Selective monocyclization of epoxy terpenoids promoted by zeolite NaY. A short biomimetic synthesis of elegansidiol and farnesiferols B-D

Article abstract of DOI:10.1021/ol062798i

Epoxy terpenes cyclize readily, by confinement within zeolite NaY, to form exomethylenic cyclohexanols as the major products. The selective monocyclization of 10,11-epoxyfarnesyl acetate within NaY provides a short and efficient biomimetic route to (±)-elengasidiol and (±)-farnesiferols B-D.

Full text of DOI:10.1021/ol062798i

ORGANIC
LETTERS
2007
Vol. 9, No. 4
583-586
Selective Monocyclization of Epoxy
Terpenoids Promoted by Zeolite NaY. A
Short Biomimetic Synthesis of
Elegansidiol and Farnesiferols B−D
Constantinos Tsangarakis, Elias Arkoudis, Christos Raptis, and
Manolis Stratakis*
Department of Chemistry, UniVersity of Crete, Voutes 71003 Iraklion, Greece
stratakis@chemistry.uoc.gr
Received November 17, 2006
ABSTRACT
Epoxy terpenes cyclize readily, by confinement within zeolite NaY, to form exomethylenic cyclohexanols as the major products. The selective
monocyclization of 10,11-epoxyfarnesyl acetate within NaY provides a short and efficient biomimetic route to ( )-elengasidiol and ( )-farnesiferols
D.
±
±
B
−
It is an incontravertable fact that Nature has developed the
means to construct complex secondary metabolites with
unparalleled efficiency and elegance. These accomplishments
might be said to be due to the enzymes she harnesses, which
are particularly adept and stereoselective catalysts. As a
result, synthetic chemists expend a great deal of effort
attempting to mimic the work done by enzymes as they strive
for ever greater efficiency in their own syntheses. An under-
utilized enzyme mimic is the zeolite. Zeolites are mixed
aluminosilicates that catalyze reactions1 by confining the
substrates within “active site” cavities, just as enzymes do.
However, unlike enzymes, they are stable to a broad range
of conditions, can be used with a variety of solvents, and
can be easily removed by filtration. We reasoned that zeolites
with suitable cavity dimensions to host organic molecules,
especially the slightly acidic NaY, would be particularly well
suited to promoting the efficient cyclization of various
common epoxy terpenoids. The results of our investigation,
and the successful application of this new method to the
biomimetic syntheses of (()-elengasidiol and (()-farnesif-
erols B-D, are reported herein.
The acid-catalyzed cyclization of epoxy polyenes has attrac-
ted much interest during the past 50 years,2 especially due to
the early discovery that an analogous enzyme-catalyzed reac-
tion is involved in the biosynthesis of a vast number of impor-
tant terpenoids.3 On many occasions organic chemists have
attempted to reproduce this fascinating enzymatic reaction
using acid-catalysis with varying degrees of success. Super-
acids, such as FSO3H, which are superior catalysts in the
cyclization of polyene terpenoids, failed to provide cycliza-
tion products from epoxy polyenes, providing instead sol-
volysis products.4 On the other hand, Lewis acids such as
8
9
BF3,5 ZrCl4,6 FeCl3,7 Sc(OTf)3, Bi(OTf)3, and, especially,
(1) Sen, S. E.; Smith, S. M.; Sullivan, K. A. Tetrahedron 1999, 55,
12657-12698.
(2) (a) Johnson, W. S. A fifty-year loVe affair with organic chemistry;
American Chemical Society: Washington, DC, 1998. (b) Yoder, R. A.;
Johnston, J. N. Chem. ReV. 2005, 105, 4730-4756.
(3) (a) van Tamelen, E. E. Acc. Chem. Res. 1975, 8, 152-158. (b)
Eschenmoser, A.; Arigoni, D. HelV. Chim. Acta 2005, 88, 3011-3050.
(4) Vlad, P. F. Pure Appl. Chem. 1993, 65, 1329-1336.
(5) van Tamelen, E. E.; Storni, A.; Hessler, E. J.; Schwartz, M. J. Am.
Chem. Soc. 1963, 85, 3295-3296.
(6) Vidari, G.; Beszant, S.; Merabet, J. E.; Bovolenta, M.; Zanoni, G.
