Stereoselective synthesis of (-)-deacetylanisomycin

Article abstract of DOI:10.1002/ejoc.200300091

A stereoselective synthesis of (-)-deacetylanisomycin has been achieved from a nitrone derived from 1-threose in 6 steps and 53.7% overall yield, The key step of the synthesis is the nucleophilic addition of a Grignard derivative with complete diastereofacial selectivity. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300091

FULL PAPER
Stereoselective Synthesis of (؊)-Deacetylanisomycin
Pedro Merino,*[a] Santiago Franco,[a] Diego Lafuente,[a] Francisco Merchan,[a]
Julia Revuelta,[a] and Tomas Tejero[a]
´
Dedicated to Prof. E. Melendez on the occasion of his retirement
Keywords: Nitrogen heterocycles / Nucleophilic addition / Nitrones / Hydroxylamines / Grignard reaction
A stereoselective synthesis of (−)-deacetylanisomycin has
been achieved from a nitrone derived from -threose in 6 Germany, 2003)
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
l
steps and 53.7% overall yield. The key step of the synthesis
is the nucleophilic addition of a Grignard derivative with
complete diastereofacial selectivity.
Introduction
has previously been used for synthesizing 2 by Petrini et
al.[10] However, the reaction showed poor selectivity (dr ϭ
3:2).
Anisomycin (1) is a dihydroxylated pyrrolidine originally
isolated from various species of Streptomyces.[1] Since its
initial isolation 1 has aroused considerable interest due to
its potent and specific antibiotic activity[2] against several
microorganisms. It also inhibits the ribosomal peptide syn-
thesis[3] and exhibits high antitumor activity.[4] In light of
these diverse biological activities, it is not surprising that
anisomycin has received considerable attention as a syn-
thetic target, with no less than 20 total syntheses of the
molecule having been reported to date.[5Ϫ8] These syntheses
include preparation of (Ϫ)-deacetylanisomycin 2 since it is
well documented that anisomycin 1 can be easily prepared
from 2.[9]
Results and Discussion
Our synthesis starts with nitrone 4, which can be easily
obtained from commercially available (Ϫ)-2,3-O-isopro-
pylidene--threitol in three steps and in a 51.6% overall
yield (Scheme 1). Nucleophilic additions to acyclic α-alkoxy
nitrones have been used previously for highly stereoselective
syntheses of a variety of nitrogen-containing compounds in
our laboratory.[11]
In light of the high interest in anisomycin and its deacetyl
derivative 2, we undertook a study designed to provide a
highly stereoselective synthesis of 2. Specifically, we envis-
aged the use of a nucleophilic addition to an -threose-de-
rived nitrone for the introduction of the (4-methoxyphe-
nyl)methyl moiety. Nucleophilic addition to a cyclic nitrone
Scheme 1
Nitrone 4 was treated with p-methoxybenzylmagnesium
chloride or bromide under several different reaction con-
ditions and in the presence or absence of additives in order
to achieve the best selectivity (Scheme 2, Table 1). The ab-
sence of an additive, the use of THF as solvent, and ad-
dition of excess p-methoxybenzylmagnesium chloride (3.0
[a]
Laboratorio de Sintesis Asimetrica, Departamento de Quimica
Organica, Facultad de Ciencias-ICMA, Universidad de
Zaragoza,
50009 Zaragoza, Aragon, Spain
Fax: (internat.) ϩ 34-976/762075
E-mail: pmerino@posta.unizar.es
Eur. J. Org. Chem. 2003, 2877Ϫ2881
DOI: 10.1002/ejoc.200300091
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2877

P. Merino, S. Franco, D. Lafuente, F. Merchan, J. Revuelta, T. Tejero
FULL PAPER
Scheme 2
Figure 1. Preferential attacks for the nucleophilic addition to 4
equiv.) at Ϫ20 °C (Entry 4) afforded a single isomer (by
NMR) with the required configuration, isolated in an 84%
yield.
