PuPHOS: A synthetically useful chiral bidentate ligand for the intermolecular Pauson-Khand reaction

Article abstract of DOI:10.1021/jo0486894

Here we describe the synthesis and use of the Pulegone-derived bidentate P,S ligands PuPHOS and CyPuPHOS in the intermolecular Pauson-Khand reaction. Ligand exchange reaction of hexacarbonyldicobalt-alkyne complexes with PuPHOS provides a diasteromeric mi

Full text of DOI:10.1021/jo0486894

PuPHOS: A Synthetically Useful Chiral Bidentate Ligand for the
Intermolecular Pauson-Khand Reaction
Xavier Verdaguer,*,§ Agust´ı Lledo´,§ Cristina Lo´pez-Mosquera,§ Miguel Angel Maestro,†
Miquel A. Perica`s,§ and Antoni Riera*,§
Unitat de Recerca en S´ıntesi Asime`trica (URSA), Parc Cientı´fic de Barcelona and Departament de
Quı´mica Orga`nica, Universitat de Barcelona, c/Josep Samitier, 1-5. 08028-Barcelona, Spain, and
Servicios Xerais de Apoio a´ Investigacio´n, Campus Zapateira, s/n, Universidade da Corun˜a,
15071, A Corun˜a, Spain
xverdaguer@pcb.ub.es; ariera@pcb.ub.es
Received July 29, 2004
Here we describe the synthesis and use of the Pulegone-derived bidentate P,S ligands PuPHOS
and CyPuPHOS in the intermolecular Pauson-Khand reaction. Ligand exchange reaction of
hexacarbonyldicobalt-alkyne complexes with PuPHOS provides a diasteromeric mixture of
complexes (up to 4.5:1) from which the major isomers can be conveniently separated by simple
crystallization. An isomerization-crystallization sequence of the original mixture results in a
dynamic resolution that allows the preparation of the pure major Co2(µ-TMSC2H)(CO)4-PuPHOS
(15a) in a multigram scale. Pauson-Khand reaction of 15a with norbornadiene provided, for the
first time, the corresponding enone 18 with up to 93% yield and 97% ee. The use of (+)-18 as a
surrogate of chiral cyclopentadienone is also demonstrated. Copper-catalyzed Michael addition of
a Grignard reagent followed by removal of the TMS group with TBAF were the most reliable
methods to transform (+)-18 into valuable starting materials 20a-e for the enantioselective
synthesis of cyclopentenoid systems.
Introduction
asymmetric process. Probably a logical approach toward
this goal would be the development of chiral ligands that
(i) bind alkyne-dicobalt hexacarbonyl complexes in high
diastereoselectivity, (ii) give stereospecific cyclization
reactions (in other words, that diastereomerically pure
ligand complexes give enantiomerically pure adducts),
and (iii) increase the reaction rate (ligand-accelerated
reaction) in relation to the nonligand complexes. In 1988
Brunner pioneered the field by describing the first PKR
The Pauson-Khand reaction1 (PKR) is one of the most
useful reactions for the construction of cyclopentanic
compounds. The number of references on this reaction
has grown exponentially in the past decade, which shows
the increasing interest of synthetic chemists on this
transformation.
(2) (a) Rivero, M. R.; De la Rosa, J. C.; Carretero, J. C. J. Am. Chem.
Soc. 2003, 125, 14992-14993. (b) Areces, P.; Duran, M. A.; Plumet,
J.; Hursthouse, M. B.; Light, M. E. J. Org. Chem. 2002, 67, 3506-
3509. (c) Carretero, J. C.; Adrio, J. Synthesis 2001, 1888-1896. (d)
Marchueta, I.; Montenegro, E.; Panov, D.; Poch, M.; Verdaguer, X.;
Moyano, A.; Perica`s, M. A.; Riera, A. J. Org. Chem. 2001, 66, 6400-
6409. (e) Verdaguer, X.; Vazquez, J.; Fuster, G.; Bernardes-Genisson,
V.; Greene, A. E.; Moyano, A.; Perica`s, M. A.; Riera, A. J. Org. Chem.
1998, 63, 7037-7052. (f) Adrio, J.; Carretero, J. C. J. Am. Chem. Soc.
1999, 121, 7411-7412. (g) Fonquerna, S.; Moyano, A.; Perica`s, M. A.;
Riera, A. J. Am. Chem. Soc. 1997, 119, 10225-10226. (h) Tormo, J.;
Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron 1996,
52, 14021-14040. (i) Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera,
A.; Greene, A. E.; Piniella, J. F.; Alvarez-Larena, A. J. Organomet.
Chem. 1992, 433, 305-310. (j) Castro, J.; Sorensen, H.; Riera, A.;
Morin, C.; Moyano, A.; Perica`s, M. A.; Greene, A. E. J. Am. Chem.
Soc. 1990, 112, 9388-9389.
(3) (a) Gibson, S. E.; Lewis, S. E.; Loch, J. A.; Steed, J. W.; Tozer,
M. J. Organometallics 2003, 22, 5382-5384. (b) Hiroi, K.; Watanabe,
T.; Kawagishi, R.; Abe, I. Tetrahedron: Asymmetry 2000, 11, 797-808.
(c) Hiroi, K.; Watanabe, T.; Kawagishi, R.; Abe, I. Tetrahedron Lett.
2000, 41, 891-895.
(4) Titanium: (a) Sturla, S. J.; Buchwald, S. L. J. Org. Chem. 1999,
64, 5547-5550. (b) Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc.
1999, 121, 7026-7033. Rhodium: Jeong, N.; Sung, B. K.; Choi, Y. K.
J. Am. Chem. Soc. 2000, 122, 6771-6772. Iridium: Shibata, T.; Takagi,
K. J. Am. Chem. Soc. 2000, 122, 9852-9853.
Perhaps the greatest unaccomplished target on this
field is the development of general catalytic asymmetric
versions. Although several useful versions based on the
chiral auxiliary approach2 have been developed, and great
progress has been achieved in catalytic intramolecular
reactions,3 many of which are mediated by metals other
than cobalt,4 we are still far from achieving a practical
§ Universitat de Barcelona.
† Universidade da Corun˜a.
(1) Selected reviews: (a) Blanco-Urgoiti, J.; Anorbe, L.; Perez-
Serrano, L.; Dominguez, G.; Perez-Castells, J. Chem. Soc. Rev. 2004,
33, 32-42. (b) Gibson, S. E.; Stevenazzi, A. Angew. Chem., Int. Ed.
2003, 42, 1800-1810. (c) Brummond, K. M.; Kent, J. L. Tetrahedron
2000, 56, 3263-3283. (d) Keun Chung, Y. Coord. Chem. Rev. 1999,
188, 297-341. (d) Buchwald, S. L.; Hicks, F. A. In Compr. Asymmetric
Catal. 1999, I-III, pp 491-510. (e) Schore, N. E. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, UK,
1991; Vol. 5, pp 1037-1064. (f) Chung, Y. K. Coord. Chem. Rev. 1999,
188, 297-341.
10.1021/jo0486894 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/15/2004
J. Org. Chem. 2004, 69, 8053-8061
8053

Verdaguer et al.
SCHEME 1. Synthesis of Borane-Protected
Bidentate Ligands
FIGURE 1. Distinct types of chiral cobalt complexes with
chiral ligands or chelating auxiliaries.
of a cobalt complex such as I coordinated with a chiral
ligand (see Figure 1). The use of monophosphine Glyphos
allowed a complete stereospecific PKR between phenyl-
acetylene and norbornene.5 However, the coordination of
the phosphine to the complex was unselective affording
a 1:1 mixture of diastereomers which, in addition,
epimerized at 60 °C in toluene.
Results and Discussion
Synthesis of the Ligands. Multigram amounts of the
borane-protected PuPHOS 2 can be easily obtained from
a four-step procedure starting from natural (+)-pulegone
5 (Scheme 1). Eliel12 conjugate addition of benzylthiol to
5 followed by Na/NH3 reduction efficiently afforded
mercapto alcohol 6 as a mixture of diastereomers. Dean-
Stark reflux of 6, paraformaldehyde and a catalytic
amount of p-toluenesulfonic acid in toluene gave a
mixture of diastereomeric oxathianes that was crystal-
lized in hexanes at -78 °C.13 In this way, crystalline
oxathiane 7 was obtained in 40% yield from pentane. This
compound was treated with sec-butyllithium at -78 °C
to generate the anion, which was allowed to react with
chlorodiphenylphosphine to yield the chiral phosphine 1
as a single diastereomer. PuPHOS was conveniently
protected with borane to give 2 as a highly crystalline
solid in 87% yield from 7. Following the same synthetic
scheme, borane-protected CyPuPHOS (4) was also pre-
pared from 7 by phosphinylation with chlorodicyclohex-
ylphosphine in good overall yield (50%).
