Site-recognition of one of the two alkoxy carbonyl groups present in the dienophile for Diels-Alder reaction

Article abstract of DOI:10.1016/S0040-4039(01)02031-7

Recognition of one alkoxy carbonyl group from the two in a molecule by a Lewis acid was investigated using 1a-e in the Diels-Alder reaction with diene 6. Combination of 1a and BF₃·OEt₂ provided the highest efficiency to afford 7a, thus showing evidence for the site-selective coordination of BF₃·OEt₂ to the MOM-oxy carbonyl group in 1a. Furthermore, the generality and high reactivity of this combination were confirmed with dienes 11-14.

Full text of DOI:10.1016/S0040-4039(01)02031-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9229–9232
Site-recognition of one of the two alkoxy carbonyl groups
present in the dienophile for Diels–Alder reaction
Yuichi Kobayashi* and Yohei Kiyotsuka
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501,
Japan
Received 28 September 2001; revised 24 October 2001; accepted 26 October 2001
Abstract—Recognition of one alkoxy carbonyl group from the two in a molecule by a Lewis acid was investigated using 1a–e in
the Diels–Alder reaction with diene 6. Combination of 1a and BF3·OEt2 provided the highest efficiency to afford 7a, thus showing
evidence for the site-selective coordination of BF3·OEt2 to the MOM-oxy carbonyl group in 1a. Furthermore, the generality and
high reactivity of this combination were confirmed with dienes 11–14. © 2001 Elsevier Science Ltd. All rights reserved.
O
R1
*
Chelation control of a- or b-alkoxy carbonyl com-
pounds by a Lewis acid is a powerful method to furnish
high stereoselectivity in their reactions. Simple com-
pounds possessing one alkoxy carbonyl group in a
molecule have been studied extensively, and the prefer-
able combinations of alkoxy groups and Lewis acids
are elucidated.1 However, compounds with two types of
alkoxy carbonyl sites have been paid little attention,2
though products derived from these compounds are
more useful intermediates in organic synthesis because
of their greater possibility for further conversion by
taking advantage of these alkoxy carbonyl groups.
Fundamentally, differentiation of the two carbonyl
groups in a coordination step by a Lewis acid is an
important process to produce one stable conformer of a
given compound. Although the previous investigation
with the simple compounds can suggest a Lewis acid
capable of strong coordination to a given alkoxy car-
bonyl group, a guideline to attain the maximum differ-
entiation has not been fully established. We chose a
2-ene-1,4-dicarbonyl compound of the general structure
1, and the Diels–Alder reaction of 1 (Eq. (1)) was
investigated.3 In practice, high selectivity and reactivity
were observed. In addition, the synthetic potential of
the products 3 was demonstrated by several successful
transformations.
OR2
OTBS
O
1
1a: R1 = i-Pr, R2 = MOM
1b: R1 = c-C6H11, R2 = MOM
1c: R1 = Me, R2 = MOM
1d: R1 = c-C6H11, R2 = PMB
1e: R1 = i-Pr, R2 = PMB
OTBS
(1)
*
*
O
O
+
1
2
R2O
R1
*
3
A convenient approach to 1 we have established is
represented by (R)-1a (Scheme 1). The kinetic
t-BuOOH
1) MOMCl
2) BuLi
Ti(OPr)4
O
O
L-(+)-DIPT
39–41%
then (CH2O)n
3) TBSCl
OH
OH
(R)-4
> 95% e.e.
4
65%
O
NBS
O
OMOM
then
C5H5N
OTBS
O
OTBS
OMOM
Keywords: asymmetric induction; Diels–Alder reactions; furans;
stereoselection.
