Enantioselective synthesis of (+)-obolactone based on a symmetry-breaking wacker monooxidation of a diene

Article abstract of DOI:10.1021/ol400232m

A concise synthesis of the dihydro-α-pyrone/dihydro-γ-pyrone natural product (+)-obolactone (13) is disclosed. The dienediol acetonide 23 (≥97% ee) was obtained from 1,5-dichloropentane-2,4-dione in four steps. A Wacker monooxidation of 23 furnished the monoketone 24 in 64% yield. The OH group of the ensuing dihydro-γ-pyrone 31 was esterified under Mitsunobu conditions with cinnamic acid (→ 80% inversion and 20% retention of configuration). A ring-closing metathesis formed the dihydro-α-pyrone moiety of the target in the terminating step.

Full text of DOI:10.1021/ol400232m

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1294–1297
Enantioselective Synthesis of
(þ)-Obolactone Based on a Symmetry-
Breaking Wacker Monooxidation of a Diene
€
Patrick Walleser and Reinhard Bruckner*
€
Institut fu€r Organische Chemie, Albert-Ludwigs-Universitat, Albertstraße 21,
79104 Freiburg im Breisgau, Germany
reinhard.brueckner@organik.chemie.uni-freiburg.de
Received January 26, 2013
ABSTRACT
A concise synthesis of the dihydro-R-pyrone/dihydro-γ-pyrone natural product (þ)-obolactone (13) is disclosed. The dienediol acetonide 23
(g97% ee) was obtained from 1,5-dichloropentane-2,4-dione in four steps. A Wacker monooxidation of 23 furnished the monoketone 24 in 64%
yield. The OH group of the ensuing dihydro-γ-pyrone 31 was esterified under Mitsunobu conditions with cinnamic acid (f 80% inversion and 20%
retention of configuration). A ring-closing metathesis formed the dihydro-R-pyrone moiety of the target in the terminating step.
Ten years ago, a Gif-sur-Yvette team isolated the title
compound (13) from the trunk bark of a tropical tree
Scheme 1. Previous Total Syntheses3ꢀ5 of (þ)-Obolactone (13)a
(Cryptocarya obovata R. Br.) indigenous to northern
Vietnam.1 Obolactone acts against nasopharyngeal carci-
noma KB cells (IC50 = 3 μM) and against Trypanosoma
brucei brucei, which causes African sleeping sickness
(IC50 = 5.3 μM).2 The asymmetric unit of crystalline 13
(mp 116 °C) contained four distinct conformers according
to an X-ray analysis.1 The latter revealed two stereo-
centers, either R,R or S,S configured, one dihydro-
R-pyrone ring, and one dihydro-γ-pyrone moiety.1
The CD spectrum showed that the correct assignment
was R,R.1
She et al. reported the first total synthesis of (þ)-
obolactone (11 steps).3 Total syntheses by Shabita et al.
(17 steps)4 and Krishna et al. (16 steps)5 followed.
(1) Dumontet, V.; Hung, N. V.; Adeline, M.-T.; Riche, C.; Chiaroni,
ꢀ
ꢀ
A.; Sevenet, T.; Gueritte, F. J. Nat. Prod. 2004, 67, 858–862.
(2) Davis, R. A.; Sykes, M. L.; Avery, V. M.; Suraweera, L.; Fechner,
G. A.; Quinn, R. J.; Demirkiran, O. Bioorg. Med. Chem. Lett. 2010, 20,
4057–4059.
(3) Zhang, J.; Li, Y.; Wang, W.; She, X.; Pan, X. J. Org. Chem. 2006,
71, 2918–2921.
a Σ = TBDPS = tert-butyldiphenylsilyl; σ = TBS = tert-butyldi-
methylsilyl; Bn = benzyl; PMB = p-methoxybenzyl; THP = tetrahy-
dropyran-2-yl.
(4) Sabitha, G.; Prasad, M. N.; Shankaraiah, K.; Yadav, J. S.