The lack of diastereoselectivity in the preparation of
complexes I directed our efforts toward the use of
bidentate ligands able to form conformationally restricted
complexes. A bidentate ligand can bind to an alkyne-
dicobaltcarbonyl complex in two possible modes, as shown
in Figure 1: the chelated complex II and the bridged
complex III. Complexes of type II were studied with use
of phosphinooxazoline or 2-(2-phosphinoaryl)dihydro-
oxazole ligands but again the diastereoselectivity in the
complexation was very low.6 Encouraged by the success
of chelated chiral auxiliaries IV,7 we studied the use
chiral bidentate (P,S) ligands.8 To this end, we designed
and prepared two chiral phosphines9,10 bearing a R-S-
CH-PPh2 fragment in order to favor the bridged coordi-
nation versus the chelated one. Although the best com-
plexation diastereoselectivities were found with camphor-
derived ligands,10 the best results were obtained with the
pulegone-derived phosphines9 which allowed the develop-
ment of an asymmetric ligand-based methodology of
intermolecular PKR. Here we provide a full description
of the preparation of the bidentate ligands PuPHOS (1)
and CyPuPHOS (3), their use in PKR, and the synthetic
potential of the resulting optically pure intermolecular
cycloaddition adducts.11
The X-ray diffraction of 2 allowed the confirmation of
the S configuration of the newly formed chiral center,
since the phosphorus was placed in the equatorial posi-
tion in the oxathiane ring (Figure 2).
Ligand Exchange with Dicobalthexacarbonyl
Complexes. Free phosphines can be released by treating
the borane complexes with 1,4-diazabicyclo[2.2.2]octane
(DABCO).14 Thus, the corresponding P,S-cobalt com-
plexes were prepared in situ by treatment of the parent
alkynehexacarbonyl complexes 8-11 with the borane-
protected P,S ligands in the presence of 2 equiv of
DABCO. By heating the mixture in toluene at 80 °C,
deprotection and complexation with the free P,S ligand
occurred smoothly yielding a mixture of diastereomeric
complexes 12a/12b-16a/16b (Table 1). TLC analysis
showed that initial complexation when using PuPHOS
took place without appreciable diastereoselectivity as
previuosly reported for simple phosphines.5 However,
(5) (a) Hay, A. M.; Kerr, W. J.; Kirk, G. G.; Middlemiss, D.
Organometallics 1995, 14, 4986-4988. (b) Bladon, P.; Pauson, P. L.;
Brunner, H.; Eder, R. J. Organomet. Chem. 1988, 355, 449-454. (c)
Brunner, H.; Niedernhuber, A. Tetrahedron: Asymmetry 1990, 1, 711-
714.
(6) (a) Castro, J.; Moyano, A.; Perica`s, M. A.; Riera, A.; Alvarez-
Larena, A.; Piniella, J. F. J. Am. Chem. Soc. 2000, 122, 7944-7952.
(b) Castro, J.; Moyano, A.; Perica`s, M. A.; Riera, A.; Alvarez-Larena,
A.; Piniella, J. F. J. Organomet. Chem. 1999, 585, 53-58.
(7) Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera, A.; Bernardes,
V.; Greene, A. E.; Alvarez-Larena, A.; Piniella, J. F. J. Am. Chem. Soc.
1994, 116, 2153-2154.
(8) Sulfur coordination to cobalt was first introduced to control the
regioselectivity of the PKR. Kraft, M. E.; Juliano, C. A.; Scott, I. L.;
Wright, C.; McEachin, M. D. J. Am. Chem. Soc. 1991, 113, 1693-1703.
(9) Preliminary communication: Verdaguer, X.; Moyano, A.; Perica`s,
M. A.; Riera, A.; Maestro, M. A.; Mahia, J. J. Am. Chem. Soc. 2000,
122, 10242-10243.
(12) Eliel, E. L.; Lynch, J. E.; Kume, F.; Frye, S. V. Org. Synth. 1987,
65, 215-223.
(10) Verdaguer, X.; Perica`s, M. A.; Riera, A.; Maestro, M. A.; Mahia,
J. Organometallics 2003, 22, 1868-1877.
(11) PuPHOS and CyPuPHOS are odorless compounds. Its name
derives from the natural compound from which they are synthesized:
Pulegone.
(13) (a) Lynch, J. E.; Eliel, E. L. J. Am. Chem. Soc. 1984, 106, 2943-
2948. (b) Eliel, E. L.; Lynch, J. E. Tetrahedron Lett. 1981, 22, 2855-
2858.
(14) Imamoto, T.; Tsuruta, H.; Wada, Y.; Masuda, H.; Yamaguchi,
K. Tetrahedron Lett. 1995, 36, 8271-8274.
8054 J. Org. Chem., Vol. 69, No. 23, 2004

Pulegone-Derived P,S Ligands PuPHOS and CyPuPHOS
TABLE 1. Thermal Reaction of P,S Ligands with Alkyne-Dicobalthexacarbonyl Complexes
entry
R
starting complex
L
T (°C)
time (h)
yield (%)
dra
1:1
4.5:1
3:1
3:1
1:1
1.6:1
Xa/Xb
1
2
3
4
5
6
Ph
8b
9
10
11
11
11
PuPHOS
65
70
60
80
65
85
18
17
17
17
5
91
84
99
91
87
68
12a/12b
13a/13b
14a/14b
15a/15b
16a/16b
16a/16b
CMe2OH
PuPHOS
But
PuPHOS
TMS
PuPHOS
TMS
CyPuPHOS
CyPuPHOS
TMS
28
a Established by 1H NMR spectroscopy of the resulting mixture of complexes. b Starting complex 8 was prepared in situ (Co2(CO)8/
phenylacetylene/toluene) prior to ligand addition.
along with the high yields on the isomerization of the
mother liquors (86%) allowed the transformation of
virtually all the initial complex mixture into the pure
major diastereomer. For example, in the case of com-
plexes 15a/15b, a 68% yield of 15a was obtained by
means of a single crystallization-isomerization-crystal-
lization sequence. Most remarkably, the present meth-
odology proved to be suitable for the preparation of pure
15a on a multigram scale.
The stereochemistry of the major isomer 13a was
firmly established by X-ray analysis.9 The most important
features of the crystal structure were the diequatorial
binding of the bidentate ligand to the cobalt cluster and
the phosphorus coordination to the pro-R cobalt atom.15
To gain further insight into the structure and the relative
thermodynamic stability of the two diastereomers, a
theoretical study was undertaken. Because of the size of
the molecule, a geometry optimization of diastereomers
FIGURE 2. Ortep plot of borane-protected phosphine 2
showing 50% probability ellipsoids.
13a and 13b was performed at the semiempirical
PM3(tm) level.16 Although the geometry and structural
features of the PM3-modeled major isomer 13a were
quite similar to those of the X-ray structure, the energy
of the two isomers was identical, thus indicating that the
semiempirical calculations did not accurately reproduce
the energy differences between the two diastereomers.
However, a DFT single-point calculation at the B3LYP/
6-31G(d) level17 with use of the previously calculated PM3
geometries showed that major 13a was 0.5 kcal/mol more
stable than 13b in reasonable agreement with experi-
mental data.18 Finally, a detailed analysis of structures
13a and 13b (Figure 3) may provide an explanation for
continued heating allowed thermodynamic equilibration
to a biased mixture of diastereomers. Although equilibra-
tion could not be established for phenylacetylene complex
8, for complex 9, prepared from 2-methyl-3-butyn-2-ol,
the equilibration ended with a 4.5:1 mixture of diaster-
eomers 13a and 13b (Table 1, entry 2). Moreover,
complexes derived from tert-butylacetylene (10) or tri-
methylsilylacetylene (11) gave a 3:1 mixture of isomers.
Ligand exchange reaction with the more electron-rich
CyPuPHOS occurred in good yield (87%) but with no
diastereoselectivity in the first place. Continued heating
at 85 °C for 28 h resulted in a biased 1.6:1 mixture of
diastereomers (Table 1, entries 5 and 6).
Tetracarbonyl complexes 16a/16b bearing the CyPu-
PHOS ligand were viscous red oils which could not be
separated by either chromatography or crystallization.
Conversely, diastereomeric complexes 12a/12b with Pu-
PHOS were separated by standard column chromatog-
raphy. Finally and most conveniently, the major diaster-
eomers 13a-15a were isolated by simple crystallization
in a toluene/ethanol solvent mixture. Thus, by repeating
the sequence of equilibration-crystallization, high yields
of the major isomer were obtained in a truly dynamic
resolution process. The robustness of complexes 13-15,
(15) The nomenclature is referred to the cluster terminal carbon
atom. According to the alternative prochirality nomenclature in 2D
the pro-R (pro-S) ligand would correspond to the Re (Si) ligand, see:
Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John
Wiley & Sons: New York, 1994.
(16) Spartan 02; Wavefunction, Inc.; Irvine, CA.
(17) Kong, J.; White, C. A.; Krylov, A. I.; Sherrill, D.; Adamson, R.
D.; Furlani, T. R.; Lee, M. S.; Lee, A. M.; Gwaltney, S. R.; Adams, T.
R.; Ochsenfeld, C.; Gilbert, A. T. B.; Kedziora, G. S.; Rassolov, V. A.;
Maurice, D. R.; Nair, N.; Shao, Y.; Besley, N. A.; Maslen, P. E.;
Dombroski, J. P.; Daschel, H.; Zhang, W.; Korambath, P. P.; Baker,
J.; Byrd, E. F. C.; Van Voorhis, T.; Oumi, M.; Hirata, S.; Hsu, C.-P.;
Ishikawa, N.; Florian, J.; Warshel, A.; Johnson, B. G.; Gill, P. M. W.;
Head-Gordon, M.; Pople, J. A. J. Comput. Chem. 2000, 21, 1532-1548.
