A catalytic enantioselective tandem allylation strategy for rapid terpene construction: Application to the synthesis of pumilaside aglycon

Article abstract of DOI:10.1021/ja400506j

Catalytic enantioselective 1,2-diboration of 1,3-dienes followed by cascade allylborations with dicarbonyls provides rapid entry into carbocyclic reaction products. The stereochemical course of this reaction was studied along with its application in the synthesis of pumilaside aglycon.

Full text of DOI:10.1021/ja400506j

Communication
pubs.acs.org/JACS
A Catalytic Enantioselective Tandem Allylation Strategy for Rapid
Terpene Construction: Application to the Synthesis of Pumilaside
Aglycon
Grace E. Ferris, Kai Hong, Ian A. Roundtree, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
observation that the reaction products bear the structural
ABSTRACT: Catalytic enantioselective 1,2-diboration of
1,3-dienes followed by cascade allylborations with
dicarbonyls provides rapid entry into carbocyclic reaction
products. The stereochemical course of this reaction was
studied along with its application in the synthesis of
pumilaside aglycon.
hallmarks of terpene natural products. Accordingly, this tandem
allylation strategy might offer an exceptionally rapid entry to
these important compounds.
Study of the abovedescribed synthesis strategy commenced
with the examination of the coupling between geranial-derived
diene 5 and succinic dialdehyde.5 The general procedure is
straightforward: Pt-catalyzed enantioselective diboration of the
diene at 60 °C for 12 h in toluene solvent was followed by
addition of the dialdehyde. After stirring for 24 h at 60 °C, the
reaction was subject to alkaline workup. Upon completion of
the reaction sequence, cyclic diol 6 was isolated in 80% yield.
Not only is this process efficient, but the stereoselection is
remarkable: diol 6 was obtained in >15:1 diastereoselection and
in 98:2 enantiomeric ratio. Single-crystal X-ray analysis of 6
showed it to be configured as depicted in Scheme 2.
atalytic enantioselective reactions that convert simple
C
building blocks into complex structures are powerful tools
for organic synthesis. Critical to the utility of such methods is
that the product structures bear functionality and stereo-
chemistry that is appropriate for important synthesis objectives.
In this connection, we have been developing a series of catalytic
enantioselective diboration reactions that provide reactive
bis(boryl) intermediates that may engage in multiple bond-
forming operations.1,2 One such diboration applies to 1,3-
dienes: the 1,2-diboration of these substrates provides an α-
chiral allylboron reagent (1, Scheme 1) that can engage in
Scheme 2
Scheme 1
Following the conditions described above, a series of other
dienes and dicarbonyls were examined in the tandem allylation
reaction. As depicted in Table 1, reaction efficiency is generally
good, and the derived cyclic diols can be isolated in good to
excellent yields. Interestingly, and in contrast to the geranial-
derived diene in Scheme 2, the isomeric neral-derived diene
furnishes the trans 1,4-diol as the reaction product (entry 1,
Table 1). As depicted in entries 2 and 3, the reaction extends to
phthalic dialdehyde and provides enantiomerically enriched
reduced benzoquinones as the reaction product. Because the
1,2-diboration also extends to simple cis dienes and exocyclic
asymmetric carbonyl allylation (1→2→3).3 In considering how
this transformation might apply to the construction of
carbocyclic natural products, it was considered that if a second
carbonyl was tethered to the first, the allylboron generated
upon the first carbonyl allylation might participate in a
subsequent intramolecular allylation (3→4).4 It was presumed
that this second allylation would be subject to the conforma-
tional preferences of a chelated intermediate and might occur
with useful levels of stereoinduction. The overall reaction
cascade would therefore offer a single-pot reaction that converts
a 1,3-diene and a dicarbonyl to a carbocyclic product bearing
four contiguous stereocenters. Of critical consequence is the
Received: January 16, 2013
Published: February 7, 2013
© 2013 American Chemical Society
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Communication
dienes, cyclic diols bearing tertiary centers and spirocycles can
be accessed with excellent diastereo- and enantioselection
(entry 5 and 6). Importantly, high levels of regioselectivity were
observed with nonsymmetric carbonyls. In these cases (entries
7−9), the first addition occurs to the less hindered aldehyde,
with cyclization occurring on the remaining carbonyl.
Importantly, when this reactivity extends to ketoaldehydes,
