Intramolecular Cycloaddition Reactions of Silyl Nitronate Tethered to Vinylsilyl Group: 2-Nitroalkanols as Precursors for Amino Polyols

Article abstract of DOI:10.1021/ol035423v

(Matrix presented) A method for converting 2-nitroalkanols to precursors for stereodefined amino polyols is described. Diphenylvinylsilylation of the 2-nitroalkanols' hydroxy groups and subsequent silyl nitronate generation by using TMS-CI and Et₃

Full text of DOI:10.1021/ol035423v

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3875-3878
Intramolecular Cycloaddition Reactions
of Silyl Nitronate Tethered to Vinylsilyl
Group: 2-Nitroalkanols as Precursors
for Amino Polyols
,†
Takayuki Kudoh,‡ Teruhiko Ishikawa,* Yoshihiro Shimizu,‡ and Seiki Saito‡,*
Department of Bioscience and Biotechnology, School of Engineering and School of
Education, Okayama UniVersity, Tsushima, Okayama, Japan 700-8530
seisaito@biotech.okayama-u.ac.jp
Received July 29, 2003
ABSTRACT
A method for converting 2-nitroalkanols to precursors for stereodefined amino polyols is described. Diphenylvinylsilylation of the 2-nitroalkanols’
hydroxy groups and subsequent silyl nitronate generation by using TMS-Cl and Et3N in CH CN at 0 °C to room temperature led to fused-
3
bicyclic heterocycles through stereoselective intramolecular nitronate-olefin [3 + 2] cycloaddition reaction. Some examples for transforming
the cycloadducts to amino polyols are also presented.
Silicon-tethered strategies for controlling regio- and stereo-
selectivity of 1,3-dipolar cycloaddition reactions have re-
ceived much attention and been accepted as a powerful tool
for the construction of complex molecules.1 In our own
efforts pertinent to this field, we have disclosed the potential
of silicon-tethered intramolecular nitrone cycloaddition as
an efficient method for the synthesis of stereodefined amino
polyols as shown in Scheme 1 (route A).2 In this transforma-
tion, a chiral R- or â-hydroxy ester can lead to a nitrone (B)
through a series of reactions involving DIBALH reduction,
introduction of a vinylsilyl group to a hydroxy group (A),
and condensation with an N-benzylhydroxylamine. Thus-
obtained silicon-tethered system B, on being heated at ele-
vated temperature, afforded a cycloadduct (C) with a high
level of diastereoselectivity as a precursor for an amino
polyol (D).
Relying again on the silicon-tethered strategy of this class,
we have undertaken further development of a method for
synthesizing amino polyols of type H concerned with route
B. We thought that if 2-nitroalkanols (E) are treated with a
chlorovinylsilane reagent in the presence of base, double
silylation of E at both the hydroxy and nitro groups might
proceed. In addition, the silylation of nitro group would result
in the formation of a silyl nitronate under the conditions.
Thus, E could lead to desired system F in one pot under the
reaction conditions as indicated above. Probably, F would
immediately undergo cycloaddition reaction in the same pot,
giving rise to isoxazolidines (G), which could be a precursor
for intended amino polyols H.
To the best of our knowledge, there has been no previous
report concerned with route B.3 Due to the apparent ad-
vantages such as ready availability of 2-nitroalkanols E via
the Henry reaction4 and the operational simplicity of a pro-
cess, route B deserves consideration in terms of practicality.
Furthermore, recent advances in catalytic asymmetric Henry
reactions5 will make route B highly attractive. Also, stereo-
‡ School of Engineering.
† School of Education.
(1) (a) Rong, J.; Roselt, P.; Plavec, J.; Chattopadhyaya, J. Tetrahedron
1994, 50, 4921-4936. (b) Righi, P.; Marotta, E.; Landuzzi, A.; Rosini, G.
J. Am. Chem. Soc. 1996, 118, 9446-9447. (c) Righi, P.; Marotta, E.; Rosini,
G. Chem. Eur. J. 1998, 4, 2501-2512. (d) Denmark, S. E.; Hurd, A. R.;
Sacha, H. J. J. Org. Chem. 1997, 621, 1668-1674. (e) Garner, P.; Cox, P.
B.; Anderson, J. A.; Protasiewicz, J.; Zaniewski, R. J. Org. Chem. 1997,
62, 493-498. (f) Young, D. G. J.; G.-Bengoa, E.; Hoveyda, A. H. J. Org.
Chem. 1999, 64, 692-693. (g) Marrugo, H.; Dogbe´avou, R.; Breau, L.
Tetrahedron Lett. 1999, 40, 8979-8983.
(2) Ishikawa, T.; Kudo, T.; Shigemori, K.; Saito, S. J. Am. Chem. Soc.
2000, 122, 7633-7637.
10.1021/ol035423v CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/19/2003

