Characterization of the isochromen-4-yl-gold(I) intermediate in the gold(I)-catalyzed glycosidation of glycosyl ortho-alkynylbenzoates and enhancement of the catalytic efficiency thereof

Article abstract of DOI:10.1002/anie.201103409

Gold standard: The title gold complex (see scheme) was characterized unambiguously as an important intermediate in the title reaction. Protonolysis of this vinyl gold(I) complex was critical for regeneration of the active gold(I) species for the catalytic

Full text of DOI:10.1002/anie.201103409

DOI: 10.1002/anie.201103409
Glycosylation
Characterization of the Isochromen-4-yl-gold(I) Intermediate in the
Gold(I)-Catalyzed Glycosidation of Glycosyl ortho-Alkynylbenzoates
and Enhancement of the Catalytic Efficiency Thereof**
Yugen Zhu and Biao Yu*
We have recently developed a new glycosylation protocol
with glycosyl ortho-alkynylbenzoates as donors and a gold(I)
complex (e.g., [Ph3PAuOTf], OTf = O3SCF3) as catalyst.[1]
The power and versatility of this gold(I)-catalyzed glycosyla-
tion method have been demonstrated in the effective
construction of a wide variety of glycosidic linkages and the
total synthesis of complex oligosaccharides and glycoconju-
gates.[1–6] Moreover, the unprecedented activation mechanism
has endowed this protocol with unique merits, including
1) the absence of competitive nucleophilic species (which
usually occur in the leaving entity or promoter in classical
glycosylation reactions), which enables glycosylation-initiated
Scheme 1. The proposed mechanism for the gold(I)-catalyzed glycosi-
dation of glycosyl o-alkynylbenzoates.
polymerization of tetrahydrofuran to proceed smoothly;[3]
2) the lack of deteriorative electrophilic species (such as the
soft Lewis acidic species used as promoters in classical
glycosylation reactions), which enables flavonol 3-OH deriv-
atives vulnerable toward electrophiles to be glycosylated
efficiently;[4] and 3) the mild and nearly neutral conditions,
which allow the extremely acid-labile aglycones, such as the
N-Boc-protected purine derivatives (Boc = tert-butoxycar-
bonyl) and dammarane derivatives, to be glycosylated effec-
tively.[5,6]
gold(I) intermediates in these transformations were charac-
terized.[9] Herein we report the isolation and characterization
of the isochromen-4-yl-gold(I) intermediate D, which has
enabled us to gain insight into the detailed catalytic cycle so as
to provide a solution to enhance the catalytic efficiency of the
gold(I)-catalyzed glycosylation reaction.
Unexpected but easily understandable results were
obtained when we attempted to glycosylate with 3,4,6-tri-O-
acetyl-2-deoxy-2-p-methoxybenzylideneamino-b-d-glucopyr-
anosyl-o-hexynylbenzoate (1) as donor (Scheme 2).[10] Under
the normal conditions (0.1 equiv [Ph3PAuOTf], toluene, 4 ꢀ
molecular sieves (M.S.), RT),[1] the coupling reaction of donor
1 with n-pentenol (2) was hardly observable; upon raising the
loading of the gold(I) catalyst to 0.5 equiv, the reaction
proceeded smoothly, albeit leading to the b-glycoside 3 and a-
glycoside 4 in 37 and 47% yield, respectively (within 4 h). The
a-glycoside 4 was assumed to be derived from the corre-
sponding 2-p-methoxybenzylideneamino-a-glucoside by
hydrolysis of the N-p-methoxybenzylidene group. It has
been shown that the 2-N-substituent in a-d-glucosamine
derivatives is much more labile than the corresponding 2-N-
