Total diastereofacial selective iodofunctionalization of terpene derivatives based on Ipy2BF4

Article abstract of DOI:10.1021/jo034517f

Acetonides 1, easily obtained from simple terpenes, react with bispyridine iodonium (I) tetrafluoroborate (Ipy₂BF₄) and tetrafluoroboric acid in the presence of nucleophiles to give the corresponding adducts 2 with complete regio and diastereofacial control. Acetonides 1 containing a properly located phenyl or benzyloxy group easily undergo iodocyclization to furnish compounds 3 and 4.

Full text of DOI:10.1021/jo034517f

Tota l Dia ster eofa cia l Selective Iod ofu n ction a liza tion of Ter p en e
Der iva tives Ba sed on Ip y2BF 4
J ose´ Barluenga,*,† Mo´nica Alvarez-Pe´rez,† Fe´lix Rodr´ıguez,† Fracisco J . Fan˜ana´s,†
J ose´ A. Cuesta,‡ and Santiago Garc´ıa-Granda‡
Instituto Universitario de Quı´mica Organometa´lica “Enrique Moles”, Unidad Asociada al C.S.I.C.,
and Departamento de Qu´ımica Fı´sica y Analı´tica, Universidad de Oviedo, J ulia´n Claverı´a, 8,
E-33006, Oviedo, Spain
barluenga@sauron.quimica.uniovi.es
Received April 22, 2003
Acetonides 1, easily obtained from simple terpenes, react with bispyridine iodonium (I) tetrafluo-
roborate (Ipy2BF4) and tetrafluoroboric acid in the presence of nucleophiles to give the corresponding
adducts 2 with complete regio and diastereofacial control. Acetonides 1 containing a properly located
phenyl or benzyloxy group easily undergo iodocyclization to furnish compounds 3 and 4.
SCHEME 1. Con ver sion of Dia lk ylbor oxyca r ben e
Com p lexes in to Aceton id es by Sequ en tia l
In tr a m olecu la r C-H In ser tion Rea ction a n d
Oxid a tion
In tr od u ction
Modern organic chemistry is focused on the search for
new and efficient reactions to prepare polyfunctional
compounds in an enantioselective manner.1 Also, the
application of methods and tools of organic chemistry to
study biological problems is of great interest.2 Among all
the procedures, technologies, and strategies available,
organometallic compounds have been widely applied to
total synthesis as they allow access to complex frame-
works of organic molecules in an easy way.3 Recently,4
we have disclosed an efficient and diastereoselective
synthesis of 1,3-diols via an intramolecular C-H inser-
tion reaction in boroxycarbene complexes (Scheme 1).
Overall, this methodology results in a clear and efficient
modification of terpenes in a regio- and diastereoselective
manner.5 Moreover, addition reactions to unsaturated
systems promoted by halogens are valuable processes for
the stereoselective functionalization of carbon-carbon
double bonds.6 In this context, many examples of dias-
tereofacial selective iodocyclization reactions have been
reported;7 however, the related intermolecular version
has been achieved with less success,8 and in most of the
cases, this reaction is circumscribed to the carbohydrate
area.9 Taking into account that terpenes play a central
role in many biological processes10 besides the importance
of iodine-containing molecules in medicinal chemistry11
made us to think that chiral iodine-containing compounds
derived from terpenes could find application as biologi-
(7) For reviews of halocyclization, see: (a) Bartlett, P. A. In
Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press: Orlando,
1984; Vol. 3, p 411. (b) Cardillo, G.; Orena, M. Tetrahedron 1990, 46,
3321. (c) Harding, K. E.; Tiner, T. H. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
1991; Vol. 4, p 363. (d) Robin, S.; Rouseau, G. Tetrahedron 1998, 54,
13681. (e) Kitagawa, O.; Taguchi, T. Synlett 1999, 1191.
