A stereocontrolled synthesis of (-)-detoxinine from L-ascorbic acid

Article abstract of DOI:10.1016/S0957-4166(99)00316-X

A stereoselective synthesis of (-)-detoxinine, the core unit of the detoxifying agent detoxin D₁, is presented. The approach, characterized by the use of an inexpensive starting material and by the easy and stereoselective preparation of the ke

Full text of DOI:10.1016/S0957-4166(99)00316-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2961–2973
A stereocontrolled synthesis of (−)-detoxinine from
L-ascorbic acid
Giuliano Delle Monache,a Domenico Misitib and Giovanni Zappia b,∗
aCentro di Studio per la Chimica dei Recettori e delle Molecole Biologicamente Attive-Istituto di Chimica,
Università Cattolica del S. Cuore, Largo F. Vito 1, 00168 Roma Italy
bDipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive,
Università ‘La Sapienza’, P.le A. Moro 5, 00185 Roma Italy
Received 21 June 1999; accepted 30 July 1999
Abstract
A stereoselective synthesis of (−)-detoxinine, the core unit of the detoxifying agent detoxin D1, is presented.
The approach, characterized by the use of an inexpensive starting material and by the easy and stereoselective
preparation of the key 4,5-disubstituted oxazolidin-2-one 11, proves to be a suitable alternative to the known
procedures. © 1999 Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
The detoxin complex is a collection of twelve depsipeptides, isolated from Streptomyces caespitosus
var. detoxicus 7072 GC1, which displays a unique detoxifying effect against the nucleoside antibiotic
blasticidin S.1,2 Coadministration of blasticidin S and the detoxin complex reduces the cytotoxicity of
the antibiotic without affecting the activity in the treatment of rice blast disease.3 Moreover, in vivo
studies showed that its administration decreased eye irritation caused by the antibiotic together with a
remarkable decrease of conjunctivitis in rats.3 Detoxin D1 1 was identified as the most active component
of the complex.4
Ten of the twelve components of the detoxin complex possess the uncommon amino acid (−)-
detoxinine 2 as the core scaffold. Albeit (−)-detoxinine itself did not show any particular biological
activity, we hypothesized that its incorporation into oligopeptides could promote new and interesting
biological responses, as for detoxin D1.
∗
Corresponding author.
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00316-X

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Besides the obvious interest in highly functionalized amino acids, the synthesis of (−)-detoxinine
has also been undertaken for the application of new synthetic methods which have previously been
reported for both enantiomers5 and for the racemic form.6 Most of the syntheses were based on an
acetate aldol addition as the key bond-forming event either with a protected 3-hydroxy pyrrolidine or
before pyrrolidine ring formation. Recently, an asymmetric tandem inter [4+2]/intra [3+2] nitroalkene
cycloaddition7 was employed to introduce all the functional groups.
In previous reports8 we highlighted the stereoselective formation of 4,5-disubstituted oxazolidin-
2-ones, via a highly stereoselective iodocyclocarbamation of an electron poor N-Cbz Z-allylamine,
and their use in the synthesis of natural products. These reports have described inter alia the stereo-
selective syntheses of (2R,3S)-3-hydroxy ornithine,8b proclavaminic acid8c and threo-γ-hydroxy-L-β-
lysine lactone,8d as well as a general method for the asymmetric synthesis of threonine analogues,8e
using L-serine as starting material. This paper deals with a stereocontrolled synthesis of (−)-detoxinine
and represents a further extension of the use of chiral 4,5-disubstituted oxazolidin-2-ones as valuable
intermediates.
2. Results and discussion
A retrosynthetic approach to (−)-detoxinine revealed that the natural product could be obtained from
the nitrile A (Scheme 1), which in turn was expected to arise from the differentially protected 3-hydroxy
pyrrolidine B, by the elaboration of the 1,2-dihydroxy function. On the other hand, hydroxy-pyrrolidine
itself may derive from the alkaline hydrolysis of the 4,5-disubstituted 2-oxazolidinone C, bearing a
suitable leaving group (X in Scheme 1) in the C-5 side chain. The key step for the set-up of all stereogenic
centers and the functional groups is the stereoselective iodo-cyclocarbamation reaction of the electron
poor allyl amine D. The last intermediate was foreseen to originate from the differentially protected
α-hydroxy ester E, which can be obtained from L-ascorbic acid.9
Thus the α-hydroxy ester9 3 was treated with PhCOOH/Ph3P/DIAD, following a slightly modified
procedure of Abushanab et al.9 to give the corresponding diester (83% yield) with inversion of configu-
ration at C-2. The latter was reduced (LiAlH4, 1 M in THF) to afford the diol 4 in 92% yield (Scheme 2).
The last compound was easily converted into the azide 5, by regioselective protection of the primary
hydroxy function with t-butyldimethylsilylchloride/imidazole in THF at −5°C, followed by activation
of the secondary alcohol as the mesylate and nucleophilic displacement with NaN3. The azide 5 was
obtained in 76% yield from 4 and reduced with H2 in the presence of catalytic 10% Pd/C, followed by
treatment with N-benzyl-oxycarbonyloxy succinimide, to give the N-Cbz compound 6 (97% yield).
Exposure of 6 to tetrabutylammonium fluoride (TBAF) in THF afforded, in quantitative yield, the
N-Cbz aminoalcohol 7.