substituent in the b-counterpart.[11] Hydrolysis of the imine
consumed H+ generated in situ; thus, protodeauration of the
isochromen-4-yl-gold(I) complex 5 (i.e., intermediate D in
Scheme 1) to regenerate the active [Ph3PAu]+ would be
hampered, leading to a stop of the activation of the donor and
accumulation of the gold(I) complex 5. Indeed, we managed
after many attempts to isolate the desired gold(I) complex 5
in a high 91% yield (based on the amount of starting
[Ph3PAuOTf]) by flash chromatography on silica gel. Com-
plex 5 was unambiguously characterized by spectroscopic (1H,
13C, and 31P NMR and MS) and X-ray diffraction analysis
(Figure 1).[12]
This glycosylation protocol has been developed on the
basis of mechanistic rational as depicted in Scheme 1.[1b]
À
Activation of the C C triple bond positioned in the o-
alkynylbenzoate moiety in donor A with a gold(I) complex
(e.g., [Ph3PAuOTf]) led to isochromen-4-yl-gold(I) complex
D and sugar oxocarbenium ion B. Capture of the putative
sugar oxocarbenium species B or related intermediates[7] by
the nucleophilic acceptor HNu provided glycoside C. The H+
released from HNu then protodeaurated the vinyl gold(I)
complex D to give isocoumarin E with regeneration of the
active AuI species to complete the catalytic cycle. Activation
À
of a C C triple bond with gold(I) species toward nucleophilic
attack has been reported for numerous gold(I)-catalyzed
transformations.[8] Recently, a few of the proposed vinyl
[*] Y. Zhu, Prof. B. Yu
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: byu@mail.sioc.ac.cn
[**] This work was financially supported by the National Natural Science
Foundation of China (20932009 and 20921091) and the Ministry of
Science and Technology of China (2010CB529706).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103409.
Angew. Chem. Int. Ed. 2011, 50, 8329 –8332
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8329

Communications
O2NC6H4OH (pKa = 7.16) were
measured to be first-order for
both alcohol and the complex 5,
with rate constants of k = 0.022,
0.485, and 1.4 mLminÀ1 mmolÀ1,
respectively, at 258C (see the Sup-
porting Information).
These results prompted us to
examine the gold(I)-catalyzed gly-
cosylation with a focus on the
effect of acidity on the reaction.
The coupling of perbenzoyl-b-d-
glucopyranosyl-o-hexynylbenzoate
7 and sugar primary alcohol 8,
which could proceed smoothly
under the normal conditions
(0.1 equiv [Ph3PAuOTf], CH2Cl2,
4 ꢀ M.S., RT) to give the coupled
Scheme 2. Glycosylation with 2-p-methoxybenzylideneamino-b-d-glucopyranosyl-o-hexynylbenzoate 1
as donor and [Ph3PAuOTf] as catalyst.
disaccharide 9 in excellent yiel-
d,[1a,b] were selected as the model
reaction (Table 1, entry 1). Lowering the gold(I) catalyst
loading to 0.01 equiv resulted in a sluggish reaction (Table 1,
entry 2); addition of 0.1 equiv HOTf rescued the reaction
(Table 1, entry 3). In the presence of 0.1 equiv HOTf, the
Table 1: Gold(I)-catalyzed coupling of glycosyl o-hexynylbenzoate 7 and
alcohol 8 with or without HOTf as a co-catalyst.
Figure 1. ORTEP diagram of complex 5 with 30% probability ellip-
soids; hydrogen atoms are omitted for clarity. Key bond lengths [ꢀ]
and angles [o]: Au1–C8 2.068(7), Au1–P1 2.2843(18), C7–C8 1.444(12),
C8–C9 1.351(13); C7-C8-Au1 122.2(6), C9-C8-Au1 118.3(7), C8-Au1-P1
176.0(2).
