Synthesis, resolution and applications of 3,3′-bis(RO)-MeO-BIPHEP derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.03.073

A series of optically pure 3,3′-bis(RO)-MeO-BIPHEP derivatives are prepared and used in palladium catalyzed asymmetric transformations. The phosphine oxide of (±)-5 is prepared in four steps from p-methoxyphenol and resolved using the novel resolving reag

Full text of DOI:10.1016/j.tetlet.2004.03.073

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3597–3601
Synthesis, resolution and applications of 3,30-bis(RO)-MeO-
BIPHEP derivativesq
Evgueni Gorobets, Guang-Ri Sun, Bronwen M. M. Wheatley, Masood Parvez
and Brian A. Keay*
Department of Chemistry, University of Calgary, Calgary, Alta, Canada T2N 1N4
Received 3 February 2004; revised 3 March 2004; accepted 10 March 2004
Abstract—A series of optically pure 3,30-bis(RO)-MeO-BIPHEP derivatives are prepared and used in palladium catalyzed asym-
metric transformations. The phosphine oxide of ( )-5 is prepared in four steps from p-methoxyphenol and resolved using the novel
resolving reagent chloro(
prepared in six steps from p-methoxyphenol and the phosphine oxides of 6 and 7, and 10 are resolved using di-p-toluoyl- and
dibenzoyl-
-tartaric acid, respectively. (R)-3,30-Bispivalate 8 is superior to the other catalysts in asymmetric Heck reaction with 2,3-
L-menthoxy)dimethylsilane. Subsequent conversions provide catalysts 8 and 9. Ligands 6, 7 and 10 are
L
dihydrofuran while (R)-(+)-bis(tolyloxy) 10 and (+)-(R)-sugar derivative 9 are better in the Pd-catalyzed polyene cyclization;
however, the absolute sense of chirality in the product from the polyene cyclization was reversed to that obtained when (R)-(+)-
BINAP and (R)-(+)-MeO-BIPHEP were used.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Since we reported the synthesis of (+)-xestoquinone in
R
R
1996 in 68% ee using an asymmetric palladium catalyzed
polyene cyclization (PCPC) as the key step,1 we have
been interested in finding methods for increasing the
enantioselectively in palladium catalyzed polyene cycli-
zations 1 fi 3.2;3 While investigating the effect of sub-
stituents on the PCPC we found that the placement of a
methyl group ortho to the triflate, that is, 2 (Scheme 1)
resulted in the formation of 4 in >96% ee when compared
to 71% ee with the reaction of 1 fi 3. PM3(tm) semi-
empirical calculations4 indicated that group ortho to the
triflate in 2 might be interacting strongly with one of the
30 hydrogen atoms in (S)-BINAP after oxidative inser-
tion of the Pd atom leading to (S)-4, while the same
interaction is not observed in the isomer leading to (R)-4.
Hence the %ee in the PCPC of 2 fi 4 was higher than that
of 1 fi 3. From these calculation and experimental
results, we rationalized that if the above hypothesis is true
that placement of a group other than hydrogen in the
3- and 30-positions of BINAP should also result in an
a
OTf
O
O
O
O
3 R=H 71%ee
1 R=H
4 R=Me >96% ee
2 R=Me
OR
5 R=H
6 R=Me
R1
MeO
MeO
PPh2 7 R=iPr
O
8 R=COC(Me)3
PPh2
O
9 R=COR1
10 R=Tolyl
O
O
O
OR
Scheme 1. Reagents and conditions: (a) Pd2(dba)3, (S)-BINAP, PMP,
toluene, 110 ꢁC.
increase in the %ee in the PCPC of 1 fi 3. As the
placement of substituents in the 3- and 30-position of
BINAP is not a trivial exercise,5 we decided to focus on
the development of a series 3,30-bis(substituted)-MeO-
BIPHEP6 derivatives (5–10) in which we could system-
atically adjust the size of the group easily in the 3- and
30-positions.7;8 We herein report the synthesis, resolution
and asymmetric applications of a series of new 3,30-
bis(substituted)-MeO-BIPHEP derivatives 5–10.
