Catalytic enantioselective total synthesis of (-)-platyphyllide and its structural revision

Article abstract of DOI:10.1021/jo1003746

Figure presented The catalytic asymmetric total synthesis of platyphyllide has been accomplished. A key highly substituted cyclohexene derivative has been obtained by the catalytic asymmetric Diels-Alder reaction of Danishefsky diene with an electron-deficient alkene. The Diels-Alder adduct was converted to a protected cyclohexane-1,3-dione in chiral form by catalytic Ito-Saegusa oxidation. Although the reported structure of platyphyllide was successfully synthesized, the optical rotation was opposite that of the natural compound. The absolute configuration of natural (-)-platyphyllide is revised to be a (6S,7S)-enantiomer.

Full text of DOI:10.1021/jo1003746

pubs.acs.org/joc
SCHEME 1. Asymmetric Diels-Alder Reaction Catalyzed by
Chiral Yb Complex
Catalytic Enantioselective Total Synthesis of
(-)-Platyphyllide and Its Structural Revision
Shiharu Hiraoka, Shinji Harada, and Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba
University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
nishida@p.chiba-u.ac.jp
Received March 3, 2010
chose Yb(OTf )3 as a central metal which is combined
with our original axially chiral ligands BINAMIDE or
BINUREA and amine.3 These complexes catalyzed the
Diels-Alder reaction in a highly diastereo- and enantio-
selective manner to give densely functionalized chiral cyclo-
hexenes (Scheme 1).
Although the Diels-Alder reaction using Danishefsky
diene often gave a mixture of adduct 3 and corresponding
enone, these cyclic silyl enol ethers (3) were isolated in a pure
form. Since there have been few examples of the direct use of
the silyl enol moiety and methoxy group,4 we studied nona-
flation5 followed by a variety of transition-metal-catalyzed
coupling reactions of the silyl enol ethers to expand the utility
of Diels-Alder adducts.3a In this paper, we report a new
synthetic utility of an oxygen functionality of Diels-Alder
adducts and its application to a catalytic asymmetric total
synthesis of platyphyllide.
The catalytic asymmetric total synthesis of platyphyllide
has been accomplished. A key highly substituted cyclohex-
ene derivative has been obtained by the catalytic asym-
metric Diels-Alder reaction of Danishefsky diene with an
electron-deficient alkene. The Diels-Alder adduct was
converted to a protected cyclohexane-1,3-dione in chiral
form by catalytic Ito-Saegusa oxidation. Although the
reportedstructureofplatyphyllide wassuccessfully synthe-
sized, the optical rotation was opposite that of the natural
compound. The absolute configuration of natural (-)-
platyphyllide is revised to be a (6S,7S)-enantiomer.
(-)-Platyphyllide is a norsesquiterpene lactone that was
isolated from Senecio platyphylloides in 1977 by Bohlmann
et al., who also determined its structure, including the
relative configuration.6
The asymmetric total synthesis of platyphyllide was ac-
complished by Kanematsu et al., who proposed the absolute
stereochemistry of (-)-platyphyllide as shown in Figure 1.
Their synthesis included an asymmetric reduction of the
racemic dienone 5 and subsequent separation of the corre-
sponding trans and cis isomers, as shown in Scheme 2.7
The Diels-Alder reaction is widely used in organic synth-
esis to construct substituted six-membered carbocycles. A
catalytic asymmetric version of this reaction has been studied
extensively and has been used in the enantioselective synth-
esis of natural compounds.1 Danishefsky diene2 is a well-
known substrate for the Diels-Alder reaction to give oxy-
gen-functionalized cyclohexenes and has been recognized as
a useful diene in organic synthesis. However, this reactive
diene has not been fully utilized due to its instability, which
limits the applicable reaction conditions. Thus, the develop-
ment of a catalytic Diels-Alder reaction of Danishefsky
diene has been a difficult problem. Recently, we developed
a catalytic asymmetric version of the Diels-Alder reaction
of Danishefsky diene with electron-deficient alkenes. We
(3) (a) Sudo, Y.; Shirasaki, D.; Harada, S.; Nishida, A. J. Am. Chem. Soc.
