Biomimetic cyclization of small terpenoids promoted by zeolite NaY: Tandem formation of α-ambrinol from geranyl acetone

Article abstract of DOI:10.1002/adsc.200505059

Zeolite NaY promotes efficiently the biomimetic cyclization of small acyclic terpenes. Geranyl and neryl acetone undergo a novel tandem 1,5-diene cyclization/carbonyl-ene reaction to form the natural product α-ambrinol isolated in >65% yield.

Full text of DOI:10.1002/adsc.200505059

FULL PAPERS
Biomimetic Cyclization of Small Terpenoids Promoted by Zeolite
NaY: Tandem Formation of a-Ambrinol from Geranyl Acetone
Constantinos Tsangarakis, Manolis Stratakis*
Department of Chemistry, University of Crete, 71409 Iraklion, Greece
Phone: (þ30)-2810-393-687, fax: (þ30)-2810-393-601, e-mail: stratakis@chemistry.uoc.gr
Received: January 27, 2005; Accepted: April 18, 2005
Dedicated to Professor Anastasios Varvoglis on the occasion of his retirement.
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/
Abstract: Zeolite NaY promotes efficiently the biomi- Keywords: a-ambrinol; green chemistry; heterogene-
metic cyclization of small acyclic terpenes. Geranyl ous catalysis; terpenes; zeolites
and neryl acetone undergo a novel tandem 1,5-diene
cyclization/carbonyl-ene reaction to form the natural
product a-ambrinol isolated in >65% yield.
Introduction
moters for the cyclization of epoxide-containing poly-
enes, with moderate to good product selectivity. It was
The acid-promoted cyclization of polyene terpenoids is postulated that cyclization is initiated at the opening
one of Natureꢀs most significant pathways for the forma- of the zeolite pores, since the size of the substrates
tion of a wide variety of cyclic or polycyclic biomole- does not allow them to diffuse into the interior of the
cules. The high degree of diastereoselectivity in these bi- cages.
ogenetic pathways is controlled by confinement of the
acyclic polyene molecules within the cavities of the en-
zymes called cyclases.[1] The conformational immobility Results and Discussion
of the reacting substrates in the confined environment
allows the cascade attack of the proximal double bonds Geranyl acetate was chosen as a model terpenoid sub-
to an intermediate carbocation,[2] proceeding in a highly strate and the reaction occurred by substrate adsorption
stereoselective manner. Non-enzymatic cyclization of into NaYin a hexane slurry. At low loading levels of n¼
the acyclic terpenoids has been achieved by various 0.1–0.2, which practically means around 15–25 mg of
means, such as catalysis by protic acids,[3] super acids[4] geranyl acetate per 1 g of NaY, facile cyclization oc-
or Lewis acids,[5] via radical-initiated pathways,[6] and curred at 258C after 15–20 minutes, to form a mixture
by photoinduced electron-transfer.[7] The acid-catalyzed of g-cyclogeranyl acetate (1a), a-cyclogeranyl acetate
cyclization of polyenes (e.g., by FSO3H) requires very (1b) and the minor terpenic alcohol 1c as a single diaster-
low reaction temperatures (approximately À808C), eomer[13] (Scheme 1). The products were extracted from
multimolar excess of the acid relative to the substrate, the porous material by adding moistened THF or meth-
while toxic nitro compounds are preferentially used as anol (see Experimental Section). The ratio of 1a/1b var-
solvents.[8] In addition, increasing the reaction tempera- ies with the reaction time. At the initial stages, 1a is
ture results in a significant decrease of product selectivi- formed predominately, whereas for prolonged intrazeo-
ty.[8b]
lite treatment (1–2 hours), 1a isomerizes to 1b which fi-
We sought to examine the efficiency of the confined nally becomes the major or only product. Alcohol 1c was
environment of zeolite NaY to carry out the biomimetic formed in 1–10% relative yield depending on the
cyclization of polyene terpenoids. Zeolite NaY, whose amount of H2O present in the interior of the zeolite cag-
pore size is around 7.5 Š,[9] is slightly acidic and contains es, despite its extensive drying at 120–1308C under vac-
both Brønsted[10] and Lewis[11] acid sites. The use of acid- uum. At higher loading levels of approximately 2–
ic zeolites in the cyclization of terpenoids is very limited 3 mmol of geranyl acetate per 1 g of NaY, the cyclization
in the literature. Sen and co-workers[12] have used the H- proceeds in >75% isolated yield, however, it requires
form of the small-pore zeolites A and ZSM-5, as pro- heating to 708C for 12–24 hours, with formation of
1280
ꢁ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/adsc.200505059
Adv. Synth. Catal. 2005, 347, 1280–1284

Formation of a-Ambrinol from Geranyl Acetone
FULL PAPERS
2b, the minor terpenic diol 2c (1–15%) was isolated
and fully characterized,[13] while the aromatic p-cymene
was formed in 2–4% relative yield. Under superacidic
conditions,[15] or in the presence of Tl(ClO4)3,[16] geraniol
is known to undergo cyclization to form mainly iridoid-
type bicyclic furans.
