Development of novel hemilabile Segphos P-P=O ligands

Article abstract of DOI:10.1248/cpb.55.955

Development of novel chiral hemilabile Segphos P-P=O ligands is described. The ligands are examined for enantioselective Pd-catalyzed allylic alkylation of cyclic allylic acetates.

Full text of DOI:10.1248/cpb.55.955

June 2007
Notes
Chem. Pharm. Bull. 55(6) 955—956 (2007)
955
Development of Novel Hemilabile Segphos P–PꢀO Ligands
Yoshimasa FUKUDA, Kazuhiro KONDO,* and Toyohiko AOYAMA*
Graduate School of Pharmaceutical Sciences, Nagoya City University; 3–1 Tanabe-dori, Mizuho-ku, Nagoya 467–8603,
Japan. Received March 17, 2007; accepted April 7, 2007; published online April 10, 2007
Development of novel chiral hemilabile Segphos P–PꢀO ligands is described. The ligands are examined for
enantioselective Pd-catalyzed allylic alkylation of cyclic allylic acetates.
Key words chiral hemilabile P–PꢀO ligand; Segphos; enantioselective Pd-catalyzed allylic alkylation; cyclic allylic acetate
Recently, we have developed hemilabile ligands with both
In summary, we have shown that hemilabile Segphos
soft and hard coordinated centers within one molecule.1—7) P–PꢀO ligands are promising in enantioselective Pd-cat-
As part of our research program in relation to hemilabile lig- alyzed allylic alkylation of cyclic allylic acetates. Further ap-
ands, we began to develop new hemilabile Segphos P–PꢀO plication for the hemilabile Segphos P–PꢀO ligands, and de-
ligands. The synthesis of the hemilabile Segphos P–PꢀO lig- velopment of new hemilabile ligands are now in progress.
ands 4 was easily performed as shown in Chart 1.8,9) Treat-
ment of the Segphos derivatives 1 with BH3·THF in THF at
0 °C, and subsequent oxidation of 2 with 1% H2O2 in EtOAc
at 0 °C afforded 3 with small amounts of impurities. Finally,
removal of BH3 in 3 with Et2NH at rt provided the desired
4a—c in 47—61% overall yields.
Experimental
IR spectra were measured on a SHIMADZU FTIR-8100 diffraction grat-
ing IR spectrophotometer. H- (270 MHz) and 13C-NMR (68 MHz) spectra
1
were measured on a JEOL JNM-EX-270 NMR spectrometer. EI and FAB-
MS spectra were measured on a JEOL JMS-SX-102A instrument. Commer-
cially available reagents were used without any purification. Toluene was
Investigations of the Pd-catalyzed asymmetric allylic sub- distilled from Na under a nitrogen atmosphere. Silica gel column chro-
matography was performed on Fuji silysia PSQ 60B.
stitution of acyclic substrates have spanned a variety of new
and known ligands.10) But, since the corresponding substitu-
Table 1
tions on cycloalkenyl acetates have been a formidable chal-
lenge,10) we chose the above reaction as a test system. With
the hemilabile Segphos P–PꢀO ligands 4a—c in hand, the
Pd-catalyzed enantioselective allylic alkylation of 2-cyclo-
hexenyl acetate (5) with dibenzyl malonate as a pronucle-
ophile was examined under standard conditions of the com-
bination of BSA and KOAc (Table 1). As can be seen in en-
tries 1—6, compared with Segphos 1a—c, hemilabile Seg-
phos P–PꢀO ligands 4a—c exhibited better reactivity and
enantioselectivity. Encouraged by the promising results with
hemilabile Segphos P–PꢀO ligands 4a, the solvent effect
was examined (entries 7—9). The use of toluene as a solvent
gave the best enantioselectivity (64% ee, entry 9).
