Intramolecular C-H insertion reactions of boroxy Fischer carbene complexes. Regio-and diastereoselective modification of terpenes

Article abstract of DOI:10.1021/ja991161+

In-situ-generated dialkylboroxy and diaminoboroxy Fischer carbene complexes lead to oxaborolane or oxazaborolidine derivatives via an intramolecular C-H insertion reaction. Further oxidation of these intermediates yields 1,3-diol or 1,2-amino alcohol derivatives. Diastereoselectivities as high as 99% are reached when starting from boroxy Fischer carbene complexes derived from terpenes, which represents a regio-and diastereoselective modification of this type of natural product. The influence of the C_β substituents relative to the boron atom on the reaction path is studied, and a mechanism is proposed after identification of an intermediate by NMR. In addition, theoretical calculations show the presence of a boron-metal interaction, which could result as key step to the C-H insertion reaction.

Full text of DOI:10.1021/ja991161+

8776
J. Am. Chem. Soc. 1999, 121, 8776-8782
Intramolecular C-H Insertion Reactions of Boroxy Fischer Carbene
Complexes. Regio- and Diastereoselective Modification of Terpenes
Jose´ Barluenga,*,† Fe´lix Rodr´ıguez,† Je´roˆme Vadecard,† Maximilian Bendix,†
Francisco J. Fan˜ana´s,† Fernando Lo´pez-Ortiz,‡, and Miguel A. Rodr´ıguez§,|
Contribution from the Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”,
Unidad Asociada al C.S.I.C., UniVersidad de OViedo, Julia´n ClaVer´ıa, 8, E-33071 OViedo, Spain,
Departamento de Geometr´ıa, Topolog´ıa y Qu´ımica Orga´nica, Facultad de Ciencias Experimentales,
UniVersidad de Almer´ıa, E-04120 Almer´ıa, Spain, and Departamento de Qu´ımica,
UniVersidad de La Rioja, E-26071 Logron˜o, Spain
ReceiVed April 12, 1999
Abstract: In-situ-generated dialkylboroxy and diaminoboroxy Fischer carbene complexes lead to oxaborolane
or oxazaborolidine derivatives via an intramolecular C-H insertion reaction. Further oxidation of these
intermediates yields 1,3-diol or 1,2-amino alcohol derivatives. Diastereoselectivities as high as 99% are reached
when starting from boroxy Fischer carbene complexes derived from terpenes, which represents a regio- and
diastereoselective modification of this type of natural product. The influence of the Câ substituents relative to
the boron atom on the reaction path is studied, and a mechanism is proposed after identification of an intermediate
by NMR. In addition, theoretical calculations show the presence of a boron-metal interaction, which could
result as key step to the C-H insertion reaction.
Introduction
complexes offer the opportunity to modulate the carbene
reactivity by steric and electronic variation of the Lewis acidic
component. In particular, only a few examples of boroxy Fischer
carbene complexes have been described, and they were found
to decompose to a mixture of unidentified products upon
standing at room temperature.8 However, we have recently
reported new synthetic applications of this type of complexes.9
On the other hand, whereas some C-H insertion reactions are
known for cationic iron carbene complexes,10 only one example
that involves group 6 non-heteroatom-stabilized Fischer carbene
complexes has been reported.11 In addition, Wulff et al. propose
the formation of butanolide derivatives via a C-H insertion
Fischer-type alkoxy and aminocarbene complexes have
attracted much interest as useful synthons in organic and
organometallic synthesis.1 By contrast, the synthesis and
chemistry of bimetallic systems, in which the carbene hetero-
atom is bound to a second, electron-deficient metal2 (metal )
Si,3 Ti,4 Zr,5 Hf,6 and Th7), have been much less explored. Such
† Universidad de Oviedo.
‡ Universidad de Almer´ıa.
§ Universidad de La Rioja.
NMR studies.
| Theoretical calculations studies.