(8) For some examples, see: (a) Cambie, R. C.; J urlina, J . L.;
Rutledge, P. S.; Woodgate, P. D. J . Chem. Soc., Perkin Trans. 1 1982,
315. (b) Carlon, F. E.; Draper, R. W. J . Chem. Soc., Perkin Trans. 1
1983, 2793. (c) Barluenga, J .; Campos, P. J .; Gonza´lez, J . M.; Sua´rez,
J . L.; Asensio, G. J . Org. Chem. 1991, 56, 2234. (d) Bueno, A. B.;
Carren˜o, M. C.; Garc´ıa-Ruano, J . L.; Arraya´s, R. G.; Zarzuelo, M. M.
J . Org. Chem. 1997, 62, 2139.
(9) For a few examples on this area, see: (a) Maag, H.; Rydzewsky,
R. M. J . Org. Chem. 1992, 57, 5823. (b) McDonald, F. E.; Danishefsky,
S. J . J . Org. Chem. 1992, 57, 7001. (c) Danishefsky, S. J .; Koseki, K.;
Griffith, D. A.; Gervay, J .; Peterson, J . M.; McDonald, F. E.; Oriyama,
T. J . Am. Chem. Soc. 1992, 114, 8331. (d) Kirschning, A.; Monenschein,
H.; Schmeck, C. Angew. Chem., Int. Ed. 1999, 38, 2594. (e) J arreton,
O.; Skydstrup, T.; Espinosa, J .-F.; J ime´nez-Barbero, J .; Beau, J .-M.
Chem. Eur. J . 1999, 5, 430. (f) Boschi, A.; Chiappe, C.; De Rubertis,
A.; Ruasse, M. F. J . Org. Chem. 2000, 65, 8470. (g) McDonald, F. E.;
Reddy, K. S.; D´ıaz, Y. J . Am. Chem. Soc. 2000, 122, 4304.
(10) See, for example: (a) Thompson, J . E.; Walker, R. P.; Wratten,
S. J .; Faulkner, D. J . Tetrahedron 1982, 38, 1865. (b) Ogasawara, M.;
Matsubara, T.; Suzuki, H. Biol. Pharm. Bull. 2001, 24, 720. (c)
Camacho, M. R.; Phillipson, J . D.; Croft, S. L.; Marley, D.; Kirby, G.
C.; Warhurst, D. C. J . Nat. Prod. 2002, 65, 1457.
† Instituto Universitario de Qu´ımica Organometa´lica “Enrique
Moles”.
‡ Departamento de Qu´ımica F´ısica y Anal´ıtica (X-ray service).
(1) Nicolaou, K. C.; Sorensen, E. J . Classics in Total Synthesis;
Verlag Chemie: Weinheim, 1996.
(2) Hinterding, K.; Alonso-D´ıaz, D.; Waldmann, H. Angew. Chem.,
Int. Ed. 1998, 37, 688.
(3) (a) Boudier, A.; Bromn, L. O.; Lotz, M.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 4414. (b) Noyori, R. In Asymmetric Catalysis
in Organic Synthesis; Wiley: New York, 1994. (c) Ojima, I. Catalytic
Asymmetric Synthesis, 2nd ed., VCH: New York, 2000.
(4) Barluenga, J .; Rodr´ıguez, F.; Vadecard, J .; Bendix, M.; Fan˜ana´s,
F. J .; Lo´pez-Ortiz, F. J . Am. Chem. Soc. 1996, 118, 6090.
(5) Barluenga, J .; Rodr´ıguez, F.; Vadecard, J .; Bendix, M.; Fan˜ana´s,
F. J .; Lo´pez-Ortiz, F.; Rodr´ıguez, M. A. J . Am. Chem. Soc. 1999, 121,
8776.
(11) For an example, see: (a) Stark, H.; Purand, K.; Huels, A.;
Ligneau, X.; Garbage, M.; Schwartz, J .-C.; Schunack, W. J . Med. Chem.
1996, 39, 1220. For an excellent paper on the bioactivity of naturally
occurring organohalogen compounds, see: (b) Gribble, G. W. Acc. Chem.
