Sonogashira-Hagihara reactions of halogenated glycals

Article abstract of DOI:10.3762/bjoc.8.75

Herein, we report on our findings of the Sonogashira-Hagihara reaction with 1-iodinated and 2-brominated glycals using several aromatic and aliphatic alkynes. This Pd-catalyzed cross-coupling reaction presents a facile access to alkynyl C-glycosides and sets the stage for a reductive/oxidative refunctionalization of the enyne moiety to regenerate either C-glycosidic structures or pyran derivatives with a substituent in position 2.

Full text of DOI:10.3762/bjoc.8.75

Sonogashira–Hagihara reactions of
halogenated glycals
Dennis C. Koester and Daniel B. Werz*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 675–682.
Institut für Organische und Biomolekulare Chemie,
Georg-August-Universität Göttingen, Tammannstr. 2,
37077 Göttingen, Germany
doi:10.3762/bjoc.8.75
Received: 01 March 2012
Accepted: 04 April 2012
Published: 02 May 2012
Email:
Daniel B. Werz* - dwerz@gwdg.de
This article is part of the Thematic Series "Synthesis in the
glycosciences II".
* Corresponding author
Keywords:
Guest Editor: T. K. Lindhorst
C-glycosides; enyne; glycals; reductive/oxidative refunctionalization;
Sonogashira–Hagihara reaction
© 2012 Koester and Werz; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Herein, we report on our findings of the Sonogashira–Hagihara reaction with 1-iodinated and 2-brominated glycals using several
aromatic and aliphatic alkynes. This Pd-catalyzed cross-coupling reaction presents a facile access to alkynyl C-glycosides and sets
the stage for a reductive/oxidative refunctionalization of the enyne moiety to regenerate either C-glycosidic structures or pyran
derivatives with a substituent in position 2.
Introduction
Carbohydrates are key players in a plethora of biological emerged as valuable synthetic targets, not only for medicinal
processes, such as cell-development, metastasis, cell–cell chemists, but also for methodologists [8]. In particular, glycals
aggregation and viral infection [1-4]. Many different monosac- have transpired as versatile building blocks in the synthesis of
charide units and the large variety of possibilities to link two various C-glycosides. Most of the reported preparations of
subunits result in an immense variety of highly complex alkyl- and aryl-C-glycosides rely on glycals as starting ma-
biomolecules [5-7]. In order to mimic certain subunits of oligo- terials. Transition-metal-catalyzed cross-coupling reactions play
saccharides, e.g., for the inhibition of glycosidases or glycosyl- a key role in the assembly of these structures; thus, many metal-
transferases, modified mono- or disaccharides have come into ated glycals have been employed in their synthesis. Scheme 1
the focus of medicinal chemists [8,9]. An important class of provides a brief overview.
carbohydrate mimetics are the C-glycosides [10-13]. In such
compounds the oxygen of the O-glycosidic bond is substituted In 1990 Beau and co-workers utilized 1-stannylated glycals
by a methylene unit rendering them stable to enzymatic degrad- of type 1 in a Stille cross-coupling for the synthesis of aryl-
ation or hydrolysis. During the past decades C-glycosides have C-glycosides such as 2 (R = Ar) [14,15]. To generate these
675