5
(R)-1a
92%
* Corresponding author. Tel.: +81-45-924-5789; fax: +81-45-924-5789;
e-mail: ykobayas@bio.titech.ac.jp
Scheme 1. Synthesis of (R)-1a.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02031-7

9230
Y. Kobayashi, Y. Kiyotsuka / Tetrahedron Letters 42 (2001) 9229–9232
Table 1. Diels–Alder reaction of 1a–d with cyclopentadiene (6)a
Entry
For 1 and 7
Dienophile
Lewis acid (equiv.) Temp. (°C)
Major isomer
Ratio of
isomersb
Combined yield (%)
R1
R2
Major:othersc
1
2
3
4
5
6
7
8
Pr-i
Pr-i
Pr-i
Pr-i
Pr-i
Pr-i
Pr-i
MOM 1a
–
0
7a
7a
7a
7a
7a
7a
7a
7b
7c
7d
1:1
10:1
6:1
13:1
1:1
7:1
4:1
5:1
3.5:1
5:1
Ndd
87
85
MOM 1a
MOM 1a
MOM 1a
MOM 1a
MOM 1a
MOM 1a
BF3·OEt2 (1.5)
BF3·OEt2 (1.5)
BF3·OEt2 (2.0)
Ti(OPr-i )4 (2.0)
ZnCl2 (2.0)
Et2AlCl (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
–78
–50
–78
–78
–78
–78
–78
–78
–78
90
Ndd
87
Ndd
77
C6H11-c MOM 1b
Me MOM 1c
C6H11-c PMB 1d
9
10
91
Ndd
a Reactions were examined using racemic 1a–d and 6 (3 equiv.) in CH2Cl2 for 1–2 h.
b Determined by 1H NMR (300 MHz) spectroscopy.
c The other three corresponding isomers were combined as ‘others’.
d Not determined.
O
resolution4 of racemic furyl alcohol 4 by using the
1a–d
OTBS
Sharpless reagent5 (t-BuOOH,
L
-(+)-DIPT, Ti(OPr)4)
other three
stereoisomers
+
+
is a key step of this method to afford (R)-4 with
>95% e.e. (determined by 1H NMR spectroscopy of
the MTPA ester) in 39–41% yields (78–82% yields
based on the enantiomer). The other steps involved in
the method also proceeded efficiently. Needless to
R1
OR2
O
(2)
7a: R1 = i-Pr, R2 = MOM
7b: R1 = c-C6H11, R2 = MOM
7c: R1 = Me, R2 = MOM
6
say, use of
D
-(−)-DIPT in the kinetic resolution
7d: R1 = c-C6H11, R2 = PMB
affords (S)-1a. For the preliminary investigation, the
racemic dienophile 1a was synthesized by this method
without carrying out the kinetic resolution. Similarly,
other dienophiles, 1b (R1=c-C6H11, R2=MOM), 1c
(R1=Me, R2=MOM), 1d (R1=c-C6H11, R2=PMB
(p-methoxybenzyl)), and 1e (R1=i-Pr, R2=PMB)
were prepared in racemic forms with comparable
efficiency.
Catalytic ability of other Lewis acids such as Ti(OPr-
i )4, ZnCl2, and Et2AlCl was investigated. These cata-
lysts, however, did not provide a better result than
BF3·OEt2 (entries 5–7). In entry 7, alcohol 8 was pro-
duced in a 3:1 ratio of 8 and 7a.
Next, other dienophiles 1b–e were examined in order
to optimize the R1 and R2 groups in dienophile 1.
The cyclohexyl candidate 1b under the conditions elu-
cidated for 1a (Table 1, entry 4) furnished 7b and the
other three isomers in a 5:1 ratio (entry 8). This
result implies the bigger cyclohexyl group obstructs
the coordination of BF3·OEt2 to the MOM-oxy car-
bonyl group. On the other hand, a mixture of 7c and
the other isomers was obtained from 1c in a ratio of
3.5:1 (entry 9), thus indicating that the methyl group
was much smaller than the i-Pr group for discrimina-
tion of the olefin face in the transition state. Exam-
ined next was the PMB ether 1d, which gave a
mixture of 7d, the other three isomers, and alcohol 9
in a ratio of 10:2:5 (entry 10). The alcohol was
formed probably by BF3·OEt2-induced deprotection of
the PMB group. The observed instability of the PMB
group against BF3·OEt2 led us to abandon investiga-
tion of 1e. Taking together these results, it can be
concluded that i-Pr and MOM groups are the most
suitable substituents as R1 and R2, respectively, in
dienophile 1.8
First, racemic 1a with the i-Pr and MOM groups as
R1 and R2, respectively, was subjected to a Diels–
Alder reaction with cyclopentadiene (6), the most
reactive diene, in order to find the best conditions in
terms of stereoselectivity and reactivity (Eq. (2)). The
results are summarized in Table 1. In the presence of
BF3·OEt2 (1.5 equiv.), the reaction in CH2Cl2 at
−78°C afforded diastereoisomer 7a6 as a major isomer
in a 10:1 ratio of 7a and three other stereoisomers
(entry 2), while
a
control experiment without
BF3·OEt2 even at higher temperature (0°C) was slug-
gish, furnishing a mixture of 7a and the isomers in a
1:1 diastereomeric ratio (entry 1). The low tempera-
ture of −78°C was critical in order to attain the high
diastereoselectivity, since a reaction at −50°C resulted
in a lower ratio of 6:1 (entry 3). Significantly impor-
tant also is the stoichiometry of BF3·OEt2, as is indi-
cated in entry 4, where use of 2.0 equiv. improved
the ratio to 13:1. A larger quantity (3.0 equiv.), how-
ever, changed the selectivity marginally.7

Y. Kobayashi, Y. Kiyotsuka / Tetrahedron Letters 42 (2001) 9229–9232
9231
O
O
OTBS
Pr-i
OMOM
Et
OH
14
13
11
12
C6H11-c
OTBS
O
O
8
9
OH
The relative stereochemistry of products 15–18 is specu-
lated as drawn in Fig. 1 in analogy to 7a.6 The position
of the methyl group was tentatively assigned as 16.
