The asymmetric synthesis of cyclopentane derivatives by palladium- catalyzed coupling of prochiral alkylboron compounds

Article abstract of DOI:10.1016/S0957-4166(98)00386-3

Treatment of the prochiral triflate 2a with Pd₂(dba)₃·CHCl₃, (S)- (R)-BPPFOAc and K₂CO₃, in THF at 40°C, gave the cyclopentane derivative 10 in 58% yield and in 28% ee after oxidative work-up and benzoylation. Moreover, reaction of the prochiral triflate 2c with Pd₂(dba)₃·CHCl₃, (S)-(R)-PPFA and K₂CO₃, in THF at 40°C, afforded the cyclopentane derivative 3b, with a quaternary carbon center, in 42% yield and in 31% ee after oxidative work-up.

Full text of DOI:10.1016/S0957-4166(98)00386-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3751–3754
The asymmetric synthesis of cyclopentane derivatives by
palladium-catalyzed coupling of prochiral alkylboron compounds
Suk Young Cho and Masakatsu Shibasaki ∗
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 31 August 1998; accepted 21 September 1998
Abstract
Treatment of the prochiral triflate 2a with Pd2(dba)3·CHCl3, (S)-(R)-BPPFOAc and K2CO3, in THF at 40°C,
gave the cyclopentane derivative 10 in 58% yield and in 28% ee after oxidative work-up and benzoylation.
Moreover, reaction of the prochiral triflate 2c with Pd2(dba)3·CHCl3, (S)-(R)-PPFA and K2CO3, in THF at 40°C,
afforded the cyclopentane derivative 3b, with a quaternary carbon center, in 42% yield and in 31% ee after oxidative
work-up. © 1998 Elsevier Science Ltd. All rights reserved.
Palladium-catalyzed coupling reactions of organic halides or organic triflates with organoboron
compounds, generally referred to as Suzuki–Miyaura reactions,1 are powerful methods for various
carbon–carbon bond-forming reactions. However, only limited attention has been paid to an asymmetric
Suzuki–Miyaura reaction,2 which would provide an efficient method for the synthesis of a variety of
optically active carbon centers that would be difficult to obtain by other methods. Using our experience
in the field of palladium-catalyzed asymmetric Heck reactions,3 we focused on an asymmetric design of
a palladium-catalyzed Suzuki–Miyaura reaction. In this paper we report a catalytic asymmetric synthesis
of cyclopentane derivatives by palladium-catalyzed coupling of prochiral alkylboron compounds.
Our basic strategy involves enantiotopic group selective ring closure of the prochiral triflates 2a and 2c,
and bromide 2b. This closure, catalyzed by a palladium complex with an asymmetric ligand, would lead
to the optically active cyclopentane derivatives 3a and 3b after oxidative work-up. Prochiral substrates
2a, 2b and 2c were expected to be readily prepared from the corresponding substrates, with two olefinic
moieties, using hydroboration (Scheme 1). Initially, the feasibility of an asymmetric coupling of 2a
promoted by a palladium complex with an asymmetric ligand, was examined in detail, and this allowed
the development of an efficient synthetic route to 1a (shown in Scheme 2). Thus, ethyl acetoacetate 4
was converted to the alkenyl triflate 1a, which possesses two olefinic moieties, in 40% overall yield
for the three steps. Hydroboration of 1a was carried out using 2.5 mol equivalents of 9-BBN (THF,
40°C, 1 h), because this convenient reagent readily allowed the preparation of a variety of functionalized
alkylboron derivatives from their corresponding terminal alkenes. The resulting THF solution of the
∗
Corresponding author.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00386-3

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S. Y. Cho, M. Shibasaki / Tetrahedron: Asymmetry 9 (1998) 3751–3754
alkylboron compound 2a was degassed three times (freeze–pump–thaw cycle method (FPT method))
before coupling was attempted. After several attempts at coupling, it was found that the use of the
Pd2(dba)3·CHCl3 complex as a palladium source, and K2CO3 as a base were the most effective. Many
asymmetric couplings were carried out as follows.
Scheme 1.
A stirred suspension of Pd2(dba)3·CHCl3 (10 mol%), an asymmetric ligand (20 mol%) and K2CO3 (5
mol equiv.), in THF, was degassed three times (FPT method), and the suspension was stirred at 40°C for
1 h. To this suspension was added the degassed THF solution of 2a, and the resulting reaction mixture
was stirred at 40°C for 12 h. Oxidative work-up with 3 N NaOH and 35% H2O2, at 0°C, gave the
cyclopentane derivative 3a. As shown in Table 1, the use of (R)-BINAP gave no product 3a (entry 1,
Table 1). However, the use of monodentate ligands4 such as (R)-MOP(OCH3), (R)-MOP(O-i-Pr) and
(R)-MOP(OH), resulted in the formation of 3a in good yields albeit with low ees (up to 14% ee) (entries
2 and 3, Table 1). To the best of our knowledge, this is the first reported example of an intramolecular
asymmetric Suzuki–Miyaura reaction. The use of the bidentate ligand (S)-(R)-BPPFOAc5 afforded the
desired product 10 in 58% yield and 28% ee (entry 5, Table 1).
In an attempt to further improve the above result, solvent effects were investigated (CH2Cl2 or DMF
were used); however, THF was found to be the best solvent for the present asymmetric Suzuki–Miyaura
reaction. The ee of 3a was determined at the stage of the benzonate 10 by HPLC analysis using a
chiral stationary column (Chiralpak OJ, hexane:isopropanol 5000:1). We further continued to improve an
intramolecular asymmetric Suzuki–Miyaura reaction. The precise mechanism for the coupling between
Table 1
Asymmetric cross-coupling reaction of alkenyl triflate 2a and bromide 2ba

