Interrupted Pummerer Reaction in Latent-Active Glycosylation: Glycosyl Donors with a Recyclable and Regenerative Leaving Group

Article abstract of DOI:10.1002/anie.201507861

Latent O-glycosides, 2-(2-propylthiol)benzyl (PTB) glycosides, were converted into the corresponding active glycosyl donors, 2-(2-propylsulfinyl)benzyl (PSB) glycosides, by a simple and efficient oxidation. Treatment of the PSB donor and various acceptors with triflic anhydride provided the desired glycosides in good to excellent yields. The leaving group, which was activated by an interrupted Pummerer reaction, can be recycled (PSB-OH) and regenerated as the precursor (PTB-OH). A natural hepatoprotective glycoside, leonoside F, was efficiently synthesized in a convergent [3+1] manner with this newly developed method. The present total synthesis also led to a structural revision of this phenylethanoid glycoside.

Full text of DOI:10.1002/anie.201507861

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201507861
German Edition: DOI: 10.1002/ange.201507861
Glycosides
Interrupted Pummerer Reaction in Latent-Active Glycosylation:
Glycosyl Donors with a Recyclable and Regenerative Leaving Group
Penghua Shu, Xiong Xiao, Yueqi Zhao, Yang Xu, Wang Yao, Jinyi Tao, Hao Wang,
Guangmin Yao, Zimin Lu, Jing Zeng, and Qian Wan*
Abstract: Latent O-glycosides, 2-(2-propylthiol)benzyl (PTB)
glycosides, were converted into the corresponding active
glycosyl donors, 2-(2-propylsulfinyl)benzyl (PSB) glycosides,
by a simple and efficient oxidation. Treatment of the PSB
donor and various acceptors with triflic anhydride provided
the desired glycosides in good to excellent yields. The leaving
group, which was activated by an interrupted Pummerer
reaction, can be recycled (PSB-OH) and regenerated as the
precursor (PTB-OH). A natural hepatoprotective glycoside,
leonoside F, was efficiently synthesized in a convergent [3+1]
manner with this newly developed method. The present total
synthesis also led to a structural revision of this phenylethanoid
glycoside.
of the latent LGs into active LGs plays a crucial role. Current
modifications involving reduction/acetylation,[3a] reductive
debromination,[5] allyl isomerization,[3c,e] hydrogenation,[3d]
deacylation,[3f] and Sonogashira coupling[3g] usually require
toxic metal salts,[3a] stoichiometric amounts of Zn powder,[3a,5]
transition/rare-earth metals (Ir, Sm, Pd),[3c–e,g,5] basic amide
hydrolysis,[3f] or high reaction temperatures.[3a,5] Such require-
ments present a challenge to the practical utility of the
methodology. Glycosyl sulfoxide donors and related sulfonate
promoters (diphenyl sulfoxide, sulfonamide and thiolsulinate
etc.) are well-studied and the literature is replete with
examples of their synthesis and applications.[6] To our surprise,
although significant contributions (Kahne glycosylation,[7a]
Crich-type b-selective mannosylation,[7b] Gin dehydrative
glycosylation,[7c] and Gin oxidative glycosylation[7d] etc.)
have been made in this field, the simple transformation of
sulfides into sulfoxides and utilization in latent-active
approach has not been explored, as there are only a few
applications in the literature.[7e–f] We became interested in
using sulfoxides to remotely activate the glycosyl leaving
group, particularly through the Pummerer and interrupted
Pummerer reactions. In these two reactions, the thionium ion
or sulfonium ion resulting from activation of the sulfoxide can
react with different nucleophiles and has found great utility in
organic synthesis (Scheme 1).[8] In this premise, we now report
C
arbohydrates, essential molecules of life, are involved in
various important biological processes and functions.[1] It is
well-known that traditional oligosaccharide synthesis is
a laborious process involving multistep operations.[2] To
streamline the oligosaccharide assembly process, a latent-
active strategy arising from the studies of p-acetamidophenyl
thioglycosides and p-nitrophenyl thioglycosides was intro-
duced by Roy et al.[3a] in 1992. Since then, this concept has
been further investigated by the groups of Fraser-Reid,[3b]
Boons,[3c] Kim,[3d] Wang,[3e] Demchenko,[3f] and Yu.[3g] In this
strategy,[4,2b] an active leaving group (LG) can be selectively
stimulated over the latent LG in the presence of
a suitable promotor. Subsequently, through a simple
modification, the latent LG of the resulting glycoside
can be converted into a similar but active LG. By
taking advantage of this latent-active concept, the
manipulation of anomeric leaving groups and tedious
protection and deprotection procedures can be mini-
mized, and is highly beneficial for complex target
synthesis.[2]
In most of the reported latent-active methods,
simple, efficient, and chemoselective transformation Scheme 1. The standard Pummerer reaction and interrupted Pummerer reaction.