Neryl acetate reacted more slowly compared to geran-
yl acetate, and gave in addition to the cyclogeranyl ace-
tates 1a and 1b (ꢀ60% relative yield), the aromatic
component p-cymene (ꢀ30%) and various amounts
(ꢀ10–15%) of the allylic alcohol 3a.[17] Formation of
p-cymene can be envisioned through intramolecular nu-
cleophilic attack of the terminal double bond at the allyl-
ic carbon atom to eliminate the acetate functionality and
form a mixture of p-menthadienes. Such compounds (li-
monene, terpinolene, etc.) are known to dehydrogenate
readily to p-cymene within NaY.[18] The surprising for-
mation of 3a can be tentatively rationalized by invoking
an electron-transfer (ET) mechanism. Ionization of or-
Scheme 1. Cyclization of geranyl acetate and geraniol by con-
finement within zeolite NaY.
1b in >92% selectivity. Under these higher loading ganic compounds via an ET pathway within faujasites
level conditions, 1c was formed in traces (<0.5%). The under non-irradiative conditions is well known.[19] The
mass balance of all intrazeolite reactions was always postulated radical cation of neryl acetate most probably
>75%.
reacts with molecular oxygen to form an allylic hydro-
Under the same reaction conditions (reaction time, peroxide, which in turn is reduced to the allylic alcohol
loading levels) applied to geranyl acetate, geraniol un- 3a (Scheme 2). We have noticed in our laboratory that
dergoes analogous cyclization reaction (Scheme 1) generally hydroperoxides are partially reduced to the
without suffering from significant dehydration, to form corresponding alcohols by confinement within NaY, or
a mixture of g- and a-cyclogeraniol[14] (2a and 2b, respec- even by silica gel under chromatographic conditions.
tively) in 65% isolated yield. The ratio of 2a/2b again de- Under an inert atmosphere (nitrogen gas), allylic alco-
pends on the reaction conditions. In addition to 2a and hol 3a was formed in <3% relative yield, which most
Scheme 2. Postulated pathway for the formation of by-product 3a, and the transformations of neryl acetate within NaY.
Adv. Synth. Catal. 2005, 347, 1280–1284
asc.wiley-vch.de
ꢁ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1281

Constantinos Tsangarakis, Manolis Stratakis
FULL PAPERS
likely indicates that the oxygen atom of the hydroxyl tion has been studied in the past (Scheme 3) and found
functionality arises from the participation of molecular to give mainly the chromene 5a when treated with strong
oxygen, in accordance with the above-postulated mech- Brønsted acids,[8b] such as FSO3H or ClSO3H, and the bi-
anism. Nevertheless, this ene-type allylic hydroxylation cyclic ether 5b in low diastereomeric excess as the major
reaction seems to be general with other trisubstituted al- product under Lewis acid conditions[21] (BF3 or SnCl4).
kenes, and is currently under investigation from the
mechanistic and synthetic points of view.
