Alkynylation of Pentose Derivatives with Stereochemical Fidelity: Implications for the Regioselectivity of Alkynyl Diol Cycloisomerizations to Cyclic Enol Ethers

Article abstract of DOI:10.1021/acs.orglett.9b01024

This work characterizes a previously undetected epimerization in the preparation of alkynyl diols from pentose precursors utilizing the Ohira-Bestmann reagent. Lithium trimethylsilyldiazomethane (Colvin reagent) additions to the d-ribose and d-lyxose-derived benzylidene acetals provide the respective alkynyl diol stereoisomers, without epimerization. Regioselective tungsten-catalyzed cycloisomerizations of the d-ribose- and d-lyxose-derived alkynyl diols yield rigid bicyclic pyranose glycals, confirming the stereochemical fidelity of the Colvin alkynylation process.

Full text of DOI:10.1021/acs.orglett.9b01024

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Alkynylation of Pentose Derivatives with Stereochemical Fidelity:
Implications for the Regioselectivity of Alkynyl Diol
Cycloisomerizations to Cyclic Enol Ethers
Frank E. McDonald,* Dian Ding, Andrew J. Ephron,† and John Bacsa
Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States
S
* Supporting Information
ABSTRACT: This work characterizes a previously undetected
epimerization in the preparation of alkynyl diols from pentose
precursors utilizing the Ohira−Bestmann reagent. Lithium
trimethylsilyldiazomethane (Colvin reagent) additions to the
D-ribose and D-lyxose-derived benzylidene acetals provide the
respective alkynyl diol stereoisomers, without epimerization.
Regioselective tungsten-catalyzed cycloisomerizations of the D-ribose- and D-lyxose-derived alkynyl diols yield rigid bicyclic
pyranose glycals, confirming the stereochemical fidelity of the Colvin alkynylation process.
ur laboratory previously described the synthesis of
seven-membered cyclic enol ethers 2, prepared by
with diazophosphonate 6 gave the alkynyl diol 7 (Scheme 1).
As this transformation yielded a single diastereomer, we were
O
tungsten carbonyl-catalyzed cycloisomerizations of alkynyl
diols 1 (eq 1).1,2 The alkynyl diol substrates included
Scheme 1. Synthesis and Crystal Structure of D-
Arabinoseptanose Glycal 8, Arising from Epimerization at
C3 in the Alkynylation Step
dioxolane spacers between the terminal alkyne and vicinal
diol moieties as a necessary condition for seven-membered
ring formation. We recently re-explored this work, aiming to
extend its synthetic applications, but uncovered a previously
undetected epimerization in the preparation of alkynyl diols
closely related to 1.
In our initial report,1 we claimed that all four diastereomers
of 1 gave the corresponding septanose glycals 2 with the
assignment of regioselectivity for the seven-membered ring
secured by O-acylation of secondary alcohols to the acetate
esters 3 (eq 1). This manuscript describes how we identified
epimerization of these compounds at carbon 3 (C3) and
offers a reliable method for synthesizing alkynyl diols with
stereochemical fidelity. We also discuss the implications of
substrate stereochemistry on the regioselectivity of tungsten-
catalyzed cycloisomerizations of alkynyl diols.
initially unaware that the propargylic center at C3 of
compound 7 had epimerized.5 Tungsten carbonyl-catalyzed
cycloisomerization1,2 of the alkynyl diol 7 produced the
septanose glycal 8. In a serendipitous opportunity, we
obtained a crystal structure of 8, revealing that the chiral
center at C3 was opposite to the configuration of the D-
ribofuranose starting material. Thus, compound 8 corre-
sponded to the D-arabino stereochemistry.
For several of the substrates reported earlier,1 we prepared
the alkynyl diols by the Ohira−Bestmann protocol3 from
pentose precursors protected as acetonides. In this extension
of our work, we chose benzylidene acetal protection,
intending late-stage chemoselective deprotection in the
presence of acid-sensitive enol ether and/or glycoside
functional groups. Beginning with D-ribofuranose 4 and the
known benzylidene acetal 5,4 Ohira−Bestmann alkynylation
Received: March 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01024
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
At the same time, we converted D-lyxofuranose 9 into the
mixture of benzylidene acetal diastereomers 10a and 10b,
followed by Ohira−Bestmann alkynylation, affording alkynyl
diols 11a and 11b (Scheme 2). Although the acetal
chemical shifts compared with 7 or 11a,b, as expected for
diastereomers.
As the Ohira−Bestmann conditions exposed the furanose
substrates 5 and 10 to refluxing methanolic potassium
carbonate, followed by slow addition of the diazophosphonate
6, we realized that epimerization of the open-chain
aldehyde−diol intermediate (Figure 1, i → ii) likely occurred
Scheme 2. Synthesis of D-Xyloseptanose Glycals 12a and
12b with Epimerization at C3 Confirmed by the Crystal
Structure of 12a
Figure 1. Competitive epimerization vs alkynylation depicted for
alkynylation of benzylidene-protected D-ribofuranose 5.
faster than alkynylation. In hindsight, we recognized that ii
was probably thermodynamically favored over diastereomer i,
minimizing gauche interactions between the aldehyde and diol
substituents on the dioxolane ring. However, the Colvin
protocol proceeded at low temperature in THF under aprotic
conditions that disfavored epimerization prior to carbon−carbon
bond formation.8
In contrast to our initial report, tungsten-catalyzed
cycloisomerization of the ribo-alkynyl diol 14 gave the six-
membered D-ribopyranose glycal 16 (Scheme 4). Similarly,
diastereomers 11a and 11b were difficult to separate,
tungsten carbonyl-catalyzed cycloisomerization of the mixture