Tetrahedron. Lett. 2002, 43, 2687-2690.
10.1021/ol062798i CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/17/2007

MeAlCl210 have been widely used, often providing efficient
polycyclization with good diastereoselectivity. It should be
noted here that a free-radical-based methodology for the cas-
cade polycyclization of epoxy terpenes catalyzed by titano-
cene(III) has also recently been established.11 Unfortunately,
Lewis acids, however adept they may have proved to be in
catalyzing polycyclization, cannot be expected to exert the
control necessary to effect monocyclization of these sub-
strates, but we felt the right zeolite might be able to
accomplish this goal by making use of the confined spaces
present in its architecture.
Table 1. NaY-Promoted Cyclization of Epoxy Terpenoids
Our belief was based on the fact that, recently, we12 and
others13 had reported the efficient biomimetic cyclization of
small acyclic terpenoids, such as geranyl derivatives, by
adsorption within the confined environment of a zeolite. We
found that zeolite NaY, a mildly acidic (containing both
Lewis and Brønsted acidic sites14) catalyst, promoted these
cyclizations in surprisingly high yields and with good
selectivities. Precedent for the use of acidic zeolites in the
cyclization of epoxy terpenoids, however, is limited. Sen and
co-workers used the small-pore highly acidic zeolites (HA
and HZSM-5) as promoters for the cyclization of certain
specific silyl-substituted epoxide-containing polyenes, with
moderate to good product selectivity.15 In this case it was
postulated that cyclization was initiated at the opening of
the zeolite pores, since the size of those epoxy polyenes does
not allow them to diffuse into the interior of the cages.
We felt that the larger pore size and the low acidity of
NaY should make it a mild and selective cyclization
promoter. We were gratified to find that, with the exception
of 6,7-epoxygeranyl acetate (1), NaY does indeed promote
the fast cyclization of several epoxy terpenoids to form
stereoselectively and regioselectively mainly the exometh-
ylenic cyclohexanols (4a,b or 8a-c, Table 1). The formation
of 4 or 8 depends on the configuration of the adjacent
nucleophilic double bond. Alkenes with the E configuration
afford the cis cyclization products (4), while those with the
Z afford trans (8). The bicyclic ethers (5 or 9) and the allylic
alcohols (6 or 10) are formed as side products. Once again,
the products stereochemistry depends on the configuration
of the nucleophilic double bond.
sub.
X
yield, %
products (relative ratios)
1
78
76
92
78
85
2
3a
3b
7a
7b
-OH
4a/5a/6a ) 70/20/10
4b/5b/6b ) 70/25/5
8a/9a/10a/2 ) 40/20/10/30
8b/9b/10b/5b ) 70/6/22/2
-CH2COMe
-OAc
-CH2COMe
a Exo/endo ) 6-12/1, depending on the substrate and the reaction time.
to completion within 10-15 min. On the other hand, the
neryl derivatives (7a,b) require approximately 45 min
reaction time. At higher loading levels (1 mmol of geranyl
derivative per 1 g of NaY), the reactions are completed on
heating at 70 °C for 1 h.17 The combined products yield
varies from 75% to 90%. Isomerization of the exo to the
endo double bond (in the cases of products 4 or 8) occurs
slowly in the presence of NaY. Prolonged intrazeolite
treatment of the polyene epoxides (1-2 h) results in a drop
of the exo/endo ratio from a typical 8-12/1 to approximately
4-6/1. The methodology described herein is very simple and
provides a powerful and direct route to a series of useful
exomethylenic cyclohexanols. For instance, cyclized products
4a, 5a,18 and 4b11a have been used as valuable blocks in the
synthesis of terpenoids. In addition, we would like to point
out that in our hands treatment of 3b with a catalytic amount
of SnCl419 gave the dicyclization product 11 and the bicyclic
Generally, at low loading levels (0.1 mmol of substrate
per 1 g of dry NaY16) the reaction of the geranyl derivatives
(1, 3a,b) proceeds smoothly at ambient temperature, going
(7) Sen, S. E.; Roach, S. L.; Smith, S. M.; Zhang, Y. Z. Tetrahedron
Lett. 1998, 39, 3969-3972.
(8) Bogenstatter, M.; Limberg, A.; Overman, L. E.; Tomasi, A. L. J.
