Highly diastereoselective Friedel-Crafts reaction of furans with 8-phenylmenthyl glyoxylate

Article abstract of DOI:10.1021/ol061943p

(Chemical Equation Presented) The Friedel-Crafts reaction of (1R)-8-phenylmenthyl glyoxylate with variously substituted furans was found to be efficiently promoted by SnCl₄ or magnesium salts with high diastereoselectivities. MgBr₂ performs especially well under simple, undemanding conditions, giving both high yields and high diastereoselectivities (>90%). The reaction afforded chiral substituted furan-2-yl-hydroxyacetic acid esters, compounds of potentially high synthetic interest.

Full text of DOI:10.1021/ol061943p

ORGANIC
LETTERS
2006
Vol. 8, No. 22
5045-5048
Highly Diastereoselective Friedel
Reaction of Furans with
−Crafts
8-Phenylmenthyl Glyoxylate
Piotr Kwiatkowski,† Jakub Majer,† Wojciech Chaładaj,† and Janusz Jurczak*,†,‡
Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland,
and Department of Chemistry, Warsaw UniVersity, 02-093 Warsaw, Poland
jurczak@icho.edu.pl
Received August 5, 2006
ABSTRACT
The Friedel−Crafts reaction of (1R)-8-phenylmenthyl glyoxylate with variously substituted furans was found to be efficiently promoted by
SnCl4 or magnesium salts with high diastereoselectivities. MgBr2 performs especially well under simple, undemanding conditions, giving both
high yields and high diastereoselectivities (>90%). The reaction afforded chiral substituted furan-2-yl-hydroxyacetic acid esters, compounds
of potentially high synthetic interest.
The optically active furanyl R-hydroxyacetic acid esters (I)
and products of their reductions, i.e., 1,2-diols of type II,
are of great synthetic importance (Scheme 1).1 The latter
alcohols, as a result of the presence of the furanyl moiety in
their structure, can be easily converted under oxidizing
conditions to very interesting linear (III)2 as well as cyclic
products (IV)3,4 (Scheme 1). Such an approach was utilized,
e.g., for the synthesis of multifunctional chain compounds2
or higher-carbon sugars.3 Diols bearing aryl substituents in
position 5 were applied in the synthesis of spiroketal moiety
of papulacandin D.4a They can be transformed also to amino
alcohol derivatives of type V,5 leading under oxidizing
conditions to dihydropyridones VI useful in the synthesis
of aza sugars.5,6
Scheme 1. Application of Furanyl R-Hydroxyacetic
Derivatives or Corresponding Diols in the Synthesis
The literature reports only a few methods for the synthesis
of optically pure 2-furylcarbinols of type I. The most efficient
methods rely on the enzymatic resolution of racemic mixtures
using a lipase7 or on kinetic resolution using the Sharpless
(2) Pikul, S.; Raczko, J.; Ankner, K.; Jurczak, J. J. Am. Chem. Soc. 1987,
109, 3981.
(3) Achmatowicz, O., Jr.; Burzynska, M. H. Carbohydr. Res. 1985, 141,
67.
(4) (a) Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863. (b) Harris,
J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem. 1999, 64, 2982.
(5) Liao, L.-X.; Wang, Z.-M.; Zhang, H-X.; Zhou, W.-S. Tetrahedron:
Asymmetry 1999, 10, 3649.
(6) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401.
(7) Zhang, W.; Wang, P. G. J. Org. Chem. 2000, 65, 4732.
† Polish Academy of Sciences.
‡ Warsaw University.
(1) (a) Jurczak, J.; Kobrzycka, E.; Raczko, J. Pol. J. Chem. 1999, 73,
29. (b) Raczko, J. Pol. J. Chem. 1999, 73, 77.
