Stereoselectivity of 1,3-dipolar cycloadditions of L-valine-derived nitrones with methyl acrylate

Article abstract of DOI:10.1016/S0040-4020(03)00424-1

Chiral nitrones derived from L-valine react with methyl acrylate to afford the corresponding diastereomeric 3,5-disubstituted isoxazolidines. The dibenzylsubstituted nitrone gave also 3,4-disubstituted isoxazolidine in 4% yield, additionally. The stereoselectivity was dependent on the steric hindrance of the nitrone and reaction conditions. High pressure decreased the reaction time of the cycloadditions. The major products were found to have the C-3/C-6 erythro and C-3/C-5 trans relative configuration. The major cycloadduct undergoes N-O cleavage and deprotection to a chiral diaminodiol derivative.

Full text of DOI:10.1016/S0040-4020(03)00424-1

Tetrahedron 59 (2003) 3333–3339
Stereoselectivity of 1,3-dipolar cycloadditions of L-valine-derived
nitrones with methyl acrylate
a
Iva Blanarikova-Hlobilova, Zuzana Kubanova, Lubor Fisera, Michal K. Cyranski,
a
a
b
,
*
´
´
´
´
´
ˇ
Piotr Salanski,c Janusz Jurczakb,c and Nada Pronayova
d
´
´
aDepartment of Organic Chemistry, Slovak University of Technology, SK-812 37 Bratislava, Slovak Republic
bDepartment of Chemistry, University Warsaw, PL-02 093 Warsaw, Poland
cInstitute of Organic Chemistry, Polish Academy of Sciences, PL-01 224 Warsaw, Poland
dCentral Laboratory of Chemical Techniques, Slovak University of Technology, SK-812 37, Bratislava, Slovak Republic
Received 19 November 2002; revised 17 February 2003; accepted 13 March 2003
Abstract—Chiral nitrones derived from L-valine react with methyl acrylate to afford the corresponding diastereomeric 3,5-disubstituted
isoxazolidines. The dibenzylsubstituted nitrone gave also 3,4-disubstituted isoxazolidine in 4% yield, additionally. The stereoselectivity was
dependent on the steric hindrance of the nitrone and reaction conditions. High pressure decreased the reaction time of the cycloadditions. The
major products were found to have the C-3/C-6 erythro and C-3/C-5 trans relative configuration. The major cycloadduct undergoes N–O
cleavage and deprotection to a chiral diaminodiol derivative. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
of potential interest. With our continuing efforts to utilize
chiral 1,3-dipolar cycloadditions4– 7 we have recently
published the preparation of L-valine and L-phenylalanine-
derived nitrones.8 With the goal of developing a simple
route to the synthesis of non-proteinogenic g-substituted
b,g-diamino acids of general formula 1 isosteric to
aminostatine 2 via an asymmetric 1,3-dipolar cycloaddition,
we now report the stereoselectivity of the cycloaddition of
chiral nitrones 3–5 (Fig. 2) derived from L-valine with
methyl acrylate together with the subsequent transformation
of so prepared cycloadducts ((Figs. 1 and 2)).
The nitrone-olefin 1,3-dipolar cycloaddition is a powerful
reaction in that it can create as many as three new
contiguous stereogenic centres in a single step.1 Based on
an evaluation of the nitrone cycloaddition, it was felt that
the stereochemistry of these new centers could be controlled
if the reaction system were properly designed.1–3 Regio-
and stereoselective nitrone cycloaddition, followed by
reduction of the N–O bond to produce both an amino and
a hydroxy function, allows the synthesis of many products
Figure 1.
Keywords: cycloaddition; chiral nitrones; isoxazolidines; high pressure.
*
Corresponding author. Tel./fax: þ421-2-368-560; e-mail: fisera@cvt.stuba.sk
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00424-1

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I. Blanarikova-Hlobilova et al. / Tetrahedron 59 (2003) 3333–3339
3334
The stereoselectivity of the cycloaddition is dependent on
the substituent being attached on the nitrogen atom in the
starting nitrone as well upon reaction conditions (Table 1).
It is noteworthy to mention that our attempts to accelerate
the cycloaddition of nitrones 3–5 by high pressure were
successful. Indeed, high pressure decreased the reaction
Figure 2.
Scheme 1.
Diastereoselective synthesis of b,g-diamino acids has
received considerable attention due to the wide range of
biological activity of these compounds. For instance the
aminostatine (2) substrate analogue of statine led to potent
aspartyl proteinase inhibition of human renin.9
2. Results and discussion
The diastereomerically pure nitrones 3–5 were subjected to
1,3-dipolar cycloaddition. Our concern was to study the
asymmetric induction from the nitrone part. The cyclo-
additions afforded the corresponding diastereomeric
isoxazolidines 6–8 as a mixture of diastereoisomers in a
good overall yield (Scheme 1).
