Bowl-shaped tris(2,6-diphenylbenzyl)tin hydride: A unique reducing agent for radical and ionic chemistry

Article abstract of DOI:10.1002/1521-3773(20010119)40:2<411::AID-ANIE411>3.0.CO;2-I

Unique selectivity, hitherto not observable in ordinary radical and ionic reactions, is achieved with the bowl-shaped tris(2,6-diphenylbenzyl)tin hydride (TDTH; see structure), which has been successfully utilized as a new reducing agent.

Full text of DOI:10.1002/1521-3773(20010119)40:2<411::AID-ANIE411>3.0.CO;2-I

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vertically provided uniform wetting of the substrate in the
well area and favored heterogeneous film growth. The films
prepared by parallel synthesis were shown to have similar
morphology to those synthesized under conventional condi-
tions but their X-ray diffraction patterns indicate lesser
orientation of crystallites. Parallel synthesis was used to
screen the composition space of organic-free clear synthesis
solution for ZSM-5 film growth. The composition SiO2:(0.5 ±
0.7)NaOH:(1/300 ± 1/700)Al2O3:80H2O resulted in continu-
ous ZSM-5 films of Si/Al ꢀ 20:1.
Experimental Section
Two types of silicon sources were used: sodium silicate solution (14%
NaOH and 27% SiO2), and tetraethylorthosilicate (TEOS). Sodium
silicate was filtered by using a Buchner funnel with a coarse fritted disc
immediately before use. When TEOS was used as the silicon source, it was
first dissolved in tetrapropylammonium hydroxide (TPAOH) to form a
clear solution of composition TEOS:0.15TPAOH:0.7NaOH:98H2O,
which was then filtered before use with
a PTFE filter (0.45mm).
Tetrapropylammonium bromide (TPABr) solution (25 wt%) was prepared
and filtered with 0.45 mm cellulose acetate membranes.
[30] R. Aiello, F. Crea, A. Nastro, C. Pellegrino, Zeolites 1987, 7, 549.
[31] V. P. Shiralkar, A. Clearfield, Zeolites 1989, 9, 363.
[32] W. Schwieger, K.-H. Bergk, D. Freude, M. Hunger, H. Pfeifer in
Zeolite Synthesis (Eds.: M. L. Occelli, H. E. Robson), American
Chemical Society, Washington, 1989, p. 274.
The synthesis mixture was prepared by mixing a measured amount of
chemicals in a transparent LDPE vial of volume 1 mL (Nalgene). When
sodium silicate solution was used, H2SO4 (5n, VWR) was added to adjust
the alkalinity of the final solution. After thorough shaking, a clear synthesis
solution was formed and aged for one day at room temperature without
stirring before being introduced into the well for reaction. Occasionally, the
synthesis mixtures turned turbid immediately after mixing, but the solution
became clear after standing for several hours.
[33] R. Lai, G. R. Gavalas, Microporous Mesoporous Mater. 2000, 38, 239.
The substrates employed were nonporous a-alumina disks of diameter
2.5 cm. Prior to seeding the substrates were cleaned by a procedure
described in reference [22]. Seeding of the entire substrate surface with a
monolayer of silicalite particles was carried out using
a previously
Bowl-Shaped Tris(2,6-diphenylbenzyl)tin
Hydride: A Unique Reducing Agent for
Radical and Ionic Chemistry**
developed protocol.[12, 33] The seeds about 0.4 mm in size were finer than
the substrate roughness and did not cause problems in sealing under
pressure against the Teflon surfaces.
