Enantioselective construction of all-carbon quaternary stereocenters using palladium-catalyzed asymmetric allylic alkylation of γ-acetoxy-α, β-unsaturated carbonyl compounds

Article abstract of DOI:10.1002/adsc.200505149

We have successfully demonstrated that γ-acetoxy-α,β- unsaturated carbonyl compounds are useful starting materials for Pd-catalyzed asymmetric allylic alkylation to construct all-carbon quaternary stereocenters. With the use of 2-5 mol % of Pd catalyst an

Full text of DOI:10.1002/adsc.200505149

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DOI: 10.1002/adsc.200505149
Enantioselective Construction of All-Carbon Quaternary
Stereocenters Using Palladium-Catalyzed Asymmetric Allylic
Alkylation of g-Acetoxy-a,b-unsaturated Carbonyl Compounds
Tetsuhiro Nemoto, Tomoaki Fukuda, Takayoshi Matsumoto, Tsukasa Hitomi,
Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba, 263-8522, Japan
Fax: (þ83)-43-290-2987, e-mail: hamada@p.chiba-u.ac.jp
Received: April 13, 2005; Accepted: June 17, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: We have successfully demonstrated that g-
acetoxy-a,b-unsaturated carbonyl compounds are
useful starting materials for Pd-catalyzed asymmetric
allylic alkylation to construct all-carbon quaternary
stereocenters. With the use of 2–5 mol % of Pd cat-
alyst and 4–10 mol % of P-chirogenic diaminophos-
phine oxides, asymmetric allylic alkylation of g-acet-
oxy-a,b-unsaturated carbonyl compounds with vari-
ous prochiral nucleophiles derived from cyclic b-
keto esters proceeded in the presence of Zn(OAc)2,
providing the corresponding products with an all-car-
bon quaternary stereocenter in up to 95% ee.
action system, pentavalent phosphorus compounds, the
preligands, are activated in situ by N,O-bis(trimethylsi-
lyl)acetamide (BSA)-induced tautomerization, afford-
ing trivalent phosphorus compounds, which function as
the actual ligands.[8] In the course of our studies on asym-
metric synthesis of all-carbon quaternary stereocenters
using DIAPHOXs, g-acetoxy-a,b-unsaturated carbonyl
compounds stood out as potential substrates.[9] Asym-
metric allylic alkylation of g-acetoxy-a,b-unsaturated
carbonyl compounds with b-keto esters gives character-
istic reaction adducts with three different carbonyl
groups. The densely functionalized structure is useful
for natural product synthesis.[10] Despite the versatility,
there is no direct access to this class of chiral building
blocks. Herein, we report the enantioselective construc-
tion of all-carbon quaternary stereocenters using Pd-
catalyzed asymmetric allylic alkylation of g-acetoxy-
a,b-unsaturated carbonyl compounds with cyclic b-
keto esters as prochiral nucleophiles.
Keywords: all-carbon quaternary stereocenter; asym-
metric allylic alkylation; asymmetric catalysis; diami-
nophosphine oxide; palladium
The efficient creation of all-carbon quaternary centers is
a formidable challenge in organic synthesis, due to steric
À
repulsion during the C C bond forming process. This
challenge is magnified when the carbon center is stereo-
À
genic. The catalytic asymmetric C C bond formingreac-
tion is the most effective method for the synthesis of all-
carbon quaternary stereocenters.[1] There are, however,
few catalytic asymmetric processes available to con-
struct such a congested chiral center with a synthetically
useful level of enantioselection.[2] Pd-catalyzed asym-
metric allylic alkylation (AAA) using prochiral nucleo-
philes is one of the most straightforward approaches to-
ward this end. Limited success of this type reaction has
been reported since the 1980 s.[3–6] We recently succeed-
ed in the Pd-catalyzed asymmetric construction of all-
carbon quaternary stereocenters using novel pentava-
lent chiral phosphorus ligands: P-chirogenic diamino-
Figure 1. Structure of P-chirogenic diaminophosphine oxides:
phosphine oxides (DIAPHOXs) (Figure 1).[7] In this re- DIAPHOXs.
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Adv. Synth. Catal. 2005, 347, 1504 – 1506

