From d-to l-Monosaccharide Derivatives via Photodecarboxylation-Alkylation

Article abstract of DOI:10.1021/acs.orglett.9b03016

Photodecarboxylation-alkylation of conformationally locked monosaccharides leads to inversion of stereochemistry at C5. This allows the synthesis of l-sugars from their readily available d-counterparts. Via this strategy, methyl l-guloside was synthesized from methyl d-mannoside in 21% yield over six steps.

Full text of DOI:10.1021/acs.orglett.9b03016

This is an open access article published under a Creative Commons Non-Commercial No
Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and
redistribution of the article, and creation of adaptations, all for non-commercial purposes.
Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
From D- to L‑Monosaccharide Derivatives via
Photodecarboxylation−Alkylation
I. C. Steven Wan, Martin D. Witte,* and Adriaan J. Minnaard*
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
S
* Supporting Information
ABSTRACT: Photodecarboxylation−alkylation of conformationally
locked monosaccharides leads to inversion of stereochemistry at C5.
This allows the synthesis of L-sugars from their readily available D-
counterparts. Via this strategy, methyl L-guloside was synthesized
from methyl D-mannoside in 21% yield over six steps.
odern photoredox catalysis has opened new doors for
boxylative photoalkylation would provide a unique opportunity
Morganic synthesis and has challenged bond disconnec- to invert the stereochemistry at C5, which leads to the
tion approaches.1 It exploits the reactivity of carbon-centered
corresponding C6 functionalized L-sugars and sugar deriva-
tives. In contrast to the commonly found C6-deoxy sugars L-
rhamnose and L-fucose, L-sugars oxidized at C6 are not readily
available. Therefore, the latter have to be prepared either from
C6-deoxy sugars via C−H activation22 or via epimerization
protocols that are mostly lengthy.23 As such, the decarbox-
ylative photoalkylation would fill an unmet need in the
synthesis of L-sugar derivatives, which are a rare but integral
part of biology.24 The challenge in this strategy is the control
of stereochemistry at the (re)formed C5 stereocenter. It
seemed most productive to rely on substrate control, in this
case control over the conformation of the six-membered ring
upon formation of the radical. Inspired by the work of the
Overman group,25 we decided to adopt their method for the
activation of the carboxylic acid at C6using the N-
hydroxyphthalimide ester (NHP ester) as the redox active
group (Figure 1).
While performing our studies, the Wang group published
their results on the decarboxylative photoalkylation of
furanoses and pyranoses.26 Their results showed that the
alkylation of benzyl and benzoyl-protected glycuronides led to
retention of configuration at C5. Here, we present an approach
in a complementary vein, leading, in contrast, to an inversion of
configuration at C5. To illustrate the scope and utility of our
method, we demonstrate how methyl L-guloside is prepared
from methyl D-mannoside in six steps and an overall yield of
21%.
radicals that are generated either by hydrogen atom transfer
(HAT) or via decarboxylation.2,3 Both processes are
productive, provided that the resulting radical is stabilized by
either orbital overlap of the singly occupied p-orbital with a σ-
bond (hyperconjugation)4 or by neighboring heteroatoms with
lone pairs (conjugation).5
Photoredox catalysis has been utilized in the synthesis of
natural products6−8 and even to derivatize complex bio-
molecules.5,9,10 Its application in the field of carbohydrate
chemistry enables the synthesis of derivatives that are difficult
to access via existing synthesis routes. We showcased this by
employing photocatalytic HAT for the site-selective alkylation
of unprotected glucosides.11 C3-alkylated allosides were
prepared using this approach. Taylor and co-workers recently
demonstrated that, in the presence of diarylborinic acids, the
strategy can be extended to differently configured glycosides.12
We subsequently realized that decarboxylative photo-
alkylation could provide another means to prepare carbohy-
drate derivatives. If C6 in a hexose is a carboxylic acid, as in
uronic acids, it should be amendable to this strategy. In
particular, their pyranoside forms should be suitable substrates.