Am. Chem. Soc. 1999, 121, 12206-12207.
(9) Lacey, J. R.; Anzalone, P. W.; Duncan, C. M.; Hackert, M. J.; Mohan,
R. S. Tetrahedron Lett. 2005, 46, 8507-8511.
(15) (a) Sen, S. E.; Zhang, Y. Z.; Roach, S. L. J. Org. Chem. 1996, 61,
9534-9537. (b) Sen, S. E.; Zhang, Y. z.; Smith, S. M. J. Org. Chem. 1998,
63, 4459-4465.
(10) (a) Corey, E. J.; Sodeoka, M. Tetrahedron Lett. 1991, 32, 7005-
7008. (b) Huang, A. X.; Xiong, Z. M.; Corey, E. J. J. Am. Chem. Soc.
1999, 121, 9999-10003.
(16) Zeolite NaY was dried and activated as described in ref 12.
(17) Typical cyclization procedure: 9,10-Epoxygeranylacetone (3b, 200
mg, 0.95 mmol) was adsorbed onto dry zeolite NaY (1 g) that had been
previously suspended in hexane (15 mL). The resultant slurry was heated
to 70 °C for 1 h and then filtered. The solid residue was washed with
methanol (2 × 10 mL) for 30 min each time. The combined extracts were
evaporated under reduced pressure to afford 184 mg of a mixture containing
4b, 5b, and 6b (see Table 1).
(11) (a) Justicia, J.; Rosales, A.; Bunuel, E.; Oller-Lopez, J. L.; Valdivia, N.;
Haidour, A.; Oltra, J. E.; Barrero, A. F.; Cardenas, D. J.; Cuerva, J. M.
Chem. Eur. J. 2004, 10, 1778-1788. (b) Barrero, A. F.; del Moral, J. F. Q.;
Sanchez, E. M.; Arteaga, J. F. Eur. J. Org. Chem. 2006, 10, 1627-1641.
(12) Tsangarakis, C.; Stratakis, M. AdV. Synth. Catal. 2005, 347, 1280-
1284.
(13) Yu, W.; Bian, F.; Gao, Y.; Yang, L.; Liu, Z.-L. AdV. Synth. Catal.
(18) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Palomino, P. L. Tetra-
hedron 1994, 50, 13239-13250.
(19) van Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Le Gall, T.; Shin,
D.-S.; Falck, J. R. J. Org. Chem. 1995, 60, 7209-7214.
2006, 348, 59-62.
(14) Rao, V. J.; Perlstein, D. L.; Robbins, R. J.; Lakshminarasimhan, P. H.;
Kao, H.-M.; Grey, C. P.; Ramamurthy, V. Chem. Commun. 1998, 269-270.
584
Org. Lett., Vol. 9, No. 4, 2007

ether 5b in a relative ratio 3/1 (70% yield), while the Ti(III)
radical-based methodology20 provides mainly bicyclic diol
12 as a mixture of four stereoisomers (Scheme 1). Therefore,
Scheme 2. Mechanistic Aspects for the NaY-Catalyzed
Cyclization of Epoxy Terpenoids
Scheme 1. Cyclization of 3b Catalyzed by SnCl4, Ti(III), or
NaY
To prove the worth of our new method in a synthetic arena,
we chose to apply the protocol to the synthesis of several
natural products. To this end, the higher terpene analogue,
10,11-epoxyfarnesyl acetate (14),23 was treated within NaY.
The resulting reaction went to completion after 15 min to
afford selectively the monocyclization products 15 and 16,
the bicyclic ether 17, and the corresponding allylic alcohol
18 (analogous to the products 6 or 10), in a relative ratio
15/16/17/18 ) 50/7/30/13, and in 75% combined isolated
yield (Scheme 3). The isomeric alcohols 15 and 16 were
easily isolated from the crude reaction mixture by column
chromatography, and hydrolyzed almost quantitatively using
K2CO3 in methanol to afford the racemic sesquiterpene
elegansidiol (19),24 along with its minor endocyclic isomer
20 (ratio 19/20 ∼ 8/1). Reaction of the so-formed 19 and 20
with PBr3 (1.1 equiv) afforded selectively and in high yield
the corresponding allylic bromides 21 and 22. Finally,
alkylation of the potassium salt of 7-hydroxycoumarin
(umbelliferone) with the allylic bromides 21 and 22 (K2-
CO3 in acetone) yielded a mixture of farnesiferols B25 (23)
and D23c (24) in a ratio of 8/1, and in 78% isolated yield
from 19/20 (3 steps). In addition, the analogous 3-step
transformation of the minor product 19 furnished farnesiferol
C (25),24a in 86% overall yield.
the newly developed zeolite NaY methodology compliments
the existing cyclization protocols by allowing access to the
products of monocyclization.
