Deoxygenative Divergent Synthesis: En Route to Quinic Acid Chirons

Article abstract of DOI:10.1021/acs.orglett.0c02995

The installation of vicinal mesylate and silyl ether groups in a quinic acid derivative generates a system prone for stereoselective borane-catalyzed hydrosilylation through a siloxonium intermediate. The diversification of the reaction conditions allowed the construction of different defunctionalized fragments foreseen as useful synthetic fragments. The selectivity of the hydrosilylation was rationalized on the basis of deuteration experiments and computational studies.

Full text of DOI:10.1021/acs.orglett.0c02995

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Letter
Deoxygenative Divergent Synthesis: En Route to Quinic Acid
Chirons
Suvi Holmstedt,* Lijo George, Alisa Koivuporras, Arto Valkonen, and Nuno R. Candeias*
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ABSTRACT: The installation of vicinal mesylate and silyl ether
groups in a quinic acid derivative generates a system prone for
stereoselective borane-catalyzed hydrosilylation through a siloxo-
nium intermediate. The diversification of the reaction conditions
allowed the construction of different defunctionalized fragments
foreseen as useful synthetic fragments. The selectivity of the
hydrosilylation was rationalized on the basis of deuteration
experiments and computational studies.
Scheme 1. B(C6F5)3-Catalyzed Selective Deoxygenation of
1,2-Diols and Primary Alkyl Tosylates
ynthetic strategies remain critically dependent on hemi-
synthesis or chiral pool synthesis despite the plethora of
S
currently available catalytic asymmetric transformations.1 The
contemporary mandatory transition from fossil to biobased
carbon resources calls for the development of synthetic
transformations that maximize the full potential of chemical
entities or fragments created by nature. Saccharides are the
main components of biomass, and the efforts done for their
integration in biorefineries have augmented the development
of methods for removal of their oxygen functionalities.2
Dehydration3 and selective cleavage of C−O bonds4 of
saccharides have been explored in the expansion of the
biomass-derived chemical space.5 Yamamoto’s seminal B-
(C6F5)3-catalyzed hydrosilylation of C−O bonds6 has been
used in the extensive deoxygenation of saccharides7 and
recently in the regioselective deoxygenation of saccharides8
and polyols8c to provide new chiral entities (Scheme 1a).
Alternative boron catalysts such as Piers’ borane (HB(C6F5)2)9
10
and more recently B((3,5-CF3)2C6H3)3 have been demon-
strated to catalyze the silylative deoxygenation of biomass-
derived sugars.11 The outcome of this deoxygenation method
depends on several stereochemical and electronic parameters:
first and foremost is the structure of the oxygenated
substrate,8a as vicinal groups can assist the C−O bond
cleavage.8c The second parameter is the hydrosilane employ-
ed,8b,c and the third is the fluoroarylborane catalyst.12 Gagne
and co-workers have recently progressed the field by replacing
́
−
hydrosilanes by hydroboranes as precursors of H−B(C6F5)3
hydride in the C−O bond cleavage with different selectivities
than the ones observed in the hydrosilylation.13
Morandi14 and Oestreich15 have expanded the B(C6F5)3-
catalyzed hydrosilylation of C(sp3)−O bonds to 1,2-diols and
primary tosylates, respectively. Both methods are effective in
cleaving the terminal C−O bond, the former due to the
formation of a cyclic siloxane intermediate and the latter due to
the higher reactivity of the tosylate compared with the silyl
Received: September 8, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02995
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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ether. Although suitable for the cleavage of primary tosylates
containing a primary silyl ether (Scheme 1b, R = TBDMS, n =
3−5), or an aryl ether (Scheme 1b, R = Ar, n = 1 or 5),
rearranged products from anchimeric assistance were observed
for 1,2-diols (Scheme 1b, bottom). Indeed, the nonselective
opening of a three-membered silyloxonium ion leads to the
indiscriminate formation of a primary and secondary silyl
ether. Substituents’ migration competing with direct deoxyge-
nation processes was further explored by Morandi, providing a
reductive pinacol-type rearrangement of vicinal diols.16 On a
related note, the B(C6F5)3-catalyzed hydrosilylation of
tetrasubstituted epoxides leads to a migratory ring-opening
process after the formation of a silyloxonium ion intermedi-
ate.17 While the B(C6F5)3-catalyzed hydrosilylation of C−O
bonds has been rapidly expanding the accessibility to
saccharides-derived chiral fragments for synthesis,8c,10,11,13,18
we envisioned that different chiral synthons19 could be reached
by focusing on natural cyclitols.