After decarboxylation, the resulting radical at C5 is stabilized
by the ring oxygen, similar to the classical Barton radical
decarboxylation.13−16 The radical has nucleophilic character
and can attack electron-poor SOMOphiles, such as Michael
acceptors, forming a carbon−carbon bond at the β-position of
the SOMOphile.
We initiated our investigation with the hypothesis that
radical 1′, generated from the NHP ester 1, would add to a
Modification, including homologation, of the C6 hydroxyl
group in readily available D-sugars, such as glucose, mannose,
galactose, and N-acetylglucosamine, has been extensively
studied and is well-developed.17−21 Nonetheless, the decar-
Received: August 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03016
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Scope of the Decarboxylative Photoalkylation
Reaction*
Figure 1. Our previous work on glucoside C−H activation and new
approaches to C5 activation via photodecarboxylation.
SOMOphile, e.g., a Michael acceptor, to give the photo-
alkylation products (see Scheme 1). To indicate the stereo-
chemistry at C5 throughout this paper, regardless the exact
nature of the substituent, and relate this to accepted
nomenclature in carbohydrate chemistry, we denote products
with retention of stereochemistry as “D” and those with
inversion as “L”. Initial success was obtained with methyl
acrylate under the reaction conditions proposed by Overman,
leading to the separable diastereomers 2a and 2b in 24% and
45% yield, respectively. Other SOMOphiles, such as phenyl
vinyl sulfone, acrylonitrile, and methyl vinyl ketone worked as
well with comparable yields and again with a slight preference
for the L-isomer (Scheme 1, products 3, 4, and 5).
Cyclopentenone gave somewhat lower yields (6), because of
a troublesome purification. Diethyl vinylphosphate as a
SOMOphile caused problems in purification and multiple
addition but still afforded the desired product (7). Use of the
less-polarized SOMOphile 3-methoxy methyl acrylate gave the
corresponding xyloside, rather than the desired product (8).
Reduction of the substrate is an expected side reaction, also
observed by Okada in the original report of the reaction
associated with NHP esters.27 Alkynes were not suitable as
SOMOphiles; methyl propiolate provided a mixture of
uncharacterized products, whereas phenyl acetylene yielded
the xyloside. For both alkynes, the desired products (9 and 10)
were not obtained.
The study proceeded with the NHP esters of methyl 2,3,4-
O-tribenzyl-β-glucuronide and methyl 2,3,4-O-tribenzyl-α-
mannuronide (34 and 35; see the Supporting Information).
The yields and D:L ratios for β-glucuronide products 11 and 12
were comparable to those of α-glucuronide 2 and 4. We
obtained the products of the α-mannuronide 13 as an
inseparable mixture of the expected diastereomers with, in
this case, a slight preference for D-isomer 13a.
At this point, it was clear that, although the reaction protocol
was fine, the stereochemistry of the product was not fully
under control. In the literature, the stereoselectivity of radical
glycosylation at C1, a related process, has been well-studied.
Protected glucosides give α-C-glycosides via a radical
intermediate that adopts a boat conformation so that the C2
acyl/alkoxy substituent is axial, maximizing overlap of the lone
pair on the ring oxygen, the radical at C1, and the σ*CO orbital
at C2.28,29 Under similar conditions, xylosides yield mainly β-
*
a
Only the L-products are shown. Ru(bpy)3Cl2·6H2O. Solvent: 7:3
THF:water. bRu(bpy)3(PF6)2. Solvent: dry THF. cTCNHPI ester was
used instead. dYield for the L-product. Products are separable by
column chromatography, but the D-product was impure. D:L ratio
e
determined by HPLC. Yield adjusted for co-eluting phthalimide.
f Yield calculated after subsequent deprotection. gMixture of
h
diastereomers. D-product contaminated with coeluting unknown.
iReduction to xyloside. Intractable mixture.
j
C-glycosides, presumably via the inverted 1C4 chair inter-
mediate, because of its stability, relative to the boat
conformer.30 Moreover, the reactivity of the SOMOphile has
an effect on the stereoselectivity.31 We concluded that the
fluxional nature of the glycosyl radical was the reason for the
poor stereoselectivities observed with perbenzylglycuronides.
