Stereoselective propargylation of glycals with allenyltributyltin(IV) via a Ferrier type reaction

Article abstract of DOI:10.1016/j.tetlet.2012.03.115

Stereoselective introduction of an unsubstituted propargyl group to various glycals was achieved using a Ferrier type reaction with allenyltributyltin(IV). The stereoselectivity was observed based on the conformational preference of glycals as well as steric control of rigid bicyclic systems.

Full text of DOI:10.1016/j.tetlet.2012.03.115

Tetrahedron Letters 53 (2012) 2833–2836
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective propargylation of glycals with allenyltributyltin(IV) via a Ferrier
type reaction
⇑
Mark D. Drew, Mark C. Wall, Joseph T. Kim
Sanofi, Tucson Research Center, 2090 E. Innovation Park Drive, Oro Valley, AZ 85755, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective introduction of an unsubstituted propargyl group to various glycals was achieved using a
Ferrier type reaction with allenyltributyltin(IV). The stereoselectivity was observed based on the confor-
mational preference of glycals as well as steric control of rigid bicyclic systems.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 6 March 2012
Revised 21 March 2012
Accepted 27 March 2012
Available online 4 April 2012
Keywords:
C-Glycosides
Propargylation
Allenyltributyltin
Ferrier reaction
Vinylogous anomeric effect
Introduction
with both substituted achiral and enantioenriched allenylsilanes
resulting in a substituted propargyl group in the ring.11 Isobe’s
In recent years, C-glycosides have attracted significant attention
within the scientific community.1 Various subunits of C-glycosides
are found in nature including aloin,2 anthraquinones,3 showdomy-
cin, and formycin.4 In addition, C-glycosides have been used as
chiral building blocks5 for the synthesis of biologically active natu-
ral products such as palytoxin, spongistatin, tautomycin, ciguatoxin,
okadaic acid, and halichondrin, etc.6 Furthermore, due to their
stable pharmacophore nature, C-glycosides were also studied as
potential novel enzyme inhibitors in inflammation pathways, cello-
group reported that propargylic and acetylenic silyl groups on pro-
pyne produced C-glycosidation products with appropriate choice
of silyl groups.12 In the case of unsubstituted propargylation, only
one example was shown by Kobayashi’s group where they used
allenylboronic acid pinacol ester.13 Herein, we report broad
examples of unsubstituted propargylation of glycals using
commercial allenyltributyltin via a Ferrier type reaction.
biase, b-D-galactosidase, phosphorylases, immune pathway, and
lectin binding.7 For these reasons, the development of efficient
and selective construction of C-glycosidic linkages continues to be
an important task. One of the most common methods of construct-
ing a C-glycosidic bond involves an electrophilic substitution
reaction where carbon nucleophiles react with an oxocarbenium
ion. Due to the facile generation of an oxocarbenium ion intermedi-
ate, 2,3-unsaturated glycosides (known as ‘glycal’) have proven
useful for a broad range of applications via a Ferrier type reaction
(Scheme 1).8
Nu
O
X
O
Nu
O
+
LA
RO
RO
RO
RO
RO
RO
-
X
Scheme 1.
OAc
OAc
The exceptional synthetic utility of the Ferrier type reaction
using glycal systems has been demonstrated by allyl-, alkyl-,
aryl-, allenyl-, and alkynylations.9 However, there are very limited
examples of introducing a propargyl group to glycals.10 Very
recently, Panek’s group reported stereoselective C-glycosidations
O
O
conditions
AcO
AcO
or
OAc
SnBu3
B(pin)
1
2
Scheme 2. Initial attempts under various conditions. Reagents and conditions:
Lewis acid: TMSOTf, TMSI, BF3ÁOEt2, InCl3, In(OTf)3, AlMe3, AgOTf, I2; solvent: DCM,
CH3CN, CH3NO2, THF, benzene, toluene; temperature: RT to À78°.
⇑
Corresponding author. Tel.: +1 520 544 5856; fax: +1 520 575 8283.
