Synthesis and application of chiral spiro phospholane ligand in Pd-catalyzed asymmetric allylation of aldehydes with allylic alcohols

Article abstract of DOI:10.1021/ol050556x

(Chemical Equation Presented) A novel chiral monodentate spiro phenylphospholane ligand 4 was prepared from a readily accessible, enantiomerically pure 1,1′-spirobiindane-7,7′-diol in high yield. This ligand has proven to be efficient for Pd-catalyzed enantioselective allylation of aldehydes with allylic alcohols. Aromatic, heteroaromatic, and aliphatic aldehydes gave homoallylic alcohols in good enantioselectivities (up to 83% ee) and excellent anti diastereoselectivities (up to 99:1 dr).

Full text of DOI:10.1021/ol050556x

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2333-2335
Synthesis and Application of Chiral
Spiro Phospholane Ligand in
Pd-Catalyzed Asymmetric Allylation of
Aldehydes with Allylic Alcohols
Shou-Fei Zhu, Yun Yang, Li-Xin Wang, Bin Liu, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity,
Tianjin 300071, China
qlzhou@nankai.edu.cn
Received March 14, 2005
ABSTRACT
A novel chiral monodentate spiro phenylphospholane ligand 4 was prepared from a readily accessible, enantiomerically pure 1,1
′-spirobiindane-
7,7 -diol in high yield. This ligand has proven to be efficient for Pd-catalyzed enantioselective allylation of aldehydes with allylic alcohols.
′
Aromatic, heteroaromatic, and aliphatic aldehydes gave homoallylic alcohols in good enantioselectivities (up to 83% ee) and excellent anti
diastereoselectivities (up to 99:1 dr).
Catalytic enantioselective allylation of aldehydes represents
one of the most efficient strategies for the synthesis of chiral
homoallylic alcohols, which are versatile intermediates for
variety of synthetically useful compounds.1 Three types
allylic reagents have been used so far in catalytic enantio-
selective allylation of aldehydes: allylmetal reagents in chiral
Lewis acid- or Lewis base-catalyzed allylation; allylic halides
in chromium-, zinc-, or indium-mediated allylation; and allyl
esters in palladium-catalyzed allylation. The first two
protocols have been extensively studied and well docu-
mented.2 It was just quite recently that Zanoni and co-
workers3 first used allyl esters in their pioneering work in
the catalytic enantioselective allylation of benzaldehyde by
umpolung of π-allylpalladium complexes. However, although
allylic alcohols have been used as allylic donators in Pd-
catalyzed allylation of carbonyl compounds,4 to our knowl-
edge the asymmetric, catalytic, direct allylation of aldehydes
with allylic alcohols has not been reported yet. In fact, the
direct use of allylic alcohols in asymmetric allylation of
aldehydes is advantageous in view of synthetic efficiency
and green chemistry. Such use facilitates access to a broad
range of chiral homoallylic alcohols without having to
transform them to their derivatives bearing a wasteful leaving
group. Herein we report our results on the investigation in
Pd-catalyzed asymmetric allylation of aromatic, hetero-
aromatic, and aliphatic aldehydes with allylic alcohols in the
presence of Et3B, providing the corresponding homoallylic
alcohols in good enantioselectivities and excellent dia-
stereoselectivities.
The allylation of benzaldehyde with cinnamyl alcohol was
chosen as a model reaction. In the initial investigation, the
(1) (a) Yanagisawa A. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Heidelberg, 1999;
Chapter 27.
(2) Denmark, S. E.; Fu, J.-P. Chem. ReV. 2003, 103, 2763.
(3) Zanoni, G.; Gladiali, S.; Marchetti, A.; Piccinini, P.; Tredici, I.; Vidari,
G. Angew. Chem., Int. Ed. 2004, 43, 846.
(4) (a) Takahara, J. P.; Masuyama, Y.; Kurusu, Y. J. Am. Chem. Soc.
1992, 114, 2577. (b) Kimura, M.; Tomizawa, T.; Horino, Y.; Tanaka, S.;
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Hirashita, T.; Yamamura, H.; Kawai, M. Org. Lett. 2000, 2, 847. (d) Jang,
T.-S.; Keum, G.; Kang, S. B.; Chung, B. Y.; Kim, Y. Synthesis 2003, 775.
10.1021/ol050556x CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/11/2005