The Matsuda group showed that the stereochemical
outcome of radical glycosylations can be controlled by locking
4
the substrate either in the C1 conformation using the butane
diacetal (BDA) protecting group or in the C4 conformation,
1
using a boronate ester.32 They revealed that conformationally
restricted C1 radicals are predominantly attacked from the
axial direction, because of the overlap in the transition state of
the σ*‡ orbital of the forming C−C bond with the lone pair of
the ring oxygen. This special case of the anomeric effect
determines the outcome of the reaction. Approach from the
top face, although less hindered, disrupts this favorable overlap,
leading to a less-stable transition state.
We realized that a similar approach could be used to
enhance the L-selectivity of the decarboxylative photoalkylation
B
DOI: 10.1021/acs.orglett.9b03016
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of glycuronides. The rigid 6,6-trans-fused bicyclic system that
is formed upon protection of a 1,2-trans diol with the BDA
group33−36 should restrict the conformational freedom of the
glycosyl radical. This reasoning is supported by our DFT
calculation (ZORA-BLYP-D3(BJ)/TZ2P) of the BDA-man-
nosyl, BDA-galactosyl, and BDA-2-deoxyglucosyl C5 radical.
Scheme 2. L-Selective Decarboxylative Alkylation of
Methyl-α-Mannoside 14
4
The C1conformer is, by far, the most stable conformer. (See
the Supporting Information.) This is consistent with the ab
initio calculations of Matsuda et al. on the conformers of a C1
radical.30 As in the case of a C1 radical, axial attack of the C5
radical should be favored, leading to the L-product (see Figure
2).
To assess the generality of the approach, the methyl
glycosides of N-acetylglucosamine, 2-deoxyglucose, and
galactose were similarly converted to the corresponding
NHP esters and subjected to decarboxylative photoalkylation
with various SOMOphiles (see Scheme 1, 18−24). The
mannuronides and galacturonides provided the L-product with
high selectivity upon alkylation with acrylonitrile (18 and 24),
while the NHP esters of N-acetylglucosaminuronide and 2-
deoxyglucuronide showed a somewhat lower L-selectivity upon
alkylation (22 and 24). The stereoselectivity was sensitive for
the SOMOphile used (18, 19 and 21). Nevertheless, the L-
product was always favored. This scope demonstrated the
functional group tolerance of the current strategy as well, as
free hydroxyl groups and amides were tolerated. During the
course of the investigation, the NHP ester of methyl
galacturonide was found to be susceptible to hydrolysis, and,
therefore, the reaction was performed in anhydrous tetrahy-
drofuran (THF) with the organic soluble Ru(bpy)3(PF6)2.
Yields and selectivities were comparable, as expected. The
procedure was further fine-tuned by switching N-hydroxyph-
thalimide to N-hydroxytetrachlorophthalimide (TCNHPI), the
latter pioneered by Baran and co-workers as a redox-active
group.38,39 This avoided coelution of the byproduct
phthalimide. To demonstrate the utility of the methodology
for oligosaccharide synthesis, L-thio-guloside 20, a donor in
glycosylation reactions, was prepared in 48% yield.
Figure 2. (Top) Results of DFT geometry optimization of the
mannosyl radical for both the chair and the half-chair conformer.
(Bottom) Prediction of the stereochemical outcome of the C5
alkylation in both the α-galactosyl and α-mannosyl radical modeled
after Matsuda et al. The chair conformation and Newman projection
viewed from the ring oxygen are depicted.