Synthesis 2010, 7, 1171–1175.
(5) Steps 1ꢀ4: Wu, Y.; Esser, L.; De Brabander, J. K. Angew. Chem.,
Int. Ed. 2000, 39, 4308–4310. Wu, Y.; Esser, L.; De Brabander, J. K.
Angew. Chem. 2000, 112, 4478–4480. Steps 5ꢀ16: Krishna, P. R.;
Srinivas, P. Tetrahedron Lett. 2010, 51, 2295–2296.
As Scheme 1 summarizes all approaches aimed at syn-
1,3-diol monoethers first, i.e., the silyl ether 5, the tetra-
hydropyran 6, and the silyl ether 7. Another common
r
10.1021/ol400232m
Published on Web 03/01/2013
2013 American Chemical Society

feature was the use of styryl methyl ketone (10) for
introducing the phenyl ring and establishing the dihy-
dro-γ-pyrone moiety thereafter. The dihydro-R-pyr-
one stemmed either from a ring-closing metathesis of
acrylate 113,4 or from the lactonization of the silylated
seco-ester 12.5
Scheme 3. Modified Wacker Monooxidation of Nona-1,8-diene
197 and a Wacker-Type Monooxidation/Methoxycarbonyla-
tion of Nona-1,8-dienediol ent-159
Scheme 2. Retrosynthetic Analysis of (þ)-Obolactone (13).
Identifying the Anti-Configured 1,3-Diol 15 as a Precursor and
Preparing it via a Three-Step Route10 Rather than by a One-
Step Access12
Following a three-step sequence by Rychnovsky et al.,10
the anti-configured 1,3-diol 15 was synthesized from 1,5-
dichloropentane-2,4-dione (16) in 60% overall yield (lit.10
51%) and with g97% ee11 (Scheme 2). Krische et al.
published an intriguing one-step synthesis of the same
1,3-diol enantiomer 15 from propane-1,3-diol.12 We repro-
duced their reaction but abandoned it upon scale-up because
of the high costs for the catalyst (5 mol % of [Ir(cod)Cl]2)
and the ligand [10 mol % of 2,20-bis(diphenylphosphino)-
5,50-dichloro-6,60-dimethoxy-1,10-biphenyl].
In our retrosynthetic analysis (Scheme 2, top row), (þ)-
obolactone (13) was traced back to an anti-configured 1,3-
diol, namely compound 14. The latter also represents a
methyl ketone. This feature suggested that it might be
accessible from a Wacker oxidation.6 Ideally, the latter
would act on the anti-configured dienediol 15. The chal-
lenge in transforming 15 into 14 was to oxidize one CdC
bond while leaving the other CdC bond intact. This
defined the key step of our approach. Converting anti-diol
14 into target 13 would entail cinnamoylation, dihydro-γ-
pyrone formation with retention of configuration, acry-
loylation with inversion of configuration, and dihydro-R-
pyrone formation by metathesis.
Scheme 4. Nona-1,8-diene-4,6-diol 15 and the Corresponding
Acetonide (23) in Symmetry-Breaking Wacker Monooxidations
The desired Wacker monooxidation of nona-1,8-diene-
diol 15 had little literature precedence (Scheme 3). The
monooxidation of the parent diene 19 succeeded in 40%
yield7 under nonclassical8 conditions. In a Wacker-type
etherification/methoxycarbonylation, nona-1,8-dienediol
ent-15 gave the THP-containing methyl ester 21 in twice
the yield.9 This gradation is plausible expecting that 20
should be as susceptible as 19 to CdC oxidation whereas
21, due to an increase of ring strain, should not.
Attempted Wacker monooxidations of the unprotected
dienediol 15 under an atmosphere of O2 in the presence of
PdCl2 (10mol %) and CuCl (1.0 equiv) failed(Scheme4).13
They delivered neither the monoketone-containing 1,3-diol
14 nor the corresponding hemiketal 22. Protecting the
hydroxy groups of dienediol 15 with dimethoxypropane
provided the acetonide 23 in 95% yield.14 Under the
(6) Reviews: (a) Henry, P. M. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley & Sons: New
York, 2002; pp 2119ꢀ2139. (b) Takacs, J. M.; Jiang, X.-t. Curr. Org.