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10.1021/ja991161+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/10/1999

Regio- and DiastereoselectiVe Modification of Terpenes
J. Am. Chem. Soc., Vol. 121, No. 38, 1999 8777
Scheme 1
mixtures are obtained. On the other hand, starting from
diaminochloroborane 4g (X ) N),17 oxazaborolidine 8g (X )
N) and 1,2-amino alcohol 10 can be prepared (Table 1, entries
12-14). Carbene complexes 5g-7g (X ) N) and, therefore,
oxazaborolidine 8g and 1,2-amino alcohol 10 can be also
indirectly obtained by reaction of acylmetalates 1-3 with boron
tribromide at -78 °C, presumably leading to the corresponding
dibromoboroxy carbene complex 11-13, and further treatment
with an excess of diisopropylamine at the same temperature
(Table 1, entries 12-14). It is interesting to note that the nature
of the metal plays a role in the reaction rate, while the product
distribution remains unaffected (Table 1, entries 1-3, 4-6, and
12-14). Thus, 2 or 3 h and around 12 h were required for the
formation of oxaborolanes 8a,b at room temperature by starting
from carbenes 6a,b (M ) Mo) and 7a,b (M ) W), respectively.
A mechanistic proposal that accounts for the formation of
oxaborolanes 8 is outlined in Scheme 2 and involves intramo-
lecular hydride transfer to the carbene carbon atom in the
complex 7, favored presumably by an initial interaction between
the boron atom and the metal of carbene complex, as depicted
in the transition state I, to give formally the carbocation
intermediate II, which rapidly affords the oxaborolane deriva-
tives 8 likely by simultaneous formation of a carbon-carbon
bond and loss of the metal fragment.18 The results are in
agreement with the proposed mechanism. In fact, the hydride
transfer is observed only in the cases in which the early-
developing carbocation can be stabilized. Moreover, NMR
monitoring of the reaction course of 7g (X ) N) at -50 °C
allowed identification of the intermediate III (Scheme 2). The
2D 1H,13C HMBC spectrum19 showed correlations of the
methyne proton at 5.31 ppm with aromatic carbons (119.4, 157.3
ppm) and one of the carbonyl groups bound to tungsten (203.6
ppm), while the diastereotopic methyl groups (2.68, 2.74 ppm)
correlate with a carbon at 189.2 ppm. The 183W chemical shift
of III (-66.8 ppm) measured from the 1H,183W HMBC
spectrum20 is unusually high (∆δ ≈ 2600 ppm) compared with
those of other related tungsten complexes,21 implying a strong
variation in the electronic surrounding around the tungsten
atom,22 and suggests that the metal actually coordinates to the
boron atom.
reaction of an in-situ-generated non-heteroatom-stabilized chro-
mium carbene complex.12 Recently, two examples of C-H
insertion reactions involving stabilized Fischer carbene com-
plexes have been reported.13 Previously, we described, for the
first time, the preparation of boroxy Fischer carbene complexes
and their transformation into oxaborolane or oxazaborolidine
derivatives via a C-H insertion process.14 In the present paper,
we describe in full our findings on the intramolecular C-H
insertion reactions of boroxy Fischer carbene complexes and
mechanistic aspects of this reaction on the basis of both
experimental and theoretical investigations. This process has
been widely applied to the regio- and diastereoselective
modification of terpenes. The scope and limitations of this
methodology are defined.
Results and Discussion
The treatment of pentacarbonylmetal acylate intermediates
1-3, formed by reaction of metal hexacarbonyl and the
corresponding organolithium compound,15 with dialkylchloro-
boranes 4 (X ) CH)16 in diethyl ether at -78 °C readily led to
dialkylboroxycarbene complexes 5-7. On warming to room
temperature, these compounds underwent loss of the metal
fragment affording the oxaborolane derivatives 8 (X ) CH).