It was somewhat surprising that while 6,7-epoxygeraniol
(3a) cyclizes to form mainly 4a, the corresponding acetate
1 does not afford any cyclization products. Instead, (4E,6E)-
2,6-dimethylocta-4,6-dien-3-one (2) was produced in 78%
isolated yield. It is known that dienone 2 along with its
(4E,6Z)-geometrical isomer are formed upon treatment of
linallol oxide with 25% H2SO4, or through the acid-catalyzed
isomerization of myrcene-6,7-epoxide (13).21 In our case,
formation of 2 from 1 can be envisoned to have occurred
through an epoxide to ketone isomerization in combination
with an elimination of the acetate functionality and diene
isomerization. At this stage, however, we do not want to
speculate as to why we see this switch in mode of reaction
upon going from 3a to its acetoxy analogue 1, especially in
the light of our observation that 13 does not form 2, but
mainly the cyclization products. Further experiments are in
progress to examine this interesting transformation.
From a mechanistic point of view, a concerted cyclization
mechanism, as postulated by Corey and Staas,22 could explain
the observed diastereoselection in the cyclization of epoxy
compounds 3a,b and 7a-c (Scheme 2). The zeolite’s acidic
sites activate, through epoxide binding, the tertiary gem-
dimethyl carbon atom for nucleophilic attack by the adjacent
double bond thus forming the cyclohexyl ring, via the
pseudo-chair transition states TSI and TSII, in which the
relative configuration of the nucleophilic double bond dictates
the stereochemistry of the cyclized products (cis-C or trans-
C). Regioselective elimination of a proton from the methyl
group of cis-C or trans-C gives the exomethylenic cyclo-
hexanols 4 or 8 as major products, while intramolecular
nucleophilic attack by the hydroxyl group affords the bicyclic
ethers 5 or 9 (Table 1).
Our synthesis of farnesiferols B and D is the first to be
reported. Two independent syntheses of farnesiferol C are
already known,26 albeit with use of different and less efficient
strategies. Attempts to perform the more direct biomimetic syn-
thesis of these farnesiferols by using the intrazeolite trans-
formation of epoxide 2627 were unsuccessful. Upon adsorp-
(23) The BF3-catalyzed cyclization of 14 gives a complex reaction mix-
ture, with a very low yield of bicyclic hydroxy acetates, without any monocycli-
zation products such as 15 or 16 being formed: van Tamelen, E. E.; Storni,
A.; Hessler E. J.; Schwartz, M. A. Bioorg. Chem. 1982, 11, 133-170.
(24) For the isolation and two multistep syntheses of elegansidiol, see:
(a) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Herrador, M. M.; Alvarez-
Manzaneda, R.; Quilez, J.; Chahboun, R.; Linares, P.; Rivas, A. Tetrahedron
Lett. 1999, 40, 8273-8276. (b) Audran, G.; Galano, J. M.; Monti, H. Eur.
J. Org. Chem. 2001, 12, 2293-2296. (c) Barrero, A. F.; Alvarez-Manzaneda,
E. J.; Chahboun, R.; Rivas, A. R.; Palomino, P. L. Tetrahedron 2000, 56,
6099-6113.
(25) (a) Caglioti, L.; Naef, H.; Arigoni, D.; Jeger, O. HelV. Chim. Acta
1959, 42, 2557-2570. (b) Nassar, M. I. Pharmazie 1994, 49, 542-543.
(c) Iranshahi, M.; Amin, G.; Shafiee, A. Pharm. Biol. 2004, 42, 440-442.
(26) (a) Demnitz, F. W. J.; Philippini, C.; Raphael, R. A. J. Org. Chem.
1995, 60, 5114-5120. (b) Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1981,
29-32.
(20) Barrero, A. F.; Cuerva, J. M.; Herrador, M. M.; Valdivia, N. V. J.
