A Novel Class of Nonbiaryl Atropisomeric P,O-Ligands for Palladium-Catalyzed Asymmetric Allylic Alkylation

Article abstract of DOI:10.1021/ol0258233

(matrix presented) A novel class of nonbiaryl atropisomeric P,O-ligands possesing an N,N-dialkyl-1-naphthamide skeleton has been synthesized via an efficient chemical resolution process. It represents the first example of axially chiral P,O-ligands devoid

Full text of DOI:10.1021/ol0258233

ORGANIC
LETTERS
2002
Vol. 4, No. 9
1615-1618
A Novel Class of Nonbiaryl
Atropisomeric P,O-Ligands for
Palladium-Catalyzed Asymmetric Allylic
Alkylation†
Wei-Min Dai,* Kelly Ka Yim Yeung, Jin-Teng Liu, Ye Zhang, and Ian D. Williams
Department of Chemistry and Open Laboratory of Chirotechnology of The Institute of
Molecular Technology for Drug DiscoVery and Synthesis, The Hong Kong UniVersity
of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
chdai@ust.hk
Received March 5, 2002
ABSTRACT
A novel class of nonbiaryl atropisomeric P,O-ligands possessing an N,N-dialkyl-1-naphthamide skeleton has been synthesized via an efficient
chemical resolution process. It represents the first example of axially chiral P,O-ligands devoid of central chirality. Up to 94.7% ee was
obtained for the Pd-catalyzed asymmetric allylic alkylation (AAA). Effects of solvent, base, and the bulk of the C8 oxygen group of the P,O-
ligand on the AAA reaction were examined.
Catalytic asymmetric synthesis is commonly achieved through
organometallic chemistry of transition metals by employing
chiral ligands, in particular, the phosphorus based ligands.1
Bidentate chiral ligands enjoy wide application in both
academic research and industrial processes because they form
relatively rigid metal complexes and afford better stereo-
differentiation in catalysis. For instance, C2 symmetric chiral
diphosphines (P,P-ligands) have been widely used in asym-
metric hydrogenation and other catalytic reactions as rep-
resented by (R)- or (S)-BINAP and Trost’s diphosphine 1a
(Figure 1).2 The latter is one of the most successful chiral
P,P-ligand systems for asymmetric allylic alkylation (AAA)
based on the “chiral pocket” concept.2c,d,f Non-C2 symmetric
chiral bidentate ligands, including chiral P,N-3 and dinitrogen2f,4
† The Institute of Molecular Technology for Drug Discovery and
Synthesis is supported by The Areas of Excellence Scheme (AoE/P-10/01)
established under The University Grants Committee of Hong Kong SAR,
China.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994. (b) Catalytic Asymmetric Synthesis, 2nd ed; Ojima, I.,
Ed.; Wiley-VCH: New York, 2000.
(2) For recent reviews, see: (a) Frost, C. G.; Howarth, J.; Williams, J.
M. J. Tetrahedron: Asymmetry 1992, 3, 1089. (b) Hayashi, T. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993;
pp 325-365. (c) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96,
395. (d) Trost, B. M. Acc. Chem. Res. 1996, 29, 355. (e) Pfaltz, A.; Lautens,
M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, pp 833-884. (f) Trost,
B. M.; Lee, C. In Catalytic Asymmetric Synthesis, 2nd ed; Ojima, I., Ed.;
Wiley-VCH: New York, 2000; pp 593-649.
(3) For selected examples, see: (a) Matt, P. v.; Pfaltz, A. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 566. (b) Sprinz, J.; Helmchen, G. Tetrahedron Lett.
1993, 34, 1769. (c) Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote,
S. J. Tetrahedron Lett. 1993, 34, 3149. (d) Kubota, H.; Koga, K. Tetrahedron
Lett. 1994, 35, 6689. (e) Schnyder, A.; Hintermann, L.; Togni, A. Angew.
Chem., Int. Ed. Engl. 1995, 34, 931. (f) Mino, T.; Imiya, W.; Yamashita,
M. Synlett 1997, 583. (g) Pretot, R.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
1998, 37, 323. (h) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 2897. (i) Kudis, S.; Helmchen, G. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 3047. (j) Vyskoil,.; Smrina, M.; Hanu, V.; Pola´ek,
M.; Koovsk, P. J. Org. Chem. 1998, 63, 7738. (k) Gilbertson, S. R.; Chang,
C.-W. T. J. Org. Chem. 1998, 63, 8424. (l) Cahill, J. P.; Guiry, P. J.
Tetrahedron: Asymmetry 1998, 9, 4301. (m) Stranne, R.; Vasse, J.-L.;
Moberg, C. Org. Lett. 2001, 3, 2525. (n) You, S.-L.; Zhu, X.-Z.; Luo, Y.-
M.; Hou, X.-L.; Dai, L.-X. J. Am. Chem.. Soc. 2001, 123, 7471. Also see:
(o) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336.
10.1021/ol0258233 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/03/2002

