Solid-phase selenium-catalyzed selective allylic chlorination of polyprenoids: Facile syntheses of biologically active terpenoids

Article abstract of DOI:10.1021/jo060760d

Regioselective halogenation of the terminal isopropylidene unit of different acyclic polyolefinic polyprenoids (farnesyl acetate, geranylgeranyl acetate, squalene, etc.) using NCS/catalytic polymer-supported selenenyl bromide is described; good to excellent yields are obtained (68-96%). The first applications of this protocol include the concise synthesis of bioactive terpenoids 1-3.

Full text of DOI:10.1021/jo060760d

Both the generation of compounds as 1-3 and, in most of
cases, the synthetic use as starting materials of simple acyclic
terpenoids involve the selective functionalization of the terminal
isopropylidene unit located in the extreme of the molecule,
opposite to the one usually functionalized in this kind of
molecules. This requires discrimination between two or more
trisubstituted double bonds possessing a very similar electronic
distribution, which poses a serious synthetic problem.
Solid-Phase Selenium-Catalyzed Selective Allylic
Chlorination of Polyprenoids: Facile Syntheses of
Biologically Active Terpenoids
Alejandro F. Barrero,*,† Jose´ F. Qu´ılez del Moral,†
M. Mar Herrador,† Manuel Corte´s,‡ Pilar Arteaga,†
Julieta V. Catala´n,† Elena M. Sa´nchez,† and
Jesu´s F. Arteaga†
A number of synthetic methodologies have been published
trying to overcome this problem. Considering the protocols
oriented to obtain the corresponding epoxide, moderate results
are obtained in the selective formation of bromohydrins,6
whereas the asymmetric dihydroxylation process has proven to
give better selectivities.7 Allylic functionalization has been
achieved by using either SeO2 or Pd(II) complexes,8 but these
strategies give poor results when more than two double bonds
are involved. Allylic chlorination using gaseous chlorine9 at
reflux in apolar solvents leads to the formation of chloro
derivatives via an ene-type reaction. A method for the efficient
allylic chlorination of monoolefins using NCS and catalytic
PhSeCl has been reported recently,10 a protocol based on
previous works by Sharpless et al. which used NCS and diphenyl
diselenide.11
Department of Organic Chemistry, Institute of Biotechnology,
UniVersity of Granada, AVda. FuentenueVa, 18071, Granada,
Spain, and Pontificia UniVersidad Cato´lica de Chile, Facultad
de Qu´ımica, Casilla 306, Correo 22, Santiago, Chile
afbarre@goliat.ugr.es
ReceiVed April 11, 2006
Solid-phase stoichiometric or catalytic oxyselenenylation-
deselenenylation reactions using polymer-supported selenium
reagents have been reported recently.12 Despite the recognized
environmentally friendly nature of this solid-phase protocol,
where the selenocatalyst is entirely separated by filtration of
reaction mixture, there are no reports to date13 on the application
of this technique to the selective allylic chlorination of polyenes.
Continuing with our interest in the synthesis of bioactive
terpenoids from acyclic polyprenic synthons,14 we present in
this work our results on the allylic chlorination of a series of
Regioselective halogenation of the terminal isopropylidene
unit of different acyclic polyolefinic polyprenoids (farnesyl
acetate, geranylgeranyl acetate, squalene, etc.) using NCS/
catalytic polymer-supported selenenyl bromide is described;
good to excellent yields are obtained (68-96%). The first
applications of this protocol include the concise synthesis
of bioactive terpenoids 1-3.