Org. Chem. 2001, 66, 4074-4078.
(21) Ho, T.-L.; Liu, S.-H. Liebigs Ann. Chem. 1983, 761-769.
(22) Corey, E. J.; Staas, D. D. J. Am. Chem. Soc. 1998, 120, 3526-
3527.
Org. Lett., Vol. 9, No. 4, 2007
585

Scheme 3. Selective Monocyclization of 14 Promoted by
NaY: Synthesis of Elegansidiol and Farnesiferols B-D
Scheme 4. Mechanistic Arguments on the Selective and
Regioselective Monocyclization of Epoxyfarnesyl Acetate in
NaY
walls of the zeolite cage. The methyl group hydrogens
adjacent to the carbocation are more accessible for proton
abstraction by the “zeolite wall” relative to the hydrogen
atoms on the cyclohexyl ring. In addition, the fast deprto-
tonation of cis-C prevents nucleophilic attack by the adjacent
C2-C3 double bond to form a dicyclization product.
The current synthesis of elegansidiol and farnesiferols by
using a controlled cyclization mediated by the zeolite
environment may be considered as biomimetic. The incom-
plete cyclization of epoxy polyene terpenoids in Nature
requires the suitable positioning of a basic amino acid residue
within the cyclase cavity such that the monocyclized car-
bocation is deprotonated, thus terminating the polycyclization
sequence.28 In NaY, the oxygen atoms in the interior of the
zeolite cage play exactly the same role.
In conclusion, we have presented a simple, mild (as harsh
Lewis acids are avoided), and efficient biomimetic method-
ology for the monocyclization of epoxy terpenes. The
developed procedure was applied to the short syntheses of
the natural products elengasidiol and farnesiferols B-D. To
the best of our knowledge, NaY is the only known acidic
catalyst that can induce a selectiVe monocyclization reaction
of epoxy polyene terpenoids. As is clearly evident in the case
of epoxides 3b and 14, this methodology provides a valuable
tool for the direct synthesis of a wide variety of monocyclized
naturally occurring terpenoids. Further synthetic applications
and mechanistic studies into this interesting reaction mode
are currently under investigation.
tion of 26 within NaY an intense red color appeared
immediately, which faded away upon treatment with metha-
nol (after 20 min), and the epoxide was subsequently
recovered intact. On prolonged intrazeolite treatment of 26
at 70 °C (2 h) the reaction turned brown-black and only traces
of an unidentified organic material were isolated. The red
color may be attributed to the formation of a charge-transfer
complex between the coumarin moiety of 26 and an acidic
site in the zeolite wall. van Tamelen and Coates27b have
studied the cyclization of 26 in the presence of BF3. They
observed formation of a complex mixture of products, among
which was farnesiferol C (8%); however, no farnesiferol B
or D was seen.
Acknowledgment. This project was co-funded by the
European Social Fund and National resources (program
PYTHAGORAS-II). We thank Dr. Tamsyn Montagnon for
assistance during the preparation of this manuscript.
Supporting Information Available: Experimental details
The selective formation of the monocyclized exo-isomers
in the case of 4, 8, or 14 could be envisioned to occur through
a kinetically controlled deprotonation of the monocyclized
carbocation cis-C, for instance (Scheme 4) by the oxygen
atom of the Si-O-Si or Si-O-Al bonds in the interior
for the synthesis of epoxy terpenoids and their intrazeolite
1
reactions. Copies of H, 13C NMR, MS and HRMS spectra
of key compounds and reactions. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL062798I
(27) (a) Cravotto, G.; Balliano, G.; Robaldo, B.; Bosso-Oliaro, S.;
Chimichi, S.; Boccalini, M. Bioorg. Med. Chem. Lett. 2004, 14, 1931-
1934. (b) van Tamelen, E. E.; Coates, R. M. Bioorg. Chem. 1982, 11, 171-
196.
(28) For a typical example, see: Matsuda, S. P. T.; Darr, L. B.; Hart, E.
A.; Herrera, J. B. R.; McCann, K. E.; Meyer, M. M.; Pang, J. H.;
Schepmann, H. G. Org. Lett. 2000, 2, 2261-2263.
586
Org. Lett., Vol. 9, No. 4, 2007