Res. 1998, 31, 141.
(6) (a) Review: Rodriguez, J .; Dulce`re, J .-P. Synthesis 1993, 1177.
(b) Neidleman, S. L.; Geigert, J . Biohalogenation: Principles, Basic
Roles and Applications, Ellis Horwood: Chichester, UK, 1986.
10.1021/jo034517f CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/19/2003
J . Org. Chem. 2003, 68, 6583-6586
6583

Barluenga et al.
SCHEME 2. Dia ster eofa cia l Selective Ad d ition of
Meth a n ol to Aceton id e 1a P r om oted by Ip y2BF 4
F IGURE 1. Model for the approach of iodonium ion to
acetonides 1a and 1b.
cally active molecules. All these facts prompted us to
investigate the convenience of using the reagent bispy-
ridine iodonium (I) tetrafluoroborate (Ipy2BF4)12 as a
promoter to accomplish diastereofacial selective inter-
molecular iodofunctionalization reactions of unsaturated
moieties derived from terpenes. On this basis, in this
paper we describe a novel strategy to propagate the
chirality of a terpene through the combination of the
powerful chemistry of boroxycarbene complexes to acti-
vate C-H bonds with the ability of Ipy2BF4 reagent in
addition reactions to unsaturated systems.
established for 2a . From ent-1a , derived from (+)-R-
pinene, was obtained ent-2a with good yield and again
as a single stereoisomer (entry 5). The behavior of
different terpene-based substrates was investigated using
methanol as a nucleophile. The regio- and stereoselec-
tivity of the reaction was tested on compounds 1b-d , also
derived from (-)-R-pinene. Under related conditions, 1b,c
led exclusively to adducts 2e,f, respectively, correspond-
ing to the Markonikov addition products as single dias-
tereoisomers (entries 6 and 7). The complete regio- and
diastereoselectivity observed in the reaction of 1d to give
2g (entry 8) are also remarkable. The structure of 2e-g
was determined by NMR experiments and, in the case
of 2e, was confirmed by X-ray analysis.15 In the same
way, acetonides 1e-g derived from (+)-2-carene and (+)-
3-carene, gave 2h -j, respectively, through efficient and
clean reactions as single diastereoisomers (entries 9-11).
The results described are fully compatible with an
electrophilic addition process. An initial formation of a
cyclic iodonium ion, followed by its subsequent capture
by the nucleophile, led to the formation of anti adducts.
The regiochemistry observed in the addition products is
that expected for a process controlled by the electronic
effects of the substituents. To account for the complete
diastereofacial selectivity observed, it is reasonable to
assume an initial coordination of the iodonium ion to the
allylic oxygen of the acetonide, thus favoring the ap-
proach of the iodine atom to the same face of the olefin
in which this oxygen is placed, as depicted in Figure 1
for compounds 1a and 1b.
