Regioselective and stereoselective synthesis of tetrahydrofurans from a functionalized allylic silane and an aldehyde via formal [3+2]-cycloaddition reaction

Article abstract of DOI:10.1016/j.tetlet.2008.08.046

Allylsilanes are known as useful reagents for the stereoselective formation of ring systems. Previous studies have shown that tetrahydrofurans can be constructed via formal [3+2]-cycloadditions of aldehydes and allylsilanes. A new challenge is to understand the intermediate, after a nucleophile attacks a carbonyl activated by the Lewis acid, in which two silyl-protected alkoxy groups with chemical equivalency could undergo formal cycloaddition reaction to afford a disubstituted and/or a trisubstituted tetrahydrofuran. Preparation of the protected α-hydroxy aldehyde and a functionalized allylic silane is discussed, as well as their formal cycloaddition reaction to form tetrahydrofurans.

Full text of DOI:10.1016/j.tetlet.2008.08.046

Tetrahedron Letters 49 (2008) 6245–6249
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Tetrahedron Letters
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Regioselective and stereoselective synthesis of tetrahydrofurans from
a functionalized allylic silane and an aldehyde via formal [3+2]-
cycloaddition reaction
*
Steven R. Angle , Inchang Choi
Department of Chemistry, Wright State University, Dayton, OH 45435, United States
Department of Chemistry, University of California-Riverside, Riverside, CA 92521, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Allylsilanes are known as useful reagents for the stereoselective formation of ring systems. Previous stud-
ies have shown that tetrahydrofurans can be constructed via formal [3+2]-cycloadditions of aldehydes
and allylsilanes. A new challenge is to understand the intermediate, after a nucleophile attacks a carbonyl
activated by the Lewis acid, in which two silyl-protected alkoxy groups with chemical equivalency could
undergo formal cycloaddition reaction to afford a disubstituted and/or a trisubstituted tetrahydrofuran.
Received 23 May 2008
Revised 8 August 2008
Accepted 11 August 2008
Available online 15 August 2008
Preparation of the protected
a-hydroxy aldehyde and a functionalized allylic silane is discussed, as well
as their formal cycloaddition reaction to form tetrahydrofurans.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
study of a similar formal [3+2]-cycloaddition reaction, only THF
was obtained; no tetrahydropyran was observed.6 Accordingly,
pathways a and f are also unlikely. This leaves two likely pathways
for the proposed cycloaddition reaction: pathways b and e. These
two pathways would generate constitutional isomers 5 and 8,
respectively (Scheme 1). The reaction of the allylic silane with
the aldehyde should afford intermediate 3, with two chemically
similar triethyl siloxy groups. Either siloxy group could undergo
reaction with the silyl-stabilized cation (pathway b or e) to form
trisubstituted THF 5 or disubstituted THF 8.
An attempt to prepare (E)-alkene 14 via a trialkylaluminate
intermediate resulted in a difficult to separate mixture of primary
alcohols in low yield. Accordingly, an alternative method for the
synthesis of 14 was explored (Scheme 2). Terminal alkyne 10
was treated with DIBAl-H to generate (E)-alane complex 11, which
yielded (E)-vinyl iodide 12 upon reaction with I2.16 Metal–halogen
exchange, followed by addition of ethylene oxide, afforded b-hy-
droxy allylic silane 13 in 30% yield from 11. Protection of 13 as
Allylic silanes are important reagents that undergo highly
stereoselective reactions with a variety of electrophiles including
carbonyl groups, iminium ions, and enones.1–4 They have also
played a key role in the synthesis of natural products exhibiting
a variety of biological activities such as superstolide A,5 (À)-allo-
muscarine,6 (+)-epimuscarine,6 (9S)-dihydroerythronolide A,7 and
( )-peduncularine.8
Previous studies from our research group6,9,10 and others7,8,11–14
show that allylsilanes are potent nucleophiles that can be used to
prepare tetrahydrofurans (THFs) and tetrahydropyrans (THPs).
The mechanistic details of the addition of allylic silanes and allylic
stannanes to aldehydes have been controversial. As part of an
effort to understand the transition state of this formal [3+2]-cyclo-
addition, we prepared a functionalized allylic silane and studied its
Lewis acid-mediated reaction with a-triethylsiloxy aldehydes. The
result may shed some light on the orientation of the Lewis acid-
activated aldehyde relative to the allylsilane in the transition state.
the triethylsilyl ether gave 14. The known
a-triethylsilyloxyalde-
hyde 1 was prepared by DIBAl-H reduction of the corresponding
ester.10
2. THF synthesis
With the requisite allylic silane 14 and aldehyde 1 in hand, we
were poised to examine the formal [3+2]-cycloaddition reaction. A
series of reaction conditions were studied in an attempt to opti-
mize formation of THF products (Table 1). Under most conditions
trisubstituted THF 15 was formed along with desilylated THF 16.
The diastereomer ratio of 15 and 16 varied from 3.0:1 to 3.3:1
(1H NMR analysis). It is important to note that another potential
constitutional isomer, disubstituted THF 8 (Scheme 1), could have
been formed in this formal cycloaddition reaction; THF 8 was not
The formal [3+2]-cycloaddition reaction might produce a mix-
ture of six different compounds via pathways a–f (Scheme 1).
Based on results from previous studies,15 a triethylsilyl-protected
hydroxy group is a better nucleophile than a Lewis acid-complexed
alkoxide ion. Thus, pathways c and d are unlikely. In addition, in a
* Corresponding author. Tel.: +1 937 775 3035; fax: +1 937 775 2421.
E-mail address: steven.angle@wright.edu (S. R. Angle).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.046