Thus, for the addition in the presence of Lewis acids an
initial coordination of the Lewis acid leads to a structure
The configuration of the newly generated chiral center in similar to A. Further addition of Grignard reagent can only
syn-5a could not be deduced from the NMR spectra but occur on the other face leading to structure B, which gives
we anticipated a syn configuration on the basis of previous rise to the anti adduct. Obviously, one should consider the
nucleophilic additions to α-alkoxy nitrones[12] The unam- conformational equilibrium due to rotation around the
biguous assignment of the configuration was possible after NϪO bond and, in fact, such a possibility may explain the
the total synthesis of the target compound as discussed be- only moderate degree of selectivity observed for additions
low.
The stereochemical course of the reaction in the absence selectivity observed for the reaction without additive.
of any additive can be rationalized by invoking a Houk With syn-5 accessible in a totally diastereoselective way,
in the presence of Lewis acids, in contrast to the complete
model A (Figure 1). Coordination of the Grignard com- we investigated the necessary transformations towards the
pound favours attack at the less-hindered Re face leading target compound (Scheme 3). Attempts at O-debenzylation
to the syn adduct. This coordination (prior to the transfer- and subsequent complete reduction of the hydroxyamino
ence of R) has been studied by us theoretically for α-amino moiety by hydrogenolytic methods failed and free amino 6
nitrones[13] and it can also be invoked in the case of α-al- was obtained. It has been observed in our laboratory that
koxy nitrones. We have also experimentally demonstrated O-benzyl groups cannot be easily eliminated by hydro-
(NMR spectroscopy) that Et2AlCl coordinates to the genolysis in the presence of a free amino group.[15] De-
nitrone oxygen, as can be inferred from the displacement of benzylation of the hydroxy group was achieved in quantitat-
the chemical shift corresponding to the azomethine pro- ive yield with sodium in liquid ammonia. Unfortunately,
ton.[14] Moreover, in that study it was also shown that ad- mesylation of compound 7 followed by acidic treatment did
dition of a second equivalent of coordinating agent led to not afford the target compound 2, probably because com-
additional deshielding of the azomethine proton, thus indi- pound 7 was also mesylated at the amino moiety to a great
cating an additional coordination at the nitrone oxygen. extent, as was evident from the NMR spectra of some iso-
The theoretical study of the process is in complete agree- lated by-products. Among these, dimesylated derivative 8
ment with the experimental observations.[14]
could be completely characterized.
Table 1. Nucleophilic additions of p-methoxybenzylmagnesium halides to nitrone 4
Entry[a]
X
Solvent
Time (h)
Temp. (°C)
Additive
syn:anti
Yield (%)[b]
1
2
3
4
5
6
7
Cl
Cl
Cl
Cl
Br
Cl
Cl
Et2O
Et2O
THF
THF
THF
THF
THF
12
12
12
4
4
6
Ϫ80
Ϫ50
Ϫ80
Ϫ20
Ϫ20
Ϫ20
Ϫ20
none
none
none
none
none
Et2AlCl
BF3·Et2O
Ϫ
Ͻ 10[c]
36[c]
45[c]
84
66
68
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
30:70
40:60
6
52
[a]
[b]
[c]
All reactions were carried out with excess Grignard reagent (3.0 equiv.). Isolated yields. considerable amounts of nitrone 4 were
found in the crude product indicating low conversion.
2878
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2877Ϫ2881

Stereoselective Synthesis of (Ϫ)-Deacetylanisomycin
FULL PAPER
mycin (2) from commercially available (Ϫ)-2,3-O-isopro-
pylidene--threitol. The synthesis is an extension of our
previously disclosed methodology for the stereocontrolled
addition of nucleophiles to α-alkoxy[11] and demonstrates
once again the usefulness of our nitrone-based method-
ology for the synthesis of nitrogenated compounds. The
high yields obtained in all steps and the mild conditions
used make this approach amenable to large scale synthesis.