Scheme 1. Silicon-Tethered Intramolecular [3 + 2]
Table 1. One-Pot Conversion of 2-Nitroalkanols 1 to
Isoxazolidines 2a
Cycloaddition Reactions
entry
1
R1
R2 time, h
2
yield, % (dr)b
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
isopropyl
n-pentyl
cyclohexyl
phenyl
phenyl
4-(OMe)phenyl
H
H
H
H
Me
H
24
24
10
8
30
12
25
14
24
2a
2b
2c
2d
2e
2f
2g
2h
2i
75 (5:1)
78 (5:1)
90 (>99:1)
82 (>99:1)
93 (>99:1)
82 (>99:1)
88 (>99:1)
82 (>99:1)
95 (>99:1)
1 g 4-(OMe)phenyl Me
1h
1i
2-furyl
2-furyl
H
Me
a Conditions: chlorodimethylvinylsilane (220 mol %), Et3N (400 mol
%), DMAP (catalytic amount)/MeCN, 0 °C to room temperature. b Based
on products, which show very high purity by NMR diagnosis, obtained by
exhaustively removing the volatiles under high vacuum after an aqueous
workup; diastereomeric ratios (dr) determined by NMR are indicated in
parentheses.
presence of triethylamine (400 mol %) and a catalytic amount
of DMAP. The desired cycloaddition reactions proceeded
at 0 °C to room temperature after mixing 1 with the silylation
agent at 0 °C, although prolonged reaction time was
sometimes required. Then, after a usual aqueous workup,
all the volatile components were removed under reduced
pressure and finally under high vacuum to afford 2a-i. Thus-
obtained adducts were so pure that we could not only
determine % yields on the basis of recovered weight but also
subject the adducts to NMR experiments for structure
elucidation or diasteremeric ratio analysis. NOE data gave
the unequivocal structures of these adducts. A very high
diastereomeric ratio (>99:1) generally resulted except for
the cases of 1a,b (dr ) 5:1, entries 1 and 2 in Table 1).6
Unfortunately, however, those cycloadducts 2a-i were too
labile to be purified by silica gel chromatography or to be
transformed to amino polyols under the conditions employed
for reductive cleavage of two of N-O bonds or well-known
oxidation of Si-C bonds by Tamao’s procedures.7 A difficult
to identify, multicomponent mixture was obtained for these
transformations.
chemical outcomes of the cycloaddition may be predict-
able on the basis of a possible bicyclo[3.3.0]-type transition
state and, hence, might result in a very high level of ster-
eoselectivity because of the rather rigid transition state
structure of this class.2 In this communication are described
the successful results of not only the cycloaddition reaction
(F to G) but also some examples for the conversion of the
cycloadducts to amino polyol derivatives including a ribose
backbone.
Table 1 summarizes the results of one-pot conversions of
2-nitroalkanols (1) to isoxazolidines (2) by treatment with
chlorodimethylvinylsilane (220 mol %) in acetonitrile in the
(3) When 4-hydroxy-2-isoxazoline-2-oxides, prepared through base-
promoted reaction of aldehydes bearing a leaving group on the R carbon
with actiVated primary nitroalkanes, were treated with TMS-Cl (1 equiv)
and imidazole at room temperature, heterotricyclic compounds were obtained
as precursors for linear aminopolyhydroxylated structures; see ref 1c.
Tandem inter [4 + 2]/intra [3 + 2] cycloaddition between siloxynitroalkene
and chiral vinyl ether was successfully used for the synthesis of cyclic
polyhydroxylated amine structures; see ref 1d. For a review, see: Ono, N.
The Nitro Group in Organic Synthesis; Wiley-VCH: New York, 2001; pp
263-274.
(4) (a) Hanessian, S.; Kloss, J. Tetrahedron Lett. 1985, 26, 1261-1264.
(b) Rosini, G. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 321-340; see also the review
in ref 3, pp 30-65.
(5) (a) Sasai, H.; Suzuki, T.; Itoh, N.; Tanaka, K.; Date, T.; Okamura,
K.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115, 10372-10373. (b) Trost,
B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861-863 (c) For
review, see: Shibasaki, M.; Gro¨ger, H. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz A., Yamamoto, H., Eds.; Springer: Berlin,
1999; Vol. III, pp 1075-1090.
After screening silylation agents for both the hydroxyl and
nitro groups, we found that chlorodiphenylvinylsilane for the
former and chlorotrimethylsilane for the latter gave a solution
to this problem.8 Thus, a hydroxyl group of 1a-f was
selectively silylated with chlorodiphenylvinylsilane and imi-
(6) All of the products gave satisfactory spectroscopic data (NMR, IR,
and MS). The stereochemistry of all of the cycloadducts was determined
by NOE measurements and JH-H values; see Supporting Information.
(7) For reviews, see: (a) Tamao, K. In AdVances in Silicon Chemistry;
Larson, G. L., Ed.; Jai Press: Greenwich, 1996; Vol. 3, pp 1-62. (b) Jones,
G. R.; Landais, Y. Tetrahedron 1996, 57, 7599-7662. See also: (c) Tamao,
K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics 1983, 2, 1694-
1696.
3876
Org. Lett., Vol. 5, No. 21, 2003

