Simple enantioselective approach to synthetic limonoids

Article abstract of DOI:10.1021/ja802376g

An enantioselective and short approach to the synthesis of limonoids has been applied successfully to the simplest limonoid, 2. The carbon atoms of the tetracyclic framework were assembled in a single operation from the acylsilane 3 and the acetylenic sulfone 4 to form the chiral epoxide 5. Successive cationic and free-radical cyclizations starting with 5 generated the tetracyclic intermediates 9a, which was transformed into limonoid 2 by a sequence consisting of (1) oxidative cleavage of the exocyclic double bond, (2) stereoselective α-methylation, (3) furyl attachment, and (4) introduction of a 16-keto function. Copyright

Full text of DOI:10.1021/ja802376g

Published on Web 04/30/2008
Simple Enantioselective Approach to Synthetic Limonoids
Douglas C. Behenna and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received April 1, 2008; E-mail: corey@chemistry.harvard.edu
Since the determination of the structure of the citrus bitter
principle limonin (1) in 1960,1 the number of structurally defined
members of this class of natural products (now called limonoids)
has grown to several hundred.2 Membership in this class is even
larger when the numerous glycoside derivatives are counted.
by such biosynthetic processes from the simpler predecessor 2.
Relatively little effort has been invested in the synthesis of
limonoids, which is somewhat surprising in view of their variety,
widespread occurrence, and significant biological activity.3,4
Some years ago, we published a stereocontrolled synthesis of
the racemic limonoid azadiradione.5 More recently, Ley and co-
workers have achieved a noteworthy total synthesis of azadirachtin
from the chiral starting material galactose.6,7 We describe herein
the first enantioselective synthesis of a limonoid, the protolimonoid
2, by a route which is both short and stereocontrolled (Scheme 1).
Our synthesis commences with a one-flask carbonyl addition/
Brook rearrangement/elimination8 reaction to unite all the carbons
required for the synthesis of the A-D rings. The known acylsilane
3,9 which was generated by a uniquely site-selective and enanti-
oselective dihydroxylation reaction,10 underwent sequential nu-
cleophilic addition, Brook rearrangement, and elimination upon low
temperature reaction with R-lithiosulfone 4.11 Epoxy silyl enol ether
The various limonoids represent a structurally very diverse group
since they are extensively modified from a simpler precursor in
terms of degree and location(s) of oxygenation, ring cleavage, and
C-C rearrangement. However, all of these compounds are derivable
1
5 was produced in excellent yield as a 10:1 mixture (by H NMR
analysis) favoring the (E)-silyl enol ether.12 Brief exposure of
Scheme 1. Synthesis of Protolimonoid 2
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2008 American Chemical Society