Entry
Gold(I) catalyst[a]
HOTf [equiv][b]
Yield [%][c]
1
2
3
4
5
6
7
8
9
[Ph3PAuOTf] (0.1 equiv)
[Ph3PAuOTf] (0.01 equiv)
[Ph3PAuOTf] (0.01 equiv)
[Ph3PAuOTf] (0.005 equiv)
[Ph3PAuOTf] (0.001 equiv)
[Ph3PAuOTf] (0.0001 equiv)
5 (0.1 equiv)
5 (0.01 equiv)
5 (0.001 equiv)
5 (0.0001 equiv)
–
–
95
23
92
86
82
trace
0
92
82
0.1
0.1
0.1
0.1
–
0.1
0.1
0.1
The isochromen-4-yl-gold(I) complex 5 was quite stable,
and it remained intact in the solid state under ambient
conditions for at least 30 days or in CDCl3 at ambient
temperature for at least five days. Protodeauration of 5 (in
CDCl3) took place instantly and quantitatively upon addition
of a strong protic acid such as TfOH or CF3COOH; however,
the protodeauration did not proceed at all in the presence of
common alcohols such as MeOH or EtOH. The kinetics of the
protodeauration of 5 with acidic alcohols (CF3)2CHOH
10
trace
[a] A CH2Cl2 solution of [PPh3AuOTf] (5.8ꢁ10À3 m) was freshly prepar-
ed[1b] and the corresponding amount of catalyst was transferred by
syringe. [b] The reaction proceeded better in the presence of acid-washed
molecular sieves (AW M.S.; AW300 from Alfa Aesar) than in the presence
of normal molecular sieves; however, HOTf was required as the co-
catalyst to promote the reaction. [c] Yield of isolated product. Bz=ben-
zoyl.
(pKa = 9.39),
m-O2NC6H4OH
(pKa = 8.38),
and
p-
8330
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8329 –8332

reaction could proceed satisfactorily with only 0.005 or
0.001 equiv gold(I) catalyst (Table 1, entries 4 and 5). How-
ever, 0.0001 equiv gold(I) catalyst was not sufficient to
promote the reaction, even in the presence of 0.1 equiv
HOTf (Table 1, entry 6). Expectedly, isochromen-4-yl-gold(I)
complex 5 itself could not promote the glycosylation reaction
(Table 1, entry 7); together with 0.1 equiv HOTf, the reaction
proceeded as well as with [Ph3PAuOTf] as the catalyst
(Table 1, entries 8–10).
Our previous puzzles, that the gold(I)-catalyzed glycosy-
lation reaction could not proceed in the present of a base[1c]
and that addition of TfOH could accelerate greatly the
reaction rate,[6] have thus been solved. Moreover, a solution to
lower the catalyst loading in the gold(I)-catalyzed glycosyla-
tion has emerged. The scope of this alternative was then
examined briefly (Scheme 3). Thus, catalyzed by 0.005 equiv
[Ph3PAuOTf] and 0.1 equiv HOTf (CH2Cl2, acid-washed
M.S., RT, 3 h), glycosylation of the sugar primary alcohol
13, admantanol 14, cholesterol 15, and the hindered sugar 4-
OH derivative 16 with perbenzoyl glucopyranosyl o-hexynyl-
benzoate 7 gave the coupled b-glycosides (17–20) in excellent
yields (87–99%). With rhamnopyranosyl, 2-deoxy-glucopyr-
anosyl, and 2-deoxy-2-azido-glucopyranosyl o-hexynylben-
zoate 10–12 as donors and sugar alcohol 13 as acceptor, the
glycosylation also proceeded smoothly to provide the corre-
sponding disaccharides 21–23 in high yields (88–100%).
We then revisited a difficult glycosylation reaction with
the present new conditions (Scheme 4). Previous coupling of
the glucosamine 4-OH derivative 24 with 2-azido-glucopyr-
anosyl o-hexynylbenzoate 12 (toward the total synthesis of
TMG-chitotriomycin
(TMG = N,N,N-trimethyl-d-glucosa-
mine) required 0.5 equiv of [Ph3PAuOTf] to promote the
reaction to completion.[2] In this case, with the assistance of
0.1 equiv HOTf, 0.01 equiv [Ph3PAuOTf] could promote the
coupling to provide the a-disaccharide 25 in a satisfactory
86% yield.
Scheme 4. A challenging glycosidic coupling with low loading of
[Ph3PAuOTf] catalyst. Phth=phalimido, MP=p-methoxyphenyl.