Next, the reaction of 2-cyclopentyl acetate (7) with diben-
zyl malonate was examined under the above same conditions
(Table 2). Among the hemilabile Segphos P–PꢀO ligands
4a—c employed, the use of DTBM-Segphos P–PꢀO 4c was
found to be effective, affording the corresponding product 8
in 86% yield and 65% ee. The enantioselectivity in entry 9,
Table 1 and entry 3, Table 2 obtained by hemilabile Segphos
P–PꢀO ligands, are of the good level reported in the litera-
ture.11—17)
Yield
(%)
Eea)
(%)
Entry
Ligand
Solvent
1
2
3
4
5
6
7
8
9
(S)-Segphos P–PꢀO 4a
(S)-Segphos 1a
(S)-DM-Segphos P–PꢀO 4b
(S)-DM-Segphos 1b
DMF
DMF
DMF
DMF
88
46b)
95
53
29
24
11
51
—
49
58
64
30
59
ꢁ14b,c)
75b)
Traceb)
81
(S)-DTBM-Segphos P–PꢀO 4c DMF
(S)-DTBM-Segphos 1c
(S)-Segphos P–PꢀO 4a
(S)-Segphos P–PꢀO 4a
(S)-Segphos P–PꢀO 4a
(S)-DM-Segphos P–PꢀO 4b
DMF
CH3CN
THF
Toluene
Toluene
87
89
90
89
10
11
(S)-DTBM-Segphos P–PꢀO 4c Toluene
a) Determined by HPLC analysis. b) Remainder of mass balance was the acetate
5. c) A small amount of unknown impurities was included.
Table 2
Entry
Hemilabile ligand
Yield (%)
Eea) (%)
1
2
3
(S)-Segphos P–PꢀO 4a
(S)-DM-Segphos P–PꢀO 4b
(S)-DTBM-Segphos P–PꢀO 4c
73b)
89
86
58
50
65
a) Determined by HPLC analysis. b) Remainder of mass balance was the acetate
7.
Chart 1. Synthesis of Hemilabile Segphos P–PꢀO Derivatives
∗ To whom correspondence should be addressed. e-mail: kazuk@phar.nagoya-cu.ac.jp; aoyama@phar.nagoya-cu.ac.jp © 2007 Pharmaceutical Society of Japan

956
Representative Procedure for Synthesis of Hemilabile (S)-Segphos
P–PꢀO Ligand 4a To a stirred solution of (S)-Segphos (1a) (1.00 g,
1.64 mmol) in THF (30 ml) was added BH3·THF (1.0 M in THF, 2.50 ml,
2.50 mmol) at 0 °C. The reaction mixture was stirred for 0.5 h at the same
temperature and quenched with water. The mixture was warmed up to rt and
extracted with EtOAc. The organic extracts were washed with brine, dried
(Na2SO4) and concentrated. The crude product 2a was used for the next step
without further separation.
To a stirred solution of the crude product 2a in EtOAc (15 ml) was added
1% H2O2 aq. (15 ml) at 0 °C. After stirring for 3 h at rt, to the reaction mix-
ture was added saturated Na2S2O3 aq. (15 ml) at 0 °C. The whole mixture
was stirred for 10 min at rt and extracted with EtOAc. The organic extracts
were washed with brine, dried (Na2SO4) and concentrated. The crude prod-
uct 3a was used for the next step without further purification.
Vol. 55, No. 6
13C-NMR (CDCl3): dꢀ20.95, 24.94, 26.61, 35.41, 57.03, 66.91, 127.25,
127.99, 128.00, 128.10, 128.12, 128.35, 129.43, 135.26, 135.28, 167.90,
167.96. FAB-MS: m/zꢀ365 (Mꢃꢃ1). EI-MS: m/zꢀ273 (MꢃꢂBn), 229,
183, 91 (bp). HR-MS (EI, MꢃꢂBn) m/z Calcd for C16H17O4: 273.1127;
Found: 273.1123.
2-Cyclopent-2-enylmalonic Acid Dibenzyl Ester (8): Colorless oil. IR
(neat): nꢀ1751, 1732 cmꢂ1 1H-NMR (CDCl3): dꢀ1.53—1.68 (m, 1H),
.
2.02—2.16 (m, 1H), 2.20—2.40 (m, 2H), 3.36 (d, Jꢀ9.2 Hz, 1H), 3.35—
3.46 (m, 1H), 5.14 (s, 4H), 5.60—5.65 (m, 1H), 5.76—5.82 (m, 1H), 7.23—
7.39 (m, 10H). 13C-NMR (CDCl3): dꢀ27.77, 31.80, 45.43, 56.98, 66.94,
66.97, 128.03, 128.04, 128.07, 128.17, 128.40, 131.13, 132.98, 135.27,
168.20, 168.26. FAB-MS: m/zꢀ351 (Mꢃꢃ1). EI-MS: m/zꢀ259 (MꢃꢂBn),
215, 169, 91 (bp). HR-MS (EI, MꢃꢂBn) m/z Calcd for C15H15O4: 259.0970;
Found: 259.0970.
