Mild TiIII- and Mn/ZrIV-catalytic reductive coupling of allylic halides: Efficient synthesis of symmetric terpenes

Article abstract of DOI:10.1021/jo062630a

(Chemical Equation Presented) Two new efficient methods for the regioselective homocoupling of allylic halides using either catalytic Ti ^III or the combination Mn/Zr^IV catalyst have been developed. The regio- and stereoselectivity of the process proved to increase significantly when the Mn/Zr^IV catalyst is used as the coupling reagent and when cyclic substituted allylic halides are used as substrates. The use of Lewis acids such as collidine hydrochloride allowed the quantity of catalyst to be lowered up to 0.05 equiv. We have proved the utility of these protocols with the synthesis of different terpenoids such as (+)-β-onoceradiene (1), (+)-β-onocerine (2), squalene (5), and advanced key-intermediates in the syntheses of (+)-cymbodiacetal (3) and dimeric ent-kauranoids as xindongnin M (4a).

Full text of DOI:10.1021/jo062630a

Mild TiIII- and Mn/ZrIV-Catalytic Reductive Coupling of Allylic
Halides: Efficient Synthesis of Symmetric Terpenes†
Alejandro F. Barrero,* M. Mar Herrador, Jose´ F. Qu´ılez del Moral, Pilar Arteaga,
Jesu´s F. Arteaga, Horacio R. Die´guez, and Elena M. Sa´nchez
Department of Organic Chemistry, Institute of Biotechnology, UniVersity of Granada, AVda. FuentenueVa,
18071 Granada, Spain
afbarre@goliat.ugr.es
ReceiVed December 21, 2006
Two new efficient methods for the regioselective homocoupling of allylic halides using either catalytic
TiIII or the combination Mn/ZrIV catalyst have been developed. The regio- and stereoselectivity of the
process proved to increase significantly when the Mn/ZrIV catalyst is used as the coupling reagent and
when cyclic substituted allylic halides are used as substrates. The use of Lewis acids such as collidine
hydrochloride allowed the quantity of catalyst to be lowered up to 0.05 equiv. We have proved the
utility of these protocols with the synthesis of different terpenoids such as (+)-â-onoceradiene (1), (+)-
â-onocerine (2), squalene (5), and advanced key-intermediates in the syntheses of (+)-cymbodiacetal (3)
and dimeric ent-kauranoids as xindongnin M (4a).
Introduction
organometallic compounds with allylic halides,4 the coupling
of π-methallylnickel(I) bromide with halides,5 the homocoupling
of alkyl halides via activated copper,6 the reductive coupling
of allylic halides by chlorotris(triphenylphosphine) cobalt(I),7
the coupling of allylic halides promoted by Te2- species,8 and
so on. Within the field of terpenoid synthesis, the homocoupling
Several publications have described methods to achieve the
homocoupling of both alkyl and allylic halides, including the
electrochemical coupling of allylic halides by using a copper
anode,1 the coupling of two allylic moieties via the reaction of
allylic or benzylic halides with SmI2 in THF,2 the reduction of
organic halides with lanthanum metal,3 the reaction of allylic
(4) Yamamoto, Y.; Maruyama, K. J. Am. Chem. Soc. 1978, 100, 6282-
† Dedicated to Professor Miguel Yus on the occasion of his 60th birthday.
(1) Tokuda, M.; Endate, K.; Suginome, H. Chem. Lett. 1988, 945-948.
(2) Krief, A.; Laval, A. Chem. ReV. 1999, 99, 745-777.
(3) Nishino, T.; Watanabe, T.; Okada, M.; Nishiyama, Y.; Sonoda, N.
J. Org. Chem. 2002, 67, 966-969.
6284.
(5) Corey, E. J.; Semmelhack, M. F. J. Am. Chem. Soc. 1967, 89, 2755-
2757.
(6) Ginah, F. O.; Donovan, T. A.; Suchan, S. D.; Pfenning, D. R.; Ebert,
G. W. J. Org. Chem. 1990, 55, 584-589.
10.1021/jo062630a CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/22/2007
2988
J. Org. Chem. 2007, 72, 2988-2995

TiIII- and Mn/ZrIV-Catalytic ReductiVe Coupling
SCHEME 1. Possible Mechanistic Pathways for the
Homocoupling of Allylic Halides
reaction of allylic halides using Rieke barium9 is very interesting,
giving satisfactory results in the coupling of (E,E)-farnesyl
barium with farnesyl bromide. This process represents the first
direct synthesis of squalene by the coupling of two E,E-farnesyl
units. Most of the above-mentioned methods use stoichometric
quantities of reducing species.
FIGURE 1. Natural dimeric structures.
Titanocene chloride10 has been widely used through SET
processes in the homolytic opening of oxiranes11 and in pinacol
coupling reactions.12 It has also been used in the reduction of
glycosyl bromides13and vic-dibromides14 and in the homocou-
pling of allylic and benzylic halides15 with satisfactory results.
These reactions take place under mild conditions and are
tolerated by a large number of functional groups, such as
alcohols, amines, amides, ketones, acids, and esters.13d By
comparison with their TiIII analogues, ZrIII complexes have been
much less used in organic synthesis. Zirconocene chloride can
be obtained by reduction of Cp2ZrCl2 with sodium-amalgam in
THF or toluene.16b,c,17 Cp2ZrCl has been used to achieve
pinacolinic couplings with aliphatic aldehydes.17 These pina-
colinic couplings have also been successfully achieved using
catalytic amounts of Cp2ZrCl2 in the presence of Mg and
TMSCl.18 Cp2ZrCl also provokes the slow reduction of glycosyl
halides to glycals,10,13d although when this reagent was prepared
in situ, it proved to be more efficient than Cp2TiCl for the
reduction of aliphatic halides.