Chem. 2003, 7, 369–396. (c) Hintermann, L. In Transition Metals for
Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, 2004; Vol. 2, pp 379ꢀ388. (d) Hintermann, L. In Handbook
of CꢀH Transformations: Applications in Organic Synthesis; Dyker, G.,
Ed.; Wiley-VCH: Weinheim, 2005; pp 287ꢀ298. (e) Cornell, C. N.;
Sigman, M. S. Inorg. Chem. 2007, 46, 1903–1909.
(7) Zweni, P. P.; Alper, H. Adv. Synth. Catal. 2004, 346, 849–854.
(8) Review: Michel, B. W.; Sigman, M. S. Aldrichimica Acta 2011, 44,
55–62.
(9) Yang, Z.; Zhang, B.; Zhao, G.; Ynag, J.; Xie, X.; She, X. Org.
Lett. 2011, 13, 5916–5919.
(11) Initially, the enantiopurity of diol 17 was assessed by compar-
ing its specific rotation [[R]20 = þ23.0 (c = 0.88, CHCl3)] to the
D
published value [[R]24 = þ21.1 (c = 1.13, CHCl3)10a]. The specific
D
rotation of diol 15 [[R]20D = þ27.7 (c = 0.32, CHCl3)] is missing in refs
10a and 12; [R]24 = þ35.0 (c = 1.00, CHCl3) is published in the
D
Supporting Information of: Lu, Y.; Krische, M. J. Org. Lett. 2009, 11,
3108–3111. The absolute value of the specific rotation of follow-up
product (þ)-obolactone (13) superceded that of other synthetic
specimens2ꢀ4 but lagged that of natural 13.1 This led us to believe that
our ee was in the upper 90% percentile rank.
(12) Lu, Y.; Kim, I. S.; Hassan, A.; Del Valle, D. J.; Krische, M. J.
Angew. Chem., Int. Ed. 2009, 48, 5018–5021. Lu, Y.; Kim, I. S.; Hassan,
A.; Del Valle, D. J.; Krische, M. J. Angew. Chem. 2009, 121, 5118–5121.
(13) Procedure: Li, D.-R.; Zhang, D.-H.; Sun, C. Y.; Zhang, J.-W.;
Yang, L.; Chen, J.; Liu, B.; Su, C.; Zhou, W.-S.; Lin, G.-Q. Chem.;Eur.
J. 2006, 12, 1185–1204.
(10) (a) Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky, D.
J. Org. Chem. 1991, 56, 5161–5169. (b) Rychnovsky, S. D.; Yang, G.;
Hu, Y.; Khire, U. R. J. Org. Chem. 1997, 62, 3022–3023.
Org. Lett., Vol. 15, No. 6, 2013
1295

previously sketched conditions, this substrate underwent
a Wacker monooxidation furnishing the monoketone 24
in 64% yield (Scheme 4). An 18% yield of the undesired
diketone 25 resulted as well. These percentages arose after
the reaction was monitored by TLC and the reaction
mixture worked up when the monoketone was deemed to
be the most prominent constituent. Compound 25 eluted
later than 24 during purification by column flash chro-
matography on silica gel.15
NEt3 for 30 min.17 Addition to cinnamaldehyde (26) led to
the β-hydroxyketone(s) 29 in 70% yield. Oxidation with
IBX18 rendered the enol-3019 of the desired diketone keto-
30 (99% yield).20 The dihydro-γ-pyranone 31 was completed
in 75% yield by a pTsOH H2O-induced cyclodehydration.