a novel active glycosyl donor, 2-(2-propylsulfinyl)benzyl
(PSB) glycoside, which can be prepared by a selective
oxidation of the corresponding latent 2-(2-propylthiol)benzyl
(PTB) glycoside under mild reaction conditions.
[*] P. Shu, X. Xiao, Y. Zhao, Y. Xu, W. Yao, J. Tao, H. Wang,
Prof. Dr. G. Yao, Prof. Dr. Z. Lu, Prof. Dr. J. Zeng, Prof. Dr. Q. Wan
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource
Evaluation, School of Pharmacy
Huazhong University of Science and Technology
13 Hangkong Road, Wuhan, Hubei, 430030 (China)
E-mail: wanqian@hust.edu.cn
O-alkyl glycosides are ideal candidates for the prepara-
À
tion of latent glycosides because of the rather stable C O s-
bonds. Despite the several advantages of O-alkyl glycosides,
such as easy preparation and convenient manipulation of
protecting groups, they are not commonly used as glycosyl
donors.[9] The groups of Fraser-Reid,[10a] Inanaga,[10b] Davis,[10c]
Kim,[3d] and Hotha[10d] have succeeded in using O-alkyl groups
as leaving groups. More recently, based on the success of the
Prof. Dr. Q. Wan
Institute of Brain Research
Huazhong University of Science and Technology (China)
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201507861.
14432
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 14432 –14436

Angewandte
Chemie
Yu glycosylation,[11] Yu and co-workers designed a novel O-
benzyl glycosyl donor, ortho-(methyltosylaminoethynyl)ben-
zyl glycoside, for a latent-active approach.[3g] The new glycosyl
donors could be activated by a catalytic amount of TMSOTf
and other Lewis acids at room temperature. Inspired by the
methods of Kim and Yu, we envisioned that treatment of the
PSB glycosides with Tf2O would induce an annulation
through five- or six-membered-ring formation to activate
the leaving group.
procedure,[18] and served as a reference for monitoring the
reaction. However, we did not observe any formation of 5 or
its hydrolyzed form during the reaction. These observations
suggested that this novel glycosylation proceeded through an
interrupted Pummerer reaction rather than a Pummerer
reaction. It is notable that the active leaving group 4 (PSB-
OH) could be easily recovered from the reaction mixture and
regenerated as the precursor (PTB-OH).[19]
To illustrate the scope of this new glycosylation method,
a variety of acceptors (2b–p; oxo and mercapto nucleophiles),
in addition to 2a, were coupled with 1 (Table 1). Primary,
secondary, and tertiary alcohols, as well as amino acid, thiol,
and even naturally occurring ste-
Initial experiments for transglycosylation were performed
with the PSB glycoside 1[12] as a glycosyl donor and 2a as the
glycosyl acceptor (Scheme 2). In a representative procedure,
roids were found to be suitable
glycosyl acceptors using this pro-
tocol. From these examples, it is
worth noting that: 1) a variety of
b-glycoside bonds could be linked
to GalO-6, GalS-6, GalO-4, GluO-6
,
GluO-4, GluO-3, GluO-2, and ManO-2
in good to excellent yields,
Scheme 2. New glycosyl donor with recyclable leaving group.