Received: August 30, 2000
Revised: November 2, 2000 [Z15732]
Kouji Sasaki, Yuichiro Kondo, and Keiji Maruoka*
Trialkyltin hydrides (R3SnH) are widely utilized in numer-
ous radical reactions including reductive dehalogenations,[1, 2]
desulfurizations,[3] and radical cyclizations.[4] Among several
R3SnH (R ˆ Me, Bu, Ph), Bu3SnH is the most popular reagent
in radical chemistry. The Bu3SnH-mediated radical reactions
exhibit high regio- and stereoselectivity by changing radical
initiators (azobisisobutyronitrile (AIBN), benzoyl peroxide
(BPO), hn, Et3B, etc.) and/or the reaction conditions.[5]
Alternatively, such stereoselectivity is also achievable by
replacing Bu3SnH or Ph3SnH[6] with the sterically more
hindered (Me3Si)3SiH.[7] However, it is apparent that there
[1] P. G. Schultz, X. D. Xiang, Curr. Opin. Solid State Mater. Sci. 1998, 3,
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[2] T. Bein, Angew. Chem. 1999, 111, 335; Angew. Chem. Int. Ed. 1999, 38,
323.
[3] J. R. Engstrom, W. H. Weinberg, AIChE J. 2000, 46, 2.
[4] E. Danielson, J. H. Golden, E. W. McFarland, C. M. Reaves, W. H.
Weinberg, X. D. Wu, Nature 1997, 389, 944.
[5] X. D. Xiang, X. D. Sun, G. Briceno, Y. L. Lou, K. A. Wang, H. Y.
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[6] H. Chang, I. Takeuchi, X. D. Xiang, Appl. Phys. Lett. 1999, 74, 1165.
[7] S. J. Taylor, J. P. Morken, Science 1998, 280, 267.
[8] A. Holzwarth, P. W. Schmidt, W. E. Maier, Angew. Chem. 1998, 110,
2788; Angew. Chem. Int. Ed. 1998, 37, 2644.
[*] Prof. K. Maruoka, K. Sasaki, Y. Kondo
Department of Chemistry, Graduate School of Science
Kyoto University
[9] S. M. Senkan, Nature 1998, 394, 350.
[10] P. J. Cong, R. D. Doolen, Q. Fan, D. M. Giaquinta, S. H. Guan, E. W.
McFarland, D. M. Poojary, K. Self, H. W. Turner, W. H. Weinberg,
Angew. Chem. 1999, 111, 508; Angew. Chem. Int. Ed. 1999, 38, 483.
[11] C. Hoffmann, A. Wolf, F. Schüth, Angew. Chem. 1999, 111, 2971;
Angew. Chem. Int. Ed. 1999, 38, 2800.
[12] R. Lai, G. R. Gavalas, Ind. Eng. Chem. Res. 1998, 37, 4275.
[13] Y. S. Yan, M. E. Davis, G. R. Gavalas, Ind. Eng. Chem. Res. 1995, 34,
1652.
Kyoto 606-8502 (Japan)
Fax : (‡ 81)75-753-4041
and
Department of Chemistry, Graduate School of Science
Hokkaido University
Sapporo, 060-0810 (Japan)
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Reserarch from the Ministry of Education, Science, Sports and
Culture.
[14] E. R. Geus, M. J. den Exter, H. van Bekkum, J. Chem. Soc. Faraday
Trans. 1992, 88, 3101.
[15] J. Coronas, J. L. Falconer, R. D. Noble, AIChE J. 1997, 43, 1797.
Angew. Chem. Int. Ed. 2001, 40, No. 2
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411

COMMUNICATIONS
is a limit to such steric approaches due to the troublesome
introduction of sterically hindered alkyl groups in the
preparation of bulky R3SnH. In this context, we have focused
on the possibility of using a bowl-shaped trialkyltin hydride of
type 2 to obtain high stereoselectivity by remote steric control
as illustrated by the stereoselective reduction of vinyl radical 1
(Scheme 1). Herein we report that the bowl-shaped tris(2,6-
diphenylbenzyl)tin hydride (TDTH) can be successfully
utilized as a new reducing agent, and in particular achieves
a unique selectivity not observable in ordinary radical and
ionic reactions involving previously known R3SnH and
(Me3Si)3SiH.[8±11]
The requisite TDTH can be conveniently prepared from
commercially available 2-chloro-6-phenyltoluene in the four-
step sequence shown in Scheme 2. The structure of TDTH,
Figure 1. Structure of TDTH (ORTEP representation).