3
Scheme 6. Converting the Homoallyl Alcohol Moiety of Inter-
mediate 31 into the Dihydro-R-pyranone Moiety of (þ)-Obo-
lactone (13). Competition between Mitsunobu Inversion (f 33)
and “Mitsunobu Esterification” (f epi-33) in the Cinnamate-
Forming Step
Scheme 5. Elaborating the Wacker Monooxidation Product 24
into the Dihydro-γ-pyranone Moiety of (þ)-Obolactone (13)
In order to establish the dihydro-γ-pyranone moiety of
(þ)-obolactone (13), we had to cinnamoylate the kinetic
enolateof monoketone 24(Scheme 5). However, treatment
of 24 with LDA or LiHMDS followed by addition of
cinnamoyl chloride (27)16 or of the Weinreb amide 28 of
cinnamic acid provided none of the desired diketone keto-
30 or a tautomeric enol. We avoided this difficulty by an
aldolization/oxidation sequence. The dibutylboron eno-
late of monoketone 24 formed with the desired regioselec-
tivity upon exposure to 1.1 equiv of both Bu2BOTf and
In order to ensure the syn-orientation of the C,O bonds
in (þ)-obolactone (13), the anti-configured homoallylic
alcohol 31 was to be combined with an R,β-unsaturated
carboxylic acid under Mitsunobu conditions21 (Scheme 6,
top). The standard inducers PPh3/DEAD or PPh3/DIAD
(20) Procedure: More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001–
3003.
(21) Reviews: (a) But, T. Y. S.; Toy, P. H. Chem. Asian J. 2007, 2,
1340–1355. (b) Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P.;
Swamy, K. C. K. Chem. Rev. 2009, 109, 2551–2651.
(14) Krische et al. synthesized the acetonide 23 from the 1,3-diol 15,
Me2C(OMe)2 (15 equiv), and pyridinium p-toluenesulfonate (10 mol %)
in CH2Cl2 in 91% yield.12
(22) ADDP (azodicarboxylic acid dipiperidide) was prepared as
described byMakriyannis, A.; Swissman, E. E. J. Org. Chem. 1973, 38,
1652-1557.
(15) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–
2925.
(16) Diketone formation from lithium enolates and acyl chlorides has
been rarely described, e.g.: (a) Mayweg, A. V. W.; VanDeusen, C.;
Wender, P. A. Org. Lett. 2003, 5, 277–279. (b) Koehler, M. F. T.;
Sendzik, M.; Wender, P. A. Org. Lett. 2003, 5, 4549–4552.
(17) Procedure: Cote, B.; Coleman, P. J.; Connell, B. T.; Evans, D. A.
J. Am. Chem. Soc. 2003, 125, 10893–10898.
(18) Reviews: (a) Zhdankin, V. V. Curr. Org. Synth. 2005, 2, 121–145.
(b) Satam, V.; Harad, A.; Rajule, R.; Pati, H. Tetrahedron 2010, 66,
7659–7706. (c) Kirsch, S. F.; Duschek, A. Angew. Chem., Int. Ed. 2011,
50, 1524–1552. Kirsch, S. F.; Duschek, A. Angew. Chem. 2011, 123,
1562–1590.
(19) The isolated enol (δCHdC(OH) = 5.70, δOH = 15.3 ppm; δCHd
C(OH) = 175.9, δCHdC(OH) = 99.6, δCdO = 196.7 ppm) possessed structure
enol-30 rather than iso-enol-30 because HMBC cross-peaks related 40-H
(δ =4.31ppm) toδCdO (C-2) and 6-H (δ=7.60ppm) toδCHdC(OH) (C-4).
60-H (δ = 3.89 ppm) and these 13C nuclei entertained no cross-peak.
(23) Conditions from Yamamiya, Y.; Kuwamura, Y.; Ito, S.; Tsunoda,
T. Tetrahedron Lett. 1995, 36, 2529–2530. Note that we employed ADDP
(ref 22) instead of TMAD (N,N,N0,N0-tetramethylazodicarboxamide).
(24) This eluent was found abandoning efforts to separate the
mixture of diastereomeric crotonates, which we had obtained from a
condensation of the homoallylic alcohol 31 and trans-crotonic acid
under Mitsunobu conditions. The analogous acrylates did not result
under similar conditions.