(18) A difference of 1.03 kcal‚mol-1 would be necessary at 70 °C to
attain a 4.5:1 ratio of diastereomers.
J. Org. Chem, Vol. 69, No. 23, 2004 8055

Verdaguer et al.
TABLE 2. PKR of PuPHOS and CyPuPHOS Complexes with Norbornadiene
entry
complex
R
conditionsa
time
yield (%)
eeb
product
1
2
3
4
5
6
12a
Ph
Tol./50 °C
30 min
3 d
99
92
93
94
52
98
99
57
97
95
27
70
(+)-17
(+)-18
(+)-18
(-)-18
(+)-18
(+)-19
15a
TMS
Tol./50 °C
15a
TMS
CH2Cl2/NMO/rt
CH2Cl2/NMO/rt
CH2Cl2/NMO/45 °C
CH2Cl2/NMO/rt
3 d
15b
TMS
3 d
16a/16bc
13a
TMS
5 d
CMe2OH
4 d
a All reactions were conducted in Schlenk flasks under nitrogen with 10 equiv of norbornadiene. b Enantiomeric excess (%) was determined
either by HPLC (Chiracel-OD, 17 and 19) or GC (â-DEX, 18). c Mixture of diastereomers in a 1.6:1 ratio.
days again provided the corresponding adduct in high
enantiomeric excess, 97% ee (Table 2, entry 3). We
assume that thermal activation promotes isomerization
of the P,S ligand during the PKR, leading to a nonstereo-
selective process, while N-oxide conditions prevent the
undesired isomerization. Submission of the minor dia-
stereomer 15b to similar reaction conditions provided the
final cyclopentenone with opposite absolute configuration.
As previously established, coordination of phosphorus to
either cobalt center determines the absolute configuration
of the final products. Hence, coordination to the pro-R
cobalt center as in 15a provides dextrorotatory 4-substi-
tuted exo-tricyclo[5.2.1.02,6]-4,8-decadien-3-ones with the
(1S,2S,6R,7R) absolute configuration.
On the basis of the data displayed in Table 2 we
conclude that stereoselectivity in the intermolecular PKR
of complexes 12-16 ultimately depends on the electronic
nature of the alkyne moiety. Complex 13a derived from
the electron-rich 2-methyl-3-butyn-2-ol gives a low stereo-
FIGURE 3. PM3 optimized structures of complexes 13a and
specific process, even under N-oxide promoted conditions
13b and DFT single-point relative energies.
(Table 2, entry 6). In contrast, complex 12a bearing a
the energy differences observed between major and minor
isomers. A five-membered ring is formed upon coordina-
tion of the P,S ligand on two adjacent pseudoequatorial
sites of the alkyne-Co2(CO)6 complex. For isomer 13a,
the diphenylphosphine moiety is linked to the pro-R
cobalt, in a way that the phenyl groups attached to P
and the carbonyl ligands on Co adopt an alternated
disposition, thus minimizing steric repulsion. In contrast,
minor diastereomer 13b, where P is attached to a pro-S
cobalt center, shows an eclipsed disposition of the phenyl
and carbonyl groups. Such unfavorable interaction in
minor complex 13b could account for the energy differ-
ences observed experimentally.
Pauson-Khand Reaction of PuPHOS and CyPu-
PHOS Complexes. The intermolecular PKR of the
resulting P,S-cobalt complexes with norbornadiene was
examined under thermal and N-oxide activation condi-
tions (Table 2). Heating the diastereomerically pure
complex 12a with 10 equiv of norbornadiene at 50 °C led
to rapid cyclization. After 30 min in a stereospecific
process the corresponding exo-cyclopentenone 17 was
obtained in quantitative yield and 99% ee (Table 1, entry
1). Under the same conditions, the PKR of the tri-
methysilyl complex 15a provided 18 in high yield but
decreased enantiomeric excess (57% ee). The reaction of
15a in the presence of N-methylmorpholine N-oxide
(NMO) in dichloromethane at room temperature for 3
mild electron-withdrawing phenyl group yields a stereo-
specific reaction even under thermal activation. Tri-
methysilylacetylene complex 15a is a middle ground case.
While cyclization under thermal conditions provided low
enantiomeric excess, good enantioselectivities were
achieved in the presence of NMO. Finally, the PKR of a
mixture of complexes 16a/16b (1.6:1) under N-oxide
conditions afforded the corresponding cyclopentenone in
27% ee, the expected enantiomeric excess for a completely
stereospecific reaction. This observation indicates that
the more electron-rich cyclohexylphosphine ligand does
not increase the undesired ligand isomerization.
Synthetic Potential of Optically Pure exo-4-(Tri-
methylsilyl)tricyclo[5.2.1.02,6]-4,8-decadien-3-one (18).
The intermolecular PKR adducts of norbornadiene are
interesting starting materials for the preparation of
cyclopentanic compounds. The bicyclo[2.2.1]heptene frag-
ment can be regarded both as a stereoselective controlling
group for the conjugate addition to the cyclopentenone
and as a masked alkene since it is easily removed
through a retro-Diels-Alder reaction (Figure 4). This
synthetic strategy has been applied successfully in the
synthesis of natural products such as Brefeldin-A with
R1 as a covalently attached chiral auxiliary.19
(19) Bernardes, V.; Kann, N.; Riera, A.; Moyano, A.; Perica`s, M. A.;
Greene, A. E. J. Org. Chem. 1995, 60, 6670-6671.
8056 J. Org. Chem., Vol. 69, No. 23, 2004

Pulegone-Derived P,S Ligands PuPHOS and CyPuPHOS
TABLE 3. Reaction Conditions and Yields for Michael Additions and Desilylation Reactions on 18
entry
1
substrate
route
A
reagents
R
yield
81
product
(+)-18
(i) 1.0 equiv of CuI, 2.0 equiv of CH3Li
(ii) 1.3 equiv of HF-Pyr
(i) 1.0 equiv of CuCN, 2.0 equiv of BuLi
(ii) 1.3 equiv of HF-Pyr
1.2 equiv of TBAF anhydrous, THF
3 Å mol sieves
Me
20a
2
3
(+)-18
(+)-18
A
B
n-Bu
99
99
20b
21
-
4
5
6
7
21
C
C
C
D
1.0 equiv of CuI, 2.0 equiv of CH3Li
1.0 equiv of CuI, 2.0 equiv of i-PrMgCl
1.0 equiv of CuI, 2.0 equiv of PhLi
1.3 equiv of n-BuMgCl
Me
73
69
57
92
20a
20c
20d
22b
21
i-Pr
Ph
21
(+)-18
n-Bu
0.1 equiv of CuI, Et2O
8
9
(+)-18
(+)-18
(+)-18
D
D
D
1.3 equiv of i-PrMgCl
i-Pr
Ph
92
78
80
22c
22d
22e
0.1 equiv of CuI, Et2O
1.3 equiv of PhMgBr
0.1 equiv of CuI, Et2O
10
1.3 equiv of CH2CHMgBr
0.1 equiv of CuI, Et2O
vinyl
11
12
13
14
22b
22c
22d
22e
E
E
E
E
0.1 equiv of TBAF‚H2O, THF
0.1 equiv of TBAF‚H2O, THF
0.1 equiv of TBAF‚H2O, THF
0.1 equiv of TBAF‚H2O, THF
n-Bu
i-Pr
Ph
82
92
92
85
20b
20c
20d
20e
vinyl
1,4-addition products, which, under these conditions,
were somewhat unstable and difficult to handle. To avoid
decomposition the intermediate 1,2-silyl ketones were
readily treated with HF-Pyr, producing cyclopentanones
20a and 20b in good yield (Table 3, entries 1 and 2). The
conjugate addition occurred in a completely stereoselec-
tive fashion by attack to the less hindered face of the
enone. These compounds were spectroscopically identical
with those previously obtained in our chiral auxiliary
approach.2d,e This methodology, however, was not con-
venient for less reactive cuprates such as lithium diphen-
ylcuprate, therefore, we examined the removal of the
TMS group prior to conjugate addition. Few studies have
addressed the desilylation of vinylic silanes. Among
these, Krafft described the deprotection of an analogous
trimethylsilylenone by treatment with KButO/DMSO.22
Unfortunately, the formation of 21 did not take place
under these conditions. The first attempts with HF-Pyr
were also unsuccessful. Using TBAF in THF, we isolated
the desired product, albeit in low yield. We then estab-
lished that oxidation of the product during the reaction
workup was one of the main side reactions and that
anhydrous conditions provided higher yields. After much
experimentation, working with strictly anhydrous TBAF
under argon we obtained 21 in 99% yield (Table 3, entry
3). The presence of either water or oxygen in the reaction
mixture results in the enone-oxide 23 as the major side
FIGURE 4. Retrosynthetic analysis of cyclopentenones based
on PKR adducts.
Among the intermolecular PKR adducts prepared by
the present approach, that derived from trimethylsilyl-
acetylene is the most promising from a synthetic point
of view. We hypothesized that the characteristics of the
norbornadiene adducts in combination with the presum-
ably easy removal of the TMS group make the optically
pure adduct 18 a useful “chiral cyclopentadienone syn-
thon”.20 The synthetic potential of this adduct has been
recently expanded by Evans et al., who report a promis-
ing tandem conjugate addition/Peterson olefination.21 To
further explore the synthetic potential of adduct 18, we
studied the removal of the TMS groups and a wide array
of organometallic compounds for Michael addition reac-
tions.