reaction. However, the yields and the enantioselectivities of
the allylation products were still unsatisfactory (entries 2 and
3). To achieve a full spectral comparison of spiro phosphorus
ligands, the monodentate spiro phospholane ligand 4 was
synthesized and found to be efficient for the Pd-catalyzed
allylation of aldehydes with allylic alcohols in high yields,
excellent diastereoselectivities, and good enantioselectivities.
The ligand (R)-4 was synthesized from enantiomerically
pure (R)-1,1′-spirobiindane-7,7′-diol (SPINOL, (R)-5) in high
yield as shown in Scheme 1. The diol (R)-5 was converted
Figure 1. Chiral Spiro Monodentate Phosphorus Ligands
monodentate spiro ligands phosphoramidite 15 (Figure 1)
previously developed in our group was tested in this reaction.
The palladium acetate (5 mol %) and ligand (10 mol %)
were premixed in THF and stirred at 25 °C for 30 min, and
then benzaldehyde 12, cinnamyl alcohol 11, and triethylboron
were added sequentially. After the starting material was
completely consumed, the reaction mixture was quenched
with hydrochloric acid, and the product was purified by flash
chromatography. It was disappointing that the allylation
product 1,2-diphenylbut-3-en-1-ol (13a) was obtained in only
48% yield with 19% ee for the anti isomer (anti/syn ) 94:6,
Table 1, entry 1).
Scheme 1. Synthesis of Phospholane Ligand 4
Table 1. Pd-Catalyzed Asymmetric Allylation of
Benzaldehydes with Cinnamyl Alcohol: Ligands and Umpolung
Reagentsa
into bistriflate 6 in quantitative yield7 and cynated with
Zn(CN)2 catalyzed by Pd(PPh3)4 at 145 °C for 24 h to afford
dicarbonitrile 7. The use of Zn(CN)2 as a cyanation reagent8
is crucial for obtaining dinitrile 7 in high yield. When KCN
or NaCN was applied, there was no target compound given
even under harsh conditions. Hydrolysis of dinitrile 7 with
diluted H2SO4 at reflux for 48 h produced diacid 8 smoothly.
The reduction of 8 with LiAlH4 in refluxing ether for 24 h
yielded the benzyl diol 9 in 94% yield. Following the
standard procedure, we converted the diol 9 to chloride 10
with SOCl2, and condensation was performed with phenyl-
phosphine to provide phenylphospholane ligand 4 in 94%
yield.9 Though this synthetic route takes six steps, its overall
yield is quite high (74%).
When the ligand (R)-4 was used in the allylation of
benzaldehyde with cinnamyl alcohol, both the yield and the
enantioselectivity of the reaction were remarkably improved
(Table 1, entry 4). The enantioselectivity (82% ee) achieved
with ligand 4 is not only higher than those obtained with
the chiral spiro phosphorus ligands 1-3 but also higher than
the highest ee value (70% ee) reported by Zanoni and co-
workers3 in the catalytic asymmetric aldehyde allylation by
umpolung of π-allylpalladium complexes.
time
(h)
yield
(%)b
anti/
sync
entry
ligand
M
% eed
1
2
3
4
5
6
(R)-1
(R)-2
(R)-3
(R)-4
(R)-4
(R)-4
Et3B
Et3B
Et3B
Et3B
Et2Zn
SnCl2
12
24
12
12
24
48
48
40
38
80
41
0
94/6
84/16
94/6
98/2
97/3
19
30
10
82
54
a Reaction conditions: Pd(OAc)2, 0.05 equiv; ligands, 0.1 equiv; M, 5
equiv; PhCHO, 1.2 equiv; cinnamyl alcohol, 1.0 equiv (0.14 mmol); THF
0.8 mL at 25 °C. b Isolated yield. c Determined by GC or 1H NMR.
d Determined by chiral HPLC using a chiralpak AD-H column. The absolute
configurations were (1R,2S)-.
We next tested another two monodentate spiro ligands,
phosphite 2 and phosphonite 3, which are highly efficient
in the rhodium-catalyzed hydrogenation of functionalized
olefins and other asymmetric reactions,6 in this allylation
(5) (a) Fu, Y.; Xie, J.-H.; Hu, A.-G.; Zhou, H.; Wang, L.-X.; Zhou. Q.-
L. Chem. Commun. 2002, 480. (b) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.;
Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2002, 41, 2348.
(6) (a) Fu, Y.; Guo, X.-X.; Zhu, S.-F.; Hu, A.-G.; Xie, J.-H.; Zhou, Q.-
L. J. Org. Chem. 2004, 69, 4648. (b) Fu, Y.; Hou, G.-H.; Xie, J.-H.; Xing,
L.; Wang, L.-X.; Zhou, Q.-L. J. Org. Chem. 2004, 69, 8157. (c) Shi, W.-
J.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Zhou, Q.-L. Tetrahedron: Asymmetry
2003, 14, 3867.
(7) Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Fan, B.-M.; Duan, H.-
F.; Zhou, Q.-L. J. Am. Chem. Soc. 2003, 125, 4404.
(8) Tuyet, T. M. T.; Harada, T.; Hashimoto, K.; Hatsuda, M.; Oku, A.
J. Org. Chem. 2000, 65, 1335.
(9) Xiao, D.-M.; Zhang, Z.-G.; Zhang, X.-M. Org. Lett. 1999, 1, 1679.
2334
Org. Lett., Vol. 7, No. 12, 2005