2) extremely hindered nucleo-
philes such as the adamantine
trifluoromethanesulfonic anhydride (Tf2O, 1.2 equiv) was
added to a solution of 1 (1.2 equiv) and 2 (1.0 equiv) in
CH2Cl2 in the presence of 4 Š molecular sieves (M.S.) at 08C.
The solution was stirred at 08C for 1 hour and then quenched
by addition of saturated aqueous NaHCO3. Aqueous workup
of the reaction mixture followed by silica gel column
chromatography afforded the desired b-(1!4)-disaccharide
3a[13] (95%) and a relatively polar compound (4; 92%).
A plausible pathway for this transformation is shown in
Scheme 3. After activation of the sulfoxide A by Tf2O,[7a–c,14,15]
alcohols 2c, 2i, and 2j could also be glycosylated in good
yields, 3) gratifyingly, acid-labile groups such as benzylidene
(3l and 3n) and acetonide (3 f and 3g) were tolerated well
even in the absence of acid scavenger,[20] 4) in certain cases,
the preactivation procedure (see footnote [c]) increased the
reaction efficiency (3e, 3 f, 3g, and 3m),[21] 5) the thiol 2g and
thiol ether groups (2n, 3n, and 3g) remained intact in the
presence of the sulfoxide triflic anhydride reagent.[22] Most
importantly, the successful synthesis of the b-(1!2)-disac-
charide 3n implied that the sequential glycosylation for
oligosaccharide synthesis would be possi-
ble by employing this approach since the
resulting PTB disaccharide 3n could be
used in the next glycosylation after
a simple selective oxidation.
Having investigated the preparation
and applicability of the PSB glycosyl
donor for chemical glycosylations, we
next investigated the stability of the PTB
glycoside under reaction conditions com-
monly used for the activation of thiogly-
cosides. Experiments were performed
with 2-hydroxy PTB glycoside 6 as an
acceptor and disarmed methyl peracety-
lated 1-thio-b-d-glycopyranoside
7 as
Scheme 3. Proposed mechanism for activation.
a low reactivity donor, which usually
requires strong promoters to activate
an intramolecular nucleophilic attack of the anomeric oxygen
atom onto the cationic sulfur atom leads to the oxocarbenium
ion B and cyclic benzylsulfonium ion C (five-membered
ring).[16] The intermediate C then undergoes hydrolysis to
form 4. The oxocarbenium ion B undergoes glycosylation in
the presence of nucleophiles to form the target glycoside.
Pathway a (Scheme 3) would be akin to an intramolecular
interrupted Pummerer reaction.[17] In contrast, the nonpolar
stable compound 5 was synthesized according to literature
(Scheme 4). Interestingly, both NIS/TfOH and MeOTf
could promote the glycosylation reactions to produce the
PTB disaccharide 8 in excellent yield. These preliminary
studies indicated that the PTB glycosides are relatively stable
under the conditions for activation of thioglycosides.
To further demonstrate the potential of this new glycosyl
donor in the synthesis of complex oligosaccharides, we
initiated a total synthesis of hepatoprotective Leonoside
F,[23a,b] which was recently isolated from Chinese motherwort
Angew. Chem. Int. Ed. 2015, 54, 14432 –14436
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 14433

.
Angewandte
Communications
Table 1: b-Selective glycosylation with a variety of acceptors.[a,b]
selectively oxidized into the corre-
sponding active PSB donor 14
(91%).[24] Subsequent glycosylation
between 14 and 2e in a convergent
[3+1] manner yielded the phenyl-
ethanoid glycoside 15 (86%). Final
removal of acetate and benzyl
groups furnished the target trisac-
charide 16 (90% over two steps).
The synthetic compound 16 was
apparently not the natural leonosi-
de F.[25] After carefully examining
the
four
different
synthetic
attempts[26] and structural data
from isolations, we suspected that
the methoxy group might be located
at the para-position of phenyl group
instead of at the meta-position as
proposed in the previous assign-
ments. As such, a replacement of
2e by 2e’ was made, and a straight-
forward synthesis of the revised
structure 17 (81% over three
steps) from the PSB glycosyl
donor 14 was achieved after
another [3+1] glycosyl coupling
and routine global deprotection.