The practicality of this route to deacetylanisomycin 2
compares favourably with that of previous syntheses also
based on nucleophilic additions to CϭN bonds in which
moderate selectivities were obtained.[7,10] Our synthesis
shows complete diastereoselectivity (only one isomer is de-
tected by NMR spectroscopy) in the key nucleophilic ad-
dition step. The reversal of the selectivity by precomplexing
the nitrone with diethylaluminium chloride is of particular
value, which should see use in the concise synthesis of the
epimer at C-2 of both deacetylanisomycin (2) and anisomy-
cin (1). Further studies in this direction are underway and
will be reported in due course.
Experimental Section
General Remarks: The reaction flasks and other glass equipment
were heated in an oven at 130 °C overnight and assembled in a
stream of Ar. All reactions were monitored by TLC on silica gel
60 F254; the positions of the spots were detected with 254 nm UV
light or by spraying with ethanolic phosphomolybdic acid. Flash
chromatography was performed with a Buchi MPLC system using
solvents that were distilled prior to use. Melting points are uncor-
rected. 1H and 13C NMR spectra were recorded with a Varian Un-
ity (300 MHz) or on a Bruker (300 MHz) instrument. Chemical
shifts are reported in ppm (δ) relative to CHCl3 (δH ϭ 7.26 and
Scheme 3
δ
C ϭ 77.0 for 1H and 13C, respectively) in CDCl3. Optical rotations
On the other hand, chemical reduction of hydroxylamine
syn-5 using Zn/Cu couple afforded compound 9, which was
chemoselectively O-debenzylated with sodium in liquid am-
monia to give compound 10 in quantitative yield. Hydro-
genolysis of 9 was only effective on the N-benzyl group and
compound 6 was again obtained. Compound 10 has been
used successfully by Larcheveque and co-workers[7] for the
synthesis of (Ϫ)-deacetylanisomycin, so at this point we had
achieved the formal synthesis of the target compound.
However, we decided to study some modifications to the
procedure described by Larcheveque in order to improve
the overall yield of the synthesis. Thus, treatment of 10 with
mesyl chloride and in situ acid-mediated cleavage (HCl/
MeOH) of the acetonide moiety afforded cyclic compound
11 in good chemical yield (78%). Finally, N-debenzylation
of 11 by catalytic hydrogenation provided (Ϫ)-deacetylani-
somycin 2 as a white crystalline compound in quantitative
yield. The physical and spectroscopic properties of com-
pound 2 were fully consistent with those reported in the
literature (see Exp. Sect.).
were recorded at 25 °C with a PerkinϪElmer 241 polarimeter. El-
emental analysis were performed on a PerkinϪElmer 240B mic-
roanalyzer. 4-O-Benzyl-2,3-O-isopropylidene--threose was pre-
pared from (Ϫ)-2,3-O-isopropylidene--threitol as described pre-
viously.[16]
Nitrone 4: A well-stirred solution of freshly prepared aldehyde 3
(10.0 g, 40 mmol) in dry dichloromethane (200 mL) was treated
with N-benzylhydroxylamine (4.92 g, 40 mmol) and anhydrous
magnesium sulfate (4.82 g, 40 mmol). The resulting mixture was
vigorously stirred at room temperature for 4 h. The reaction mix-
ture was filtered and the filtrate evaporated under reduced pressure
to yield a residue which was applied to a short pad of silica gel and
eluted with ethyl acetate. Evaporation of the solvent gave the pure
nitrone 4 (12.23 g, 86%) as a white solid. M.p. 68Ϫ70 °C. [α]D
ϭ
ϩ20 (c ϭ 0.40, CHCl3). 1H NMR (CDCl3): δ ϭ 1.34 (s, 3 H), 1.43
(s, 3 H), 3.72 (d, J ϭ 6.6 Hz, 1 H, 10.5 Hz), 3.89 (dd, J ϭ 2.8,
10.5 Hz, 1 H), 4.15 (ddd, J ϭ 2.8, 6.6, 7.3 Hz, 1 H), 4.57 (s, 2 H),
4.85 (s, 2 H), 4.99 (dd, J ϭ 5.6, 7.3 Hz, 1 H), 6.78 (d, J ϭ 5.6 Hz,
1 H), 7.21Ϫ7.40 (m, 10 H) ppm. 13C NMR (CDCl3): δ ϭ 26.3,
26.8, 69.5, 71.5, 73.2, 73.6, 79.8, 110.7, 127.4, 127.7, 128.2, 129.0,
129.2, 129.3, 132.2, 137.2, 138.2 ppm. C21H25NO4 (335.43): calcd.