Treatment of (+)-18 with lithium dimethyl cuprate or
lithium dibutylcyanocuprate afforded the corresponding
(20) Substrate-controlled conjugated addition on 18, removal of TMS
fragment, and retro-Diels-Alder reaction will provide chiral cyclopen-
tenones that could formally arise from the aforementioned achiral
cyclopentadienone.
(21) (a) Iqbal, M.; Li, Y.; Evans, P. Tetrahedron 2004, 60, 2531-
2538. (b) Iqbal, M.; Evans, P. Tetrahedron Lett. 2003, 44, 5741-5745.
(22) Krafft, M. E.; Wright, C. Tetrahedron Lett. 1992, 33, 151-152.
J. Org. Chem, Vol. 69, No. 23, 2004 8057

Verdaguer et al.
the modeled diastereomeric structures indicates that an
eclipsed disposition of the Co(CO)2-PPh2 moiety is likely
to account for energy differences between the two dia-
stereomers. Most remarkably, intermolecular PKR of the
trimethylsilylacetylene complex 15a occurred in a com-
pletely stereospecific fashion to yield optically enriched
cyclopentenone (+)-18 (97% ee). By means of stereose-
lective conjugate addition and TMS removal (+)-18 can
be used as a chiral cyclopentadienone synthon. The
developed procedures pave the way for the use of (+)-18
as a promising starting material in the enantioselective
synthesis of natural cyclopentanic products. This ap-
proach is currently being studied in our laboratories.
Experimental Section
[(2S,4aR,7R,8aR)-Hexahydro-4,4,7-trimethyl-4H-ben-
zoxathiin-2-yl]diphenylphosphine Borane Complex, Pu-
PHOS-BH3 (2). To a cooled (-78 °C) solution of oxathiane 7
(905 mg, 4.52 mmol) in THF (10 mL) was added dropwise
s-BuLi 1.3 M in cyclohexane (3.65 mL, 4.74 mmol). The
temperature was allowed to rise to -20 °C. After 20 min of
stirring at this temperature, chlorodiphenylphosphine (0.94
mL, 4.98 mmol) was then added with a syringe at -20 °C.
After that, the temperature was slowly allowed to reach room
temperature. After 4.5 h the reaction was quenched at 0 °C
by the addition of BH3‚S(CH3)2 (0.58 mL, 5.88 mmol). The
reaction mixture was diluted with Et2O and water was added
(CAUTION! bubbling occurs). The aqueous layer was washed
with Et2O and the combined organic layers were washed with
brine and dried (MgSO4). Solvent removal under vacuum
afforded a crude product that was purified by flash chroma-
tography (SiO2, hexane/AcOEt, of increasing polarity) yielding
1.56 g (87%) of 2 as a colorless crystalline solid. Mp 177-179
°C. [R]D +27.6 (c 0.95, CHCl3). IR (KBr) υmax 2923, 2394, 1437,
FIGURE 5. Ortep drawing of 22c showing 50% probability
ellipsoids.
SCHEME 2
product in the desilylation procedure. This compound (23)
was readily prepared in good yield from 21 by oxidation
with H2O2/NaOH (Scheme 2). Zwanenburg et al.23 previ-
ously reported 23 in racemic form. As expected, 21 was
a good substrate for conjugated additions. Stoichiometric
amounts of dialkyl and diaryl cuprates afforded the 1,4-
addition products in a completely stereoselective manner
(Table 3, entries 4-6).
In our search for practical reaction conditions a comple-
mentary route to 1,4-addition compounds was studied.
The use of magnesiocuprate reagents (RMgX/CuI cat.)
was found to be the most convenient from an experimen-
tal point of view. The addition of butyl, isopropyl, phenyl,
or vinyl radicals provided the stable 1,2-trimethysilyl
ketones 22b-e in excellent yield (Table 3, entries 7-10).
Single-crystal X-ray diffraction of 22c allowed us to
ascertain that the incoming alkyl group and the TMS
group adopted a trans stereochemistry (Figure 5). At this
stage, TMS removal with 0.1 equiv of commercial TBAF
allowed the preparation of 20b-e in good to excellent
yields (Table 3, entries 11-14).
1
1148, 1057 cm-1. H NMR (300 MHz, CDCl3) δ 0.30-1.70 (br
m, BH3), 0.90 (d, J ) 6 Hz, 3H), 0.78-1.00 (m, 2H), 1.02-1.17
(m, 1H), 1.25 (s, 3H), 1.45 (s, 3H), 1.51-1.60 (m, 1H), 1.64-
1.73 (m, 1H), 1.77-1.89 (m, 2H), 3.37-3.45 (td, J ) 4 and 11
Hz, 1H), 5.75 (d, J ) 2 Hz, 1H), 7. 40-7.55 (m, 6H), 7.77-
7.83 (m, 2H), 7.90-7.97 (m, 2H) ppm. 13C NMR (75 MHz,
CDCl3) δ 21.8 (CH3), 22.1 (CH3), 24.4 (CH2), 29.4 (CH3), 31.4
(CH), 34.7 (CH2), 41.7 (CH2), 41.8 (C), 51.5 (CH), 67.2 (CH2),
76.6 (CH), 128.3 (d, J ) 10 Hz, CH), 131.39 (d, J ) 15.4, 2.4
Hz, CH), 133.7 (dd, J ) 9, 76.1 Hz, CH) ppm. 31P NMR (121
MHz, CDCl3) δ 23.59 ppm. Anal. Calcd for C23H32BOPS: C,
69.35; H, 8.10; S, 8.05. Found: C 69.42; H, 8.27; S, 7.81.
[(2S,4aR,7R,8aR)-Hexahydro-4,4,7-trimethyl-4H-benz-
oxathiin-2-yl]dicyclohexylphosphine Borane Complex,
CyPuPHOS-BH3 (4). 4 was prepared as described for
PuPHOS‚BH3 with chlorodicyclohexylphosphine and BH3-
THF (1.0 M solution in THF) and isolated as a pale yellow
crystalline solid after flash chromatography purification (SiO2,
hexane/ethyl acetate 95:5) in 50% yield. Mp 126-128 °C. [R]D
-2.4 (c 0.93, CHCl3). IR (film) νmax 2928, 2852, 2378, 1448,
1386, 1148, 1056, 1003, 914, 733 cm-1 1H NMR (400 MHz,
.
Conclusions
CDCl3) δ 0.8-2.2 (m, 33H), 0.93 (d, J ) 6 Hz, 3H), 1.28 (s,
3H), 3.33 (td, J ) 10 and 4 Hz, 1H), 5.43 (d, Jp ) 3 Hz, 1H)
ppm. 13C NMR (100 MHz, CDCl3) δ 21.8 (CH3), 22.3 (CH3),
24.5 (CH2), 26.2 (CH2, d, JP ) 1 Hz), 26.3 (CH2, d, JP ) 1 Hz),
26.8-27.6 (4 × CH2, m), 27.9 (CH3), 30.4 (CH, d, JP ) 30 Hz),
30.9 (CH, d, JP ) 30 Hz), 31.6 (CH), 34.8 (CH2), 41.7 (CH2),
44.2 (Cq, d, JP ) 5 Hz), 51.2 (CH), 74.4 (CH, d, JP ) 37 Hz),
78.9 (CH, d, JP ) 6 Hz) ppm. 31P NMR (121 MHz, CDCl3) δ
In summary, here we have described the preparation
of chiral phosphines PuPHOS and CyPuPHOS and
studied their use as bidentated ligands in intermolecular
PKR. In the case of PuPHOS, the ligand exchange
reaction with alkyne-dicobalt complexes, crystallization
of the major isomer, and thermodynamic equilibration
of the mother liquors resulted in a practical dynamic
resolution that allowed the preparation of diastereomeri-
cally pure Co2-alkyne-PuPHOS complexes. Analysis of
36.2 ppm (br doublet). MS (EI) m/e 410 (M+, 1.2%), 409 (M+
-
H, 3.1%), 199 (M+ - Cy2PBH3, 100%). HRMS (EI) Calcd for
C23H44BOPS (M+) 410.2944, found 410.2953.
General Procedure for the Synthesis of Tetracarbonyl
Complexes: Co2(µ-PhC2H)(CO)4(µ-C23H32OPS), 12a and
12b. A dicobalthexacarbonyl complex of phenylethyne 8 (100
mg, 0.25 mmol), phosphine-borane complex 2 (100 mg, 0.25
(23) Dols, P. P. M. A.; Arnouts, E. G.; Rohaan, J.; Klunder, A. J. H.;
Zwanenburg, B. Tetrahedron 1994, 50, 3473-3490.