derivatives. However, the formation of a three-membered
silyloxonium ion intermediate resulted in rearranged products,
and a lack of regioselectivity was observed when considering
aliphatic 1,2-vicinal diol systems. Gratifyingly, treatment of 15
with different catalyst loadings and amounts of triethylsilane
resulted in formation of 16 and/or 17 in different ratios
(Scheme 3 and Table S1 in SI for further experiments). Silyl
Scheme 3. Deoxygenation of Quinic Acid Derivative 15
Quinic acid 1 was provisionally considered as one suitable
feedstock for the biobased benzoic acid production20 or other
aromatics.21 However, high cost associated with the use of
glucose as feedstock for bacterial production of quinic acid22
has again relegated this cyclitol to the chiral pool.23
Nevertheless, quinic acid and its acyl-derivatives are wide-
spread secondary metabolites of the shikimic acid pathway24 in
plants and can be obtained for instance from coffee beans,
plants, fruits, and even food wastes.25 Herein we present our
efforts toward the selective cleavage of C(sp3)−O bonds of a
common quinic acid-derived precursor with judiciously
selected O-substituents, into diverse chiral fragments (Scheme
1c).
Aware of putative effects imposed by the diverse
conformations of cyclitols on the regioselectivity of deoxyge-
nation using the B(C6F5)3/SiH system, the vicinal cis diol
moiety of quinide 2 was derivatized to several functional
groups. Besides conferring the desired conformational effect,
further deprotection after deoxygenation would provide
substrates prone to typical C−C oxidative cleavage and
subsequently give chiral linear C7 fragments. Attempts on the
hydrosilylation of cyclitol derivatives 3−13 (Scheme 2) failed
in providing any deoxygenated products (see Supporting
Information section 1 for complete rationale).
a
15 (0.14 mmol) and B(C6F5)3 in CH2Cl2, at r.t. followed by addition
b
c
of Et3SiH. Ratio determined from isolated yields. [15] = 0.05 M.
d
[15] = 0.3 M.
ethers derived from primary and secondary alcohols have been
reported to be more reactive toward B(C6F5)3-catalyzed
reduction with hydrosilanes than the ones derived from
tertiary homologues.6c,d On the other hand, the neighboring
group assistance can deeply impact the regioselectivity.
Notably, cleavage of the primary mesylate in 15 was
accompanied by stereospecific migration of the silyloxy
group from the vicinal tertiary carbon to provide 17 (Scheme
3). The absolute configuration of the deoxygenated product
was determined through X-ray diffraction analysis of the 3,5-
dinitrobenzoyl derivative 18, obtained after desilylation of 17
and benzoylation of the triol 17′.
Attempts to overcome the higher propensity of C4 toward
deoxygenation by replacing the mesylate with protecting
groups proved futile. Instead, B(C6F5)3/SiH treatment of 20
having the secondary hydroxyl protected as silyl ether (20b)
resulted in fast intramolecular cyclization to bicyclic compound
21 in up to 88% yield (Scheme 4). Exposure of MOM-ether
20c to the same conditions resulted in the formation of
compound 20d in 78% yield (Scheme 5). Treatment of methyl
ether 20d with additional triethylsilane (1.1 equiv) in the
presence of B(C6F5)3 led to formation of cyclic ether 21, as
deduced from crude NMR. Carbamoyl protected 20e was
unreactive toward B(C6F5)3-catalyzed hydrosilylation, and only
starting material was recovered, despite the harsh reaction
conditions used (20 mol % catalyst, excess of silane and
refluxing toluene). The structural complexity of compound
2126 was broken down through oxidative cleavage of the C−C
bond upon desilylation and oxidation of the cis glycol moiety
via Malaprade oxidation to provide dialdehyde 22 in excellent
yield. The cyclic ethers 22 and 23 are envisioned as interesting
synthetic intermediates due to the presence of oxygen
functionality-containing substituents at C1 and C3 positions
of the tetrahydrofuran core.27 The selective deprotection of the
The discouraging lack of reactivity of the silylated quinic
acid derivatives prompted us to explore the anchimeric
assistance by silyl ethers in the C−O bond cleavage of
tosylates, as previously reported by Oestreich and co-
workers.15 Excellent chemoselectivity was reported for the
deoxygenation of primary alkyl tosylates from nonvicinal diol
Scheme 2. Quinic Acid Derivatives Explored in B(C6F5)3-
Catalyzed Hydrosilylation
B
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a
Scheme 4. Formation and Controlled Cleavage of Bicyclic Tetrahydrofuran 21
a
n.d. = yield not deternined; n.r. = no reaction.