the selectivity to E/Z ˆ 10.8:1 at the ex-
pense of chemical yield (38%). In marked
contrast, however, radical reduction of 3
with TDTH (1.1 equiv) and catalytic Et3B
(0.5 equiv) in CH2Cl2 afforded 4 in 97%
yield with excellent stereoselectivity
(E/Z ˆ 46.5:1), implying the importance
of our new strategy on remote stereo-
chemical control to achieve high selectivity
of the radical cyclization.[14]
R1
R
conventional
steric control
remote steric
control
R1
R1
•
Sn
•
Sn
H
R
H
•
H
R2
?
R
H
R2
H
R2
1
Ph
Ph
Ph
Sn
H
Sn
H
We also examined the intramolecular
cyclization of the one-carbon elongated o-
halophenyl ether, o-iodophenyl 4-phenyl-
butynyl ether (5), which can be categorized
Ph
(TDTH)
Ph
Ph
2
Scheme 1. Bowl-shaped tris(2,6-diphenylbenzyl)tin hydride (TDTH) (2) allows the remote
stereochemical control in vinyl radical reductions.
as
a
heptynyl radical cyclization
(Scheme 4). Interestingly, radical cycliza-
tion of 5 with Bu3SnH gave the target cyclic
ether 6 with low selectivity (E/Z ˆ 1.5:1),
cat. (PhCO2)2
(5 mol%)
NBS
cat. [NiCl2(dppe)]
CH3
CH3
CH2Br
Ph
(5 mol%)
PhMgBr
87%
Ph
Cl
Ph
Ph
Ph
Ph
Ph
93%
Ph
radical initiator
CH2)3SnOH
Ph
CH2)3SnH
Ph
R3MH
I
+
Ph
Ph
1) Mg, then SnCl4
LiAlH4
79 %
solvent
O
O
O
2) aq. NaOH
83%
(TDTH)
(E)-4
(Z)-4
3
Scheme 2. Four-step synthesis of TDTH from commercially available
Scheme 3. Influence of R3MH on the radical cyclization of 3 to 4.
Reagents, conditions, and selectivities: cat. AIBN/Bu3SnH/benzene, 808C,
1 h: 99% (E/Z ˆ 1:37); cat. Et3B/Bu3SnH/CH2Cl2, ꢁ788C, 2 h: 99%
(E/Z ˆ 5.1:1); cat. Et3B/Ph3SnH/CH2Cl2, ꢁ788C, 2 h: 88% (E/Z ˆ 3.1:1);
cat. Et3B/(Me3Si)3SiH/CH2Cl2, ꢁ788C, 3 h: 38% (E/Z ˆ10.8:1); cat.
AIBN/TDTH/benzene, 808C, 2.5 h: 57% (E/Z ˆ 22.8:1); cat. Et3B/TDTH/
CH2Cl2, ꢁ788C, 2.5 h: 97% (E/Z ˆ 46.5:1).
2-chloro-6-phenyltoluene.
NBS ˆ N-bromosuccinimide.
dppe ˆ 1,2-bis(diphenylphosphanyl)ethane;
which was determined by single-crystal X-ray diffraction
analysis (Figure 1),[12] reveals the presence of a molecular
pocket about the tin atom.
Intramolecular radical cyclization of the o-halophenyl
ether, o-iodophenyl 3-phenylpropynyl ether (3) under stan-
dard radical reaction conditions (catalytic AIBN (0.2 equiv),
Bu3SnH (1.1 equiv), benzene reflux) gave rise to an E/Z
Ph
Ph
Ph
cat Et3B
R3MH
I
+
CH2Cl2
–78 °C, 1~7 h
O
O
O
mixture of cyclic ether
4
in 99% yield (E/Z ˆ 1:37;
(E)-6
(Z)-6
5
Scheme 3).[13] Reaction of 3 in CH2Cl2 with Bu3SnH or
Ph3SnH (1.1 equiv) and catalytic Et3B (0.4 equiv) as radical
initiator at ꢁ788C yielded 4 in 88 ꢀ 99% yield with moderate
stereoselectivity (E/Z ˆ 3.1 ꢀ 5.1:1). Switching R3SnH (R ˆ
Bu, Ph) to bulky (Me3Si)3SiH (1.1 equiv) further enhanced
Scheme 4. Influence of R3MH on the radical cyclization of 5 to 6.