The reaction was repeated with (R)-1a of 95% e.e. and
diene 6 under the best conditions exploited above
(Table 1, entry 4), producing (2R,3R)-7a in 90% yield
(Scheme 2). The chirality of the product was deter-
mined by the specific rotation of the derived ester 10
((1) H+; (2) H5IO6, THF/H2O; (3) CH2N2; 59% yield;
[h]D25=+100 (c 1.00, MeOH); lit.9 [h]2D5=+135 (c 1.455,
MeOH).
In addition to the important role of the substituent
(i-Pr) and the protective groups (TBS, MOM) in 1a to
achieve the diastereoselective Diels–Alder reaction,
these groups in adducts 7a, 15–18 are potentially useful
for further transformations. This synthetic advantage
was successfully practiced with adduct 7a, as is pre-
sented in Scheme 3. Treatment of 7a with 10% HCl in
MeOH furnished diol 19 in 77% yield. Oxidation of 19
with KIO4 in THF/H2O proceeded regioselectively to
afford, after esterification, ester 20, which upon oxida-
tion with H5IO6 produced half-acid 21 in 52% yield. On
the other hand, AcOH furnished selective deprotection
of the TBS group in 7a to provide alcohol 22 in 95%
yield. Subsequent reduction with simple NaBH4 pro-
ceeded in a highly site-selective manner,11 and the
resulting diol 23, upon oxidation with H5IO6, furnished
aldehyde 24 in good yield.
Other dienes 11–14 were subjected to the Diels–Alder
reaction with dienophile 1a in the presence of
BF3·OEt2. The results are summarized in Table 2, and
the major products are presented in Fig. 1. Although
11–14, especially 14,10 are less reactive dienes in the
Diels–Alder reaction than 6, as were reconfirmed by us
(entries 2, 4, 6, and 8; cf. Table 1, entry 1), the high
reactivity of 1a compensated the low reactivity of these
dienes to produce diastereoisomers 15–18 at −78°C
within 7 h (entries 1, 3, 5, and 7). When acyclic dienes
12 and 13 were the substrates, somewhat lower selectiv-
ities for production of 16 and 17 were observed, while
cyclic diene 11 furnished the almost same selectivity as
diene 6. Noteworthy is that furan (14) could participate
in the reaction even at −78°C to provide 18, though the
somewhat unstable nature of product 18 restricted the
quantity of BF3·OEt2 to 1.3 equiv., thus furnishing a
slightly lower yield of 68% as listed in entry 7.
O
O
OTBS
OTBS
Pr-i
Pr-i
O
O
OMOM
15
OMOM
16
O
R
R1
O
BF3·OEt2
O
O
O
+
OTBS
(R)-1a
6
OTBS
R
R2
95% e.e.
O
Pr-i
OMOM
17
Pr-i
OMOM
18
(2R,3R)-7a: R1 = CH2OTBS
O
R2 =
3 steps
(see text)
Pr-i
OMOM
10: R1 = R2 = OMe
Scheme 2.
Figure 1. Products derived from 1a and dienes 11–14.