Purification by flash chromatography allowed the isolation
of the pure diastereoisomers 6ab, 7ab, 8ab and 9b, while the
isolation and/or characterization of minor isomers was
possible only for some of them. The regioselectivity of the
cycloaddition of the nitrones 4,5 was high; indeed
5-substituted isoxazolidines were formed exclusively. On
the other hand, although the cycloaddition of the nitrone 3
proceeded with the formation of the 5-substituted isoxazo-
lidines 6a–d, surprisingly the 4-substituted isoxazolidine
9b was formed in 4% yield. The oily isoxazolidine 9b was
reduced with DIBALH to yield the primary alcohol 10b and
the unexpected structure of the 4-substituted regioisomer
was subsequently confirmed by X-ray crystallographic
analysis of 10b (Fig. 3).
Figure 3.

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3335
Table 1. 1,3-Dipolar cycloaddition of chiral L-valine-derived nitrones 3–5 to methyl acrylate
Entry
Nitrone
Adduct
Reaction condition
yield
(%)
a
b
c
d
1
2
3
4
5
6
7
8
3
3
3
3
4
4
4
4
4
5
5
5
6
6
6
6
7
7
7
7
7
8
8
8
1108C, 3 daysa
rt, 30 daysa
82
–
59
–
22
–
12
–
14
15
5
5
–
6
5
7
–
13
13
–
–
–
–
–
rt, 2 days, 10 Kbara
608C, 2 days, 10 Kbara
1108C, 1 ha
84
80
89
91
84
85
87
92
90
85
54
52
51
62
64
54
54
45
58
64
19
20
44
34
36
36
41
50
37
36
408C, 12 hb
rt, 4 daysb
rt, 2 days, 10 Kbarb
608C, 2 days, 10 Kbarb
1108C, 1 ha
9
10
11
12
5
5
–
–
–
–
408C, 12 hb
rt, 4 daysb
a
Toluene.
CH2Cl2.
b
times of the cycloadditions (Table 1, entry 1, 2 versus 3, 4).
On the other hand, high pressure changed only slightly the
ratio of diastereoisomers of the nitrone cycloaddition.
Selectivity of the cycloadditions with nitrone 5 depend on
the reaction conditions. The cycloaddition in boiling toluene
gave threo–trans diastereoisomer 8b as a major product in
contrast to the cycloaddition in CH2Cl2 where erythro–
trans isoxazolidine 8a were formed as a major adduct
(Table 1, entry 10 versus 11, 12).
X-Ray analyses of 8a and hydroxymethyl derivative 11a
shows C-10/C-3 erythro and C-3/C-5 trans stereochemistry
and therefore reveals that the isoxazolidines 6a–8a (TS 1)
and also 6b–8b (TS 2) result from an exo attack of methyl
acrylate to (Z)-nitrone 3–5 (Fig. 4). It should be mentioned
that the corresponding (E)-nitrones were not detected by 1H
NMR analysis. Moreover, there was no thermal intercon-
version between the adducts in refluxing toluene, thus
indicating that the cycloaddition proceeded irreversibly
under the reaction conditions to give the kinetically
controlled products 6–9.
The ratio of diastereoisomers was determined from
quantitative 13C NMR spectra, by integration of the peaks
from C-3 and C-4 of the isoxazolidines, respectively. The
structural assignments of the products are based on analysis
of NMR spectra. The stereochemistries of the cycloadducts
were deduced by NOE experiments. The most important
and decisive information obtained from these experiments is
the presence or absence of the NOE interaction between the
protons H-4/H-3, H-4/H-5 and H-3/H-5 in the correspond-
ing cycloadducts. For instance the trans relationship of the
substituents at C-3 and C-5 in 8a has been assigned on the
basis of NOEDS. A 27% enhancement on signal H-4B and
7% enhancement on signal H-3 following saturation of
signal H-4A show a trans relationship between the H-3 and
H-5 protons; irradiation of H-4B causes only enhancement
on H-4A (22%). Moreover, the missing interactions between
H-4A and H-5 and between H-4B and each of H-3 and H-5
confirming this trans relationship between the H-3 and H-5
protons. Subsequently the stereochemistry was confirmed
by X-ray-crystallographic analysis in the cases of 8a, 10b
and 11a (the oily methyl ester 6a was converted with
DIBALH into the hydroxymethyl derivative 11a).
Next, we decided to exploit our knowledge of these
cycloadditions in the development of a synthetic method
to g-substituted b,g-diamino acids of general formula 1
from amino acid precursors. Our retrosynthetic strategy is
outlined in Figure 1. As shown in Scheme 2, 1,3-dipolar
cycloaddition of amino acid derived nitrone 3 prepared from
L-valine with methyl acrylate gave the diastereomerically
pure isoxazolidine 6a in 52%. NO-heterocycles are prone to
hydrogenolysis since the relatively weak N–O bond is
easily cleaved.7c The C–COOMe functionalized isoxazoli-
dine 6a was reduced with DIBALH to yield the primary
alcohol 11a confirmed by X-ray crystallographic analysis.
Direct hydrogenolysis of 11a in the presence of catalyst
palladium on carbon in methanol in the presence of Boc2O
resulted in a cascade reaction sequence involving isoxazo-
lidine N–O bond cleavage, N-debenzylation and N-Boc
protection affording chiral diamino diol 12 in 56% yield.
Unfortunately, the last transformation to b,g-diamino acid
13 was not successful. Although different agents were used
Figure 4.

