Efficient pseudo-enantiomeric carbohydrate olefin ligands

Article abstract of DOI:10.1021/ol3015896

Highly efficient pseudo-enantiomeric olefin ligands were designed from d-glucose and d-galactose. These ligands yield consistently excellent levels of enantioselectivity in Rh(I)-catalyzed 1,4-additions of aryl- and alkenylboronic acids to achiral enones and high diastereoselectivity with chiral substrates. Contrary to established olefin ligands, they are obtained enantiomerically pure via short syntheses without racemic resolution steps, making them a valuable addition to the arsenal of chiral ligands with olefinic donor sites.

Full text of DOI:10.1021/ol3015896

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Efficient Pseudo-enantiomeric
Carbohydrate Olefin Ligands
Holger Grugel, Fabian Albrecht, Tobias Minuth, and Mike M. K. Boysen*
Institute of Organic Chemistry, Gottfried-Wilhelm-Leibniz University of Hannover,
D-30167 Hannover, Germany
mike.boysen@oci.uni-hannover.de
Received June 19, 2012
ABSTRACT
Highly efficient pseudo-enantiomeric olefin ligands were designed from D-glucose and D-galactose. These ligands yield consistently excellent
levels of enantioselectivity in Rh(I)-catalyzed 1,4-additions of aryl- and alkenylboronic acids to achiral enones and high diastereoselectivity with
chiral substrates. Contrary to established olefin ligands, they are obtained enantiomerically pure via short syntheses without racemic resolution
steps, making them a valuable addition to the arsenal of chiral ligands with olefinic donor sites.
7
8
€
Asymmetric catalysis using metal complexes of chiral
ligands is of great importance in the synthesis of natural
products, pharmaceuticals, and drug candidates. Unsur-
prisingly, the design of new chiral ligands is a very active
field of research. Amino acids, terpenes, and alkaloids
from the chiral pool are important enantiomerically pure
starting materials useful in ligand design.
Grutzmacher, and shortly afterward, Hayashi published
further examples. Today, many structurally diverse olefin
ligands are known and used,9,10 but only a few are derived
from chiral pool compounds (e.g., from the terpenes
carvone6 and R-phellandrene9d). Most are prepared as
racemates and have to be resolved by chiral HPLC making
their synthesis tedious.
Chiral bidentate olefins1 are a highly useful addition
to the arsenal of tools for asymmetric catalysis and
have become ligands of choice for rhodium-catalyzed
1,4-additions.2À4 The first examples were bicyclic diolefins
developed independently by Hayashi5 and Carreira.6
OlefinÀphosphine hybrids were first described by
Scheme 1. Synthesis of gluco-enoPhos Ligands from Glucal 1
(1) (a) Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 3364. (b) Defieber,
€
C.; Grutzmacher, H.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47,
4482. (c) Shintani, R.; Hayashi, T. Aldrichimica Acta 2009, 42, 31.
(2) For reviews on asymmetric 1,4-additions, see: (a) Hayashi, T.;
Yamasaki, K. Chem. Rev. 2003, 103, 2829. (b) Edwards, H. J.; Hargrave,
J. D.; Penrose, S. D.; Frost, C. G. Chem. Soc. Rev. 2010, 39, 2093. (c)
Tian, P.; Dong, H.-Q.; Lin, G.-Q. ACS Catal. 2012, 2, 95.
(3) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579.
(4) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4229.
(5) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am.
Chem. Soc. 2003, 125, 11508.
(6) Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E. M. Org. Lett.
Carbohydrates have long been avoided as starting ma-
terials for ligand design. Even as the first ligands based on
2004, 6, 3873.
(7) Maire, P.; Deblon, S.; Breher, F.; Geier, J.; Bohler, C.; Ruegger,
€
€
(8) Shintani, R.; Duan, W.-L.; Nagano, T.; Okada, A.; Hayashi, T.
Angew. Chem., Int. Ed. 2005, 44, 4611.