In addition to Et3B, other well-known umpolung reagents
such as Et2Zn and SnCl2 were also tested in the direct
aldehyde allylation with allylic alcohols. Et2Zn promoted the
reaction with lower yield and enantioselectivity, while SnCl2
gave no reaction (entries 5 and 6).
Scheme 2
Under the optimal conditions, the allylation of various
aldehydes with cinnamyl alcohol was examined, and the
results are summarized in Table 2. For all substrates, the
Table 2. Pd-Catalyzed Et3B-Promoted Asymmetric Allylation
of Aldehydes with Allylic Alcoholsa
π-allyl palladium complex as 3-phenylprop-2-en-1-ol (11)
in the allylation reaction. The same level of enantiocontrol
obtained for these two compounds implied that the stereo-
chemical memory effect does not exist in our system.3,10 The
simple allylic alcohol 15 also reacted with benzaldehyde
under the standard conditions, giving 1-phenyl homoallylic
alcohol 16 in good yield and enantioselectivity (Scheme 2).
In summary, a new type of chiral spiro monodentate
phospholane ligand 4 has been developed and successfully
applied in palladium-catalyzed allylation of aldehydes. The
enantioselectivities (up to 83% ee) achieved by ligand 4
represent the best results in the Pd-catalyzed asymmetric
allylation of aldehydes by umpolung of π-allylpalladium
complexes. In the reaction, the allylic alcohols were first used
as allylic reagents. This makes the manipulation of the
reaction simpler and the synthesis of optically active homo-
allylic alcohols more efficient.
time
(h)
yield
(%)
anti/
syn
entry
R
% ee
1
2
3
4
5
6
7
8
C6H5 (12a)
12
48
17
12
12
12
12
32
80 (13a)
97 (13b)
91 (13c)
71 (13d)
99 (13e)
95 (13f)
73 (13g)
50 (13h)
98/2
99/1
95/5
97/3
99/1
99/1
99/1
99/1
82
74
69
58
79
73
78
83
4-MeOC6H4 (12b)
2-MeOC6H4 (12c)
4-CF3C6H4 (12d)
1-Np (12e)
2-Np (12f)
2-furyl (12g)
c-C6H11 (12h)
a Conditions for the reactions and analyses are the same as those in Table
1.
reactions demonstrate excellent diastereoselectivities. The
electronic features of aromatic aldehydes apparently affect
the yield and enantioselectivity of the reaction. The electron-
rich aldehydes 12b and 12c showed higher yields but lower
enantioselectivities (Table 2, entries 2 and 3), while electron-
deficient aldehyde 12d gave a lower yield and lower
enantioselectivity (entry 4). Similar to benzaldehydes, R- and
â-naphthaldehydes and furaldehyde also reacted with cin-
namyl alcohol to produce the corresponding homoallylic
alcohols in good yields and enantiomeric excesses (entries
5-7). It was delightful to find that the allylation of aliphatic
aldehyde cyclohexanecarboxaldehyde was realized under the
same conditions in 83% ee, albeit the yield was not very
high (entry 8).
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China, the Major Basic Research
Development Program (Grant G2000077506), the Ministry
of Education of China, and the Committee of Science and
Technology of Tianjin City for financial support.
Supporting Information Available: Experiment details
and spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL050556X
When racemic 1-phenylprop-2-en-1-ol (14) was used as
an allylic reagent, 79% ee was achieved (Scheme 2).
Compound 14 is expected to form the same intermediate
(10) Lloyd-Jones, G. C.; Stephen, S. C.; Murray, M.; Butts, C. P.;
Vyskocˇil, Sˇ.; Kocˇovsky, P. Chem. Eur. J. 2000, 6, 4348.
Org. Lett., Vol. 7, No. 12, 2005
2335