E-mail address: joseph.kim@sanofi.com (J.T. Kim).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.115

2834
M. D. Drew et al. / Tetrahedron Letters 53 (2012) 2833–2836
Table 1
BF3ÁOEt2 mediated propargylation of glycals with allenyltributyltin(IV)
Entry
Glycal
Product
Time (min)
20
Yielda (%)
>99
Ratiob
a:b
OAc
OAc
O
O
1
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
2:1
AcO
AcO
OAc
OTBS
OTBS
O
O
2
3
4
5
6
7
8
15
93
1.7:1
2:1
2:1
3:1
5:1
5:1
AcO
OBz
AcO
OBz
OAc
O
O
30
>99
>99
97
BzO
BzO
OPiv
OBz
O
OPiv
O
60
PivO
OBn
PivO
OBn
OPiv
O
O
O
O
O
120
180
240
120
BnO
OAc
BnO
OAc
OBn
O
89
AcO
AcO
OPiv
OAc
O
OPiv
1g
1h
2g
2h
>99
92
PivO
OBn
PivO
OBn
OPiv
O
8:1
8:1
BnO
O
BnO
OBn
O
O
O
O
t Bu
t Bu
Si
Si
9
1i
2i
20
70
10
10
10
10
10
97
O
O
O
t Bu
t Bu
OAc
O
O
O
t
t
Bu
Bu
Si
Si
10
11
12
13
14
1j
2j
96
a
a
only
O
t
Bu
Bu
t
OAc
Ph
O
Ph
O
1k
1l
2k
2l
>99
91
only
OAc
O
O
O
O
O
4:1
AcO
AcO
AcO
AcO
AcO
AcO
AcO
AcO
OAc
O
1m
1n
1o
2m
2n
2o
>99
>99
51
1:4
OAc
O
1:4
OAc
O
15
1:1.4
OAc
a
Isolated yield.
b
Ratio was determined by 1H NMR.

M. D. Drew et al. / Tetrahedron Letters 53 (2012) 2833–2836
2835
Results and discussion
X
AcO
O
O
AcO
(1)
As shown in Scheme 2, our initial attempts were made by
reacting tri-O-acetyl- -glucal with either allenylboronic acid pina-
AcO
O
D
OAc
OAc
col ester or allenyltributyltin under various Lewis acid conditions
and solvents (DCM, THF, actonitrile, toluene, etc.). The use of allen-
ylboronic acid pinacol ester did not give satisfactory results, giving
low reaction yields or no reaction. The best result was obtained
with allenyltributyltin and BF3ÁOEt2 as Lewis acid in DCM at rt.14
The reaction went smoothly to complete conversion within
20 min, producing the desired propargylated C-glycosides
4H5
5H4
VAE
favored
Nu-
disfavored
+
(2)
O
O
O
O
OAc
quantitatively with
a:b ratio = 2:1. The diastereoselectivity was
+
determined by 1H NMR analysis of the crude reaction mixture.
In order to assess the scope of this reaction, the optimal condi-
tions were applied to various glycals producing 2,3-unsaturated
C-glycosides efficiently (Table 1). The propargylation of tri-O-ben-
Figure 3. The ground-state conformational preference of 3,4-di-O-acetyl-
due to vinylogous anomeric effect.
D
-xylal
zoyl-
tri-O-acetyl-
D
-glucal and TBS-protected
D-glucal gave a similar result to
Si
O
O
D
-glucal in terms of the reaction yield and the ratio
(entries 2 and 3). Changing to bulkier protecting groups such as
pivalic ester did not improve the ratio (entries 4 and 7). It is worth
mentioning that the reaction with tri-O-benzyl-glycals went
efficiently, showing a slight improved ratio (entries 5 and 8).
Presumably, electron-rich benzyloxy group at C-5 could stabilize
the oxocarbenium ion from the b face to form a five-membered
ring dioxonium ion intermediate, which would be quenched with
O
+
O
LA
O
SnBu3
Figure 4. A proposed transition state for highly stereoselective propargylation of
glycal 1j.
allenyltributyltin from the
Compared to the reactions with
tion with tri-O-acetyl- -galactal afforded an improved ratio,
:b = 5:1 (entry 6). Undoubtedly, the conformation of glycals plays
a
face (Fig. 1).
