Diastereospecific intramolecular Ullmann couplings: Unique chiral auxiliary for the preparation of 3,3′-disubstituted MeO-BIPHEP derivatives

Article abstract of DOI:10.1021/ol060484p

A chiral auxiliary is described that provides only one diastereomer during Intramolecular Ullmann couplings. Treatment of five Ullmann coupling precursors with Cu powder in DMF at 115 °C provides 2,2′,3,3′,6,6′- hexasubstituted 1,1′-biphenyls as single di

Full text of DOI:10.1021/ol060484p

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1483-1485
Diastereospecific Intramolecular Ullmann
Couplings: Unique Chiral Auxiliary for
the Preparation of 3,3′-Disubstituted
MeO-BIPHEP Derivatives
E. Gorobets,† R. McDonald,‡ and B. A. Keay*,†
Department of Chemistry, UniVersity of Calgary, Calgary, AB, Canada T2N 1N4, and
Department of Chemistry, UniVersity of Alberta, Edmonton, AB, Canada T6G 2G2
keay@ucalgary.ca
Received February 26, 2006
ABSTRACT
A chiral auxiliary is described that provides only one diastereomer during intramolecular Ullmann couplings. Treatment of five Ullmann coupling
precursors with Cu powder in DMF at 115
from 66% to 91%.
°C provides 2,2′,3,3′,6,6′-hexasubstituted 1,1′-biphenyls as single diastereomers in yields ranging
One of the most powerful methods for the preparation of
enantiomerically enriched compounds is catalytic asymmetric
synthesis. The design and synthesis of chiral bisphosphine
ligands is an important area of research toward developing
highly enantioselective transition-metal-catalyzed asymmetric
reactions.1 Given that subtle steric and/or electronic perturba-
tions of a ligand can dramatically affect the catalytic activity
and selectivity,2,3 we embarked on a program to prepare 3,3′-
disubstituted MeO-BIPHEP4 (1-5) and BINAP5 (6) deriva-
tives (Scheme 1). Since the original preparation of MeO-
BIPHEP (1) involved a cumbersome resolution step by co-
Scheme 1
† University of Calgary.
‡ University of Alberta.
(1) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(2) (a) Berthod, M.; Mignani, G.; Woodward, G.; Lemaire, M. Chem.
ReV. 2005, 105, 1801. (b) Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron
2005, 61, 857.
(3) (a) Chen, Y.; Yekta, S.; Yudin, A. Chem. ReV. 2003, 103, 3155. (b)
Kocˇovsky´, P.; Vyskocˇyl, S.; Smrcˇina, M. Chem. ReV. 2003, 103, 3213. (c)
Pu, L. Chem. ReV. 1998, 98, 2405. (d) Brunel, J. M. Chem. ReV. 2005,
105, 857.
(4) (a) Gorobets, E.; Wheatley, B. M. M.; Hopkins, J. M.; McDonald,
R.; Keay, B. A. Tetrahedron Lett. 2005, 46, 3843. (b) Gorobets, E.; Sun,
G.-R.; Wheatley, B. M. M.; Parvez, M. R.; Keay, B. A. Tetrahedron Lett.
2004, 45, 3597.
crystallization with dibenzoyl-L-tartaric acid6 that did not
work on some of our 3,3′-substituted MeO-BIPHEP deriva-
(5) Hopkins, J. M.; Dalrymple, S. A.; Parvez, M.; Keay, B. A. Org. Lett.
2005, 7, 3765.
(6) Schmid, R.; Foricher, J.; Cereghetti, M.; Scho¨nholzer, P. HelV. Chim.
Acta 1991, 74, 370.
10.1021/ol060484p CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/09/2006

