Synthesis of labdane diterpenes galanal A and B from (+)-sclareolide

Article abstract of DOI:10.1021/ol501121v

The first chemical synthesis of galanal A and B was achieved by a concise and highly efficient pathway starting from commercially available (+)-sclareolide and features a Wittig reaction and a titanocene-mediated radical cyclization as the key steps.

Full text of DOI:10.1021/ol501121v

Letter
pubs.acs.org/OrgLett
Synthesis of Labdane Diterpenes Galanal A and B from
(+)-Sclareolide
Chebolu Naga Sesha Sai Pavan Kumar and Rong-Jie Chein*
Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan
S
* Supporting Information
ABSTRACT: The first chemical synthesis of galanal A and B
was achieved by a concise and highly efficient pathway starting
from commercially available (+)-sclareolide and features a
Wittig reaction and a titanocene-mediated radical cyclization as
the key steps.
alanal A (1) and B (2) are diterpenes that were first
G
isolated by H. Itokawa et al. in 19861 from Zingiberaceae
(Alpinia galanga) seeds with (+)-labdadienedial (3) and
miogadial (4). The structures of galanal A and B were clearly
established on the basis of spectroscopic and chemical evidence.
The latter studies2 of diterpenoids and miogatrial (5), based on
the pungent principle of Myoga (Zingiber mioga Roscoe), have
further demonstrated the antifungal3 and antimicrobial4
activities and the inhibition of human platelet aggregation
and human 5-lipoxygenase.5 Although synthetic approaches to
(+)-labdadienedial (3)6 and miogadial (4)7 have been reported
by several groups, there is no synthetic precedent for galanal A
and B. The novel galanal motif contains labdane-type A and B
six-membered rings and a seven-membered C ring bearing an
unsaturated aldehyde and a secondary hydroxyl group with a
trans configuration. The location of the aldehyde functionality
at the junction of the trans B/C fused ring would add another
dimension of complexity when planning a synthetic strategy.
Herein, we report the first chemical synthesis of galanal A and B
from commercially available (+)-sclareolide (6).
Figure 1. Major labdane-type diterpenes (1−5) found in A. galanga
and Zingiber mioga Roscoe.
The information obtained from nature and a series of
literature searches resulted in the retrosynthetic analysis
depicted in Scheme 2. Construction of the all-carbon
quaternary center of the key intermediate I could be achieved
through an intramolecular radical reaction of epoxide III. A
Lewis acid single electron-transfer reagent would bind to the
oxygen atom of the epoxide and trigger the formation of radical
intermediate II. The radical carbon center would rapidly invert,
and the intramolecular equatorial addition of this β-oxy radical
to an unsaturated group, such as a nitrile or carbonyl, would
avoid the 1,3-diaxial interaction with the methyl group at the
bridgehead during the axial addition, leading to a stereoselective
7-exo-dig cyclization process. The 6−6−7 tricyclic product I
could then be readily converted to the target compounds
galanal A and B.
To design a possible synthetic route that addresses the
intricate stereochemistry, we sought inspiration from the
biochemical pathway used by nature for a potential bioinspired
strategy. The large superfamily of labdane-type diterpenoids is
now understood to originate from protonation-initiated
cyclization of (E,E,E)-geranylgeranyl diphosphate by diterpene
cyclase (Figure 1),8 and the product from this reaction,
labdadienyl diphosphate, is then elaborated into diverse
labdane-type diterpenoids. Interestingly, labdadienedial (3),
miogadial (4), and miogatrial (5) are secondary metabolites
resulting from labdadienyl diphosphate via double bond
migration and oxidation. Moreover, the coexistence of galanal
A and galanal B with substances such as 3, 4, and 5 in plants
clearly suggests the existence of a common biosynthetic
pathway. For these reasons, we speculated that galanal A and
B are downstream products of labdadienyl diphosphate in their
natural biosynthetic pathway (Scheme 1) and that synthesis of
the “C” ring involves cyclization of an intermediate derived
from miogadial, miogatrial, or oxidized labdadienyl diphos-
phate.