C 70.96, H 7.09, N 3.94; found C 71.10, H 7.21, N 3.81.
Conclusion
(2S,3S,4R)-1-O-Benzyl-4-(benzylhydroxyamino)-2,3-O-isopro-
pylidene-5-(4-methoxyphenyl)pentan-1,2,3-triol (syn-5): A freshly
We have presented a short (nine steps) and highly ef-
ficient (27.7% overall yield) synthesis of (Ϫ)-deacetylaniso- prepared solution of p-methoxyphenylmethylmagnesium chloride
Eur. J. Org. Chem. 2003, 2877Ϫ2881
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P. Merino, S. Franco, D. Lafuente, F. Merchan, J. Revuelta, T. Tejero
FULL PAPER
(16.89 mmol, 5.63 mL of a 3.0  solution in tetrahydrofuran) was
added dropwise to a cooled (Ϫ20 °C) solution of nitrone 4 (2 g,
5.63 mmol) in dry tetrahydrofuran (60 mL). During the addition
the temperature of the reaction mixture was not allowed to rise
above Ϫ20 °C. The mixture was stirred for 4 h at Ϫ20 °C, quenched
with saturated aqueous ammonium chloride (30 mL), stirred again
at ambient temperature for 15 min and diluted with diethyl ether
(50 mL) and saturated aqueous ammonium chloride (50 mL). The
organic layer was separated and the aqueous layer extracted with
diethyl ether (3 ϫ 30 mL). The combined organic extracts were
washed with brine, dried (MgSO4) and the solvent evaporated un-
der reduced pressure. The crude product was purified by flash chro-
matography (silica gel, hexane/ethyl acetate, 4:1) to afford 2.26 g
(84%) of syn-5 as a colourless oil. [α]D ϭ Ϫ10 (c ϭ 0.27, CHCl3).
1H NMR (CDCl3): δ ϭ 1.21 (s, 3 H), 1.46 (s, 3 H), 2.96 (dd, J ϭ
2.9, 11.4 Hz, 1 H), 3.01 (dd, J ϭ 2.9, 11.7 Hz, 1 H), 3.16Ϫ3.22 (m,
1 H), 3.29 (dd, J ϭ 5.1, 10.3 Hz, 1 H), 3.38 (dd, J ϭ 5.1, 10.3 Hz,
1 H), 3.76 (s, 3 H), 3.8 (d, J ϭ 13.0 Hz, 1 H), 3.93 (dd, J ϭ 1.8,
8.1 Hz, 1 H), 4.14 (d, J ϭ 13.2 Hz, 1 H), 4.36 (s, 2 H), 4.33Ϫ4.40
(m, 1 H), 5.3 (br. s, 1 H, exch. with D2O), 6.76Ϫ6.82 (m, 2 H),
7.06Ϫ7.11 (m, 4 H), 7.18Ϫ7.30 (m, 8 H) ppm. 13C NMR (CDCl3):
δ ϭ 26.8, 27.0, 29.5, 55.2, 61.0, 65.0, 70.4, 73.6, 76.0, 79.4, 108.8,
114.0, 127.2, 127.4, 127.6, 128.3 (2C), 129.0, 130.2, 137.8, 138.1
(2C), 158.0 ppm. C29H35NO5 (477.59): calcd. C 72.93, H 7.39, N
2.93; found C 73.05, H 7.50, N 2.71.
130.4, 158.2 ppm. C15H23NO4 (281.35): calcd. C 64.03, H 8.24, N
4.98; found C 63.89, H 8.43, N 5.12.