dazole to 3a-f, which were purified by passing through a
silica gel pad. When thus-purified 3a-f were dissolved in
CH3CN followed by the addition of TMS-Cl (150 mol %)
and triethylamine (200 mol %) at 0 °C, the formation of
silyl nitronate resulted, and the desired cycloaddition reac-
tions immediately followed at 0 °C to room temperature.
The results pertinent to this transformation are summarized
in Table 2.
Scheme 2
Table 2. Conversion of O-(Diphenylvinylsilyl)-2-nitroalkanols
3 to Isoxazolidines 4a
entry
3
R1
R2 time, h
4
yield, % (dr)b
1
2
3
4
5
6
3a isopropyl
3b n-pentyl
3c n-pentyl
3d phenyl
3e phenyl
H
H
Me
H
Me
H
3
9
96
5
25
9
4a
4b
4c
4d
4e
4f
99 (5:1)
99 (5:1)
92 (>99:1)
94 (>99:1)
95 (>99:1)
98 (>99:1)
3f
4-(OMe)phenyl
a Chlorotrimethylsilane (150 mol %), Et3N (200 mol %), MeCN, 0 °C
to rt. b Based on products, which show very high purity by NMR diagnosis,
obtained by exhaustively removing the volatiles under high vacuum after
an aqueous workup; diastereomeric ratios (dr) determined by NMR are
indicated in parentheses.
In every case the cycloadducts (isoxazolidines 4a-f) were
furnished in almost quantitative yields with diastereomeric
ratios almost equal to those for the dimethylvinylsilyl version
1 (Table 1). In sharp contrast to 1, however, the cycloadducts
were so stable that they could be purified by silica gel column
chromatography. It should also be pointed out that nitrogen-
linked quaternary stereogenic centers were uneventfully
introduced with a very high level of diastereomeric ratios
(entries 3 and 5 in Table 2), although the reactions were
rather sluggish. Thus, a novel route to fused-heterobicyclic
ring systems involving 1,2-oxasilolane and N-(trimethylsi-
loxy)isoxazolidine rings has been established featuring the
Henry reaction, an O-diphenylvinylsilylation, a trimethylsilyl
nitronate formation, and a [3 + 2] cycloaddition reaction.
Scheme 2 shows possible transition states deduced from
models leading to 4 (TE1) and a minor diastereomer 59 (TZ2)
(entries 1 and 2 in Tables 1 and 2): TZ2 should suffer from
severe A1(3)-like strain between the N-OTMS and C-R1 or
C-OSi groups. For other transition states such as TE2 and
TZ1, an expected cycloaddition seems impossible because
of difficulty in overlapping between a terminal vinylic carbon
and a negative end of the 1,3-dipole: this situation seems
plausible when we represent TE2 and TZ1 by Newman
projections arranging the developing carbon-carbon bond
directly end on.10 The formation of the minor product 5 may
imply the existence of equilibrium between E and Z
nitronates under the given reaction conditions as shown in
Scheme 3.11
Scheme 3
Transformations of cycloadducts 4 to amino polyols were
successful, and representative examples are shown in Scheme
(9) The relative configuration of minor diastereomer was assigned as 5
by careful analysis of NMR spectra.
(10) It is possible to align the alkene with the dipole in TZ1 and TE2 by
puckering the five-membered transition state structure down, instead of up.
However, this leads to severe steric constraint between a phenyl group on
the silicon atom and R1 substituent in the transition state.
(8) When chlorodiphenylvinylsilane was employed as a bis-silylating
agent, a difficult to separate, multicomponent mixture was furnished as
products.
Org. Lett., Vol. 5, No. 21, 2003
3877