Resu lts a n d Discu ssion
The acetonide 1a , derived from (-)-R-pinene,5 led to
the exclusive formation of 2a in 84% yield upon reaction
from -60 to -30 °C with Ipy2BF4 (1.1 equiv) and
tetrafluoroboric acid (1.5 equiv) in a solution containing
a 3:1 mixture of dichloromethane/methanol, as depicted
in Scheme 2. The structure and absolute configuration
of the generated stereocenters of 2a were unequivocally
determined by NMR spectral analysis and confirmed by
X-ray analysis.13
On this ground, we have explored the scope of this
reaction by varying the nucleophile and the unsaturated
system. The results are summarized in Table 1. Entries
1-4 correspond to the reaction of 1a with different
nucleophiles. Thus, to introduce the acetoxy group, a
larger excess of acetic acid (1:1 mixture of dichlo-
romethane/acetic acid) was used and the reaction was
carried out at room temperature (entry 2). In the case of
formation of azido derivative 2c, an equivalent of trim-
ethylsilyl azide was used as a nucleophile and boron
trifluoride was used instead of tetrafluoroboric acid (entry
3).14 To introduce the hydroxy group, a 1:1 mixture of
dichloromethane/acetonitrile was used as a solvent and
6% of water was added. In this case, the reaction was
carried out at room temperature and in the presence of
air (entry 4). The amount of water should be carefully
controlled to obtain the product 2d . When an excess of
water was used, a mixture of 2d and the corresponding
diol derived from the hydrolysis of the acetonide was
noticed. In all of the cases examined (2a -d ), single
diastereoisomers were formed and their stereochemis-
tries tentatively assigned on the basis of that firmly
The same iodofunctionalization reaction was attempted
with acetonides 1h and 1i, derived from (-)-phenylap-
opinene16 and (-)-myrtenol, respectively. However, treat-
ment of 1h with Ipy2BF4 and tetrafluoroboric acid in
dichloromethane at room temperature, in the presence
or absence of nucleophile, afforded the adduct 3 in 70%
yield as a single diastereoisomer. Likewise, acetonide 1i
in similar reaction conditions gave rise exclusively to 417
in 40% yield (Scheme 3). The structure and absolute
configuration of the generated stereocenters of 3 were
unequivocally determined by two-dimensional (COSY,
HMQC, HMBC, and NOESY) NMR spectral analysis.18
(15) Crystal data for 2e: recrystallized from dichloromethane/
chloroform 1:10, C23H33IO3, Mr ) 484.39, orthorhombic, space group
P212121, a ) 8.47 (6) Å, b ) 13.710 (15) Å, c ) 19.471 (4) Å, V ) 2260
(16) Å3, Z ) 4, Dx ) 1.424 Mg/m3, Mo KR radiation (λ ) 0.71073 Å), µ
) 1.436 mm-1, T ) 293 (2) K, final conventional R1 ) 0.042 and wR2
) 0.097 for 2860 “observed” reflections and 244 parameters. The
absolute configuration was checked by refining the Flack parameter
to ø ) 0.03 (4).
(12) Ipy2BF4 is a commercial reagent from either Novabiochem or
Aldrich. For a brief overall view on early applications, see: Barluenga,
J . Pure Appl. Chem. 1999, 71, 431.
(13) Crystal data for 2a : recrystallized from dichloromethane/
chloroform 1:10, C23H33IO3, Mr ) 484.39, trigonal, space group P32, a
) b ) 13.8260(9) Å, c ) 10.0880(6) Å, V ) 1670.1(2) Å3, Z ) 3, Dx
)
1.444 Mg/m3, Cu KR radiation (λ ) 1.54184 Å), µ ) 11.436 mm-1, T )
293 (2) K, final conventional R1 ) 0.041 and wR2 ) 0.1176 for 2389
reflections and 239 parameters. The absolute configuration was
checked by refining the Flack parameter to ø ) 0.007 (13).
(14) Barluenga, J .; Alvarez-Pe´rez, M.; Fan˜ana´s, F. J .; Gonza´lez, J .
M. Adv. Synth. Catal. 2001, 343, 335.
(16) Brown, H. C.; Weissman, S. A. J . Org. Chem. 1990, 55, 1217.
(17) Debenzylation and related reactions promoted by Ipy2BF4 are
subjects of study in our laboratory.
(18) Absolute configuration for 4 was assigned on the basis of that
established for 3.
6584 J . Org. Chem., Vol. 68, No. 17, 2003

Terpene Derivatives Based on Ipy2BF4
TABLE 1. Dia ster eofa cia l Selective Iod ofu n ction a liza tion Rea ction of Ter p en e-Der ived Alk en es Usin g Ip y2BF 4
a
b
Isolated yield based on acetonides 1. Mixture of dichloromethane/acetic acid (1:1) was used at room temperature. c TMSN3 (1 equiv)
d
and BF3 instead of HBF4 were used. Mixture dichloromethane/acetonitrile (1:1) containing 6% H2O was used at room temperature.