€
€
H.; Schonberg, H.; Grutzmacher, H. Chem.;Eur. J. 2004, 10, 4198.
r
10.1021/ol3015896
XXXX American Chemical Society

monosaccharides were reported over 30 years ago,11 only
now the potential of carbohydrates in asymmetric synth-
esis is broadly exploited.12 We have developed carbohy-
drate bis(oxazolines) that gave excellent results in copper-
catalyzed reactions.13,14 The design of novel olefin hybrid
ligands based on carbohydrates is attractive, as unsatu-
rated monosaccharide derivatives are easily available and
phosphorus donor sites can be conveniently incor-
porated into the pyranoside framework by phosphinite
formation.11,15 Starting from commerically available glu-
cal 1, we recently prepared new olefinÀphosphinite hybrid
EtO-gluco-enoPhos (3a) which gave the (R)-configured
1,4-addition product of cyclohexenone with phenylboro-
nic acid.16,17 After this initial success, we aimed for both a
broad application of the new ligand and a possibility to
obtain enantiomeric addition products.
1 and 5). Thus, the anomeric substituent is not essential for
an efficient asymmetric induction.
To access the (S)-enantiomers of the 1,4-addition pro-
ducts 8aa and 8ba, the enantiomeric ligands to 3a,b are
necessary, which poses a considerable obstacle, as L-glu-
cose derivatives are prohibitively expensive and therefore
not an option for ligand synthesis. As D- and L-arabinose
are available at reasonable price, we explored an olefin
phosphinite ligand based on this monosaccharide. Unfor-
tunately, this ligand led to the formation of product 8aa in
76% ee and 92% yield,16b which made arabinose unsui-
table for the preparation of an enantiomeric hybrid ligand
pair.
To explore the influence of the anomeric substituent on
stereoselectivity, simplified ligand H-gluco-enoPhos (3b)
was prepared via a Ferrier rearrangement18 with tri-
ethylsilane19 (Scheme 1). First trials of 3b in 1,4-additions
with phenyboronic acid (7a) and cyclohexenone 6a or
cyclopentenone 6b gave >90% yield of the (R)-configured
products 8aa and 8ba in 98% ee and 99% ee, respectively.
These results were almost identical to those obtained with
EtO-gluco-enoPhos (3a) (Table 1, entries 2 and 6 vs entries
Figure 1. D-gluco- and D-galacto-configured carbohydrate scaf-
folds as pseudo-enantiomers.
(9) Selected examples for diolefins: (a) Otomaru, Y.; Okamoto, K.;
Shintani, R.; Hayashi, T. J. Org. Chem. 2005, 70, 2503. (b) Helbig, S.;
Sauer, S.; Cramer, N.; Laschat, S.; Baro, A.; Frey, W. Adv. Synth. Catal.
2007, 349, 2331. (c) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q.
J. Am. Chem. Soc. 2007, 129, 5336. (d) Okamoto, K.; Hayashi, T.;
Rawal, V. H. Org. Lett. 2008, 10, 4387. (e) Nishimura, T.; Nagaosa, M.;
Hayashi, T. Chem. Lett. 2008, 37, 860. (f) Hu, X.; Zhuang, M.; Du, H.
Org. Lett. 2009, 11, 4744. (g) Li, Q.; Dong, Z.; Yu, Z.-X. Org. Lett. 2011,
13, 1122. (h) Trost, B. M.; Burns, A. C.; Tautz, T. Org. Lett. 2011, 13,
4566.
The application of a pseudo-enantiomeric carbohydrate
scaffold is an option to avoid ligand syntheses from
expensive L-carbohydrates. This strategy has been success-
fully employed by Kunz and RajanBabu for chiral carbo-
hydrate auxiliaries20 and ligands.21 The synthesis of such
pseudo-enantiomeric ligands uses diastereomeric com-
pounds as starting materials.22 Elegant and attractive as
this approach is, the development of an efficient pseudo-
enantiomeric ligand is by no means a trivial feat. The
challenge lies in finding a carbohydrate scaffold which
reverses the asymmetric induction and does this with the
same high level of enantioselectivity as the original ligand.
Therefore, the development of pseudo-enantiomers is a
processof trial and error, justasany designofa newligand,
and not necessarily successful. We decided to explore D-
galactose, the C4-epimer of D-glucose (Figure 1), as a
candidate for the preparation of pseudo-enantiomeric
olefin hybrid ligands.