The employment of acyclic polyprenoids possessing different
olefinic double bonds as building blocks for the construction
of bioactive molecules has constituted the basis of a number of
synthetic strategies, among which biomimetic cyclizations are
worth underlining.1 Additionally, some hydroxylated poly-
prenoids can be considered as interesting synthetic targets, such
as the bioactive terpenoids 1-3. 12-Hydroxyfarnesol (1) is a
synthetic compound which has been reported to possess
interesting anti-ulcer activities;2 16-hydroxygeranylgeraniol (2)
is a natural compound isolated from Boletinus caVipes, present-
ing a potent activity inhibitory of the superoxide anion genera-
tion in macrophage cells3 and an antimicrobial activity against
Helicobacter pylori;4 and the squalene hydroxyderivative 3 is
a natural product isolated from the plant Croton hieronymi.5
(2) Sato, A.; Nakajima, K.; Kuwana, N.; Takahara, Y.; Kijima, S.; Abe,
S.; Yamada, K. Br. Pat. GB 2068370, 1981.
(3) Kamo, T.; Sato, K.; Sen, K.; Shibata, H.; Hirota, M. J. Nat. Prod.
2004, 67, 958-963.
(4) Tago, K.; Minami, E.; Masuda, K.; Akiyama, T.; Kogen H. Bioorg.
Med. Chem. 2001, 9, 1781-1791.
(5) Catala´n, C. A. N.; De Heluani, C. S.; Kotowicz, C.; Gedris, T. E.;
Herz, W. Phytochemistry 2003, 64, 625-629.
(6) (a) Van Tamelen, E. E.; Sharpless, K. B.; Eugene, E. Tetrahedron
Lett. 1967, 28, 2655-2659. (b) Van Tamelen, E. E.; Nadeau, V. J. Am.
Chem. Soc. 1967, 89, 176-177.
(7) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu,
D.; Zhang, X. L. J. Org. Chem. 1992, 57, 2768-2771. (b) Vidari, G.;
Dapiaggi, A.; Zanoni, G.; Garlaschelli, L. Tetrahedron Lett. 1993, 34, 6485-
6488. (c) Xu, D.; Park, C. Y.; Sharpless, K. B. Tetrahedron Lett. 1994, 16,
2495-2498. (d) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem.
Soc. 1994, 116, 12109-12110.
(8) El Firdoussi, L.; Baqqa, A.; Allaoud, S.; Ait Allal, B.; Karim, A.;
Castanet, Y.; Mortreux, A. J. Mol. Catal. 1998, 135, 11-22.
(9) Mignani, G.; Grass, J. P.; Chabardes, P.; Morel, D. Tetrahedron Lett.
1992, 33, 495-498.
(10) Tunge, J. A.; Mellegaard, S. R. Org. Lett. 2004, 6, 1205-1207.
(11) Hori, T.; Sharpless, K. B. J. Org. Chem. 1979, 44, 4204-4208.
For more details of 6, see Supporting Information.
(12) (a) Nicolau, K. C.; Pastor, J.; Barluenga, S.; Wissinger, N. Chem.
Commun. 1998, 1947-1948. (b) Fujita, K.; Taka, H.; Ikeda, Y.; Taguchi,
Y.; Fujie, K.; Saeki, T.; Sakuma, M. Synlett 2000, 1509-1511. (c) Nicolau,
K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q. Barluenga, S. Mitchell,
H. J. J. Am. Chem. Soc. 2000, 122, 9939-9953.
(13) For examples of selenium-based approaches for solid-phase syn-
thesis, see: Uehlin, L.; Wirth, T. Org. Lett. 2001, 3, 2931-2938 and
references cited therein.
† University of Granada.
‡ Pontificia Universidad Cato´lica de Chile.
(1) (a) Ho, T.-L. In Carbocycle Construction in Terpene Synthesis; VCH
Publishers: New York, 1988. (b) Corey, E. J.; Cheng, X.-M. In The logic
of Chemical Synthesis; Wiley & Sons: New York, 1989.