10.1021/ol061943p CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/06/2006

Scheme 2. Friedel-Crafts Reaction of Variously Substituted Furans with the Glyoxylate 1
reagent.8 The appropriate 1,2-diols of type II can be obtained
(Scheme 2). Glyoxylate 1 had been originally applied to the
nucleophilic additions of organometallic species (e.g., Grig-
nard reagents) and ene reaction by Whitesell.17,18 In the
literature, there are also examples of application of the
glyoxylate 1, e.g., in Diels-Alder,19 Morita-Baylis-Hill-
man,20 nitroaldol,21 allyl,22 and vinyl substitution reactions.23
Besides, it was also used by Bigi et al. in the Friedel-Crafts
reaction, but only with phenols13a,b and O-protected phenols13c
in the presence of TiCl4 or SnCl4, leading to 2- and
4-hydroxymandelic esters, respectively with high stereose-
lectivities. According to the literature, these Lewis acids are
also the most efficient in other types of reactions with
glyoxylate 1 (usually, 1 equiv is needed).18-23
In this paper, we describe a highly diastereoselective
Friedel-Crafts reaction of (1R)-8-phenylmenthyl glyoxylate
(1) with variously substituted furans 2a-n (Scheme 2, 14
examples). In our study, SnCl4 gave higher diastereoselec-
tivities (>98% de) compared to those of TiCl4. We have
studied extensively the reaction of 1 with benzyl furfuryl
ether (2a), which was originally used by Achmatowicz in
the total synthesis of racemic uloses.3 This reaction, in the
presence of a stoichiometric amount of SnCl4, proceeds to
give good yield and very high diastereoselectivity (Table 1,
entry 1). We have tested also several other furan systems in
this reaction, e.g., furan itself, and 2-methyl-, benzyl-, and
phenyl-substituted furans, and each time we have observed
also a very high diastereoselectivity (>99% de, Table 1,
entries 2-6). This procedure can be successfully applied even
to 2-trimethylsilylfuran (2j), unprotected furfuryl alcohol
(2k), and furans bearing an electron-withdrawing group (2l)
via Sharpless asymmetric dihydroxylation of 5-substituted
vinylfurans,4 and the simplest one of them, the unsubstituted
diol (R ) H) can be obtained from the sugar derivatives
(e.g., D-glucal).9
The most attractive methods appear to be direct ones
employing a synthesis from the corresponding furans and
aldehydes. Such an approach can be performed in two
ways: by addition of lithiated furans to the carbonyl group
or by the Lewis acid catalyzed Friedel-Crafts reaction. Until
now, there was no effective diastereoselective10 or enanti-
oselective11,12 synthetic method for furan derivatives of type
I based on the latter approach. However, there are known
examples of efficient diastereoselective13 and enantioselec-
tive11,14,15 Friedel-Crafts reactions of carbonyl compounds
with other aromatic derivatives.
Following our attempts to use chiral metallosalen com-
plexes,12 we decided on more detailed investigation of the
possibility of using chiral derivatives of glyoxylic acid. Until
now, menthyl glyoxylate has been tried for this reaction,10,12b
but as one could expect, it gave low asymmetric inductions.
Because of that, we used its 8-phenylmenthyl derivative 116
(8) Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. J. Org. Chem.
1989, 54, 2085.
(9) Sobhana Babu, B. S.; Balasubramanian, K. K. J. Org. Chem. 2000,
65, 4198.
(10) Jurczak, J.; Belniak, S.; Kozluk, T. Bull. Pol. Acad. Sci. 1991, 39,
271.
(11) (a) Gathergood, N.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem.
Soc. 2000, 122, 12517. (b) Zhuang, W.; Gathergood, N.; Hazell, R. G.;
Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009.
(12) (a) Kwiatkowski, P.; Wojaczynska, E.; Jurczak, J. Tetrahedron:
Asymmetry 2003, 14, 3643. (b) Kwiatkowski, P.; Wojaczynska, E.; Jurczak,
J. J. Mol. Catal. A: Chem. 2006, 257, 124.
(16) (a) Whitesell, J. K.; Liu, C.-L.; Buchanan, C. M.; Chen, H.-H.;
Minton, M. A. J. Org. Chem. 1986, 51, 551. (b) Ort, O. Org. Synth. 1987,
65, 203.
(17) Whitesell, J. K.; Bhattacharya, A.; Henke, K. J. Chem. Soc., Chem.
Commun. 1982, 988.
(18) (a) Whitesell, J. K.; Bhattacharya, A.; Aguilar, D. A.; Henke, K. J.
Chem. Soc., Chem. Commun. 1982, 989. (b) Whitesell, J. K.; Bhattacharya,
A.; Buchanan, C. M.; Chen, H. H.; Deyo, D.; James, D.; Liu, C.-L.; Minton,
M. A. Tetrahedron 1986, 42, 2993.
(19) (a) Mulzer, J.; Meyer, F.; Buschmann, J.; Luger, P. Tetrahedron
Lett. 1995, 36, 3503. (b) Kosior, M.; Asztemborska, M.; Jurczak, J. Synthesis
2004, 87.
