Enantioselective synthesis of iridal, the parent molecule of the iridal triterpenoid class

Article abstract of DOI:10.1021/ol8005425

The monocyclic triterpene iridal 1 (parent molecule) is synthesized by an approach that allows access for several representatives of the iridal family as well as diversely substituted analogues. The success of the proposed synthetic plan depends upon the effortless stereoselective establishment of the trans C10/C11 dimethyl relationship in B-ring moiety 7 using a domino-based methodology and the higly efficient Miyaura-Suzuki type sp³-sp ² segment coupling 7 and 8, respectively.

Full text of DOI:10.1021/ol8005425

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1787-1790
Enantioselective Synthesis of Iridal, the
Parent Molecule of the Iridal
Triterpenoid Class
Andrei Corbu, Maurizio Aquino, T. V. Pratap, Pascal Retailleau, and
Sime´on Arseniyadis*
Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-YVette, France
simeon.arseniyadis@icsn.cnrs-gif.fr
Received March 10, 2008
ABSTRACT
The monocyclic triterpene iridal 1 (parent molecule) is synthesized by an approach that allows access for several representatives of the iridal
family as well as diversely substituted analogues. The success of the proposed synthetic plan depends upon the effortless stereoselective
establishment of the trans C10/C11 dimethyl relationship in B-ring moiety 7 using a domino-based methodology and the higly efficient
Miyaura-Suzuki type sp3-sp2 segment coupling 7 and 8, respectively.
The iridals comprise several families of naturally occurring
mono- or bicyclic A-seco triterpenes that have in common
a central B-ring nucleus bearing adjacent quaternary carbons,
a three carbon side chain, and a formylolefin. While the
monocyclic iridal parent molecule 11 contains a homofarnesyl
chain at C11, some members are hydroxylated at C16, C17,
C21, or C23 and epoxidized or dihydroxylated at ∆22,23, and
others are bicyclic 2, 3, or spirocyclic 4 (Figure 1). Dis-
covered by Marner et al.,2 the title compounds show a broad
range of biological activities including antitumor, MDR
reversal,3 antiplasmodial,4 membrane reinforcing,5 and pro-
tein kinase C activation.6 The challenging structures, fasci-
nating biosynthetic origins, and wide-ranging biological
Figure 1. Iridal triterpenoids accessible from hydrindene-diols 5a
(1) Krick, W.; Marner, F.-J.; Jaenicke, L. Z. Naturforsch. 1983, C 38,
and 5b.
179–184.
(2) (a) Marner, F.-J.; Krick, W.; Gellrich, B.; Jaenicke, L.; Winter, W.
J. Org. Chem. 1982, 47, 2531–2538. (b) Marner, F.-J. Curr. Org. Chem.
1997, 1, 153–186. (c) Lamshoft, M.; Schmickler, H.; Marner, F.-J. Eur. J.
Org. Chem. 2003, 727-733.
activities of these terpenoids have, curiously, not stimulated
synthetic efforts.
(3) Bonfils, J.-P.; Pinguet, F.; Culine, S.; Sauvaire, Y. Planta Med. 2001,
67, 79–81.
(4) Benoit-Vical, F.; Imbert, C.; Bonfils, J.-P.; Sauvaire, Y. Phytochem-
istry 2003, 62, 747–751.
J. Med. Chem. 2001, 44, 3872–3880. (b) Wender, P. A.; Kogen, H.; Lee,
H. Y.; Munger, J. D.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc.
1989, 111, 8957–8958. (c) Wender, P. A.; Koehler, K. F.; Sharkey, N. A.;
Dell’Aquila, M. L.; Blumberg, P. M. Proc. Natl. Acad. Sci. U.S.A. 1986,
83, 4214–4218.
(5) Littek, A.; Marner, F.-J. HelV. Chim. Acta. 1991, 74, 2035–2042.
(6) (a) Shao, L.; Lewin, N. E.; Lorenzo, P. S.; Hu, Z.; Enyedy, I. J.;
Garfield, S. H.; Stone, J. C.; Marner, F.-J.; Blumberg, P. M.; Wang, S.
10.1021/ol8005425 CCC: $40.75
Published on Web 04/09/2008
2008 American Chemical Society