Beilstein J. Org. Chem. 2012, 8, 675–682.
Scheme 1: Different strategies to access C-glycosides starting from 1-substituted glycals.
1-substituted glycals a prefunctionalization of the pseudo- ing. In a careful optimization study, Tan and co-workers found
anomeric carbon is mandatory. Recent advances in the field of that several alkenes hydroborated in situ with 9-BBN can be
C–H functionalization allowed for the mild and selective utilized in a Suzuki–Miyaura coupling with iodoglucals 6 to
borylation of unfunctionalized glycals. Starting from yield aliphatic C-glycosides [19]. This method impressively
persilylated glycals Ishikawa and Miyaura applied an Ir-cata- demonstrates the power of the Suzuki–Miyaura coupling in the
lyzed C–H-functionalization with B2pin2 to obtain 1-borylated formation of C(sp2)–C(sp3) bonds for the preparation of carbo-
glycals, such as 3, in excellent yields and selectivity. They eleg- hydrate mimetics. Friesen and co-workers reported on a syn-
antly demonstrated the use of these compounds in the synthesis thesis of aryl-C-glycosides employing different metalated
of aryl-, allyl- and benzyl-C-glycosides [16]. The group of arenes with persilylated 1-iodoglucals [20]. These proved to be
Minehan described another fascinating approach to aryl- particularly reactive to organozinc and organoboron com-
C-glycosides in 2003 [17]. They showed that aryl-C-glycosides pounds, whereas Hayashi successfully disclosed an approach to
can be prepared from glycalyl indium(III) compounds (e.g., 4) react simple stannylated or even electron-poor olefins with
in a Pd-catalyzed cross-coupling reaction with iodoarenes.
2-bromoglucals in Stille and Heck reactions, respectively [21].
The dienes obtained during these transformations were success-
However, it is not only metalated sugar derivatives that have fully converted in Diels–Alder reactions to afford carbocyclic
prevailed in the synthesis of C-glycosides, but also some elec- chiral compounds with a sugar backbone.
trophilic coupling reagents, such as glycalyl phosphates, and
bromo- and iodoglycals. Glycal phosphates of type 5 were In 2008, Gagné introduced a Ni-mediated Negishi coupling to
employed as electrophiles in a Stille cross-coupling reaction synthesize alkyl- and aryl-C-glycosides from glycosyl halides
[18]. These building blocks exhibit a high stability and effi- [22]. Worthy of note is that this transformation displays a
ciency in their formation and are therefore particularly interest- C(sp3)–C(sp3) coupling in the case of alkyl-C-glycosides and a
676

Beilstein J. Org. Chem. 2012, 8, 675–682.
C(sp2)–C(sp3) coupling in the preparation of aryl-C-glycosides. We started our investigations with the persilylated 1-iodoglucal
Although the diasteroselectivity of the reaction is highly 7, which is easily available by a sequence of lithiation and
dependent on the type of monosaccharide, this approach is iodination from the parent, fully TIPS-protected congener [25].
unique due to its use of fully functionalized sugars, thus The Sonogashira reaction was carried out under standard condi-
avoiding further refunctionalization steps to obtain the native tions. Pd(PPh3)2Cl2 was used as catalyst, and CuI served as
C-glycoside.
cocatalyst. The reaction was performed at room temperature for
12 h in neat triethylamine acting as the solvent as well as base.
As coupling partners, a variety of commercially available
Results and Discussion
Despite the numerous organometallic reactions performed with alkynes as depicted in Table 1 were investigated. The yields
substituted glycals, to the best of our knowledge there has been proved to be good to excellent (72% to 92%). Aromatic as well
no in-depth study of the synthesis of 1- and 2-alkynylated as aliphatic alkynes could be employed for this reaction leading
glycals by means of the Sonogashira–Hagihara reaction to date. to excellent results. Fluorinated alkynyl-C-glycosides (Table 1,
Herein, we wish to report on our findings with respect to the entry 4) may be readily functionalized at the aromatic core,
reaction of persilylated 1-iodoglucal 7 and peracetylated whereas TMS-protected enynes (Table 1, entry 6) allow for
2-bromogalactal 10 with readily available alkynes 8a–8h. We further manipulations on the alkynyl residue. Our previous
became interested in this chemistry whilst searching for a studies also revealed that even carbohydrate-derived alkynes
method to synthesize (1→6)-linked C-glycosidic disaccharide can be utilized under these reaction conditions in an efficient
mimetics [23]. The simplicity of the transformation, the mild manner [23].
reaction conditions, and the commercial availability of the cata-
lyst render this method highly useful for the preparation of Our recent interest in domino reactions starting with 2-bromin-
internal alkynes [24].
ated glycals [26-28] motivated us to investigate also the behav-
Table 1: Sonogashira–Hagihara reactions of 1-iodoglucal 7 with different alkynes 8a–8h.
entry
alkyne
product
yield [%]a
1
92
8a
9a
9b
9c
2
3
72
86
8b
8c
677