cleavage of the exocyclic N-O bonds of 4a or 4b by means
of catalytic hydrogenolysis in the presence of di-tert-butyl
dicarbonate13 afforded 6a or 6b, respectively. Tamao oxida-
tion7 of 6a was followed by acetylation to give isoxazolidine
7. Mo(CO)6-mediated endocyclic N-O bond cleavage14 of
7 gave 8 in acceptable yield. Similarly, 6b was converted to
9 under the given reaction conditions. An N-O bond
cleavage of 9 in a similar way as that of 7 to 8 conversion
was followed by Palikh-Doering oxidation15 to afford
aldehyde 10, which on treatment with TBAF in THF
followed by acetylation led to 4-aminoribose derivatives 11
in good yield.
Scheme 4 a
In conclusion, we have demonstrated that the intramo-
lecular [3 + 2] cycloaddition reactions of silyl nitronate
tethered to vinylsilyl group can provide a novel method for
synthesizing fused heterobicyclic compounds involving 1,2-
oxasilolane and N-(trimethylsiloxy)isoxazolidine rings as
promising precursors for amino polyols. The 2-nitroalkanols
available uneventfully through the Henry reaction can be
employed as a starting material even in an optically active
form if so desired.5 Hence, the process will open a general
strategy for the asymmetric synthesis of amino polyol
derivatives including 5-substituted-4-aminoribose frame-
works, a biologically important class of amino sugars.
a Conditions: (i) H2, Pd-C, (Boc)2O/AcOEt, rt, 45 h; (ii) KF,
KHCO3, 30% H2O2, THF-MeOH, rt, 30 min. (iii) Ac2O, Et3N,
DMAP/CH2Cl2, rt 3 h; (iv) Mo(CO)6, MeCN-H2O, reflux, 8 h;
(v) TBDMSOTf, Et3N, CH2Cl2, rt; (vi) SO3-Py, Et3N/DMSO; (vii)
TBAF, THF.
4. It turned out that a series of reactions involving reductive
cleavage of an exocyclic N-O bond, oxidation of Si-C
bond, and final cleavage of an endocyclic N-O bond was
effective for this purpose in general.12 For example, reductive
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H and 13C NMR
spectra for 2, 4, and 7-11. This material is available free of
charge via the Internet at http://pubs.acs.org.
(11) One promising indirect way of observing the existence of such
geometrical isomers of the silyl nitronate is to analyze the products
distribution for an appropriate intermolecular cycloaddition reaction. We
have not done it yet. Two possible mechanisms deserve consideration for
such a geometrical isomerization of the nitronate: one involves a proto-
nation-deprotonation process and the other involves the 1,3-migration of a
trimethylsilyl group from one oxygen to another oxygen. For discussion
with respect to the 1,3-migration, see: Colvin, E. W.; Beck, A. K.; Bastani,
B.; Seebach, D.; Dunitz, J. D. HelV. Chim. Acta 1980, 63, 697-710.
(12) No effort has been made to optimize each step of these transforma-
tions. It turned out that similar reaction conditions as those employed for
4a or 4b were ineffective for cycloadduct 4c or 4e having a tertiary carbon
linking to the nitrogen atom,. We are now making extensive efforts to
establish the reaction conditions applicable to the transformation of 4c or
4e to amino polyol derivatives, which will be published elsewhere.
OL035423V
(13) Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetrahedron Lett.
1989, 30, 837-838; see also ref 2.
(14) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; Sarlo, F. D. Tetrahedron
Lett. 1990, 31, 3351-3354.
(15) Parikh, J.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
3878
Org. Lett., Vol. 5, No. 21, 2003