glucoBox - A new carbohydrate-based bis(oxazoline) ligand. Synthesis and first application

Article abstract of DOI:10.1039/b612986b

The synthesis of a new bis(oxazoline) ligand from d-glucosamine and its application in enantioselective copper(i) catalysed cyclopropanations of olefins is described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b612986b

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COMMUNICATION
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glucoBox—a new carbohydrate-based bis(oxazoline) ligand. Synthesis
and first application{
Mustafa Irmak, Annika Groschner and Mike M. K. Boysen*
Received (in Cambridge, UK) 7th September 2006, Accepted 29th September 2006
First published as an Advance Article on the web 23rd October 2006
DOI: 10.1039/b612986b
was first treated with trimethylsilylchloride (TMSCl) and hexa-
methyl disilazane (HMDS) in pyridine7a to exclusively yield per-
O-silyl protected derivative 2 as a crystalline solid. Under these
conditions the amino function remains unprotected.7b Reaction of
2 with dimethylmalonyl dichloride in the presence of triethyl amine
as base, conditions originally employed for preparation of
bis(amides) from cyclohexyl amine derivatives,8 yielded bis(amide)
3. After O-silyl deprotection with trifluoroacetic acid in methanol,
the unprotected bis(amide) 4 was obtained and directly used for
further transformations (Scheme 1).
The synthesis of a new bis(oxazoline) ligand from D-glucosa-
mine and its application in enantioselective copper(I) catalysed
cyclopropanations of olefins is described.
Over the last two decades bis(oxazolines) have emerged as one of
the most versatile ligand classes for metal catalysed asymmetric
transformations.1 They are prepared from chiral b-amino alcohols
and dicarboxylic acid derivatives by condensation1c and are
applied in several important and synthetically valuable enantiose-
lective reactions. Among them the cyclopropanation of olefins
with diazoesters first reported independently by Pfaltz et al.,2a
Masamune and co-workers2b,2c and Evans et al.2d is a prominent
example and also a kind of ‘‘sharpening stone’’ for new ligand
structures.
Even though D-glucosamine, an inexpensive amino sugar from
the chiral pool, contains a b-amino alcohol substructure and its
N-acylated derivatives form oxazolines quite easily, this carbohy-
drate has rarely been employed for the synthesis of chiral oxazoline
ligands. To date only a handful of examples of such structures
have appeared. The groups of Kunz and Gla¨ser3, Uemura and co-
workers4 as well as Die´guez and colleagues5 reported on bidentate
phosphorus-containing mono(oxazolines) based on glucosamine
and their application in palladium catalysed reactions. The only
contribution so far concerning carbohydrate bis(oxazolines) was
published by Hartinger et al.6 in 2005 describing two ferrocene-
bridged structures also derived from glucosamine. The publication
included MS studies of palladium complexes of these ligands but
no data on application have been reported so far.
In this communication we disclose a facile synthesis of a new
carbohydrate bis(oxazoline) ligand with a dimethylmethylene
bridge (glucoBox) from glucosamine hydrochloride. Further, the
first results obtained for its application in the copper(I) catalysed
cyclopropanation of olefins with ethyl diazoacetates are presented.
For ligand synthesis we selected a route via the bis(amide) of
glucosamine with dimethylmalonyl dichloride and subsequent
cyclisation to yield the bis(oxazoline). All attempts to form the
bis(amide) directly from unprotected glucosamine and malonyl
dichloride under mildly basic conditions (sodium methoxide in
methanol, triethylamine in DMF) only led to decomposition of the
acid chloride component. Therefore glucosamine hydrochloride (1)
Institute of Organic Chemistry, Leibniz University of Hannover,
Schneiderberg 1B, D-30167 Hannover, Germany.