10.1021/jo060760d CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/23/2006
J. Org. Chem. 2006, 71, 5811-5814
5811

TABLE 1. Allylic Chlorination of Polyolefinic Polyprenoids Using NCS/Catalytic Polymer-Supported Selenenyl Bromide
a Isolated yield after column chromatography except for entries 13 and 14. b Vinylic chlorides analogous to 6 were easily detected by 1H NMR in minor
quantities in all reactions.
easily available polyolefinic polyprenoids (Table 1) using NCS
and catalytic solid-supported selenenyl bromide with the aim
of contributing to the search for easier and more selective ways
of functionalizing these compounds. An increase in the ef-
ficiency of this transformation would permit widening substan-
tially its use and applications. As result of the analysis of the
most likely mechanism of these allylic chlorinations,10 it was
envisioned that the combined effects of the relatively big size
of the electrophile (polymer-supported-Se+), together with a
minimum concentration of this species in the reaction medium,
could lead to a position selectivity for the terminal isopro-
pylidene group in polyolefinic polyprenoids, on the basis of its
(14) (a) Barrero, A. F.; Cuerva, J. M.; Herrador, M. M.; Valdivia, M. V.
J. Org. Chem. 2001, 66, 4074-4078. (b) Barrero, A. F.; Herrador, M. M.;
Qu´ılez del Moral, J. F.; Valdivia, M. V. Org. Lett. 2002, 4, 1379-1382.
(c) Justicia, J.; Rosales, A.; Bun˜uel, E.; Oller-Lo´pez, J. L.; Valdivia, M.
V.; Ha¨idour, A.; Oltra J. E.; Barrero, A. F.; Ca´rdenas, D.; Cuerva J. M.
Chem. Eur. J. 2004, 10, 1778-1788.
5812 J. Org. Chem., Vol. 71, No. 15, 2006

SCHEME 1. General Approach
SCHEME 2. Synthesis of 1 and 2
lesser steric demand (Scheme 1). Achieving success with this
selective functionalization plan would imply having easy access
to otherwise difficult to generate allyl chloro derivatives, which
could be either used directly in coupling reactions or be
transformed in other derivatives as allylic hydroxylated poly-
prenoids. Furthermore, this derivatization might further enable
us to accomplish asymmetric transformations, such as the
Sharpless asymmetric epoxidation protocol.
26 together with a 18% of dichloro derivative 27 and a 14% of
unaltered starting material were obtained.16 An acceptable yield
of 27 (70%) was obtained by increasing the quantity of NCS
(2.2 equiv) used. Other selective functionalizations reported for
squalene17 are less efficient that the one herein described.
We faced then the challenge of functionalizing selectively
solanesyl acetate (28), a molecule presenting nine trisubstituted
double bonds. Thus, when 28 was made to react with NCS/
polymer-bound selenenyl bromide for 2 h, a 60% of a 3:1
mixture favoring the terminal chlorinated product 29 against
internal functionalizated derivatives was found, together with
a 20% of recovered starting material (Table 1, entry 14).18
Efforts to further transform the starting material led to a loss of
position selectivity.
With these results in mind, we anticipated that different
triterpenoids such as 1-3 could be easily synthesized using this
catalytic protocol. The synthesis of 1 has been accomplished
from chloro derivative 18 via a simple two-step sequence
(Scheme 2).
Thus, AgBF4-mediated hydrolysis of 18 led to a 40% yield
of the corresponding primary hydroxy derivative 30, together
with an additional 45% yield of the secondary alcohol 31. The
efficiency of this process was improved by conversion of 31
into 30 in 41% yield via mesylation and subsequent hydrolysis
with acetone/H2O. Saponification of the acetate with K2CO3/
MeOH afforded the desired diol 1. Following the same sequence,
compound 2 was obtained from geranylgeranyl acetate with a
global yield of 37%, which means a considerable improvement
of the only previous synthesis of this compound.
To test this idea, geranyl acetate (4) was made to react with
1.1 equiv of NCS and 0.025 equiv of polymer-supported
selenenyl bromide in DCM (Table 1, entry 1). The reaction was
completed after 6 h, and a 91% yield of secondary allylic
chloride 5 was obtained. In addition, minor quantities of (2E)-
6-chloro-3,7-dimethylocta-2,6-dienyl acetate (6) were also
found.11 This result shows a remarkable selectivity toward the
double bond C(6)-C(7) and also corroborates the regioselec-
tivity of the process toward the secondary isopropenyl chloride.