D
-galactal is more stable than tri-O-acetyl-
in the 4H5 conformation in acetone: 88% and 59%, respectively).17
Conversely,
-arabinal is known to exist predominantly in the 5H4
D-glucal (molar fractions
D-glucal derivatives, the reac-
D
L
a
conformation, even though the other 4H5 conformation has no
1,3-diaxial interactions. This preferred conformation can be ex-
plained by a ‘vinylogous anomeric effect (VAE)’, a vinylogous
hyperconjugative interaction between the lone pair on the oxygen
and the oxygen-C3 antibonding orbital.18 In order to make a favor-
able overlap between the antibonding rÃCX orbital with the lone-
pair orbital, no through the
C–X bond favors an axial orientation (Fig. 3).
Such stereoelectronic interactions also induce C–X bond length-
ening and enhanced reactivity in the conformers.19 The beneficial
outcome of VAE can be found in the reaction with all 3,4-di-O-acet-
an important role in regard to the stereoselective outcome. As
shown in Figure 2, glycals in solution adopt both 4H5 and 5H4
half-chair conformations in equilibrium. There are several known
factors influencing the peracetylated glycal conformations. Firstly,
the allylic effect dictates the pseudo-axial orientation of the acet-
oxy group at C-3.15 Secondly, 1,3-diaxial interactions disfavor the
5H4 conformation when there is a substituent at C-5. Thirdly, the
4-OAc group prefers an axial orientation when the 3-OAc group
is oriented pseudo-equatorially. When the two acetoxy groups
are oriented equatorially at C-3 and C-4 adjacent to the double
bond, the formation of a nearly coplanar structure destabilizes its
conformation.16 Therefore, the 4H5 conformation of tri-O-acetyl-
p bond delocalization, a vinylogous
yl-glycals. It is interesting to see when 3,4-di-O-acetyl-
was subjected to the reaction conditions, the ratio improved to
:b = 4:1 (entry 12). A similar reactivity was observed in the reac-
tions with 3,4-di-O-acetyl- -arabinal (entry 13) and 3,4-di-O-acet-
yl-
-xylal (entry 14). As shown in Figure 3, the 5H4 conformational
preference of
-xylal over 4H5 resulted in a more favorable nucleo-
philic attack from the b-face. However, the reaction with 3,4-di-O-
acetyl-6-deoxy- -glucal gave almost no stereoselectivity, indicat-
L-arabinal
a
D
Ph
O
D
BF3·OEt2
O
O
O
BnO
BnO
BnO
BnO
+
D
+
BnO
OBn
L
ing no conformational preference in solution (entry 15).
Figure 1. The hypothesis of neighboring group participation.
Next, we drew our attention to more rigid bicyclic ring systems.
Initially, when the PMP-acetal protected glycal was subjected to
the reaction conditions, it gave a complex mixture of products.
However, when di-tert-butylsilyl protection was introduced to
the ring, the reaction went smoothly producing the desired prod-
ucts. Noticeably, the sterically bulky di-tert-butylsilyl protection
not only provides the glycal a more rigid bicyclic conformation,
but also efficiently blocks the nucleophile from the b-face produc-
5H4
4H5
CH2OAc
O
AcO
AcO
AcO
O
CH2OAc
OAc
ing a-glycosides as the major product (Fig. 4). The most dramatic
OAc
CH2OAc
O
AcO
AcO
steric effect was found with di-tert-butylsilyl galactal. Only one
stereoisomer was observed in the crude reaction mixture (entry
10). A similar effect was observed when a phenyl group was di-
rectly introduced into the ring (entry 11).
In conclusion, we have developed a propargylation reaction of
glycals using commercial allenyltributyltin via a Ferrier type reac-
tion. The stereoselectivity of the reaction was observed based on
the conformational preference of glycals. It is also worth mention-
AcO
O
CH2OAc
OAc
AcO
AcO
AcO
O
O
Figure 2. The equilibrium of glycal conformation in solution.