S. Y. Cho, M. Shibasaki / Tetrahedron: Asymmetry 9 (1998) 3751–3754
3753
organic triflates or organic halides with organoboron compounds, particularly the transmetallation step,
has not been fully elucidated,1 and so we also examined the use of an alkenyl bromide with two olefinic
moieties for an intramolecular asymmetric coupling. As shown in Scheme 2, the bromide 1b was prepared
from 6, by a modified Shapiro reaction, using 2,4,6-triisopropylbenzenesulfonyl hydrazide.6 However, as
shown in Table 1 (entries 10–13), less satisfactory results were obtained for the asymmetric coupling.
Scheme 2. (a) Allyl chloride (2.5 equiv.), BnEt3NCl, KOHaq, benzene, rt, 65%. (b) LiCl, DMF, reflux, 90%. (c) 2,4,6-Triisopro-
pylsulfonyl hydrazide, MeOH, H+, 70%. (d) (1) 2 Equiv. BuLi, −78°C–0°C, TMEDA/pentane, (2) BrCH2CH2Br, 0°C, 50%. (e)
(1) Ethylene glycol, TsOH, benzene, reflux, (2) LiAlH4, Et2O, 2 steps 90%. (f) (1) TBDMSCl, imidazole, DMF, (2) FeCl3·SiO2,
acetone, 2 steps 95%. (g) KHMDS, PhNTf2, THF, −78°C, 66–68%
Although the highest ee of 3a was still low, we next investigated the catalytic asymmetric construction
of a quaternary carbon center7 using the alkenyl triflate 1c. The requisite triflate 1c was prepared as shown
in Scheme 2, and, after hydroboration under the standard conditions, an intramolecular asymmetric
coupling was attempted using the resulting organoboron compound 2c. The results are summarized
in Table 2. When the reaction was carried out using (S)-(R)-BPPFOAc as the asymmetric ligand, the
coupling proceeded smoothly giving the cyclopentane derivative 3b after oxidative work-up in 65% yield
but only 2% ee. However, it was found that the use of (R)-BINAP monooxide,8 prepared in situ, resulted
in the formation of 3b in 60% yield and 16% ee. In an attempt to improve this result, ligand effects
were further examined. (S)-(R)-PPFA9 proved to be the best ligand for this asymmetric coupling reaction,
giving the coupling product 3b in 31% ee and 42% yield. The ee of 11 was determined by HPLC analysis
using a chiral stationary column (Chiralpak OJ, hexane:isopropanol 9:1).
The absolute configuration of coupling products 3a and 3b could be easily determined as follows
(Scheme 3). The product 3a was converted into the corresponding tosylate, and then further transformed
into the known alkyl ketone 13,10 by a substitution reaction with a copper reagent followed by ozonolysis
Table 2
Asymmetric cross-coupling reaction of alkenyl triflate 2ca

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S. Y. Cho, M. Shibasaki / Tetrahedron: Asymmetry 9 (1998) 3751–3754
of the resulting exo-olefin, in 35% overall yield. The absolute configuration of 3a was determined as
(R) by comparison of the optical rotation with published data. The absolute configuration of coupling
product 3b was determined using the HPLC analysis of compound 14. Ozonolysis of the exo-olefin
functionality of 4-nitrobenzonate 11, in methanol at 0°C for 2 h, gave dialkyl ketone 14 in 30% yield.
In contrast, optically active α,α0-disubstituted β-keto ester 15,11 obtained from the Michael addition
of chiral β-enamino esters to ethyl acrylate, was converted to 14 in 59% yield. This was achieved by
the protection of the ketone, reduction with LAH, mononitrobenzoylation and then deprotection. The
absolute configuration of 3b was determined by comparison of HPLC analysis with 14. Therefore, the
absolute configuration of the coupling product 3b was determined as the (R)-form.
Scheme 3. (a) (1) TsCl, py, (2) Et2CuLi·LiBr, 2 steps 55%. (b) O3, Me2S, 60%. (c) (1) Bu4NF/THF, (2) PNBCl, Et3N, 2 steps
90%. (d) O3, Me2S, 36%. (e) (1) KHMDS, TBDMSCl, −78°C, (2) LiAlH4/Et2O, 0°C, (3) PNBCl, Et3N, (4) Bu4NF, AcOH, 4
steps 46%
In conclusion, we have succeeded in carring out the first example of an intramolecular asymmetric
Suzuki–Miyaura reaction, leading to cyclopentane derivatives either with a tertiary or quaternary carbon
center. Although enantiomeric excesses of products are still low to moderate, we believe that the present
results will pave the way for further progress.
Acknowledgements
We thank Prof. A. Togni, for giving us an arsine compound (PAsFA). We also thank Dr. M. Sawamura
for giving us a trans-chelating chiral diphosphine ligand (R,R)-(S,S)-TRAP.
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