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I. Blanarikova-Hlobilova et al. / Tetrahedron 59 (2003) 3333–3339
3336
Scheme 2. (i) Methyl acrylate, toluene, 1108C, 5 days; (ii) DIBALH, THF, 1 h, 2108C; (iii) (1) H2–Pd/C, MeOH, 48 h, rt, (2) Boc2O, dioxane – H2O, 10 h, rt.
for oxidation of chiral diamino diol 12 such as NaIO4–
Ag2O,10 NaIO4 –NaClO2 –NaH2PO4,11 NaIO4 –Br2 –
NaHCO3 and NaIO4–RuCl3 reactions afforded only
mixture of three unstable products, but b,g-diamino acid 13
was not formed.
spectra of tetrachloromethane solutions were obtained
using Perkin Elmer 781 Infrared Spectrophotometer.
Optical rotations [a] were measured on an IBZ Messtechnik
Polar-LmP polarimeter at the sodium D line (589 nm) using
a 1 dm cell with chloroform as solvent.
12
13
4.2. General procedure for atmospheric pressure
cycloadditions of nitrones 3–5 to methyl acrylate
3. Conclusion
To a stirred solution of the nitrone (1.0 mmol) in toluene or
in CH2Cl2 (5 mL) was added methyl acrylate (2 mmol), and
the solution was heated at reflux. The resulting mixture was
evaporated under reduced pressure. The crude mixture was
purified by column chromatography on silica gel eluting
with EtOAc/hexanes to give mixture of diastereoisomers.
The ratio of diastereoisomers and reaction conditions are
summarised in the Table 1. Chromatography conditions and
physical properties of products are shown below.
Chiral nitrones derived from L-valine react with methyl
acrylate to afford the corresponding diastereomeric 3,5-
disubstituted isoxazolidines. The dibenzylsubstituted
nitrone gave also 3,4-disubstituted isoxazolidine in 4%
yield, additionally. The stereoselectivity of the cyclo-
addition was dependent on the steric hindrance of the
nitrone and reaction conditions. High pressure decreased the
reaction time of the cycloadditions. The major products
were found to have the C-3/C-6 erythro and C-3/C-5 trans
relative configuration. An efficient synthetic pathway to
chiral diamino diol 12 member of very rare class of chiral
compounds,14 has been established from L-valine via
enantiomerically pure isoxazolidine intermediate 9a in 8
steps with overall yield of 18%.
4.3. General procedure for high pressure cycloadditions
of nitrones 3–5 to methyl acrylate
Reactions of nitrones with methyl acrylate were carried out
at rt or 608C in toluene, or in CH2Cl2 for several days under
10 Kbar pressure. The reaction mixture (1 mmol of nitrone,
2 mmol of dipolarophile and 0.5 mL of solvent) was placed
in a Teflon ampoule which was inserted into the high-
pressure vessel filled with n-hexane as a transmission
medium. After decompression, the mixture was purified by
flash column chromatography on silica gel eluting with
EtOAc/hexanes to give mixture of diastereoisomers.
4. Experimental
4.1. General methods
All starting materials and reagents are commercially
available (Fluka, Merck or Avocado) and were used without
further purification. Solvents were dried using standard
procedures. Thin-layer chromatography (TLC) was used for
monitoring of reaction courses and was carried out on
aluminium plates coated with silica 60F254 (0.25 mm
thickness, Merck). Eluents are indicated in the text. All
column chromatography was done by using the flash
chromatography technique, and was carried out on silica
60 (0.040–0.063 mm, Merck). Melting points were deter-
mined on a Kofler hot plate apparatus and are uncorrected.
Elemental analyses were performed by the microanalysis
service of the Department of Analytical Chemistry, Slovak
University of Technology, Bratislava.
4.3.1. (3R,5R,10S)-[2-Benzyl-3-(10-dibenzylamino-20-
methylpropylidene)-isoxazolidin-5-yl]-carboxylic acid
methyl ester (6a). The product 6a was isolated by flash
column chromathography on silica gel eluting with EtOAc/
hexanes (4:96) as
a colourless oil in 46% yield.