Bearing in mind the mechanism proposed for the reactions
mediated by these two reagents, we surmised that these species
could well intervene efficiently in the homocoupling of allylic
halides (Scheme 1).
In a previous paper19a we described the first results of a new
catalytic method for the homocoupling of allylic bromides
mediated by TiIII, including the enantioselective preparation of
onocerane derivatives 1 and 2. We describe here the complete
development of the process, the ability of ZrIV to catalyze these
homocouplings in the presence of manganese metal (to our
knowledge no precedence of ZrIV catalyzing these kind of
processes can be found in the literature), and finally, new
applications toward the synthesis of symmetric terpenes, such
as the preparation of advanced key-intermediates in the syn-
theses of (+)-cymbodiacetal (3)20 and dimeric ent-kauranoids
(4), such as xindongnin M (4a),21 and an improved synthetic
way to prepare squalene (5) (Figure 1).
(7) Momose, D.; Iguchi, K.; Sugiyama, T.; Yamada, Y. Tetrahedron Lett.
1983, 24, 921-924.
(8) Clive, D. L. J.; Anderson, P. C.; Moss, N.; Singh, A. J. Org. Chem.
1982, 47, 1641-1647.
(9) (a) Wu, T.-C.; Hiong, H.; Rieke, R. D. J. Org. Chem. 1990, 55, 5045-
5051. (b) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am. Chem. Soc.
1991, 113, 5893-5895. (c) Corey, E. J.; Noe, M. C.; Shieh, W.-C.
Tetrahedron Lett. 1993, 34, 5995-5998.
(10) Spencer, R. P.; Schwartz, J. Tetrahedron 2000, 56, 2103-2112.
(11) (a) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110,
8561-8562. (b) For a recent review of different cyclization reactions
mediated by Cp2TiCl and its use in the construction of natural products:
Barrero, A. F.; Qu´ılez del Moral, J. F.; Arteaga, J. F.; Sa´nchez, E. M. Eur.
J. Org. Chem. 2006, 7, 1627-1641. (c) Barrero, A. F.; Qu´ılez del Moral,
J. F.; Sa´nchez, E. M.; Arteaga, J. F. Org. Lett. 2006, 8, 669-672.
(12) Gansa¨uer, A.; Moschioni, M.; Bauer, D. Eur. J. Org. Chem. 1998,
1923-1927.
(13) (a) Cavallaro, C. L.; Schwartz, J. J. Org. Chem. 1995, 60, 7055-
7057. (b) Spencer, R. P.; Schwartz, J. Tetrahedron Lett. 1996, 37, 4357-
4360. (c) Spencer, R. P.; Schwartz, J. J. Org. Chem. 1997, 62, 4204-
4205. (d) Spencer, R. P.; Cavallaro, C. L.; Schwartz, J. J. Org. Chem. 1999,
64, 3987-3995. (e) Hansen, T.; Krintel, S. L.; Daasbjerg, K.; Skrydstrup,
T. Tetrahedron Lett. 1999, 40, 6087-6090. (f) Hansen, T.; Daasbjerg, K.;
Skrydstrup, T. Tetrahedron Lett. 2000, 41, 8645-8649.
(14) Davies, S.; Thomas, S. E. Synthesis 1984, 1027-1029.
(15) (a) Yanlong, Q.; Guisheng, L.; Huang, Y. J. Organomet. Chem.
1990, 381, 29-34. (b) Rasmus, J. E.; Larsen, J.; Skrydstrup, T.; Daasbjerg,
K. J. Am. Chem. Soc. 2004, 126, 7853-7864.
Results and Discussion
The development of these synthetic methods began with the
use of geranyl bromide (6) and its geometric stereoisomer neryl
bromide (7).19a The treatment of 6 and 7 in THF with an excess
of Cp2TiCl led rapidly to the formation of the homocoupling
products being the RR′ coupling majority together with lesser
quantities of the Rγ′ adduct (8 and 9) (Figure 2). Digeranyl
and isodigeranyl, regioisomers derived from the coupling of 6
(obtained with 57% and 32%, respectively), are naturally
occurring terpenes found in the commercially available bergamot
oil.22
According to these results, we surmised that the process may
well begin with a fast single-electron transfer (SET) from Cp2-
(19) (a) Barrero, A. F.; Herrador, M. M.; Qu´ılez del Moral, J. F.; Arteaga,
P.; Arteaga, J. F.; Piedra, M.; Sa´nchez, E. M. Org. Lett. 2005, 7, 2301-
2304. (b) Barrero, A. F.; Herrador, M. M.; Qu´ılez del Moral, J. F.; Arteaga,
P.; Arteaga, J. F.; Piedra, M.; Sa´nchez, E. M. Synfacts 2005, 1, 157.
(20) (a) Bottini, A. T.; Dev, V.; Garfagnoli, D. J.; Hope, H.; Joshi, P.;
Lohani, H.; Mathela, C. S.; Nelson, T. E. Phytochemistry 1987, 26, 2301-
2302. (b) D’Souza, A.; Paknikar, S. K.; Dev, V.; Beauchamp, P. S.; Kamat,
S. P. J. Nat. Prod. 2004, 67, 700-702.
(21) Han, Q.-B.; Lu, Y.; Zhang, L.; Zheng, Q.; Sun, H. Tetrahedron
Lett. 2004, 45, 2833-2837.