Scheme 1
.
Retrosynthetic Analysis Based on a Domino Reaction (5a f 6) and an sp3-sp2 Miyaura-Suzuki Coupling (7 + 8) as Key
Construction Steps
Indeed, there have been only a few attempts to develop
efficient synthetic routes in spite of the broad range of
biological activities displayed by the iridals.7 Inspired by the
potential therapeutic applications of iridals, we have initiated
a program directed toward the development of enantiose-
lective methods for their synthesis. Crucial problems to be
addressed in this connection are methods for constructing
the central B-ring,8 offering linking possibilities and stereo-
chemical control at the quaternary centers. An experimentally
appealing means for the synthesis of the central B-ring
involves the approach that we reported in our previous paper,
where Pb(OAc)4-mediated domino9 reactions of unsaturated
1,2-diols of type 5 (Figure 1) provided access to the triterpene
core of iridals.10 Our attention focused initially on iridals 1
and 2, the parent molecule, and γ-irigermanal, respectively.
For this to be achieved, optically homogeneous unsaturated
bicyclic diol 5a would serve as a B-ring precursor, while
iripallidal 3 and spiroiridal 4 would require the domino
substrate diol 5b. Although this approach does not afford
an opportunity for a direct control of the C6 stereochemistry,
access would be gained in later steps.
a stereodefined cyclohexane precursor allowing for side chain
elaboration at C5 (two-carbon homologation), C7 (formyl-
olefination), and C13 (“farnesylation”). This requires the
stereochemistry at C10, C11 to be established in the central
B-ring building block and orthogonal protection of the
different hydroxyl groups. The required unsaturated diol 5a
provided a convenient route to the complex oxygen hetero-
cycle 6 possessing functionality and absolute configuration
that are appropriate for the central B-ring elaboration.11 The
domino product 6 obtained in a large scale (20-50 g batches)
not only provides the two adjacent quaternary stereocenters
but also offers handles for the attachment of the missing
carbons. The sequence began with the three-step conversion
of key intermediate 5a into the tetrasubstituted cyclohexane
12 using our published procedures.10
Scheme 2. Preparation of the C6-epi B-Ring Precursor
The retrosynthetic scheme to which we were attracted
involved disconnection of the strategic bonds as indicated
in Scheme 1. We subdivided the task into its four obvious
components: the cyclohexane 7, the 15-nor farnesyl chain
8, the two-carbon homologation source 11, and the formyl-
olefination source 9. Thus, geranylacetone-derived E-vinyl
iodide 8, carboethoxy ylide 11, and propenyllithium 9
together with the hydrindene-diol 5a, assembled from (S)-
(+)-Hajos-Parrish ketone 10, would provide the entire iridal
triterpene backbone. We describe in this contribution the total
synthesis of iridal parent molecule 1, which also enables
acquisition of other iridals, in the correct stereochemical
series. The groundwork of this approach has been to prepare
Starting from isopropylidene alcohol 12, benzyl protection
at C13, acetonide cleavage, subsequent selective protection
of the resulting diol 13 as its corresponding tert-butyldi-
methylsilylether, and finally Dess-Martin oxidation provided
14 in 80% isolated yield. The TBS-protected aldol 14
requires a two-carbon homologation and further necessitates
the appropriate adjustment of C6 stereochemistry (an inver-
sion of configuration is required). Fluoride-mediated desi-
lylation caused partial crotonization of the aldol giving rise
to the enone 15, along with C6(S) 16 and C6(R) 17 aldols.
Instead, by effecting the deprotection at 0 °C, aldols 16 and
17 could be obtained as the major constituents (2:1 ratio of
16:17, nearly 80% combined yield) of a three-component
(7) Marner, F. J.; Kasel, T. J. Nat. Prod. 1995, 58, 319–323.
(8) The constant structural motif in the iridal series is the central
six-membered B-ring, incorporating two adjacent quaternary centers at
C10, C11. The same ring system, albeit with different locations of
unsaturation and oxygen functionality, is found in a great number of
related molecules.
(9) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115–136. (b) Tietze, L. F.;
Haunert, F. In Stimulating Concepts in Chemistry; Shibasaki, M., Stoddart,
J. F., Vogtle, F., Eds.; Wiley-VCH: Weinheim, Germany, 2000; pp 39-64.
(c) Domino Reactions In Organic Synthesis.; Tietze, L. F., Brasche, G.,
Gericke, K. M., Eds.; Wiley-VCH: Weinheim, Germany, 2006; ISBN:
3-527-29060-5.
(10) Corbu, A.; Gauron, G.; Castro, J. M.; Dakir, M.; Arseniyadis, S.
Org. Lett. 2007, 9, 4745–4748.
(11) Both quaternary stereogenic centers are obtained as required; no
stereoisomer formation was detected.
1788
Org. Lett., Vol. 10, No. 9, 2008