(2S,3S,4R)-2,3-O-Isopropylidene-1-O-mesyl-4-(mesylamino)-5-(4-
methoxyphenyl)pentane-1,2,3-triol (8): A cooled (0 °C) solution of
amino alcohol 7 (141 mg, 0.5 mmol) in dichloromethane (10 mL)
was treated sequentially with DMAP (6 mg, 48 µmol), triethyl-
amine (40 µL) and mesyl chloride (60 µL, 0.39 mmol). The re-
sulting solution was stirred at ambient temperature for 4 h at which
time additional mesyl chloride (30 µL, 0.20 mmol) was added. The
reaction mixture was stirred for a further 12 h and then treated
with water (15 mL). The crude mixture was extracted with di-
chloromethane (3 ϫ 25 mL) and the combined organic extracts
were dried (MgSO4), filtered and the solvents evaporated under
reduced pressure. After flash chromatography of the residue, dimes-
ylated compound 8 was isolated (118 mg, 54%) as an oil. [α]D
ϭ
1
Ϫ24 (c ϭ 0.25, EtOH). H NMR (CDCl3): δ ϭ 1.40 (s, 3 H), 1.41
(s, 3 H), 2.88 (s, 3 H), 3.06 (dd, 1 H, J ϭ 11.03, 12.5 Hz), 3.19 (s,
3 H), 3.24Ϫ3.40 (m, 3 H), 3.64 (dd, J ϭ 3.3, 12.5 Hz, 1 H), 3.74
(s, 3 H), 3.76Ϫ3.81 (m, 2 H), 3.95 (br. s, 1 H, exch. with D2O),
6.80Ϫ6.84 (m, 2 H), 7.22Ϫ7.26 (m, 2 H) ppm. 13C NMR (CDCl3):
δ ϭ 27.1, 27.2, 34.7, 35.0, 40.0, 55.6, 56.2, 66.5, 75.5, 76.5, 109.2,
114.6, 131.5, 132.3, 159.6 ppm. C17H27NO8S2 (437.50): calcd. C
46.67, H 6.22, N 3.20; found C 46.73, H 6.04, N 3.53.
(2S,3S,4R)-1-O-Benzyl-4-(benzylamino)-2,3-O-isopropylidene-5-(4-
methoxyphenyl)pentane-1,2,3-triol (9): Zn dust (1.0 g, 15.3 mmol)
was added to a solution of copper() acetate (45 mg, 0.30 mmol)
in acetic acid (4 mL) and the mixture was stirred at ambient tem-
perature for 15 min under argon. A solution of syn-5 (1.43 g,
3.0 mmol) in acetic acid (4 mL) and water (1.5 mL) was added and
the mixture was heated at 70 °C for 1 h. After cooling to 20 °C the
disodium salt of EDTA (3.0 g) was added and the solution was
basified (pH 10) by addition of aqueous NaOH (3 ⁾. The solution
was extracted with ethyl acetate (3 ϫ 30 mL), the combined organic
extracts were washed with saturated aqueous EDTA (30 mL) and
brine (30 mL). The organic layer was separated, dried (MgSO4) and
the solvents evaporated under reduced pressure to give the crude
product which was purified by flash chromatography (silica gel,
hexane/ethyl acetate, 4:1) to provide pure 9 (1.14 g, 82%) as an oil.
[α]D ϭ Ϫ8 (c ϭ 0.20, CHCl3). 1H NMR (CDCl3): δ ϭ 1.37 (s, 3
H), 1.42 (s, 3 H), 1.85 (br. s, 1 H, exch. with D2O) 2.72 (dd, J ϭ
5.2, 9.4 Hz, 1 H), 2.75Ϫ2.81 (m, 1 H), 2.84 (dd, J ϭ 5.2, 9.4 Hz, 1
H), 3.42Ϫ3.45 (m, 2 H), 3.70 (d, J ϭ 13.2 Hz, 1 H), 3.77 (s, 3 H),
3.82 (d, J ϭ 13.2 Hz, 1 H), 3.81Ϫ3.86 (m, 1 H), 4.33 (dt, J ϭ 8.0,
4.8 Hz, 1 H), 4.46 (s, 2 H), 6.76Ϫ6.84 (m, 2 H), 7.02Ϫ7.07 (m, 2
H), 7.15Ϫ7.35 (m, 10 H) ppm. 13C NMR (CDCl3): δ ϭ 27.0, 27.2,
36.8, 51.6, 55.2, 58.1, 71.0, 73.4, 76.3, 78.8, 108.8, 113.9, 126.8,
127.4, 128.1, 128.3, 128.4, 130.1, 131.0, 138.1 (2C), 138.2,
158.2 ppm. C29H35NO4 (461.59): calcd. C 75.46, H 7.64, N 3.03;
found C 75.36, H 7.81, N 3.15.