(20) Bauer, T.; Tarasiuk, J. Tetrahedron: Asymmetry 2001, 12, 1741.
(21) (a) Solladie´-Cavallo, A.; Khiar, N. J. Org. Chem. 1990, 55, 4750.
(b) Kudyba, I.; Raczko, J.; Urbanczyk-Lipkowska, Z.; Jurczak, J. Tetra-
hedron 2004, 60, 4807. (c) Kudyba, I.; Raczko, J.; Urbanczyk-Lipkowska,
Z.; Jurczak, J. J. Org. Chem. 2004, 69, 2844.
(22) (a) Yamamoto, Y.; Maeda, N.; Maruyama, K. J. Chem. Soc., Chem.
Commun. 1983, 774. (b) Kiegiel, K.; Baakier, T.; Kwiatkowski, P.; Jurczak,
J. Tetrahedron: Asymmetry 2004, 15, 3869.
(13) Diastereoselective Friedel-Crafts reactions with chiral glyoxylates
and pyruvates: (a) Bigi, F.; Casnati, G.; Sartori, G.; Dalprato, C.; Bortolini,
R. Tetrahedron: Asymmetry 1990, 1, 861. (b) Bigi, F.; Bocelli, G.; Maggi,
R.; Sartori, G. J. Org. Chem. 1999, 64, 5004. (c) Bigi, F.; Sartori, G.; Maggi,
R.; Cantarelli, E.; Galaverna, G. Tetrahedron: Asymmetry 1993, 4, 2411.
(d) Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G.; Soncini, P.; Fava, G.
G.; Belicchi, M. F. Tetrahedron Lett. 1985, 26, 2021. (e) Casiraghi, G.;
Bigi, F.; Casnati, G.; Sartori, G.; Soncini, P.; Fava, G. G.; Belicchi, M. F.
J. Org. Chem. 1988, 53, 1779. (f) Bauer, T.; Gajewiak, J. Synthesis 2004,
20.
(14) For reviews on stereoselective Friedel-Crafts reactions, see: (a)
Bandini, M., Melloni, A., Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004,
43, 550. (b) Jørgensen, K. A. Synthesis 2003, 1117.
(15) Selected enantioselective Friedel-Crafts reactions of aldehydes: (a)
Ishii, A.; Kojima, J.; Mikami, K. Org. Lett. 1999, 1, 2013. (b) Ishii, A.;
Soloshonok, V. A.; Mikami, K. J. Org. Chem. 2000, 65, 1597. (c) Yuan,
Y.; Wang, X.; Li, X.; Ding, K. J. Org. Chem. 2004, 69, 146. (d) Corma,
A.; Garcia, H.; Moussaif, A.; Sabatem, M. J.;Zniber, R.; Redouane, A. Chem.
Commun. 2002, 1058. (e) Zhuang, W.; Poulsen, T. B.; Jørgensen, K. A.
Org. Biomol. Chem. 2005, 3284. (f) Zhu, C.; Yuan, C.; Lv, Y. Synlett 2006,
1221.
(23) Mikami, K.; Wakabayashi, H.; Nakai, T. J. Org. Chem. 1991, 56,
4337.
5046
Org. Lett., Vol. 8, No. 22, 2006

of that, we decided to try other easily available magnesium
salts. The best results were obtained for magnesium bromide,
which appeared to be much more active than MgCl2,
requiring only 2 h at room temperature to complete the
reaction (entry 3) with a slight increase of the asymmetric
induction. Magnesium bromide etherate can be also used
successfully (entry 4).
We have also investigated the effect of the presence of
water and the possibility of using catalytical amounts of
MgBr2. In the case of using anhydrous MgBr2, trace amounts
of byproducts are observed. Addition of water in an amount
of ca. 0.5-0.7 equiv with respect to the magnesium salt had
practically no influence on the asymmetric induction nor the
yield (entry 5), but it did help to eliminate byproducts.24 In
order to obtain such hydrated magnesium bromide, it is
enough to keep anhydrous MgBr2 or its etherate in an open
flask for ca. 12 h.25 The presence of water in an amount
slightly exceeding 1 equiv slows down the reaction rate
substantially, but the selectivity is still high (entry 6). In the
case of using MgBr2‚6H2O, the reaction practically does not
occur.