Upon treatment with NaY, however, no 5a or 5b was
produced. Instead, the natural product (ꢁ)-a-ambrinol
On the other hand, neryl alcohol dehydrates substan- (5c) was mainly formed in a highly diastereoselective
tially under the reaction conditions (NaY) and gives cy- manner (>97% de), accompanied by dihydro-a-ionone
clogeraniols 2a and 2b in only 15–20% relative yield, ac- (5d) as a by-product (Scheme 4). The relative yield of a-
companied by acomplicated non-polarproduct mixture. ambrinol compared to dihydro-a-ionone depends on
The higher terpene analogue farnesyl acetate, afford- the reaction time. By adsorbing 0.5 mmol of geranyl ace-
ed at loading levels of 50 mg per 1 g of NaY (12 hours at tone in 1 g of NaY, and refluxing at 708C for 6 hours the
708C), drimenyl acetate[20] (4a), in low yield (up to 20%). ratio of 5c/5d was 60/40, however, for prolonged reac-
The majority of the reaction mixture consisted of a non tion times (up to 48 hours) a ꢀ95/5 relative ratio of 5c/
polar fraction containing at least 8 sesquiterpenes pos- 5d can be achieved. Dihydro-a-ionone itself was also
sessing the molecular formula C15H24 (GC-MS). It is found to give slowly a-ambrinol (35% relative yield af-
likely that they arise from elimination of the acetate ter 3 days at 708C). Moreover, the geometrical isomer of
group whereby the resulting carbocation undergoes sev- geranyl acetone, neryl acetone, cyclizes within NaY
eral skeletal rearrangements to form the sesquiterpene more slowly compared to geranyl acetone giving, how-
mixture. In addition, farnesol suffers within NaY from ever, mainly 5c relative to 5d, just as geranyl acetone did.
substantial dehydration, as judged by the formation of
The formation of a-ambrinol (5c) from geranyl ace-
a complicated reaction mixture (mostly non polar ses- tone can be explained by considering an initial cycliza-
quiterpenes).
tion of the 1,5-diene moiety to form an intermediate
mixture of g- and a-cyclogeranyl derivatives 5e and 5d,
respectively (Scheme 5). The isomeric 5e undergoes a
tandem intermolecular carbonyl-ene reaction to form
a-ambrinol. In addition, 5d slowly isomerizes to the
less thermodynamically favourable 5e, which in turn
gives 5c. It is likely that the carbonyl group of 5e is acti-
vated by coordination to a Naþ within the zeolite super-
cages, to undergo the intermolecular ene attack. Okachi
We next studied the NaY-promoted transformation of and Onaka[22] have shown that formaldehyde encapsu-
geranyl acetone. Its acid-catalyzed cyclization in solu- lated within NaY is highly activated by Naþ coordina-
Scheme 3. Cyclization of geranyl acetone under Brønsted or Lewis acid conditions.
Scheme 4. Cyclization of geranyl acetone promoted by NaY.
1282
ꢁ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2005, 347, 1280–1284

Formation of a-Ambrinol from Geranyl Acetone
FULL PAPERS
tones the valuable natural product (ꢁ)-a-ambrinol
(5c) was formed in one step, via a tandem cyclization/
ene reaction, in relatively good yield and by using an en-
vironmentally friendly procedure. We are currently ex-
ploring new applications of NaY and other acidic zeo-
lites[26] in the cyclization of terpenes and epoxyterpenes.
Experimental Section
General Remarks
Nuclear magnetic resonance spectra were obtained on a
500 MHz instrument. Isomeric purities were determined by
1H NMR, 13C NMR and by GC or GC-MS on an HP-5 capillary
column. All spectra reported herein were taken in CDCl3. The
terpenes used in this study are commercially available. Zeolite
NaY (obtained from Aldrich or Degussa) was dried at 120–
1308C under vacuum (10À4 torr) for atleast 6hoursprior to use.