(22) Soucek, M.; Herout, V.; Sorm, F.; Ceskoslov, A. Collect. Czech.
Chem. Commun. 1961, 26, 2551-2556.
(16) (a) Fochi, G.; Guidi, G.; Floriani, C. J. Chem. Soc., Dalton Trans.
1984, 1253-1256. (b) Cuenca, T.; Royo, P. J. Organomet. Chem. 1985,
293, 61-67. (c) Paul, R. C.; Raj, T.; Parkash, R. Indian J. Chem. 1972,
10, 939-940.
(17) Barden, M. C.; Schwartz, J. J. Org. Chem. 1997, 62, 7520-7521.
(18) Kantam, M. L.; Aziz, K.; Likhar, P. R. Synth. Commun. 2006, 36,
1437-1445.
J. Org. Chem, Vol. 72, No. 8, 2007 2989

Barrero et al.
SCHEME 2. 6-Exo-Trig Cyclization Reaction
FIGURE 2. Coupling of allylic bromides using Cp2TiCl2/Mn.
TiCl (generated in situ) to the corresponding halogenated
derivative to give an allylic radical species (I). This would then
either dimerize to give the coupling products or suffer a second
SET process to give an allyltitanium species (II), which would
react with a molecule of unaltered halogenated derivative to
also produce the coupling products (Scheme 1).
easily obtained by regioselective chlorination of â-pinene)25
were made to react with only 0.2 equiv of Cp2TiCl2 and an
excess of Mn. It was then found that these reactions took place
rapidly (5-15 min) to form the hoped-for coupling products
(8, 9, 12, 13, 16, 18, 20, 22, and 24) (Table 1, entries 1, 2,
4-11), with acceptable selectivity and yields ranging from good
to excellent (64-98%). The results obtained with compound
19 deserve special consideration. In this case, the starting
material was recovered after 23 h of reaction (Table 1, entry
3). Nevertheless, when the concentration of the coupling reaction
of 19 was increased from 0.07 to 0.8 M, 85% of the coupling
products 20 was yielded in only 5 min (Table 1, entry 4). The
need for a higher concentration in this case compared with the
rest of the allylic halides studied may be attributed to the greater
stability of the intermediate radical. This concentration effect
may suggest that compounds 20 are formed by radical dimer-
ization.
The results shown in Table 1 allowed us to extend the
catalytic coupling reaction to different structures deriving from
allylic halides and are in accordance with the proposed absence
of radicals during the coupling process, given that under these
catalytic conditions the concentration of radical I (Scheme 1)
would be much lower and the probability of coupling would
fall significantly versus the much more favorable cyclization
process (Table 1, entries 5-9).
To provide more data about the mechanistic aspects of this
coupling, we carried out the reaction with the compounds 10
and 11, in which the R,â-unsaturated methyl ester group ought
to favor the radical cyclization process.23 The treatment of 10
and 11 with TiIII produced similar results to those obtained with
6 and 7, and the homocoupling products 12 and 13 were
obtained in yields of 84% and 60%, respectively, and no
cyclization products were observed. On the other hand, when
10 and its geometric stereoisomer 11 were treated with n-Bu3-
SnH/AIBN in benzene at 80 °C under free-radical-forming
conditions, the corresponding cyclization product, methyl 1-p-
menthen-9-oate (14),24 was formed via a 6-exo-trig process
involving allylic radical Ia (Scheme 2). In both cases the
cyclization yields were about 70%, together with a 10% yield
of coupling products. Thus, the tendency of Ia to cyclize rather
than to dimerize seems to confirm the involvement of an
allyltitanium species in the formation of the coupling com-
pounds. Additionally, this process constitutes an efficient and
new mild method for the biomimetic preparation of p-menthanes
starting from geraniol or nerol.
Once we had established the presence of the allyltitanium
species as intermediates in this reaction and bearing in mind
that in this double SET process Cp2TiClBr is released, we
anticipated that the excess of Mn in the medium ought to permit
the regeneration of TiIII from Cp2TiClBr and thus render the
process susceptible to catalysis by titanium. Gratifyingly, when
6 was made to react with 0.4 equiv of Cp2TiCl2 and an excess
of Mn, the hoped-for conversion took place efficiently, produc-
ing 88% coupling products 8. To our knowledge this protocol
constitutes the only catalytic process involving the reduction
of allylic halides.
To find out the extent to which the quantity of TiIII could be
reduced in this catalytic process, we made several assays
lowering the proportion of Cp2TiCl2 used and deduced that the
minimum quantity necessary for the reaction to take place was
0.2 equiv. Experiments made with lesser quantities of TiIII
invariably showed the presence of unaltered starting material
even after prolonged reaction times.
Once we had established the catalytic process, we began to
study the possibility of further decreasing the quantities of Cp2-
TiCl2 and Mn by using electrophilic salts such as 2,4,6-collidine
hydrochloride and LiCl (Table 2).