C O M M U N I C A T I O N S
epoxide 5 to 1.2 equiv of MeAlCl2 at -78 °C provided two
diastereomeric tricyclic ketones in a 1.5:1.0 ratio with ketone 6 as
the minor component. The predominating diastereomer in the
mixture, in which the appendage R to the carbonyl is axially
oriented, could be isomerized to 6 by treatment of the crude mixture
with sodium ethoxide in ethanol. Overall, the cationic cyclization
and epimerization permit the rapid stereoselective establishment
of three rings and five stereocenters in 43% yield.13
We next turned our attention to the efficient construction of the
D ring. First, ketone 6 was diastereoselectively reduced with the
aluminum ate complex formed from DibalH and n-BuLi.14 This
reagent provided significantly higher yields of alcohol 7 than DibalH
alone (by about 20%). Alcohol 7 was converted to xanthate 8 under
standard conditions. Slow addition of a solution of AIBN and
Bu3SnH to a heated solution of xanthate 8 resulted in smooth
radical-mediated 5-exo-dig cyclization to form 9a (2:1 ratio of E/Z
isomers). Ozonolysis of 9a gave a single ketone, 9b (cis C/D ring
junction).
When ketone 9b was deprotonated under reversible conditions
favoring the more stable ∆(13-17) enolate (KOt-Bu in t-BuOH
solvent, 23 °C) and treated with methyl iodide, the required angular
methylation occurred with the cis C/D fused product predominating
(5:1).15 This selectivity improved to 10:1 when the methylation
was performed at a lower temperature (0-4 °C) with t-amyl alcohol
as solvent. The dependence of diastereoselectiVity on temperature
for this methylation is noteworthy. The angularly methylated
tetracyclic ketone was transformed into the corresponding vinyl
triflate 10 by deprotonation and subsequent reaction with N-phenyl
triflimide. Standard Stille coupling conditions were unsatisfactory
for attachment of the furan appendage to the hindered vinyl triflate
10. However, the Cu(I)-promoted Stille reaction developed in these
laboratories16 proved uniquely effective in providing an excellent
yield of the required pentacyclic furan 11.
Introduction of the limonoid carbonyl at C(16) by an epoxidation/
rearrangement combination7a did not proceed in high yield so we
used a hydroboration/oxidation sequence,17 which provided con-
sistently better yields of the desired ketone. The diastereomeric
mixture of R-furyl ketones thus formed was equilibrated under mild
basic conditions to give exclusively the desired 17-R-oriented furan.
Clean desilylation of the 3-oxygen was achieved with HF to afford
protolimonoid 2 in 75% yield overall from furan 11.
of the 16-keto group in 2 provides a solution to the challenge of
selective oxidation in the presence of the easily oxidizable 3-furyl
appendage. The synthetic technology residing in the sequence
outlined in Scheme 1 may be applicable to many other synthetic
problems, including the stereocontrolled construction of a range
of other limonoids. We call attention to these features of the present
synthesis because, so far, very few laboratories have taken
advantage of the powerful synthetic tools that have been applied
in the present study. In our view, the tandem combination of cationic
and radical cyclization can potentially lead to short syntheses of
numerous interesting polycyclic molecules.
Supporting Information Available: Experimental procedures for
the steps shown in Scheme 1 are given along with characterization
data for each product and selected NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Arigoni, D.; Barton, D. H. R.; Corey, E. J.; Jeger, O.; Caglioti, L.;
Dev, S.; Ferrini, P. G.; Glazier, E. R.; Melera, A.; Pradhan, S. K.; Schaffner,
K.; Sternhell, S.; Templeton, J. F.; Tobinaga, S. Experientia 1960, 16, 41–
49. (b) Arnott, S.; Davie, A. W.; Robertson, J. M.; Sim, G. A.; Watson,
D. G. Experientia 1960, 16, 49–51.
(2) For reviews on the large family of limonoids, see: (a) Roy, A.; Saraf, S.
Biol. Pharm. Bull. 2006, 29, 191–201. (b) Taylor, D. A. H. Prog. Chem.
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and insect antifeedent activity. See, for example: Champagne, D. E.; Koul,
O.; Isman, M. B.; Scudder, G. G. E.; Towers, G. H. N. Phytochemistry
1992, 31, 377–394.
(4) Substantial quantities of limonoids, such as limonoid glycosides, are injested
by humans who eat citrus fruits without ill effects.
(5) (a) Corey, E. J.; Reid, J. G.; Myers, A. G.; Hahl, R. W. J. Am. Chem. Soc.
1987, 109, 918–919. (b) Corey, E. J.; Hahl, R. W. Tetrahedron Lett. 1989,
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limonoid analogues and fragments from natural products. See, for example: (a)
Ferna´ndez-Mateos, A.; Coca, G. P.; Rubio Gonza´lez, R. Tetrahedron 2005,
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(11) For details involving the synthesis of compound 4, see Supporting
Information.
(12) The E geometry of the silyl enol ether 5 was inferred from the synthesis of
analogous (Z)-silyl enol ethers via a chelated Z-allylic lithium reagent; for
an example of (Z)-silyl enol ether formation, see ref 8d.
(13) The phenylethynyl analogue of substrate 5 was also prepared and subjected
to cationic cyclization. However, the cyclization results were considerably
inferior to those with 5.
(14) Kim, S.; Han Ahn, K. J. Org. Chem. 1984, 49, 1717–1724.
(15) Audouin, M.; Levisalles, J. Bull. Soc. Chim. Fr. 1975, 695–701.
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There are a number of aspects of the synthesis of limonoid 2
that require comment, apart from the obvious brevity of the overall
process. The tetracyclic core is generated rapidly by a novel
combination of cationic triple annulation and free-radical-induced
ring closure with control of stereochemistry. The substrate for this
highly effective process (5) is assembled in a single step from the
readily available components 3 and 4. The chiral component 3,
which contains the critical initiating stereocenter, can be made from
achiral ingredients by a highly effective catalytic asymmetric
reaction. The difficult problem of ensuring the required cis C/D
ring fusion is solved in an effective and simple way, as is the
stereoselective introduction of the 17-furyl appendage. The value
of the powerful bimetallic (Cu, Pd) coupling16 to overcome the
steric barrier to traditional Stille coupling is dramatically illustrated
by the formation of 11. Further, the highly effective introduction
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