The crude product 3a was dissolved in Et2NH (5 ml) and the reaction mix-
ture was stirred for 30 min at rt. The mixture was directly concentrated and
purified by silica gel column chromatography (hexane : EtOAc, 1 : 1) to af-
ford hemilabile (S)-Segphos P–PꢀO 4a (482 mg, 47%) as white powders. IR
Acknowledgements We thank the Ministry of Education, Culture,
Sports, Science and Technology, Japan for support. K. K. was financially
supported by Takeda Science Foundation. We are grateful to Takasago Inter-
national Corporation for gifts of SEGPHOS derivatives.
1
(nujol): nꢀ1173 cmꢂ1. H-NMR (CDCl3): dꢀ4.81 (d, Jꢀ1.5 Hz, 1H), 5.22
(d, Jꢀ1.5 Hz, 1H), 5.64 (d, Jꢀ1.5 Hz, 1H), 5.68 (d, Jꢀ1.5 Hz, 1H), 6.54 (dd,
Jꢀ3.4, 8.1 Hz, 1H), 6.61 (d, Jꢀ8.1 Hz, 1H), 6.73 (dd, Jꢀ1.6, 8.1 Hz, 1H),
6.97 (dd, Jꢀ8.1, 14.0 Hz, 1H), 7.18—7.47 (m, 16H), 7.58 (dd, Jꢀ1.6,
7.8 Hz, 1H), 7.63 (dd, Jꢀ1.6, 7.8 Hz, 1H), 7.66 (dd, Jꢀ1.6, 7.8 Hz, 1H),
7.70 (dd, Jꢀ1.6, 7.8 Hz, 1H). 31P-NMR (CDCl3) d: 14.39 (s), 27.33 (s).
FAB-MS: m/zꢀ627 (Mꢃꢃ1). EI-MS: m/zꢀ441 (MꢃꢂPPh2), 425 (bp). HR-
MS (EI, MꢃꢂPPh2) m/z Calcd for C26H18O5P: 441.0892; Found: 441.0884.
(S)-DM-Segphos P–PꢀO (4b): Pale yellow powders. IR (nujol):
References and Notes
1) Kondo K., Kazuta K., Fujita H., Sakamoto Y., Murakami Y., Tetrahe-
dron, 58, 5209—5214 (2002).
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Aoyama T., Synlett, 2003, 2047—2051 (2003).
3) Kondo K., Kazuta K., Saitoh A., Murakami Y., Heterocycles, 59, 97—
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Tetrahedron, 60, 10701—10709 (2004).
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(2006).
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3814 (2006).
7) Fukuda Y., Kondo K., Aoyama T., Tetrahedron Lett., 48, 3389—3391
(2007).
8) For a general synthetic method, see: Grushin V. V., Chem. Rev., 104,
1629—1662 (2004).
9) For the definition of hemilabile ligands, see: Braunstein P., Naud F.,
Angew. Chem. Int. Ed., 40, 680—699 (2001).
10) For a review, see: Trost B. M., Vranken D. L. V., Chem. Rev., 96,
395—422 (1996).
11) A selected successful example, see: Trost B. M., Bunt R. C., J. Am.
Chem. Soc., 116, 4089—4090 (1994).
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T., Tetrahedron: Asymmetry, 10, 1025—1028 (1999).
13) A selected successful example, see: Kudis S., Helmchen G., Angew.
Chem. Int. Ed., 37, 3047—3050 (1998).
14) A selected successful example, see: Zhang W., Shimanuki T., Kida T.,
Nakatsuji Y., Ikeda I., J. Org. Chem., 64, 6247—6251 (1999).
15) A selected successful example, see: Evans D. A., Campos K. R.,
Tedrow J. S., Michael F. E., Gagné M. R., J. Am. Chem. Soc., 122,
7905—7920 (2000).