(25) Grynkiewicz, G. Rocz. Chem. 1976, 50, 1449–1451.
(26) Farina, V. Tetrahedron Lett. 1989, 30, 6645–6648.
(27) β-Hydroxylactones are amenable to competing OH and CO2H
€
activations in the presence of PPh3 and DEAD, too: Bruntrup, G.;
Chucholowski, A.; Mulzer, J. Angew. Chem., Int. Ed. Engl. 1979, 18,
€
622–623. Bruntrup, G.; Chucholowski, A.; Mulzer, J. Angew. Chem.
1979, 91, 654–655.
(28) Recent reviews: (a) Vougioukalakis, G. C.; Grubbs, R. H. Chem.
Rev. 2010, 110, 1746–1787. (b) Majumdar, K. C.; Chattopadhyay, B.;
Ray, K. Curr. Org. Synth. 2010, 7, 153–176. (c) Cossy, J.; Arseniyadis, S.;
Meyer, C. Metathesis in Natural Product Synthesis; Wiley-VCH: Wein-
heim, 2010. (d) Prunet, J. Eur. J. Org. Chem. 2011, 3634–3647. (e) Kotha,
S.; Dipak, M. K. Tetrahedron 2012, 68, 397–421.
1296
Org. Lett., Vol. 15, No. 6, 2013

of such a transformation were unable to join 31 and
cinnamic acid (32), though. In contrast the combination
PBu3/ADDP22 gave the desired cinnamate 33 in 59%
yield.23 Surprisingly, the diasteromeric cinnamate epi-33
was obtained, too (15% yield). 33 and epi-33 were separated
by flash chromatography on silica gel.15 Employing toluene/
EtOAc as the mobile phase24 33 eluted first.
64% of the hitherto unknown (þ)-epi-obolactone (epi-13).
Starting from 1,5-dichloropentane-2,4-dione (16) our routes
totaled 10 steps. The overall yields were 9% obolactone30 (lit.3
15%, lit.4 2%, lit.5 9%) and 9% epi-obolactone.
The syn,anti-pairs 13/epi-13 and 33/epi-33 reveal a 13C
NMR difference shared by a variety of O,O-diprotected
1,3-diols RCH2C1H(OR1)C2H2C3H(OR3)CH2R0:Thesum
of the 13C NMR shifts of nuclei C-1 and C-3 is higher in the
syn- than in the anti-isomer (Scheme 8). In 1,3-diols and
O-monoprotected 1,3-diols the same 13C NMR criterion
allows to distinguish syn- and anti-configurations safely.31
Hydrogen bonding between the 1-OH and the 3-OR or
3-OH group was considered a prerequisite for this NMR
effect.31 This appeared plausible because it implies a clear
conformational bias.31 While the protected 1,3-diols of
Having a configurationally inverted CꢀO bond, the
major cinnamate 33 must have formed after activation of
the OH group of the homoallyl alcohol 31, the overall
reaction being a Mitsunobu inversion. The minor cinna-
mate epi-33 retained the CꢀO bond configuration of its
predecessor 31 (which became clear when esterification of
31 with cinnamoyl chloride, NEt3, and DMAP yielded epi-
33, too). This meant that under Mitsunobu conditions
cinnamate epi-33 formed after activation of the CO2H
group (of the carboxylic acid 31), the overall process
representing a kind of “Mitsunobu esterification”. There
seems to be scarce precedence for such configurationally
retentive esterifications. The acetate 35 formed from the
secondary alcohol 34 without the epimer, which would
haveemerged from a “Mitsunobu inversion“ (Scheme 7).25
Acetate 37 emerged from a “Mitsunobu esterification“ of
the secondary alcohol 36 with a 70:30 preference over the
Mitsunobu inversion product epi-37.26,27
Scheme 8 lack hydrogen bonds the gradient (δC‑1 þ δC‑3 syn
)
> (δC‑1 þ δC‑3 anti
)
persists, possibly because 1,3-spaced
OR substituents favor different backbone conformers.32
Mono-Wacker oxidations of 1,ω-dienes have been
rarely used synthetically. The success of our application
should encourage other workers to consider it a worth-
while option.33
Scheme 8. Tentative Criterion for Differentiating syn- and anti-
Configured O,O-Diprotected 1,3-Diols
Scheme 7. Ester Formations under Mitsunobu Conditions with
Retention of the Configuration of the CꢀO Bond: Precedents
for the “Mitsunobu Esterification” 31 f epi-33 (Scheme 6)
The terminating step of our approach to (þ)-obolactone
(13) was a ring-closing metathesis28 of the homoallylic cinna-
mate 33 (Scheme 6, bottom).29 Employing 5 mol % of the
Grubbs II catalyst 13 resulted in 71% yield. Under the same
conditions the epimeric cinnamate epi-33 ring-closed to give
€
Acknowledgment. We thank Dr. M. Keller (Institut fur
Organische Chemie, Universitat Freiburg) for NMR spec-
tra and the IRTG 1038 (DFG) for financial support.