Reagents, conditions, and selectivities: cat. Et3B (0.2 equiv)/Bu3SnH
(1.1 equiv): 71% (E/Z ˆ 1.5:1); cat. Et3B (1 equiv)/(Me3Si)3SiH (1.1 equiv):
57% (E/Z ˆ 44:1); cat. Et3B (0.6 equiv)/TDTH (1.1 equiv): 76% (E/Z ˆ
>100:1).
412
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whereas use of TDTH afforded 6 with virtually complete
stereoselectivity (E/Z ˆ >100:1).
virtually complete discrimination of two structurally different
aldehyde carbonyl groups can be realized with TDTH as
hydride donor. Notably, an ordinary selective reducing agent,
l-Selectride gave a disappointing result in terms of the
chemoselectivity.
A similar tendency is also observed in the stereoselective
radical cyclization of iodoacetal 7 (diastereomeric ratio ˆ 1:1)
to cyclic acetal 8 (diastereomeric ratio ˆ 1:1) with high Z
selectivity using TDTH (Scheme 5).
Experimental Section
Ph
Ph
Radical cyclization of 3 with TDTH: To the solution of TDTH (280.4 mg,
0.33 mmol) in CH2Cl2 (2.5 mL) was added 3 (100.2 mg, 0.3 mmol) in
CH2Cl2 (1 mL) and Et3B (150 mL, 0.15 mmol of a 1m solution in hexane)
under Ar at ꢁ788C. After the reaction mixture had been stirred at ꢁ788C
for 2.5 h, it was poured into an aqueous saturated solution of NaHCO3 and
then extracted with diethyl ether. The combined extracts were dried over
Na2SO4. Evaporation of solvents and purification of the residue by column
chromatography on silica gel (diethyl ether/hexane (1/20)) gave 4 as a
colorless oil and a small amount of 3 which was recovered (4: 60.8 mg,
0.292 mmol, 97% yield; 3: 0.008 mmol, 3% yield). The ratio of (E)/(Z)-4
was determined by 1HNMR analysis ((E)/(Z)-4 ˆ 46.5/1.0). (E)-4; 1HNMR
(300 MHz, CDCl3, 208C, TMS): d ˆ 7.45 ± 7.20 (m, 6H; Ar-H), 7.16 (t,
J(H,H) ˆ 7.8 Hz, 1H; Ar-H), 6.86 (d, J(H,H) ˆ 7.8 Hz, 1H; Ar-H), 6.68 (t,
Ph
Et3B (0.2~1 equiv)
R3MH
I
+
CH2Cl2
O
O
OEt
OEt
O
OEt
–78°C, 1~4 h
(E)-8
(Z)-8
7
Scheme 5. Influence of R3MH on the radical cyclization of 7 to 8.
Reagents, conditions, and selectivities: cat. Et3B (0.2 equiv)/Bu3SnH
(1.2 equiv): 92% (E/Z ˆ 1:3.1); cat. Et3B (0.2 equiv)/Ph3SnH (1.2 equiv):
98% (E/Z ˆ 1:4.3); cat. Et3B (1 equiv)/(Me3Si)3SiH (1.2 equiv): 76%
(E/Z ˆ 1:6.7); cat. Et3B (1 equiv)/TDTH (1.2 equiv): 76% (E/Z ˆ 1:65.8).