6246
S. R. Angle, I. Choi / Tetrahedron Letters 49 (2008) 6245–6249
O
TESO
+
R3Si
c
OTES
H
1
2
O
TESO
BF3
BF3 OEt2
d
b
a
CH2Cl2, -78 ºC
e
f
+
R3Si
TESO
3
OTES
OTES
OTES
HO
TESO
HO
SiR3
O
O
SiR3
SiR3
5
from b
O
4
from pathway a
6
from c
TESO
OH
TESO
OH
TESO
R3Si
SiR3
TESO
O
O
R3Si
O
7 from d
8 from e
9 from f
Scheme 1. Possible products from formal [3+2]-cycloaddition reaction.
a
b
50%
PhMe2Si
AliBu2
PhMe2Si
I
PhMe2Si
H
12
10
11
c
74%
d
PhMe2Si
OH
PhMe2Si
OTES
13
87%
14
Scheme 2. Alternate route for formation of (e)-pentenyl silyl ether 14. Reagents and conditions: (a) DIBAL-H, hexanes, À78 °C to 40 °C; (b) I2, THF, À78 °C to rt; (c) (i) t-BuLi,
ether, À78 °C, (ii) ethylene oxide; (d) TESCl, Et3N, CH2Cl2, 0 °C to rt.
observed. The formation of constitutional isomer 15 (but not 8)
was also confirmed by NMR studies, including COSY, of compounds
15 and 16,17 and the X-ray crystal structure of 19a.
The stereochemistry of the major diastereomer of trisubstituted
THF 15 was determined as described below (Scheme 3). Oxidation
of 15 (3:1 mixture of diastereomers) afforded ketone 17 as a single
diastereomer. This oxidation reaction confirmed that the carbon
with the secondary alcohol was the diastereomeric center. Subse-
quent reduction of ketone 17 with NaBH4 gave 15 as 5.5:1 mixture
of diastereomers in 80% yield.
The two diastereomers of 15a/b were separated by HPLC. The
major diastereomer 15a was desilylated to afford diol 16a (99%
yield) and the desilylation of THF 15b gave diol 16b in 91% yield.
The 3.3:1 mixture of diastereomers 16a/b was reacted with p-
nitrobenzoyl chloride to give a mixture of diesters 18a/b in 71%
yield (Scheme 4). After separation, 18a was recrystallized to afford
X-ray quality crystals. X-ray analysis showed 17a (and thus 15a) to
have a trans–trans relative stereochemistry of substituents about
the THF ring (Fig. 1).
The regioselective outcome of the formal [3+2]-cycloaddition
reaction shows that in intermediate 3, the triethyl siloxy group
on the aldehyde backbone attacks the b-silylcation/siliranium ion
(pathway b in Scheme 1), whereas its counterpart triethyl siloxy
group on the allylic silane does not (pathway e in Scheme 1). In
an effort to see if the triethyl siloxy group on the allylic silane could
act as a nucleophile toward the b-silylcation/siliranium intermedi-
ate, an aldehyde lacking an a-triethyl siloxy group (benzaldehyde)
was used in the formal cycloaddition reaction under same reaction
conditions (Scheme 5). We did not observe (1H NMR analysis) any
cyclized product 20 in this reaction. The only isolable product of
the reaction was a compound tentatively assigned as terminal
alkene 21 (by 1H NMR, 13C NMR).
This result might be explained by proposed intermediate 19 in
Scheme 5. After nucleophilic addition of allylic silane 2 to benz-
aldehyde, backside approach of the silyloxy group to the b-silyl
cation via the si-face was blocked by the bridging b-silylcation/
siliranium ion, and re-face approach was also hindered by a bulky
phenyl group. Such difficulty in accessing the silyloxy group may