mixture where enone 15 accounted for around 15%. Con-
siderable experimentation was needed to optimize the
selectivity of this reaction, and the best results are sum-
marized in Scheme 3.
Scheme 3. Installation of the Last Stereogenic Center (C6)
Figure 2. ORTEP drawing of p-nitrobenzoyl ester 19.
Thus, careful desilylation followed by equilibration of the
resulting C6(S)/C6(R) aldol mixture with K2CO3 in methanol
at room temperature gave a three-component mixture con-
taining 16 (43%), 17 (30%), and 15 (16%). A final 1.4:1
mixture of C6(S) 16/C6(R) 17 was formed upon resubjection
to equilibration, and the ratio did not change after prolonged
stirring. The efficiency of this process was improved by
recycling the C6-R aldol after chromatographic separation.
The aldol product 17 carries the whole stereochemical
imprint of the subgoal system 7.
The stage was at hand to put into practice the strategy
implied in Scheme 1. With the aim of introducing the C1,
C2, C25 unit as a potential formylolefin, 17 was reacted with
(2-propenyl)lithium to yield the corresponding carbinol 18
(76% based on recovered 17, no trace of the C7 epimer could
be detected). Swern oxidation of the free alcohol at C5 gave
the desired aldehyde 20, which was poised for a C5-C4
bond-forming step for the completion of the C5-C3 side
chain. This was achieved by a Wittig olefination, which
furnished the R,ꢀ-unsaturated ester 21. The stereochemistry
of C6(R) in the original aldol 16 follows from the X-ray
structure determination of the key domino product 6,10 while
the C6(S) configuration for the epimeric aldol 17 was
confirmed by an X-ray diffraction analysis of the crystalline
para-nitrobenzoate derivative 19 (Scheme 4) (Figure 2)
derived from its corresponding carbinol 18.
olefination. Dauben-Michno oxidative rearrangement12 of
21 provided the transposed enones 22EZ and 22EE in a 6.4:1
ratio and 52% combined yield (over two steps). The major
compound (22EZ) contains all the necessary stereochemical
information to reach the goal system 1, while its geometrical
isomer (at the R,ꢀ-unsaturated aldehyde moiety) 22EE could
be used for the synthesis of natural iridals with a ∆7,2
E-geometry. The requisite B-ring building block, 7Z, together
with its geometrical isomer, 7E,13 was readily accessed
carrying out in parallel the sequence described in Scheme
5. Thus, elaboration of 22 to the requisite substrate 7 began
with the protection of the unstable aldehyde function as a
TBS-ether 23 by a Luche reduction and a subsequent sily-
lation. Selective reduction of the acrylate moiety then in 23
leaving intact the ∆7,2 olefin was achieved using the Mg/
MeOH reduction.14 Subsequent reduction and MOM protec-
tion of the resulting alcohol at C3 afforded 24Z uneventfully.
For 24E, we decided to proceed via a C3-OTBS protection
to explore an alternative deprotection/selective oxidation path
and check function compatibility for the postcoupling opera-
tions (Scheme 6). Following debenzylation, the correspond-
ing C13 alcohols were converted to the target 7Z and 7E
iodides. The geometrically pure E-vinyl iodide 8 which
would serve as a farnesyl chain precursor was prepared from
geranyl acetone in two straightforward steps, employing
published procedures.15
Thus, conversion of geranyl acetone into the required
terminal alkyne followed by a sequential carboalumination-
iodinolysis16 allowed for the preparation of 8 in quantity.
To accomplish the key segment coupling of 7 and 8, we
Scheme 4. Addition of the Missing Carbons
(12) (a) Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 643–
685. (b) Babler, J. H.; Olsen, D. O.; Arnold, W. H. J. Org. Chem. 1974,
39, 1656–1658.
(13) (a) Takahashi, K.; Suzuki, S.; Hano, Y.; Nomura, T. Biol. Pharm.
Bull. 2002, 25, 432–436. (b) Fang, R.; Houghton, P. J.; Luo, C.; Hylands,
P. J. Phytochemistry 2007, 68, 1242–1247.
(14) For the original procedure (reduction of acrylonitriles) see: Profitt,
J. A.; Watt, D. S.; Corey, E. J. J. Org. Chem. 1975, 40, 127. Adapted to
R,ꢀ,-unsaturated esters by: Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G.
Tetrahedron Lett. 1987, 28, 5287-5290.
(15) Negishi, E.; King, A. O.; Klima, W. L. J. Org. Chem. 1980, 45,
2526–2528.
Another concern in this scheme was the regioselective
placement of the C1, C25 carbons during the formyl
(16) Negishi, E.; Takahashi, T. Synthesis 19881-19, and references cited
therein.
Org. Lett., Vol. 10, No. 9, 2008
1789