ˆ
J(H,H) ˆ 7.8 Hz, 1H; Ar-H), 6.50 (t, J(H,H) ˆ 2.5 Hz, 1H; C CHPh), 5.24
Such selectivity in vinyl radical reduction appears feasible
in acyclic systems. For example, E-bromostilbene is trans-
formed to Z-stilbene with excellent stereoselectivity (Z/E ˆ
>100:1) on treatment with TDTH (1.1 equiv) and catalytic
Et3B (0.2 equiv) in CH2Cl2 at low temperature, while the
selectivity is only moderate (Z/E ˆ 3.4:1) in the case of
Bu3SnH under similar reduction conditions (Scheme 6).
ˆ
(d, J(H,H) ˆ 2.5 Hz, 2H; C CH2O); (Z)-4; d ˆ 7.53 (d, J(H,H) ˆ 7.6 Hz,
1H; Ar-H), 7.41 (t, J(H,H) ˆ 7.8 Hz, 2H; Ar-H), 7.32 ± 7.20 (m, 4H; Ar-H),
6.96 (t, J(H,H) ˆ 7.6 Hz, 1H; Ar-H), 6.92 (d, J(H,H) ˆ 7.6 Hz, 1H; Ar-H),
ˆ
6.85 (t, J(H,H) ˆ 3.0 Hz, 1H; C CHPh), 5.43 (d, J(H,H) ˆ 3.0 Hz, 2H;
ˆ
C CH2O).
Received: August 30, 2000 [Z15730]
[1] Review: H. G. Kuivila, Synthesis 1970, 499.
cat. Et3B
R3SnH
cat. Et3B
R3SnH
[2] a) D. P. G. Hamon, K. R. Richards, Aust. J. Chem. 1983, 36, 2243; b) S.
Takano, S. Nishizawa, M. Akiyama, K. Ogasawara, Synthesis 1984,
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e) H. G. Davies, S. M. Roberts, B. J. Wakefield, J. A. Winders, J. Chem.
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1983, 339; d) C. G. Gutierrez, L. R. Summerhays, J. Org. Chem. 1984,
49, 5206; e) Y. Watanabe, T. Araki, Y. Ueno, T. Endo, Tetrahedron
Lett. 1986, 27, 5385.
Ph
Br
Ph
Ph
Ph
Br
Ph
Ph
+
CH2Cl2
CH2Cl2
–78°C, 2~3 h
Ph
Ph
–78°C, 2~3 h
(Z)-9
Z- & E-stilbene
(E)-9
95% (Z/E = 3.4 : 1)
93% (Z/E = 3.4 : 1) cat Et3B/Bu3SnH
82% (Z/E = 92.4 : 1)
cat Et3B/TDTH
74% (Z/E = >100 : 1)
Scheme 6. Influence of R3MH on the selectivity in the vinyl radical
reduction of acyclic systems.
The synthetic power of TDTH has been further demon-
strated in ionic reactions by the chemoselective, electrophilic
reduction of structurally similar aldehyde substrates with
trialkyltin hydride. For example, treatment of one equivalent
each of hydrocinnamaldehyde and a-phenylpropionaldehyde
in CH2Cl2/diethyl ether (v/v, 7/1) with R3SnH (R ˆ Bu, Ph;
1 equiv) under the influence of Me2AlCl (2.2 equiv) as Lewis
acid at low temperature afforded a mixture of less hindered
3-phenyl-1-propanol and more hindered 2-phenyl-1-propanol
with only moderate selectivity (Scheme 7).[15] However,
[4] Reviews: a) D. P. Curran in Comprehensive Organic Synthesis, Vol. 4
(Eds.: B. M. Trost, I. Fleming, M. F. Semmelhack), Pergamon, Oxford,
1991, pp. 779 ± 831; b) D. P. Curran, N. A. Porter, B. Giese, Stereo-
chemistry of Radical Reactions, Wiley-VCH, Weinheim, 1996, pp. 23 ±
115; c) B. Giese, Radicals in Organic Synthesis, Pergamon, Oxford,
1986.
[5] W. P. Neumann, Synthesis 1987, 665.