[a]2D5¼þ32.1, (CHCl3, c 0.3); nmax (CCl4) 1741, 1505,
1
1218, 1094 cm21; H NMR (400 MHz, CDCl3): d¼7.35–
7.21 (m, 15H, H–Ph), 4.06, 3.73 (2£d, 2£1H, J¼13.2 Hz,
NCH2Ph), 3.77 [d, 2H, J¼13.4 Hz, N(CH2Ph)2], 3.69 (s,
3H, COOCH3), 3.66 (m, 1H, H-3), 3.60 (app dd, 1H,
J4A,5¼J4B,5¼8.8 Hz, H-5), 3.42 [d, 2H, J¼13.4 Hz,
N(CH2Ph)2], 3.17 (m, 1H, J3,4A¼8.8 Hz, J4A,5¼8.8 Hz,
J4A,B¼12.2 Hz, H-4A), 2.56 (ddd, 1H, J3,4B¼6.9 Hz,
The 1H and 13C NMR spectra of deuterochloroform
solutions were obtained using Varian VXR 300
(300 MHz) and Bruker DRX-400 (400 MHz) instruments,
tetramethylsilane being the internal reference. The IR
0
0
J4B,5¼8.9 Hz, J4A,B¼12.3 Hz, H-4B), 2.41 (dd, 1H, J1 ,2
¼
0
0
0
0
1.2 Hz, J3,1 ¼10.8 Hz, H-1 ), 2.28 (m, 1H, J1 ,2 ¼1.2 Hz,
0
0
0
0
0
J2 ,3 ¼7.2 Hz, J2 ,4 ¼7.0 Hz, H-2 ), 1.08, 0.99 (2£d, 2£3H,

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I. Blanarikova-Hlobilova et al. / Tetrahedron 59 (2003) 3333–3339
3337
J2 ,3 ¼7.2 Hz, J2 ,4 ¼7.0 Hz, H-30, H-40); 13C NMR
(125 MHz, CDCl3): d¼173.8 (CO), 139.8–127.1 (C-Ph),
77.0 (C-5), 65.9 (C-3), 62.2 (NCH2Ph), 59.6 (C-10), 54.5
[N(CH2Ph)2], 52.1 (COOCH3), 33.8 (C-4), 25.5 (C-20),
23.9, 18.9 (C-30, C-40); for C30H36N2O3 (472.62) calcd C,
76.24, H, 7.68, N, 5.93; found: C, 76.47, H, 7.77, N, 5.69.
NMR (125 MHz, CDCl3): d¼175.5 (CO), 140.0–127.4,
(C–Ph), 69.4 (C-3), 67.1 (C-5), 61.9 (C-10), 59.5 (NCH2Ph),
54.6 [N(CH2Ph)2], 52.7 (COOCH3), 51.0 (C-4), 25.8 (C-20),
24.5, 19.5 (C-30, C-40); for C30H36N2O3 (472.62) calcd C,
76.24, H, 7.68, N, 5.93; found: C, 75.99, H, 7.85, N, 6.14.
0
0
0
0
4.3.5. (3R,5R,10S)-[2-Benzyl-3-(10-benzyloxycarbonyl-
amino-20-methylpropylidene)-isoxazolidin-5-yl]-car-
boxylic acid methyl ester (7a). The product 7a was isolated
by flash column chromathography on silica gel eluting with
EtOAc/hexanes (10:90!20:80) as a colourless solid in 42%
yield. Mp 126–1278C (from EtOAc/hexanes), [a]2D5¼260.7
(CHCl3, c 0.5); nmax (CCl4) 3475, 1737, 1507, 1216, 1180,
1095 cm21; 1H NMR (300 MHz, CDCl3): d¼7.32 (m, 10H,
H–Ph), 5.12 (s, 2H, OCH2Ph), 4.70 (app t, 1H,
4.3.2. (3S,5S,10S)-[2-Benzyl-3-(10-dibenzylamino-20-
methylpropylidene)-isoxazolidin-5-yl]-carboxylic acid
methyl ester (6b). The product 6b was isolated by flash
column chromathography on silica gel eluting with EtOAc/
hexanes (4:96) as
a colourless oil in 18% yield.
[a]2D5¼þ72.9, (CHCl3, c 0.55), 1H NMR (300 MHz,
CDCl3): d¼7.34 (m, 15H, H–Ph), 4.58 (‘t’, 1H,
J4A,5¼7.3 Hz, J4B,5¼8.5 Hz, H-5), 4.12, 3.92 (2£d, 2£1H,
J¼13.7 Hz, NCH2Ph), 3.80 (s, 3 H, COOCH3), 3.81, 3.73
[2£d, 2£2H, J¼13.7 Hz, N(CH2Ph)2], 3.63 (m, 1H, H-3),
2.63 (m, 1H, J3,4A¼7.3 Hz, J4A,5¼7.3 Hz, J4A,B¼12.8 Hz,
0
J4A,5¼J4B,5¼8.1 Hz, H-5), 4.57 (d, 1H, J1 ,NH¼10.3 Hz,
NH), 4.24, 3.80 (2£d, 2£1H, J¼12.4 Hz, NCH2Ph), 3.73 (s,
0
0
0
3H, COOCH3), 3.57 (m, 1H, J1 ,2 ¼2.6 Hz, J3,1 ¼9.8 Hz,
0
H-4A), 2.50 (ddd, 1H, J3,4B¼4.3 Hz, J4B,5¼8.5 Hz, J4A,B
¼
J1 ,NH¼10.3 Hz, H-10), 3.18 (m, 1H, H-3), 2.58 (m, 2H,
0
0
0
0
0
12.8 Hz, H-4B), 2.40 (t, 1H, J3,1 ¼6.4 Hz, J1 ,2 ¼1.2 Hz,
H-4A,B), 2.21 (m, 1H, H-20), 0.88, 0.38 (2£d, 2£3H, J2 ,3
¼
0
0
0
H-10), 1.88 (m, 1H, J1 ,2 ¼1.2 Hz, J2 ,3 ¼J2 ,4 ¼6.8 Hz, H-2 ),
J2 ,4 ¼6.8 Hz, H-3 , H-4 ); 13C NMR (75 MHz, CDCl3):
d¼173.2 (CO), 156.9 (CO), 136.9–127.5 (C-Ph), 77.2
(C-5), 66.8 (OCH2Ph), 65.6 (C-3), 62.3 (NCH2Ph), 56.0
(C-10), 52.3 (COOCH3), 33.6 (C-4), 27.6 (C-20), 20.9, 14.5
(C-30, C-40); for C24H30N2O5 (426.51) calcd C, 67.59, H,
7.09, N, 6.57; found: C, 67.47, H, 7.07, N, 6.69.