2008, 130, 12588. (b) Harada, S.; Toudou, N.; Hiraoka, S.; Nishida, A.
Tetrahedron Lett. 2009, 50, 5652.
(4) For examples of natural product syntheses or synthetic studies
without elimination of the alkoxy group of Danishefsky-type diene, see:
~
(a) Yamamoto, N.; Isobe, M. Tetrahedron 1993, 49, 6581. (b) Farina, F.;
Noheda, P.; Paredes, M. C. J. Org. Chem. 1993, 58, 7406. (c) Asenjo, P.;
~
Farina, F.; Martın, M. V.; Paredes, M. C.; Soto, J. J. Tetrahedron Lett. 1995,
36, 8319. (d) Asenjo, P.; Farina, F.; Martın, M. V.; Paredes, M. C.; Soto, J. J.
~
Tetrahedron 1997, 53, 1823. (e) Trotter, N. S.; Larsen, D. S.; Stoodley, R. J.;
Brooker, S. Tetrahedron Lett. 2000, 41, 8957. (f ) Kotha, S.; Stoodley, R. J.
Bioorg. Med. Chem. 2002, 10, 621. (g) Bourghli, L. M. S.; Stoodley, R. J.
Bioorg. Med. Chem. 2004, 12, 2863.
(5) Lyapkolo, I. M.; Webel, M.; Reibig, H.-U. Eur. J. Org. Chem. 2002,
67, 1015.
(6) (a) Bohlmann, F.; Knoll, K.-H.; Zdero, C.; Mahanta, P. K.; Grenz,
M.; Suwita, A.; Ehlers, D.; Le Van, N.; Abraham, W.-R.; Natu, A. A.
Phytochemistry 1977, 16, 965. (b) Bohlmann, F.; Eickeler, E. Chem. Ber.
1979, 112, 2811.
(7) Nagashima, S.; Ontsuka, H.; Shiro, M.; Kanematsu, K. Heterocycles
1995, 41, 245.
(1) For recent examples within 2009, see: (a) Shimizu, Y; Shi, S. -L.;
Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2010, 49, 1103.
(b) Dunn, T. B.; Ellis, J. M.; Kofink, C. C.; Manning, J. R.; Overman, L. E.
Org. Lett. 2009, 11, 5658. (c) Nicolaou, K. C.; Tria, G. S.; Edmonds, D. J.;
Kar, M. J. Am. Chem. Soc. 2009, 131, 15909. (d) Yamatsugu, K.; Yin, L.;
Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed.
2009, 48, 1070. (e) Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2009, 131, 13606. (f ) Tang, Y.; Cole, K. P.; Buchanan, G. S.; Li,
G.; Hsung, R. P. Org. Lett. 2009, 11, 1591 See also references cited therein.
(2) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807.
DOI: 10.1021/jo1003746
r
Published on Web 05/11/2010
J. Org. Chem. 2010, 75, 3871–3874 3871
2010 American Chemical Society

Hiraoka et al.
JOCNote
FIGURE 1. Proposed structure of (-)-platyphyllide.
FIGURE 2. Retrosynthetic analysis of dienone 5.
SCHEME 2. Synthetic Pathway and Determination of the
Absolute Configuration Reported by Kanematsu
SCHEME 3. Ito-Saegusa Oxidation of 3-Methoxy-1-silyloxy-
cyclohexenone 12
SCHEME 4. Synthesis of Intermediate 5
However, the enantiopurity of their compounds was not
reported at any stage in their synthetic pathway.
The absolute configuration was determined to be (6R,7R)
by X-ray analysis of p-bromobenzoyl derivative 10 of their
intermediate 9. This is the only chemical synthesis of chiral
platyphyllide to date.8
In the retrosynthesis of Kanematsu’s intermediate, our
Diels-Alder adduct 3 should be recognized as a starting
material (Figure 2).
this preliminary result, we began the total synthesis of opti-
cally active platyphyllide (4), as shown in Scheme 4.