(2S,3S,4R)-4-Amino1-O-benzyl-2,3-O-isopropylidene-5-(4-methoxy-
phenyl)pentane-1,2,3-triol (6): A solution of syn-5 (478 mg, 1 mmol)
in methanol (15 mL) was treated with Pearlman’s catalyst (13 mg)
and the resulting suspension was stirred under a hydrogen atmos-
phere at 1500 psi for 24 h. The mixture was filtered through a pad
of Celite and the filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel, hex-
ane/ethyl acetate, 1:9) to give 345 mg (93%) of amine 6 as an oil.
1
[α]D ϭ Ϫ12 (c ϭ 0.12, CHCl3). H NMR (CDCl3): δ ϭ 1.31 (br.
s, 2 H, exch. with D2O), 1.43 (s, 3 H), 1.47 (s, 3 H,) 2.51 (dd, J ϭ
9.3, 13.2 Hz, 1 H), 2.80 (dd, J ϭ 4.9, 13.2 Hz, 1 H), 2.93Ϫ3.1 (m,
1 H), 3.57 (dd, J ϭ 4.4, 10.2 Hz, 1 H), 3.63 (dd, J ϭ 5.4, 10.2 Hz,
1 H), 3.81 (s, 3 H), 3.78Ϫ3.85 (m, 1 H), 4.23Ϫ4.30 (m, 1 H), 4.57
(s, 2 H), 6.83Ϫ6.89 (m, 2 H), 7.09Ϫ7.15 (m, 2 H), 7.27Ϫ7.40 (m,
5 H) ppm. 13C NMR (CDCl3): δ ϭ 27.2, 27.3, 41.0, 53.6, 55.2,
70.9, 73.5, 81.2, 91.0, 109.1, 113.9, 127.6, 128.0, 128.4, 130.2, 131.0,
138.1, 158.2 ppm. C22H29NO4 (371.47): calcd. C 71.13, H 7.87, N
3.77; found C 71.29, H 7.61, N 3.59.
(2S,3S,4R)-4-Amino-2,3-O-isopropylidene-5-(4-methoxyphenyl)-
pentane-1,2,3-triol (7):
A solution of compound 6 (279 mg,
0.75 mmol) in diethyl ether (3 mL) was added to a solution of so-
dium (75 mg, 3 mmol) in liquid ammonia (10 mL) cooled to Ϫ50
°C. The mixture was stirred for 15 min and then treated with solid
ammonium chloride until the solution became colourless. The am-
monia was allowed to evaporate at ambient temperature and water
(5 mL) was then added. The aqueous solution was extracted with
(2S,3S,4R)-4-(Benzylamino)-2,3-O-isopropylidene-5-(4-methoxy-
phenyl)pentane-1,2,3-triol (10): A solution of compound 9 (923 mg,
dichloromethane (3 ϫ 10 mL), dried (MgSO4) and the solvents eva- 2.0 mmol) in diethyl ether (8 mL) was added to a solution of so-
porated under reduced pressure. The residue was filtered through
a short pad of silica gel and eluted with ethyl acetate. Evaporation
dium (200 mg, 8 mmol) in liquid ammonia (25 mL) cooled to Ϫ50
°C. The mixture was stirred for 15 min and then treated with solid
ammonium chloride until the solution became colourless. The am-
of the solvent afforded essentially pure 7 (211 mg, 100%) as an oil.