8058 J. Org. Chem., Vol. 69, No. 23, 2004

Pulegone-Derived P,S Ligands PuPHOS and CyPuPHOS
mmol), DABCO (41 mg, 0.37 mmol), and toluene (2 mL) were
charged in a Schlenk flask under nitrogen. The reaction
mixture was heated to 65 °C for 18 h, removing periodically
the CO by means of vacuum and nitrogen refilling. Complex-
ation was monitored by TLC. Upon reaction completion the
solvent was removed in vacuo. The residue was then purified
by flash chromatography on SiO2 to yield 164 mg (91%) of a
12a/12b mixture as a red-purple viscous oil. 1H NMR analysis
revealed the existence of a 1/1 mixture of diastereomeric
complexes. IR (KBr) νmax 1962, 1991, 2022 cm-1. 1H NMR (300
MHz, C6D6): first fraction, δ 0.25-0.45 (m, 2H), 0.71 (d, J )
6 Hz, 3H), 0.75-0.98 (m, 2H), 0.97 (s, 3H), 1.09 (s, 3H), 1.16-
1.30 (m, 3H), 1.58-1.68 (m, 1H), 2.75-2.87 (td, J ) 4 and 11
Hz, 1H), 4.99 (s, 1H), 5.93 (d, J ) 7 Hz, 1H), 7.03-7.25 (m,
9H), 7.88 (d, J ) 7 Hz, 2H), 7,93-8.08 (m, 4H) ppm; second
fraction, δ 0.20-0.60 (m, 2H), 0.70 (d, J ) 6 Hz, 3H), 0.70-
1.80 (m, 6H), 0.96 (s, 3H), 1.08 (s, 3H), 2.90-3.10 (m, 1H), 5.44
(b s, 1H), 5.87 (d, J ) 6 Hz, 1H), 6.92-7.28 (m, 9H), 7.62-7-
78 (m, 2H), 7.81-7.98 (m, 4H) ppm. 13C NMR (75 MHz,
C6D6): first fraction, δ 18.7, 21.9, 24.8, 27.4, 31.0, 34.1, 41.0,
48.5 (JP ) 6 Hz), 50.0, 73.9, 78.9, 92.5, (JP ) 23 Hz), 98.7
(JP ) 16 Hz), 126.9, 128.2, 128.6, 128.8, 130.0, 130.4, 133.4
(JP ) 12 Hz), 131.7-134.2 (JP ) 34 Hz), 134.7 (JP ) 12 Hz),
135.5-135.9 (JP ) 34 Hz), 142.3, 202.0-207.0 (b, 4CO) ppm;
second fraction, δ 18.7 (br), 21.8, 24.6, 27.6, 31.2, 34.3, 41.0,
48.0 (br), 50.4, 73.2, 78.9, 88.2 (br), 126.7, 128.7, 129.9, 130.2,
130.3, 131.7, 132.6 (JP ) 12 Hz), 134.6 (br, JP ) 12 Hz), 142.4,
ppm. 31P NMR (121 MHz, C6D6) δ -27.99first, -28.78scnd ppm.
HRMS (FAB+) calcd for C35H35Co2O5PS [M+] 716.0606, found
716.0597.
130.0, 130.2, 133.2 (JP ) 22 Hz), 133.6-134.1 (JP ) 34 Hz),
135.9-136.3 (JP ) 34 Hz) ppm. 31P NMR (121 MHz, C6D6):
major fraction, δ -27.95 (br s) ppm. HRMS (FAB+) calcd for
C32H39Co2O4PS [M+ - CO] 668.0970, found 668.0957.
Co2(µ-Me3SiC2H)(CO)4(µ-C23H32OPS), 15a and 15b. Di-
cobalt hexacarbonylcomplex 11 (100 mg, 0.26 mmol), phos-
phine-borane 2 (100 mg, 0.25 mmol), DABCO (45 mg, 0.4
mmol), and toluene (2 mL) were used according to the General
Procedure. The reaction mixture was heated at 80 °C for 17
h. Purification by flash chromatography yielded 163 mg (91%)
of 15a/15b as a red viscous oil that solidified upon standing.
1H NMR analysis showed a 3/1 ratio of diastereomeric com-
plexes. Crystallization in toluene/ethanol mixtures afforded 92
mg of the major pure diastereomer. Further equilibration of
the minor isomer enriched mother liquor at 80 °C for 18 h
afforded the starting 3/1 ratio of diastereomers in 86% yield.
Mp 163 °C. [R]D +134.8 (c 0.008, CHCl3). IR (KBr) νmax 1956,
1985, 2018 cm-1. 1H NMR (300 MHz, C6D6): major fraction, δ
0.25-1.30 (m, 7H), 0.53 (s, 9H), 0.69 (d, J ) 6 Hz, 3H), 0.98
(s, 3H), 1.11 (s, 3H), 1.55-1.67 (m, 1H), 2.73-2.85 (m, 1H),
4.85 (s, 1H), 5.99-6.02 (d, J ) 8 Hz, 1H), 7.00-7.25 (m, 6H),
7.92-8.03 (m, 4H) ppm; distinct signals from the minor
fraction, δ 0.54 (s, 9H), 0.86 (s, 3H), 1.04 (s, 3H), 2.87-3.01
(br s, 1H), 5.51 (br s, 1H), 5.92-5.95 (br d, J ) 8 Hz, 1H) ppm.
13C NMR (75 MHz, C6D6): major fraction, δ 1.0, 18.16, 21.9,
24.8, 27.3, 31.0, 34.1, 41.0, 48.5, 50.1, 78.8, 86.8, 93.2 (JP ) 22
Hz), 128.6-128.7 (JP ) 9 Hz), 130.0, 133.3-133.5 (JP ) 12
Hz), 134.7-134.8 (JP ) 12 Hz) ppm. 31P NMR (121 MHz,
C6D6): major fraction, δ -26.42 (br s) ppm. HRMS (FAB+)
calcd for C28H39Co2OPSSi [M+ - 4CO] 600.0892, found 600.0914.
Co2(µ-HOMe2CC2H)(CO)4(µ-C23H32OPS), 13a and 13b.
Dicobalt hexacarbonylcomplex 9 (96 mg, 0.26 mmol), phos-
phine-borane 2 (100 mg, 0.25 mmol), DABCO (56 mg, 0.5
mmol), and toluene (1.5 mL) were used according to the
General Procedure. The reaction mixture was heated at 70 °C
for 17 h. Purification by flash chromatography yielded 148 mg
(84%) of the 13a/13b mixture as a red viscous oil that solidified
upon standing. 1H NMR analysis showed a 4.5/1 ratio of
diastereomeric complexes. Crystallization in toluene/ethanol
mixtures afforded the major pure diastereomer. Mp 184 °C.
IR (KBr) νmax 1944, 1970, 1979, 2022 cm-1. 1H NMR (300 MHz,
C6D6): major fraction, δ 0.25-0.38 (m, 2H), 0.69 (d, J ) 6 Hz,
3H), 0.72-0.83 (m, 1H), 0.87-1.02 (m, 1H), 0.97 (s, 3H), 1.11
(s, 3H), 1.10-1.30 (m, 3H), 1.55-1.68 (m, 1H), 1.72 (s, 3H).
1.73 (s, 3H), 1.76 (d, J ) 8 Hz, 1H), 2.80 (td, J ) 5 and 10 Hz,
1H), 4.95 (s, 1H), 5.52 (d, J ) 7 Hz, 1H), 7.01-7.25 (m, 6H),
7.91-8.00 (m, 4H) ppm; distinct signals from the minor
fraction,δ 2.94 (br s, 1H), 5.39 (br d, J ) 7 Hz, 1H) ppm. 13C
NMR (75 MHz, C6D6): major, δ 18.8, 21.9, 24.8, 27.3, 31.0,
33.0, 34.2, 41.0, 48.8 (JP ) 7 Hz), 50.0, 72.4, 73.1, 78.8, 92.5
(JP ) 23 Hz), 128.7 (JP ) 9 Hz), 130.1, 130.4, 133.1-133.3
(JP ) 12 Hz), 134.9-135.0 (JP ) 12 Hz) ppm. 31P NMR (121
MHz, C6D6): major, δ -28.33 (br s) ppm.
Co2(µ-Me3SiC2H)(CO)4(µ-C23H41OPS), 16a and 16b. Di-
cobalt hexacarbonylcomplex 11, phosphine-borane 4, DABCO,
and toluene were used according to the General Procedure.
The reaction mixture was heated at 65 °C for 5 h. Purification
by flash chromatography yielded 87% of 16a/16b as a red
viscous oil that solidified upon standing. 1H NMR analysis
showed a 1:1 ratio of diastereomeric complexes. Further
heating (85 °C, 28 h) of the initial mixture provided a 1.6:1
biased mixture of diastereomers. IR (film) νmax 2014, 1980,
1
1952 cm-1. H NMR (400 MHz, C6D6): mixture of diastereo-
mers, δ 0.26-2.46 (m), 0.57maj (s, 9H), 0.58min (s, 9H), 0.71maj
(t, J ) 6 Hz, 3H), 0.71min (t, J ) 6 Hz, 3H), 1.04 (s, 3H), 1.05
(s, 3H), 1.19 (s, 3H), 2.93maj (td, J ) 10 and 4 Hz, 1H), 3.12min
(td, J ) 10 and 4 Hz, 1H), 4.62maj (s, 1H), 5.11min (s, 1H), 5.78min
(d, JP ) 8 Hz, 1H), 5.99maj (d, JP ) 7 Hz, 1H) ppm. 13C NMR
(100 MHz, C6D6): characteristic signals of the diastereomeric
mixture, δ 1.2 (CH3), 1.3 (CH3), 79.6 (CH), 78.8 (CH), 85.6 (CH),
83.6 (CH), 91.3 (d, Jp ) 17 Hz, CH), 205.3 (br, CO) ppm. 31P
NMR (121 MHz, C6D6) δ -15.45maj, -18.75min ppm. MS (ESI)
m/e 725 (M+ + H), 697 (M+ + H - CO), 669 (M+ + H - 2CO),
641 (M+ + H - 3CO), 613 (M+ + H - 4CO). HRMS (FAB,
NBA) calcd for C29H51Co2O2PSSi (M+ - 3CO) 640.1781, found
640.1780.