Keywords: Asymmetric Heck; Asymmetric polyene cyclizations; Palla-
dium; 3,30-Disubstituted BIPHEP derivatives.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.03.073
* Corresponding author. Tel.: +1-403-220-5340; fax: 1-403-284-1372;
e-mail: keay@ucalgary.ca
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.073

3598
E. Gorobets et al. / Tetrahedron Letters 45 (2004) 3597–3601
O
OH
O
PPh2
OH
O
b (74%)
a (99%)
PPh2
MeO
MeO
MeO
MeO
13
12
11
j (86, 94%
and 94%),
d (81, 76%
and 95%)
c
(99%)
OR1
X
OPiv
OR
O
PPh2
e (72%)
O
MeO
PPh2
PPh2
MeO
R1
R
2
18 R1=H; a R=Me; b R=iPr,
19 R1=I;
c R=Tolyl
14 R=H
15 R=I
(+/-)-16 R1=Piv, X=O
(+/-)-5 R1=H, X=LP
d
f
(98%)
(79%)
LP=lone pair
g,
e (89, 91%
and 83%)
separate
(96%)*
l (95%)
l (82%)
l (82%)
(+)-6
(+)-7
OR
O
PPh2
PPh2
O
OR1
MeO
MeO
(+)-10
MeO
MeO
PPh2
PPh2
c (94%)
i (98%)
(+)-8
(+)-9
OR
Figure 1. ORTEP diagram of ())-Sax-17 drawn with 30% probability
ellipsoids. Hydrogen atoms are represented as spheres of arbitrary size.
OR1
(+/-)-20a R=Me; b R=iPr c=tolyl
(+)-20a R=Me; b R=iPr c=tolyl
(-)-Rax-17 R1=SiMe2-L-Men
(+)-Rax-5 R1=H
k
h
(91%, 77% and 68%)
(89%)
Compounds (+)-6, (+)-7 and (+)-10 were prepared by
either alkylation of 13 with MeI or i-PrBr or by treat-
ment with 4-iodotoluene in the presence of CuBr and
caesium carbonate in refluxing pyridine to give 18a–c,
respectively (Scheme 2).16 Introduction of an iodine
atom (LDA, I2) gave 19a–c, which was subsequently
Ullmann coupled to give ( )-20a–c. Co-crystallization
Scheme 2. Reagents and conditions: (a) Ph2PCl, Et3N, DCM, rt, 12 h,
H2O2; (b) LDA, THF, )60 ꢁC, 6 h; (c) pivalyl chloride, Et3N, DCM;
(d) LDA, THF, )75 ꢁC, 2 h, then I2, rt, 1 h; (e) Cu powder, DMF,
100 ꢁC, 1.5 h; (f) AlH3, THF, 67 ꢁC, 12 h (79%); (g)
Me2SiCl, Et3N, DCM, 0 ꢁC, 1 d; (h) HF–pyr, THF, )70 ꢁC to rt, 1 h;
(i) 2,3:4,6-di-O-isopropylidene-2-keto- -gulonyl chloride, Et3N,
L-menthol–
L
DMAP, DCM, rt, 30 min; (j) MeI, DMF, K2CO3, rt, 24 h or i-PrBr,
DMF, K2CO3, 45 ꢁC, 6 h or 4-iodotoluene, Cs2CO3, pyr, CuBr, 115 ꢁC,
1 d (94%); (k)
CH3CN, separate or
48 h, 145 ꢁC; *48% of each diastereomer.
of ( )-20a and 20b first with di-p-toluoyl-
-(+)-DTTA), filtering and a subsequent co-crystalli-
zation of the remaining mother liquor with -())-DTTA
in CHCl3 provided ())-20a and (+)-20b, respectively.
