Rapid de Novo Preparation of 2,6-Dideoxy Sugar Libraries through Gold-Catalyzed Homopropargyl Orthoester Cyclization

Article abstract of DOI:10.1021/acs.orglett.9b03812

A flexible de novo route capable of producing libraries of 2,6-dideoxy sugars is described. We have found that Au(JackiePhos)SbF₆MeCN promotes the conversion of homopropargyl orthoesters into functionalized 2,3-dihydro-4H-pyran-4-ones in good t

Full text of DOI:10.1021/acs.orglett.9b03812

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rapid de Novo Preparation of 2,6-Dideoxy Sugar Libraries through
Gold-Catalyzed Homopropargyl Orthoester Cyclization
Subbarao Yalamanchili, William Miller, Xizhao Chen, and Clay S. Bennett*
Department of Chemistry, Tufts University, 62 Talbot Avenue, Medford, Massachusetts 02155, United States
S
* Supporting Information
ABSTRACT: A flexible de novo route capable of producing
libraries of 2,6-dideoxy sugars is described. We have found
that Au(JackiePhos)SbF6MeCN promotes the conversion of
homopropargyl orthoesters into functionalized 2,3-dihydro-
4H-pyran-4-ones in good to excellent yields (71−90%). These
latter compounds can be easily converted into a number of
otherwise difficult to access 2,6-dideoxy sugars.
t is estimated that nearly 20% of all natural products possess
glycans, many of which contain 2,6-dideoxy sugars. The
glycans can play a critical role in modulating natural product
bioactivity.1 In extreme cases, deoxy sugars may comprise a
significant portion of a natural product, such as in the
antibiotic saccharomicin B (Figure 1).2−4 Altering the
pyran-4-ones, a process that requires harsh oxidations that do
not always proceed to completion.49−59 Thus, a general
approach to deoxy sugar library construction remains elusive.
To address this issue, we sought an approach that would
allow us to access all four possible diastereomers of suitably
functionalized 2,3-dihydro-4H-pyran-4-ones. To this end, we
drew inspiration from prior work by the Rhee lab, who
demonstrated that homopropargyl acetals could be cyclized
into the corresponding tetrahydro-4H-pyran-4-ones using
gold(I) catalysts.60,61 We envisioned that applying this
cyclization chemistry to homopropargyl orthoesters 1−3
would provide access to all four possible diastereomers of
2,3-dihydro-4H-pyran-4-one [4−6 (Scheme 1)]. These latter
compounds could then be converted into an array of 2,6-
dideoxy sugars, such as 7−12.
I
To test the key gold-catalyzed cyclization, 1,2-anti- and 1,2-
syn-substituted homopropargyl orthoesters 1−3 were prepared.
The synthesis of the 1,2-anti-substituted homopropargyl
orthoester (−)-1 began with protecting methyl (R)-(+)-lactate
as a tert-butyldimethylsilyl ether (TBS) (Scheme 2),62 followed
by reduction using DIBAL-H63 to afford aldehyde (+)-14 in
78% yield over two steps. Alkynylation under conditions
described by Marshall afforded (−)-15 in 82% yield as a 16:1
mixture of isomers when (S)-BINOL was used as the chiral
ligand.64 After separation of the diastereomers, we were
pleased to find that benzylation of the newly formed hydroxyl
under standard Williamson ether conditions proceeded
smoothly with concomitant deprotection of the alkyne to
give (−)-16 in 84% yield. Removal of the TBS group using
TBAF afforded alcohol (−)-17 in 93% yield. Finally, treating
(−)-17 with trimethyl orthoformate and magnesium chloride
provided the key orthoester substrate (−)-1 in 86% yield.65 To
test the general applicability of the proposed cyclization, we
also synthesized orthoester (+)-2 possessing the more labile
naphthylmethyl (Nap) ether.66 Gratifyingly, the synthesis of
Figure 1. Heptadecasaccharide antibiotic saccharomicin B.
composition of these sugars through glycorandomization can
dramatically affect the bioactivity of a natural product,
including increasing potency or mitigating toxicity.5−9 While
glycorandomization holds promise as a new tool for drug
discovery,10−12 a major hurdle to its implementation is the lack
of availability of deoxy sugars.
