First enantioselective total synthesis of (+)-(R)-pinnatolide using an asymmetric domino allylation reaction

Article abstract of DOI:10.1021/ol301932d

An efficient total synthesis of (+)-(R)-Pinnatolide is described. As a key step an asymmetric multicomponent domino allylation reaction of methyl levulinate is used to form the quaternary stereogenic center in a highly selective way.

Full text of DOI:10.1021/ol301932d

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4035–4037
First Enantioselective Total Synthesis of
(þ)‑(R)‑Pinnatolide Using an Asymmetric
Domino Allylation Reaction
Lutz F. Tietze,*,† Thomas Wolfram,† Julian J. Holstein,‡ and Birger Dittrich‡
€
Institute of Organic and Biomolecular Chemistry, Georg-August-University of Gottingen,
Tammannstr. 2, D-37077 Gottingen, Germany, and Institute of Inorganic Chemistry,
€
€
Georg-August-University of Gottingen, Tammannstr. 4, D-37077 Gottingen, Germany
€
ltietze@gwdg.de
Received July 12, 2012
ABSTRACT
An efficient total synthesis of (þ)-(R)-Pinnatolide is described. As a key step an asymmetric multicomponent domino allylation reaction of methyl
levulinate is used to form the quaternary stereogenic center in a highly selective way.
In 1991, Bohlmann et al. isolated the isoprenoide
Pinnatolide (1) from the aerial parts of the Athanasia
species, e.g. A. pinnata or A. crithmifolia, and determined
its constitution, however without giving the absolute con-
figuration of the stereogenic center (Figure 1).1 Unfortu-
nately, neither the optical rotation nor a CD spectrum of
the natural product is available.
The asymmetric allylation of ketones is still an impor-
tant field of research.3 Whereas several selective methods
for aryl and R,β-unsaturated alkyl ketones are known,4 for
the allylation of saturated alkyl ketones our procedure is
still the only one which gives high selectivities with the
advantage of forming the corresponding ethers of the ob-
tained tertiary alcohols in a domino process with a benzyl
protecting group. As starting material for the synthesis of 1
the commercially available methyl levulinate (2) and the
trimethylsilyl ether of (R)-phenylbenzylcarbinol5 (4) as a
chiral inductor were employed. The new auxiliary 4 has
several advantages over the norpseudoephedrine derived
auxiliary6 which has been previously used by us. Thus, it
can easily be obtained via an enantioselective reduction of
Figure 1. (þ)-(R)-Pinnatolide (1).
Here we describe the first stereoselective synthesis of
(þ)-(R)-Pinnatolide (1) using the auxiliary mediated multi-
component domino allylation reaction of aliphatic methyl
ketones developed in our group.2
(2) Tietze, L. F.; Kinzel, T.; Brazel, C. Acc. Chem. Res. 2009, 42, 367.
(3) Reviews: (a) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763.
(b) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
(4) (a) Wooten, A. J.; Kim, J. G.; Walsh, P. J. Org. Lett. 2007, 9, 381.
(b) Kii, S.; Maruoka, K. Chirality 2003, 15, 68. (c) Wada, R.; Oisaki, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8910. (d) Wadamoto,
M.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 14556. (e) Miller, J. J.;
Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 2752. (f) Barnett, D. S.;
Moquist, P. N.; Schaus, S. E. Angew. Chem., Int. Ed. 2009, 48, 8679.
(5) Tietze, L. F.; Kinzel, T.; Wolfram, T. Chem.;Eur. J. 2009, 15, 6199.
† Institute of Organic and Biomolecular Chemistry.
‡ Institute of Inorganic Chemistry.
(1) Bohlmann, F.; Zdero, C.; Lehmann, L. Phytochemistry 1991, 30,
1161.
r
10.1021/ol301932d
2012 American Chemical Society
Published on Web 08/02/2012

