Synthesis of Bradyrhizose from d -Glucose

Article abstract of DOI:10.1021/acs.orglett.9b04279

We describe the synthesis of the unusual bicyclic sugar bradyrhizose in 14 steps and a 6% overall yield from d-glucose. The synthesis involves the elaboration of a trans-fused carbocyclic ring onto the preexisting glucopyranose framework followed by adjus

Full text of DOI:10.1021/acs.orglett.9b04279

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Bradyrhizose from D‑Glucose
Philemon Ngoje†,‡ and David Crich*,†,‡,§,∥
†Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 250 West Green Street, Athens, Georgia 30602,
United States
‡Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
§Department of Chemistry, University of Georgia, 140 Cedar Street, Athens, Georgia 30602, United States
∥Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, Georgia 30602, United States
S
* Supporting Information
ABSTRACT: We describe the synthesis of the unusual
bicyclic sugar bradyrhizose in 14 steps and a 6% overall
yield from D-glucose. The synthesis involves the elaboration of
a trans-fused carbocyclic ring onto the preexisting glucopyr-
anose framework followed by adjustment of the oxidation
levels. Key steps include radical extension of the glucopyr-
anose side chain, ring closing metathesis, allylic oxidation, Luche reduction, hydroxy-directed epoxidation, and acid-catalyzed
epoxide opening at the more substituted position.
Scheme 2. Key Steps of the Lowary Synthesis from myo-
Inositol
radyrhizose, a rare bicyclic sugar, is an important
component of the lipopolysaccharide O-antigen side
B
chain of Bradyrhizobium species (BTAil and ORS278 strains).
As a molecular signal, it is thought to be involved in facilitating
the fixation of nitrogen in tropical leguminous Aeschynomenes
species especially Aeschynomene indica and Aeschynomene
sensitiva through a symbiotic process.1−5 Isolation and
characterization of this sugar revealed that the monomeric
unit consists of an inositol-type backbone that is trans-fused to
a pyranose ring resulting in a bicyclic compound, whose α-
(1→7)-linked oligomer adopts a compact 2-fold right-handed
helicoidal structure.6
The unusual structure of bradyrhizose coupled with the need
to investigate its biological properties has stimulated interest in
its chemical synthesis. A first synthesis was achieved by Yu and
co-workers in a 9% overall yield and 26 steps from D-glucal, the
key steps being Ferrier rearrangement of a ramified
glucopyranoside derivative and subsequent adjustment of the
oxidation levels (Scheme 1).7 A second synthesis was reported
by Lowary and co-workers, who employed myo-inositol as the
starting material, to which a glucopyranose ring was appended
with an overall yield of 6% in 25 steps (Scheme 2).8 The
construction of bicyclic mimetics of bradyrhizose and of
related compounds has also been reported.9
Our laboratory has been interested in the synthesis of
structurally related oxabicyclic motifs in connection with
studies of the influence of pyranose side chain conformation
on anomeric reactivity10 and as analogues of the structurally
unique aminoglycoside antibiotic apramycin with its broad
spectrum of activity toward multidrug, carbapenem, and
aminoglycoside resistant enterobacteriaceae and ESKAPE
pathogens.11−13 Building on aspects of the chemistry
developed in these projects, and inspired by earlier syntheses
of apramycin14,15 and of inositol variants from cis-arene glycols
by the laboratories of Carless,16 Ley,17 Hudlicky,18 and
Motherwell,19 we envisioned a synthesis of bradyrhizose
from glucose comprised of (i) chain elongation at the
glucopyranose 6 position, (ii) annulation of an unsaturated
six-membered carbocyclic ring spanning the glucopyranose 4
and 6 positions, and (iii) adjustment of the oxidation level in
the newly appended ring to afford the target compound. We
report here on the reduction of this concept to practice,
resulting in a 14-step synthesis of bradyrhizose from D-glucose.
Scheme 1. Key Steps of the Yu Synthesis from D-Glucal
Received: November 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04279
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Following the literature protocol, D-glucose 1 was subjected
to Fischer glycosylation20 in benzyl alcohol at reflux giving 2.
Subsequent selective installation of a 4,6-O-benzylidene acetal
under standard conditions gave 3α in 85% yield and the
corresponding β-anomer in 6% yield.21 In principle, a mixture
of the two anomers of 3 could be advanced through the
synthesis, but to simplify the NMR spectra, only the major
anomer was taken forward. Thus, the α-anomer of 3 was
subjected to benzylation with benzyl bromide and sodium
hydride at 0 °C affording 4.22 Acid-catalyzed removal of the
benzylidene acetal23 was followed by selective Appel24
iodination of the primary hydroxyl group, resulting in
compound 6 in excellent yield (Scheme 3).
ethyl methallyl sulfone under conditions prescribed by Zard
and co-workers30 gave only a low yield of the desired product.
The optimum yield of 68% (Table 1, entry 6), however, was
obtained under photocatalytic conditions with blue light
irradiation of 6 and 2-pyridyl methallyl sulfone in acetonitrile