[6] a) D. L. J. Clive, P. L. Beaulieu, J. Chem. Soc. Chem. Commun. 1983,
307; b) D. L. J. Clive, P. L. Beaulieu, L. Set, J. Org. Chem. 1984, 49,
1313; c) D. L. J. Clive, G. J. Chittattu, V. Farina, W. A. Kiel, S. M.
Menchen, C. G. Russell, A. Singh, C. K. Wong, N. J. Curtis, J. Am.
Chem. Soc. 1980, 102, 4438; d) D. L. J. Clive, G. J. Chittattu, C. K.
Wong, J. Chem. Soc. Chem. Commun. 1978, 41; e) H. C. Brown, K.-T.
Liu, J. Am. Chem. Soc. 1970, 92, 3502.
Ph
Ph
OH
CHO
Me2AlCl/R3SnH
[7] a) C. Chatgilialoglu, Acc. Chem. Res. 1992, 25, 188; b) T. B. Lowinger,
L. Weiler, J. Org. Chem. 1992, 57, 6099.
+
+
OH
CH2Cl2/diethyl ether
Ph
CHO
Ph
[8] Reaction bowls: a) K. Goto, N. Tokitoh, R. Okazaki, Angew. Chem.
1995, 107, 1202; Angew. Chem. Int. Ed. Engl. 1995, 34, 1124; b) T.
Sasaki, K. Goto, N. Tokitoh, R. Okazaki, J. Org. Chem. 1996, 61, 2924;
c) T. Sasaki, K. Goto, R. Okazaki, Angew. Chem. 1997, 109, 2320;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2223; d) K. Goto, M. Holler, R.
Okazaki, J. Am. Chem. Soc. 1997, 119, 1460.
Scheme 7. Influence of R3MH on the chemoselective, electrophilic reduc-
tion of similar aldehyde substrates. Reagents, conditions, and selectivities:
Bu3SnH, ꢁ788C, 0.5 h: 81% (43:57); Ph3SnH, ꢁ788C, 1 h: 93% (38:62);
TDTH, ꢁ78 ꢀꢁ 208C, 1.5 h: 82% (>100: < 1); l-Selectride, ꢁ788C, 0.5 h:
99% (45:55).
Angew. Chem. Int. Ed. 2001, 40, No. 2
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413

COMMUNICATIONS
[9] Molecule capsules: a) R. S. Meissner, J. Rebek, Jr., J. Mendoza,
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coupling event. In order to streamline this process, a number
of elegant chemoselective and orthogonal glycosylation
strategies have been developed with the goal of circumventing
deprotection and anomeric derivatization steps in the iter-
ative glycosylation sequence. Within this context, two key
strategies, which use well-established glycosylation methods,
have been explored. One approach employs carbohydrate
coupling partners with identical anomeric latent leaving
groups; the reactivities of each of the leaving groups are
differentiated by varying the electronic nature of proximal
protective groups.[2] The success of this approach to oligosac-
charide synthesis thus relies on intricate selection of protec-
tive groups to establish a suitable reactivity hierarchy among
the carbohydrate building blocks.[2e] In an alternative strategy,
the anomeric latent leaving groups in the carbohydrate
coupling partners are mutually distinct, possessing chemically
orthogonal reactivities; successive glycosylations are per-
formed with a number of different reagents that are specific
for a certain latent leaving group.[3]
We now report a novel approach to iterative oligosacchar-
ide synthesis which employs a chemoselective glycosylation
strategy that: 1) is not dependent on the careful selection and
placement of specific protective groups in the carbohydrate
coupling partners to electronically influence anomeric reac-
tivity; 2) avoids the need for C1-derivatized carbohydrate
building blocks with chemically distinct anomeric latent
leaving groups; and 3) requires only a single glycosylation
method to effect iterative one-pot anomeric bond construc-
tions.