1
[α]D ϭ ϩ20 (c ϭ 0.12, CHCl3). H NMR (CDCl3): δ ϭ 1.23 (br. monia was allowed to evaporate at ambient temperature and water
s, 2 H, exch. with D2O), 1.40 (s, 3 H), 1.42 (s, 3 H,) 2.36Ϫ2.51 (m, (10 mL) was then added. The aqueous solution was extracted with
1 H), 2.45 (br. s, 1 H, exch. with D2O) 2.98 (dd, J ϭ 2.44, 13.6 Hz, dichloromethane (3 ϫ 25 mL), dried (MgSO4) and the solvents eva-
1 H), 3.23 (dt, J ϭ 3.7, 10.6 Hz, 1 H), 3.61 (dd, J ϭ 6.6, 11.0 Hz, porated under reduced pressure. The residue was filtered through
1 H), 3.72Ϫ3.80 (m, 2 H), 3.76 (s, 3 H), 4.05Ϫ4.13 (m, 1 H),
6.80Ϫ6.86 (m, 2 H), 6.98Ϫ7.13 (m, 2 H) ppm. 13C NMR (CDCl3): Evaporation of the solvent afforded 10 (743 mg, 100%) as a white
δ ϭ 27.0, 27.1, 37.8, 52.6, 55.2, 62.5, 77.2, 82.4, 108.5, 114.0, 130.0,
solid. M.p. 80Ϫ82 °C; ref.[7] m.p. 82Ϫ83 °C. [α]D ϭ ϩ47 (c ϭ 0.96,
a short pad of silica gel and eluted with hexane/ethyl acetate (7:3).
2880
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Eur. J. Org. Chem. 2003, 2877Ϫ2881

Stereoselective Synthesis of (Ϫ)-Deacetylanisomycin
FULL PAPER
1
CHCl3), ref.[7] [α]D ϭ ϩ46 (c ϭ 0.96, CHCl3). H NMR (CDCl3): 13.5 Hz, 1 H), 2.91 (dd, J ϭ 8.0, 13.5 Hz, 1 H), 3.21 (m, 1 H), 3.30
δ ϭ 1.42 (s, 3 H), 1.44 (s, 3 H), 2.10 (br. s, 2 H, exch. with D2O), (dd, J ϭ 6.0, 12.5 Hz, 1 H), 3.72 (d, J ϭ 3.0 Hz, 1 H), 3.75 (s, 3
2.43 (dd, J ϭ 11.6, 14.5 Hz, 1 H), 3.10Ϫ3.20 (m, 2 H), 3.52 (d, J ϭ
13.0 Hz, 1 H), 3.55 (dd, J ϭ 8.7, 11.0 Hz, 1 H), 3.78 (d, J ϭ
H), 4.10 (d, J ϭ 5.0 Hz, 1 H), 5.20 (br. s, 3 H), 6.76 (m, 2 H), 7.12
(m, 2 H) ppm. 13C NMR (CD3OD): δ ϭ 34.3, 53.2, 55.5, 64.2, 78.0,
13.0 Hz, 1 H), 3.79 (s, 3 H), 3.86 (dd, J ϭ 3.4, 11.0 Hz, 1 H), 3.98 79.0, 14.6, 131.0, 133.0, 159.8 ppm. C12H17NO3 (223.27): calcd. C
(dd, J ϭ 3.4, 8.7 Hz, 1 H), 4.07 (dt, J ϭ 3.4, 8.7 Hz, 1 H), 6.79 (m,
2 H), 6.9Ϫ7.04 (m, 4 H), 7.13Ϫ7.21 (m, 3 H) ppm. 13C NMR
(CDCl3): δ ϭ 26.9, 27.0, 34.5, 52.7, 55.0, 58.0, 62.8, 76.1, 81.0,
108.4, 114.0, 127.3, 128.0, 128.4, 129.7, 129.8, 138.5, 158.3 ppm.