tertiary alcohols are crafted in a highly selective fashion.
Extension of this transformation to seven-membered ring
synthesis has yet to be successful; use of valeric dialdehyde in
place of succinic dialdehyde gave complex mixtures. Presumably
other 1,5-dialdehydes with alternate conformational preferences
may ameliorate this situation. As a last point of note, a general
feature of the tandem allylation products is that the
stereoisomers are often readily separable by chromatography
such that isomerically pure compounds can be easily obtained
even from moderately selective reactions; thus, given the level
of functional group complexity that is quickly established in this
reaction, even nonselective reactions may find use in complex
molecule synthesis.
Table 1. Tandem Diene Diboration/Double Allylation of
Dicarbonyls
a
The stereochemical outcome of the reactions in Table 1 can
be readily understood on the basis of a trans-decalin-like
transition state structure with intramolecular allylboration
occurring through a chairlike six-membered array (Scheme
3).6 The outcome of entry 6 (Table 1), wherein the only
Scheme 3. Model for Stereoinduction in Tandem Allylations
stereogenic element in the intermediate resides at C-5, reveals
an inherent preference for an axial orientation of the C5-
OB(pin) group (A, Scheme 3). While this preference is indeed
surprising, it is in line with observations about the axial
preference of C4 alkoxy groups in cyclohexanone derivatives.7
This feature is thought to arise from either (a) electrostatic
attraction between the axial oxygen that bears a δ- and either
the carbonyl carbon8 or axial hydrogens α to the carbonyl,9
both of which bear δ+; (b) hydrogen bonding between the axial
C4 heteroatom and acidic axial hydrogens adjacent to the
carbonyl;10 or (c) hyperconjugative interactions between the
C−O σ* and an adjacent axial CH donor.11 In the context of
this tandem reaction sequence, 1,4-syn selectivity is highest with
geranial-derived substrates (i.e., Scheme 2 and entries 7−9 in
Table 1) suggesting that the axial preference for an OB(pin),
acting in concert with a preference for the larger R2 to reside in
an equatorial site, enhances selectivity for reaction through
structure A. In contrast, the influence of substituents at C4 in
neral-derived substrates and cis dienes (R1 larger than R2,
entries 1 and 5, Table 1) counteracts the axial preference of the
OB(pin) group sufficiently to turn over diastereoselection:
reaction occurs through B and furnishes the trans 1,4-diol.
As suggested in the introduction, the rapid increase in
molecular complexity that accompanies the tandem allylation
reaction described herein should facilitate rapid construction of
a
Entries 1, 4, and 6 employed 2 equivalents of dicarbonyl; entries 2, 3,
7, and 8 employed 1 equiv. dicarbonyl; entry 5 employed 3 equiv
dicarbonyl; entry 9 employed 2 equivalents of diene/B2(pin)2.
Diastereoselectivity determined by H NMR analysis; yield refers to
isolated yield of the regioisomer mixture. (S,S) ligand employed for
1
b
this experiment.
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Journal of the American Chemical Society
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complex molecular structures. The validity of this assertion was
probed by targeting the aglycon of the glycoterpene natural
product pumilaside B.12 As shown in Scheme 4, a carbocyclic
Scheme 4. Synthesis of Pumilaside Aglycon
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obtained was spectroscopically identical with the compound
reported by Kitajima and co-workers.15
In conclusion, a strategy for constructing highly substituted
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ASSOCIATED CONTENT
* Supporting Information
Procedures, characterization and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
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AUTHOR INFORMATION
Corresponding Author
morken@bc.edu
Notes
■
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The NIH (GM-59471) is acknowledged for financial support
and AllyChem is acknowledged for a donation of B2(pin)2. We
thank Dr. Bo Li of the Boston College crystallography lab for
crystal structure analysis.
(13) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
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(15) While the 13C NMR and H NMR spectra of the enantiomeri-
cally enriched material prepared by us are identical to that reported by
Kitajima, the rotation is increased (+49.95° vs +10°) and the melting
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point of the synthetic material is lower (108−110 °C vs 172−175 °C).
We are currently working to understand this discrepancy.
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