0
0
0
0
0
0
0
0
0
0
1.00, 0.82 (2£d, 2£3H, J2 ,3 ¼J2 ,4 ¼6.8 Hz, H-3 , H-4 ); 13C
NMR (75 MHz, CDCl3): d¼173.2 (CO), 140.5–126.8
(C–Ph), 76.5 (C-5), 65.6 (C-3), 61.9 (NCH2Ph), 61.1
(C-10), 55.4 [N(CH2Ph)2], 52.4 (COOCH3), 35.9 (C-4), 29.2
(C-20), 21.6, 20.3 (C-30,C-40); for C30H36N2O3 (472.62)
calcd C, 76.24, H, 7.68, N, 5.93; found: C, 76.41, H, 7.53, N,
6.04.
0
0
0
0
4.3.6. (3S,5S,10S)-[2-Benzyl-3-(10-benzyloxycarbonyl-
amino-20-methylpropylidene)-isoxazolidin-5-yl]-car-
boxylic acid methyl ester (7b). The product 7b was
isolated by flash column chromathography on silica gel
eluting with EtOAc/hexanes (10:90!20:80) as a colourless
solid in 40% yield. Mp 42–448C (from EtOAc/hexanes),
[a]2D5¼235.8 (CHCl3, c 0.5); nmax (CCl4) 3430, 1727, 1516,
4.3.3. (3R,5S,10S)-[2-Benzyl-3-(10-dibenzylamino-20-
methylpropylidene)-isoxazolidin-5-yl]-carboxylic acid
methyl ester (6c). The product 6c was isolated by flash
column chromathography on silica gel eluting with EtOAc/
hexanes (4:96). Following NMR signals came from
1
enriched mixture of diastereoisomers. H NMR (300 MHz,
1458, 1230, 1053 cm21
;
1H NMR (300 MHz, CDCl3):
0
CDCl3/TMS): d¼7.31 (m, 15H, H–Ph), 4.58 (‘t’,
J4A,5¼J4B,5¼8.1 Hz, H-5), 3.92, 3.80 (2£d, 2£1H, J¼
13.2 Hz, NCH2Ph), 3.55 (s, 3H, H-COOCH3), 3.77 3.54
[2£d, 2£2H, J¼13.2 Hz, N(CH2Ph)2], 3.51 (m, 1H, H-3),
d¼7.32 (m, 10H, H–Ph), 5.13 (d, 1H, J1 ,NH¼10.3 Hz, NH),
5.09 (s, 2H, OCH2Ph), 4.43 (app dd, 1H, J4A,5¼7.7 Hz,
J4B,5¼8.9 Hz, H-5), 4.23 (d, 1H, J¼12.8 Hz, NCH2Ph), 3.76
(s, 3H, COOCH3), 3.69 (d, 1H, J¼12.8 Hz, NCH2Ph), 3.60
0
0
0
0
2.79 (m, 2H, H0-4A,B), 2.66 (dd, 1H, J3,1 ¼10.3 Hz,
(m, 1H, H-3), 3.26 (ddd, 1H, J1 ,2 ¼1.7 Hz, J3,1 ¼11.1 Hz,
J1 ,NH¼10.3 Hz, H-10), 2.82 (m, 1H, J4A,5¼7.7 Hz, J4A,B
¼
0
0
0
0
0
0
0
J1 ,2 ¼1.7 Hz, H-1 ), 2.29 (m, 1H, J1 ,2 ¼1.7 Hz, J2 ,3
¼
0
0
0
0
0
0
0
J2 ,4 ¼6.8 Hz, H-2 ), 1.10, 0.99 (2£d, 2£3H, J2 ,3 ¼J2 ,4 ¼6.8
Hz, H-30,40); 13C NMR (75 MHz, CDCl3/TMS): d¼171.2
(COOCH3), 139.9–126.8 (C–Ph), 74.5 (C-5), 65.5 (C-3),
63.7 (C-10), 60.4 (NCH2Ph), 55.1 (N(CH2Ph)2), 52.2
(COOCH3), 36.0 (C-4), 26.7 (C-20), 23.1, 19.6 (C-30,40);
for C30H36N2O3 (472.62) calcd C, 76.24, H, 7.68, N, 5.93;
found: C, 76.11, H, 7.78, N, 5.81.
13.2 Hz, H-4A), 2.45 (m, 1H, J4B,5¼8.9 Hz, H-4B), 1.71 (m,
1H, H-20), 0.83, 0.51 (2£d, 2£3H, J2 ,3 ¼6.8 Hz,
0 0
0
0
J2 ,4 ¼6.4 Hz, H-3 , H-4 ); 13C NMR (75 MHz, CDCl3):
d¼173.3 (CO), 156 (CO), 136.9–127.7 (C–Ph), 77.9 (C-5),
66.6 (OCH2Ph), 64.3 (C-3), 63.4 (NCH2Ph), 60.9 (C-10),
52.4 (COOCH3), 36.1 (C-4), 31.0 (C-20), 19.4, 19.3 (C-30,
C-40); for C24H30N2O5 (426.51) calcd C, 67.59, H, 7.09, N,
6.57; found: C, 67.63, H, 7.26, N, 6.10.