General Procedure for the Intrazeolite Reactions
To a slurry containing 1 g of dry NaY in 10 mL of hexane, were
added 0.3 g of geranyl acetate and the heterogeneous mixture
was refluxed at 708C for 12 hours. The reaction mixture was
cooled to room temperature and then filtered. The filtrate
was kept and the solid material was further repeatedly treated
with 2ꢂ10 mL of methanol for 30 minutes each time, and then
filtered again. The combined solvent extracts were evaporated
to afford 0.25 g of the cyclized products (mainly 1b). An alter-
native extraction procedure can be applied by adding 10 mL of
moistened tetrahydrofuran to the hexane slurry, stirring for 2
hours and then filtration. The later protocol generates often
some impurities in the crude reaction mixture by the air oxida-
tion of THF. If necessary, the crude products were chromato-
graphed to remove solvent impurities. The yields of the isolat-
ed products after chromatography vary from 60 to 70%. For the
case of geranyl acetone, the reaction was performed by reflux-
ing for 24 hours a slurry containing 0.5 g of the terpene and 2 g
of NaYin 20 mL of hexane, to afford 0.44 g of 5c and 5d in a ra-
tio 4/1. a-Ambrinol (5c) can be easily separated from dihydro-
a-ionone by flash column chromatography using hexane/ethyl
acetate¼5/1 as eluent (0.30 g, 60% yield). The isolated yield
can rise up to 75% by extending the reaction time to 48 hours.
Scheme 5. Proposed mechanism for the formation of a-am-
brinol (5c) from geranyl acetone within NaY.
tion, and affords readily carbonyl-ene reactions with a
variety of alkenes. To the best of our knowledge, this is
the first example of a tandem 1,5-diene cyclization/car-
bonyl-ene reaction, and needs further attention from
the synthetic point of view. Kraus and Kim reported re-
cently[23] the first example of a tandem Diels–Alder/car-
bonyl-ene reaction, which leads stereoselectively to the
formation of cis-decalins.
a-Ambrinol (5c) is a constituent of many essential
oils,[24] and a valuable fine chemical in the perfume in-
dustry. Apart from a limited number of literature syn-
thetic procedures,[25] many patented syntheses can be
also found. However, the shortest reported synthetic
methodology requires four consecutive steps, which re-
veals the superiority of our novel methodology not only
because of its simplicity, but from the environmental
point of view. Hence, the environmentally benign nature
of the zeolite medium and its application in the “one-
NMR Spectral Data
pot” synthesis of a-ambrinol (5c) from the relatively 1a: 1H NMR: d¼4.83 (br s, 1H), 4.60 (br s, 1H), 4.26 (dd, 1H,
J1 ¼11.0 Hz, J2 ¼5.0 Hz), 4.22 (dd, 1H, J1 ¼11.0 Hz, J2 ¼
cheap mixture of geranyl and neryl acetone, justifies fur-
ther exploration and optimization (such as to carry out
the reaction in the presence of microwave irradiation).
11.0 Hz), 2.17 (m, 2H), 2.05 (m, 2H), 2.02 (s, 3H), 1.55 (m,
1H), 1.43 (m, 1H), 1.33 (m, 1H), 0.99 (s, 3H), 0.87 (s, 3H); 13
C
NMR: d¼171.22, 147.09, 109.73, 62.81, 52.12, 37.85, 34.31,
33.40, 28.73, 25.04, 23.37, 21.07.
1b: 1H NMR: d¼5.46 (br s, 1H), 4.18 (dd, 1H, J1 ¼11.5 Hz,
J2 ¼6.0 Hz), 4.06 (dd, 1H, J1 ¼11.5 Hz, J2 ¼3.5 Hz), 2.03 (s,
3H), 1.97 (br m, 2H), 1.79 (br s, 1H), 1.73 (s, 3H), 1.47 (m,
1H), 1.20 (m, 1H), 0.94 (s, 3H), 0.92 (s, 3H): 13C NMR: d¼
171.09, 132.24, 123.17, 64.29, 48.74, 31.99, 31.73, 27.33, 27.00,
Conclusion
In conclusion, we have shown that zeolite NaY pro-
motes the efficient biomimetic cyclization of small acy-
clic terpenoids. For the case of geranyl and neryl ace- 22.96, 22.87, 21.16.
Adv. Synth. Catal. 2005, 347, 1280–1284
asc.wiley-vch.de
ꢁ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1283

Constantinos Tsangarakis, Manolis Stratakis
FULL PAPERS
1c: 1H NMR: d¼4.34 (br d, 2H), 2.47 (br s, 1H), 2.07 (s, 3H),
1.78 (m, 1H), 1.62 (m, 2H), 1.42 (m, 3H), 1.27 (m, 1H), 1.23 (s,
3H), 1.03 (s, 3H), 0.88 (s, 3H); 13C NMR: d¼170.96, 72.66,
63.52, 54.83, 42.42, 41.82, 34.14, 32.72, 24.04, 21.75, 21.26, 20.04.