Therefore, we embarked on the synthesis of the BDA-locked
NHP-esters of glycuronides. Mannuronide 17 was prepared in
50% yield over three steps without intermediate purification by
reacting the C3-OH and C4-OH in 14 with butanedione,
oxidizing the primary OH with TEMPO/BAIB37 and
esterifying the resulting acid with N-hydroxyphthalimide (see
Scheme 2).
NHP-ester 17 was subjected to the photoalkylation reaction
with acrylonitrile to give 18 in 77% yield, with a rewarding D:L
ratio of 1:11, overwhelmingly favoring the L-isomer. The
presence of the D-isomer was confirmed after quantitative
removal of the BDA group.33 A small amount of double
addition product was also isolated (18s). In an attempt to
minimize the formation of 18s, the amount of acrylonitrile and
Hantzsch ester was varied, but this did not result in a
To compare our results with those of Wang et al., the
TCNHPI -ester of methyl 2-deoxyglucuronide 26 was used in
their benchmark reaction with the p-fluoroaniline imine of
ethyl glyoxylate (Scheme 3). Contrary to the aforementioned
SOMOphiles, the isolated product 27 had the D-configuration.
Combining this result with the previously observed low
selectivity with the NHP esters of the perbenzyl glycosides,
we hypothesize that the addition of radical 1′ to the imine is
reversible, leading to the thermodynamic product, whereas the
addition to a Michael acceptor is irreversible, leading to a
1
significantly improved yield. Compound 25 adopts the C4
conformer, as judged from the coupling constants in the
variable temperature 1H NMR spectra (J1,2 = 1.5 Hz in 18 and
8.2 Hz in 25).
C
DOI: 10.1021/acs.orglett.9b03016
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
workup using NaBH4, afforded methyl L-guloside 29 in 59%
yield with retention of stereochemistry.
Scheme 3. (Top) Photoalkylation of 26 with an Imine
SOMOphile, According to Wang et al. (Bottom) An
Explanation of the Observed D-Selectivity in the Case of
Imine Addition
In this investigation, we have synthesized alkylated glyco-
sides from their corresponding NHP esters via decarboxylative
photoalkylation. The stereochemical outcome of the reaction
4
could be controlled by locking the substrate in a C1 chair
conformation via its butane diacetal derivative. This strategy
provides the products with inversion of stereochemistry at C5,
when Michael acceptors are used as SOMOphiles. Compared
to most of the previous strategies to prepare L-hexoses, the
current strategy has the advantage that the pyranose
connectivity is preserved. This is important, since most
synthetic manipulations of monosaccharides rely heavily on
the substrate control provided by the rigid pyranose form.46
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.9b03016.
Experimental details; DFT calculations; experimental
procedures; NMR and HRMS spectra of the new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: a.j.minnaard@rug.nl (A. J. Minnaard).
*E-mail: m.d.witte@rug.nl (M. D. Witte).
ORCID
mixture of D- and L-products. This also explains the poor
selectivity observed in the reaction of NHP-glycoside esters
without conformational lock (see Scheme 3, bottom).
Martin D. Witte: 0000-0003-4660-2974
With these results in hand, we decided to apply our
methodology to the synthesis of L-gulose from D-mannose. L-
Gulose is a rare sugar that has been synthesized previously via
different routes40−43 and is part of the important anticancer
drug bleomycin A2.44 L-Guluronic acid forms, together with D-
mannuronic acid, the biopolymer alginic acid, which is widely
found in the cell walls of brown algae and the pathogenic
bacterium P. aeruginosa.45 A strategy to introduce the required
hydroxymethylene unit was found using ethyl (Z)-β-
bromoacrylate as the SOMOphile, which eliminates HBr
after photoalkylation to produce the corresponding alkene 28
in 70% yield (Scheme 4). We noted that ozonolysis, followed
by reductive workup, invariably led to epimerization of the
axial C5 substituent. Therefore, the BDA group was removed
first, allowing ring flip, so that the C5 substituent would be
equatorial. In the event, ozonolysis, followed by reductive
Adriaan J. Minnaard: 0000-0002-5966-1300
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank P. van der Meulen, Dr. J. Kemmink, R. Sneep, and T.