A similar resolution on ( )-20c using dibenzoyl- -tar-
D-tartaric acid
(
D
D
-(+)-DTTA, 95% EtOH, separate or
D-(+)-DTTA,
L
L
-())-DBTA, CHCl3, separate; (l) HSiCl3, xylene,
L
taric acid ( -())-DBTA) gave (+)-20c. Subsequent
L
reduction with trichlorosilane17 gave (+)-6, (+)-7 and
9
4-Methoxyphenol (11) was treated with ClPPh2 fol-
10
lowed by H2O2 to give 12 that was subsequently
(+)-10.à
migrated to the ortho-position by treatment with LDA
giving 13 (Scheme 2).11 Protection of the hydroxyl group
as a pivalate 14 and introduction of an iodine atom
between the methoxyl and diphenylphosphonyl groups
provided 15.6 Ullmann coupling6;12 of 15 gave ( )-16,
which was reduced with AlH313 to give ( )-5. Resolution
of ( )-5 or the corresponding phosphine oxide using
reported methods for BINAP14 or MeO-BIPHEP6 did
not work and led us to develop a new resolution method
for biaryl systems containing hydroxyl groups. Treat-
The enantiomeric purity of compounds 6, 7 and 10 was
1
determined by integrating the MeO signals in the H
NMR spectrum of the corresponding
L
-())-DBTA
complex with the corresponding bisphosphine oxides.
The enantiopurity of 5 was determined in a similar
manner by examination of the 1H NMR of (+)- and ())-
17.
With (+)-5–10 in hand we compared the efficacy of these
ligands in the asymmetric Heck arylation of 2,3-dihydro
furan and compared the results to those obtained with
(+)-BINAP18 and (+)-MeO-BIPHEP6 (Table 1). In our
hands Hayashi’s reaction conditions19 reported with (+)-
BINAP and Hunig’s base at 40 ꢁC for 24 h afforded lower
product conversion and provided 21 and 23 in similar
ratio and %ee§ to that reported by Hayashi. (+)-MeO-
ment of ( )-5 with chloro(L-menthyloxy)dimethyl-
silane15 gave two diastereomers ())-Rax-17 (Rf 0.23) and
())-Sax-17 (Rf 0.20) that were separated by silica gel
column chromatography (hexanes/Et2O, 20:1). The lat-
ter diastereomer crystallized from hexanes and the
absolute stereochemistry was found to be Sax from
the X-ray crystal structure (Fig. 1). Removal of the silyl
group from ())-Rax-17 and ())-Sax-17 provided (+)-Rax-
5 and ())-Sax-5, respectively. (+)-Rax-5 was subsequently
converted into (+)-8 and 9 using standard procedures.
à
All compounds gave spectral data and/or elemental analyses in
accordance with their structures.
§
Enantiomeric excesses of 21 and 23 were determined from
a
ꢀ
Compound
())-Sax-17:
monoclinic
ꢀ
C2;
b ¼ 105:3695ð10Þꢁ,
a ¼ 28:3813ð7Þ A,
Cyclodex-B column (30 m · 0.32 mm i.d.), which provided base line
separation for each enantiomer. The retention times for ( )-21, 22
and ( )-23 were 26.5/26.9, 29.1 and 31.5/31.9 min, respectively.
ꢀ
b ¼ 9:6063ð2Þ A,
c ¼ 11:1778ð4Þ A,
V ¼
3
ꢀ
2938:52ð14Þ A ; Z ¼ 2; R ¼ 0:042; Rw ¼ 0:083.