The observed preferred chemoselectivity for C−O bond
cleavage of the secondary carbon over the primary mesylate in
15 suggests the formation of the three-membered silyloxonium
ion as proposed previously by Oestreich. The higher
propensity of C4 for deoxygenation compared to C1 is
justified by the easier formation of the strained three-
membered silyloxonium ion in C4−C5 than in C1−C2, as
the later will turn C2 into a spiro carbon. Such events should
become less energy demanding after removal of one of the
carbocycle substituents. Additionally, the easier access of the
hydride to C4 over C5 renders this process highly
regioselective in the opening of the siloxonium. Motivated by
the excellent regioselectivity in opening of the putative three-
membered silyloxonium ion with hydrosilanes, compound 29,
an analogue of 15, was submitted to similar deoxygenation
protocol. The treatment of cyclohexanol derivative 29 with
B(C6F5)3 and silyl hydrides resulted in cleavage of the C−O
bond and migration of the silyl ether moiety to the primary
carbon (Scheme 5), contrasting with the previously reported
lack of selectivity for deoxygenation of primary tosylates vicinal
to a secondary silyl ether.15 While no alkyl migration was
observed in the deoxygenations of quinic acid derivatives,
which was expected given the precedents on the hydro-
silylation of epoxides in acyclic systems17 the migration of
hydride from the primary to tertiary carbon was considered.31
When using Et3SiD as a reducing agent, the deuteration
occurred selectively at the primary carbon, affording d-30 in
57% after isolation. Similar behavior was observed in the
hydrosilylation of 15 with Et3SiD. The delivery of the
deuteride to the opposite face of the silyl ethers of the
cyclohexane derivative (absolute configuration determined
from inspection of vicinal coupling constants) seems to
indicate a different mechanism when comparing with the
tertiary silyl ether/primary mesylate counterpart.
Scheme 5. B(C6F5)3-Catalyzed Siloxonium Opening with
Et3SiD
tertiary silyl ether of 21 followed by similar cleavage with
catechol borane and desilylation also provided compound 17a.
A sequence of silyl ethers’ cleavage and primary alcohol
protection resulted in 17b that was submitted to Malaprade
oxidation providing dialdehyde 19, envisioned as a rich
fragment for stereoselective synthesis due to the three
functionalities and structural similarities with Perlin alde-
hydes.28 Impelled by the bicyclic skeleton of 21, the controlled
modification of its stereogenic carbons was attempted. The
lack of reactivity of 21 toward cleavage of the O−Si bond by
B(C6F5)3-catalyzed hydrosilylation was overcome by reduction
with catechol borane, as recently developed by Gagne,
resulting in the selective cleavage of the C−O bond from the
secondary carbon to provide 25 in 88% yield.
Selective oxidation of primary alcohol moiety of 25 followed
by one-pot esterification and desilylation led to 28, a known
intermediate in the synthesis of homocitric acid.29 Even though
not attempted, it is worth noticing that the use of
deuteriocatecholborane in the manipulation of 21 would
provide an entry for the preparation of labeled homocitrate.
Although of potential interest for biological studies, deuterium
labeling at position 5 remains unveiled.29a,30
13
́
In order to get further insight on the formation of the
silyloxonium intermediate and its regioselective opening, a
simplified system was studied by means of Density Functional
Theory32 (Scheme 6), and geometries of the transition states
C
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Scheme 6. Free Energy Profile (M06-2X/6-311++G**//M06-2X/6-31G**) and Mechanistic Representation for
a
Deoxygenation of Model Substrate sm, via Siloxonium and 1,2-Hydride Shift
a
Values are presented in kcal/mol, referring to the initial pair of sm and Et3Si−H−B(C6F5)3.
were calculated (please consult Figure S1 and full computa-
tional account in the SI). The energetically favorable
interaction of the mesylate group of sm with silylium ion in
int1 increases the electrophilic character of the primary carbon,
triggering the formation of the silyloxonium ion int2 through a
21.4 kcal/mol energy barrier. C−O bond lengths in the
siloxonium int2 differ by 0.05 Å, with the most substituted
bond being elongated. The equilibration of the siloxonium to
int3, where the above-mentioned C−O bond is clearly broken
(dC−O = 2.385 Å), is energetically more favorable by 4.5 kcal/
mol. The 1,2-hydride shift for neutralization of the positive
charge on the tertiary carbon is a favorable process with int4
being 11.9 kcal/mol more stable than int3. Additionally, the
energy barrier for the 1,2-hydride migration through ts2 is only
2.5 kcal/mol. The hydride delivery from the hydridoborate
anion to the electrophilic carbon of the oxocarbenium is
almost spontaneous and int4 can simply overcome the barely
existent energy barrier of 2.4 kcal/mol for ts3 to ultimately
form the very stable silyl ether int5. The overall process is
energetically favored as demonstrated by the ΔGf of prod
(52.9 kcal/mol) with the rate limiting step being the formation
of the siloxonium int2.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02995.