Therefore, commercially available (+)-sclareolide (6) was
readily converted to olefin 8 in 68% yield using a two-step
protocol9 and subsequently reduced with LiAlH4 to afford
aldehyde 9 in 90% yield, as shown in Scheme 3. After
Received: April 18, 2014
Published: May 5, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Scheme 1. Hypothetical Biosynthetic Pathway of Galanal A
and B
Scheme 3. Synthesis of 12 and 13, Precursors for the 7-exo-
dig Radical Cyclization
Scheme 2. Retrosynthetic Analysis of Galanal A and B
Scheme 4. Conversion of Epoxides 12 and 13 to Triols 14
and 15 for Structural Elucidation
considerable optimization, we were pleased to find that the
treatment 9 with a solution of phosphorus ylide 1010 in hot
toluene efficiently furnished the (E)-olefin 11 as a single isomer
in 85% yield. The terminal double bond of compound 11 was
then selectively epoxidized by m-CPBA to afford an inseparable
mixture of 12 and 13 in a 10:1 ratio.
To determine the relative configuration of the epoxide, the
10:1 mixture of 12 and 13 was reduced sequentially with
DIBAL-H and LiAlH4 to afford triols 14 and 15 (Scheme 4) in
the same ratio. The NMR spectra of the minor product 15 is
consistent with the data reported by J. D. Connolly.11
Of Lewis acidic electron-transfer reagents, titanocene
complexes are the most promising.12 When the mixture of
epoxides 12 and 13 was treated with Cp2TiCl2 and Zn metal,
the Ti(III) species generated in situ reacted with the oxirane
moiety to effect homolytic cleavage of the most substituted C−
O bond, to give the more stable tertiary radical intermediate.
Subsequent equatorial addition of the β-titanoxyl radical to the
nitrile resulted in the generation of an iminyl radical, which
afforded the corresponding ketone after work-up. As predicted,
compound 16 with the hydroxymethyl group in an axial
position, 1,3 with respect to an angular methyl group, was
obtained exclusively in 60% yield (Scheme 5) with trace
amounts of side products resulting from ring-opening of the
oxirane. The structural connectivity of 16 was confirmed by
single-crystal X-ray diffraction analysis, as shown in Figure 2.
DIBAL-H reduction of 16 followed by selective oxidation of the
primary alcohol with TEMPO13 gave a 1:5 ratio of galanal A
and galanal B. The two final products were separated by
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Organic Letters
Letter
Scheme 5. Synthesis of Galanals through Titanocene-
Mediated Radical Cyclization
ACKNOWLEDGMENTS
■
We thank Academia Sinica and Ministry of Science and
Technology (Taiwan) for financial support and the MS
laboratory and the X-ray laboratory of the Institute of
Chemistry, Academia Sinica, for data analysis.
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column chromatography and were identical in all respects to
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In conclusion, novel diterpenes galanal A and B were
synthesized in eight steps with a total yield of 15% starting from
commercially available (+)-sclareolide. This method shows the
importance of a bioinspired strategy in constructing the
complex “C” ring that is embedded in the galanals with a
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ASSOCIATED CONTENT
* Supporting Information
■
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The titanocene chemistry has been used in “bioinspired syntheses”
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Oltra, J. E.; Cuerva, J. M.; Bunuel, E.; Cardenas, D. J. J. Am. Chem. Soc.
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dez-Mateos, A.; Madrazo, S. E.;
Detailed experimental procedures, X-ray crystallographic data
of compound 16, and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
́
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AUTHOR INFORMATION
Corresponding Author
■
Chem. Soc. Rev. 2011, 40, 3525−3537. (l) Jimen
́
ez, T.; Morcillo, S. P.;
Martín-Lasanta, A.; Collado-Sanz, D.; Cardenas, D. J.; Gansauer, A.;
́
̈
*E-mail: rjchein@chem.sinica.edu.tw.
Notes
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1996, 61, 7452−7454.
The authors declare no competing financial interest.
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