2a: 1H NMR: d¼4.96 (br s, 1H), 4.76 (br s, 1H), 3.73 (dd, 1H,
J1 ¼11.0 Hz, J2 ¼5.0 Hz), 3.63 (dd, 1H, J1 ¼11.0 Hz, J2 ¼
11.0 Hz), 2.12 (m, 2H), 2.04 (m, 2H), 1.20–1.58 (m, 3H), 0.96
(s, 3H), 0.87 (s, 3H).
[9] A. Dyer, An Introduction to Zeolite Molecular Sieves,
Wiley, Bath, UK, 1988.
[10] V. Jayathirma Rao, D. L. Perlstein, R. J. Robbins, P. H.
Lakshminarasimhan, H.-M. Kao, C. P. Grey, V. Rama-
murthy, Chem. Commun. 1998, 269.
[11] H. W. G. van Herwijnen, U. H. Brinker, Tetrahedron
2002, 58, 4963.
[12] a) S. E. Sen, Y. Zhi Zhang, S. L. Roach, J. Org. Chem.
1996, 61, 9534; b) S. E. Sen, Y. Zhi Zhang, S. M. Smith,
J. Org. Chem. 1998, 63, 4459.
[13] Alcohol 1c reacted with LiAlH4 to form the correspond-
ing known diol 2c: T. Oritani, K. Yamashita, Agric. Biol.
Chem. 1987, 51, 1271.
[14] a) M. J. Quirin, M. Taran, B. Delmond, Can. J. Chem.
1996, 74, 1852; b) M. Bovolenta, F. Castronovo, A. Vada-
la, G. Zanoni, G. Vidari J. Org. Chem. 2004, 69, 8959.
[15] G. Carr, C. Dean, D. Whittaker, J. Chem. Soc. Perkin
Trans. 2 1989, 71.
2b: 1H NMR: d¼5.60 (br s, 1H), 3.75 (s, 2H), 2.00 (m, 2H),
1.75 (s, 3H), 1.45 (m, 1H), 1.20 (m, 1H), 1.03 (s, 3H), 0.89 (s, 3H).
2c: 1H NMR: d¼3.94 (m, 2H), 1.80 (m, 1H), 1.64 (m, 1H),
1.61 (m, 1H), 1.45 (m, 2H), 1.32–1.41 (m, 2H), 1.38 (s, 3H),
1.05 (s, 3H), 0.79 (s, 3H); 13C NMR: d¼74.87, 62.03, 56.03,
43.23, 42.22, 33.53, 32.87, 23.46, 21.61, 20.22.
3a: 1H NMR: d¼5.37 (br. t, 1H, J¼7.0 Hz), 4.96 (s, 1H), 4.85
(s, 1H), 4.60 (m, 2H), 4.02 (m, 1H), 2.17 (m, 2H), 2.05 (s, 3H),
1.77 (s, 3H), 1.74 (s, 3H), 1.63 (m, 2H); 13C NMR: d¼171.14,
147.39, 142.29, 119.58, 111.04, 75.04, 61.06, 33.13, 28.00, 23.32,
21.06, 17.69.
5c: 1H NMR: d¼5.46 (br s, 1H), 2.07 (dd, 2H, J1 ¼13.0 Hz,
J2 ¼2.0 Hz), 2.00 (m, 2H), 1.84 (br s, 1H), 1.71 (m, 1H), 1.18–
1.51 (m, 5H), 1.22 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H); 13C
NMR: d¼137.36, 122.01, 70.26, 49.82, 47.24, 38.95, 33.28,
31.10, 29.24, 28.00, 25.97, 25.02, 22.75.
[16] Y. Yamada, H. Sanjoh, K. Iguchi, J. Chem. Soc. Chem.
Commun. 1976, 997.