This transformation involves the insertion of the carbene ligand
into the boron Câ-H bond. Further oxidation of 8 (X ) CH)
with hydrogen peroxide in basic media yielded 1,3-diols 9 as
mixtures of diastereoisomers (Scheme 1 and Table 1). We have
observed that oxaborolanes 8 (X ) CH) are produced in
moderate yield when either R1 and R2 are alkyl groups (Table
1, entries 1-6) or R1 and R2 are H and a donor group,
respectively (Table 1, entries 7-11). Conversely, the reaction
does not work for R1 ) H and R2 ) alkyl (c-C6H11 or n-C6H13)
or electron-withdrawing groups (4-ClC6H4), and complex
Ab Initio Calculations. To corroborate the proposed in-
tramolecular interaction between the boron atom and the metal
of the carbene complex, we carried out theoretical calculations
on boroxy Fischer carbene complexes. To the best of our
knowledge, no ab initio calculations have been described for
this kind of complexes. The size of the molecule under study
(17) Diaminochloroboranes have been prepared as described in the
literature, see: Aubrey, D. W.; Lappert, M. F.; Majumdar, M. K. J. Chem.
Soc. 1962, 4088.
(18) According to the suggestion of a reviewer and in order to establish
the intramolecular nature of the process, we carried out a crossover
experiment with carbene complexes 16e and 21e, which after usual workup
resulted in the exclusive formation of diols 18e and 22e.
(19) Bax, A.; Summers, M. F. J. Am. Chem. Soc. 1986, 108, 2093.
(20) (a) Benn, R.; Brenneke, H.; Heck, J.; Rufinska, A. Inorg. Chem.
1987, 26, 2826. (b) Benn, R.; Rufinska, A.; King, M. A.; Osterberg, C. E.;
Richmond, T. J. Organomet. Chem. 1989, 376, 359. (c) Machioni, A.;
Pregosin, P. S.; Ru¨egger, H.; van Koten, G.; van der Schaaf, P. A.;
Abbenhuis, R. A. T. M. Magn. Reson. Chem. 1994, 235, 32.
(21) We could obtain the183W chemical shift (-2769 ppm) for carbene
complex 16d through a 1H,183W HMQC experiment. For other 183W δ values
of related tungsten complexes, see: (a) Minelli, M.; Enemark, J. H.;
Brownlee, T. T. C.; O’Connor, M. J.; Wedd, A. G. Coord. Chem. ReV.
1985, 68, 169. (b) Barluenga, J.; Toma´s, M.; Ballesteros, A.; Santamar´ıa,
J.; Carbajo, R. J.; Lo´pez-Ortiz, F.; Garc´ıa-Granda, S.; Pertierra, P. Chem.
Eur. J. 1996 2, 88.
(12) Wang, S. L. B.; Su, J.; Wulff, W. D.; Hoogsteen, K. J. Am. Chem.
Soc. 1992, 114, 10665.
(13) (a) Barluenga, J.; Aznar, F.; Ferna´ndez, M. Chem. Eur. J. 1997, 3,
1629. (b) Takeda, K.; Okamoto, Y.; Nakajima, A.; Yoshii, E.; Koizumi, T.
Synlett 1997, 1181.
(14) 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.
(15) (a) Fischer, E. O.; Maasbo¨l, A. Chem Ber. 1967, 100, 2445.
(16) Dialkylchloroboranes have been prepared as described in the
literature, see: Brown, H. C.; Ganesan, K.; Dhar, R. K. J. Org. Chem.
1992, 57, 3767.
(22) We could not measure the 11B NMR spectrum for III because, at
the low temperature needed (-50 °C), the quadrupolar nature of the boron
resulted in an exceedingly large line width.

8778 J. Am. Chem. Soc., Vol. 121, No. 38, 1999
Barluenga et al.