With allylic bromide 10 as the starting material, we reduced
the initial quantity of Cp2TiCl2 to 0.1 equiv, obtaining 31% of
homocoupling products and recovering 27% of 10 after 90 min
(Table 2, entry 2). When using 0.05 equiv of TiIII and 1.5 equiv
of Mn, no reaction took place and the starting material was
recovered after 90 min (Table 2, entry 3). Nevertheless, when
2,4,6-collidine hydrochloride (2.5 equiv) was added to the
reaction medium, the homocoupling of 10 or 11 completed in
20 min (Table 2, entries 4 and 5), although the corresponding
reduction product was formed to some extent (12%). If 2,4,6-
collidine hydrochloride is replaced by LiCl (2.5 equiv) (Table
2, entry 6), the hoped-for homocoupling products 12 (38%) were
now accompanied by the formation of the trans-halogenated
derivative 27 (17%). It is believed that 2,4,6-collidine hydro-
To widen the scope of this catalytic procedure, apart from
the previously reported allylic terpenic halides 6, 7, 10, 11, and
21,19a other structurally varied allylic bromides such as 15, 17,
19, and 23 and the secondary chloro derivative 25 (which is
(23) Zhang, W. Tetrahedron 2001, 57, 7237-7262.
(24) Compound 14 was obtained as a mixture of diastereoisomers at a
1:1 ratio.
(25) Barrero, A. F.; Qu´ılez del Moral, J. F.; Herrador, M. M.; Corte´s,
M.; Arteaga, P.; Catala´n, J. V.; Sa´nchez, E. M.; Arteaga, J. F. J. Org. Chem.
2006, 71, 5811-5814.
2990 J. Org. Chem., Vol. 72, No. 8, 2007

TiIII- and Mn/ZrIV-Catalytic ReductiVe Coupling
TABLE 1. Coupling of Allylic Halidesa under Catalytic Conditionsb of TiIII
a Prepared by the reaction of the corresponding alcohols with Ph3P/CBr4 in benzene except for the commercially available 6, 15, 17, and 19 and for the
b
secondary chloro derivative 25, which is easily obtained by regioselective chlorination of â-pinene. 0.2 equiv of Cp2TiCl2 and 8.0 equiv of Mn, THF, rt.
c Molar concentration compared to the starting material. d Determined by GC-MS analysis. e A certain degree of E/Z isomerization was observed. In most
cases the different isomers obtained in each coupling process could be isolated either by column chromatography on AgNO3 (20%)-silica gel or by HPLC.
f Isolated yield after column chromatography. g Determined by GC-MS analysis. h This yield includes 15% of the γγ′ regioisomer.
J. Org. Chem, Vol. 72, No. 8, 2007 2991

Barrero et al.
TABLE 2. Effect of 2,4,6-Collidine Hydrochloride and LiCl on the Reductive Coupling of Allylic Bromides
equiv of
2,4,6-collidine
hydrochloride
compd
(yield, %)
entry
allylic bromide
equiv of Cp2TiCl2
equiv of Mn
concna (M)
time (min)
equiv of LiCl
1
2
3
4
5
6
10
10
10
10
11
10
0.2
0.1
0.05
0.05
0.05
0.05
8.0
8.0
1.5
1.5
1.5
1.5
0.07
0.07
0.07
0.07
0.07
0.07
10
90
90
20
20
60
0
0
0
0
0
2.5
0
0
0
2.5
2.5
0
12 (85)
12 (31)b
no reaction
12 (58)c
13 (55)d
12 (38)e
a Molar concentration of the starting material. b 27% of 10 was recovered. c A 12% yield of the reduced product was obtained. d A 12% yield of the
reduced product was obtained. e A 17% yield of the trans-halogenated compound 27 was also obtained.
TABLE 3. Coupling of Allylic Bromides under Catalytic Conditions of ZrIV
entry
allylic halide
Cp2ZrCl2
concna (M)
time
coupling products
ratiob (RR′/Rγ′)
yieldc (%)
1
2
3
4
5
6
7
23
23
23
6
19
10
25
0.2
0.2
0.3
0.3
0.3
0.3
0.3
0.07
0.8
0.8
0.8
0.8
0.8
0.8
28 h
21 h
no reaction
24
24
8
20
12
35d
65
10 min
20 min
30 min
20 min
24 h
70:30
81:19
48:52
82:18
84
82e
78
no reaction
a Molar concentration compared to the starting material. b Determined by GC-MS analysis. c Isolated yield after column chromatography. d Even after
21 h, 32% of starting material 23 was recovered. e This yield includes 14% of the γγ′ regioisomer.
chloride or LiCl establish a Lewis acid-base interaction with
the allylic bromide, which facilitates its reduction and subse-
quent coupling. Thus we conclude that the quantity of Cp2TiCl2
and Mn used in the standard protocol (3.0 and 8.0 equiv,
respectively) can be considerably reduced to 0.05 equiv of Cp2-
TiCl2 and 1.5 equiv of Mn with no significant loss of efficiency
in the process.
Another factor that has been analyzed during this work is
the influence of the type of C-X bond (X ) Cl, Br, I) upon
the coupling reactions. As expected, the main difference
observed was the lesser reactivity of the chloro derivative, 27,
compared to the bromo and iodo derivatives, 10 and 28. Thus,
while with 10 and 28 the coupling reaction completed in 10
and 5 min with yields of 85% and 84%, 27 generated 57%
coupling products 12 in 75 min, with 10% of the starting
material being recovered. The differences in reactivity found
can be attributed to the different speeds at which radical I was
formed due to the different dissociation energies of the C-X.26
Nevertheless, an increase to 0.8 M in the concentration of the
starting material led to a 35% yield of the coupling products
24 with 32% of the starting material being recovered (Table 3,
entry 2). However, although it has been reported that THF
solutions of Cp2ZrCl are deep red,16b,17 in our case, the
combination of Cp2ZrCl2 and Mn in THF remained colorless,
which suggests that ZrIII species were not originated. Thus, with
the aim of gaining an insight into the real active species in this
process, we proceeded to reduce Cp2ZrCl2 with Na(Hg)
amalgam16b to obtain a deep red solution, thus confirming the
presence of ZrIII species. Addition of myrtenyl bromide to this
ZrIII solution did not lead to any coupling adduct in our hands.