E-mail: mike.boysen@oci.uni-hannover.de; Fax: +49 511 762 3011;
Tel: +49 511 762 4643
{ Electronic supplementary information (ESI) available: Experimental
details and spectra for the new glucoBox ligand, spectroscopic and other
analytical details of cyclopropanation products. See DOI: 10.1039/
b612986b
Scheme 1 Preparation of glucoBox ligand 6. Conditions: (a) TMSCl,
HMDS, pyridine, rt; (b) Et3N, DCM, 0 uC to rt; (c) MeOH–TFA 9 : 1, rt;
(d) AcCl, rt; (e) NaHCO3, NEt4Cl, MeCN, rt.
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Scheme 2 Asymmetric cyclopropanations performed with copper(I)-
glucoBox. Absolute configurations of the products were assigned by
optical rotation and comparison with literature values (cf. electronic
supplementary information{).
Most syntheses of carbohydrate oxazolines from N-acyl
glucosamines use 1-O-acylated compounds as starting materials
that are cyclised under Brønsted acid or Lewis acid catalysis. We
therefore attempted to activate the anomeric position of
peracetylated or perbenzoylated derivatives of 4 with different
Lewis acids such trimethylsilyl triflate,9a,9b stannic chloride9c or
ferric chloride.9d We also treated the acylated derivatives with
hydrogen bromide9e,9f to subsequently activate the resulting
anomeric bromide with tetraalkyl ammonium bromide via in situ
anomerisation.9g However, all these methods were not successful
with our acylated precursors, leading either to incomplete
transformation or extensive decomposition of the starting material.
Therefore we were extremely pleased to find that the desired
bis(oxazoline) 6 could be obtained directly from unprotected
bis(amide) 4 by simple stirring in acetyl chloride and subsequently
treating the resulting bis(glucosyl chloride) 5 with sodium
hydrogen carbonate and triethylammonium chloride in a one-
pot reaction. These conditions were originally described for
oxazoline synthesis from N-acetyl glucosamine.10 Thus glucoBox
ligand 6{ was prepared from 1 in four steps in an excellent overall
yield of 81% (Scheme 1).
Fig. 1 Comparison of glucoBox ligand 6 to known bis(oxazolines).2d All
values given refer to the cyclopropanation of styrene (8a) with ethyl
diazoacetate (7), configurations for the major trans products are given.
These results are very promising, as the carbohydrate scaffold of 6
offers many opportunities for structural modifications. By
optimising the ligand structure through modification, it should
be possible to further increase the optical yields and thus to obtain
tailor-made ligands for the cyclopropanation reaction.
Fig. 1 shows a comparison of the results achieved in the
cyclopropanation of styrene (8a) with ethyl diazoacetate (7) with
new ligand 6 to those reported for known bis(oxazolines)2d derived
from biogenic amino acid (S)-valine (10) and non-biogenic (R)-
tert-leucine (11). The absolute stereochemistry of the major trans
products is displayed as well. While all three ligands lead to
essentially the same trans : cis ratios, the enantomeric excesses
differ substantially. While glucoBox 6 is inferior to tert-butyl
substituted ligand 11, it gives substantially better results than valine
derived ligand 10. This can be explained by the steric demand of
the substituent at the stereocenter adjacent to the coordinating
nitrogen atom: exchanging the isopropyl residue of 10 for a bulkier
tert-butyl group in 11 results in increased enantioselectivity. The
steric demand of the ‘‘substituent’’ in ligand 6 (the sugar moiety)
appears to be somewhere between that of the isopropyl and the
tert-butyl group, as is reflected by the results obtained for the
cyclopropanations.
With glucoBox ligand 6 in hand we began our evaluation studies
regarding its efficiency in metal catalysed asymmetric transforma-
tions. As a first model reaction we chose the enantioselective
copper(I)catalysedcyclopropanationofalkeneswithdiazoacetates.
Styrene (8a), para-methoxy styrene (8b) and 1,1-diphenyl ethene
(8c) as alkene components were reacted with ethyl diazoacetate in
the presence of the preformed complex of ligand 6 with copper(I)
triflate (Scheme 2).§ The results are summarised in Table 1.