Numerous approaches to the synthesis of deoxy sugars have
been developed.13−15 In many cases, deoxy sugar mono-
saccharide construction relies on de novo synthesis.16−38 While
there are a myriad of approaches to de novo synthesis, the
majority of routes that have been reported are target specific. A
more flexible approach relies on carrying out modifications on
glycals,39−48 which permits the generation of multiple different
sugars from the same starting material. However, this strategy
is cost-effective only when the glycal in question can be
generated from readily available sugars, which is often not the
case. Furthermore, modification of glycals often involves
transforming them into the corresponding 2,3-dihydro-4H-
Received: October 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03812
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Organic Letters
Letter
Scheme 1. Proposed Synthesis and Derivatization of Enone
Precursors into Hard To Access Deoxy Sugars
Table 1. Optimization of Gold Cyclization
catalyst
(mol %)
yield
a
entry anion
additive
ligands
(%)
1
2
3
4
5
6
SbF6 none
JohnPhos,
MeCN
JohnPhos,
MeCN
JohnPhos,
MeCN
(C6F5)3P
3.0
3.0
5.0
7.0
7.0
3.5
0
11
6
SbF6 TTBP
SbF6 TTBP
Cl DTBP,
4 Å MS
SbF6 DTBP,
4 Å MS
5
JackiePhos,
MeCN
JackiePhos,
MeCN
86
87
SbF6 DTBP,
4 Å MS
a
Based on isolated weight.
Scheme 2. Synthesis of Orthoesters (−)-1, (+)-1, (+)-2,
(−)-3, and (+)-3
tion of the orthoester to afford alcohol (−)-17 as the major
product. Reasoning that the loss of the orthoester was due to
trace amounts of acid, we conducted the reaction in the
presence of 2,4,6-tri-tert-butylpyrimidine (TTBP). Adding the
acid scavenger afforded desired ketone (+)-4 in a modest 11%
yield. Increasing the catalyst load to 5% did not have a major
impact on the reaction (Table 1, entry 3). We next examined
electron deficient ligands to determine if they would further
improve the yield. While tris(pentafluorophenyl)phosphine61
failed to improve the yield of the reaction, the use of the
JackiePhos ligand68 led to the formation of the desired
pyranone (+)-4 in excellent yield (Table 1, entry 5). Further
optimization of the reaction revealed that the catalyst load
could be reduced to 3.5% without any deleterious effect on the
reaction. Smaller catalyst loads led to a corresponding decrease
in the yield.
Having established the optimal conditions for cyclization, we
turned our attention to examining the scope of the reaction.
We found that the 1,2-anti orthoesters (−)-1, (+)-1, and (+)-2
consistently gave excellent yields of the desired ulose (Table 2,
entries 1−3, respectively). On the other hand, 1,2-syn
orthoesters (−)-3 and (+)-3 reacted to afford the desired
products in slightly attenuated yields (Table 2, entries 4 and 5,
respectively). The lower yields with the syn isomers may be
due to an unfavorable steric interaction between the axial
benzyl ether and the substituents on C-2 of the pyranose ring
initially formed in the reaction (Figure 2).60,69 Importantly, the
gold-catalyzed cyclizations could be run on multigram scale,
providing access to significant quantities of all of the 2,3-
dihydro-4H-pyran-4-one diastereomers needed for deoxy sugar
construction.
We next turned our attention to transforming the cyclization
products into various D- or L-deoxy sugars. Our initial targets
were L-digitoxose and L-olivose, which could be readily
obtained from (−)-5 (Scheme 3). To this end, treating
(−)-5 with cesium carbonate and ethanethiol afforded ketone
(−)-22 as a 12.5:1 mixture of isomers.70 Reduction of (−)-22
using sodium borohydride stereoselectively generated L-
digitoxose (−)-7 in 80% yield.71 To access L-olivose (−)-8,
the enone was selectively reduced under Luche conditions to
provide allylic alcohol (−)-23.72 Acetate protection and
hydration of the glycal with triphenylphosphine hydrogen
this substrate proved to be uneventful, and we were able to
obtain (+)-2 through a similar sequence using (R)-BINOL to
set the stereochemistry of the propargylic alcohol (+)-15.