The NMR spectra of the synthetic
17 were virtually identical to those
reported in the literature.[23a,27]
Other relevant reported struc-
tures of phenylethanoid glyco-
sides, cistanoside E,[23a,28a,b] leo-
noside E,[23a] leonoside F,[23b] and
scrophuside[28c] will be re-exam-
ined accordingly.[29]
[a] Yield is that of the isolated product. Used 1.2 equiv 1. [b] Tf2O (1.2 equiv) was added to the mixture of
the glycosyl donor and the acceptor in CH2Cl2, 08C, 1 h. [c] Tf2O (1.2 equiv) was added to the solution of
glycosyl donor at À408C, followed by the addition of acceptor. [d] Additional DTBMP (1.0 equiv) was
used. DTBMP=2,6-di-tert-butyl-4-methylpyridine.
In conclusion, we have dis-
covered the 2-(2-propylthiol)-
benzyl (PTB) anomeric moiety
as a new leaving group, which
allows rapid oligosaccharide
assembly through latent-active
Scheme 4. Stability of PTB glycoside. Reaction conditions a: 7 (1.2 equiv), NIS (2.4 equiv), TfOH
(0.24 equiv), 08C, CH2Cl2, 3 h. 92%. Reaction conditions b: 7 (1.2 equiv), MeOTf (1.2 equiv), RT, CH2Cl2,
24 h, 65%, with 25% of 6 recovered. NIS=N-iodosuccinimide.
(Leonurus japonicus Houtt)[23c] and Chinese foxglove
(Rehmannia glutinosa), and collectively form two of the
fifty fundamental herbs of traditional Chinese medicine.
Leonoside F bears a branched trisaccharide moiety and
a phenylethanoid aglycon.[23a,b] In this work, a convergent
[3+1] approach is incorporated into our newly developed
glycosylation, mediated by an interrupted Pummerer reac-
tion, to synthesize this natural product (Scheme 5). To prove
the possibility of using the present glycosylation method in
the latent-active assembly strategy, the active PSB glycoside
10 (1.2 equiv) was coupled with the latent PTB glycoside 9 in
the presence of Tf2O to give the b-(1!3)-disaccharide 11
(81%), which was then converted into the acceptor 12 (64%,
with 10% of 11 recovered) by a selective reductive opening of
the 4,6-benzylidene acetal. The active PSB donor 1 was
coupled with 12 under similar glycosylation conditions to
produce the b-(1!6)-trisaccharide 13 (93%), which was then
and convergent synthetic concepts. The PSB glycoside donor
can be converted from the corresponding stable PTB glyco-
side by an efficient oxidation. After coupling, the leaving
group is recycled as PSB-OH, which can be used in the
synthesis of the latent PTB glycoside after a simple reduction.
We have demonstrated the potential of the new approach in
a complex natural product synthesis. The present total
synthesis has led to the revision of the structure of leonoside F
from 16 to 17.
14434 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 14432 –14436

Angewandte
Chemie
[2] a) G.-J. Boons, Tetrahedron
1996, 52, 1095 – 1121; b) J. T.
Smoot, A. V. Demchenko,
Adv. Carbohydr. Chem. Bio-
chem. 2009, 62, 161 – 250;
c) X. Zhu, R. R. Schmidt,
Angew. Chem. Int. Ed.
2009,
48,
1900 – 1934;
Angew. Chem. 2009, 121,
1932 – 1967; d) S. Kaeothip,
A. V. Demchenko, Carbo-
hydr. Res. 2011, 346, 1371 –
1388; e) T. J. Boltje, T.
Buskas, G.-J. Boons, Nat.
Chem. 2009, 1, 611 – 622;
f) Y. Yang, X. Zhang, B.
Yu, Nat. Prod. Rep. 2015,
32, 1331 – 1355.
[3] a) R. Roy, F. O. Andersson,
M. Letellier, Tetrahedron
Lett. 1992, 33, 6053 – 6056;
b) Review for NPGs: B.
Fraser-Reid, U. E. Udo-
dong, Z. F. Wu, H. Ottosson,
J. R. Merritt, C. S. Rao, C.
Roberts, R. Madsen, Synlett
1992, 927 – 942; c) G.-J.