The cyclopropanation of all alkenes proceeded in good yields
with trans : cis ratios for 9a and 9b comparable to those reported in
the literature.2 We were pleased to find that enantiomeric excesses
for all trans as well as for all cis products are well above 70%.
It is important to note that ligand 6 is prepared in a few simple
steps from inexpensive glucosamine whereas ligand 11 requires the
rather costly tert-leucine as a starting material. Thus, by improving
the efficiency of ligand 6 by modification, it might be possible to
obtain a low-price alternative to 11.
Table 1 Asymmetric cyclopropanation of alkenes with ethyl diazoa-
cetate (7) catalysed by copper(I) triflate with glucoBox ligand 6
We thank Edison D´ıaz Go´mez for assistance with the
determination of optical yields via the dirhodium method.
Financial support of this work by the VW Stiftung and the
Fonds der Chemischen Industrie is gratefully acknowledged.
Yielda
Entry Alkene Product (%)
ee trans ee cis
(%)
trans : cis (%)
1
2
3
a
8a
8b
8c
9a
9b
9c
60
72
85
70 : 30b
65 : 35b
—
82c
77d
75d
82c
80c
b
Based on 7, isolated yields after chromatography. Determined
Notes and references
c
d
after separation of the isomers. Determined by GC. Determined
by 1H NMR with Rh2[R-(+)-MTPA]4 as chiral complexing reagent
(dirhodium method).11
25
{ Spectroscopic data for glucoBox ligand 6: [a]D + 53 (c 1.9 in
chloroform); dH (400 MHz; CDCl3) 1.58 (6H, s, (CH3)2C), 1.98, 2.05,
2.16, (each 6H, each s, CH3CO), 3.86 (2H, ddd, J4,5 9.2, J5,6 4.8, H-5), 4.13
178 | Chem. Commun., 2007, 177–179
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(2H, dd, J5,69 2.7, J6,69 12.3, H-69), 4.18 (2H, ddd, J1,2 7.5, J2,3 2.4, J2,4 1.3,
H-2), 4.22 (2H, dd, J5,6 4.8, J6,69 12.3, H-6), 4.94 (2H, ddd, J3,4 2.4, J2,4 1.3,
J4,5 9.2, H-4), 5.31 (2H, dd # t, J2,3 J3,4 2.4, H-3), 6.05 (2H, d, J1,2 7.5,
H-1); dC (100 MHz, CDCl3) 20.7, 20.8, 20.9 (each 2 6 t, CH3CO), 23.8 (2
6 t, (CH3)2C), 39.2 (q, (CH3)2C), 62.8 (2 6 s, C-6), 64.8 (2 6 t, C-2), 67.8
(2 6 t, C-5), 68.3, (2 6 t, C-4), 70.1, (2 6 t, C-3), 100.0 (2 6 t, C-1), 170.6,
170.2, 169.5, 169.2 (each 2 6 q, CH3CO, CN).; HRMS (ESI)
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C29H39O16N2 [M
+
H]+ calcd. 671.2300, found 671.2298,
C29H38O16N2Na [M + Na]+ calcd. 693.2119, found 693.2036.
§ General conditions for cyclopropanation: in a dry box CuOTf?0.5C6H6
(1.8 mg, 7.2 mmol, 1 mol%) and glucoBox ligand 6 (5.2 mg, 8 mmol,
1.1 mol%) were placed into a flame-dried flask. Under nitrogen
dichloromethane (2 cm3) was added and the resulting mixture was stirred
for 2 h at room temperature. To this preformed catalyst solution the alkene
component (5 mmol) was added. The mixture was cooled to 0 uC and ethyl
diazoacetate (0.7 mmol) dissolved in dichloromethane (1 cm3) was slowly
added over a period of 2.5 h with a syringe pump at the same temperature.
The mixture was allowed to warm to room temperature and was stirred for
another 16 h. The solvent was removed under reduced pressure and the
residue purified by flash chromatography on silica gel.
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