Table 1. Diols 9 and Amino Alcohol 10 from C-H Insertion in the Boroxy Fischer Carbene Complexes 5-7, and Further Oxidation
entry
carbene complex
R
X
R1
R2
R3
diol
yield (%)a
de (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5a
6a
7a
5b
6b
7b
6c
7c
6d
6e
6f
(E)-PhCHdCH
(E)-PhCHdCH
(E)-PhCHdCH
Ph
Ph
Ph
Ph
Ph
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
Me
Me
Me
Me
Me
Me
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
H
H
H
H
9a
9a
9a
9b
9b
9b
9c
9c
9d
9e
9f
51
53
50
53
55
55
52
57
11
12
12
31
33
30
10
10
32
20
24
Ph
Ph
(E)-PhCHdCH
64
49
59
Me
4-MeOC6H4
4-MeOC6H4
Me
Me
Me
2-Naphc
Ph
H
5g
6g
7g
Me
Me
Me
iPr
iPr
iPr
10
10
10
67 (66)d
65 (68)d
70 (60)d
Ph
Ph
N
N
a Based on M(CO)6. b Determined by NMR. c 2-Naph ) 2-naphthyl. d In parentheses are represented the yields obtained in the indirected reaction
i
of acylmetalates 1, 2, or 3 with BBr3 and further treatment with Pr2NH.
Scheme 2
been split to [441/2111/21] and [341/3111/31], respectively.30
This basis set combination will hereafter be referred to as II.
The accuracy of the HF/II and MP2/II levels of theory has
already been demonstrated in the calculation of the optimized
geometries of metal carbene complexes.30 Improved energies
were obtained from single-point calculations at the MP2 level
using the II basis set augmented with one diffuse function for
C, O, and B31 and one set of f functions for W (zf ) 0.823) and
Mo (zf ) 1.043).32 This basis set combination will hereafter be
denoted IIID, where D stands for diffuse functions.
The most relevant geometrical parameters of the optimized
structures of (CO)5WdCH(OBH2) with the HF/II and MP2/II
wave functions are given in Figure 1. Several features are
noteworthy. At the HF/II level of theory, the W-B interatomic
distance is very large (3.773 Å). Thus, the experimental
coordination is not reproduced at this level. After inclusion of
correlation at the MP2/II level, the W-B interatomic distance
and the C2-O3-B4 bond angle are drastically reduced to 2.908
Å and 101.8°, respectively, which indicates that correlation
effects are attractive due to the W-B interaction. Moreover,
the tungsten-carbene carbon bond length is larger at the HF/II
level than at the MP2/II level [from 2.149 (HF/II) to 2.109 Å
(MP2/II), ∆ ) 0.040 Å].
In view of the observed structural changes due to the W-B
interaction, and taking into account that the atomic radius for
coordinated tungsten is identical to that for molybdenum (1.39
Å for both metals),33 we found it of interest to compare the
W-B interaction with the Mo-B interaction. The MP2/II-
optimized structure for (CO)5ModCH(OBH2) is represented in
Figure 2. It can be observed that the replacement of W by Mo
causes a reduction in the metal-boron interatomic distance
(2.848 Å, ∆ ) -0.060 Å), and the effect of this is transmitted
through the rest of the structure: an increase in the metal-
carbene carbon (2.111 Å, ∆ ) +0.002 Å) and O-B (1.478 Å,
∆ ) +0.011 Å) bond lengths and a reduction in the carbene
carbon-oxygen distance (1.302 Å, ∆ ) -0.006 Å) and C2-
O3-B4 bond angle (98.6°, ∆ ) -3.2°). All these structural
necessitates the use of (CO)5MdCH(OBH2) as a model for the
ab initio calculations. All calculations were carried out using
the Gaussian 94 program package.23 The molecular geometries
were initially optimized, within appropriate molecular symmetry
constraints (Cs), at the Hartree-Fock self-consistent field (HF)
level of theory, and electron correlation, keeping the core orbitals
frozen, was included in further optimizations using Møller-
Plesset perturbation theory24,25 with second-order corrections
(MP2) employing Schlegel’s analytical gradient procedure.26 All
optimized structures reported in this paper are minima on the
potential energy surface (all eigenvalues of the Hessian matrix
are positive).25
The following basis set combination has been employed: for
C, O, B, and H, the standard split-valence 6-31G(d) basis set,27,28
with six d functions, and for W and Mo, the Hay-Wadt small-
core effective core potential,29 where the minimal basis set has
(23) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T. A.; Petersson,
G. A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski,
V. G.; Ortiz, J. V.; Foresman, J. B.; Cioslowski, J.; Stefanov, B.;
Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.;
Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Binkley, J. S.; Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-
Gordon, M.; Gonzalez, C.; Pople, J. A. Gaussian 94 (Revision C.3);
Gaussian, Inc.: Pittsburgh, PA, 1995.