Boons, S. Isles, Tetrahedron
Lett. 1994, 35, 3593 – 3596;
d) K. S. Kim, J. H. Kim, Y. J.
Lee, Y. J. Lee, J. Park, J. Am.
Chem. Soc. 2001, 123, 8477 –
8481; e) P. Wang, P. Haldar,
Y. Wang, H. Hu, J. Org.
Chem. 2007, 72, 5870 –
5873; f) S. J. Hasty, M. A.
Kleine, A. V. Demchenko,
Angew. Chem. Int. Ed.
2011,
50,
4197 – 4201;
Scheme 5. Total synthesis of revised leonoside F using a latent-active strategy. CC=cyanuric chloride,
THF=tetrahydrofuran, UHP=urea–hydrogen peroxide.
Angew. Chem. 2011, 123,
4283 – 4287; g) X. Chen, D.
Shen, Q. Wang, Y. Yang, B.
Yu, Chem. Commun. 2015,
51, 13957 – 13960.
Acknowledgements
[4] T. C. Shiao, R. Roy, Top. Curr. Chem. 2011, 301, 69 – 108.
[5] J. R. Merritt, J. S. Debenham, B. Fraser-Reid, J. Carbohydr.
Chem. 1996, 15, 65 – 72.
[6] a) D. Crich, L. B. L. Lim, Org. React. 2004, 64, 115 – 251; b) M. C.
Aversa, A. Barattucci, P. Bonaccorsi, Tetrahedron 2008, 64,
7659 – 7683; c) S. C. Ranade, A. V. Demchenko, J. Carbohydr.
Chem. 2013, 32, 1 – 43.
[7] Selected references: a) D. Kahne, S. Walker, Y. Cheng, D. V.
Engen, J. Am. Chem. Soc. 1989, 111, 6881 – 6882; b) D. Crich, S.
Sun, J. Org. Chem. 1996, 61, 4506 – 4507; c) B. A. Garcia, J. L.
Poole, D. Y. Gin, J. Am. Chem. Soc. 1997, 119, 7597 – 7598; d) V.
Di Bussolo, Y.-J. Kim, D. Y. Gin, J. Am. Chem. Soc. 1998, 120,
13515 – 13516; e) L. A. J. M. Sliedregt, G. A. van der Marel, J. H.
van Boom, Tetrahedron Lett. 1994, 35, 4015 – 4018; f) X. He,
T. H. Chan, Synthesis 2006, 1645 – 1651.
We thank the National Natural Science Foundation of China
(21272082, 21402055, 21472054), the State Key Laboratory of
Bio-organic
and
Natural
Products
Chemistry
(SKLBNPC13425), Natural Science Funds of Hubei Province
for Distinguished Young Scholars (2015CFA035), the Speci-
alized Research Fund for the Doctoral Program of Higher
Education (20120142120092), “Thousand Talents Program”
Young Investigator Award, and Huazhong University of
Science and Technology (2014ZZGH015) for support.
Keywords: glycosylation · natural products · oxidation · sulfur ·
synthetic methods
[8] Selected reviews: a) S. C. Bur, A. Padwa, Chem. Rev. 2004, 104,
2401 – 2432; b) L. H. S. Smith, S. C. Coote, H. F. Sneddon, D. J.
Procter, Angew. Chem. Int. Ed. 2010, 49, 5832 – 5844; Angew.
Chem. 2010, 122, 5968 – 5980; c) S. Akai, Y. Kita, Top. Curr.
Chem. 2007, 274, 35 – 76; d) K. S. Feldman, Tetrahedron 2006, 62,
5003 – 5034.
How to cite: Angew. Chem. Int. Ed. 2015, 54, 14432–14436
Angew. Chem. 2015, 127, 14640–14644
[1] A. Varki, R. D. Cummings, J. D. Esko, H. H. Freeze, C. R.
Bertozzi, P. Stanyley, G. W. Hart, M. E. Etzler, Essentials of
Glycobiology, 2nd ed., CSH Laborotory Press, New York, 2009.