Beilstein J. Org. Chem. 2012, 8, 675–682.
Table 1: Sonogashira–Hagihara reactions of 1-iodoglucal 7 with different alkynes 8a–8h. (continued)
4
82
8d
9d
5
90
79
8e
9e
6
8f
9f
7
83
90
8g
9g
8
8h
9h
aIsolated yields.
iour of peracetylated 2-bromogalactal 10 in Sonogashira–Hagi- use of an elevated temperature did not lead to the formation of
hara reactions (Table 2). We found that 10 is much less reactive an enediyne. Further refunctionalization of the enynes was
than 7. This may be due to a more facile oxidative addition to achieved by selective reduction of the triple bond by making
the C–I bond compared to the C–Br bond. Furthermore, we use of Raney nickel (Table 3). We found that the electron-rich
assume that the electron density at C-2 of the sugar core is enol ether moiety remains untouched, when reaction times of
particularly high, rendering the 2-palladated glycal a bad elec- less than four hours were chosen in the case of the enynes
trophile towards electron-poor or electron-neutral alkynes. To 9e–9h. It should be noted that methanol was a crucial part of the
push the reaction an elevated temperature was necessary, and solvent mixture, otherwise no reaction was observed. Interest-
only moderate yields were obtained.
ingly, when we employed the perbenzylated enyne 9ea the yield
of the alkyne-reduced product decreased tremendously. A mix-
Efforts to react perbenzylated 2-chloro-1-iodoglucal 12 in a ture of completely reduced products was obtained. Thus, we
twofold Sonogashira reaction with an excess of phenylacetylene assume that not only electronic effects, but also the sterically
resulted in a chemoselective monoalkynylation of the pseudo- encumbered TIPS groups render the reduction of the olefinic
anomeric position in quantitative yield (Scheme 2). Even the moiety much more difficult.
Scheme 2: Sonogashira–Hagihara reaction of 1-iodo-2-chloroglucal 12 with phenylacetylene (8a) to afford 13.
678

Beilstein J. Org. Chem. 2012, 8, 675–682.
Table 2: Sonogashira–Hagihara reactions of 2-bromogalactal 10 with different alkynes.
entry
alkyne
product
yield [%]a
1
66
8a
11a
11b
11c
2
3
45
8f
traces
8g
aIsolated yields.
Table 3: Reduction of carbohydrate-derived enynes 9e–9h and 11a–11b.
entry
substrate
time [h]
solvent
product
yield [%]a
MeOH:THF
(1:1)
1
3
88
9e
14a
14b
MeOH:THF
(1:1)
2
12
11
9ea
679

Beilstein J. Org. Chem. 2012, 8, 675–682.
Table 3: Reduction of carbohydrate-derived enynes 9e–9h and 11a–11b. (continued)
MeOH:THF
3
4
5
4
4
7
63
(1:1)
9h
9e
9e
14c
THF
0
14c
MeOH:THF
(1:1)
58
14c
MeOH:DCM:EtOAc
(3:1:1)
6b,c
12
12
97
11a
11b
14d
MeOH:DCM:EtOAc
(3:1:1)
7b
86
14e
aIsolated yields; bPearlman’s catalyst (Pd(OH)2/C) was used instead of Raney-Ni; cFully reduced carbohydrate mimetic was observed; a final proof of
the stereochemistry by NOESY effects was not possible due to strongly overlapping signals. However, the stereochemistry given is highly reasonable
because of the shielding of the top face by three substituents [29].
In contrast to the other enynes the carbohydrate derivative 11a coordinates the epoxide oxygen allowing the hydride to attack
was fully reduced in a diastereoselective manner and in excel- from the same side, leading to β-configured alkyl-C-glycosides.
lent yield to the pyran 14d by employing Pearlman’s catalyst The epoxidation/ring-opening sequence of TIPS-protected
(rt, overnight), whereas in the case of enyne 11b, under the glucals proved to be challenging; for the respective product 15c
same reaction conditions, only the triple bond was reduced to only a yield of 13% was observed.
furnish enol ether 14e selectively.
Conclusion
In three cases we further functionalized the 1-alkylated glycals We investigated the behaviour of 1-iodinated and 2-brominated
by an epoxidation/epoxide-opening sequence [30-33]. glycals in Sonogashira–Hagihara cross-coupling reactions with
Dimethyldioxirane (DMDO) was used as a neutral epoxidation various alkylated and arylated alkynes. 1-Alkynylated glycals
reagent leading to a facial-selective epoxide formation [34-36]. were obtained in very good yields whereas the alkynylation in
The so-obtained highly reactive acetal epoxide was either position 2 gave poorer results. Chemoselective reduction of the
attacked by a superhydride, such as LiBHEt3 [31], or by a triple bond in the resulting enyne system by the action of
Lewis acidic hydrogen transfer agent, such as DIBAL-H Raney-Ni furnished enol ethers, which could be readily refunc-
[32,33]. In the former case, an SN2-type reaction takes place tionalized. Methanol proved to be an essential co-solvent in
leading to the α-gluco-configured C-glycoside 15a in a order to execute the Ni-catalyzed reduction. The enol ether
moderate yield of 30% (Table 4). The aluminium centre double bond could be further hydroxylated by an epoxidation/
680