Scheme 1. Synthesis of Nonbiaryl Atropisomeric P,O-Ligandsa
Figure 1. Structures of known P,P- and P,O-ligands for AAA.
ligands, give excellent regioselectivity and enantioselectivity
in AAA. The diphosphine 1a can form a P,O-chelate with
palladium as well.5 One such complex, being catalytically
active, was confirmed by X-ray crystallographic analysis.5b
Non-C2 symmetric ligands 1b,c were reported to give low
and reversed ee’s in AAA compared to that of 1a.5a
Interestingly, ligand 1d competes between P,O- and P,N-
chelation with palladium and gives up to ca. 80% ee’s in
AAA.5c Very recently, the amide-based P,O-ligands 2-4
were reported to give 74-90% ee’s in AAA.6 Notably, ligands
4a,b possess both central and axial chiralities; however, the
amide moiety in 2 seems conformationally labile and unlikely
to contribute to asymmetric induction. We report here a novel
class of nonbiaryl atropisomeric7 P,O-ligands 9-11 devoid
of central chirality and demonstrate their application in
AAA.8
a (a) t-BuMe2SiCl, imidazole, DMF, 45 °C, 20 h (96%); (b)
s-BuLi, THF, -78 °C, 1 h; then Ph2PCl, -78 °C, 4 h (87%); (c)
TBAF, THF, rt, 40 min (95%); (d) (1S)-(-)-camphanic chloride,
DMAP, CH2Cl2, rt, 12 h (7, 49% and 8, 48%); (e) 10% KOH, THF,
rt, 4 h (80%); (f) NaH, MeI, THF, rt, 4 h (91%); (g) NaH, BnBr,
THF, rt, 24 h (61%).
with (1S)-(-)-camphanic chloride (DMAP, CH2Cl2, rt)
furnished the diastereomers (aR)-(-)-7 and (aS)-(+)-8, which
were separated by flash column chromatography over silica
gel. Attempts to grow single crystals of (aS)-(+)-8 in CH2-
Cl2-hexane at 5-10 °C for a week resulted in hydrolysis
of the ester to give single crystals of both the alcohol (aS)-
(+)-9 and (1S)-(-)-camphanic acid. Alkaline saponification
of (aR)-(-)-7 and (aS)-(+)-8 gave (aR)-(-)-9 and (aS)-(+)-
9, respectively, which were methylated to afford the P,O-
ligands (aR)-(+)-10 and (aS)-(-)-10. Similarly, benzylation
of (aR)-(-)-9 gave (aR)-(-)-11. The absolute stereochemistry
of (aS)-(+)-9 and (aR)-(+)-10 was determined by X-ray
crystallographic analysis (Figure 2, also see Supporting
Information). It should be emphasized that the chiral axes
in 7-11 are quite stable at ambient temperature due to an
electronic effect of the C8 oxygen with the amide carbonyl
group.11 In fact, no racemization was detected after refluxing
(aR)-(+)-10 in toluene for 10 h.
Our synthesis started with the known 1-naphthamide 59
as shown in Scheme 1. Protection of the 8-hydroxyl group
in 5 afforded the TBDMS ether. The latter was metalated at
the C2 position, directed by the amide moiety,10 followed
by reacting with PPh2Cl to afford racemic 6. Removal of
the silyl group in 6 and reaction of the resultant 8-naphthol
(4) For a recent review on nitrogen-containing ligands, see: Fache, F.;
Schulz, E.; Tommasino, M. L.; Lenaire, M. Chem. ReV. 2000, 100, 2159.
(5) (a) Trost, B. M.; Breit, B.; Organ, M. G. Tetrahedron Lett. 1994,
35, 5817. (b) Butts, C. P.; Crosby, J.; Lloyd-Jones, G. C.; Stephen, S. C.
Chem. Commun. 1999, 1707. (c) Kim, Y. K.; Lee, S. J.; Ahn, K. H. J. Org.
Chem. 2000, 65, 7807.
(6) (a) Clayden, J.; Johnson, P.; Pink, J. H.; Helliwell, M. J. Org. Chem.
2000, 65. 7033. (b) Clayden, J.; Lai, L. W.; Helliwell, M. Tetrahedron:
Asymmetry 2001, 12, 695. (c) Mino, T.; Kashihara, K.; Yamashita, M.
Tetrahedron: Asymmetry 2001, 12, 287. (d) Gilbertson, S. R.; Lan, P. Org.
Lett. 2001, 3, 2237. Also see: Lloyd-Jones, G. C.; Stephen, S. C. Chem.
Eur. J. 1998, 4, 2539
(7) Clayden, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 949.
(8) Preliminary results were reported at The 2nd National Symposium
on Organic Chemistry in conjunction with The 1st National Symposium
on Chemical Biology, Hangzhou, China, November 1-4, 2001, p 108 and
Singapore International Chemical Conference-2, Singapore, December 18-
20, 2001, p 42.
We evaluated 7, 8, 10, and 11 in the AAA of 1,3-
diphenylprop-2-enyl acetate 12. The results are summarized
in Table 1. With 1:1.4 ratio of Pd:ligand, the reaction
(9) Clayden, J.; Frampton, C. S.; McCarthy, C.; Westlund, N. Tetra-
hedron 1999, 55, 14161.
(10) Snieckus, V. Chem. ReV. 1990, 90, 879.
(11) Clayden, J.; McCarthy, C.; Helliwell, M. Chem. Commun. 1999,
2059.
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Org. Lett., Vol. 4, No. 9, 2002