0
0
4.3.4. (3S,4S,10S)-[2-Benzyl-3-(10-dibenzylamino-20-
methylpropylidene)-isoxazolidin-4-yl]-carboxylic acid
methyl ester (9b). The product 9b was isolated by flash
column chromathography on silica gel eluting with EtOAc/
4.3.7. (3R,5R,10S)-{2-Benzyl-3-[10-(tert-butoxycarbonyl-
amino)-20-methylpropylidene]-isoxazolidin-5-yl}-car-
boxylic acid methyl ester (8a). The product 8a was isolated
by flash column chromathography on silica gel eluting with
EtOAc/hexanes (15:85) as a colourless solid in 39% yield.
Mp 82–838C (from EtOAc/hexanes), [a]2D5¼269.8 (CHCl3,
c 0.5); nmax (CCl4) 3475, 1750, 1733, 1504, 1373, 1210,
1
hexanes (4:96) as a colourless oil in 4% yield. H NMR
(300 MHz, CDCl3): d¼7.31 (m, 15H, H–Ph), 4.22 (dd, 1H,
J5A,4¼6.7 Hz, J5A,B¼8.5 Hz, H-5A), 4.06 (m, 1H,
J4,5A¼6.7 Hz, J4,5B¼9.6 Hz, J4,3¼1.8 Hz, H-4), 3.99 (dd,
1
0
1H, J3,1 ¼10.5 Hz, J3,4¼1.8 Hz, H-3), 3.95, 3.77 (2£d,
1172 cm21; H NMR (300 MHz, CDCl3): d¼7.36 (m, 5H,
2£1H, J¼13.2 Hz, NCH2Ph), 3.82, 3.43 [2£d, 2£2H,
J¼12.9 Hz, N(CH2Ph)2], 3.80 (s, 3H, COOCH3), 3.55 (dd,
1H, J5B,4¼9.4 Hz, J5A,B¼8.5 Hz, H-5B), 2.43 (dd, 1H,
H–Ph), 4.69 (app t, 1H, J4A,5¼J4B,5¼8.3 Hz, H-5), 4.32 (d,
0
1H, J1 ,NH¼10.2 Hz, NH), 4.23, 3.78 (2£d, 2£1H,
J¼12.4 Hz, NCH2Ph), 3.79 (s, 3H, COOCH3), 3.48 (ddd,
1H, J1 ,2 ¼2.9 Hz, J3,1 ¼J1 ,NH¼10.2 Hz, H-10), 3.15 (ddd,
0
0
0
0
0
0
0
0
0
J3,1 ¼10.5 Hz, J1 ,2 ¼1.5 Hz, H-1 ), 2.35 (m, 1H, H-2 0), 1.14,
0
1.06 (2£d, 2£3H, J2 ,3 ¼J2 ,4 ¼6.8 Hz, H-3 , H-4 ); 13C
1H, J3,6¼9.3 Hz, J3,4A¼2.9 Hz, J3,4B¼6.1 Hz, H-3), 2.61
0
0
0
0

´ ´ ´
I. Blanarikova-Hlobilova et al. / Tetrahedron 59 (2003) 3333–3339
3338
0
0
(m, 2H, H-4A,B), 2.21 (m, 1H, H-20), 0.88, 0.37 (2£d, 2£3H,
1.21, 1.12 (2£d, 2£3H, J2 ,3 ¼J2 ,4 ¼6.8 Hz, H-3 , 4 ); 13C
NMR (75 MHz, CDCl3): d¼139.9–127.3 (C–Ph), 80.1
(C-5), 66.0 (C-3), 64.9 (CH2OH), 63.2 (NCH2Ph), 59.9
(C-10), 54.5 [N(CH2Ph)2], 31.2 (C-4), 25.8 (C-20), 23.8, 19.4
(C-30, C40); for C29H36N2O2 (444.61) calcd C 78.34, H 8.16,
N 6.30; found: C 78.17, H 8.31, N 6.42.
0
0
0
0
J2 ,3 ¼7.0 Hz, J2 ,4 ¼6.7 Hz, H-30, H-40); 13C NMR
(75 MHz, CDCl3): d¼173.8 (CO), 156.8 (CO), 137.4–
128.8 (C–Ph), 79.7 [C(CH3)3], 77.7 (C-5), 66.5 (C-3), 62.7
(NCH2Ph), 55.7 (C-10), 52.8 (COOCH3), 34.1 (C-4), 28.8
[C(CH3)3], 28.0 (C-20), 20.7, 14.9 (C-30, C-40); for
C21H32N2O5 (392.49) calcd C, 64.26, H, 8.22, N, 7.14;
found: C, 64.05, H, 8.43, N, 6.95.