(+)-(1S,2S,6S,7R)-4-Phenyltricyclo[5.2.1.0 2,6]deca-4,8-
dien-3-one, 17.6,9 The first fraction of pure major 12a (29 mg,
0.040 mmol), norbornadiene (40 µL, 0.4 mmol), and toluene
(2 mL) were charged in a Schlenk flask under nitrogen and
heated to 50 °C with stirring. TLC monitoring showed the
reaction was complete after 30 min. Purification by flash
chromatography on SiO2 (hexane/AcOEt, 5%) yielded 9 mg
(99%) of (+)-17 as a white solid (99% ee). HPLC analysis:
CHIRALCEL OD (25 cm), 2% IPA-98% hexane, 0.5 mL/min,
λ ) 254 nm. tR (+) isomer ) 16.8 min, tR (-) isomer )
20.6 min.
Co2(µ-ButC2H)(CO)4(µ-C23H32OPS), 14a and 14b. Dico-
balt hexacarbonyl complex 10 (100 mg, 0.27 mmol), phosphine-
borane 2 (108 mg, 0.27 mmol), DABCO (45 mg, 0.4 mmol), and
toluene (2 mL) were used according to the General Procedure.
The reaction mixture was heated at 60 °C for 17 h. Purification
by flash chromatography yielded 191 mg (99%) of 14a/14b as
1
a red solid. H NMR analysis revealed a 3/1 ratio of diaster-
eomeric complexes. Crystallization in hexane afforded the
major pure diastereomer. IR (KBr) νmax ) 1941, 1964, 1977,
2018 cm-1. 1H NMR (300 MHz, C6D6): major fraction, δ 0.26-
0.38 (m, 2H), 0.69 (d, J ) 6 Hz, 3H), 0.72-0.83 (m, 1H), 0.88-
1.02 (m, 1H), 1.00 (s, 3H), 1.10-1.28 (m, 3H), 1.15 (s, 3H), 1.47
(s, 9H), 1.59-1.63 (m, 1H), 2.78-2.87 (td, J ) 5 and 10 Hz,
1H), 4.97 (s, 1H), 5.61-5.64 (d, J ) 7 Hz, 1H), 7.01-7.25 (m,
6H), 7.91-8.00 (m, 4H) ppm; distinct signals from the minor
fraction, δ 1.50 (s, 9H), 2.92-3.05 (br s, 1H), 5.42 (br d, 1H),
5.53 (br s, 1H) ppm. 13C NMR (75 MHz, C6D6): major fraction,
δ 18.7, 21.9, 24.7, 27.3, 31.0, 33.3, 34.1, 36.9, 41.0, 48.8 (JP )
7 Hz), 50.0, 73.3, 78.7, 92.5, (JP ) 22 Hz), 128.7 (JP ) 9 Hz),
(+)-(1S,2S,6S,7R)-4-(1-Hydroxy-1-methylethyl)tricyclo-
[5.2.1.0 2,6]deca-4,8-dien-3-one, 19.9,5a The major crystalline
diastereomer 13a (15 mg, 0.021 mmol), norbornadiene (21 µL,
0.21 mmol), N-methylmorpholine N-oxide (14 mg, 0.12 mmol),
and CH2Cl2 (1.5 mL) were charged in a Schlenk flask tube
under nitrogen and stirred at room temperature for 4 days to
yield 4.3 mg (98%) of (-)-19 in 50% ee as calculated by HPLC
J. Org. Chem, Vol. 69, No. 23, 2004 8059

Verdaguer et al.
analysis: CHIRALCEL OD (25 cm), 5% IPA--5% hexane, 1.0
mL/min, λ ) 254 nm. tR (-) isomer ) 6.5 min, tR (+) isomer )
7.3 min.
and 400 mg of 3 Å molecular sieves in pellets. The system was
flushed with argon and 10 mL of anhydrous THF was added.
Then 1.1 mL of a 1.0 M solution of TBAF in THF (1.10 mmol,
1.2 equiv) dried over 3 Å molecular sieves were added
dropwise. When complete disappearance of the starting prod-
uct was observed by TLC (ca. 1 h) 10 mL of ether and then 15
mL of saturated aqueous NH4Cl solution were added. The
organic layer was quickly separated and the aqueous one was
extracted twice with ether. The combined organic layers were
dried with MgSO4, filtered, and evaporated under reduced
pressure. The crude was immediately purified by flash chro-
matography (SiO2/CH2Cl2) to afford 134 mg (quant.) of a yellow
oil that solidified on the freezer at -20 °C. [R]D +261 (c 0.15,
(+)-(1S,2S,6R,7R)-4-(Trimethylsilyl)tricyclo[5.2.1.0 2,6]-
deca-4,8-dien-3-one, 18.9,16 Thermal conditions: The major
crystalline diastereomer 15a (16 mg, 0.022 mmol), norborna-
diene (20 µL, 0.2 mmol), and toluene (1.0 mL) were charged
in a Schlenk flask under nitrogen and heated at 50 °C for 3
days. This procedure resulted in complete conversion of the
starting complex (TLC) and yielded (+)-18 in 57% ee as
calculated by GC analysis. N-Oxide conditions: The major
crystalline diastereomer 15a (21 mg, 0.029 mmol), norborna-
diene (50 µL, 0.5 mmol), N-methylmorpholine N-oxide (20 mg,
0.17 mmol), and CH2Cl2 (1.0 mL) were charged in a Schlenk
flask under nitrogen and stirred at room temperature for
3 days to yield 6 mg (93%) of (+)-18 in 97% ee as calculated
by GC analysis: Supelco â-DEX 120, 30 m, 150 °C. tR (-)
isomer ) 31.7 min, tR (+) isomer ) 33.4 min. Mp 102-103 °C.
[R]D +78.5 (c 0.88, CHCl3). IR (KBr) υmax 3064, 3029, 2977,
1684, 1570, 1302, 1254, 1246 cm-1.1H NMR (300 MHz, CDCl3)
δ 0.15 (s, 9H), 1.17 (d, J ) 9 Hz), 1.36 (dt, J ) 2 and 9 Hz,
1H), 2.26 (dt, J ) 2 and 6 Hz, 1H), 2.67 (s, 1H), 2.82 (dt, J )
1 and 5 Hz, 1H), 2.88 (s, 1H), 6.16-6.27 (2 × dd, JA ) 3 and
5 Hz, JB ) 3 and 6 Hz, 2H), 7.58 (d, J ) 3 Hz, 1H) ppm. 13C
NMR (75 MHz, CDCl3) δ -1.9 (CH3), 41.3 (CH2), 42.9 (CH),
43.8 (CH), 52.0 (CH), 53.4 (CH), 137.4 (CH), 138.2 (CH), 152.1
(C), 172.8 (CH), 213.0 (C) ppm. E.M. (CI-NH3) m/z 219
(M+ + 1, 50%), 236 (M+ + 18, 100%). HRMS (CI-NH3) calcd
for C13H18OSi 218.1127, found 218.1122.
CHCl3). IR (film) νmax 2973, 1703, 1579, 1341, 1178, 710 cm-1
.
1H NMR (400 MHz, CDCl3) δ 1.30 (d, J ) 9 Hz, 1H), 1.41 (dt,
J ) 9 and 1 Hz, 1H), 2.27 (ddd, J ) 5, 1 and 1 Hz, 1H), 2.72
(m, 1H), 2.86 (m, 1H), 2.93 (m, 1H), 6.22 (dd, J ) 6 and 3 Hz,
1H), 6.26 (dd, J ) 6 and 2 Hz, 1H), 6.29 (dd, J ) 6 and 3 Hz,
1H), 7.57 (dd, J ) 6 and 3 Hz, 1H) ppm. 13C NMR (100 MHz,
CDCl3) δ 41.3 (CH2), 42.8 (CH), 43.7 (CH), 50.6 (CH), 52.1
(CH), 137.4 (CH), 138.4 (CH), 138.4 (CH), 166.1 (CH), 210.5
(CdO) ppm.
(+)-(1S,2R,5S,6R,7R)-5-Methyltricyclo[5.2.1.02,6]dec-8-
en-3-one, 20a.2e Route C: Dry CuI (366 mg, 1.92 mmol) was
placed in a 25-mL flask fitted with a septum and an argon
inlet. The system was flushed with argon and 5 mL of
anhydrous Et2O was added. The resulting suspension was
cooled to -78 °C, and 1.6 M MeLi in ether (2.4 mL, 3.84 mmol)
was then added dropwise. After 20 min, a solution of enone
21 (140 mg, 0.96 mmol) in ether (4 mL) was added to the
transparent solution via cannula. When no starting material
could be detected by TLC (ca. 25 min) the reaction was treated
under vigorous stirring with aqueous NH4Cl (10 mL) for 1 h.