(30) Frenking, G.; Antes, I.; Bo¨hme, M.; Dapprich, S.; Ehlers, A. W.;
Jonas, V.; Neuhaus, A.; Otto, M.; Stegmann, R.; Veldkamp, A., Vyboish-
chikov, S. F. In ReViews in Computational Chemistry; Lipkowitz, K. B.,
Boyd, D. B., Eds.; VCH: New York, 1996; Vol. 8.
(31) Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer, P. v. R.
J. Comput. Chem. 1983, 4, 294.
(24) Møller, C.; Plesset, M. S. Phys. ReV. 1934, 46, 618.
(25) Hehre, W. J.; Radom, L.;. Schleyer, P.v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; J. Wiley: New York, 1986.
(26) Schlegel, H. B. J. Comput. Chem. 1982, 3, 214.
(32) Ehlers, A. W.; Bo¨hme, M.; Dapprich, S.; Gobbi, A.; Ho¨llwath, A.;
Jonas, V.; Ko¨hler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G. Chem.
Phys. Lett. 1993, 208, 111.
(33) Mu¨ller, U. Inorganic Structural Chemistry; Wiley: Chichester, UK,
1993.
(27) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213.
(28) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56,
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Regio- and DiastereoselectiVe Modification of Terpenes
J. Am. Chem. Soc., Vol. 121, No. 38, 1999 8779
Figure 1. Computer plot of the MP2/II-optimized structure for
(CO)5WdCH(OBH2); values in parentheses are obtained at the HF/II
level.
Figure 2. Computer plot of the MP2/II-optimized structure for
(CO)5ModCH(OBH2).
Table 2. Calculated Total Energies (Hartrees) and Relative
Energies (in Parentheses, kcal/mol) for (CO)5MdCH(OBH2)a
changes reveal that the Mo-B interaction should be larger than
the W-B interaction, but that both are the same in nature.
We have also attempted to quantify the magnitude of the
metal-boron interaction in boroxy Fischer carbene complexes.
First, taking our MP2/II-optimized geometries as the starting
point, we considered a (B4-O3-C2)(O3-C2-M1) plane-
plane angle of 180.0° instead of 0.0°, and we tried to optimize
these at the same level of theory. However, all attempts to
minimize these structures led to the previously calculated
structures [(B4-O3-C2)(O3-C2-M1) plane-plane angle of
0.0°], which indicates the strong character of the metal-boron
interaction. Therefore, we have included only the MP2/II single-
point calculation resulting from our MP2/II-optimized geom-
etries considering a (B4-O3-C2)(O3-C2-M1) plane-plane
angle of 180.0°. Table 2 shows the calculated total and relative
energies at the MP2/II//MP2/II and MP2/IIID//MP2/II levels.
From the MP2/II level, we derive that this interaction should
be 18.5 and 19.8 kcal/mol for W and Mo, respectively. These
results indicate that, in boroxy Fischer carbene complexes, the
intramolecular Mo-B interaction should be stronger than the
W-B interaction by 1.3 kcal/mol at the MP2/II//MP2/II level.
Single-point calculations at the MP2 level using the larger basis
set IIID denote a slight increase of the metal-boron interaction
for molybdenum (20.1 kcal/mol) but not for tungsten (18.5 kcal/
mol), and places the tungsten-boron attraction at a level 1.6
kcal/mol less than that for molybdenum.