Beilstein J. Org. Chem. 2012, 8, 675–682.
Table 4: Diastereoselective epoxidation/epoxide opening sequence employing different hydride sources to afford 15a–15c.
entry
substrate
product
yield [%]a
1b
30
14b
15a
15b
2c
3c
40
13
14b
14c
15c
*Stereochemistry depending on the hydride source; aIsolated yields; bLiBHEt3 was employed as a hydride source; cDIBAL-H was employed as a
hydride source.
epoxide opening sequence. Depending on the hydride source Acknowledgements
α- and β-configured alkyl-C-glycosides were obtained diaste- This work was supported by the Deutsche Forschungsgemein-
reoselectively in moderate yield. These investigations with schaft and the Fonds der Chemischen Industrie (Emmy Noether
respect to the Sonogashira–Hagihara coupling complement the Fellowship to D.B.W. and Dozentenstipendium to D.B.W.).
rich organometallic chemistry that has already been performed D.C.K. is grateful to the Fonds der Chemischen Industrie for a
with borylated, stannylated and phosphorylated glycals.
Ph.D. fellowship. The authors acknowlegde Reinhard Machinek
(University of Göttingen) for giving every possible support
during NMR spectroscopy measurements. Martin Pawliczek is
acknowledged for a donation of 2-bromogalactal. The authors
also thank Professor Dr. Lutz F. Tietze (University of
Göttingen) for helpful discussions and generous support of our
work.
Supporting Information
Supporting Information containing all experimental details
and analytical data of all new compounds given in this
article as well as their 1H and 13C NMR spectra is
provided.
References
1. Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046–1051.
Supporting Information File 1
doi:10.1038/nature05819
Experimental procedures, analytical data and NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-75-S1.pdf]
2. Varki, A. Glycobiology 1993, 3, 97–130. doi:10.1093/glycob/3.2.97
3. Dwek, R. A. Chem. Rev. 1996, 96, 683–720. doi:10.1021/cr940283b
681