€
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of NMR spectra,
Table Supplement to Scheme 8, and complete citation for
ref 33. This material is available free of charge via the
Internet at http://pubs.acs.org.
(29) Ring-closing metatheses of cinnamates yielding dihydro-R-pyra-
nones: (a) Chandra, J. S.; Reddy, M. V. R.; Ramachandran, P. V.
J. Org. Chem. 2002, 67, 7547–7550. (b) Garcı
Carda, M.; Marco, J. A. Org. Lett. 2003, 5, 1447–1449. (c) Murga, J.;
Garcıa-Fortanet, J.; Carda, M.; Marco, J. A. J. Org. Chem. 2004, 69, 7277–
7283. (d) Dıaz-Oltra, S.; Murga, J.; Falomir, E.; Carda, M.; Marco, J. A.
´
a-Fortanet, J.; Murga, J.;
´
´
Tetrahedron 2004, 60, 2979–2985. (e) Kiran, I. N. C.; Reddy, R. S.;
Suryavanshi, G.; Sudalai, A. Tetrahedron. Lett. 2011, 52, 438–440.
(30) The specific rotation of our obolactone was [R]20D = þ262 (c =
0.15, CHCl3). This equals the average value of the natural product
[[R]20D = þ286 (c = 1.12, CHCl3)]1 and the earlier synthetic specimens:
[R]25D = þ243 (c = 1.35, CHCl3),3 [R]25D = þ252 (c = 1.20, CHCl3),4
and [R]25D = þ260 (c = 0.16, CHCl3).5 Our obolactone exhibited mp
115ꢀ117 °C, which matches the previously reported values of 116 °C1
and 116ꢀ118 °C.3,5
(33) Selected examples of Wacker-type reactions in natural product
synthesis: (a) Kuramochi, A.; Usuda, H.; Yamatsugu, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 14200–14201. (b) Liao, X.;
Zhou, H.; Wearing, X. Z.; Ma, J.; Cook, J. M. Org. Lett. 2005, 7, 3501–
3504. (c) Paterson, I.; Razzak, M.; Anderson, E. A. Org. Lett. 2008, 10,
3295–3298. (d) Fleck, M.; Bach, T. Angew. Chem., Int. Ed. 2008, 47, 6189–
6191. Fleck, M.; Bach, T. Angew. Chem. 2008, 120, 6284–6286. (e) Deng, J.;
Zhu, B.; Lu, Z.; Yu, H.; Li, A. J. Am. Chem. Soc. 2012, 134, 920–923. For a
more extensive list of related references, see the Supporting Information.
(31) Hoffmann, R. W.;Weidmann, U. Chem. Ber. 1985, 118, 3980–3992.
(32) Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054–2070.
Hoffmann, R. W. Angew. Chem. 2000, 112, 2134–2150.
The authors declare no competing financial interest.
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