Finally, the 1,2-syn diastereomers (+)-3 and (−)-3 were
synthesized, albeit with a lower dr, through a similar sequence
(see the Supporting Information).67
With the requisite orthoesters in hand, we turned our
attention to the key gold-catalyzed cyclization reaction. Our
initial attempts at cyclization used AuSbF6 with the JohnPhos
ligand as described by Rhee and co-workers (Table 1, entry
1).60 Unfortunately, these conditions resulted in decomposi-
B
DOI: 10.1021/acs.orglett.9b03812
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Cyclization of Orthoester Substrates into Glycals
Scheme 4. Derivatization of Enone (+)-6 into D-Boivinose 9
and D-Oliose 10
9.73 To prepare D-oliose (+)-10, enone (+)-6 was subjected to
a Luche reduction to stereoselectively generate alcohol
(−)-26.45 Acetate protection followed by hydration afforded
D-oliose (+)-10 in 78% yield over two steps.
Having established scalable routes to the four diastereomeric
2,6-dideoxy sugars, we turned our attention to deoxy amino
sugar synthesis. To install amino functionality, 1,4-conjugate
addition of thiophenol to enone (−)-5 was followed by
addition of O-benzylhydroxylamine to generate oxime (−)-28
(Scheme 5).39,74,75 Refluxing (−)-28 in THF in the presence
of 3 equiv of lithium aluminum hydride reduced the oxime to
the corresponding amine to afford L-ristosamine (−)-11.76,31
Scheme 5. Derivatization of Enone (−)-5 into L-Ristosamine
11 and L-Saccharosamine 12
a
Based on isolated weight.
Figure 2. Possible steric interaction arising during cyclization of syn-
homopropargyl orthoesters.
Scheme 3. Derivatization of Enone (−)-5 into L-Digitoxose
7 and L-Olivose 8
To synthesize L-saccharosamine (−)-12, we first unmasked
the C-4 hydroxyl on (−)-5 because the Nap group can
interfere with installation of the C-3 methyl group (Scheme
5).39,77 The resultant enone was subjected to a 1,4-conjugate
addition/oxime formation sequence to afford (−)-29 in 76%
yield over three steps. Treatment of the oxime with methyl
cerium under conditions previously described by Scharf
afforded L-saccharosamine (−)-12 as a single isomer in 64%
yield.39
In summary, we have developed a flexible de novo route for
preparing an array of difficult to access 2,6-dideoxy sugars. This
process provides access to all four diastereomers of protected
2,3-dihydro-4H-pyran-4-ones starting from inexpensive D- or L-
methyl lactate. The resulting pyranones can be readily
transformed into a variety of orthogonally protected 2,6-
dideoxy- and 2,3,6-trideoxy-3-amino sugars. We anticipate this
approach will both greatly accelerate deoxy sugar oligosac-
charide synthesis and be an invaluable tool for glycodiversi-
fication studies of bioactive natural products.
bromide afforded L-olivose hemiacetal (−)-8 in 88% yield over
two steps.
A similar approach was used to obtain D-boivinose (+)-9 and
D-oliose (+)-10 (Scheme 4). Treating enone (+)-6 with
adamantanethiol, cesium carbonate, and triethyl amine cleanly
afforded ketone (+)-25 as a single anomer.70 The ketone was
then reduced using sodium borohydride to afford D-boivinose
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(14) Hou, D.; Lowary, T. L. Recent Advances in the Synthesis of 2-
Deoxy-Glycosides. Carbohydr. Res. 2009, 344, 1911−1940.
(15) Ding, F.; Cai, S.; William, R.; Liu, X. W. Pathways Leading to 3-
Amino- and 3-Nitro-2,3-Dideoxy Sugars: Strategies and Synthesis.
RSC Adv. 2013, 3, 13594−13621.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03812.
■
S
Experimental details and 1H NMR and 13C NMR
spectra (PDF)
(16) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless,
K. B.; Walker, F. J. Total Synthesis of the L-Hexoses. Science 1983,
220, 949−951.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: clay.bennett@tufts.edu.
ORCID
(19) Ahmed, M. M.; Berry, B. P.; Hunter, T. J.; Tomcik, D. J.;
O’Doherty, G. A. De Novo Enantioselective Syntheses of Galacto-
Sugars and Deoxy Sugars via the Iterative Dihydroxylation of
Dienoate. Org. Lett. 2005, 7, 745−748.
Clay S. Bennett: 0000-0001-8070-4988
Notes
The authors declare no competing financial interest.
(20) Ahmed, M. M.; O’Doherty, G. A. De Novo Synthesis of
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ACKNOWLEDGMENTS
■
The authors thank the National Science Foundation (CHE-
1566233) and the National Institutes of Health (R01-
GM115779 and U01-GM120414) for generous financial
support.
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