[17] The spectroscopic data of by-product 3a are identical
with that of the secondary allylic alcohol produced
from the reaction of neryl acetate with singlet oxygen
(1O2) and subsequent reduction of the allylic hydroper-
oxides with PPh3. Photooxygenation of neryl acetate is
locoselective giving a mixture of secondary and tertiary
allylic hydroperoxides (ca. 1/1) from the exclusive reac-
tion of less hindered gem-dimethyl double bond.
Acknowledgements
This work was supported by the Greek General Secretariat of
Research and Technology (PENED 2001).
References and Notes
[1] I. Abe, M. Rohmer, G. D. Prestwich, Chem. Rev. 1993,
93, 2189.
[2] a) A. Eschenmoser, L. Ruzicka, O. Jeger, D. Arigoni,
Helv. Chim. Acta 1955, 38, 1890; b) E. E. van Tamelen,
Pure Appl. Chem. 1981, 53, 1259; c) K. U. Wendt, G. E.
Schulz, E. J. Corey, D. R. Liu, Angew. Chem. Int. Ed.
2000, 39, 2812.
[3] V. A. Stair, A. V Semenovskii, V. F. Kucherov, Izv. Akad.
Nauk. SSSR, Ser. Khim. 1962, 470; Chem. Abstr. 1962, 57,
62913.
[4] P. F. Vlad, Pure Appl. Chem. 1993, 65, 1329.
[5] H. Ishibashi, K. Ishihara, H. Yamamoto, Chem. Rec.
2002, 2, 177.
[6] a) A. J. McCarroll, J. C. Walton, Angew. Chem. Int. Ed.
2001, 40, 2224; b) J. Justicia, A. Rosales, E. Bunuel,
J. L. Oller-Lopez, M. Valdivia, A. Haidour, E. J. Oltra,
A. Barrero, D. J. Cardenas, J. M. Cuerva, Chem. Eur. J.
2004, 10, 1778.
[18] M. Stratakis, M. Stavroulakis, N. Sofikiti, J. Phys. Org.
Chem. 2003, 16, 16.
[19] a) W. H. Zhu, E. L. Clennan, Chem. Commun. 1999,
2261; b) I. Casades, M. Alvaro, H. Garcia, M. Espla,
Chem. Commun. 2001, 982.
[20] H. Akita, M. Nozawa, A. Mitsuda, H. Ohsawa, Tetrahe-
dron: Asymmetry 2000, 11, 1375.
[21] K. H. Schulte-Elte, G. Ohloff, Helv. Chim. Acta 1975, 58,
18.
[22] T. Okachi, M. Onaka, J. Am. Chem. Soc. 2004, 126, 2306.
[23] G. A. Kraus, J. Kim, Org. Lett. 2004, 6, 3115.
[24] a) P. Weyerstahl, H. Marschall. M. Weirauch, K. Thefeld,
H. Suburg, Flav. Fragnance J. 1998, 13, 295; b) C. Demet-
zos, T. Anastasaki, D. Perdetzoglou, J. Biosc. 2002, 57,
89.
[25] a) O. Takazawa, H. Tamura, K. Kogami, K. Kazuo,
Chem. Lett. 1980, 10, 1257; b) M. Yamashita, K. Nishii,
M. Yamashita, Chem. Express 1989, 4, 33; c) P. Naegeli,
Y. Wirz-Habersack, S. Duebendorf, Tetrahedron: Asym-
metry 1992, 3, 221.
[7] V. Rosales, J. Zambrano, M. Demuth, Eur. J. Org. Chem.
2004, 1798.
[8] a) M. P. Polovinka, D. V. Korchagina, Y. U. Gatilov, I. Y.
Bagriaanskaya, V. A. Barkhash, V. V. Shcherbukhin,
N. S. Zevirov, V. B. Perutskii, N. D. Ungur, P. F. Vlad, J.
Org. Chem. 1994, 59, 1509; b) P. J. Linares-Palomino, S.
Salido, J. Altarejos, A. Sanchez, Tetrahedron Lett. 2003,
44, 6651.
[26] J. H. Clark, Acc. Chem. Res. 2002, 35, 791.
1284
ꢁ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2005, 347, 1280–1284