Pd-Catalyzed AAA of g-Acetoxy-a,b-unsaturated Carbonyl Compounds
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Table 1. Optimization of the reaction conditions.
Table 2. Asymmetric allylic alkylation using various sub-
strates.
[a]
Isolated yield.
Determined by HPLC analysis.
[b]
[c] The absolute configuration was determined to be S. See the
supporting information for details.
[a]
Isolated yield.
Determined by HPLC analysis.
5 mol % of the Pd catalyst was used.
1d was used as the ligand.
[b]
We initially examined the catalytic asymmetric allylic
alkylation of g-acetoxycrotonic acid ethyl ester (2a) with
ethyl 2-oxocyclohexanecarboxylate (3a)(Table 1). First,
we investigated the effect of the addition of acetate salt
using 1 mol % of (h3-C3H5PdCl)2 and 4 mol % of (S,RP)-
[c]
[d]
Ph-DIAPHOX (1a). Similar to the previous case, thy that no conjugate addition of the nucleophile to the
Zn(OAc)2 was the best additive for asymmetric induc- substrate occurred in this catalytic process. To the best of
tion.[7] Further optimizations for the ester substituent our knowledge, this is the first application of g-acetoxy-
of g-acetoxycrotonates were preformed in the presence a,b-unsaturated carbonyl compounds to Pd-catalyzed
of Zn(OAc)2, revealing that the substrate with a tert-bu- asymmetric allylic alkylation for construction of quater-
tyl ester (2c) gave the best selectivity. The effect of the nary carbons.
ligand structure was also investigated using 1b–1d,
In conclusion, we have achieved the Pd-catalyzed
and the corresponding product was obtained in 99% asymmetric allylic alkylation of g-acetoxy-a,b-unsatu-
yield with 95% ee, using (S,RP)-2-Np-DIAPHOX (1c) rated carbonyl compounds with cyclic b-keto esters as
as the ligand.
the prochiral nucleophiles. This contribution provides
The scope and limitations of different substrates were a new strategy for the synthesis of functionalized chiral
further examined using these efficient conditions (Ta- synthons with an all-carbon quaternary stereocenter.
ble 2). When2to 5 mol % of the catalyst was used, asym- Further studies, including diastereoselective modifica-
metric allylic alkylation of 2c using prochiral nucleo- tion of the reaction adducts, are currently in progress.
philes with a six-membered ring proceeded at room tem-
perature to provide the corresponding products in excel-
lent yield with high enantioselectivity (91–95% ee). The
reaction system was also applicable to g-acetoxy-a,b-un-
Experimental Section
saturated ketone 2d, affording the corresponding prod-
ucts in good yield with high enantioselectivity (90% ee).
In addition, nucleophiles with five-, seven-, and eight-
membered rings were investigated using 2c as the sub-
strate. As a result, the corresponding products were ob-
tained with modest to high enantioselectivity; 90% ee
(five-membered ring), 75% ee (seven-membered
ring), and 68% ee (eight-membered ring), with the use
Typical Procedure for the Pd-Catalyzed Asymmetric
Allylic Alkylation
To a stirred mixture of (h3-C3H5PdCl)2 (9.2 mg, 0.025 mmol,
2 mol % of Pd.), 1c (44.1 mg, 0.1 mmol, 4 mol %), acetate 2c
(0.50 g, 2.5 mmol), keto ester 3a (0.59 mL, 3.75 mmol), and
Zn(OAc)2 (45.9 mg, 0.25 mmol) in toluene (16.7 mL) was add-
ed BSA (2.47 mL, 10 mmol) at room temperature, and the re-