[9] a) K.-S. Kim, H.-B. Jeon in Handbook of Chemical Glycosyla-
tion: Advances in Stereoselectivity and Therapeutic Relevence
Angew. Chem. Int. Ed. 2015, 54, 14432 –14436
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 14435

.
Angewandte
Communications
(Eds.: A. V. Demchenko), Wiley-VCH, Weinheim, 2008,
pp. 185 – 223; b) J. C. López in Glycoscience: Chemistry and
Chemical Biology, 2nd ed. (Eds.: B. Fraser-Reid, K. Tatsuta, J.
Thiem), Springer, Berlin, 2008, pp. 565 – 659.
[17] The concept of the interrupted Pummerer reaction: a) D. K.
Bates, R. T. Winters, J. A. Picard, J. Org. Chem. 1992, 57, 3094 –
3097; b) D. K. Bates, M. Xia, J. Org. Chem. 1998, 63, 9190 – 9196;
c) D. K. Bates, B. A. Sell, J. A. Picard, Tetrahedron Lett. 1987, 28,
3535 – 3538.
[18] P. K. Choudhury, J. Almena, F. Foubelo, M. Yus, Tetrahedron
1997, 53, 17373 – 17382.
[19] For details see the Supporting Information.
[20] a) J. Gildersleeve, A. Smith, K. Sakurai, S. Raghavan, D. Kahne,
J. Am. Chem. Soc. 1999, 121, 6176 – 6182; b) B. A. Garcia, D. Y.
Gin, J. Am. Chem. Soc. 2000, 122, 4269 – 4279.
[21] a) X. Huang, L. Huang, H. Wang, X.-S. Ye, Angew. Chem. Int.
Ed. 2004, 43, 5221 – 5224; Angew. Chem. 2004, 116, 5333 – 5336;
b) D.-C. Xiong, A.-Q. Yang, Y. Yu, X.-S. Ye, Tetrahedron Lett.
2015, 56, 211 – 214.
[22] G. Lian, X. Zhang, B. Yu, Carbohydr. Res. 2015, 403, 13 – 22. It is
known that the most powerful conditions for thioglycoside
activation are the combination of sulfinyl derivatives with Tf2O.
[23] a) Y. Li, Z. Chen, Z. Feng, Y. Yang, J. Jiang, P. Zhang,
Carbohydr. Res. 2012, 348, 42 – 46; b) W. Feng, M. Li, X.
Zheng, K. Song, J. Wang, J. Li, M. Zhang, Chin. Pharm. J.
2014, 49, 1496 – 1502; c) X. Shang, H. Pan, X. Wang, H. He, M.
Li, J. Ethnopharmacol. 2014, 152, 14 – 32.
[10] a) B. Fraser-Reid, P. Konradsson, D. R. Mootoo, U. Udodong, J.
Chem. Soc. Chem. Commun. 1988, 823 – 825; b) J. Inanaga, Y.
Yokoyama, T. Hanamoto, Chem. Lett. 1993, 85 – 88; c) B. G.
Davis, S. D. Wood, M. A. T. Maughan, Can. J. Chem. 2002, 80,
555 – 558; d) S. Hotha, S. Kashyap, J. Am. Chem. Soc. 2006, 128,
9620 – 9621.
[11] Y. Li, Y. Yang, B. Yu, Tetrahedron Lett. 2008, 49, 3604 – 3608.
[12] L. K. Mydock, A. V. Demchenko, Org. Lett. 2008, 10, 2107 –
2110. To facilitate the investigation, several superamed glycosyl
donors were prepared at the same time. Glycosyl benzoate was
also investigated. See the Supporting Information (Table S1).
[13] S. Koto, N. Morishima, H. Sato, Y. Sato, S. Zen, Bull. Chem. Soc.
Jpn. 1985, 58, 120 – 122.
[14] Recent report on anomeric sulfonium ions in glycosylation: T.
Fang, K.-F. Mo, G.-J. Boons, J. Am. Chem. Soc. 2012, 134, 7545 –
7552.