Scheme 5
.
Preparation of the Central B-Ring Segments 7Z/E
Scheme 6. Completion of the Synthesis of Iridal 1
thesized from the C3-OTBS protected 25E starting with TBS
removal at C3 and C25. Subsequently, the C10-MOM group
was cleaved with HCl-THF to provide the corresponding
triol, whose PCC oxidation as above served to provide
aldehyde 26 in 52% overall yield. It should be pointed out
that the latter was also formed by leaving 1 in the NMR
tube (CDCl3) for eight days (1/26 ratio found to be 1:0.3).
opted to employ the Marshall protocol17 for a Suzuki-Miyaura
reaction,18 which produced the desired coupling products 25
in good yield (Scheme 6). With the whole iridal triterpene
core 25 in hand, conversion to iridal only requires depro-
tection (C1, C3, C10) and adjustment of the oxidation state
at C1. Conversion of 25Z into the target iridal 1 was readily
accomplished in two steps. Simultaneous acidic deprotection
of all protecting groups followed by a PCC-mediated
selective allylic oxidation, afforded in 53% isolated yield,
In summary, the feasibility of using a domino-based central
B-ring formation and Pd(0)-catalyzed sp3-sp2 segment
coupling as key reaction steps for the enantioselective
construction of the iridal backbone has been demonstrated.
Application of this methodology to the synthesis of congeners
from this class of natural products is under way.
Acknowledgment. The authors wish to thank Professor
Jean-Yves Lallemand (Institut de Chimie des Substances
Naturelles, CNRS, Gif-sur-Yvette) for his kind interest and
constant encouragement.
20
synthetically derived (+)-iridal 1 ([R]D 33.3°, lit. 34.4°)
was spectroscopically indistinguishable from the naturally
derived substance.1 The geometrical isomer19 26 was syn-
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Marshall, J.; Schaaf, G. M. J. Org. Chem. 2003, 68, 7428–7432.
(18) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483. Chemler,
S. R.; Trauner, D.; Danishevsky, S. Angew. Chem., Int. Ed. 2001, 40, 4544–
4568.
(19) Numerous iridals containing a ∆7,2 E double bond are known:
Takahashi, K.; Suzuki, S.; Hano, Y.; Nomura, T. Biol. Pharm. Bull. 2002,
25, 432–436.
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