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2963
Scheme 1.
Scheme 2.
The synthetic plane foresaw the conversion of 7 into the Z-α,β-unsaturated ester 8: the fully protected
aminoalcohol 7 was thus oxidized under Swern condition to the corresponding α-amino aldehyde and
immediately subjected to a modified Horner–Wadsworth–Emmons10 reaction with different phosphona-
tes, with the aim to obtain mainly the Z-isomer (Scheme 2). The results of these experiments are reported
in Table 1.
Wittig reaction with methoxycarbonyl methylidene triphenylphosphorane in MeOH at 0°C (entry 1)
gave the corresponding α,β-unsaturated ester in a fair yield, but with poor Z/E selectivity. Reaction with
methyl diphenylphosphono acetate (entries 2–3), following the procedure of Ando,11 gave mainly the Z-
isomer under all tested conditions, although with moderate yields. The most selective conditions (entry 4)
were achieved using the Still reagents12 which afforded the Z-isomer in good yield (93%) and selectivity
(Z:E 16:1).
The use of K2CO3/toluene (entry 5), suggested by Koskinen et al.13 was also tested: the reaction gave
the Z-isomer with a good selectivity but in yield lower than those previously obtained.
The electron poor Z-allyl amine 8 was then subjected to an iodocyclocarbamation reaction14 using
an excess of I2 in CH3CN. After the time required for consumption of α,β-unsaturated ester (12 h), we
obtained a complex mixture of products, coming not only from the iodocyclocarbamation reaction but
also from iodoetherification reactions15 and removal of the acetonide group. Among various attempts to
suppress these side reactions, we found that the use of AgOTf:NaHCO3:I2 (2:4:2) in CH3CN could solve
the problem. Under these conditions, the cyclization occurred within 2 h in a chemo- and stereoselective

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Table 1
Selective formation of the Z-α,β-unsaturated ester 8
fashion to give the epimeric iodo trans oxazolidin-2-ones 9 and 10 in 81% yield (based on the recovery
of 20% of 8) and a ratio of 92:8 (Scheme 3).
Scheme 3.
The trans orientation of the cyclic carbamates 9 and 10 was confirmed by the coupling constant
1
between H-4 and H-5 (J4,5=3.5 Hz) in the H NMR spectrum. This is in agreement with our earlier
results8 and those reported in the literature.16 The stereochemical course of this iodine mediated
cyclization can be qualitatively explained on the basis of the allylic 1,3 strain,17 in accord with our
previous observations.8
Reductive removal of the iodo group was achieved directly on the epimeric mixture of 9 and 10, under
radical-induced conditions (n-Bu3SnH/AIBN), to give the ester 11 (93% yield), which was converted by
LiAlH4 reduction into the alcohol 12 (94% yield). Attempts to reduce directly the epimeric mixture of
9 and 10 to the alcohol 12, using different reducing reagents and conditions, were frustrated by the low
yield obtained (40% yield).
The synthetic strategy then required conversion of the hydroxy function in 12 into the chloride
function as in 13. Initial attempts to perform directly the transformation under standard conditions18