ꢀ
(10) Selected examples for olefinÀphosphine hybrids: (a) Kasak, P.;
Arion, V. B.; Widhalm, M. Tetrahedron: Asymmetry 2006, 17, 3084. (b)
~
Stremmler, R. T.; Bolm, C. Synlett 2007, 1365. (c) Mariz, R.; Briceno,
A.; Dorta, R.; Dorta, R. Organometallics 2008, 27, 6605.
(11) (a) Cullen, W. R.; Sugi, Y. Tetrahedron Lett. 1978, 19, 1635. (b)
Jackson, R.; Thompson, D. J. J. Organomet. Chem. 1978, 159, C29. (c)
Selke, R. React. Kinet. Catal. Lett. 1979, 10, 135. (d) Sinou, D.; Descotes,
G. React. Kinet. Catal. Lett. 1980, 14, 463.
€
€
(12) For reviews, see: (a) Lehnert, T.; Ozuduru, G.; Grugel, H.;
Albrecht, F.; Telligmann, S. M.; Boysen, M. M. K. Synthesis 2011, 2685.
ꢀ
ꢁ
(b) Woodward, S.; Dieguez, M.; Pamies, O. Coord. Chem. Rev. 2010,
254, 2007. (c) Benessere, V.; Del Litto, R.; De Roma, A.; Ruffo, F.
Coord. Chem. Rev. 2010, 254, 390. (d) Boysen, M. M. K. Chem.;Eur. J.
ꢀ
ꢁ
2007, 13, 8648. (e) Dieguez, M.; Pamies, O.; Claver, C. Chem. Rev. 2004,
104, 3189. (f) Hale, K. J. In Second Supplement to the Second ed. of
Rodd’s Chemistry of Carbon Compounds; Sainsbury, M., Ed.; Elsevier:
Amsterdam, 1993; Vol. 1E/F/G, Chapter 23b, p 273.
The synthesis of galacto-configured olefinÀphosphinite
ligands from commercially available D-galactal 4(Scheme 2)
was done analogous to the preparation of the gluco-
ligands. The Ferrier rearrangement of 4 with alcohols
leads to notoriously unsatisfactory yields;23 therefore,
(13) (a) Irmak, M.; Groschner, A.; Boysen, M. M. K. Chem. Com-
mun. 2007, 177. (b) Minuth, T.; Irmak, M.; Groschner, A.; Lehnert, T.;
Boysen, M. M. K. Eur. J. Org. Chem. 2009, 997.
(14) Irmak, M.; Boysen, M. M. K. Adv. Synth. Catal. 2008, 350, 403.
(15) Yonehara, K.; Hashizume, T.; Mori, K.; Ohe, K.; Uemura, S.
J. Org. Chem. 1999, 64, 5593.
(16) (a) Minuth, T.; Boysen, M. M. K. Org. Lett. 2009, 11, 4212. (b)
Grugel, H.; Minuth, T.; Boysen, M. M. K. Synthesis 2010, 3248.
(17) Bidentate coordination of 5a to Rh(I) was unequivocally estab-
lished by 1H and 31P NMR spectroscopy (ref 16a). The data are in good
agreement with those reported for an achiral allyl phosphinite: Curtis,
J. L. S.; Hartwell, G. E. J. Organomet. Chem. 1974, 80, 119.
(18) (a) Ferrier, R. J.; Overend, W. G.; Ryan, A. E. J. Chem. Soc.
1962, 3667. (b) Ferrier, R. J.; Prasad, N. J. Chem. Soc. C 1969, 570.
(19) (a) Nicolaou, K. C.; Hwang, C.-K.; Marron, B. E.; DeFrees,
S. A.; Couladouros, E. A.; Abe, Y.; Carroll, P. J.; Snyder, J. P. J. Am.
Chem. Soc. 1990, 112, 3040. (b) Takahashi, K.; Masumura, T.; Ishihara,
J.; Hatakeyama, S. Chem. Commun. 2007, 4158.
€
(20) Kunz, H.; Pfrengle, W.; Ruck, K.; Sager, W. Synthesis 1991,
1039.
(21) RajanBabu, T. V.; Ayers, T. A.; Halliday, G. A.; K. K. You,
Calabrese, J. C. J. Org. Chem. 1997, 62, 6012.
(22) The most prominent example of pseudo-enantiomeric ligands
are probably the ones employed in the Sharpless asymmetric dihydrox-
ylation, which are derived from diastereomeric cinchona alkaloids:
Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung,
J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.;
Zhang, X.-L. J. Am. Chem. Soc. 1992, 57, 2768.