Considering that Mn itself is not able to reduce allylically
halogenated derivatives, an activation of the C-X bond by Cp2-
ZrCl2 (acting as an efficient Lewis acid) is proposed as the
preliminary step to trigger this Cp2ZrCl2/Mn-mediated trans-
formation.27 The thus-activated C-X bond is now susceptible
to be reduced by Mn to give the corresponding organomanga-
nese derivatives (species represented in Scheme 1 by II with
M now being Mn).
Additionally, we found that the yield of this process could
be further improved when the reaction was carried out at the
same molar concentration but increasing the quantity of ZrIV
from 0.2 to 0.3 equiv (Table 3, entry 3). In this case, the
conversion is total, and 23 gave rise to the corresponding
1
coupling products 24 after only 10 min with a 65% yield. H
We then turned our attention to the behavior of the ZrIII
species analogous to those of TiIII. Bearing in mind both the
antecedents of ZrIII chemistry and the similar electronic structure
of Zr and Ti, we presumed that the ZrIII species could also affect
the homocoupling of allylic halides. We began this study by
making myrtenyl bromide (23) react under the standard catalytic
conditions used with TiIII, namely, 0.2 equiv of Cp2ZrCl2, 8
equiv of Mn, and THF (0.07 M). After 28 h, no coupling product
was formed and 23 was recovered unaltered (Table 3, entry 1).
NMR and GC-MS analyses of the coupling adducts showed a
distribution of regioisomers 70:30 favoring the RR′ regioisomer.
When these data were compared to those obtained with TiIII
(Table 1, entry 10), a noticeable increase of the reaction
regioselectivity was observed when the combination Mn/ZrIV
catalyst was used, while the efficiency of the coupling showed
(27) (a) Ma, J.; Chan, T.-H. Tetrahedron Lett. 1998, 39, 2499-2502.
(b) Li, C.-J.; Meng, Y.; Yi, X. H. J. Org. Chem. 1998, 63, 7498-7504. (c)
Kim, S.-H.; Rieke, R. D. J. Org. Chem. 2000, 65, 2322-2330. (d) Hiyama,
T.; Obayashi, M.; Nakamura, A. Organomet. 1982, 1, 1249-1251. (e)
Cahiez, G.; Chavant, P.-Y. Tetrahedron Lett. 1989, 30, 7373-7376. (f)
Suh, Y.; Lee, J.-S.; Hoi, S.; Rieke, R. D. J. Organomet. Chem. 2003, 684,
20-36.
(26) (a) 83.2 kcal/mol (C-Cl), 70.9 kcal/mol (C-Br), and 57.6 kcal/
mol (C-I). (b) Mc Givern, W. S.; North, S. W.; Francisco, J. S. J. Phys.
Chem. A 2000, 104, 436-442. (c) Blansksby, S. J.; Ellison, G. B. Acc.
Chem. Res. 2003, 36, 255-263.
2992 J. Org. Chem., Vol. 72, No. 8, 2007

TiIII- and Mn/ZrIV-Catalytic ReductiVe Coupling
SCHEME 3
SCHEME 6. Preparation of Dimeric ent-Kauranoids
SCHEME 4. Approach to the Synthesis of
(+)-Cymbodiacetal (3)
obtained with Ti.III In fact, when geranyl bromide was used as
the substrate, the 6:1 ratio of (6E,10E) and (6Z,10E) RR′ isomers
obtained with TiIII improved by up to 50:1 when ZrIV/Mn
mediated the coupling process. This seems to indicate that
geometric isomerization (trans to cis) of the allylic manganese
should be kept to a minimum during the coupling conditions,
which makes this process particularly advantageous. Finally,
as happened to be with the TiIII-mediated reactions of allylic
bromides 6 and 10, when these compounds were exposed to
the combination Mn/ZrIV catalyst, only the corresponding
homocoupling products were obtained (Table 3, entries 4 and
6). The absence of cyclization adducts seems to confirm again
that these homocoupling processes should proceed via allylic
manganese rather than via radical dimerization (Scheme 1).
SCHEME 5. Homocoupling Reaction of (R)-Perillyl
Bromide (34): Synthesis of the Advanced Intermediate 36
When the secondary allylic chloride 25 was treated under
these catalytic procedure conditions, the homocoupling products
24 were not formed and the starting material was recovered
unaltered even after prolonged reaction times (Table 3, entry
7). When 25 was exposed to catalytic TiIII, a 90% yield of
homocoupling products 24 was obtained in only 5 min (Table
1, entry 11).
Although we have already reported the synthesis of (+)-â-
onoceradiene (1) and (+)-â-onocerine (2) via TiIII-induced
homocoupling of key intermediates 29 and 30,19a we considered
that these homocoupling products could also be achieved using
Mn and catalytic Cp2ZrCl2, which would also allow the utility
of this method to be tested. Thus, when 29 and 30 were treated
using the combination Mn/ZrIV catalyst, (+)-â-onoceradiene and
(+)-â-onocerine were obtained in comparable yields to those
obtained with TiIII (Scheme 3).