[12] The single-crystal of 2 was obtained by recrystallization from diethyl
ether. Crystal structure data for 2: C57H46Sn, Mr ˆ 849.68, triclinic,
3
Å
space group P1, a ˆ 12.894, b ˆ 14.512, c ˆ 12.858 Š, Vˆ 2097.810 Š ,
Z ˆ 2, 1calcd ˆ 1.35 gcmꢁ1, R1 ˆ 0.05. Crystallographic data (excluding
structure factors) for the structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-152190. Copies of the data
can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB21EZ, UK (fax: (‡44)1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
[13] Treatment of (E)-4 (E/Z ˆ 46.5:1) with Bu3SnH (1 equiv) in benzene
under reflux for 2 h gave rise to an E/Z mixture (E/Z ˆ 2:1) of 4,
suggesting that (Z)-4 is a thermodynamic product.
[14] TDTH was found to be a slower reducing agent than Bu3SnH. For
example, reduction of benzyl p-iodophenyl ether with Bu3SnH and
TDTH (1.1 equiv) in CH2Cl2 at ꢁ788C under the influence of catalytic
Et3B (0.2 equiv) for 20 min afforded benzyl phenyl ether in 88% and
40% (recovery of p-iodophenyl ether in 56%) yields, respectively.
[15] Attempted reduction of the two different aldehydes with (Me3Si)3SiH
in the presence of Me2AlCl resulted in recovery of most of these
aldehydes.
We have recently established a dehydrative glycosidic
coupling method whereby a variety of nucleophilic acceptors
can be directly glycosylated with C1-hydroxy donors using
diphenyl sulfoxide and triflic anhydride.[4, 5] The fact that our
dehydrative coupling is not plagued by self-condensation of
the C1-hydroxy donor led us to investigate the possibility of
selective glycosylation of an alkyl hydroxy group in the
presence of a free hemiacetal functionality. In this context,
our dehydrative glycosylation reaction can serve as the basis
for a new approach to iterative chemoselective glycosylation
in which a hemiacetal donor 1 is activated with diphenyl
sulfoxide and triflic anhydride (Scheme 1). A nucleophilic
Chemoselective Iterative Dehydrative
Glycosylation**
Hien M. Nguyen, Jennifer L. Poole, and David Y. Gin*
The development of strategies for efficient construction of
complex oligosaccharides has been a long-standing challenge
in organic synthesis.[1] This is a direct result of the immense
structural diversity and biological importance of complex
glycoconjugates in nature. In traditional approaches to the
assembly of oligosaccharides, a preformed glycosyl donor
incorporating an anomeric latent leaving group is coupled
with a nucleophilic glycosyl acceptor, and the resulting
disaccharide then undergoes either a selective deprotection
or anomeric derivatization step prior to the subsequent
Ph2SO, Tf2O;
O
O
O
repeat
OH
O
etc.
O
(OR)n
(OR)n OH
(OR)n
HO
1
3
OH
(OR)n
2
Scheme 1. Chemoselective iterative dehydrative glycosylation. Tf ˆ tri-
fluoromethanesulfonyl.
[*] Prof. D. Y. Gin, H. M. Nguyen, J. L. Poole
Department of Chemistry
University of Illinois
acceptor 2, which incorporates a free alkyl hydroxy group as
well as an unprotected C1-hemiacetal functionality, is then
introduced. Ideally, the alkyl alcohol is chemoselectively
glycosylated in the presence of the hemiacetal hydroxy group
to generate, in a one-pot procedure, the hemiacetal-termi-
nated disaccharide 3, which is immediately poised for another
coupling iteration. Thus, the key issue of chemoselectivity in
this approach pertains only to the relative nucleophilicities of
the alkyl hydroxy group versus the hemiacetal hydroxy group
Urbana, IL 61801 (USA)
Fax: (‡1)217-244-8024
E-mail: gin@scs.uiuc.edu
[**] This research was supported by the National Institutes of Health
(Grant no.: GM-58833), the Arnold and Mabel Beckman Foundation
(BYI), Glaxo Wellcome Inc., and the Alfred P. Sloan Foundation.
D.Y.G. is a Cottrell Scholar of Research Corporation.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
414
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Angew. Chem. Int. Ed. 2001, 40, No. 2