An efficient and cost-effective preparation of di-O-acetyl-d-rhamnal

Article abstract of DOI:10.1016/j.tetlet.2013.04.035

We have developed a synthetic route to the frequently utilized deoxysugar building block di-O-acetyl-d-rhamnal originating from the inexpensive starting material methyl α-d-glucopyranoside. Our approach proceeds in five steps with minimal column chromatography purification needed to afford the title compound in good overall yield.

Full text of DOI:10.1016/j.tetlet.2013.04.035

Tetrahedron Letters 54 (2013) 3185–3187
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Tetrahedron Letters
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An efficient and cost-effective preparation of di-O-acetyl-D-rhamnal
⇑
Justin N. Miller, Rongson Pongdee
Department of Chemistry, Sewanee: The University of the South, 735 University Avenue, Sewanee, TN 37383-1000, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a synthetic route to the frequently utilized deoxysugar building block di-O-acetyl-D-
Received 13 March 2013
Revised 5 April 2013
Accepted 9 April 2013
Available online 16 April 2013
rhamnal originating from the inexpensive starting material methyl
proceeds in five steps with minimal column chromatography purification needed to afford the title com-
pound in good overall yield.
a-D-glucopyranoside. Our approach
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Carbohydrates
Deoxysugars
Glycosides
Natural products
Many biologically-active secondary metabolites are adorned
with carbohydrate residues that have been demonstrated to be
crucial in modulating the biological efficacy of the parent glycocon-
jugate.1,2 As a result, numerous researchers have initiated programs
aimed at investigating the effects of altering the oligosaccharide
domain of various natural product families such as the aminocoum-
arin, aureolic acid, and glycopeptide antibiotics, to mention only a
few, in attempts to discover architecturally-novel compounds with
enhanced biological profiles.3–7 A common structural motif found
within members of these secondary metabolites are 2-deoxy and
2,6-dideoxysugars.
glucal.12 While these approaches have become the standard means
to access 1 and its subsequent derivatives, the continuing rise in
cost of tri-O-acetyl-D-glucal has begun to make these approaches
cost-prohibitive for many researchers. Surprisingly, few synthetic
approaches to this critical carbohydrate building block, di-O-
acetyl-D-rhamnal (1), have been reported in the chemical literature
over the past thirty years considering its near universal role as
a synthetic intermediate to access suitably derivatized D-configured
2-deoxy and 2,6-dideoxysugars.13 Moreover, an efficient and
inexpensive route to 1 would add another readily accessible chiron
to the pool of asymmetric building blocks for use in various syn-
thetic applications.
A common entry point for the synthesis of various
2-deoxy and 2,6-dideoxysugars is di-O-acetyl- -rhamnal (1) illus-
trated in Figure 1. While the corresponding enantiomer for 1 is
readily available from -rhamnose, at a much lower cost, the
D-configured
D
During the course of our group’s work aimed at investigating
various aspects related to the angucycline antitumor antibiotics,
L
we required access to significant quantities of di-O-acetyl-
rhamnal (1). Previously, we had employed either Torri’s or Tius’
approach to access either 1 or its deacetylated derivative -rham-
nal, respectively, depending on our specific needs.9,10 However,
both of these routes required the use of tri-O-acetyl- -glucal as
D-
preparation of 1 requires substantially more time and effort to
access.8–11 Moreover, the most commonly employed synthetic
routes directed towards the production of 1 originate from the
D
commercially-available, albeit highly expensive, tri-O-acetyl-
D
-
D
Figure 1. Structure of di-O-acetyl-D-rhamnal.
⇑
Corresponding author. Tel.: +1 931 598 1846; fax: +1 931 598 1145.
E-mail address: rpongdee@sewanee.edu (R. Pongdee).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.035

3186
J. N. Miller, R. Pongdee / Tetrahedron Letters 54 (2013) 3185–3187
the corresponding anomeric bromide which immediately under-
went a Fischer–Zach reaction employing zinc metal (Zn) in a
sodium dihydrogen phosphate (NaH2PO4) buffer, following the
recently disclosed work of Shao, to afford di-O-acetyl-
D-rhamnal
(1) in good overall yield.18
In summary, we have developed
inexpensive route towards the ubiquitous deoxysugar building
block, and chiron, di-O-acetyl- -rhamnal (1). Our synthetic scheme
a simple, efficient, and
D
progresses in five steps (thirty-five percent overall yield) and
requires only a single column chromatography purification step
after reductive removal of the C(6)-I group. We anticipate that
our approach will help facilitate research programs requiring the
synthesis of various D-configured 2-deoxy- and 2,6-dideoxysugars
in both academic and industrial research laboratories.
Acknowledgments
Scheme 1. Reaction Conditions (a) l2, lmH, Ph3P, Ph-Me; (b) Ac2O, Pyr, DMAP (90%
over two-steps); (c) Ac2O, H2SO4 (88%); (d) n-Bu3SnH, Et3B, air, Ph-Me, À78 °C
(78%); (e) PBr3, CH2Cl2 then Zn, NaH2PO4, EtOAc (55%)
We gratefully acknowledge financial support from Sewanee:
The University of the South and the National Institute of Allergy
and Infectious Diseases(R15, AI084075-02). Additionally, we thank
the National Science Foundation, as part of its Major Research
Instrumentation (MRI) Program (CHE-1126231), for the acquisition
of a JEOL ECS-400 Nuclear Magnetic Resonance Spectrometer.
Accurate mass measurements were performed by Dr. William
Boggess of the Mass Spectrometry and Proteomics Facility at the
University of Notre Dame.
the starting material, which proved to be too expensive for us to
continue employing, considering the quantity of material we
required. Additionally, we explored the use of Nicolaou’s apparent
two-step route towards
pursuit of the complex deoxysugar
D
-rhamnal as described in his group’s
D
-callipeltose.11 Unfortunately,
our efforts to utilize Nicolaou’s scheme proved capricious and
resulted in dramatically lower yields upon attempting larger scale
reactions.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
04.035.
More recently, Osman described the preparation of a protected
D
-rhamnal derivative beginning from methyl a-D-galactopyrano-
side.13f However, his route was lengthy and required multiple pro-
tection/deprotection steps. As such, we deemed Osman’s synthetic
approach too laborious and inefficient to pursue for our purposes.
As a result, we elected to develop a simple, expedient, and cost-
References and notes
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Our synthetic approach towards di-O-acetyl-D-rhamnal (1)
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a-D
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a-D-glucopyranoside (2) to di-O-acetyl-
D-rhamnal (1). In turn, we concluded that it would be critical to
remove the C(6)-I functional group prior to glycal formation to
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tribromide (PBr3) in cold methylene chloride (CH2Cl2) to yield

J. N. Miller, R. Pongdee / Tetrahedron Letters 54 (2013) 3185–3187
3187
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(Sigma–Aldrich, catalog #: M9376-1KG) compared to $ 4.70 per gram for tri-O-
acetyl- -glucal.
a-D-glucopyranoside is approximately $ 0.15 per gram
D
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