(B4-O3-C2)
M
W
(O3-C2-M1) (deg)
MP2/II
MP2/IIID
0.0
-772.193313
(0.0)
-772.163876
(18.5)
-771.920267
(0.0)
-771.888636
(19.8)
-772.376845
(0.0)
-772.347386
(18.5)
-772.120254
(0.0)
-772.088252
(20.1)
180.0b
0.0
Mo
180b
a All calculations at the MP2/II-optimized geometries. Atom number-
ing as in Figures 1 and 2. b Single-point calculation considering a (B4-
O3-C2)(O3-C2-M1) plane-plane angle of 180.0° instead 0.0°.
-78 °C led to the corresponding chiral boroxycarbene com-
plexes 14-16, which were clearly identified by NMR spec-
troscopy. On heating to room temperature, these complexes
evolve to afford the oxaborolane derivatives 17. Oxidation of
17 gave rise to the 1,3-diols 18 (Scheme 3 and Table 3). To
our delight, diastereoselectivities higher than 99% were then
reached in the case of 18d and 18e (Table 3, entries 6-9). In
the same way, starting from (+)-Ipc2BCl and 2 [R ) (E)-
PhCHdCH], ent-18d was obtained with diastereoselectivity
higher than 99% (Table 3, entry 14). The absolute configuration
of the new stereogenic centers in the major and minor diaste-
reoisomers was assigned by NOE experiments of the corre-
sponding acetonides 19, generated by reaction of diols 18 and
2,2-dimethoxypropane in the presence of catalytic amounts of
pyridinium p-toluenesulfonate (PPTS)34 (Scheme 4). It is
interesting to point out that, in all the cases, a quaternary carbon
Diastereoselective CsH Insertion Reactions. To study the
influence of the chiral dialkylborane bearing a tertiary Câ-H
bond on the diastereoselectivity of the reaction, a set of
experiments using the commercially available (-)-chlorodiiso-
pinocampheylborane [(-)-Ipc2BCl] was envisaged. Thus, reac-
tion of acylmetalates 1-3 with (-)-Ipc2BCl in diethyl ether at
(34) Luke, G. P.; Morris, J. J. Org. Chem. 1995, 60, 3013.

8780 J. Am. Chem. Soc., Vol. 121, No. 38, 1999
Barluenga et al.
Scheme 3
Scheme 5
17 may be tentatively accounted for by considering transition
states IVa and IVb (Scheme 3). Assuming that a boron-metal
interaction takes place, the chairlike transition state IVa would
explain the formation of the major diastereoisomer. This
stereochemical course should be favored over that involving
the boat conformation IVb, which exhibits severe hindrance
between the metal fragment and the ring moiety. Moreover, the
higher diastereoselectivity found for R ) alkenyl groups (Table
3, entries 6-13) can be rationalized in terms of coordination
of the metal to the carbon-carbon double bond, which would
result in increasing the transition state rigidity. Thus, IVb is
even more disfavored than IVa. This coordination has been
observed by NMR during the transformation of 16d as an
intermediate species formed at -30 °C. In this intermediate,
the olefinic carbon atoms are highly shielded (79.51, 81.17 ppm)
related to the starting carbene, and the corresponding protons
Table 3. Diols 18 from C-H Insertion in the
Diisopinocampheylboroxy Fischer Carbene Complexes 14-16a and
Further Oxidation
carbene
complex
yield
(%)b
de
entry
R
diol
18a
18a
18a
18b
18c
18d
18d
18d
18e
(%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
14a
15a
16a
15b
16c
14d
15d
16d
16e
Ph
Ph
Ph
82
84
87
78
85
80
78
81
83
75
65
67
78
82
50
50
51
49
72
>99
>99
>99
>99
97
83
85
1
(5.21, 5.32 ppm) show cross-peaks in the 2D H,13C HMBC
4-MeOC6H4
2-Naph
(E)-PhCHdCH
(E)-PhCHdCH
(E)-PhCHdCH
CH2dC(Ph)
Me2CdCH
CH2dC(Me)
CH2dC(Me)
CH2dC(Me)
(E)-PhCHdCH
spectrum, with a carbonyl carbon at 196.91 ppm.