Table 1. Pd-Catalyzed AAA Using Nonbiaryl Atropisomeric
P,O-Ligands 7, 8, 10, and 11
entry
L*
solvent
base
yield (%)a ee (%), confb
1
2
3
4
5
6
7
8
9
(aR)-(+)-10 CH2Cl2 KOAc
(aR)-(+)-10 CH2Cl2 NaOAc
(aS)-(-)-10 CH2Cl2 LiOAc
(aR)-(+)-10 CH3CN NaOAc
(aR)-(+)-10c CH3CN NaOAc
(aR)-(+)-10 PhCH3 NaOAc
(aR)-(-)-11 CH2Cl2 LiOAc
96
89
97
89
89
92
99
72
81
78.6, S
94.4, S
93.2, R
94.4, S
80.3, S
94.7, S
90.2, S
87.4, S
33.1, R
(aR)-(-)-7
(aS)-(+)-8
CH2Cl2 LiOAc
CH2Cl2 LiOAc
a Isolated yield. b Enantiomeric excess and absolute configuration were
determined by HPLC over a chiral stationary phase (see Supporting
Information). c 2 mol % of Pd and 5 mol % of (aR)-(+)-10 were used, and
the reaction completed at room temperature after 5.5 h.
a phosphine phenyl group while the C8-methoxy sits to the
front of the wall. They act as two “arms” to sterically guide
Figure 2. The X-ray crystal structures of (aS)-(+)-9 (a) and (aR)-
(+)-10 (b).
completed within 4 h to afford (S)-13 in 96% yield and in
78.6% ee (entry 1). We noted influence of the metal
counterion on asymmetric induction. NaOAc (94.4% ee) and
LiOAc (93.3% ee) gave better results than KOAc (78.6%
ee) (entries 1-3). A solvent effect was not observed for AAA
carried out in CH2Cl2, CH3CN, or toluene (entries 2, 4, and
6). However, using 2.5-fold of ligand to palladium, the
reaction was slowed slightly and the ee of the product
dropped to 80.3% (entry 5). The C8-benzyloxy ligand (aR)-
(-)-11 gave slightly lower enantioselectivity (90.2% ee, entry
7 versus entry 3). Diastereomers (aR)-(-)-7 and (aS)-(+)-8
represented the matched (87.4% ee) and mismatched (33.1%
ee) combination, respectively (entries 8 and 9). Nevertheless,
in all cases, the product stereochemistry is controlled by the
axial chirality of the ligands.
We rationalize the enantioselectivity of AAA using (aS)-
(-)-10 in the cartoon I (Figure 3). Referring to the X-ray
crystal structure of (aR)-(+)-10 given in Figure 2b, the amide
and naphthalene units are nearly perpendicular. They form
a puckered “chiral wall” by adjusting the orientation of the
phosphine phenyl groups upon formation of the palladium
complex. As illustrated in I, on the rear side of the wall is
Figure 3. Proposed mechanism of enantioselectivity of (aS)-(-)-
10.
the coordinated allyl unit. The latter takes the preferred
syn,syn-geometry having the phenyl group (b) intrude into
the space between the two phenyl groups on the phosphorus.
The chelate shown in the cartoon I should be sterically
favored. We assume attack of nucleophile occurs at the allyl
terminus trans to the Pd-P bond as suggested in many
previous studies on P,N-ligands.12 Our model predicts
formation of (R)-13 in agreement with our experimental
observation (Table 1, entry 3). The steric effect observed in
(12) (a) Sprinz, J.; Kiefer, M.; Helmchen, G.; Reggelin, M.; Huttner,
G.; Walter, O.; Zsolnai, L. Tetrahedron Lett. 1994, 35, 1523. (b) Brown, J.
M.; Hulmes, D. J.; Guiry, P. J. Tetrahedron 1994, 50, 4493. (c) Dawson,
G. C.; Williams, J. M. J.; Coote, S. J. Tetrahedron: Asymmetry 1995, 6,
2535. (d) Togni, A.; Burckhardt, U.; Gramlich, V.; Pregosin, P. S.;
Org. Lett., Vol. 4, No. 9, 2002
1617