E. Gorobets et al. / Tetrahedron Letters 45 (2004) 3597–3601
Table 1. Asymmetric Heck reactions with ligands 5–10
3599
OTf
Ph
Ph
Ph
21
22
3 mol% Pd(OAc)2
6 mol% ligand
O
+
+
benzene, 40 o
iPr2NEt, 24h
C
O
O
+
sealed vial
23
O
Ligand
Conversion (%)
Ratio of products
21 (%ee)
22
23 (%ee)
1
2
3
4
5
6
7
8
(+)-(R)-BINAP
(+)-(R)-MeO-BIPHEP
(+)-(R)-5
41
65
91 (80)
83 (92)
––
0
7
9 (61)
10 (63)
––
No rxn
6
37
––
0
(+)-(R)-6
(+)-(R)-7
100 (9)
93 (77)
99 (90)
94 (81)
97 (20)
0
0
7 (0)
1 (10)
6 (53)
3 (85)
(+)-(R)-8
(+)-(R)-9
(+)-(R)-10
100
48
0
0
57
0
BIPHEP provided a slightly higher % conversion and %ee
of 21 when compared to BINAP (entry 2). Trace amounts
of conjugated isomer 22 were also observed with (+)-
MeO-BIPHEP.20;21 No reaction was observed with bis-
phenol ligand (+)-5 (entry 3) due to its low solubility in
benzene at 40 ꢁC and bismethoxy ligand (+)-6 proved
equally disappointing although solubility in benzene was
not an issue with this ligand (entry 4). Ligands (+)-7 (bis-
both BINAP and MeO-BIPHEP by providing 100%
conversion to products after only 24 h and a much-im-
proved ratio of 21/23. The %ee of 21 was similar to those
obtained with BINAP and BIPHEP. Interestingly,
ligands 6–10 suppressed the formation of conjugated
isomer 22.20
Ligands (+)-(R)-5–10 where then tried in the palladium
catalyzed polyene cyclization (1 fi 3) and compared to
the results obtained with (+)-(R)-BINAP and (+)-(R)-
MeO-BIPHEP (Table 2). (+)-(R)-BINAP and (+)-(R)-
MeO-BIPHEP afforded (S)-3 in 68% and 72% ee,
respectively, although the % yield with (+)-(R)-MeO-
BIPHEP was lower than that obtained with (+)-(R)-
BINAP (entries 1 and 2). As above in the Hayashi
reaction, ligand (+)-(R)-5 did not promote the reaction
i-PrO),
9 (bis-(sugarC@O)O) and 10 (bis-tolylO)
provided similar % conversions as BINAP and MeO-
BIPHEP (entries 5, 7 and 8) however the %ee of 21 was
slightly lower with ligands 7 and 9 while ligand 10 gave a
disappointing 20% ee of 21. The increase in the ratio of 21/
23 with ligands 7, 9 and 10 is noteworthy and longer
reaction times might have provided better % conversion
to products. To our gratification, ligand 8 out performed
Table 2. Asymmetric Pd-catalyzed polyene cyclization results with ligands 5–10
O
OTf
Pd2(dba)3, catalyst
PMP, toluene, 110 oC
(R)-3
O
+
O
O
1
O
(S)-3
O
Catalyst
Yield (%)
Ratio of enantiomers
(R)-3 (S)-3
Ee (%)
1
2
3
4
5
6
7
8
(+)-(R)-BINAP
(+)-(R)-MeO-BIPHEP
(+)-(R)-5
81
53
84
86
––
26
30
54
18
14
16
14
––
74
70
46
82
86
68
72
––
48
40
8
No rxn
69
76
(+)-(R)-6
(+)-(R)-7
(+)-(R)-8
(+)-(R)-9
(+)-(R)-10
67
59
64
72
71

3600
E. Gorobets et al. / Tetrahedron Letters 45 (2004) 3597–3601
due to solubility problems in toluene at 110 ꢁC (entry 3).
The use of pivalate ligand (+)-(R)-8 was disappointing
as it afforded essentially a racemic mixture of 3. This
reaction was repeated and when a similar %ee was
obtained the enantiopurity of ligand (+)-(R)-8 was
checked but was found to a %ee of >97%. Ligands (+)-
(R)-6 and (+)-(R)-7 provided 3 in a disappointing ee of
48% and 40%, respectively. Upon closer examination of
the HPLC trace;– however, it was noticed that the major
isomer of the reaction in both cases was the R-isomer of 3
and not the expected S-isomer when using a biaryl
ligands with absolute stereochemistry Rax (cf. entries
1 and 2, Table 2). This unexpected reversal of absolute
stereochemistry in 3 was also observed with ligands (+)-
(R)-9 and 10 but in these cases the %ee increased to 64%
and 72%, respectively (entries 7 and 8). So contrary to
the expected result from PM3 semi-empirical calcula-
tions, the use of a variety of (+)-(R)-3,30-bis(substi-
tuted)-MeO-BIPHEP ligands 6, 7, 9 and 10 did not
increase the %ee of the polyene cyclization but instead
provided similar %ee’s of 3 as those obtained with (+)-
(R)-BINAP and MeO-BIPHEP but with the opposite
sense of chirality.**
References and notes
1. (a) Maddaford, S. P.; Andersen, N. G.; Cristofoli, W. A.;
Keay, B. A. J. Am. Chem. Soc. 1996, 118, 10766–10773;
(b) Keay, B. A.; Maddaford, S. P.; Cristofoli, W. A.;
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J. A. Can. J. Chem. 1997, 75, 1163–1171; (c) Cristofoli,