Scope and Limitations. To study the scope of this transfor-
mation, and considering that it can be seen as a diastereoselective
transformation of a terpene, a set of experiments was carried
out with other commercially or easily available terpenes. So,
hydroboration of the corresponding terpene with monochlo-
roborane in diethyl ether led to the diterpenylchloroboranes 20.36
Treatment of these chloroboranes 20 with the acyl molybdates
2 at -78 °C afforded the diterpenylboroxy carbene complexes
21, which upon warming to room temperature and further
oxidation yielded the 1,3-diols 22 with good chemical yields
(Scheme 5 and Table 4). It is interesting to note the high
diastereoselctivity found in this process. In fact, only one
diastereoisomer has been observed for 22a and 22c-e (Table
4, entries 1 and 3-5). The absolute configuration of the new
stereocenters was also determined by NOE experiments of the
representative acetonides 19d,f,g and by two-dimensional
(COSY, HMQC, HMBC, and NOESY) NMR spectral analysis
of the acetonide 19e (Figure 3), generated as described in
Scheme 4. According to these results, it can be concluded that,
in all cases, the quaternary center has been generated in an
enantioselective way and the diastereoselectivity depends only
on the way in which the hydride is transferred. On the other
hand, the C-H insertion reaction of carbene complex 21g,
derived from 2-carene, bearing two tertiary Câ-H bonds
exclusively gave the regioisomer 22g, and the other possible
regioisomer has been not observed (Table 4, entry 7).
16f
18f
14g
15g
16g
ent-15de
18gd
18gd
18gd
ent-18d
86
>99
a Derived from (-)-Ipc2BCl. b Based on M(CO)6. c Determined by
NMR. d Both diastereoisomers have been isolated. e Derived from (+)-
Ipc2BCl.
Scheme 4
Otherwise, starting from molybdenum carbene complexes 24
and 26, formed by reaction of acyl molybdate 2 [R )
(E)-PhCHdCH] and chloroboranes 2336 derived from (-)-
camphene, and 25,36 derived from (+)-longifolene, respectively,
and following the sequence of reactions above-described, the
expected 1,3-diols were not observed, and we obtained a mixture
of Camph-OH or Long-OH, cinnamic acid, and molybdenum
hexacarbonyl (Scheme 6). The reluctance to the formation of
1,3-diols in these cases can be explained by considering that
the approach of the carbon-metal double bond to the C-H in
center has been created in an enantioselective way35 and that
the diastereoselectivity depends exclusively on the way that the
C-H is approaching the metal-carbon double bond. The high
stereoselectivity of the hydride attack leading to oxaborolanes
(35) Nemoto, H.; Tanabe, T.; Fukumoto, K. J. Org. Chem. 1995, 60,
6785 and references therein.
(36) Brown, H. C.; Malhotra, S. V.; Ramachandran, V. Tetrahedron:
Asymmetry 1996, 7, 3527.

Regio- and DiastereoselectiVe Modification of Terpenes
J. Am. Chem. Soc., Vol. 121, No. 38, 1999 8781
Table 4. Diols 22 from Terpenes via C-H Insertion in the
Diterpenylboroxymolybdenum Fischer Carbene Complexes 21 and
Further Oxidation
Scheme 6
Scheme 7
a Based on Mo(CO)6. b Determined by NMR. c Both diastereoisomers
have been isolated (the major diastereoisomer has been represented).
oxygen to the borane previous to the hydroboration reaction.
This result constitutes one of the few examples of a heteroatom-
directed asymmetric hydroboration.37 Reaction of acyl molyb-
date 2 [R ) (E)-PhCHdCH] with the chloroborane 27 at -78
°C gave rise to the boroxymolybdenum carbene complex 28.