The blue aqueous layer was extracted with ether (2 × 20 mL)
and the combined organic extracts were washed with brine,
dried (MgSO4), and concentrated in a vacuum to yield 113 mg
(73%) of 20a as a pale yellow oil. [R]D +115 (c 1.0, CHCl3).
(-)-(1R,2R,6S,7S)-4-(Trimethylsilyl)tricyclo[5.2.1.0 2,6]-
deca-4,8-dien-3-one, 18. N-Oxide conditions: Pure minor
diastereomer 15b yielded under analogous reaction conditions
(-)-18 in 95% ee as calculated by GC analysis.
(+)-(1S,2S,5R,6R,7R)-5-Methyltricyclo[5.2.1.02,6]dec-8-
2e,24
en-3-one, 20a.
Route A: Copper(I) iodide (0.12 g, 0.63
mmol) and ether (6 mL) were placed under nitrogen in a round-
bottomed flask. The resulting slurry was cooled to -50 °C, and
1.6 M MeLi (0.78 mL, 1.25 mmol) was added via syringe. The
mixture was stirred at -50 °C for 30 min and then allowed to
gradually warm to -10 °C. A solution of (+)-18 in ether (5
mL) was added via cannula. After 10 min at this temperature,
no more starting material was visible by TLC. At this point,
hexane and NH4Cl/NH3 10% were added to the crude until
two phases were clearly obtained. The aqueous phase was
extracted with ether, and the combined extracts were washed
with NH4Cl/NH3 10% until a colorless aqueous phase was
obtained. The organic phase was then washed with brine, dried
(MgSO4), and concentrated in vacuo to yield 119 mg of 22a as
a yellow oil, which was immediately used without further
purification. A solution of 22a (119 mg, 0.48 mmol) in aceto-
nitrile (100 µL) was treated with HF-pyr 60% (20 µL, 0.59
mmol). The reaction mixture was stirred at room temperature
until TLC analysis revealed complete conversion of the starting
material. Next, saturated NaHCO3 solution was added, and
the aqueous phase was extracted with ether. The combined
organic extracts were washed with brine, dried (MgSO4), and
concentrated in vacuo. Purification by column chromatography
(2% v/v NEt3 pretreated SiO2, hexane/AcOEt 10%) yielded 63
mg of 20a as a colorless oil (81%). [R]D +115° (c 1.0, CHCl3).
IR (film) υmax 3070, 2970, 1740, 1465, 825, 700 cm-1. 1H NMR
(200 MHz, CDCl3) δ 1.19 (d, J ) 6 Hz, 3H), 1.15-1.25 (m, 1H),
1.38-1.48 (m, 1H), 2.15-2.70 (ABX, Jab ) 18 Hz, Jax ) 7 Hz,
Jbx ) 10 Hz, 2H), 2.28-2.35 (m, 1H, m), 2.78 (s, 1H), 3.09 (s,
1H), 6.10-6.22 (m, 2H) ppm.
(+)-(1S,2S,4R,5S,6R,7R)-5-Isopropyl-4-trimethylsilyl-
tricyclo[5.2.1.02,6]dec-8-en-3-one, 22c. Route D: Into a 100-
mL flask provided with magnetic stirring, rubber septum, and
argon atmosphere was placed a suspension of anhydrous CuI
(35 mg, 0.186 mmol, 0.1 equiv) (freshly recrystallized) in 25
mL of anhydrous diethyl ether. The flask was cooled to -78
°C and 1.1 mL (2.23 mmol, 1.2 equiv) of 2.0 M isopropylmag-
nesium chloride solution in ether was added dropwise. After
the mixture was stirred for 10 min a solution of (+)-18 (406
mg, 1.86 mmol) in 5 mL of anhydrous ether was added
dropwise. The solution rapidly turned dark and was allowed
to warm to -40 °C over 2 h during which the color became
orange. The mixture was then treated with equal volumes of
saturated aqueous NH4Cl and aqueous NH4OH for 20 min.
The aqueous layer was sepaated and extracted twice with
ether. The combined organic layers were washed with brine,
dried with anhydrous MgSO4, filtered, and evaporated under
reduced pressure to yield 451 mg (92%) of the 22c as a colorless
crystalline solid. [R]D +83.5 (c 1.60, CHCl3). Mp (DSC) 57 °C.
1
IR (film) νmax 2956, 1706, 1247, 1202, 860, 838, 702 cm-1. H
NMR (400 MHz, CDCl3) δ 0.11 (s, 9H), 0.87 (d, J ) 6 Hz, 3H),
0.99 (d, J ) 6 Hz, 3H), 1.22 (d, J ) 9 Hz, 1H), 1.39 (dt, J ) 9
and 2 Hz, 1H), 1.71 (m, 1H), 1.81 (dt, J ) 9 and 4 Hz, 1H),
2.08 (dd, J ) 9 and 5 Hz, 1H), 2.16 (dd, J ) 9 and 2 Hz, 1H),
2.25 (d, J ) 9 Hz, 1H), 2.67 (s, 1H), 3.05 (s, 1H), 6.15 (dd, J )
5 and 3 Hz, 1H), 6.19 (dd, J ) 5 and 3 Hz, 1H) ppm. 13C NMR
(100 MHz, CDCl3) δ -0.9 (CH3), 16.5 (CH3), 21.4 (CH3), 32.1
(CH), 44.6 (CH + CH2), 46.9 (CH), 48.3 (CH), 50.0 (CH), 50.1
(CH), 57.8 (CH), 138.0 (CH), 138.9 (CH), 221.5 (CdO) ppm.
Anal. Calcd for C16H26OSi: C,73.22, H, 9.98. Found: C, 72.85,
H, 10.25.
(+)-(1S,2S,6R,7R)-Tricyclo[5.2.1.02,6]dec-8-en-3-one, 21.25
Route B: In a two-necked, 50-mL flask fitted with a septum
and an argon inlet were weighed (+)-18 (200 mg, 0.916 mmol)
(24) Dols, P. P. M. A.; Verstappen, M. M. H.; Klunder, A. J. H.;
Zwanenburg, B. Tetrahedron 1993, 49, 11353-11372.
(25) (a) Dols, P. P. M. A.; Klunder, A. J. H.; Zwanenburg, B.
Tetrahedron Lett. 1993, 34, 3181-3184. (b) Zhang, L.; Yang, J.; Liu,
Z. Chin. Chem. Lett. 1992, 3, 787-788.
(+)-(1S,2S,4R,5S,6R,7R)-5-n-Butyl-4-trimethylsilyltri-
cyclo[5.2.1.02,6]dec-8-en-3-one, 22b. Following the procedure
described for 22c (Route D) but using a 2.0 M butylmagnesium
chloride the target compound 22b was obtained in 92% yield
8060 J. Org. Chem., Vol. 69, No. 23, 2004

Pulegone-Derived P,S Ligands PuPHOS and CyPuPHOS
as a pale yellow oil. [R]D +74.0 (c 2.0, CHCl3). IR (film) νmax
MgSO4, filtered, and evaporated under reduced pressure. The
residue was purified by flash chromatography on SiO2 with a
hexane/ethyl acetate mixture (98:2) to yield 20d (70 mg, 92%
yield) as a colorless oil. [R]D +107 (c 1.50, CHCl3). IR (film)
νmax 2965, 1733, 1186, 763, 751, 700 cm-1. 1H NMR (400 MHz,
CDCl3) δ 1.40 (d, J ) 9 Hz, 1H), 1.53 (dt, J ) 9 and 1 Hz, 1H),
2.44 (m, 1H), 2.52 (d, J ) 1 Hz, 1H), 2.82 (ddd, J ) 17, 12,
and 1 Hz, 1H), 2.86 (m, 1H), 2.92 (s, 1H), 2.93 (m, 1H), 3.21
(s, 1H), 6.15 (dd, J ) 6 and 3 Hz, 1H), 6.18 (dd, J ) 6 and 3
Hz, 1H), 7.27 (m, 3H), 7.35 (m, 1H) ppm. 13C NMR (100 MHz,
CDCl3) δ 44.5 (CH2), 45.3 (CH), 45.4 (CH), 47.6 (CH), 51.3
(CH2), 52.1 (CH), 55.1 (CH), 126.7 (CH), 127.0 (CH), 128.9
(CH), 137.7 (CH), 138.4 (CH), 145.4 (Cq), 217.3 (CdO) ppm.
2957, 2925, 1733, 1457 cm-1 1H NMR (400 MHz, CDCl3) δ
.
0.10 (s, 9H), 0.94 (t, J ) 7 Hz, 3H), 1.18 (d, J ) 9 Hz, 1H),
1.25-1.37 (m, 4H), 1.40 (d, J ) 9 Hz, 1H), 1.44-1.62 (m, 2H),
1.69 (m, 1H), 1.96 (dd, J ) 10 and 2 Hz, 1H), 2.00 (dd, J ) 9
and 5 Hz, 1H), 2.33 (d, J ) 9 Hz, 1H), 2.72 (s, 1H), 3.05 (s,
1H), 6.15 (dd, J ) 6 and 3 Hz, 1H), 6.19 (dd, J ) 6 and 3 Hz,
1H) ppm. 13C NMR (100 MHz, CDCl3) δ -1.4 (CH3), 14.3 (CH3),
23.0 (CH2), 29.8 (CH2), 39.0 (CH2), 42.5 (CH), 44.7 (CH2), 46.4
(CH), 49.5 (CH), 50.6 (CH), 52.9 (CH), 57.9 (CH), 138.1 (CH),
138.7 (CH), 221.1 (CdO) ppm. MS (CI-CH4) m/e 277 (M+
H, 4.9%), 276 (M+, 2.5%), 235 (M+ - C3H5, 59.8%), 210 (M+
+
-
C5H6, 48.2%), 73 (C3H9Si+, 100%), 66 (C5H6+, 62.4%). HRMS
(CI-CH4) calcd for C17H29OSi (M+ + H) 277.1988, found
277.1989.