In conclusion, MgBr2 containing less than 1 equiv of water
is an efficient promoter of this reaction. The reaction in the
presence of MgBr2 is not reversible,26 and the diastereomeric
ratio is practically constant during the reaction.27 Unfortu-
nately, in order to obtain high diastereomeric excess, one
has to use stoichiometric amounts of the magnesium salts,
probably because of the strong affinity of magnesium to the
product. In the case of using catalytical amounts of MgBr2,
a substantial drop in the selectivity as well as low reaction
yield are observed (entry 7)
The results of the model reaction using a stoichiometric
amount of MgBr2, although inferior to the diastereoselec-
tivities using SnCl4, demonstrate that this reaction can be
easily conducted at room temperature without a need for
using dry solvents and reagents with very high yield.
Prompted by very good results in the reaction of 8-phenyl-
menthyl glyoxylate (1) with benzyl furfuryl ether (2a) in the
presence of the magnesium salts, we decided to investigate
the possibility of using other furans for the reaction in the
presence of conditioned MgBr2, containing ca. 0.5 equiv of
water (Table 3). Because of the very attractive properties of
MgCl2,28 we also studied systematically the possibility of
using it in the reactions in question.
Table 1. Friedel-Crafts Reaction of Furans with 1 Promoted
by SnCl4
a
product
entry
furan
time (h)
no.
yield (%)b
de (%)c
1
2
3
4
5
6
7
8
9
2a
2b
2c
2g
2h
2i
2j
2k
2l
5
2
2
2
2
4
2
2
5
3a
3b
3c
3g
3h
3i
3j
3k
3l
87
56
41
79
50
87
45
60
63
>99
>99 (S)
>99 (S)
>99
>99
>99
>99
>99
98
a The reactions were carried out using 0.5 mmol of the glyoxylate 1 in
3.0 mL of CH2Cl2, 1 equiv of SnCl4, and 1.5 equiv of furan at -78 °C.
b Isolated yield. c Diastereomeric excess determined by HPLC and 1H NMR.
(entries 7-9). However, the yields were substantially lower
(about 50%) in many cases, probably because of partial
decomposition of the furan derivatives.
Therefore, we decided to search for milder Lewis acids
that would allow these reactions to be conducted efficiently
and highly stereoselectively, catalysts that would be less toxic
than SnCl4, require less demanding conditions, and avoid
the necessity of using dry solvents. We focused our attention,
inter alia, on zinc and magnesium salts. Zinc bromide was
used by our research group in the reactions with chiral
derivatives of glyoxylic acids, often giving high stereose-
lectivities, e.g., in the allylation reaction.22b As a model furan
substrate, benzyl furfuryl ether (2a) was used, but the reaction
using zinc bromide gave a moderate diastereomeric excess
(∼65% de, Table 2, entry 1). Replacing 2a with silvan (2c)
Table 2. Screening of Lewis Acids in the Reaction of 1 with
2aa
entry
Lewis acid
ZnBr2
MgCl2
MgBr2, anhydrous
MgBr2‚Et2O
MgBr2‚0.5H2O
MgBr2‚1.5H2O
MgBr2 (20 mol %)
time (h)
yield (%)b
de (%)c
1
2
3
4
5
6
7
4
24
2
5
5
60
61
96
93
97
58
39
65
85
89
86
90
91
65
Alkyl derivatives of furan are more reactive than benzyl
furfuryl ether (2a). Because of that, MgCl2 catalyzes these
reactions, giving very good yields (usually >90% after 24
h). However, in many instances, the obtained inductions do
not exceed 90%, usually being about 85%, as in the case of
the furans 2a (Table 2, entry 2) as well as 2c (Table 3, entry
3). The rare exceptions are the furans substituted with benzyl
24
72
a The reactions were carried out using 0.5 mmol of 1 in 2.5 mL of
CH2Cl2, 1 equiv of Lewis acid (entries 1-6), and 1.5 equiv of 2a at 20 °C.
1
b Isolated yield. c Determined by HPLC and H NMR.
gave somewhat better results (80% de). These results were
utterly unsatisfactory because most of the products of these
reactions were oils.