benzylphenylketone, and the phenylbenzyl moiety in the
allylation product is an excellent protecting group, which
can be removed either by hydrogenolysis or under Birch
conditions.7 In the Supporting Information an improved
procedure is described for the synthesis of 4 with an
enantiomeric excess of >99%.
γ-lactone aldehyde (R)-8 but the γ-lactone alcohol (R)-9.9
Though 9 can easily be transformed into 8 by oxidation,
the obtained isolated yield of 55% in the deprotection step
was not satisfactory (Scheme 2).
Scheme 2. Deprotection by Using Hydrogenolysis
Scheme 1. Asymmetric Multicomponent Allylation Reaction
Treatment of 2 with allyltrimethylsilane (3) in the pre-
sence of the auxiliary 4 (>99% ee) and catalytic amounts
of triflic acid in dichloromethane at ꢀ78 °C afforded the
homoallylic ether (R,R)-6 in 91% yield with a diastereos-
electivity of 94:6 (Scheme 1).
The reaction proceeds via an intermediary formed ox-
eniumion which is favorably attacked by the allylsilane
3 from the si-face.8 Exemplarily, the most favored syn-
clinal transition state 5 is shown in Scheme 1. The well-
established inducing effect of the auxiliary 4 can be explained
by the higher steric demand of the phenyl group compared to
the benzyl group.
As the next step in the synthesis of 1, a mixture of
the homoallylic ether (R,R)-6 and its minor epimer was
ozonolyzed atꢀ78 °C in dichloromethane/methanol (10:1)
with triphenylphosphin as a peroxide scavenger to afford
the corresponding diastereomeric mixture of aldehyde 7
in 98% yield. However, hydrogenolytic deprotection of
7 using the H-Cube with 10% palladium on a charcoal
cartridgeas the catalyst, a hydrogen pressureof80bar, and
methanol as the solvent at 45 °C gave not the desired
We therefore performed a reductive workup of the
mixture obtained by ozonolysis of 6 and its epimer using
sodium borohydride in methanol to afford the alcohol
(R,R)-10 together with its isomer in 98% yield (dr 94:6). Since
the mixture of epimers could not be separated by chroma-
tography, the dinitrobenzoates were prepared using 3,
5-dinitrobenzoyl chloride (DNBCl), triethylamine, and cat-
alytic amounts of N,N-dimethylaminopyridine (DMAP)
in dichloromethane at ambient temperature. Recrystalliza-
tion afforded (R,R)-11 in 82% yield as a single stereoisomer
(Scheme 3). Furthermore, the absolute configuration of
(R,R)-11 could be confirmed by single crystal X-ray analysis.10
Solvolysis of (R,R)-11 in a dichloromethane/methanol
mixture in the presence of catalytic amounts of lithium
Scheme 3. Purification of 10
€
(6) (a) Tietze, L. F.; Dolle, A.; Schiemann, K. Angew. Chem., Int. Ed.
1992, 31, 1372. (b) Tietze, L. F.; Schiemann, K.; Wegner, C. J. Am.
Chem. Soc. 1995, 117, 5851. (c) Tietze, L. F.; Wegner, C.; Wulff, C.
Synlett 1996, 471. (d) Tietze, L. F.; Wegner, C.; Wulff, C. Eur. J. Org.
€
Chem. 1998, 1639. (e) Tietze, L. F.; Weigand, B.; Volkel, L.; Wulff, C.;
€
Bittner, C. Chem.;Eur. J. 2001, 7, 161. (f) Tietze, L. F.; Volkel, L.;
€
Wulff, C.; Weigand, B.; Bittner, C.; McGrath, P.; Johnson, K.; Schafer,
€
M. Chem. Eur. J. 2001, 7, 1304. (g) Tietze, L. F.; Holsken, S.; Adrio, J.;
Kinzel, T.; Wegner, C. Synthesis 2004, 2236.
(7) (a) Birch, A. J J. Am. Chem. Soc. 1944, 430. (b) Rabideau, P. W.;
Marcinow, Z. Org. React. 1992, 42, 1. (c) Ammonia-free (LiDBB):
(i) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924.
(ii) Donohoe, T. J.; House, D. J. Org. Chem. 2002, 67, 5015.
(8) (a) Tietze, L. F.; Schmatz, S.; Kinzel, T. J. Am. Chem. Soc. 2006,
128, 11483. (b) Tietze, L. F.; Kinzel, T.; Schmatz, S. J. Am. Chem. Soc.
2008, 130, 4386.
(9) (R)-9 is a known compound and was obtained from the natural
product nerol: (a) Ichihara, A.; Miki, S.; Kawagishi, H.; Sakamura, S.
Tetrahedron Lett. 1989, 30, 4551. (b) Kayser, M. M.; Clouthier, C. M.
J. Org. Chem. 2006, 71, 8424.
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Org. Lett., Vol. 14, No. 16, 2012

Scheme 4. Final Steps of the Total Synthesis
hydroxide at ambient temperature gave back the diaste-
reopure alcohol (R,R)-10 in quantitative yield.
It followed a hydrogenolysis using catalytic amounts of
palladium on charcoal in THF/methanol at a hydrogen
pressure of 1 atm and 45 °C to afford the γ-lactone alcohol
(R)-9 in quantitative yield and >99% ee (Scheme 2).
Mild oxidation of (R)-9 with Dess-Martin periodinane
(DMP)11 in dichloromethane at 0 °C gave the labile γ-lactone
aldehyde 8, which was not further purified but directly
treated with the commercially available dimethylvinyl
Grignard reagent 12 in THF at ꢀ60 °C to afford the allylic
alcohol (5R)-13 in 40% yield over two steps as an approxi-
mately 1:1 mixture of epimers (Scheme 4). An elimination
and readdition with the intermediary formation of an R,
β-unsaturated aldehyde from 8 causing the loss of its
stereointegrity were not observed.
Figure 2. CD and UV spectrum of (þ)-Pinnatolide (1).
(þ)-(R)-Pinnatolide (1) in 90% yield. The enantiopurity
was verified by analytical HPLC on chiral support to be
>99%. Figure 2 shows the recorded CD and UV spectra
of (þ)-(R)-1.
In summary, we have developed an efficient synthesis of
enantiopure (þ)-(R)-Pinnatolide (1) using an asymmetric
multicomponent domino allylation reaction as the key step.
Acknowledgment. Wewould liketothank theDFG and
the Fonds der Chemischen Industrie for financial support.
Finally, DMP oxidation of the diastereomeric mixture
(5R)-13 in dichloromethane at ambient temperature led to
Supporting Information Available. Experimental pro-
cedures and full analytic data for all compounds as well as
the crystallographic data of (R,R)-11. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(10) Figure and crystallographic data of dinitrobenzoate 11 are
presented in the Supporting Information.
(11) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c)
Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. (d) Boeckman,
R. K., Jr.; Shao, P.; Mullins, J. J. Org. Synth. 2000, 77, 141.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
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