16) A selected successful example, see: Shibatomi K., Uozumi Y., Tetra-
hedron: Asymmetry, 13, 1769—1772 (2002).
17) A selected successful example, see: Pámies O., Diéguez M., Claver C.,
J. Am. Chem. Soc., 127, 3646—3647 (2005).
1
nꢀ1169 cmꢂ1. H-NMR (CDCl3): dꢀ2.11 (s, 12H), 2.30 (s, 12H), 5.42 (d,
Jꢀ1.6 Hz, 2H), 5.76 (d, Jꢀ1.6 Hz, 2H), 6.64 (d, Jꢀ8.1 Hz, 1H), 6.65 (d,
Jꢀ8.1 Hz, 1H), 6.89 (d, Jꢀ8.1 Hz, 1H), 6.94 (br s, 2H), 6.95 (d, Jꢀ8.1 Hz,
1H), 7.08 (br s, 2H), 7.12 (br s, 2H), 7.16 (br s, 2H), 7.34 (br s, 2H), 7.39
(br s, 2H). 31P-NMR (CDCl3): dꢀ14.71 (s), 29.54 (s). FAB-MS: m/zꢀ739
(Mꢃꢃ1). EI-MS: m/zꢀ497 (MꢃꢂPPh2), 482, 481 (bp). HR-MS (EI,
MꢃꢂPPh2) m/z Calcd for C30H26O5P: 497.1518; Found: 497.1523.
(S)-DTBM-Segphos P–PꢀO (4c): Pale yellow powders. IR (nujol):
1
nꢀ1172 cmꢂ1. H-NMR (CDCl3): dꢀ1.32 (s, 36H), 1.35 (s, 36H), 3.66 (s,
6H), 3.67 (s, 6H), 5.12 (d, Jꢀ1.6 Hz, 2H), 5.71 (d, Jꢀ1.6 Hz, 2H), 6.69 (d,
Jꢀ8.1 Hz, 2H), 6.75 (d, Jꢀ8.1 Hz, 2H), 7.42 (s, 2H), 7.47 (s, 2H), 7.57 (s,
2H), 7.62 (s, 2H). 31P-NMR (CDCl3): dꢀ14.88 (s), 27.83 (s). FAB-MS:
m/zꢀ1196 (Mꢃꢃ1). EI-MS: m/zꢀ725 (MꢃꢂPPh2, bp), 497, 485. HR-MS
(EI, MꢃꢂPPh2) m/z Calcd for C44H54O7P: 725.3607; Found: 725.3609.
Representative Procedure for the Asymmetric Substitution (Entry 9,
Table 1) To a stirred solution of (cyclohex-2-enyl)acetate (5) (56.1 mg,
0.400 mol) in toluene (1.2 ml) were added (S)-Segphos P–PꢀO 4a (12.5 mg,
0.0200 mmol), [(h3-C3H5)PdCl]2 (3.7 mg, 0.0100 mmol), KOAc (2.0 mg,
0.0200 mmol), dibenzyl malonate (0.30 ml, 1.20 mmol) and N,O-
bis(trimethylsilyl)acetamide (BSA) (0.30 ml, 1.20 mmol) at rt. The reaction
mixture was stirred for 24 h at the same temperature. After usual work-up,
purification by silica gel column (hexane/EtOAc, 20 : 1, the silica gel was
pretreated with 3% Et3N in hexane) gave 2-cyclohex-2-enylmalonic acid
dibenzyl ester (6) (130 mg, 89%, 64% ee) as a colorless oil. The ee was de-
termined by HPLC analysis (Daicel chiralpak AD-H) using hexane/2-
propanol (9 : 1) as eluent, flow rateꢀ1.0 ml/min. tR1ꢀ8.1 min, tR2ꢀ10.1 min.
IR (neat): nꢀ1727 cmꢂ1. 1H-NMR (CDCl3): dꢀ1.26—1.82 (m, 4H), 1.88—
2.00 (m, 2H), 2.87—3.01 (m, 1H), 3.38 (d, Jꢀ9.2 Hz, 1H), 5.13 (s, 4H),
5.52 (dd, Jꢀ2.2, 10.3 Hz, 1H), 5.68—5.77 (m, 1H), 7.20—7.41 (m, 10H).