(+)-(1S,2S,5S,6R,7R)-5-Isopropyltricyclo[5.2.1.02,6]dec-
8-en-3-one, 20c. Following the procedure described for 20d
(Route E) 20c was obtained in 92% yield as a colorless oil. [R]D
(+)-(1S,2S,4R,5R,6R,7R)-5-Phenyl-4-trimethylsilyltri-
cyclo[5.2.1.02,6]dec-8-en-3-one, 22d. The procedure described
for 22c (Route D) was followed but starting from (+)-18 (109
mg) and using 1.0 M phenylmagnesium bromide solution in
THF (very slow addition of the enone was required to avoid
1,2 addition of phenylmagnesium bromide). After purification
by flash chromatography on SiO2 with a hexane/AcOEt
mixture (98:2), 115 mg of 22d (78%) was obtained as a colorless
solid. Mp (DSC) 97 °C. [R]D +74.4 (c 2.15, CHCl3). IR (KBr)
νmax 2983, 2959, 1707, 1242, 1183, 869, 841, 722, 697 cm-1. 1H
NMR (400 MHz, CDCl3) δ ) -0.03 (s, 9H), 1.31 (d, J ) 9 Hz,
1H), 1.51 (d, J ) 9 Hz, 1H), 2.33 (dd, J ) 9 and 6 Hz, 1H),
2.54 (d, J ) 9 Hz, 1H), 2.57 (dd, J ) 11 and 2 Hz, 1H), 2.85
(dd, J ) 11 and 6 Hz, 1H), 2.89 (s, 1H), 3.15 (s, 1H), 6.08 (dd,
J ) 6 and 3 Hz, 1H), 6.16 (dd, J ) 6 and 3 Hz, 1H), 7.28 (m,
1H) ppm. 13C NMR (100 MHz, CDCl3) δ -1.6 (CH3), 44.6 (CH2),
46.3 (CH), 48.1 (CH), 49.8 (CH), 54.3 (CH), 54.4 (CH), 57.8
(CH), 126.6 (CH), 127.5 (CH), 128.8 (CH), 138.3 (CH), 138.6
(CH), 147.3 (Cq), 219.8 (CdO) ppm. Anal. Calcd. for C19H24-
OSi: C, 76.97, H, 8.16. Found: C, 76.60, H, 8.42.
(+)-(1S,2S,4R,5S,6R,7R)-5-Vinyl-4-trimethylsilyltricyclo-
[5.2.1.02,6]dec-8-en-3-one, 22e. Following the procedure de-
scribed for 22c (Route D) but with 1.0 M vinylmagnesium
bromide solution in THF, 22e was obtained in 80% yield as a
pale yellow oil. [R]D +78.9 (c 0.90, CHCl3). IR (film) νmax 2959,
2942, 1732, 1641, 1389, 849 cm-1. 1H NMR (400 MHz, CDCl3)
δ 0.09 (s, 9H), 1.20 (d, J ) 9 Hz, 1H), 1.46 (dt, J ) 9 and 2 Hz,
1H), 2.11 (m, 1H), 2.15 (dd, J ) 11 and 2 Hz, 1H), 2.34 (m,
1H+1H), 2.82 (s, 1H), 3.08 (s, 1H), 4.96 (ddd, J ) 10, 2, and 1
Hz, 1H), 5.03 (ddd, J ) 17, 2, and 1 Hz, 1H), 5.82 (ddd, J )
17, 10, and 8 Hz), 6.16 (m, 1H) ppm. 13C NMR (100 MHz,
CDCl3) δ -1.4 (CH3), 44.8 (CH2), 46.3 (CH), 47.7 (CH), 47.8
(CH), 50.8 (CH), 51.5 (CH), 57.3 (CH), 113.6 (CH2), 138.3 (CH),
138.6 (CH), 143.8 (CH), 219.9 (CdO) ppm. MS (CI-CH4) m/e
180 (M+ - C5H6, 13.1%), 167 (36.4%), 149 (100%), 73 (C3H9-
Si+, 34.5%). HRMS (CI-CH4) Calcd. for C15H16OSi (M+ - C5H6)
180.0970, found 180.0970.
+83.2 (c 1.05, CHCl3). IR (film) νmax 2960, 2872, 1731, 694 cm-1
.
1H NMR (400 MHz, CDCl3) δ 0.91 (d, J ) 6 Hz, 3H), 1.01 (d,
7 Hz, 3H), 1.23 (d, J ) 9 Hz, 1H), 1.41 (dt, J ) 9 and 2 Hz,
1H), 1.48 (m, 1H), 1.62 (m, 1H), 2.06 (dd, J ) 7 and 7 Hz, 1H),
2.32 (ddd, J ) 18, 11, and 2 Hz, 1H), 2.29 (m, 1H), 2.74 (s,
1H), 3.11 (s, 1H), 6.14 (dd, J ) 6 and 3 Hz, 1H), 6.20 (dd, J )
6 and 3 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 20.7 (CH3),
34.9 (CH), 44.6 (CH2), 45.4 (CH), 46.5 (CH), 47.8 (CH), 48.1
(CH2), 48.8 (CH), 55.3 (CH), 137.6 (CH), 138.5 (CH), 218.9
(CdO) ppm. MS (CI-NH3) m/e 190 (M+, 4.2%), 191 (M+ + H,
19.9%), 125 (M+ - C5H5, 100%). HRMS (CI-NH3) calcd for
C13H19O (M+ + H) 191.1436, found 191.1442.
(+)-(1S,2S,5S,6R,7R)-5-Vinyltricyclo[5.2.1.02,6]dec-8-en-
3-one, 20e. Following the procedure described for 20d (Route
E) 20e was obtained in 85% yield as a colorless oil. [R]D +79.5
(c 0.80, CHCl3). IR (film) νmax 2963, 1729, 1640 cm-1. 1H NMR
(400 MHz, CDCl3) δ 1.26 (d, J ) 9 Hz, 1H), 1.47 (dt, J ) 9 and
2 Hz, 1H), 2.15 (dd, J ) 7 and 8 Hz, 1H), 2.32 (d, J ) 9 Hz,
1H), 2.39 (m, 1H), 2.51 (ddd, J ) 17, 11, and 2 Hz, 1H), 2.61
(dd, J ) 17 and 9 Hz, 1H), 2.83 (s, 1H), 3.13 (d, J ) 1 Hz, 1H),
5.01 (dd, J ) 10 and 1 Hz, 1H), 5.06 (ddd, J ) 17, 1, and 1 Hz,
1H), 5.90 (ddd, J ) 17, 10, and 7 Hz, 1H), 6.16 (dd, J ) 5 and
3 Hz, 1H), 6.19 (dd, J ) 5 and 3 Hz, 1H) ppm. 13C NMR (100
MHz, CDCl3) δ 43.9 (CH), 44.9 (CH2), 45.4 (CH), 47.3 (CH),
49.4 (CH2), 49.6 (CH), 54.8 (CH), 114.1 (CH2), 138.0 (CH), 138.7
(CH), 142.0 (CH), 217.5 (CdO) ppm. MS (CI-CH4) m/e 175
(M+ + H, 6.8%), 174 (M+, 5.1%), 163 (8.2%), 149 (17%), 137
(6.7%), 109 (M+ - C5H5, 100%), 91 (20.4%), 79 (16.7%). HRMS
(CI-CH4) calcd for C12H15O (M+ + H) 175.1045, found 175.1043
Acknowledgment. We thank the DGI-MYCT
(BQU2002-02459) and DURSI (2001SGR50) for finan-
cial support. X.V. thanks the DURSI for Distincio´ per a
la Promocio´ de la Recerca Universitaria. A.L. thanks
the MEC for a fellowship.
(+)-(1S,2S,5R,6S,7R)-5-Phenyltricyclo[5.2.1.02,6]dec-8-
en-3-one, 20d.19,26 Route E: In a 25-mL flask equipped with
a magnetic stirring was placed a solution of 22d (100 mg, 0.337
mmol) in THF (4 mL). TBAF‚H2O (8.8 mg, 0.03 mmol, 0.1
equiv) was added and the mixture stirred for 45 min until
disappearance of the starting product by TLC. Water (2 mL)
and diethyl ether (2 mL) were added to the reaction mixture
and the aqueous layer was separated and extracted twice with
ether. The combined organic layers were dried with anhydrous
Supporting Information Available: Tables of complete
X-ray crystal data, including ORTEP drawings, refinement
parameters, atomic coordinates, and bond distances and angles
for 2 and 22c; general experimental methods; and1H and 13C
NMR spectra of compounds 4, 12-16, 20c, 20e, 22b-e. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(26) Grieco, P. A.; Abood, N. J. Org. Chem. 1989, 54, 6008-6010.
JO0486894
J. Org. Chem, Vol. 69, No. 23, 2004 8061