Experimental details, preliminary studies on hydro-
silylation and characterization data of all synthetic
intermediates, full accounts on computational calcula-
1
tions, and H and 13C NMR copies of spectra for all
reported compounds (PDF)
Accession Codes
CCDC 2005907 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Suvi Holmstedt − Faculty of Engineering and Natural Sciences,
Tampere University, 33101 Tampere, Finland;
In conclusion, we have described the B(C6F5)3-catalyzed
defunctionalization of a cyclitol through hydride delivery to
three-membered silyloxonium ions. The success of the
deoxygenation of quinide and derivatives using this hydro-
silylation depends on the protecting groups. Nevertheless, the
achieved deoxygenations proved highly stereoselective and
allowed the diversification of chiral fragments that can be
obtained from quinic acid. The expansion of this transition-
metal-free deoxygenation protocol to cyclitols has diversified
the array of molecules and fragments that can be obtained from
biorenewables.
Email: suvi.holmstedt@tuni.fi
Nuno R. Candeias − Faculty of Engineering and Natural
Sciences, Tampere University, 33101 Tampere, Finland;
LAQV-REQUIMTE, Department of Chemistry, University of
Aveiro, 3810-193 Aveiro, Portugal; orcid.org/0000-0003-
2414-9064; Email: ncandeias@ua.pt
Authors
Lijo George − Faculty of Engineering and Natural Sciences,
Tampere University, 33101 Tampere, Finland
Alisa Koivuporras − Faculty of Engineering and Natural
Sciences, Tampere University, 33101 Tampere, Finland
D
https://dx.doi.org/10.1021/acs.orglett.0c02995
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Letter
(7) Adduci, L. L.; McLaughlin, M. P.; Bender, T. A.; Becker, J. J.;
Arto Valkonen − Department of Chemistry, University of
́
Gagne, M. R. Metal-Free Deoxygenation of Carbohydrates. Angew.
̈
̈
̈
̈
Jyvaskyla, 40014 Jyvaskyla, Finland; orcid.org/0000-0003-
Chem., Int. Ed. 2014, 53, 1646−1649.
2806-3807
́
(8) (a) Seo, Y.; Gagne, M. R. Positional Selectivity in the
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02995
Hydrosilylative Partial Deoxygenation of Disaccharides by Boron
Catalysts. ACS Catal. 2018, 8, 81−85. (b) Hein, N. M.; Seo, Y.; Lee,
́
S. J.; Gagne, M. R. Harnessing the reactivity of poly-
(methylhydrosiloxane) for the reduction and cyclization of biomass
Notes
to high-value products. Green Chem. 2019, 21, 2662−2669.
The authors declare no competing financial interest.
́
(c) Adduci, L. L.; Bender, T. A.; Dabrowski, J. A.; Gagne, M. R.
Chemoselective Conversion of Biologically Sourced Polyols into
ACKNOWLEDGMENTS
Chiral Synthons. Nat. Chem. 2015, 7, 576−581.
■
(9) (a) Parks, D. J.; Piers, W. E.; Yap, G. P. A. Synthesis, Properties,
and Hydroboration Activity of the Highly Electrophilic Borane
Bis(pentafluorophenyl)borane, HB(C6F5)2. Organometallics 1998, 17,
5492−5503. (b) Parks, D. J.; von H. Spence, R. E.; Piers, W. E.
Bis(pentafluorophenyl)borane: Synthesis, Properties, and Hydro-
boration Chemistry of a Highly Electrophilic Borane Reagent.
Angew. Chem., Int. Ed. Engl. 1995, 34, 809−811. (c) Zhang, J.;
Park, S.; Chang, S. Selective C-O Bond Cleavage of Sugars with
Hydrosilanes Catalyzed by Piers’ Borane Generated In Situ. Angew.
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The Academy of Finland is duly acknowledged for financial
support to N.R.C. (Decisions No. 326487 and 326486) and to
A. V. (No. 314343). Finnish Cultural Foundation is acknowl-
edged for financial support to S.H. (00190336). CSC−IT
Center for Science Ltd., Finland is acknowledged for the
allocation of computational resources. Professor Luis F. Veiros
́
́
(Centro de Quimica Estrutural, Instituto Superior Tecnico,
Universidade de Lisboa, Portugal) is acknowledged for fruitful
discussions on the computational section.
́
(10) Seo, Y.; Lowe, J. M.; Gagne, M. R. Controlling Sugar
Deoxygenation Products from Biomass by Choice of Fluoroarylbor-
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