Key β-methoxycyclohexenone 11 would be obtained
by the oxidation of Diels-Alder adduct 3. It is well-known
that the oxidation of silyl enol ethers to enones is promoted
by Pd(OAc)2 (Ito-Saegusa oxidation)9 or IBX-MPO.10
Although no example of oxidation of a silyl enol ether like
3 has been reported,11 a model study using chiral substrate 12
proceeded cleanly to give β-methoxyenone in 77% yield
without racemization by Ito-Saegusa oxidation (Scheme 3).
Sequential Diels-Alder reaction/oxidation of Danishefsky
diene derivatives is a new method for obtaining selectively
protected chiral cyclohexane-1,3-diones.12 Encouraged by
The asymmetric Diels-Alder reaction of TES-protected
diene 1a and dienophile 2a catalyzed by Yb(OTf )3/(S )-
BINAMIDE complex gave the adduct 12 (60% ee) in gram
scale.3a The nucleophilic attack of methyllithium to the
oxazolidinone group suffered from undesired ring-opening
of the oxazolidone unit to give a 1:1 mixture of the desired
tertiary alcohol 14 and byproducts. All efforts to transform
these byproducts to desired 14 were unsuccessful. Oxidation
of 14 to key intermediate 17 was achieved by Ito-Saegusa
oxidation in 90% yield. Moreover, the catalytic conditions of
this reaction reported by Larock et al.13 were also applicable
to give 17 in 63% yield using 10 mol % of Pd(OAc)2.14
Recrystallization of 17 gave optically pure 17 from the
filtrate after the removal of racemic crystals. β-Methoxye-
none 17 was then converted into reported dienone 5 by the
addition of Grignard reagent and subsequent acid treatment,
which achieved the formal synthesis of platyphyllide. How-
ever, compound 17 was unstable against racemization under
basic conditions and the enantiopurity of product 5 dropped
to 54% ee (ee was determined after conversion to 8 by HPLC
(8) For racemic syntheses of platyphyllide, see: (a) Hayakawa, K.;
Ohsuki, S.; Kanematsu, K. Tetrahedron Lett. 1986, 27, 947. (b) Ho, T. -L.;
Ho, M. -F. J. Chem. Soc., Perkin Trans. 1 1999, 1823.
(9) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(10) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.
Angew. Chem., Int. Ed. 2002, 41, 996.
(11) Successful examples of Ito-Saegusa or other oxidations with a
β-ethereal group have been limited to hydropyran- or hydrofuran-type
compounds; see: (a) Danishefsky, S. J.; Pearson, W. H. J. Org. Chem.
1983, 48, 3865. (b) Danishefsky, S. J.; Uang, B. J.; Quallich, G. J. Am. Chem.
Soc. 1985, 107, 1285. (c) Herrinton, P. M.; Klotz, K. L.; Hartley, W. M.
J. Org. Chem. 1993, 58, 678. (d) Evans, P. A.; Nelson, J. D. J. Org. Chem.
1996, 43, 7600. (e) Orellana, A.; Rovis, T. Chem. Commun. 2008, 730.
(12) This versatile building block has been constructed by the
Diels-Alder reaction of 1,1-dimethoxy-3-siloxy-1,3-butadiene or its deriva-
tives with alkenes. The Diels-Alder reaction of such dienes with alkyne or
quinone was also a very powerful method for synthesizing resorcinols.
However, they require several steps for preparation. For preparation, see:
(a) Banville, J.; Brassard, P. J. Chem. Soc. Perkin Trans. 1 1976, 1852. For
various conversions of the Diels-Alder adduct derived from the diene, see:
(b) Danishefsky, S.; Singh, R. K.; Gammill, R. B. J. Org. Chem. 1978, 43, 379.
(13) Larock, R. C.; Hightower, T.; Kraus, G. A.; Hahn, P.; Zheng, D.
Tetrahedron Lett. 1995, 36, 2423.