J . Org. Chem, Vol. 68, No. 17, 2003 6585

Barluenga et al.
SCHEME 3. Dia ster eoselective Iod ocycliza tion
Rea ction of 1h a n d 1i P r om oted by Ip y2BF 4
attacking the face of the olefin where the allylic oxygen
of the acetonide is placed.
Con clu sion s
We have described a simple and efficient strategy to
generate highly polyfunctional compounds in a diaste-
reoselective way by means of a new reaction sequence
based on the combination of the unusual and diastereo-
selective activation of terpenes (via C-H insertion) with
the use of Ipy2BF4 as a useful promoter of valuable
iodofunctionalization reactions. The presence of a phenyl
or benzyloxy group placed in a well-defined position of
the starting terpene-derived actonide gives rise to com-
plex cyclic molecules via diastereoselective iodocyclization
reactions. Having in mind that the highly functionalized
iodine containing products here described could be of
biological interest, it should be noted that the process
allows for the synthesis of many structurally diverse
analogues, as different building blocks can be varied
(starting terpene, side chain, nucleophile). All of these
issues and the potential of the products as chiral ligands
in organometallic chemistry are objects of study in our
laboratories.
The formation of 3 could be easily explained by
considering the iodocarbocyclization reaction in which the
phenyl group in the quaternary center of 1h acts as a
nucleophile, in a process that is favored by the ideal loca-
tion of the partners due to the terpene conformation.7e,19
In the same way, compound 1i could undergo an iodooxy-
cyclization reaction with concomitant debenzylation reac-
tion20 leading to iodo derivative 4. The absolute config-
uration of products 3 and 4 clearly indicate again that
the reactions of 1h and 1i proceed in the same diaste-
reofacially selective manner, that is, the iodonium ion
Ack n ow led gm en t. Financial support from the Di-
reccio´n General de Investigacio´n Cient´ıfica y Te´cnica
(Projects PB97-1271 and BQU-2001-3853), the Minis-
terio de Ciencia y Tecnolog´ıa (grant to M.A.-P.), and the
EU (Marie Curie fellowship to F.R.) is gratefully ac-
knowledged.
(19) (a) Barluenga, J .; Gonza´lez, J . M.; Campos, P. J .; Asensio, G.
Angew. Chem., Int. Ed. 1988, 27, 1546. (b) Goldfinger, M. B.; Crawford,
K. B.; Swager, T. M. J . Am. Chem. Soc. 1997, 119, 4578. (c) Barluenga,
J .; Romanelli, G. P.; Alvarez-Garc´ıa, L. J .; Llorente, I.; Gonza´lez, J .
M.; Garc´ıa-Rodr´ıguez, E.; Garc´ıa-Granda, S. Angew. Chem., Int. Ed.
1998, 37, 3136.
(20) (a) Rychnovsky, S. D.; Bartlett, P. A. J . Am. Chem. Soc. 1981,
103, 3963. (b) Williams, D. R.; White, F. H. J . Org. Chem. 1987, 52,
5067. (c) Kim, Y. G.; Cha, J . K. Tetrahedron Lett. 1988, 29, 2011. (d)
Zhang, H.; Wilson, P.; Ruan, Z.; Mootoo, D. R. Tetrahedron Lett. 1995,
36, 649. (e) Cipolla, L.; Lay, L.; Nicotra, F. J . Org. Chem. 1997, 62,
6678. (f) Khan, N.; Xiao, H.; Zhang, B.; Cheng, X.; Mootoo, D. R.
Tetrahedron 1999, 55, 8303.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details and spectroscopic data, X-ray crystal structure of 2a
and 2e (ORTEP, thermal ellipsoids), and tables of the crystal
data and structure refinement, atomic coordinates, bond
lengths, bond angles, isotropic displacement parameters,
hydrogen coordinates, and torsion angles. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O034517F
6586 J . Org. Chem., Vol. 68, No. 17, 2003