47) and C-3 (d 52.7) established the regiochemistry of 20.
We are grateful to the NIGMS CMLD initiative (P50 GM067041)
for financial support, and also to the National Science Foundation
for supporting the purchase of the NMR (CHE 0619339) and HRMS
(CHE 0443618) spectrometers. A.L.J. would like to thank the Henry
Luce Foundation for a Clare Boothe Luce graduate fellowship.
References and notes
1. For reviews of early work on the use of chiral dienes in DA/rDA sequences: (a)
Winterfeldt, E. Chem. Rev. 1993, 93, 827; (b) Winterfeldt, E.; Borm, C.; Nerenz, F.
Adv. Asymmetry Synth. 1997, 2, 1; (c) Klunder, A. J. H.; Zhu, J.; Zwanenburg, B.
Chem. Rev. 1999, 99, 1163; For some examples since these reviews: (d)
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2003, 9, 3849; (e) Wolter, M.; Borm, C.; Merten, E.; Wartchow, R.; Winterfeldt,
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Fendert, T.; Proksch, P.; Winterfeldt, E. Tetrahedron 2000, 56, 4173; (h)
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Corbett, M. S.; Eugenio, P.; Lajkiewicz, N. J.; Liu, X.; Sanyal, A.; Yan, W.; Yuan, Q.;
Snyder, J. K. Bioorg. Med. Chem. 2005, 13, 5299; (c) Sanyal, A.; Yuan, Q.; Snyder,
J. K. Tetrahedron Lett. 2005, 46, 2475; (d) Burgess, K. L.; Lajkiewicz, N. J.; Sanyal,
A.; Yan, W.; Snyder, J. K. Org. Lett. 2005, 7, 31; (e) Corbett, M. S.; Liu, X.; Sanyal,
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15. Optical rotatory data: ent-14: ½a D
ꢁ
ꢂ64.2 (c 0.50, MeOH); ent-15 ½a D
ꢁ
ꢂ47.8 (c
0.50, MeOH). Literature values:7 14: ½a D
ꢁ
ꢂ64.7 (c 0.09, MeOH); 15: ½a D ꢂ38.2
ꢁ
(c 0.20, MeOH).
16. Lin, L.-C.; Shen, C.-C.; Shen, Y.-C.; Tsai, T. H. J. Nat. Prod. 2006, 69, 842.
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E.; Fuchs, P. L. J. Am. Chem. Soc. 2002, 124, 11093; (b) Dudley, G. B.; Takaki, K. S.;
Cha, D. D.; Danheiser, R. L. Org. Lett. 2000, 2, 3407; (c) Kozmin, S. A.; Rawal, V.
H. J. Am. Chem. Soc. 1999, 121, 9562; (d) Asaoka, M.; Aida, T.; Sonoda, S.; Takei,
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