(23) Ciment, D. M.; Ferrier, R. J. J. Chem. Soc. C 1966, 441.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Rhodium-Catalyzed 1,4-Additions with gluco-enoPhos
(3a,b) and galacto-enoPhos (ps-ent-3a,b)*
Scheme 2. Synthesis of Pseudo-enantiomeric OlefinÀPhosphi-
nite Ligands galacto-enoPhos from Galactal 4
ligand EtO-galacto-enoPhos (ps-ent-3a) was obtained
only in modest overall yield, while H-galacto-enoPhos
(ps-ent-3b) was isolated in good overall yield. An efficient
access to ps-ent-3a was established via alcohol 2a from the
synthesis of EtO-gluco-enoPhos. A known24 Mitsunobu
epimerization produced galacto-configured alcohol 5a
which was transformed into ligand ps-ent-3a in high yield.
This approach renders the route via galactal 4 redundant
and gives access to both gluco- and galacto-configured
ligands from D-gluco alcohol 2a as a single key
intermediate.
The new ligands EtO-galacto-enoPhos (ps-ent-3a) and
H-galacto-enoPhos (ps-ent-3b) were then evaluated in the
1,4-addition of boronic acid (7a) to cyclohexenone 6a.
Independently of the anomeric substituent, ps-ent-3a and
ps-ent-3b gave product 8aa in >90% yield and excellent
99% ee (Table 1, entries 3 and 4). Most importantly, both
produced the (S)-enantiomer, completely reversing the
asymmetric induction. Thus, gluco- and galacto-config-
ured olefinÀphosphinite hybrids 3a,b and ps-ent-3a,b,
derived from inexpensive D-carbohydrate scaffolds, act
as highly efficient pseudo-enantiomeric ligand pairs.
Next the substrate spectrum of the new pseudo-enantio-
meric ligands 3a,b and ps-ent-3a,b was evaluated in 1,4-
additions of various aryl and alkenyl boronic acids (7bÀe)
to enones 6a,b and enoate 6c (Table 1, entries 7À21). All
reactions were carried under mild conditions with only a
small excess of the boronic acid component (1.5 equiv).
Regardlessofthe boronicacid, ligands3a,b and ps-ent-3a,b
consistently yielded the respective products in opposite
configuration and, in all but three cases, with excellent ee,
even for sterically demanding aryl boronic acids (7b,c) and
the more labile alkenyl boronic acid 7e. As a general trend,
galacto-configured ligands ps-ent-3a,b produced higher
yields than their gluco-configured counterparts, always
giving >90% ee. In case of gluco-ligands 3a,b, the addi-
tions of ortho-substituted aryl boronic acid 7c and
* Ligand (3.3 mol %), [RhCl(C2H4)2]2 (1.5 mol %), 6 (1 equiv), 7 (1.5
equiv). a Isolated yield after chromatography. b Determined by GC or
HPLC. c Results from ref 16.
alkenylboronic acid 7e to cyclohexenone 6a led to less
than 80% ee (entries 10 and 18), while the other reactions
produced the products in high enantioselectivity. For
enoate 6c and phenylboronic acid (7a) the corresponding
product 8ca was obtained in high enantioselectivity
(entries 20 and 21).
(25) For diastereoselective 1,4-additions of boronic acids to racemic
6-alkyl cyclohexenones, see: (a) Mediavilla Urbaneja, L.; Krause, N.
Tetrahedron: Asymmetry 2006, 17, 494. (b) Chen, Q.; Soeta, T.;
Kuriyama, M.; Yamada, K.; Tomioka, K. Adv. Synth. Catal. 2006,
€
348, 2604. (c) Burgi, J. J.; Mariz, R.; Gatti, M.; Drinkel, E.; Luan, X.;
(24) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017. (b)
Georges, M.; Mackay, D.; Fraser-Reid, B. Can. J. Chem. 1984, 62, 1539.
Blumentritt, S.; Linden, A.; Dorta, R. Angew. Chem., Int. Ed. 2009, 48,
2768.