Scheme 3. Glycosylation with glycosyl o-hexynylbenzoates in the presence of [Ph3PAuOTf] (0.005 equiv) and HOTf (0.1 equiv). Bn=benzyl.
Angew. Chem. Int. Ed. 2011, 50, 8329 –8332 ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8331

Communications
c) N. Marion, S. P. Nolan, Chem. Soc. Rev. 2008, 37, 1776 – 1782;
d) D. J. Gorin, B. D. Sherry, F. D. Toste, Chem. Rev. 2008, 108,
3351 – 3378; e) Z. G. Li, C. Brouwer, C. He, Chem. Rev. 2008,
108, 3239 – 3265; f) A. Arcadi, Chem. Rev. 2008, 108, 3266 – 3325;
g) E. Jimꢁnez-NfflÇez, A. M. Echavarren, Chem. Rev. 2008, 108,
3326 – 3350; h) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180 –
3211; i) A. Fürstner, P. W. Davies, Angew. Chem. 2007, 119,
3478 – 3519; Angew. Chem. Int. Ed. 2007, 46, 3410 – 3449; j) E.
Jimꢁnez-NfflÇez, A. M. Echavarren, Chem. Commun. 2007, 333 –
346; k) L. Zhang, J. Sun, S. A. Kozmin, Adv. Synth. Catal. 2006,
348, 2271 – 2296; l) A. S. K. Hashmi, G. J. Hutchings, Angew.
Chem. 2006, 118, 8064 – 8105; Angew. Chem. Int. Ed. 2006, 45,
7896 – 7936.
In conclusion, we have unambiguously characterized the
isochromen-4-yl-gold(I) complex 5 as an important inter-
mediate in the gold(I)-catalyzed glycosylation reaction with
glycosyl o-alkynylbenzoates as donors. Effective protodeau-
ration of this vinyl gold(I) complex has been shown to require
strong protic acid, and this acid is found to be critical for
regeneration of the active gold(I) species for the catalytic
cycle. This finding has enabled reduction of the loading of the
gold(I) catalyst in the reaction significantly (from the
previous ca. 10 mol% to the present ca. 0.5 mol%) with the
assistance of an externally added strong protic acid (e.g., ca.
10 mol% HOTf). The present protocol will be valuable to the
large-scale preparation of carbohydrates. Moreover, the
present finding has added a solid piece of evidence to
highlight the importance of the protodeauration step in the
numerous gold(I)-catalyzed transformations.[8,13] In fact, the
benefit of addition of acid to some of those gold(I)-catalyzed
reactions has already been appreciated during experimenta-
tion.[9a,14]
[9] For structurally characterized vinylgold(I) complexes involved
in gold(I)-catalyzed transformations, see: a) J. A. Akana, K. X.
Bhattacharyya, P. Müller, J. P. Sadighi, J. Am. Chem. Soc. 2007,
129, 7736 – 7737; b) L.-P. Liu, B. Xu, M. S. Mashuta, G. B.
Hammond, J. Am. Chem. Soc. 2008, 130, 17642 – 17643; c) E. Y.
Tsui, P. Müller, J. P. Sadighi, Angew. Chem. 2008, 120, 9069 –
9072; Angew. Chem. Int. Ed. 2008, 47, 8937 – 8940; d) D. Weber,
M. A. Tarselli, M. R. Gagnꢁ, Angew. Chem. 2009, 121, 5843 –
5846; Angew. Chem. Int. Ed. 2009, 48, 5733 – 5736; e) A. S. K.
Hashmi, T. D. Ramamurthi, F. Rominger, J. Organomet. Chem.
2009, 694, 592 – 597; f) A. S. K. Hashmi, A. M. Schuster, F.
Rominger, Angew. Chem. 2009, 121, 8396 – 8398; Angew. Chem.
Int. Ed. 2009, 48, 8247 – 8249; g) A. S. K. Hashmi, T. D. Ram-
amurthi, F. Rominger, Adv. Synth. Catal. 2010, 352, 971 – 975.