entries 7-9 of Table 1 may be explained by the steric
interaction between the C8-alkoxy and the nucleophile,
resulting in nucleophilic attack at the allyl terminus trans to
the Pd-O bond. However, it should be pointed out that the
above discussion is a simple treatment as many factors may
become dominant in stereodifferentiation under different
reaction conditions.5c,6d,13 The decreased ee using 2.5-fold
ligand (Table 1, entry 5) may involve a distinct Pd complex
where the phosphine may act as monodentate ligand.
AAA. Our current understanding on the amide-based phos-
phines is still limited. Further study on the catalysis and
reaction scope of such ligands is in progress.
Acknowledgment. We thank the financial support pro-
vided by the Department of Chemistry, HKUST (through a
postdoctoral fellowship to J.-T. Liu) and the Research Grants
Council of the Hong Kong Special Administrative Region,
China (through a Direct Allocation Grant, DAG99/00.SC14,
and a Competitive Earmarked Research Grant, HKUST6219/
01P).
In summary, we have synthesized a novel class of
nonbiaryl atropisomeric P,O-ligands devoid of central chiral-
ity and have demonstrated their promising application in
Supporting Information Available: Experimental pro-
cedures, spectral data, and X-ray crystallographic analysis
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
Salzmann, R. J. Am. Chem. Soc. 1996, 118, 1031. (f) Ward, T. R.
Organometallics 1996, 15, 2836. (g) Blo¨chl, P. E.; Togni, A. Organome-
tallics 1996, 15, 4125. (h) Steinhagen, H.; Reggelin, M.; Helmchen, G.
Angew. Chem., Int. Ed. Eng. 1997, 36, 2108.
(13) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.
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