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2965
(Ph3P/CCl4/CH2Cl2) were unsuccessful, a mixture of products being obtained, presumably due to the
instability of the acetonide under these conditions. The use19 of K2CO3 (2 equiv.) increased the yield of
compound 13 to 40%. However, nearly a quantitative yield (98%) of 13 was obtained when the reaction
was perfomed20 in dry pyridine, using substrate:Ph3P:CCl4 in the optimal ratio of 1:4:2. Subsequently,
compound 13, by treatment with a solution of NaOH in MeOH/H2O (75°C), underwent cleavage of
the cyclic urethane and displacement of chlorine by nitrogen, giving the corresponding pyrrolidine
which was isolated as the N-Cbz derivative 15 in 68% yield (Scheme 3). Having assembled all the
stereogenic centers and functional groups, the conversion of the 1,2-dihydroxy group into the β-hydroxy
acid completed the synthesis.
The acetonide was treated with CF3COOH in THF/H2O to give in good yield (85%) the free triol 15
(Scheme 4). Attempts to activate regioselectively the primary hydroxy group as the tosylate failed: under
the conditions studied (TsCl/CH2Cl2/Py or TsCl/Py) the main product was the azabicyclo[3.3.0]-octane
16, presumably by initial tosylation of the primary alcohol followed by five membered ring formation.21
Scheme 4.
Therefore, we protected the free hydroxy group in the pyrrolidine 14 as the tert-butyldimethylsilyl
ether 17 (t-Bu(Me)2SiCl, imidazole, 97% yield) and cleaved selectively the acetonide using
FeCl3·3H2O22 adsorbed on silica gel, to obtain the diol 18 in 93% yield (Scheme 5). Treatment
of the diol 18 with TsCl in CH2Cl2/Py gave the tosylate 19 in 86% yield, which was converted into the
nitrile 20 following standard methodology (NaCN, DMF, 83% yield).
Scheme 5.
The title compound was finally obtained from 20 by catalytic hydrogenolysis (5% Pd/C, EtOAc) to
remove the Cbz group, followed by acid hydrolysis to give 2, which showed analytical data in agreement
with those already reported.7
In summary we have presented a convenient preparation of (−)-detoxinine, the core unit of detoxin D1,
starting from L-ascorbic acid. The present method, characterized by the use of an inexpensive starting
material and by an easy and stereoselective introduction of all stereogenic centers, proves to be a suitable
alternative to the known procedures.