[15] a) A. J. Eberhart, H. J. Shrives, A. lvarez, A. Carrr, Y. Zhang,
D. J. Procter, Chem. Eur. J. 2015, 21, 7428 – 7434; b) K. Mur-
akami, H. Yorimitsu, A. Osuka, Angew. Chem. Int. Ed. 2014, 53,
7510 – 7513; Angew. Chem. 2014, 126, 7640 – 7643; c) X. Huang,
M. Patil, C. Far›s, W. Thiel, N. Maulide, J. Am. Chem. Soc. 2013,
135, 7312 – 7323; d) X. Huang, N. Maulide, J. Am. Chem. Soc.
2011, 133, 8510 – 8513; e) A. J. Eberhart, D. J. Procter, Angew.
Chem. Int. Ed. 2013, 52, 4008 – 4011; Angew. Chem. 2013, 125,
4100 – 4103; f) A. J. Eberhart, C. Cicoira, D. J. Procter, Org. Lett.
2013, 15, 3994 – 3997; g) T. Kobatake, D. Fujino, S. Yoshida, H.
Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2010, 132, 11838 –
11840; h) T. Kobatake, S. Yoshida, H. Yorimitsu, K. Oshima,
Angew. Chem. Int. Ed. 2010, 49, 2340 – 2343; Angew. Chem.
2010, 122, 2390 – 2393.
[16] a) S. Wolfe, P. M. Kazmair, H. Auksi, Can. J. Chem. 1979, 57,
2404 – 2411; b) N. Furukawa, A. Kawada, T. Kawai, H. Fujihara,
J. Chem. Soc. Chem. Commun. 1985, 1266 – 1267; c) H. H.
Wasserman, W. T. Han, J. Am. Chem. Soc. 1985, 107, 1444 –
1446; d) M. Amat, S. Hadida, G. Pshenichnyi, J. Bosch, J. Org.
Chem. 1997, 62, 3158 – 3175; e) H.-Y. Huang, H.-M. Wang, I.-J.
Kang, L.-C. Chen, J. Chin. Chem. Soc. 2003, 50, 1057 – 1060; f) I.-
J. Kang, H.-M. Wang, H.-Y. Huang, L.-C. Chen, J. Chin. Chem.
Soc. 2001, 48, 1185 – 1188; g) H.-M. Wang, I.-C. Liang, R.-S. Hou,
H.-Y. Huang, L.-C. Chen, J. Chin. Chem. Soc. 2007, 54, 127 – 130;
h) K. Kobayashi, Y. Kanbe, M. Horiuchi, Synthesis 2011, 3429 –
3434, and references therein.
[24] H. B. Jeon, K. T. Kim, S. H. Kim, Tetrahedron Lett. 2014, 55,
3905 – 3908.
[25] The slight discrepancy arose from the chemical shift of C3 and
C4 of the phenyl group: that of natural product appeared at d =
146.6 and 146.4 ppm and that of synthetic 16 at d = 147.8 and
145.1 ppm.
[26] Attempts for synthesizing Leonoside F: a) G. Gu, Y. Zhao, Z.
Guo, Carbohydr. Res. 2013, 380, 174 – 180; b) E. Clayton, M.
Hattie, A. W. Debowski, K. A. Stubbs, Aust. J. Chem. 2014, 67,
1461 – 1470; c) D. Budhadev, B. Mukhopadhyay, Carbohydr. Res.
2014, 384, 51 – 55.
[27] Detailed comparison of 13C NMR data. See the Supporting
Information (Table S2).
[28] a) H. Yamauchi, R. Kakuda, Y. Yaoita, K. Machida, M. Kikuchi,
Chem. Pharm. Bull. 2007, 55, 346 – 347; b) H. Kobayashi, H.
Karasawa, T. Miyase, S. Fukushima, Chem. Pharm. Bull. 1985,
33, 1452 – 1457; c) J. Hua, J. Qi, B.-Y. Yu, Fitoterapia 2014, 93,
67 – 73.
[29] K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed. 2005, 44,
1012 – 1044; Angew. Chem. 2005, 117, 1036 – 1069.
Received: August 22, 2015
Published online: October 8, 2015
14436 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 14432 –14436