The influence of the quantities of NCS and selenium reagent
on the process was then tested (Table 1, entries 2 and 3). The
best yield (93%) was found when 0.05 equiv of organoselenium
resin was used. These conditions were adopted for the rest of
the experiments carried out. With molecules possessing two
double bonds (Table 1, entries 1-7), good to excellent yields
(74-96%) and selectivities were found, the reaction being
compatible with tertiary acetates, unsaturated esters, ketones,
or ketals. In molecules where one of the double bonds is affected
by an electron-withdrawing group, stereoelectronic effects could
be argued to account for the selectivity observed.
However, when geranylacetone 11 (Table 1, entry 6) or its
ketal derivative 13 (Table 1, entry 7) were used as substrates,
the discrimination in favor of the terminal double bond can be
rationalized only by considering steric reasons, excluding
electronic considerations. This fact suggests that this reaction
could reasonably work with molecules presenting a higher
number of double bonds. Gratifyingly, this conjecture proved
to be right, and polyprenoids possessing 3 or 4 trisubstituted
double bonds also reacted satisfactorily (Table 1, entries 9-12).
The results obtained with farnesyl acetate (17), farnesal (19),
and geranylgeranyl acetate (23) (72, 70, and 69% yield,
respectively, of the corresponding allylic chloride) deserve
underlining. In fact, the yield afforded in the allylic chlorination
of 23 is higher than the one obtained by using other selective
functionalizations, such as the asymmetric dihydroxylation
employing the Noe-Lin catalyst.15a Comparable results can only
be achieved with the Corey-Zhang ligand.15b Attention was
then turned to squalene (25), and when it was subjected to the
above-mentioned optimized experimental conditions (Table 1,
entry 13), a 55% of the corresponding monochloro derivative
Similarly, triterpene 3 was obtained for the first time from
squalene (25) in a 32% yield (Scheme 3).
In summary, we have established the conditions for an easy
and highly selective position functionalization toward the
terminal double bond of a series of easily available terpenoids.
This methodology is compatible with the presence of different
functional groups in the starting material, allowing easy access
to functionalized synthons that can be employed in numerous
synthetic operations. The use of a polymer-supported selenium
reagent, with the well-recognized advantages associated to it,
(16) Yields obtained by conversion into the corresponding hydroxy
derivatives. With lesser dregrees of conversion, the selectivity of the reaction
toward 26 increases. Thus, a 5:1 ratio of 26/27 was found after only 10
min of reaction time, recovering 80% of squalene unaltered.
(17) Crispino, G. A.; Sharpless, K. B. Tetrahedron Lett. 1992, 33, 4273-
4274.
(15) (a) Corey, E. J.; Noe, M. C.; Lin, S. Tetrahedron Lett. 1995, 36,
8741-8744. (b) Corey, E. J.; Zhang, J. Org. Lett. 2001, 3, 3211-3214.
(18) Yields obtained by conversion into the more stable acetoxy
derivative 29a. For more details of 29a, see the Experimental Section.
J. Org. Chem, Vol. 71, No. 15, 2006 5813

SCHEME 3. Synthesis of 3
(2E,6E,10E)-12-Hydroxyfarnesol (1). Saponification of 30 (30
mg, 0.11 mmol) with K2CO3 (45 mg) in MeOH (4 mL) was
achieved in 20 min at rt to give 120 (26 mg, 99%).