Tiemersma (University of Groningen) for assistance on
analyses. The Dutch Science Foundation NWO is acknowl-
edged for funding.
REFERENCES
■
(1) McAtee, R. C.; McClain, E. J.; Stephenson, C. R. J. Trends Chem.
2019, 1 (1), 111−125.
(2) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116 (17),
10075−10166.
Scheme 4. Synthesis of Methyl β-L-Guloside 29
(3) Twilton, J.; Le, C.; Zhang, P.; Shaw, M. H.; Evans, R. W.;
MacMillan, D. W. C. Nat. Rev. Chem. 2017, 1, 0052.
(4) Nawrat, C. C.; Jamison, C. R.; Slutskyy, Y.; MacMillan, D. W. C.;
Overman, L. E. J. Am. Chem. Soc. 2015, 137 (35), 11270−11273.
(5) McCarver, S. J.; Qiao, J. X.; Carpenter, J.; Borzilleri, R. M.; Poss,
M. A.; Eastgate, M. D.; Miller, M. M.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2017, 56 (3), 728−732.
(6) Tao, D. J.; Slutskyy, Y.; Muuronen, M.; Le, A.; Kohler, P.;
Overman, L. E. J. Am. Chem. Soc. 2018, 140 (8), 3091−3102.
(7) Garnsey, M. R.; Slutskyy, Y.; Jamison, C. R.; Zhao, P.; Lee, J.;
Rhee, Y. H.; Overman, L. E. J. Org. Chem. 2018, 83 (13), 6958−6976.
D
DOI: 10.1021/acs.orglett.9b03016
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) Pitre, S. P.; Weires, N. A.; Overman, L. E. J. Am. Chem. Soc.
2019, 141 (7), 2800−2813.
(40) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem.
1999, 64 (9), 2982−2983.
̈
(41) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3 (24),
3899−3902.
(9) Bloom, S.; Liu, C.; Kolmel, D. K.; Qiao, J. X.; Zhang, Y.; Poss,
M. A.; Ewing, W. R.; Macmillan, D. W. C. Nat. Chem. 2018, 10 (2),
205−211.
̈
(42) Harris, J. M.; Keranen, M. D.; Nguyen, H.; Young, V. G.;
O’Doherty, G. A. Carbohydr. Res. 2000, 328 (1), 17−36.
(43) Wang, H.-Y. L.; O’Doherty, G. A. Chem. Commun. 2011, 47
(37), 10251.
(10) Ito, Y.; Kimura, A.; Osawa, T.; Hari, Y. J. Org. Chem. 2018, 83
(18), 10701−10708.
(11) Wan, I. C.; Witte, M. D.; Minnaard, A. J. Chem. Commun. 2017,
53 (36), 4926−4929.
(44) Umezawa, H. Prog. Biochem. Pharmacol. 1976, 11, 18−27.
(45) Davies, J. C. Paediatr. Respir. Rev. 2002, 3 (2), 128−134.
(46) Wang, T.; Demchenko, A. V. Org. Biomol. Chem. 2019, 17 (20),
4934−4950.
(12) Dimakos, V.; Su, H. Y.; Garrett, G. E.; Taylor, M. S. J. Am.
Chem. Soc. 2019, 141 (13), 5149−5153.
(13) Jin, J.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2015, 54 (5),
1565−1569.
(14) Noble, A.; McCarver, S. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2015, 137 (2), 624−627.
(15) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc.,
Chem. Commun. 1983, 53 (17), 939.
(16) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron
1985, 41 (19), 3901−3924.
̈
(17) Jager, M.; Minnaard, A. J. Chem. Commun. 2016, 52, 656−664.
(18) Descotes, G.; Martin, J.-C.; Tachi-Dung. Carbohydr. Res. 1978,
62 (1), 61−71.