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Moreover, the above synthetic approach appears very appealing for the preparation of analogues of
detoxin D1, as potential candidates against the cytotoxicity of some antibiotics.
3. Experimental
Melting points were determined in open capillaries using a Büchi apparatus and are uncorrected.
1H and 13C NMR spectra were run on a Varian Gemini 300 spectrometer at 300 MHz and 75 MHz,
respectively, in CDCl3, unless otherwise reported. Chemical shifts (δ scale) are relative to TMS as
internal reference. Proton and carbon signals were correlated by COSY and/or HECTOR experiments,
when it was required for unambiguous assignments. 1H and 13C NMR spectra for compounds 15–20, due
to the restricted rotation of the N–CO bond, were characterized by the signals of both conformers. Only
the signals of the major conformer are reported. Optical rotations were determined on a Perkin–Elmer
243 polarimeter at 23°C (concentration g/100 ml). All solvents were dried prior to use.23 Thin layer
chromatography was performed on Merck silica gel 60 F254 glass plates.
3.1. (2S,3R)-1,2-Isopropylidendioxy-butan-3,4-diol 4
To a stirred solution of the α-hydroxy ester9 3 (10.2 g, 0.05 mol), triphenylphosphine (26.3 g, 0.1 mol),
and benzoic acid (2.2 g, 0.1 mol) in dry THF (300 ml), DIAD (19.7 ml, 0.1 mol) in THF (50 ml) was
added dropwise at −5°C over 30 min. The slightly yellow solution was stirred at room temperature for
24 h, whereupon the volatile components were removed under reduced pressure and the residue purified
according to Abushanab et al.,9 to give the corresponding diester (12.8 g, 83%) as a colorless oil.
To a cooled (−15°C) and stirred solution of the above compound (12.32 g, 0.04 mol) in dry THF (200
ml) was added dropwise a solution of LiAlH4 (1 M in THF, 60 ml, 0.060 mol). After the addition was
complete the mixture was stirred at room temperature for 1 h and heated at reflux for 3 h. The mixture was
cooled at 0°C and EtOAc (150 ml) was added dropwise over 10 min and stirred at the same temperature
for 30 min, before adding cautiously H2O. The mixture was filtered over a pad of Celite, dried over
Na2SO4 and concentrated to a light, yellow oil. The oil was distilled (bp 103–110°C, 0.2 mmHg; lit.9 bp
110–120°C, 0.3 mmHg) to provide 4 (6.0 g, 92%). [α]D=−7.53 (c=3.2, EtOH); lit.9 [α]D=−7.61 (c=6.5,
EtOH).
3.2. (2R,3S)-3-Azido-4-tert-butyldimethylsilyloxy-1,2-isopropylidendioxy-butane 5
To a cooled (−5°C) solution of diol 4 (5.0 g, 30.9 mmol) and imidazole (2.24 g, 32.9 mmol) in dry
THF (60 ml) was added tert-butyldimethylsilylchloride (4.66 g, 30.9 mmol) in small portions and the
reaction mixture was stirred for 3 h at the same temperature. After this time H2O (10 ml) and Et2O
(100 ml) were added and the organic layer was extracted with HCl 1N (2×25 ml), H2O (50 ml), satd
NaHCO3 (2×25 ml) and dried over Na2SO4. The solvent was removed under reduced pressure to give a
colorless oil. The residue was dissolved in dry CH2Cl2 (60 ml), then triethylamine (5.50 ml, 39.5 mmol)
and methanesulfonyl chloride (2.8 ml, 36.2 mmol) were added at −5°C. The reaction mixture was stirred
at room temperature for 1 h. After dilution with Et2O, the mixture was washed with HCl 1N (2×25
ml), H2O (50 ml), satd aqueous NaHCO3 (50 ml) and brine. Drying followed by evaporation gave the
corresponding mesylate as an oil. The residue was dissolved in dry DMF (100 ml) and sodium azide
(16.12 g, 0.248 mol) was added. The mixture was stirred at 95°C for 10 h, cooled to room temperature,
and added to a satd aqueous solution of NaHCO3. The solution was extracted with EtOAc (3×150 ml)