W. A.; Keay, B. A. Synlett 1994, 625–627.
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Lett. 2001, 3, 181–184; (c) Che, D.; Andersen, N. G.; Lau,
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try 2000, 11, 1919–1925; (d) Andersen, N. G.; McDonald,
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3. For recent reviews involving Pd-cat polyene reactions, see:
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2945–2963; (b) deMeijere, A.; Brase, S. J. Organomet.
Chem. 1999, 576, 88–110; (c) Grigg, R.; Sridharan, V.
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Dixon, R. W.; Fielder, S. S.; Kahn, S. D.; Pietro, W. J.
Wavefunction, Inc., Irvine, CA, 1996.
We have shown that a variety of 3,30-bis(substituted)-
MeO-BIPHEP derivatives can be easily prepared and
resolved. (+)-(R)-8 proved better than BINAP and
MeO-BIPHEP in the Heck reaction between phenyltri-
flate and 2,3-dihydrofuran while (+)-(R)-6, 7, 9 and 10
unexpectedly provided (S)-3 in the intramolecular
polyene cyclization. Work is continuing to rationalize
the observed reversal of absolute stereochemistry and to
use ligands 5–10 in other transition metal catalyzed
processes.
5. Lau, S. Y. W. PhD Dissertation, University of Calgary,
Calgary, AB, Canada, 2002.
6. (a) Schmid, R.; Cereghetti, M.; Heiser, B.; Schonholzer,
P.; Hansen, H.-J. Helv. Chim. Acta 1988, 71, 897; (b)
€
Schmid, R.; Foricher, J.; Cereghetti, M.; Schonholzer, P.
Helv. Chim. Acta 1991, 74, 370–389.
7. In 1991 the first report of a 3,30-disubstitued-MeO-
BIPHEP appeared in which Brown and Woodward
prepared compound 6 as the phosphine oxide. No further
transformations with this compound could be found in the
literature. Brown, J. M.; Woodward, S. J. Org. Chem.
1991, 56, 6803–6809.
Supplementary material
8. While our work was in progress, Zhang and co-workers
reported the synthesis, resolution and application of a 3,30-
bis(substituted)-MeO-BIPHEP derivative called o-Ph-
HexaMeO-BIPHEP. (a) Tang, W.; Chi, Y.; Zhang, X.
Org. Lett. 2002, 4, 1695; (b) Tang, W.; Zhang, X. Chem.
Rev. 2003, 103, 3029–3069.
Methods for double checking the assignment of absolute
stereochemistry to ligands 5–10 is provided along with
general procedures for the Heck and intramolecular
polyene cyclizations.
9. Hall, T. J.; Hargis, J. H. J. Org. Chem. 1986, 51, 4185–
4189.
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financial support. We thank Kristine M. Muller for a
few polyene cyclization results with catalysts 5–7 and
Thomas Wood for help with some of the syntheses. In
addition NSERC and the Alberta Ingenuity Fund are
thanked for postgraduate scholarships (for B.M.M.W.).
ꢁ
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–
The enantiomeric excesses were unequivocally determined by HPLC
analysis using a Chiralcel OD-H column using n-hexane/isopropanol
(90:10).
**
The reversal of absolute stereochemistry in product 3 resulted in us
double-checking the absolute stereochemistry assigned to ligands 5–
10. See the supplemental information for more details.

E. Gorobets et al. / Tetrahedron Letters 45 (2004) 3597–3601
3601
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between phenyltriflate and 2,3-dihydrofuran.21 This led us
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