(14) The isomerized product 18 was obtained in 22% yield (containing
trace inseparable compound) at this step. So far, we do not have any
information about the mechanism of this isomerization. Further screenings
of the conditions to selectively give 18 and a mechanistic study are in
progress.
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Hiraoka et al.
JOCNote
SCHEME 5. Unexpected Total Synthesis of (þ)-ent-Platy-
SCHEME 6. Confirm the Absolute Configuration of Our
Diels-Alder Adduct
phyllide
as shown Scheme 6.17,18 The asymmetric Diels-Alder reac-
tion using (R)-BINAMIDE gave the adduct ent-12, which
should have the correct absolute configuration for the
synthesis of (-)-platyphyllide (ent-4), in 60% ee. The side
chain of ent-12 was reduced and protected by p-bromobenzoyl
group to give 22. Oxidation with DMDO and sequential desily-
lation gave the secondary alcohol as a single diastereomer, and
then (1R)-camphorsulfonyl group was introduced to the alcohol
and the major diastereomer 23 was separated. X-ray crystallo-
graphic analysis of 23 proved that the absolute configuration of
23 was as shown in Scheme 6,19 which is consistent with reported
assignment of the Diels-Alder adducts previously.
analysis). The slow addition of vinyl magnesium bromide
at -78 °C might cause racemization of the tertiary alkoxide
intermediate before the addition of Grignard reagent to
carbonyl.
Subsequent steps to platyphyllide are shown in Scheme 5.
First, the carbonyl group of dienone 5 was reduced
stereoselectively directed by the neighboring hydroxyl group
by sodium triacetoxyborohydride15 to give the desired trans
product in 3:1 selectivity, while Luche reduction predomi-
nantly gave the cis isomer (dr: 1/14). At this stage, both the
absolute and relative configurations of the two stereocenters
in platyphyllide were successfully controlled. Next, we tried
to shorten the steps to platyphyllide from 6, which required
eight steps in Kanematsu’s pathway.7 We introduced a
propargyl unit as reported by Kanematsu. Compound 8
and its diastereomer 19 were separated at this stage, and
the ee of 8 was confirmed at this stage by chiral HPLC.
The intramolecular Diels-Alder reaction proceeded quickly
under thermal conditions, and we also found aromatized
product 20 in the mixture of products. The Diels-Alder
reaction of 8 under an oxygen atmosphere gave 20 in 92%
yield with a one-pot process. The oxidation of benzyl ether
by ruthenium oxide16 gave the reported compound 9 in
moderate yield. Finally, a known elimination method gave
platyphyllide, and the total synthesis of platyphyllide was
achieved in four simple steps from 6.
Based on those studies, we revised the absolute configura-
tion of natural (-)-platyphyllide to be (6S,7S). Moreover, we
reconsidered Kanematsu’s procedure for determining the
absolute configuration (Scheme 2). They used CBS reduction
to obtain chiral diol 6 (ee: not reported) from racemic
dienone, and the absolute configuration was determined
later by X-ray analysis of p-bromobenzoyl derivative 10.
However, the reported optical rotation of propargyl inter-
mediate 8 (really ent-8) was [R]26 -24.3 (c 0.7, CHCl3),7
D
which is much lower than that of 8 in our synthesis; [R]24
D
þ76.3 (c 1.3, CHCl3, 54% ee). Thus, their compounds were
estimated to be 10-20% ee, and this may be associated with
the recrystallization of 10, such as undesired resolution or
contamination of the crystal derived from the minor enan-
tiomer.
Finally, we started the asymmetric total synthesis of nat-
ural (-)-platyphyllide. The Diels-Alder adduct ent-12 was
converted into ent-17 as described above. After the enantiopur-
ity of ent-17 was enriched to be 94% ee by recrystallization
(Scheme 7), vinyl Grignard reagent was added in one portion to
suppress racemization based on our hypothesis vide supra, to
give ent-5 in 90% ee. Diastereoselective reduction using borane-
THF complex gave the trans product selectively in 7:1 ratio.