of 1d, 1c, and 1c as the ligand, respectively. It is notewor- action mixture kept stirring at the same temperature, under an
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Tetsuhiro Nemoto et al.
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argon atmosphere. After 24 h, the mixture was concentrated
under vacuum, and the obtained residue was purified by flash
column chromatography (SiO2, hexane/ethyl acetate 20/1) to
give 4c as colorless oil; yield: 0.77 g (99%, 95% ee). IR (neat):
Nagata, H. Sakamoto, Y. Ito, J. Am. Chem. Soc. 1992,
114, 2586–2592; d) R. Kuwano, K. Uchida, Y. Ito, Org.
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[5] For examples using a-mono-substituted ketones as the
prochiral nucleophile, see: a) B. M. Trost, G. M. Schroed-
er, J. Am. Chem. Soc. 1999, 121, 6759–6760; b) S.-L. You,
X.-L. Hou, L.-X. Dai, X.-Z. Zhu, Org. Lett. 2001, 3, 149–
151; c) B. M. Trost, G. M. Schroeder, J. Kristensen, An-
gew. Chem. 2002, 114, 3642–3645; Angew. Chem. Int.
Ed. 2002, 41, 3492–3495; d) D. C. Behenna, B. M. Stoltz,
J. Am. Chem. Soc. 2004, 126, 15044–15045; e) B. M.
Trost, M. U. Frederiksen, Angew. Chem. 2005, 117,
312–314; Angew. Chem. Int. Ed. 2005, 44, 308–310.
[6] For recent representative examples of catalytic asymmet-
ric construction of all-carbon quaternary stereocenters
using a prochiral enolate as the nucleophile, see:
a) A. G. Doyle, E. N. Jacobsen, J. Am. Chem. Soc.
2005, 127, 62–63; b) M. Bella, S. Kobbelgaard, K. A. Jør-
gensen, J. Am. Chem. Soc. 2005, 127, 3670–3671; c) Y.
Hamashima, N. Sakamoto, D. Hotta, H. Somei, N. Ume-
bayashi, M. Sodeoka, Angew. Chem. 2005, 117, 1549–
1553; Angew. Chem. Int. Ed. 2005, 44, 1525–1529; d) N.
Mase, F. Tanaka, C. F. Barbas III, Angew. Chem. 2004,
116, 2474–2477; Angew. Chem. Int. Ed. 2004, 43,
2420–2423; e) M. S. Taylor, E. N. Jacobsen, J. Am.
Chem. Soc. 2003, 125, 11204–11205; f) I. D. Hills, G. C.
Fu, Angew. Chem. 2003, 115, 4051–4054; Angew.
Chem. Int. Ed. 2003, 42, 3921–3924; g) Y. Hamashima,
D. Hotta, M. Sodeoka, J. Am. Chem. Soc. 2002, 124,
11240–11241; h) D. J. Spielvogel, S. L. Buchwald, J.
Am. Chem. Soc. 2002, 124, 3500–3501; i) Y.-S. Kim, S.
Matsunaga, J. Das, A. Sekine, T. Ohshima, M. Shibasaki,
J. Am. Chem. Soc. 2000, 122, 6506–6507.
n¼2968, 2936, 2868, 1714, 1653, 1455, 1367, 1253, 1157 cmÀ1
;
1H NMR (CDCl3): d¼1.25 (t, J¼7.2 Hz, 3H), 1.46 (s, 9H),
1.43–1.55 (m, 1H), 1.66–1.75 (m, 3H), 2.02–2.05 (m, 1H),
2.41–2.51 (m, 4H), 2.69 (ddd, J¼1.2 Hz, 7.6 Hz, 14.0 Hz,
1H), 4.20 (q, J¼7.2 Hz, 2H), 5.74 (ddd, J¼1.2 Hz, 1.2 Hz,
15.2 Hz, 1H), 6.74 (ddd, J¼7.6 Hz, 15.2 Hz, 15.6 Hz, 1H); 13
C
NMR (CDCl3): d¼14.0, 22.4, 27.3, 28.0 (ꢀ3), 36.0, 37.3, 40.9,
60.5, 61.4, 80.1, 126.2, 142.1, 165.2, 171.0, 206.7; FAB-LR-MS:
m/z¼311 (MHþ), 255 (MHþ – 56); [a]D23: À81.7 (c 1.00,
CHCl3, 95% ee); FAB-HR-MS: calcd. for C17H27O5: 311.1859;
found: 311.1873.
The enantiomeric excess was determined by HPLC analysis
(DAICEL CHIRALCEL, AD-H, 2-propanol/hexane, 5/95,
flow rate 0.3 mL/min, retention time: 22.5 min [(R)-isomer]
and 23.8 min [(S)-isomer], detected at 254 nm).
Acknowledgements
This work was supported by Grant-in Aid for Encouragement
of Young Scientist (B) from the Ministry of Education, Culture,
Sport, Science, and Technology, Japan, and the Banyu Award in
Synthetic Organic Chemistry, Japan.
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Adv. Synth. Catal. 2005, 347, 1504 – 1506