2836
M. D. Drew et al. / Tetrahedron Letters 53 (2012) 2833–2836
7. (a) Schmidt, R. R.; Dietrich, H. Angew. Chem., Int. Ed. 1991, 30, 6911; (b)
Lehmann, J.; Schlesselmann, P. Carbohydr. Res. 1983, 113, 93; (c) Myers, R. W.;
Lee, Y. C. Carbohydr. Res. 1986, 152, 143; (d) Pougny, J. R.; Nassr, M. A. M.; Sinay,
P. J. Chem. Commun. 1981, 375; (e) Vyplel, H.; Scholz, D.; Macher, I.;
Schindlmaier, K.; Schuetze, E. J. Med. Chem. 1991, 34, 2759; (f) Nagy, J. O.;
Wang, P.; Gilbert, J. H.; Schaefer, M. E.; Hill, T. G.; Gallstrom, M. R.; Bednarski,
M. D. J. Med. Chem. 1992, 35, 4501; (g) Bertozzi, C.; Bednarski, M. Carbohydr. Res.
1992, 223, 243; (h) Eshdat, Y.; Ofek, I.; Yashouv-Gan, Y.; Sharon, N.; Mirelman,
D. Biochem. Biophys. Res. Commun. 1978, 85, 1551; (i) Firon, N.; Ofek, I.; Sharon,
N. Biochem. Biophys. Res. Commun. 1982, 105, 1426.
ing that steric control of a rigid bicyclic system such as di-tert-
butylsilyl glycal affords exclusively a-glycosides.
Representative procedure
BF3ÁOEt2 (150
lL, 1.2 mmol) was added to a mixture of tri-O-
acetyl- -glucal (272 mg, 1.0 mmol) and allenyltributyltin
D
(495 mg, 1.2 mmol, Alfa Aesar tech. 80%) in CH2Cl2 (5 mL) at rt.
The mixture was stirred at rt for 20 min and was quenched with
aqueous NaHCO3. The phases were separated and the aqueous
phase was thoroughly extracted with CH2Cl2. The combined organ-
ic extracts were washed (brine), dried (anhydrous Na2SO4), and
concentrated under reduced pressure. The residue was purified
by silica gel chromatography with 20% EtOAc/hexanes to give the
desired C-glycosides (250 mg, >99% yield)
8. (a) Ferrier, R. J.; Prasad, N. J. Chem. Soc. C. 1964, 5443; (b) Ferrier, R. J. Curr.
Chem. 2001, 215, 153.
9. For the original report and recent selected examples, see: (a) Danishefsky, S. J.;
Kerwin, J. F., Jr. J. Org. Chem. 1982, 47, 3803; (b) Danishefsky, S. J.; De Ninno, S.;
Lartey, P. J. Am. Chem. Soc. 1987, 109, 2082; (c) Gallagher, T.; Thorn, S. Synlett.
1996, 185; (d) Xue, S.; He, L.; Han, K.-Z.; Zheng, X.-Q.; Guo, Q-X. . Carbohydr. Res.
2005, 340, 303; (e) Isobe, M.; Huang, G. Tetrahedron 2001, 57, 10241; (f) Yeager,
A. R.; Min, G. K.; Porco, J. A.; Schaus, S. E. Org. Lett. 2006, 8, 5065; (g) Vieira, A. S.;
Fiorante, P. F.; Hough, T. L. S.; Ferreira, F. P.; Ludtke, D. S.; Stefani, H. A. Org. Lett.
2008, 10, 5215.
10. (a) Williams, D. R.; Mi, L.; Mullins, R. J.; Stites, R. E. Tetrahedron Lett. 2002, 43,
4841; (b) Nelson, S. G.; Cheung, W. S.; Kassick, A. J.; Hilfiker, M. A. J. Am. Chem.
Soc. 2002, 124, 13654.
Acknowledgment
11. Brawn, R. A.; Panek, J. S. Org. Lett. 2010, 12, 4624.
The authors gratefully acknowledge Dr. Jacques Mauger for tre-
mendous support and helpful discussion on this work.