Recrystallization of ent-6 gave racemic crystal, and almost pure
ent-6 (95% ee) was obtained from the mother liquor. Using the
procedure described above, we achieved the catalytic enantio-
selective total synthesis of natural (-)-platyphyllide (ent-4).
In conclusion, we have discovered a method for the
efficient conversion of the alkoxy silyl enol moiety in
Diels-Alder adduct using Danishefsky diene to a chiral
cyclohexane-1,3-dione equivalent by Ito-Saegusa oxida-
tion. This method was successfully applied to the catalytic
All of the spectral features (1H NMR, 13C NMR, IR,
and MS) of synthetic platyphyllide were indistinguishable
from those of natural platyphyllide, except that the optical
rotation was positive, which is opposite that of natural
(-)-platyphyllide. Furthermore, signs of optical rotation of
other intermediates 8 and 9 were also opposite to the
reported data.7
Therefore, we decided to reexamine the absolute config-
uration of the Diels-Alder adduct by X-ray crystallographic
analysis after condensation with a suitable chiral auxiliary,
(15) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(16) Schuda, P. F.; Cichowicz, M. B.; Heimann, M. R. Tetrahedron Lett.
1983, 24, 3829.
(17) We have previously determined the absolute configuration of
Diels-Alder adducts of our asymmetric reaction using (S)-BINAMIDE by
conversion to a known compound.3a For details, see the Supporting In-
formation.
(19) CCDC 773055 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(18) The absolute configuration of synthetic (þ)-platyphyllide was also
estimated by Mosher’s method. For details, see the Supporting Information.
J. Org. Chem. Vol. 75, No. 11, 2010 3873

Hiraoka et al.
JOCNote
SCHEME 7. Total Synthesis of Natural (-)-Platyphyllide
254 nm, tR: 35.1 min (major) and 36.6 min (minor)): 1H NMR
(CDCl3, 400 MHz) δ 0.69 (6H, q, J = 8.0 Hz), 0.98 (9H, t, J =
8.0 Hz), 1.65-1.74 (1H, m), 2.00-2.04 (2H, m), 2.29-2.37 (1H,
m), 3.30 (3H, s), 3.81 (1H, ddd, J = 3.0, 8.8 11.6 Hz), 3.98-4.12
(2H, m), 4.37-4.44 (2H, m), 4.70 (1H, d, J = 8.8 Hz), 5.00
(1H, s); 13C NMR (CDCl3, 100 MHz) δ 5.3, 7.0, 24.9, 29.5, 43.1,
44.0, 55.6, 62.2, 76.6, 103.2, 153.3, 153.4, 174.9; IR (neat) 1775,
1696, 1660 cm-1; LRMS(FAB) m/z 356 [M þ H]þ; HRMS-
(FAB) calcd for C17H30NO5Si 356.1893, found 356.1879; [R]25
D
þ45.8 (c 1.0, CHCl3, 60% ee). For the enantiomer ent-12 in
Scheme 7, [R]24D -61.9 (c 0.24, CHCl3, 60% ee).
(R)-4-(2-Hydroxypropan-2-yl)-3-methoxycyclohex-2-enone (17).
Ito-Saegusa Oxidation of 14. A solution of 14 (248 mg, 0.825
mmol) and Pd(OAc)2 (18.5 mg, 82.5 μmol) in DMSO (16.5 mL)
was stirred under O2 for 8 h. The solvent was distilled under
reduced pressure (0.1 mmHg) at 55 °C. The resulting residue was
purified by column chromatography (SiO2, AcOEt) to give 17
(94.3 mg, yield 62%) as a colorless solid and 18 (34.2 mg,
containing trace inseparable compound, yield <22%) as a color-
less oil.