C22H29NO4 (371.47): calcd. C 71.13, H 7.87, N 3.77; found C
71.32, H 7.76, N 3.97.
64.55, H 7.67, N 6.27; found C 64.40, H 7.81, N 6.08.
Acknowledgments
We thank the Diputacion General de Aragon (Zaragoza, Spain),
Ministerio de Ciencia y Tecnologia (Madrid, Spain) and FEDER
program for financial support (Projects P116Ϫ2001 and
BQU2001Ϫ2428).
(2R,3S,4S)-1-Benzyl-2-(4-methoxybenzyl)pyrrolidine-3,4-diol (11):
A cooled (0 °C) solution of compound 10 (500 mg, 1.35 mmol)
in dichloromethane (30 mL) was treated sequentially with DMAP
(16 mg, 0.128 mmol), triethylamine (107 µL) and mesyl chloride
(160 µL, 1.04 mmol). The resulting solution was stirred at ambient
temperature for 4 h after which time additional mesyl chloride (80
µL, 0.53 mmol) was added. The reaction mixture was stirred for an
additional 12 h and then treated with water (30 mL). The crude
mixture was extracted with dichloromethane (3 ϫ 40 mL), and the
combined organic extracts were dried (MgSO4), filtered and the
solvents evaporated under reduced pressure. The residue was taken
up with a saturated (ca. 10%) solution of HCl in MeOH (25 mL)
and the resulting solution was stirred for an additional 4 h. The
reaction mixture was filtered and the solvent evaporated under re-
duced pressure. The crude product was purified by flash chroma-
tography (silica gel, 1:4 hexane/ethyl acetate) to afford pyrrolidine
11 (330 mg, 78%) as a white solid; m.p. 80Ϫ82 °C; ref.[7] m.p.
81Ϫ82 °C. [α]D ϭ Ϫ80 (c ϭ 0.40, CHCl3), ref.[7] [α]D ϭ Ϫ82.1 (c ϭ
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1
1.13, CHCl3). H NMR (CDCl3): δ ϭ 2.14 (dd, J ϭ 3.7, 11.0 Hz,
[10]
1 H), 2.80Ϫ3.00 (m, 3 H), 3.30 (d, J ϭ 13.0 Hz, 1 H), 3.36 (dd,
J ϭ 6.0, 11.0 Hz, 1 H), 3.63 (m, 1 H), 3.75 (s, 3 H), 4.00 (m, 1 H),
4.10 (d, J ϭ 13.0 Hz, 1 H), 6.80 (m, 2 H), 7.20 (m, 2 H), 7.26 (m,
5 H) ppm. 13C NMR (CDCl3): δ ϭ 2.14 ppm. C19H23NO3 (313.39):
calcd. C 72.82, H 7.40, N 4.47; found C 72.91, H 7.29, N 4.60.
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(؊)-Deacetylanisomycin (2): A solution of 11 (157 mg, 0.5 mmol)
in methanol (10 mL) was treated with 10% Pd-C (25 mg) and the
resulting suspension was stirred under hydrogen at 70 psi for 8 h
(Parr hydrogenation apparatus). The mixture was filtered through
a pad of Celite and the filtrate was concentrated. The residue was
purified by a short flash chromatography (silica gel, chloroform/
methanol, 9:1) to afford pure 2 (112 mg, 100%) as a white solid.
M.p. 172Ϫ174 °C; ref.[7] m.p. 173Ϫ174 °C. [α]D ϭ Ϫ24 (c ϭ 0.20,
MeOH), ref.[6] [α]D ϭ Ϫ22.5 (c ϭ 1.00, MeOH). 1H NMR
(CD3OD): δ ϭ 2.54 (dd, J ϭ 2.0, 12.2 Hz, 1 H), 2.70 (dd, J ϭ 6.5,
P. Merino, T. Tejero, Tetrahedron 2001, 57, 8125.
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experiments, showed that chelated structures (pentacoordinate
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Received February 13, 2003
Eur. J. Org. Chem. 2003, 2877Ϫ2881
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2881