tives, we developed resolutions for these 3,3′-derivatives
using L-menthol-Me2SiCl4b and (S)-2-acetoxypropanoyl
chloride.4a In both cases, the resulting diastereomers were
separated on silica gel. In the latter case, the chiral auxiliary
(CA) was attached to a precursor such that diastereomers
were formed after an intermolecular Ullmann coupling
(UC).7 Since the de’s were low (1.1 to 2:1) and some of
diastereomers did not separate well on silica gel, we decided
to investigate whether a highly diastereoselective intramo-
lecular UC could be designed so that the diastereomers would
not need to be separated. We herein report a new CA for
the preparation of 1-5 that provides one diastereomer after
an intramolecular UC.
Table 1. Products Ratios from the Intramolecular UC of
Compounds 9-17
deiodized sm/UC
product (config)
UC product
(% isolated yield)
sm
% de
(R,R)-13
(S,S)-14
(S,S)-15
(R,R)-16
(R,R)-17
(R,R)-18
(R,R)-19
(R,R)-20
95:5 (nd)
23:77 (Rax
10:90 (Rax
9:91 (Sax
4:96 (Sax
17:83 (Sax
6:94 (Sax
21:79 (Sax
21 (nd)
22 (69)
23 (81)
24 (88)
25 (91)
26 (79)
27 (84)
28 (66)
)
)
71
95
)
)
)
)
)
>99
>99
>99
>99
>99
A survey of the literature8 on successful diastereoselective
intramolecular UC involving ether linkages 7 indicated that
although the % de in some cases were very high (100% de),9
the yields were moderate to good (54-78%),10,11 and harsh
conditions (e.g., BBr3) were necessary to cleave some of the
ether bridges. We decided to take a different tack involving
the design of an asymmetric linkage that would involve esters
8 (Scheme 1) rather than ethers 7 such that cleavage of the
asymmetric linkage would occur under milder reaction
conditions. Although this scenario would place the stereo-
genic centers within the linkage further away from the newly
formed axis of chirality, we were encouraged by some recent
findings in which very high % de’s were reported in oxidative
biaryls couplings12 in which the stereogenic centers were up
to 8 atoms removed13 from the axis of chirality.
that furnished UC product 23 with a gratifying 95% de (81%
yield).15 Finally, changing the CA from a lactate to the more
bulky (R)-2-hydroxy-3,3-dimethylbutyrate 1616 provided only
one diastereomer 24 (>99% de by 1H NMR) in 88% yield.
The absolute configuration of the newly formed axis of
chirality in 24 was found to be Sax from the X-ray crystal
structure (Figure 1). Compounds 16-20 were synthesized
We decided to start with the preparation of MeO-BIPHEP
(1) as a model, and the first CA used, 9, was easily prepared
from tartaric acid. Using our optimized reaction conditions
for intramolecular UC,14 compound 13 gave mainly deiodized
starting material (SM) (48%) and a very small amount of
21 (Table 1). Changing the CA to lactate derivative 10 in
which the alcohol groups of the lactates were linked via a
succinate (i.e., 14) provided Ullmann-coupled product 22 in
69% yield with a 71% de. It was felt that if the flexibility in
the CA chain was reduced that amount of dehalogenized
material would be minimized as the two aromatic rings would
be held in closer proximity to one another. Indeed, reducing
the degrees of freedom of rotation in the CA linkage by
modifying the succinate to a phthalate 11 gave precursor 15
Figure 1. X-ray crystal structure of (R,R,Sax)-24. The hydrogen
atoms have been removed for clarity.
(7) Qiu, L.; Qi, J.; Pai, C.-C.; Chan, S.; Zhou, Z.; Choi, M. C. K.; Chan,
A. S. C. Org. Lett. 2002, 4, 4599.
(8) (a) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.;
Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384. (b) Nelson,
T. D.; Crouch, R. D. Org. React. 2004, 63, 265. (c) Hassan, J.; Se´vignon,
M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359.
(9) (a) Lipshutz, B. H.; Kayser, F.; Liu, Z.-P. J. Am. Chem. Soc. 1993,
115, 9276. (b) Lipshutz, B. H.; Mu¨ller, P.; Leinweber, D. Tetrahedron Lett.
1999, 40, 3577.
(10) Sugimura, T.; Yamada, H.; Inoue, S.; Tai, A. Tetrahedron:
Asymmetry 1997, 8, 649.
(11) Qiu, L.; Wu, J.; Chan, S.; Au-Yeung, T. T.-L.; Ji, J.-X.; Guo, R.;
Pai, C.-C.; Zhou, Z.; Li, X.; Fan, Q.-H.; Chan, A. S. C. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5815.
in excellent yields over five steps starting from (R)-2-
hydroxy-3,3-dimethylbutanoic acid 2916 via diacid 30 (bot-
tom of Scheme 2).
To determine if the CA derived from (R)-2-hydroxy-3,3-
dimethylbutyrate would provide high % de’s when the 3 and
3′ positions were substituted, compounds 17-20 were
prepared and subjected to the intramolecular UC. In all four
cases, the products 25-28 were formed with >99% de (by
1H NMR) in yields ranging from 66 to 91% (Table 1). After
(12) Merlic, C. A.; Aldrich, C. C.; Albaneze-Walker, J.; Saghatelian,
A.; Mammen, J. J. Org. Chem. 2001, 66, 1297.
(13) Lipshutz, B. H.; James, B.; Vance, S.; Carrico, I. Tetrahedron Lett.
1997, 38, 753.
(14) For intramolecular UCs, we found that the amount of deiodized
material could be minimized by the addition of the SM (1 mmol in 25 mL
of DMF) via syringe pump (4.1 mL/h) to a suspension of 2.7 equiv of Cu
powder in DMF (25 mL) preheated to 115 °C.
(15) It is interesting to note that the corresponding intermolecular UC
using 6-((R)-2-acetoxy-propionyloxy)-2-(diphenylphosphinoyl)-1-iodoben-
zene afforded a 2:1 mixture of diastereomers.4a
(16) For the preparation and resolution of (R)- and (S)-2-hydroxy-3,3-
dimethylbutanoic acid, see: Kontos, Z.; Huszthy, P.; Bradshaw, J. S.; Izatt,
R. M. Tetrahedron: Asymmetry 1999, 10, 2087.
1484
Org. Lett., Vol. 8, No. 7, 2006