S. R. Angle, I. Choi / Tetrahedron Letters 49 (2008) 6245–6249
6247
Table 1
Formal [3+2]-cycloaddition reaction
OTES
OH
HO
HO
O
+
TESO
+
OTES
PhMe2Si
SiPhMe2
SiPhMe2
H
O
O
16a/b
1
15a/b
14
Entry
Reaction condition
15 (%)
16 (%)
Additive (equiv)
1
2
3
4
5
24 h at À78 °C
24 h at À78 °C
2 h at rt
1 h at rt
1 h at rt
40
49
43
66
Trace
3
20
9
None
DBMP (1.0)
DBMP (1.0)
DBMP (1.0)
None
None
49
General procedure: to a solution of 1 and 14 (1.5 equiv) in CH2Cl2 (1 M) was added BF3ÁOEt2 (1.5 equiv) at À78 °C. After being stirred for the time shown in the table, the
mixture was poured into sat. NaHCO3 with stirring.
OSiEt3
OSiEt3
OSiEt3
HO
O
HO
b
a
80%
88%
O
O
O
SiMe2Ph
SiMe2Ph
SiMe2Ph
= 5.5:1
15a/b
15a/b
17
15a 15b
d.r., 15a:15b = 3.3:1
:
Single Diastereomer
Scheme 3. Oxidation of THF. Reagents and conditions: (a) Dess–Martin periodinane, CH2Cl2, 0 °C to rt; and (b) NaBH4, MeOH, 0 °C to rt.
NO2
O2N
OH
OSiEt3
HO
HO
b
a
O
O
O
O
O
O
SiMe2Ph
SiMe2Ph
O
SiMe2Ph
and 18b (14%)
16a (99%)
16b (91%)
18a (57%)
from 3.3:1 mixture of 16a/b
15a
15b
Scheme 4. Preparation of THF derivative. Reagents and conditions: (a) TBAF, THF, 0 °C to rt; and (b) p-nitrobenzoyl chloride, pyr., DMAP, CH2Cl2, 0 °C to rt.
have led to the failure of cyclization. Moreover, the Lewis acid-
complexed alkoxide ion did not participate in a cyclization. The
major products were terminal alkene 21 derived from desilylation,
and decomposed allylsilane (deprotected b-hydroxy alkene 13).
Thus, in the formal cycloaddition reaction of functionalized
approach of the allylsilane to the aldehyde in the transition
state.2,6,9,18–24 However, a detailed understanding of the transition
states for these reactions still remains controversial. Yamamoto
et al.23,24 first proposed that the intermolecular reaction of allylst-
annanes with aldehydes in the presence of Lewis acid occurs via an
open transition state with an antiperiplanar arrangement of the
allylstannane and aldehyde being preferred. Along with Yamamoto’s
proposal, a number of proposals have been advanced to explain the
stereochemical outcome of the reaction of allylic stannanes or
allylic silanes with aldehydes under Lewis acid-promoted reaction
conditions. Denmark et al.19 demonstrated that in the intramole-
cular reaction of an allylstannane with an aldehyde in the presence
of various Lewis acids, a major diastereomer was derived from the
synclinal transition state, not from the antiperiplanar one. Several
researchers11,18,20 have supported a syn-synclinal transition state
based upon FMO theory. Consistent with the results of others
studying Lewis acid-promoted addition of allylstannanes and allyl-
silanes to aldehydes, our stereochemical results can be rationalized
allylic silane 14 with an
a-siloxy aldehyde, we might explain
why trisubstituted THF 15 was formed as follows: in intermediate
3 (Scheme 1), the triethyl siloxy group originally from aldehyde 1
was more accessible to the b-silylcation/siliranium ion compared
to its counterpart on the allylic silane. This led to the formation
of the trisubstituted THF only.
3. Study of stereochemical outcome
Addition reactions of allylic stannanes and silanes with Lewis
acid-activated aldehydes have been studied for decades, and these
highly stereoselective reactions have motivated many researchers
to attempt to understand mechanistic details, especially the

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S. R. Angle, I. Choi / Tetrahedron Letters 49 (2008) 6245–6249
NO2
O2N
O
O
O
O
O
SiMe2Ph
18a
Figure 1. Crystal structure of the major eiester 18a.
-
BF3
OH
O
SiMe2Ph
O
+
2
SiEt3
O
H
si
H
BF3 OEt2,
O
re
PhMe2Si
OH
- 78 ºC, 24 h
20
19
OH
26%
21
Scheme 5. Allylation of benzaldehyde.
by invoking a syn synclinal transition state. However, it is impossi-
ble to make any conclusive statements about the transition state
for our reaction.
References and notes
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In conclusion, we have completed the formal [3+2]-cycloaddi-
tion reaction of the functionalized allylic silane with the
a-siloxy
aldehyde under BF3 promoted-reaction condition, which generated
the regioselectively as well as stereoselectively enriched THF. This
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syn-synclinal transition state over the antiperiplanar even though
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on the 5-membered heterocyclic ring system.
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