12. Isobe, M.; Phoosaha, W.; Saeeng, R.; Kira, K.; Yenjai, C. Org. Lett. 2003, 5, 4883.
13. Dao, H. T.; Schneider, U.; Kobayashi, S. Chem. Asian J. 2011, 6, 2522.
14. While optimizing reaction conditions, the reactions were performed at various
reaction temperatures to examine the stereoselectivity. There was no
conversion at À78 °C and the reaction at À20 °C resulted in a mixture of
products. The reaction at 0° and rt gave similar results in terms of reaction
yield and diastereoselectivity, although the reaction at 0° C produced a slightly
lower yield.
References and notes
1. (a) Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407; (b) Marquez, V. E.; Lim,
M. I. Med. Res. Rev. 1986, 6, 1.
2. Gruen, M.; Franz, G. Pharmazie 1979, 34, 669.
3. Adinolfi, M.; Lanzetta, R.; Marciano, C. E.; Parrilli, M.; Giuliu, A. D. Tetrahedron
1991, 47, 4437.
4. (a) Buchanan, J. G.; Wightman, R. H. Prog. Chem. Org. Nat. Prod. 1983, 44, 243;
(b) Humber, D. C.; Mulholland, K. R.; Stoodley, R. J. J. Chem. Soc., Perkin Trans.
1990, 1, 283–292.
15. Thiem, J.; Ossowski, P. J. Carbohydr. Chem. 1984, 3, 287.
16. Liberek, B.; Tuwalska, D.; Konitz, A.; Sikorski, A. Carbohy. Res. 2007, 342, 1280.
17. (a) Thiem, J.; Ossowski, P. J. Carbohydr. Chem. 1984, 3, 287; (b) Rico, M.;
Santoro, J. Org. Magn. Reson. 1976, 8, 49.
18. Denmark, S. M.; Dappen, M. S. J. Org. Chem. 1984, 49, 798.
19. (a) Allen, F. H.; Kirby, A. J. J. Am. Chem. Soc. 1984, 106, 6197; (b) Briggs, A. J.;
Glenn, R.; Jones, P. G.; Kirby, A. J.; Ramaswamy, P. J. Am. Chem. Soc. 1984, 106,
6200; (c) Luger, P.; Kothe, G.; Paulsen, H. Chem. Ber. 1850, 1976, 109; (d) Cosse-
Barbi, A.; Dubois, J.-E. J. Am. Chem. Soc. 1987, 109, 1503; (e) Cosse-Barbi, A.;
Watson, D. G.; Dubois, J. E. Tetrahedron Lett. 1989, 30, 163; (f) Perrin, C. L.;
Armstrong, K. B.; Fabian, M. A. J. Am. Chem. Soc. 1994, 116, 715; (g) Kirby, A. J.
Adv. Phys. Org. Chem. 1994, 29, 87; (h) Yokoyama, Y.; Ohashi, Y. Bull. Chem. Soc.
Jpn. 1999, 72, 2183; (i) Uehara, F.; Sato, M.; Kanedo, C.; Kurihara, H. . J Org.
Chem. 1999, 64, 1436.
5. Hanessian, S. C. In Total Synthesis of Natural Products: The Chiron Approach;
Pergamon Press: Oxford, 1984.
6. (a) Paterson, L.; Keown, L. E. Tetrahedron Lett. 1997, 38, 5727; (b) Horita, K.;
Sakurai, J.; Nagasawa, M.; Hachiya, S.; Yonemitsu, O. Synlett 1994; (c) Smith, A.
B., III; Zhuang, L.; Brook, C. S.; Boldi, A. M.; Mcbriar, M. D.; Moser, W. H.;
Murase, N.; Nakayama, K.; Verhoest, P. R.; Lin, Q. Tetrahedron Lett. 1997, 38,
8667; (d) Wewis, M. D.; Cha, J. K.; Kishi, Y. . J Am. Chem. Soc. 1982, 104,
4976.