0
0
0
0
4.4.2. (3R,4R,10S)-2-Benzyl-3-(10-dibenzylamino-20-
methylpropylidene)-4-hydroxymethyl isoxazolidine
(10b). The product 10b was isolated by flash column
chromathography on silica gel eluting with EtOAc/hexanes
(20:80) as a colourless solid in 71% yield. Mp 167–1688C
(from EtOAc/hexanes), 1H NMR (500 MHz, CDCl3/TMS):
d¼7.33 (m, 15H, H–Ph), 4.26, 3.78 [2£d, 2£2H,
J¼12.9 Hz, H–N(CH2Ph)2], 4.11 (dd, 1H, J5A,B¼8.5 Hz,
J5A,4¼8.2 Hz, H-5A), 4.05, 3.97 (2£d, 2£2H, J¼14.3 Hz,
H–N(CH2Ph), 3.86 (dd, 1H, J5A,B¼8.5 Hz, J5B,4¼8.8 Hz,
4.3.8. (3S,5S,10S)-{2-Benzyl-3-[10-(tert-butoxycarbonyl-
amino)-20-methylpropylidene]-isoxazolidin-5-yl}-car-
boxylic acid methyl ester (8b). The product 8b was
isolated by flash column chromathography on silica gel
eluting with EtOAc/hexanes (15:85) as a colourless solid in
31% yield. Mp 72–748C (from EtOAc/hexanes),
[a]2D5¼244.5 (CHCl3, c 0.2); nmax (CCl4) 3462, 1740,
1
1718, 1495, 1370, 1211, 1168 cm21; H NMR (300 MHz,
0
CDCl3): d¼7.35 (m, 5H, H–Ph), 4.91 (d, 1H, J1 ,NH
¼
H-5B), 3.43, 3.40 (2£dd, 2£1H, J4,CH2¼7.6 Hz, J4,CH2
¼
¼
10.5 Hz, NH), 4.43 (app dd, 1H, J4A,5¼7.7 Hz, J4B,5
¼
5.6 Hz, JCH2¼10.8 Hz, CH2OH), 3.08 (app t, 1H, J3,4
0
9.4 Hz, H-5), 4.24, 3.71 (2£d, 2£1H, J¼12.8 Hz, NCH2Ph),
3.78 (s, 3H, COOCH3), 3.60 (m, 1H, H-3), 3.20 (ddd, 1H,
J3,1 ¼5.3 Hz, H-3), 2.72 (m, 1H, H-4), 2.41 (dd, 1H,
J1 ,2 ¼7.6 Hz, J1 ,3¼5.0 Hz, H-10), 2.20 (m, 1H, H-20), 1.61
0
0
0
J1 ,2 ¼2.1 Hz, J3,1 ¼8.5 Hz, J1 ,NH¼10.5 Hz, H-10), 2.85 (dt,
1H, J3,4A¼7.9 Hz, J4A,5¼7.7 Hz, J4A,B¼12.8 Hz, H-4A),
2.45 (ddd, 1H, J3,4B¼1.7 Hz, J4B,5¼9.4 Hz, J4A,B¼12.8 Hz,
(br s, 1H, OH), 0 1.20, 0.88 (2£d, 2£3H, J2 ,3 ¼6.7 Hz,
0
0
0
0
0
0
0
J2 ,4 ¼6.4 Hz, H-3 , 4 ). 13C NMR (125 MHz, CDCl3/TMS):
d¼141.1–126.7 (C–Ph), 69.5 (C-3), 68.0 (C-5), 63.7
(C-CH2OH), 63.2 (C-10), 61.3 (NCH2Ph), 56.1
(N(CH2Ph)2), 49.6 (C-4), 33.0 (C-20), 22.2, 21.7 (C-30,40);
for C29H36N2O2 (444.61) calcd C 78.34, H 8.16, N 6.30;
found: C 78.59, H 8.07, N 6.44.
0
0
H-4B), 1.68 (m, 1H, H-20), 0.83, 0.51 (2£d, 2£3H, J2 ,3
¼
0
0
0
0
J2 ,4 ¼6.8 Hz, H-3 , 4 ); 13C NMR (75 MHz, CDCl3):
d¼173.4 (CO), 156.5 (CO), 137.1–127.6 (C–Ph), 78.9
[C(CH3)3], 77.9 (C-5), 64.6 (C-3), 63.5 (NCH2Ph), 60.2
(C-10), 52.4 (COOCH3), 36.3 (C-4), 31.0 (C-20), 28.4
[C(CH3)3], 19.4 (C-30, C-40); for C21H32N2O5 (392.49)
calcd C, 64.26, H, 8.22, N, 7.14; found: C, 64.57, H, 8.18, N,
6.91.
0
0
4.4.3. (2R,4R,5S)-4,5-di-(N-tert-Butoxycarbonylamino)-
6-methylheptane-1,2-diol (12). The alcohol 11a was
dissolved in MeOH, Pd/C and Boc2O were added and the
apparatus flushed three times with H2. The reaction mixture
was hydrogenated under atmospheric pressure at room
temperature for 48 h, filtered through a pad of Celite and
then concentrated under reduced pressure. The crude
mixture was purified by column chromatography on silica
gel (CH2Cl2/MeOH, 97:3) to give diamino diol 12 as
colourless solid in 57% yield. Mp 184–1858C (from
CH2Cl2/MeOH), [a]2D5¼þ6.9 (c¼0.25, CHCl3); nmax
(CCl4) 3605, 3450, 3361, 1707, 1690, 1506, 1398, 1371,
4.4. General procedure for reduction of 6a and 9b with
DIBALH
A stirred solution of ester (0,21 mmol) in anhydrous THF
(15 mL) was cooled to 2108C before dropwise adding of
DIBALH (0.44 mL). The reaction was quenched after 1 h
stirring at 2108C by addition of MeOH (,1 mL). The
resulting mixture was poured into an 20% aqueous solution
of potassium tartrate (30 mL) and allowed to stir for 30 min.
