Angewandte
Chemie
DOI: 10.1002/anie.200805724
Carbohydrates
Stereodivergent De Novo Synthesis of Branched Amino Sugars by
Lewis Acid Promoted Rearrangement of 1,2-Oxazines**
Fabian Pfrengle, Dieter Lentz, and Hans-Ulrich Reißig*
Amino sugars and C-branched sugars are components of a
variety of antibiotics and other biologically active natural
products.[1] Hence there is a considerable interest in natural
product analogues having modified carbohydrate residues;[2]
for example, analogues of vancomycin having different amino
sugar derivatives, which show a high antibacterial activity
against resistant strains.[3] Artificial C2-branched sugars were
also used in metabolic oligosaccharide engineering[4] or as
inhibitors in Lipid A biosynthesis.[5] Furthermore they are
ideal building blocks for the synthesis of C-glycosides.[6]
Carbon chains in the 2-position were mainly introduced by
addition reactions to glycals[7] or rearrangements of C-glyco-
sides.[8] Herein we describe an efficient and stereodivergent
de novo synthesis of C2-branched amino sugars based on our
investigations towards Lewis acid promoted rearrangements
of 1,2-oxazines into bicyclic products (Scheme 1). These
studies led to new carbohydrate mimetics having either
tetrahydropyran or oxepane skeletons.[9]
We discovered that appropriately modified 1,2-oxazine
derivatives not only allow an entry into mimetics but also into
“real” carbohydrates bearing an anomeric carbon center
(Scheme 2). The amino sugar derivatives 1 are generated by
Scheme 2. Retrosynthesis of 4-amino sugar derivatives 1.
ꢀ
reduction of the keto group and cleavage of the N O bond in
bicyclic compounds 2, which are obtained by Lewis acid
promoted rearrangement of 1,2-oxazines 3. For the introduc-
tion of the desired anomeric center, an appropriate hetero-
atom has to be connected to C2 of the dioxolane ring of 1,2-
oxazines 3 (a in Scheme 2). We chose the phenylthio group,
which provided adequate electronic properties for the
rearrangement and also served as a leaving group in
subsequent glycosidation reactions. This strategy allows
control of four stereogenic centers (c, d/f, e), which are
constructed during this sequence.
The stereodivergent synthesis of the substrates 3 began
with 1,2-oxazines syn-4 and anti-4, which can be obtained in
enantiopure form by the [3+3] cyclization of lithiated
alkoxyallenes
with
aldonitrones
on
gram
scale
(Scheme 3).[10] To generate free diols syn-5 and anti-5 a new
mild method (InCl3/H2O in MeCN) was developed for the
hydrolysis of acetonides, which avoided the formation of acid
induced cyclization products.[11] The phenylthio-substituted
1,2-oxazines syn-3 and anti-3 were finally obtained via
orthoesters[12] and subsequent substitution of the methoxy
group by a phenylthio moiety.[13]
Scheme 1. Enantiopure carbohydrate mimetics by using Lewis acid
promoted rearrangements of 1,2-oxazines. TMSE=2-(trimethylsilyl)-
ethyl.
Treatment of syn-3 and anti-3 with trialkylsilyl triflates
furnished the desired bicyclic ketones (Scheme 4). Compound
[*] Dipl.-Chem. F. Pfrengle, Prof. Dr. D. Lentz,[+] Prof. Dr. H.-U. Reißig
Institut fꢀr Chemie und Biochemie, Freie Universitꢁt Berlin
Takustrasse 3, 14195 Berlin (Germany)
Fax: (+49)30-8385-5367
E-mail: hans.reissig@chemie.fu-berlin.de
[+] X-ray crystallographic analysis
[**] Support by the Fonds der Chemischen Industrie (PhD fellowship for
F. Pfrengle), the Deutsche Forschungsgemeinschaft (SFB 765), and
Bayer Schering Pharma AG is most gratefully acknowledged. We
thank D. Nikolic for experimental assistance.
Scheme 3. Synthesis of 1,2-oxazines syn-3 and anti-3. Reagents and
conditions: a) InCl3, H2O, CH2Cl2 (syn-5: 84%; anti-5: 70%);
b) HC(OMe)3, CAN, CH2Cl2, RT, 1 h; c) PhSSiMe3, TMSOTf, CH2Cl2,
RT, 3 h (syn-3: 89%; anti-3: 66%, 2 steps). TMSOTf=trimethylsilyl
trifluoromethanesulfonate; CAN=cerium ammonium nitrate.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2009, 48, 3165 –3169
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3165