(19) Ogawa, S.; Funaki, Y.; Iwata, K.; Suami, T. Bull. Chem. Soc. Jpn.
1976, 49 (7), 1975−1979.
́
(20) Durka, M.; Tikad, A.; Perion, R.; Bosco, M.; Andaloussi, M.;
Floquet, S.; Malacain, E.; Moreau, F.; Oxoby, M.; Gerusz, V.; Vincent,
S. P. Chem. - Eur. J. 2011, 17 (40), 11305−11313.
(21) Horneman, A. M.; Lundt, I. J. Carbohydr. Chem. 1995, 14 (1),
1−8.
(22) Frihed, T. G.; Pedersen, C. M.; Bols, M. Angew. Chem., Int. Ed.
2014, 53 (50), 13889−13893.
(23) Frihed, T. G.; Bols, M.; Pedersen, C. M. Chem. Rev. 2015, 115
(9), 3615−3676.
(24) de Leder Kremer, R. M.; Gallo-Rodriguez, C. Adv. Carbohydr.
Chem. Biochem. 2004, 59, 9−67.
(25) Pratsch, G.; Lackner, G. L.; Overman, L. E. J. Org. Chem. 2015,
80 (12), 6025−6036.
(26) Ji, P.; Zhang, Y.; Wei, Y.; Huang, H.; Hu, W.; Mariano, P. A.;
Wang, W. Org. Lett. 2019, 21 (9), 3086−3092.
(27) Okada, K.; Okamoto, K.; Morita, N.; Okubo, K.; Oda, M. J.
Am. Chem. Soc. 1991, 113 (24), 9401−9402.
(28) Korth, H.; Sustmann, R.; Dupuis, J.; Giese, B. J. Chem. Soc.,
Perkin Trans. 2 1986, No. 9, 1453−1459.
́
(29) Gong, H.; Gagne, M. R. J. Am. Chem. Soc. 2008, 130 (36),
12177−12183.
(30) Abe, H.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2001, 123
(48), 11870−11882.
(31) Kiya, N.; Hidaka, Y.; Usui, K.; Hirai, G. Org. Lett. 2019, 21 (6),
1588−1592.
(32) Oestreich, M. Angew. Chem., Int. Ed. 2014, 53 (9), 2282−2285.
(33) Hense, A.; Ley, S. V.; Osborn, H. M. I.; Owen, D. R.; Poisson,
J.; Warriner, S. L.; Wesson, K. E. J. Chem. Soc., Perkin Trans. 1 1997,
No. 14, 2023−2032.
(34) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J. Chem.
̈
Soc., Perkin Trans. 1 1998, No. 1, 51−66.
(35) Ley, S. V.; Priepke, H. W. M. Angew. Chem., Int. Ed. Engl. 1994,
33 (22), 2292−2294.
(36) Baeschlin, D. K.; Chaperon, A. R.; Green, L. G.; Hahn, M. G.;
Ince, S. J.; Ley, S. V. Chem. - Eur. J. 2000, 6 (1), 172−186.
́
(37) Walvoort, M. T. C.; Sail, D.; van der Marel, G. A.; Codee, J. D.
C. In Carbohydrate Chemistry: Proven Synthetic Methods, Vol. 1;
́
̌
Kovac, P., Ed.; CRC Press, 2016; pp 99−105.
(38) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.;
Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. Science
2016, 352 (6287), 801−805.
(39) DeGruyter, J. N.; Malins, L. R.; Wimmer, L.; Clay, K. J.; Lopez-
Ogalla, J.; Qin, T.; Cornella, J.; Liu, Z.; Che, G.; Bao, D.; Stevens, J.
M.; Qiao, J. X.; Allen, M. P.; Poss, M. A.; Baran, P. S. Org. Lett. 2017,
19 (22), 6196−6199.
E
DOI: 10.1021/acs.orglett.9b03016
Org. Lett. XXXX, XXX, XXX−XXX