Then CH2Cl2 (15 mL) was added to the mixture and the
aqueous phase was extracted with CH2Cl2 (3£10 mL). The
organic layers were dried and concentrated under reduced
pressure. The crude mixture was purified by column
chromatography on silica gel. Chromatography conditions
and physical properties of the products are shown below.
1146 cm21; H NMR (300 MHz, CDCl3/TMS)): d¼5.38,
1
4.55 (2£d, 2£1H, J¼9.0 Hz, J¼9.82 Hz, H–NH), 3.92 (m,
1H, H-4), 3.69 (m, 1H, H-2), 3.54 (dd, 1H, J1,2¼3.0 Hz,
J1A,B¼11.1 Hz, H-1A), 3.46 (m, 2H, H-1B, H-5), 1.76 (m,
1H, H-6), 1.42 (s, 2£9H, H–C(CH3)3), 1.23 (m, 1H, H-3),
0.94, 0.88 (2£d, 2£3H, J6,7¼6.8 Hz, J6,8¼6.8 Hz, H-7,
H-8), 13C NMR (75 MHz, CDCl3/TMS): d¼157.5, 156.8
(2C, CvO), 80.1, 79.8 (2C, C(CH3)3), 68.3 (C-2), 66.6
(C-1), 59.7 (C-5), 48.7 (C-4), 34.5 (C-3), 28.8 (C-6), 28.4
(2C, C(CH3)3), 19.9, 18.0 (2C, C-7, C-8), for C18H36N2O3
(376.49) calcd C 57.42, H 9.64, N 7.44; found: C 57.53, H
10.09, N 7.16.
4.4.1. (3R,5R,10S)-2-Benzyl-3-(10-dibenzylamino-20-
methylpropylidene)-5-hydroxymethyl isoxazolidine
(11a). The product 11a was isolated by flash column
chromathography on silica gel eluting with EtOAc/hexanes
(20:80) as a colourless solid in 88% yield. Mp 98–998C
(from EtOAc/hexanes), [a]2D5¼þ50.5 (CHCl3, c 0.5); nmax
(CCl4) 3590, 1485, 1455, 1387, 1361, 1104 cm21; 1H NMR
(300 MHz, CDCl3): d¼7.40 (m, 15H, H–Ph), 3.97 (s, 2H,
NCH2Ph), 3.85, 3.54 [2£d, 2£2H, J¼12.8 Hz, N(CH2Ph)2],
3.68 (m, 2H, H-3, CHAOH), 3.49 (m, 1H, H–CHBOH), 3.40
4.5. X-Ray diffraction study
Crystallographic data for the structures 8a,10b and 11a
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC
191162 (8a), CCDC 191163 (11a) and CCDC 191164
(10b). Copies of the data can be obtained on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (email:
deposit@ccdc.cam.ac.uk).
(m, 1H, H-5), 2.89 (dd, 1H, J3,4A¼7.4 Hz, J4A,B¼12.2 Hz,
0
0
H-4A), 2.60 (d, 1H, J3,1 ¼10.8 Hz, H-1 ), 2.39 (m, 1H,
0
0
0
0
0
J2 ,3 ¼J2 ,4 ¼6.8 Hz, H-2 ), 2.30 (ddd, 1H, J3,4B¼6.7 Hz,
J4B,5¼2.7 Hz, J4A,B¼12.2 Hz, H-4B), 1.72 (br s, 1H, OH),

´ ´ ´
I. Blanarikova-Hlobilova et al. / Tetrahedron 59 (2003) 3333–3339
3339
´ ´ ´
6. (a) Kuban, J.; Blanarikova, I.; Fengler-Veith, M.; Jager, V.;
¨
ˇ ´ ´
Fisera, L. Chem. Papers 1998, 52, 780. (b) Blanarikova, I.;
Acknowledgements
ˇ
Dugovic, B.; Fisera, L.; Hametner, C. ARKIVOC 2001, 2,
ˇ
The authors are grateful to the Slovak Grant Agency (No.
1/7314/20), M. K. C. is supported by the Polityka weekly
and PKN Orlen S.A. (2001/2002).
1091.
ˇ ´
7. (a) Kuban, J.; Blanarikova, I.; Fisera, L.; Jaroskova, L.;
´
´
´
ˇ
´
Fengler-Veith, M.; Jager, V.; KozIsek, J.; Humpa, O.; Langer,
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¨
´
V. Tetrahedron 1999, 55, 9501. (b) Kuban, J.; Kolarovic, A.;
ˇ ´ ´
Fisera, L.; Jager, V.; Humpa, O.; Pronayova, N.; Ertl, P.
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