with fac-Ir(ppy)3 as the catalyst.31
Subsequently, oxidation of 7 under Parikh−Doering
conditions32 gave ketone 9 in good yield, which on treatment
with vinyl magnesium bromide afforded alcohol 10 in 97%
yield as a single diastereoisomer consistent with earlier
observations in related systems.33 The requisite bicyclic
scaffold was obtained by ring closing methathesis with the
Grubbs second-generation catalyst in dichloromethane at 45
°C, affording 11 in 85% yield (Scheme 4), and consistent with
the literature precedent for the effective formation of
trisubstituted cyclohexenes from methallyl type precursors.34
Scheme 3. Derivatization of D-Glucose
Scheme 4. Construction of the Bicyclic Scaffold
Allylic oxidation of 11 with SeO2 in 1,4-dioxane at 80 °C
gave enone 12 in 70% yield, with regioselectivity in agreement
with Guillemonat’s rules and subsequent work.35 Regio- and
stereoselective reduction of the enone derivative 12 was
achieved under Luche’s conditions,36 resulting in the isolation
of the allylic alcohol 13 in 86% yield as a single diastereomer.
Treatment of 13 with m-CPBA at room temeprature in
dichloromethane gave epoxide 14 in 83% yield as a single
diastereoisomer, as a result of steering by hydrogen bonding by
either of the two allylic alcohols (Scheme 5).37 The relative
configuration of 14 was confirmed by the observation of strong
NOE correlations of H9 with each of the C8 methyl group,
H3, H5, and H7.
With 6 in hand, we explored conditions for the side chain
elongation with various methallylation protocols. Attempts at
cross coupling reactions using methallyl Grignard reagents in
the presence of metal catalysts such as [Pd(PPh3)]4, CuI,25 or
26
Li2CuCl4 resulted in the recovery of only starting materials.
Consequently, we turned our attention to the use of radical
allylation reactions27 and, in particular, the use of meth-
allylsulfones (Table 1). The use of triethylborane28 as the
Table 1. Radical Homologation of 6 To Give 7
Scheme 5. Adjustment of Oxidation Levels and Completion
of the Synthesis
yield
of 7
(%)
yield
of 8
(%)
sulfone
(R)
temp
entry
initiator
solvent
PhCF3
PhCF3
(°C)
1
2
2-pyridyl Et3B
2-pyridyl lauroyl
0
80
40
54
51
36
peroxide
3
4
2-pyridyl AIBN
3-pyridyl lauroyl
PhCF3
PhCF3
80
80
0
50
0
38
peroxide
5
6
ethyl
AIBN
heptane/
PhCl
acetonitrile
80
rt
10
6
a
2-pyridyl fac-Ir(ppy)3
(5 mol %),
68
13
The regioselective opening of 14 was explored under a
variety of acidic conditions (Table 2). In dry solvents, enone
12 was returned as the only product, as the result of a 1,2-
hydride shift followed by β-elimination. Reactions did not
proceed under simple aqueous acidic conditions without
excessive heating for reasons of insolubility. The use of
aqueous 1,4-dixoane as solvent proved to be more successful
when the mixture was adjusted to contain the maximum
amount of water consistent with a homogeneous solution. The
desired regio- and stereoselective ring opening of the epoxide
was best achieved by employing sulfuric acid as catalyst in a 1:3
dioxane/water mixture at 65 °C (Table 2, entry 4) when
Bu3N
a
Conducted under argon with irradiation by 12 V blue light-emitting
diode strips at room temperature.
initiator in the presence of oxygen at room temperature and
below was inefficient and resulted in the formation of
significant quantities of the simple reduction product 8.
Attention was therefore focused on thermal conditions, with
initiation by lauroyl peroxide, and azoisobutyronitrile. α,α,α-
Trifluorotoluene was selected as an environmentally friendly
radical-compatible solvent for these reactions.29 The use of
B
DOI: 10.1021/acs.orglett.9b04279
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of reactions from the key bicyclic intermediate 12 are expected
to afford a variety of stereoisomers of bradyrhizose itself.
Table 2. Optimization of Epoxide Ring Opening
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04279.
temp
(°C)
yield of yield of
entry
reagent
solvent
16 (%)
13 (%)
Complete experimental and characterization details and
copies of 1H and 13C NMR spectra of all new
compounds (PDF)
1
2
wet triflic acid 0−45
dichloromethane
1,4-dioxane/water
(1:1)
1,4-dioxane/water
(1:2)
1,4-dioxane/water
(1:3)
1,4-dioxane/water
(1:4)
1,4-dioxane/water
(1:6)
0
20
0
68
concentrated
H2SO4
concentrated
H2SO4
concentrated
H2SO4
concentrated
H2SO4
65
65
65
65
65
3
4
5
6
7
37
50
13
10
0
35
45
0
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: david.crich@uga.edu.
ORCID
concentrated
H2SO4
0
David Crich: 0000-0003-2400-0083
Notes
Sc(SO3CF3)3
rt to 45 THF
0
The authors declare no competing financial interest.
tetraol 15 was obtained in 50% yield alongside 45% of the
enone 12, which could be recycled. The relative configuration
of 15 rests on the spatial proximity of H9 to H3, H5, and H7
and of the axial C8 methyl group to H6axial, as established by
the presence of strong NOE correlations.
ACKNOWLEDGMENTS
■
The authors thank the National Institutes of Health
(GM62160) for supporting this work.
While the regiochemical outcome of the epoxide opening
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E
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