(2E,6E,10E)-14-Hydroxy-3,7,11,15-tetramethylhexadeca-
2,6,10,15-tetraenyl Acetate (32). According to the procedure
described for the preparation of 30 and 31, the resulting crude from
treating 24 with AgBF4 was purified by column chromatography
(hexane/t-BuOMe, 2.5:1) on silica gel to afford 3321 (37%) along
with 32 (39%). Data for 32: IR (film) 3430, 2924, 2854, 1740,
1651, 1447, 1383, 1233 and 1024 cm-1 1H NMR (400 MHz;
;
CDCl3) δ 1.55-1.65 (2H, m), 1.59 (3H, s), 1.61 (3H, s), 1.70 (3H,
s), 1.72 (3H, s), 1.76 (1H, s, OH), 1.90-2.15 (10H, m), 2.04 (3H,
s), 4.03 (1 H, t, J ) 6.4 Hz), 4.58 (2H, d, J ) 7.1 Hz), 4.83 (1H,
s), 4.93 (1H, s), 5.09 (1H, t, J ) 6.3 Hz), 5.14 (1H, t, J ) 6.4 Hz),
5.34 (1H, dt, J ) 6.3, 1.0 Hz); 13C NMR (100 MHz; CDCl3) δ
16.0, 16.5, 17.7, 21.1, 26.2, 26.6, 33.2, 35.8, 39.5, 39.6, 61.5, 75.6,
111.0, 118.3, 123.8, 124.7, 134.8, 135.4, 142.3, 147.5, 171.2;
HRFABMS calcd for C22H36O3Na [M + Na]+ 371.2562, found
371.2571. According to the procedure described for the conversion
of 31 into 30, the transformation of 32 into 33 via mesylation and
subsequent hydrolysis with acetone/H2O proceeded in a 45% yield.
constitutes an additional plus of this protocol. This reaction has
been applied to the rapid and efficient synthesis of three
interesting hydroxyterpenoids.
Experimental Section
General Procedure for Allylic Chlorination of Polyolefinic
Polyprenoids Using NCS/Polymer-Supported Selenelyl Bromide.
Commercially available solid-supported selenenyl bromide (0.05
mmol) was dissolved in DCM (6 mL). To this solution was added
the corresponding acyclic polyolefinic polyprenoid (1.0 mmol) at
rt. To this mixture was added N-chlorosuccinimide (1.1 mmol) (TLC
monitoring). The solution was concentrated and then suspended
with diethyl ether. The organic layer was decanted from the solid,
washed with H2O and brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The resulting crude was
purified by column chromatography on silica gel to afford the
corresponding secondary allylic chloro derivative.
16-Hydroxygeranylgeraniol (2). Saponification of 33 (53 mg,
0.15 mmol) with K2CO3 (52 mg, 0.38 mmol) in MeOH (6 mL)
was achieved in 20 min at rt to give 24 (45 mg, 98%).
(6E,10E,14E,18E)-2,6,10,15,19,23-Hexamethyltetracosa-
1,6,10,14,18,22-hexaen-3-ol (3). According to the procedure de-
scribed for the preparation of 30 and 31, the resulting crude from
treating the mixture of 26 and 27 (3:1 ratio) with AgBF4 was
purified by column chromatography (hexane/t-BuOMe, 2.5:1) on
silica gel to afford 35 (26%) and the primary alcohol (2E,6E,10E,-
14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-
hexaen-1-ol22 (20%) along with (2E,6E,10E,14E,18E)-2,6,10,15,-
19,23-hexamethyltetracosa-2,6,10,14,18,23-hexaene-1,22-diol (9%)
and (2E,6E,10E,14E,18E,22E)-2,6,10,15,19,23-hexamethyltetracosa-
2,6,10,14,18,22-hexaene-1,24-diol4 (6%). Data for (2E,6E,10E,
14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,23-
hexaene-1,22-diol: IR (film) 3387, 2922, 2855, 1658, 1446, 1382