Compound 17 (149 mg) was recrystallized from hexane/
AcOEt to give racemic 17 (53.4 mg, yield 36%) as a colorless
crystal and chiral 17 (93.8 mg, yield 63%) from the mother
liquor as a colorless oil. The enantiomeric excess was determined
to be >99.5% ee by HPLC analysis (Daicel Chiralpak IA,
hexane/iPrOH = 97/3, flow: 1.0 mL/min, 254 nm, tR: 48.7 min
(minor) and 50.5 min (major)). For the enantiomer ent-17
(Daicel Chiralpak AD-H, hexane/iPrOH = 97/3, flow: 1.0
mL/min, 254 nm, tR: 46.2 min (minor) and 48.3 min (major)):
1H NMR (CDCl3, 400 MHz) δ 1.25 (3H, s), 1.28 (3H, s),
1.79-1.88 (1H, m), 2.09-2.17 (1H, m), 2.26-2.39 (1H, m),
2.50-2.57 (1H, m), 2.64 (1H, dd, J = 5.8, 8.6 Hz), 3.08 (1H, s),
3.77 (3H, s), 5.50 (1H, s); 13C NMR (CDCl3, 100 MHz) δ 24.1,
26.1, 28.8, 35.4, 48.7, 55.8, 73.2, 104.6, 178.3, 199.2; IR(neat)
3391, 1590 cm-1; LRMS(FAB) m/z 185 [M þ H]þ; HRMS(FAB)
calcd for C10H17O3 185.1178, found185.1170; [R]23D -1.17 (c 1.0,
CHCl3, >99.5% ee). For the enantiomer ent-17 in Scheme 7,
[R]20D þ1.67 (c 0.95, CHCl3, 94% ee); mp 92.5-93.0 °C.
asymmetric total synthesis of (þ)- and (-)-platyphyllide.
The absolute configuration of natural (-)-platyphyllide was
revised to be (6S,7S) by our asymmetric total synthesis. The
absolute stereochemistry of the key intermediate obtained by
asymmetric Diels-Alder reaction using Danishefsky diene
was unambiguously determined by X-ray crystallographic
analysis.
Experimental Section
3-((1S,2S)-2-Methoxy-4-(triethylsilyloxy)cyclohex-3-enecarbo-
nyl)oxazolidin-2-one (12). Asymmetric Diels-Alder Reaction of
1a and 2a. A mixture of Yb(OTf )3 (535 mg, 0.863 mmol) and
(S)-BINAMIDE (584 mg, 1.04 mmol) in a flask with a stirring
bar was dried at 90 °C under reduced pressure (<0.1 mmHg)
for 0.5 h with stirring. After the mixture was allowed to cool to
room temperature, the flask wascharged with dry argon. CH2Cl2
(28.8 mL) and DBU (316 μL, 2.07 mmol) were successively
added, and the mixture was stirred for 2 h at room temperature.
Dienophile 2a (1.22 g, 8.64 mmol) in CH2Cl2 (14.4 mL) was
added at 0 °C. The mixture was immediately cooled to -20 °C,
diene 1a (4.15 mL, 17.2 mmol) was added dropwise, and the
mixture was stirred for 3 h at the same temperature. Water
(10 mL) was then added to quench the reaction, and the insoluble
materials were filtered through a pad of Celite. The water layer
was extracted three times with CH2Cl2, and the combined
organic layers were washed with brine and dried over Na2SO4.
After the volatile material was removed under reduced pressure,
the resulting residue was purified by column chromatography
(SiO2, hexane/AcOEt = 5/1) to give 12 (2.04 g, yield 66%) as a
colorless oil. The enantiomeric excess was determined to be 60%
ee by HPLC analysis after conversion to enone by TFA (Daicel
Chiralcel OJ-H, hexane/iPrOH = 60/40, flow: 0.75 mL/min,
Acknowledgment. We thank Professor Motohiro Aka-
zome at Chiba University for discussions about X-ray
crystallographic analysis. This work was supported by a
Grant-in-Aid for Scientific Research (B) and a Grant-in-
Aid for Young Scientists (B) from JSPS and MEXT.
Supporting Information Available: Experimental proce-
dures, spectral data, copies of 1H and 13C NMR spectra, HPLC
chart, and CIF (23). This material is available free of charge via
the Internet at http://pubs.acs.org.
3874 J. Org. Chem. Vol. 75, No. 11, 2010