Tetrahedron Letters
¯
Synthesis of leptosin, a glycoside isolated from manuka honey
Harry R. M. Aitken a, Manuel Johannes a, Kerry M. Loomes b, Margaret A. Brimble a,b,
⇑
a School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand
b School of Biological Sciences and Institute for Innovation in Biotechnology, The University of Auckland, Private Bag 92019, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The first synthesis of leptosin, a novel glycoside isolated from manuka honey is described. Utilising an
¯
Received 6 August 2013
Revised 27 September 2013
Accepted 9 October 2013
Available online 17 October 2013
acetyl protecting group strategy the glycoside was obtained with excellent anomeric selectivity by
deploying a Schmidt glycosylation as a key step.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Leptosin
Manuka honey
¯
Glycosylation
Disaccharide
Methyl syringate
For thousands of years honey has been used to treat a disparate
range of ailments.1 In the past decade, however, the medical use of
honey has undergone somewhat of a renaissance.2 In particular,
OH
O
HO
HO
O
OMe
O
HO
HO
O
manuka honey (Leptospermum scoparium or Leptospermum polyga-
¯
HO
lifolium) shows strong antibacterial properties, which had led to a
HO
MeO
OMe
growing demand for honey-impregnated wound care products
O
and other medicinal products.3 Unlike other honeys, manuka hon-
¯
leptosin, 1
Figure 1. Methyl syringate 4-O-b-
ey contains methyl glyoxal, which has been identified as one of the
major contributors to its biological activity.4
D
-gentiobiose (leptosin 1).
Furthermore, other unique compounds, such as certain phenols
may also play a role in its biological profile.5 These phenolic com-
pounds may in part be responsible for the anti-inflammatory bio-
activity, aiding the wound-healing process.6 As a result, these
compounds are becoming increasingly recognised for their poten-
tial role in treating microbial infections and reducing inflamma-
tion,5c,7 although their exact mode of action is poorly understood.4
of different honeys, they found that leptosin (1) is only present
in manuka honey,9 suggesting that it may be a suitable chemical
¯
marker for manuka honey ‘fingerprinting’. We therefore focused
¯
on the synthesis of leptosin (1) to ensure ready access to this com-
pound as an internal standard for honey analysis as the isolation of
the natural material is low yielding and inefficient9 (Fig. 1).
In our initial strategy we decided to synthesise leptosin (1) via
Koenigs–Knorr glycosylation of phenol 3 with gentiobiosyl bro-
mide (4), followed by a Zemplén deacetylation (Scheme 1). In turn
it was anticipated that Koenigs–Knorr glycosylation of bromide 5
and primary alcohol 6, both derived from glucose, would provide
gentiobiosyl bromide (4). Although gentiobiose is commercially
available, it is expensive for use in synthesis (NZ$647 per gram
from Sigma Aldrich).
The increase in demand for medical manuka honey has driven
¯
prices up and at present there are few quality assurances for those
producing and distributing honey. Consequently, the industry has
become a target for fraudulent marketing and counterfeiting. As
such, there is significant interest in the development of a set of
chemical markers specific to manuka honey, which can be used
¯
to determine the identity and purity via HPLC or mass spectrome-
try analysis.8
Recently, Kato and co-workers reported the isolation of leptosin
(1), consisting of methyl syringate and the disaccharide gentiobi-
ose connected via a b-glycosidic linkage.9 After testing a variety
Starting from D-glucose (7), the glycosyl bromide 5 was pre-
pared in a one-pot procedure using acetic anhydride and perchloric
acid in glacial acetic acid followed by the addition of acetyl bro-
mide and methanol (Scheme 2). The desired 2,3,4,6-tetra-O-ace-
tylglucosyl bromide 5 was isolated in excellent yield.10 Glycosyl
⇑
Corresponding author. Tel.: +64 9 9238259; fax: +64 9 3737422.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.