We present here new applications of these catalytic homo-
coupling protocols, such as the preparation of compound 36,
an advanced key-intermediate in the enantioselective synthesis
of (+)-cymbodiacetal (3) (Scheme 5), and the straightforward
access to the framework of naturally occurring dimeric ent-
kauranoids 4 (Scheme 6).
(+)-Cymbodiacetal (3) is a dihemiacetal bis-monoterpenoid
isolated from the essential oil of Cymbopogon martini.20 Several
varieties of this plant are cultivated for use in soaps and
perfumes. The enantioselective synthesis of (+)-cymbodiacetal
(3) was designed starting from (R)-perillyl aldehyde (32)
(Scheme 4). The key step of this strategy rests on the
homocoupling reaction of (R)-perillyl bromide (34) catalyzed
by TiIII or ZrIV to obtain the key intermediate 7,7′-bis((4R)-1,8-
p-menthadiene) (35a).
no substantial alteration. Similar results were found when either
geranyl bromide (6) (Table 3, entry 4) or cinnamyl bromide
(19) (Table 3, entry 5) was treated with 0.3 equiv of ZrIV, which
seems to confirm the increase of regioselectivity derived from
the use of this reagent in all cases. Furthermore, a thorough
analysis of the H NMR and GC-MS of the homocoupling
products now showed an almost complete geometric purity of
the RR′ and Rγ′ adducts, thus improving significantly the results
1
J. Org. Chem, Vol. 72, No. 8, 2007 2993

Barrero et al.
TABLE 4. Synthesis of Squalene (5)
in mind the higher degree of regioselectivity and geometric
purity of the Mn/Zr-mediated couplings, we hoped that this yield
could be improved using these metals. Gratifyingly, the exposure
of 39 to 0.3 equiv of ZrIV and 8 equiv of Mn led to a 51% yield
1
of squalene (Table 4, entry 2). In fact, the H NMR and GC-
MS analyses of the coupling products in both cases showed
that the 66:22:12 ratio of RR′(EE)/RR′(ZE)/Rγ′(E) regioisomers
obtained with TiIII improved considerably in the ZrIV-mediated
process, where no E/Z isomerization was noticed and a 82:18
ratio of RR′(EE)/Rγ′(E) regioisomers was obtained. This
catalytic process probably constitutes one of the easiest and most
efficient synthetic ways to prepare squalene.
coupling
products squalene
(min) yield (%) yield (%)
allylic
concn time
(M)
entry bromidea TiIII ZrIV
1
2
39
39
0.2
0
0
0.3
0.07
0.8
10
60
63
62
43
51
Conclusion
a Prepared by reaction of trans,trans-farnesol with Ph3P/CBr4 in C6H6.
In conclusion, we present new catalytic methods for the
homocoupling of allylic halides mediated either by TiIII or by
Mn/ZrIV species with good to excellent yields. Thus, on the one
hand, the range of applicability of the previously published Cp2-
TiCl-protocol coupling has been widened with the successful
homocoupling of a number of allylic halides. Furthermore, it
was found that the use of Lewis acids such as 2,4,6-collidine
hydrochloride allows for the lowering of the quantity of TiIII
up to 0.05 equiv. On the other hand, the results obtained in the
use of the combination Mn and Cp2ZrCl2 catalyst are presented.
Both methods are very mild and should tolerate most functional
groups. It is noteworthy that the regioselectivity of the process
increases significantly when the combination Mn/ZrIV catalyst
is used as the reagent and when cyclic substituted allylic halides
are used as substrates. These reagents have been employed in
the efficient synthesis of symmetric terpenes, such as the
onocerane derivatives (1 and 2), the preparation of an advanced
key-intermediate in the enantioselective synthesis of (+)-
cymbodiacetal (3), the framework of dimeric ent-kauranoids (4),
and the synthesis of squalene (5).
Allylic bromide 34 was obtained by reduction of com-
mercially available (R)-perillyl aldehyde (32) with LiAlH4/THF
and subsequent bromination with CBr4/Ph3P. (R)-Perillyl bro-
mide (34) in the presence of 0.2 equiv of TiIII or 0.3 equiv of
ZrIV underwent the expected homocoupling reaction to give 77%
and 75%, respectively, of the corresponding coupling adducts,
with the RR′ regioisomer 35a being the major reaction product
(Scheme 5). Moving forward with the synthetic planning, we
found that compound 35a could be chemo- and stereoselectively
hydroxylated to efficiently lead to tetrol 36 as the only detectable
stereoisomer using AD-mix-â,28 as evidenced by the NOE effect
observed between H2 and H4, both protons in an axial
disposition in the most stable chair conformation of the
cyclohexane ring in 36. Even though preliminary dihemiacetal
formation assays (PDC and Dess-Martin oxidations) were
disappointing in that they furnished unacceptably low yields
(approximately 5%) of the desired natural product 3, the four-
step sequence illustrated above for the preparation of 36 appears
sufficiently promising to warrant completion of the synthesis.