We found magnesium chloride to be a stereochemically
more effective (85% de) Lewis acid catalyst for the reaction
of 2a with 1 (Table 2, entry 2). However, the yield was rather
moderate, and the reaction required prolonged time. Because
(24) The TLC chromatogram of the reaction mixture is very neat.
(25) The weight of anhydrous MgBr2 was steadily rising.
(26) MgBr2 (1 equiv) added to a mixture of product 3a (65% de) causes
no change in diastereomeric ratio after 24 h.
(27) Diastereomeric excess of 3a in the reaction promoted by 1 equiv
of MgBr2 was practically constant after 5, 10, 15, 30 min, 1 h and 3 h.
(28) Despite low activity, from the application viewpoint MgCl2 seems
to be an ideal promoter-Lewis acid, because of minimum toxicity, low cost,
and ease of handling.
Org. Lett., Vol. 8, No. 22, 2006
5047

Table 3. Application of Various Furans (2a-n) in the
Magnesium-Promoted Reaction with 1: Scope and Limitationa
Figure 1. X-ray crystal structure of compound (S)-3n
lographic analysis (Figure 1). In all the cases, a product of
(S)-configuration was obtained from (1R,2S,5R)-8-phenyl-
menthyl glyoxylate (1). Such a direction of induction is in
accordance with the literature data concerning other additions
and cycloadditions to 1.17-23 One can assume with a high
likelihood that the induction direction is identical for all of
the investigated reactions of furans with aldehyde 1 in the
presence of SnCl4 or MgBr2.
In conclusion, we have developed a general, efficient, and
undemanding method for the diastereoselective synthesis of
chiral variously 5-substituted furan-2-yl-hydroxyacetic acid
esters, compounds of significant synthetic interest, with high
optical purity (de usually over 90% up to >99%). Although
SnCl4 allows for obtaining very high diastereoselectivities,
the magnesium salts seem to be more attractive since they
give better yields. The reaction is clearly and reproducible
promoted by inexpensive and low-toxicity MgBr2 and MgCl2
at room temperature without the need of using dry solvents
and inert atmosphere. According to our knowledge, this is
the first example of a highly stereoselective reaction of furans
with glyoxylates.
a The reactions were carried out using 0.5 mmol of 1 in 2.5 mL of
CH2Cl2, 1 equiv of magnesium salt, and 1.5 equiv of furan at 20 °C.
1
b Isolated yield. c Determined by HPLC and H NMR. d The reaction was
carried out at -5 °C.
(2g), phenyl (2i), and trimethylsilyl (2j), where the asym-
metric inductions in the presence of MgCl2 exceed 90% de
(Table 3, entries 9, 12, and 14, respectively). In the other
cases, much better results are obtained using the more active
MgBr2. Actually, all alkyl derivatives of furan 2c-h and
2n, and even phenylfuran (2i) and trimethylsilylfuran (2j),
in the presence of MgBr2, make it possible obtain the
products having very high diastereomeric excesses (94-
99%). Although the stereoselectivities obtained for MgBr2
are slightly lower compared to those with SnCl4, the reaction
gives clearly better yields (>90% in not more than 3 h) and
is much easier to carry out.
As shown in Table 3, the synthesis is highly selective
(usually >90% de). The differences are very small for the
furans substituted at the 2-position with alkyls of various
spatial requirements (2c-h), aryl (2i), trimethylsilyl (2j), and
even 2,3-disubstituted furans (2n). Lower selectivities (∼80%
de) are obtained only for furans 2k-m.
Acknowledgment. Financial support from the Ministry
of Science and Higher Education (Grant PBZ-KBN-126/T09/
06) and from the Foundation for Polish Science (individually
for P.K.) are gratefully acknowledged. The X-ray measure-
ments were undertaken at the Crystallographic Unit of the
Physical Chemistry Lab at the Chemistry Department of the
University of Warsaw.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds (3a-n)
with reprints of NMR spectra and X-ray information for (S)-
3n in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
Out of the 14 novel products, two compounds (3b, 3c)
have been subjected to determination of the absolute con-
figuration by chemical correlations,9,12b and the configuration
of 3n has been directly determined using X-ray crystal-
OL061943P
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Org. Lett., Vol. 8, No. 22, 2006