(2E,6E)-10-Hydroxy-3,7,11-trimethyldodeca-2,6,11-trienyl Ac-
etate (31). (2E,6E)-10-Chloro-3,7,11-trimethyldodeca-2,6,11-trienyl
acetate (18) obtained by regioselective chlorination of farnesyl
acetate (750 mg, 2.51 mmol) was dissolved in acetone (25 mL),
and then H2O (50 mL), 2,4,6-collidine (1.34 mL, 10.0 mmol), and
AgBF4 (973 mg, 5.0 mmol) were added. The resulting mixture was
refluxed at 60-70 °C for 1 h (TLC monitoring). Then, acetone
was removed under reduced pressure and the residue was extracted
with EtOAc (3 × 20 mL). The organic layer was washed with 2 N
HCl and brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure, and the resulting crude was purified by
column chromatography (hexane/t-BuOMe, 2.5:1) on silica gel to
afford 3019 (280 mg, 40%) and 31 (312 mg, 45%). Data for 31:
IR (film) 3453, 2967, 2938, 2856, 1740, 1446, 1382, 1367, 1234,
1023, 954, 898 cm-1; 1H NMR (400 MHz; CDCl3) δ 1.54 (3H, s),
1.55-1.68 (2H, m), 1.63 (3H, s), 1.66 (3H, s), 1.85-2.12 (6H,
m), 1.98 (3H, s), 3.96 (1H, t, J ) 6.5 Hz), 4.51 (2H, d, J ) 7.1
Hz), 4.76 (1H, q, J ) 1.5 Hz), 4.86 (1H, t, J ) 0.9 Hz), 5.07 (1H,
1
and 1014 cm-1; H NMR (400 MHz; CDCl3) δ 1.55-1.65 (2H,
m), 1.59 (12H, s), 1.65 (3H, s), 1.71 (3H, s), 1.93-2.15 (18H, m),
3.98 (2H, s), 4.03 (1H, t, J ) 6.3 Hz), 4.83 (1H, t, J ) 1.6 Hz),
4.93 (1 H, s), 5.13 (4H, m), 5.38 (1 H, dt, J 6.9, 1.2 Hz); 13C NMR
(100 MHz; CDCl3) δ 13.8, 16.1, 17.7, 26.4, 26.7, 28.4, 33.3, 35.8,
39.4, 39.8, 39.8, 69.1, 75.7, 111.0, 124.5, 124.5, 124.7, 124.9, 126.3,
134.6, 134.7, 134.8, 135.1, 135.1, 147.6; HRFABMS calcd for
C30H50O2Na [M + Na]+ 465.3709, found 465.3694.
Acknowledgment. This research was supported by the
Spanish Ministry of Science and Technology (Project BQU
2002-03211). We thank Dr. M. J. de la Torre for revising our
English text.
dt, J ) 6.8 Hz, J ) 1.2 Hz), 5.28 (1H, tq, J ) 7.1 Hz, 1.2 Hz); 13
C
NMR (100 MHz; CDCl3) δ 16.0, 16.5, 17.7, 21.1, 26.1, 33.2, 35.7,
39.5, 61.5, 75.6, 111.0, 118.5, 124.2, 135.2, 142.1, 147.6, 171.2;
HRFABMS calcd for C17H28O3Na [M + Na]+ 303.1936, found
303.1934. To a solution of 31 (145 mg, 0.51 mmol) in 5 mL of
pyridine at 0 °C was added DMAP (cat.). After 10 min, MsCl (0.88
mL, 3.0 mmol) was added. The reaction mixture was stirred for 1
h, quenched with saturated aqueous NaHCO3, extracted with
t-BuOMe, washed with 1 N HCl, NaHCO3, and brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
resulting crude was dissolved in acetone (5 mL) and H2O (4 mL),
and then NaOAc (100 mL) was added. The mixture was heated at
reflux for 2 h. The resulting crude was purified by column
chromatography (hexane/t-BuOMe, 2:1) on silica gel to afford 31
(53 mg, 38%) and 30 (57 mg, 41%), improving in this way the
efficiency of the process.
Supporting Information Available: Experimental procedures
1
and spectroscopic data of new compounds and H and 13C NMR
spectra of 1-3, 6, 10, 12, 16, 18, 24, 29a, 31, and 32. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO060760D
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5814 J. Org. Chem., Vol. 71, No. 15, 2006