Table 2. Diels–Alder reaction of 1a and dienes 11–14a
Entry
Diene
Equiv. of BF3·OEt2
Temp. (°C)
Major product
Product ratiob
Yield (%)c
1
11
11
12
12
13
13
14
14
2.0
0
2.0
0
2.0
0
1.3
0
–78
0
–78
0
–78
0
–78
0
15
–
16
–
17
–
18
–
12:1
–
10:1
–
9:1
–
10:1
–
84
–
85
–
85
–
68
–
2d
3
4d
5
6d
7
8d
a Reactions were carried out with three (3) equiv. of dienes in the presence or absence of BF3·OEt2 for 7 h.
b Major:other three isomers, which were determined by 1H NMR (300 MHz) spectroscopy.
c Combined yields.
d No reaction proceeded.

9232
Y. Kobayashi, Y. Kiyotsuka / Tetrahedron Letters 42 (2001) 9229–9232
O
rahedron 2000, 56, 1127–1134; (l) Wipf, P.; Wang, X.
Tetrahedron Lett. 2000, 41, 8747–8751.
OH
CO2Me
10% HCl
77%
1) KIO4
7a
4. Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. J.
Pr-i
Pr-i
2) CH2N2
55%
Org. Chem. 1989, 54, 2085–2091.
O
O
5. (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada,
Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981,
103, 6237–6240; (b) Gao, Y.; Hanson, R. M.; Klunder, J.
M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am.
Chem. Soc. 1987, 109, 5765–5780.
6. The related stereochemistry of 7a was unambiguously
determined by NOE experiment of 24, which was synthe-
sized by the method shown in Scheme 3.
OH
19
OH
20
AcOH
95%
H5IO6
52%
X
CHO
OH
CO2Me
H5IO6
Pr-i
Pr-i
O
O
CO2H
21
OMOM
24
73% from 22
OMOM
H
H
22: X = O
23: X = H, OH
11%
NaBH4
CHO
0%
H
H
Scheme 3.
Pr-i
O
OMOM
In summary, one of the alkoxy carbonyl groups in 1a
was recognized selectively by BF3·OEt2 in the Diels–
Alder reaction with several dienes 6, 11–14 affording
7a, 15–18 efficiently.12 In addition, the synthetic advan-
tage of this method was demonstrated by the further
transformation of the representative adduct 7a.
7. A similar observation regarding the stoichiometry is
reported in the Diels–Alder reaction of acrylic esters of
carbohydride-derived
alcohols:
Nagatsuka,
T.;
Yamaguchi, S.; Totani, K.; Takao, K.; Tadano, K. Syn-
lett 2001, 481–484.
8. To a solution of 1a (198 mg, 0.573 mmol) in CH2Cl2 (0.5
mL) was added BF3·OEt2 (0.147 mL, 1.16 mmol) at
−78°C. The resulting light yellow solution was stirred at
−78°C for 30 min, and 6 (0.180 mL, 1.81 mmol) was
added. After 1 h of stirring at −78°C, the mixture was
quenched with saturated NaHCO3, and chromatography
on silica gel (hexane/EtOAc) afforded 7a (211 mg, 90%):
1H NMR (300 MHz, CDCl3) l 0.08 and 0.09 (2s, 6H),
0.85 (d, J=7 Hz, 3H), 0.93 (s, 9H), 1.02 (d, J=7 Hz,
3H), 1.39 (dd, J=8.5, 2 Hz, 1H), 1.71 (d, J=8.5 Hz, 1H),
2.05–2.19 (m, 1H), 3.07–3.12 (m, 2H), 3.33–3.37 (m, 4H),
3.68 (t, J=4 Hz, 1H), 4.14 (d, J=5 Hz, 1H), 4.22 (d,
J=17 Hz, 1H), 4.27 (d, J=17 Hz, 1H), 4.56 (d, J=7 Hz,
1H), 4.63 (d, J=7 Hz, 1H), 5.94 (dd, J=6, 3 Hz, 1H),
6.30 (dd, J=6, 3 Hz, 1H).
References
1. For reviews of reactions promoted by Lewis acid chela-
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1
11. Ratio of 23 and the corresponding triol was 10:1 by H
NMR spectroscopy.
12. On the basis of the following references, we are speculat-
ing complexes such as [1a·BF2]+(BF4)− and [1a·BF2]+F−:
BF2 forms chelation at the a-MOM-oxy carbonyl site to
produce one reactive conformer in which the i-Pr group
efficiently blocks one of the olefin faces. See: (a) Evans,
D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc.
1988, 110, 1238–1256; (b) Chen, X.; Hortelano, E. R.;
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