[10] The corresponding N-p-methoxybenzylidene glucosamine tri-
chloroacetimidate and congeners were found to be effective
donors for a-selective glycosylation catalyzed by [LnNi(OTf)2],
see: E. A. Mensah, F. Yu, H. M. Nguyen, J. Am. Chem. Soc.
2010, 132, 14288 – 14302.
[11] Y. Li, C. Li, P. Wang, S. Chu, H. Guan, B. Yu, Tetrahedron Lett.
2004, 45, 611 – 613.
[12] CCDC 813882 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[13] The role of the proton in homogeneous gold catalysis has been
discussed, see: A. S. K. Hashmi, Catal. Today 2007, 122, 211 –
214.
Received: May 18, 2011
Published online: July 20, 2011
Keywords: glycosyl ortho-alkynylbenzoates · glycosylation ·
gold · homogeneous catalysis · protic acids
.
[1] a) Y. Li, Y. Yang, B. Yu, Tetrahedron Lett. 2008, 49, 3604 – 3608;
b) Y. Li, X. Yang, Y. Liu, C. Zhu, Y. Yang, B. Yu, Chem. Eur. J.
2010, 16, 1871 – 1882; c) Y. Yang, Y. Li, B. Yu, Tetrahedron Lett.
2010, 51, 1504 – 1507; d) Y. Ma, G. Lian, Y. Li, B. Yu, Chem.
Commun. 2011, 47, 7515 – 7517.
[2] a) Y. Yang, Y. Li, B. Yu, J. Am. Chem. Soc. 2009, 131, 12076 –
12077; b) Y. Yang, T. Liu, Y. Yang, Q. Wu, Q. Yang, B. Yu,
ChemBioChem 2011, 12, 457 – 467.
[3] Y. Li, B. Yu, Chem. Commun. 2010, 46, 6060 – 6062.
[4] a) W. Yang, J. Sun, W. Lu, Y. Li, L. Shan, W. Han, W. D. Zhang,
B. Yu, J. Org. Chem. 2010, 75, 6879 – 6888; b) Y. Li, W. Yang, Y.
Ma, J. Sun, L. Shan, W. D. Zhang, B. Yu, Synlett 2011, 914 – 918.
[5] J. Liao, J. Sun, Y. Niu, B. Yu, Tetrahedron Lett. 2011, 52, 3075 –
3078.
[6] Q. Zhang, J. Sun, Y. Zhu, F. Zhang, B. Yu, Angew. Chem. 2011,
123, 5035 – 5038; Angew. Chem. Int. Ed. 2011, 50, 4933 – 4936.
[7] For a recent account on the mechanism of glycosylation reaction,
see: D. Crich, Acc. Chem. Res. 2010, 43, 1144 – 1153.
[14] For selected examples of gold(I) catalysis with protic acid as co-
catalyst, see: a) J. H. Teles, S. Brode, M. Chabanas, Angew.
Chem. 1998, 110, 1475 – 1478; Angew. Chem. Int. Ed. 1998, 37,
1415 – 1418; b) E. Mizushima, K. Sato, T. Hayashi, M. Tanaka,
Angew. Chem. 2002, 114, 4745 – 4747; Angew. Chem. Int. Ed.
2002, 41, 4563 – 4565; c) E. Mizushima, T. Hayashi, M. Tanaka,
Org. Lett. 2003, 5, 3349 – 3352; d) C. Nieto-Oberhuber, M. P.
MuÇoz, S. López, E. Jimꢁnez-NfflÇez, C. Nevado, E. Herrero-
Gómez, M. Raducan, A. M. Echavarren, Chem. Eur. J. 2006, 12,
1677 – 1693; e) V. Belting, N. Krause, Org. Lett. 2006, 8, 4489 –
4492.
[8] For selected reviews on gold(I)-catalyzed transformations, see:
a) A. S. K. Hashmi, Angew. Chem. 2010, 122, 5360 – 5369;
Angew. Chem. Int. Ed. 2010, 49, 5232 – 5241; b) A. S. K.
Hashmi, M. Rudolph, Chem. Soc. Rev. 2008, 37, 1766 – 1775;
8332
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8329 –8332