Warming of the reaction mixture to room temperature followed
by oxidative workup also did not lead to the corresponding 1,3-
diol (Scheme 7). The failure to generate the expected diol in
this case could be explained in terms of an intramolecular
coordination of the ether oxygen to the boron atom, which could,
on one hand, prevent the coordination between the boron atom
and the metal, assumed for the reaction take to place, and, on
the other hand, could hinder the approach of the carbon-metal
double bond to the Câ-H by steric effects.
Finally, O-benzyl-R-terpineol was tested in this type of
process. First, hydroboration of this terpene led to a nearly
equimolecular mixture of diastereoisomer chloroboranes 29 and
30. In this case, an oxygen-directed hydroboration has not been
observed, presumably because the director group is not close
enough to the double bond to induce a diastereoselective reaction
(Scheme 8). Treatment of 2 [R ) (E)-PhCHdCH] with the
mixture of chloroboranes 29 and 30 at -78 °C afforded a
mixture of carbene complexes 31 and 32, which under the
workup conditions described above generated exclusively the
1,3-diol 33 as a 5.3:1 mixture of diastereoisomers in 34% yield
[based on the Mo(CO)6], derived from a C-H insertion reaction
of carbene complex 32 (Scheme 8). The lack of evolution of
31 to the corresponding 1,3-diol could be understood in the same
Figure 3.
the corresponding carbene complexes 24 and 26 would be
sterically hindered by both faces, as depicted in transition states
Va and Vb for the hydride transfer to the carbene carbon in
complex 24 (Scheme 6).
Finally, the influence of a dialkylborane bearing a heteroatom
on the outcome of the C-H insertion reaction was studied. In
this sense, synthesis of several chloroboranes was first carried
out. Thus, hydroboration of O-benzylterpinen-4-ol with monochlo-
roborane led to the chloroborane 27 as a single diastereoisomer
(Scheme 7). The relative stereochemistry was assigned by NMR
studies carried out with the 5-benzyloxy-5-isopropyl-2-meth-
ylcyclohexanol, obtained after oxidative workup (3 N NaOH,
30% H2O2) of 27. The exclusive formation of one diastereo-
isomer can be accounted for by a coordination of the ether
(37) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307. (b) Hodgson, D. M.; Thomson, A. J.; Wadman, S. Tetrahedron Lett.
1998, 39, 3357. (c) Garret, C. E.; Fu, G. C. J. Org. Chem. 1998, 63, 1370.

8782 J. Am. Chem. Soc., Vol. 121, No. 38, 1999
Barluenga et al.
Scheme 8
Conclusions
We have described an efficient and diastereoselective conver-
sion of boroxycarbene complexes to oxaborolane, oxazaboro-
lidine,1,3-diol, and 1,2-amino alcohol derivatives. This meth-
odology permits the regio- and diastereoselective modification
of terpenes, in which a quaternary center has been formed in
an enantioselective way. In addition, an intermediate of this
reaction has been characterized by NMR spectroscopy, and
theoretical calculations have shown the presence of a boron-
metal interaction. On the other hand, a heteroatom-directed
hydroboration has been described. Formation of other difunc-
tional compounds, of potential interest as ligands, from terpenes
and modification of other natural products by using this novel
transformation are underway.
Acknowledgment. This work was supported by DGICYT
(Grants PB92-1005 and PB94-0483) and the European Com-
munity (Human Capital and Mobility Network Contract No.
ERBCHRXCT940501). J.V. and M.B. thank European Com-
munity and Ministerio de Educacio´n y Ciencia, respectively,
for fellowships.
sense explained for the carbene complex 28. Thus, the intramo-
lecular oxygen-boron coordination would make difficult the
insertion reaction by steric or/and electronic effects. On the
contrary, for carbene complex 32, the intramolecular oxygen-
boron coordination is not possible, and then the C-H insertion
reaction occurs.
Supporting Information Available: Experimental proce-
dures and spectral data for all compounds (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA991161+