gave the chromatographically separable septanose glycals 12a
and 12b. Crystallographic analysis of 12a exhibited D-xylo
stereochemistry, consistent with epimerization at C3, which
we ultimately determined occurred in the alkynylation step.
Following precedents describing alkynylations of α-chiral
aldehydes with lithium trimethylsilyldiazomethane (13)
without epimerization,6,7 we successfully applied this method
(Colvin protocol) with benzylidene-protected furanoses 5 and
10a,b (Scheme 3). In contrast with the Ohira−Bestmann
Scheme 4. Cycloisomerizations of ribo- and lyxo-Alkynyl
Diols 14 and 15 Provide the Corresponding Cis-Fused
Pyranose Glycals 16 and 17
Scheme 3. Preparations of Alkynyl Diols 14 and 15a,b
without Epimerization in the Alkynylation Steps
the lyxo-alkynyl diols 15a,b produced the D-lyxopyranose
glycals 17a,b, which were chromatographically separable. In
both cases, the seven-membered ring septanose isomers were
not observed.
protocol, the reaction of 13 with ribose-derived furanose 5
proceeded without epimerization. A mixture of terminal
alkyne and alkynyltrimethylsilane was initially produced, but
basic methanolysis of the crude product mixture promoted
protiodesilylation to provide the alkynyl diol 14. We obtained
similar results from the benzylidene-protected lyxofuranose
We sought spectroscopic signatures to distinguish the
relative stereochemistry of alkynyl diol diastereomers.
Unfortunately, the coupling constants of the propargylic
hydrogens (H3) of all alkynyl diol diastereomers were similar
1
10a and 10b, producing 15a and 15b. H NMR data for 14
and 15a,b exhibited small but discernible differences in
3
in magnitude, exhibiting JH3,H4 coupling constants between
B
DOI: 10.1021/acs.orglett.9b01024
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
5−8 Hz. However, the alkynyl diol diastereomers did exhibit
regular differences in the relative chemical shifts for the
hydrogens at C5: the arabino-7 and xylo-11a,b diastereomers
bearing a trans-relationship at H3 and H4 (arising from
epimerization) had chemical shifts for H5 upfield of 4.0 ppm,
whereas the ribo-14 and lyxo-15a,b diastereomers bearing a
cis-relationship of H3 and H4 (absence of epimerization)
showed chemical shifts for H5 downfield of 4.0 ppm (Figure
2).
Figure 2. Diagnostic chemical shift trends for the hydrogens at C5
distinguish trans- vs cis-diastereomers at C3 and C4.
For the bicyclic glycals 16 and 17a,b, the coupling
constants confirmed the stereochemistry at C3 and C4, due
to the rigidity of the bicyclic structures (Figure 3).
Figure 4. Regioselectivity of tungsten-catalyzed cycloisomerization
depends upon the relative stereochemistry of the C3 and C4
oxygens when protected as cyclic acetals.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01024.
Figure 3. Consistent trends in the coupling constants distinguish the
cyclic glycal products.
Experimental procedures and characterization data, data
comparison between structures from ref 1 and this
work (PDF)
1H and 13C NMR spectra (PDF)
Specifically, the arabino-8 and xylo-12a,b septanose glycal
diastereomers bearing a trans-relationship of H3 and H4
exhibited relatively large JH3,H4 of 9.7 Hz, consistent with
Accession Codes
3
CCDC 1902792−1902793 contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_-
request/cif, or by emailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
anti-orientations of H3 and H4. In contrast, the ribo-16 and
lyxo-17a,b pyranose glycal diastereomers bearing cis-relation-
ships of H3 and H4 (absence of epimerization) displayed
3
smaller JH3,H4 ranging from 5.8 to 6.8 Hz, in the range
expected for gauche orientations of H3 and H4. Consistent
with these assignments, the ribo-16 pyranose glycal gave
3
larger JH4,H5 of 10.0 Hz as expected for trans-diaxial
AUTHOR INFORMATION
■
hydrogens, whereas the lyxo-17a−17b pyranose diastereomers
showed very small or nonobservable JH4,H5 < 2 Hz.
Corresponding Author
*E-mail: frank.mcdonald@emory.edu.
ORCID
3
These results demonstrate that only dioxolane-protected
alkynyl diols leading to trans-ring fusions produce the
septanose glycals by tungsten-catalyzed cycloisomerization.
As depicted for the arabino-diastereomer 7 (Figure 4), ring
strain disfavors formation of a trans-fused [4.3.0]-bicyclic
isomer, allowing the alternative pathway to the seven-
membered ring [5.3.0]-bicyclic isomer 8. However, both
pathways are now possible from the ribo-diastereomer 14: not
surprisingly, the six-membered ring isomer 16 forms faster
than the seven-membered ring.
Frank E. McDonald: 0000-0002-6612-7106
Present Address
†(A.J.E.) Department of Chemistry, University of Georgia,
Athens, GA.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Emory University supported early stages of this work through
the Program to Enhance Research and Scholarship. The
■
These findings require corrections to two of our earlier
publications.1,9
C
DOI: 10.1021/acs.orglett.9b01024
Org. Lett. XXXX, XXX, XXX−XXX

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(9) Koo, B.; McDonald, F. E. Fischer carbene catalysis of alkynol
cycloisomerization: Application to the synthesis of the altromycin B
disaccharide. Org. Lett. 2007, 9, 1737−1740.
National Institute of General Medical Sciences of the
National Institutes of Health under Award No.
R21GM127971 has supported later stages of this research.
The content is solely the responsibility of the authors and
does not necessarily represent the official views of the
National Institutes of Health.
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DOI: 10.1021/acs.orglett.9b01024
Org. Lett. XXXX, XXX, XXX−XXX