Recently, the isolation of bioactive dimeric ent-kauranoids,
such as xindongnins M-O,21 lushanrubescensin J,29 and bis-
rubescensins A-C30 from different species of Isodon rubescens,
called our attention. It was then envisioned that the dimeric
framework of these structures could be easily constructed via
the TiIII- or ZrIV/Mn-mediated homocoupling of the correspond-
ing allylic halides (Scheme 6). We chose as the starting material
ent-kaur-16-en-19-ol isolated from Odontites longiflora.31 When
its acetate derivative 37 was treated with PhSeCl and NCS,25
the mixture of allylic chlorides 38 was obtained. When this
mixture was exposed to catalytic TiIII, we found the octacyclic
structure 4, although unreacted starting material 38 remained
unaltered even after prolonged reaction times. It was neverthe-
less found that when 1.1 equiv of Cp2TiCl was used, the reaction
was completed after only 5 min and a 67% yield of dimer 4
was obtained.
Experimental Section
Homocoupling Reactions. Catalytic Protocol with TiIII. A
mixture of Cp2TiCl2 (190 mg, 0.74 mmol) and Mn dust (1620 mg,
29.44 mmol) in thoroughly deoxygenated THF (50 mL) and under
Ar atmosphere was stirred at rt until the red solution turned green.
The corresponding allylic halide (3.68 mmol) in strictly deoxy-
genated THF (1 mL) was then added to the Cp2TiCl solution. The
reaction mixture was stirred for 15 min, quenched with 1 N HCl,
extracted with t-BuOMe, washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The resulting
crude product was purified by column chromatography on silica
gel to afford the corresponding coupling products.
Representative Example. (R)-Perillyl bromide (34) (2644 mg,
12.3 mmol) was subjected to the TiIII catalytic procedure conditions
(631 mg, 2.46 mmol of Cp2TiCl2 and 5412 mg, 98.4 mmol of Mn),
and the resulting crude product was purified by column chroma-
tography on silica gel (hexane/t-BuOMe, 50:1) to afford 1275 mg
(77% yield) of a mixture of the corresponding coupling products
35 (RR′/(Rγ′ + γγ′) at a 54:46 ratio). The corresponding mixture
was subjected to flash column chromatography on AgNO3 (20%)-
silica gel (hexane/t-BuOMe, 99:1), and two fractions were obtained,
the first containing the RR′ coupling product 7,7′-bis((4R)-1,8-p-
menthadiene) (35a) and the second containing the Rγ′ coupling
product (4R)-7-((2R,4R)-1(7),8-p-menthadien-2-yl)-1,8-p-mentha-
diene (35b). Finally, t-BuOMe was added and the γγ′ coupling
product (35c) could be isolated.
Finally, we previously reported that squalene (5) can be
prepared from trans,trans-farnesyl bromide (39) using 0.2 equiv
of TiIII in only one step in 43% yield (Table 4, entry 1). Bearing
(28) (a) Anderson, P. G.; Sharpless, K. B. J. Am. Chem. Soc. 1993, 115,
7047-7048. (b) Vidari, G.; Dappiaggi, A.; Zanoni, G.; Garlaschelli, L.
Tetrahedron Lett. 1993, 34, 6485-6488.
(29) Han, Q.-B.; Lu, Y.; Wu, L.; He, Z.-D.; Qiao, C.-F.; Xu, H.-X.;
Zheng, Q.-T.; Sun, H.-D. Tetrahedron Lett. 2005, 46, 5373-5375.
(30) Huang, S.-X.; Xiao, W.-L.; Li, L.-M.; Li, S.-H.; Zhou, Y.; Ding,
L.-S.; Lou, L.-G.; Sun, H.-D. Org. Lett. 2006, 8, 1157-1160.
(31) Barrero, A. F.; Riu, M. V.; Ramirez, A.; Altarejos, J. An. Quim.
1988, 84C, 203-206.
Catalytic Protocol with ZrIV. A mixture of Cp2ZrCl2 (462 mg,
1.58 mmol) and Mn dust (2323 mg, 42.20 mmol) in deoxygenated
THF (9 mL) and under Ar atmosphere was stirred at rt. The
2994 J. Org. Chem., Vol. 72, No. 8, 2007

TiIII- and Mn/ZrIV-Catalytic ReductiVe Coupling
corresponding allylic bromide (5.28 mmol) in strictly deoxygenated
THF (1 mL) was then added (TLC monitoring). The reaction
mixture was quenched with 1 N HCl, extracted with t-BuOMe,
washed with brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The resulting crude product was purified
by column chromatography on silica gel to afford the corresponding
coupling products 35.
Representative Example. (R)-Perillyl bromide (34) (240 mg,
0.95 mmol) was subjected to the ZrIV/Mn catalytic procedure
conditions (56 mg, 0.19 mmol of Cp2ZrCl2 and 421 mg, 7.67 mmol
of Mn), and the resulting crude was purified by column chroma-
tography on silica gel (hexane/t-BuOMe, 50:1) to afford 192 mg
(75% yield) of a mixture of the corresponding coupling products
35 (RR′/(Rγ′ + γγ′) at a 63:37 ratio).
7,7′-Bis((4R)-1,8-p-menthadiene) (35a). [R]D +75.9 (c 2.65,
CH2Cl2); ν (film) 3080, 2962, 2921, 2854, 1644, 1455, 1436, 1373,
886 cm-1; δH (400 MHz, CDCl3) 1.48 (2H, ddd, J ) 5.6, 11.3,
17.1 Hz), 1.75 (6H, s), 1.80-1.85 (2H, m), 1.87-2.15 (10H, m),
2.06 (4H, bs), 4.73 (4H, bs), 5.43 (2H, bs) ppm; δC (100 MHz,
CDCl3) 20.9, 28.0, 29.0, 30.9, 36.1, 41.3, 108.5, 120.3, 137.6, 150.3
ppm; EIMS (70 eV) m/z (relative intensity) 270 (15), 227 (35),
187 (22), 159 (18), 145 (32), 134 (25), 119 (55), 105 (61), 93 (95),
91 (100), 79 (73), 67 (42), 44 (45).