Scheme 2
Scheme 3
phosphine oxides 31, 32, or 33 from the deiodized SM was
successful via a silica gel column. The enantiopurity of 31,
1
32, or 33 was then determined by measuring the H NMR
spectrum in the presence of (-)-(2R,3R)-dibenzoyltartaric
acid.17 In all cases, only one methoxy signal was observed,
indicating the sample was enantiopure. Thus, only one
diastereomer was formed during the UC reaction.
In summary, we have designed and synthesized a novel
chiral auxiliary that provides only one diastereomer in the
intramolecular UC leading to BIPHEP derivatives. The
auxiliary is easily prepared and removed after the UC and
should be useful toward the asymmetric synthesis of the
ellagitannin class of natural products.18
separation of UC products from deiodized SM and other
impurities (silica gel column), the H NMR spectrum of
1
Acknowledgment. We thank Merck Frosst Canada, the
NSERC CRD program, and the University of Calgary for
financial support.
major spot showed the presence of only one diastereomer
in all cases. Compounds 24-28 were then converted into
optically pure phosphine oxides 31-35 in high yields
(Scheme 3).
Supporting Information Available: Experimental prepa-
rations for 32-35, 16-20, and 24-28 are provided along
with all intermediates. This material is available free of
charge via the Internet at http://pubs.acs.org.
For additional confirmation that only one diastereomer was
formed from the UC and that the minor diastereomer was
not lost on the silica gel column mentioned above to remove
the deiodized SM and other impurities, the crude UC reaction
mixtures containing 24, 25, or 26, after removing the copper
salts, were treated with KOH/EtOH followed by methylation
with MeI as shown in Scheme 3. Note that upon removal of
the CA, any mixture of diastereomers formed in the UC
would now become a mixture of enantiomers (i.e., a scalemic
mixture). Separation of the possible scalemic mixture of
OL060484P
(17) Gorobets, E.; Parvez, M.; Wheatley, B. M. M.; Keay, B. A. Can. J.
Chem. 2006, 84, in press.
(18) (a) Khanbabaee, K.; van Ree, T. Synthesis 2001, 1585. (b) Quideau,
S.; Feldman, K. S. Chem. ReV. 1996, 96, 475. (c) Khanbabaee, K.; van
Ree, T. Nat. Prod. Rep. 2001, 18, 641.
Org. Lett., Vol. 8, No. 7, 2006
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