Org. Lett., Vol. XX, No. XX, XXXX
C

In order to demonstrate the efficiency of the pseudo-
enantiomeric olefinÀphosphinite ligands in the reactions
of chiral substrates,25 diastereoselective 1,4-additions to
(6R)-2-trityloxymethyl-6H-pyran-3-one (9) were tested.
Enone 926 is accessible in enantiomerically pure form by
oxidation of alcohol 2b with TPAP/NMO27 in 59% yield.
The results of the diastereoselective reactions with 9 are
summarized in Table 2. First, the 1,4-addition was con-
ducted with achiral catalyst [Rh(cod)OH]2 in the absence
of any chiral ligand. Under these substrate-controlled
conditions, the diastereomeric products 10 were obtained
in 93% yield and a ratio of 20:80 in favor of the trans-10
with (S)-configuration at the newly formed stereocenter
(entry 1). As can be seen from Table 1, gluco-configured
ligands 3a,b give (R)-configured products without excep-
tion. Therefore, substrate control of 9 and catalyst control
of EtO-gluco-enoPhos (3a) work against each other in
reaction entry 2. However, ligand 3a smoothly overrode
the substrate control in this mismatched case, giving a
diastereomeric ratio of 89:11 in favor of cis-10. The reac-
tion of 9 in the presence of H-galacto-enoPhos (ps-ent-3a),
which constitutes the matched combination of substrate
and catalyst control, led to an improved diastereomeric
ratio of 6:94 in favor of trans-10 (entry 3). These exellent
results show, that the new ligands are suitable for the
highly diastereoselective conversion of complex chiral
substrates.
In summary, we have designed the diastereomeric car-
bohydrate-based ligands gluco-enoPhos 3a,b and galacto-
enoPhos ps-ent-3a,b which give excellent results in rho-
dium-catalyzed asymmetric 1,4-additions and act as two
pairs of highly efficient pseudo-enantiomers. The ligands
achieve excellent levels of enantioselectivity with achiral
enones and enoates in the reactions of a broad number of
boronic acids. Further, they lead to highly diastereoselec-
tive reactions with complex chiral substrates, efficiently
overriding substrate control. Generally, the rhodium cat-
alysts derived from galacto-configured ligands gave higher
stereoselectivity than their gluco-configured counterparts.
Table 2. Diastereoselective 1,4-Additions of Phenylboronic
Acid (7a) to Chiral Enone 9*
product 10
entry ligand
Rh source
yielda (%) cis/trans ratiob
1
2
3
none
[Rh(cod)OH]2
93
78
86
20:80
89:11
6:94
3a
[RhCl(CH2dCH2)2]2
ps-ent-3b [RhCl(CH2dCH2)2]2
* Ligand (3.3 mol %), Rh(I) (3.3 mol %), 9 (1 equiv), 7a (1.5 equiv).
a Combined yield after chromatography. b Determined by 1H NMR.
The reason for this finding is yet unknown, but experi-
ments toward an elucidation are in progress.
The gluco-configured ligands 3a,b are accessible from
glucal 1 in just four simple steps via alcohols 2a,b. As
galacto-alcohol 5a can be prepared via the epimerization of
gluco-alcohol 2a as key intermediate, the synthesis of
pseudo-enantiomer ps-ent-3a takes only three additional
steps. With this convenient ligand synthesis and the high
stereoselectivities obtained, even on complex substrates,
our new carbohydrate olefin ligands are attractive alter-
natives to many of the currently employed ligands.
Acknowledgment. Generous financial support by the
DFG (Grant No. BO 1938/5-1) and by the Volkswagen
Foundation is gratefully acknowledged. M.M.K.B. thanks
the DFG for a Heisenberg Stipend (BO 1938/4-1).
Supporting Information Available. Experimental details
for ligand syntheses and rhodium-catalyzed 1,4-additions,
full characterization of all products, and data for the deter-
mination of all enantiomeric excesses. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(26) Benko, Z.; Fraser-Reid, B.; Mariano, P. S.; Beckwith, A. L. J.
J. Org. Chem. 1988, 53, 2066.
(27) Barili, P. L.; Berti, G.; Catelani, G.; D’Andrea, F.; Puccioni, L.
The authors declare no competing financial interest.
J. Carbohydr. Chem. 2000, 19, 79.
D
Org. Lett., Vol. XX, No. XX, XXXX