Beilstein J. Org. Chem. 2012, 8, 675–682.
4. Lorenz, B.; Álvarez de Cienfuegos, L.; Oelkers, M.; Kriemen, E.;
Brand, C.; Stephan, M.; Sunnick, E.; Yüksel, D.; Kalsani, V.; Kumar, K.;
Werz, D. B.; Janshoff, A. J. Am. Chem. Soc. 2012, 134, 3326–3329.
doi:10.1021/ja210304j
28.Leibeling, M.; Milde, B.; Kratzert, D.; Stalke, D.; Werz, D. B.
Chem.–Eur. J. 2011, 17, 9888–9892. doi:10.1002/chem.201101917
29.Cobo, I.; Matheu, M. I.; Castillón, S.; Boutureira, O.; Davis, B. G.
Org. Lett. 2012, 14, 1728–1731. doi:10.1021/ol3003139
30.Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6661–6666. doi:10.1021/ja00199a028
5. Werz, D. B.; Ranzinger, R.; Herget, S.; Adibekian, A.;
von der Lieth, C.-W.; Seeberger, P. H. ACS Chem. Biol. 2007, 2,
685–691. doi:10.1021/cb700178s
31.Inoue, M.; Yamashita, S.; Tatami, A.; Miyazaki, K.; Hirama, M.
J. Org. Chem. 2004, 69, 2797–2804. doi:10.1021/jo049877x
32.Krishnamurthy, S.; Schubert, R. M.; Brown, H. C. J. Am. Chem. Soc.
1973, 95, 8486–8487. doi:10.1021/ja00806a067
6. Laine, R. A. Glycobiology 1994, 4, 759–767.
doi:10.1093/glycob/4.6.759
7. Adibekian, A.; Stallforth, P.; Hecht, M.-L.; Werz, D. B.; Gagneux, P.;
Seeberger, P. H. Chem. Sci. 2011, 2, 337–344.
33.Majumder, U.; Cox, J. M.; Johnson, H. W. B.; Rainier, J. D.
Chem.–Eur. J. 2006, 12, 1736–1746. doi:10.1002/chem.200500993
34.Adam, W.; Chan, Y.-Y.; Cremer, D.; Gauss, J.; Scheutzow, D.;
Schindler, M. J. Org. Chem. 1987, 52, 2800–2803.
doi:10.1039/c0sc00322k
8. Koester, D. C.; Holkenbrink, A.; Werz, D. B. Synthesis 2010,
3217–3242. doi:10.1055/s-0030-1258228
9. Sears, P.; Wong, C.-H. Angew. Chem. 1999, 111, 2446–2471.
doi:10.1002/(SICI)1521-3757(19990816)111:16<2446::AID-ANGE2446
>3.0.CO;2-4
doi:10.1021/jo00389a029
35.Düfert, A.; Werz, D. B. J. Org. Chem. 2008, 73, 5514–5519.
doi:10.1021/jo800692z
Angew. Chem. Int. Ed. 1999, 38, 2300–2324.
36.Alberch, L.; Cheng, G.; Seo, S.-K.; Li, X.; Boulineau, F. P.; Wei, A.
J. Org. Chem. 2011, 76, 2532–2547. doi:10.1021/jo102382r
doi:10.1002/(SICI)1521-3773(19990816)38:16<2300::AID-ANIE2300>3
.0.CO;2-6
10.Rouzaud, D.; Sinaÿ, P. J. Chem. Soc., Chem. Commun. 1983,
1353–1354. doi:10.1039/C39830001353
11.Giese, B.; Hoch, M.; Lamberth, C.; Schmidt, R. R. Tetrahedron Lett.
1988, 29, 1375–1378. doi:10.1016/S0040-4039(00)80300-7
12.Postema, M. H. D.; Piper, J. L.; Komanduri, V.; Lei, L. Angew. Chem.
2004, 116, 2975–2978. doi:10.1002/ange.200353478
Angew. Chem. Int. Ed. 2004, 43, 2915–2918.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
doi:10.1002/anie.200353478
13.Wiebe, C.; Schlemmer, C.; Weck, S.; Opatz, T. Chem. Commun. 2011,
47, 9212–9214. doi:10.1039/c1cc13078a
14.Dubois, E.; Beau, J.-M. J. Chem. Soc., Chem. Commun. 1990,
1191–1192. doi:10.1039/C39900001191
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
15.Dubois, E.; Beau, J.-M. Carbohydr. Res. 1992, 228, 103–120.
doi:10.1016/S0008-6215(00)90552-4
(http://www.beilstein-journals.org/bjoc)
16.Kikuchi, T.; Takagi, J.; Isou, H.; Ishiyama, T.; Miyaura, N.
Chem.–Asian J. 2008, 3, 2082–2090. doi:10.1002/asia.200800157
17.Lehmann, U.; Awasthi, A.; Minehan, T. Org. Lett. 2003, 5, 2405–2408.
doi:10.1021/ol0345428
The definitive version of this article is the electronic one
which can be found at:
18.Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J. L.; Gärtner, P.; Yang, Z.
J. Am. Chem. Soc. 1997, 119, 5467–5468. doi:10.1021/ja970619+
19.Potuzak, J. S.; Tan, D. S. Tetrahedron Lett. 2004, 45, 1797–1801.
doi:10.1016/j.tetlet.2003.12.006
doi:10.3762/bjoc.8.75
20.Friesen, R. W.; Loo, R. W.; Sturino, C. F. Can. J. Chem. 1994, 72,
1262–1272. doi:10.1139/v94-160
21.Hayashi, M.; Tsukada, K.; Kawabata, H.; Lamberth, C. Tetrahedron
1999, 55, 12287–12294. doi:10.1016/S0040-4020(99)00727-9
22.Gong, H.; Gagné, M. R. J. Am. Chem. Soc. 2008, 130, 12177–12183.
doi:10.1021/ja8041564
23.Koester, D. C.; Leibeling, M.; Neufeld, R.; Werz, D. B. Org. Lett. 2010,
12, 3934–3937. doi:10.1021/ol101625p
24.Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16,
4467–4470. doi:10.1016/S0040-4039(00)91094-3
25.Friesen, R. W.; Loo, R. W. J. Org. Chem. 1991, 56, 4821–4823.
doi:10.1021/jo00016a003
26.Leibeling, M.; Koester, D. C.; Pawliczek, M.; Schild, S. C.; Werz, D. B.
Nat. Chem. Biol. 2010, 6, 199–201. doi:10.1038/nchembio.302
27.Leibeling, M.; Koester, D. C.; Pawliczek, M.; Kratzert, D.; Dittrich, B.;
Werz, D. B. Bioorg. Med. Chem. 2010, 18, 3656–3667.
doi:10.1016/j.bmc.2010.03.004
682