7,7′-Bis(1(R),2(R)-dihydroxy-8-p-menthene) (36). 7,7′-Bis-
((4R)-1,8-p-menthadiene) (35a) (285 mg, 1.06 mmol) was added
to a solution of AD-mix-â (2968 mg) and CH3SO2NH2 (207 mg,
2.11 mmol) in t-BuOH/H2O 1:1 (10 mL) at 0 °C and stirred. After
7 h, Na2S2O3 (2385 mg) was added to the reaction mixture while
stirring for 10-20 min was continued at rt. The t-BuOH was
removed and extracted with EtOAc. The organic phase was washed
with 6 N NaOH (3 × 100 mL) and brine, then dried over anhydrous
Na2SO4, and concentrated under reduced pressure, with the crude
product thus obtained being purified by column chromatography
on silica gel (t-BuOMe) to give 36 (230 mg, 65%). [R]D +9.96 (c
0.5, MeOH); ν (film) 3399, 3327, 2941, 2916, 2854, 1642, 1441,
1261, 1161, 1062, 880, 749 cm-1; δH (400 MHz, DMSO) 1.10-
1.65 (16H, m), 1.66 (6H, s), 1.80-1.90 (2H, m), 3.20 (2H, m),
4.22 (2H, d, J ) 6.7 Hz), 4.63 (2H, s), 4.64 (2H, s) ppm; δC (100
MHz, DMSO) 20.7, 25.7, 32.3, 33.5, 35.3, 43.2, 71.6, 72.9, 108.4,
149.5 ppm; HRFABMS calcd for C20H34O4Na [M + Na]+
361.2355, found 361.2354.
mmol) in strictly deoxygenated THF (1 mL) were added to the
solution of Cp2TiCl. The reaction mixture was stirred for 5 min,
quenched with 1 N HCl, extracted with t-BuOMe, washed with
brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The resulting crude product was purified by
column chromatography on silica gel (hexane/t-BuOMe, 20:1) to
afford a 67% yield of the coupling product 4. [R]D -42.0 (c 1.0,
CH2Cl2); ν (film) 2926, 2865, 1739, 1456, 1371, 1238, 1031 cm-1
;
δH (400 MHz, CDCl3) 0.94 (6H, s), 1.04 (6H, s), 1.20-1.90 (36H,
m), 2.04 (6H, s), 2.20 (4H, s), 2.39 (2H, bs), 3.87 (1H, d, J ) 11.0
Hz), 4.22 (2H, d, J ) 11.0 Hz), 5.07 (2H, bs) ppm; δC (100 MHz,
CDCl3) 18.3, 18.5, 19.1, 19.7, 21.3, 25.8, 27.7, 28.1, 36.6, 37.3,
39.6, 40.2, 40.7, 43.8, 44.0, 49.1, 49.3, 56.8, 67.4, 134.3, 147.0,
171.6 ppm; HRFABMS calcd for C44H66O4 [M + Na]+ 681.4859,
found 681.4857.
Procedure for Radical Cyclization Reaction of 10 and 11. A
solution of tributyltin hydride (228 mg, 0.76 mmol) and AIBN (7
mg, 0.04 mmol) in dry, degassed benzene (14 mL) was added
dropwise (10 mL/h) to a solution of the bromide (10 or 11) (100
mg, 0.38 mmol) in dry, degassed benzene (136 mL) heated to
80 °C under an atmosphere of argon. After the addition time plus
an additional hour (TLC monitoring), the cooled mixture was
evaporated under reduced pressure, and the residue was dissolved
in diethyl ether. An aqueous saturated KF solution (5 mL) was
added, and the mixture was stirred for 2 h at rt. After filtration
through Celite, the biphasic filtrate was extracted with diethyl ether.
The aqueous layer was extracted with diethyl ether after separation.
The combined organic extracts were concentrated under reduced
pressure, and the crude product was purified by column chroma-
tography (petroleum ether/diethyl ether, 20:1) on silica gel to afford
50 mg (72%) of the cyclized compound methyl 1-p-menthen-9-
oate (14).
Acknowledgment. This research was supported by the
Spanish Ministry of Science and Technology, Projects BQU
2002-03211 and CTQ2006-15575-C02-01. Thanks go to Dr. M.
J. de la Torre for revising our English text.
Supporting Information Available: Experimental procedures
1
and spectroscopic data of new compounds and H and 13C NMR
spectra of 4, 8b, 14, 20a, 20b, 23, 24, 25, 27, 34, 35a-c, 36, 38a,
and 39. This material is available free of charge via the Internet at
http://pubs.acs.org.
17,17′-Bis(19-acetoxy-ent-isokaurene) (4). A mixture of Cp2-
TiCl2 (37 mg, 0.14 mmol) and Mn dust (53 mg, 0.96 mmol) in
strictly deoxygenated THF (1 mL) was stirred at room temperature
until the red solution turned green. Then 38a and 38b (46 mg, 0.12
JO062630A
J. Org. Chem, Vol. 72, No. 8, 2007 2995