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and the combined organic layers were washed with brine. Drying followed by evaporation gave a yellow
oil. The residue was purified by silica gel column chromatography (n-hexane:EtOAc 95:5) to give 5 (6.9
g, 76%) as a colorless oil; [α]D=21.9 (c=0.93, CHCl3); 1H NMR δ 4.19 (1H, q, J=6.5 Hz, CHO), 4.05,
3.85 (1H each, dd, J=8.5 and 6.5 Hz, CH2O), 3.79 (1H, dd, J=10.0 and 6.5 Hz, CHAHBOSi), 3.75 (1H,
d, J=5.5 Hz, CHAHBOSi), 3.39 (1H, q, J=6.0 Hz, CHN), 1.46, 1.37 (3H each, s, 2×Me), 0.91 (9H, s,
3×Me), 0.09 (6H, s, 2×MeSi); 13C NMR δ 109.60 (s, COO), 75.66 (d, CHO), 66.43 (t, CH2O), 64.13
(d, CHN), 63.29 (t, CH2OSi), 26.33, 25.34 (q each, 2×Me), 25.70 (q, Me3), 18.20 (s, SiC), −5.55 (q,
Me2Si). Anal. calcd for C13H27N3O3Si: C 51.80, H 9.03, N 13.94. Found: C 51.65, H 9.05, N 13.97.
3.3. (2R,3S)-3-N-Benzyloxycarbonyl-4-tert-butyldimethylsilyloxy-1,2-isopropylidendioxy-butane 6
A solution of azide 5 (6.78 g, 22.53 mmol) in abs. EtOH (150 ml) was hydrogenated (1 atm) over
10% Pd/C (0.678 g) for 6 h. After that time the mixture was filtered over Celite and concentrated under
reduced pressure.
To a solution of the above crude amine in dry THF (150 ml) were added Et3N (4.09 ml, 29.37 mmol)
and N-(benzyloxycarbonyloxy) succinimide (7.28 g, 29.21 mmol) and the mixture was stirred overnight.
After that time the mixture was concentrated under reduced pressure and purified by silica gel column
chromatography (n-hexane:EtOAc 90:10) to give 6 (8.94 g, 97%) as a colorless oil. [α]D=−2.6 (c=0.33,
CHCl3); 1H NMR δ: 7.35 (5H, br s, C6H5), 5.13, 5.07 (1H each, d, J=12.0 Hz, COOCH2), 4.99 (1H, br
d, J=8.5 Hz, NH), 4.38 (1H, td, J=7.0 and 2.0 Hz, CHO), 4.03 (1H, dd, J=8.0 and 7.0 Hz, CHAHBO),
3.77 (1H, tdd, J=8.5, 5.0 and 2.0 Hz, CHN), 3.72 (1H, t, J=7.5 Hz, CHAHBO), 3.69 (1H, dd, J=10.0 and
5.0 Hz, CHCHDOSi), 3.58 (1H, dd, J=10.0 and 8.0 Hz, CHCHDOSi), 1.41, 1.34 (3H each, s, 2×Me),
0.88 (9H, s, 3×Me), 0.05 (6H, s, 2×MeSi); 13C NMR δ: 156.37 (s, CO), 136.43, 128.51, 128.12, 128.06
(s, d×2, d, d×2, C6H5), 109.10 (s, COO), 73.55 (d, CHO), 66.86, 66.20 (t each, 2×CH2O), 62.78 (t,
CH2OSi), 52.75 (d, CHN), 26.34, 25.02 (q each, 2×Me), 25.81 (q, 3×Me), 18.27 (s, SiC), −5.45, −5.54
(q each, 2×MeSi). Anal. calcd for C21H35NO5Si: C 61.58, H 8.61, N 3.42. Found: C 61.76, H 8.63, N
3.41.
3.4. (2R,3S)-3-N-Benzyloxycarbonyl-1,2-isopropylidendioxy-butan-4-ol 7
Tetrabutylammonium fluoride (1 M in THF, 21.9 ml, 21.9 mmol) was added dropwise to a solution of
silyl ether 6 (8.54 g, 20.88 mmol) in THF (85 ml) at 0°C. The solution was stirred at room temperature
for 2 h, whereupon a satd solution of NH4Cl (20 ml) was added and the mixture stirred for 10 min. The
mixture was diluted with EtOAc (200 ml), and the aqueous layer was extracted with EtOAc (3×50 ml).
The combined extracts were washed with brine, H2O, dried over Na2SO4, filtered and concentrated under
reduced pressure. Flash chromatography (eluent n-hexane:EtOAc 25:75) of the residue gave pure 7 (6.04
g, 99%) as a colorless oil; [α]D=−23.6 (c=1.54, MeOH); 1H NMR δ: 7.36 (5H, br s, C6H5), 5.32 (1H, br
d, J=8.0 Hz, NH), 5.14, 5.09 (1H each, d, J=12.0 Hz, COOCH2), 4.35 (1H, td, J=7.0 and 2.0 Hz, CHO),
4.04, 3.74 (1H each, dd, J=8.0 and 7.0 Hz, CH2O), 3.81 (2H, br d, J=8.0 Hz, CH2OH), 3.80 (1H, m,
CHN), 1.42, 1.35 (3H each, s, 2×Me); 13C NMR δ: 156.92 (s, CO), 136.24, 128.55, 128.21, 128.04 (s,
d×2, d, d×2, C6H5), 109.57 (s, COO), 75.85 (d, CHO), 67.11 (t, CH2O), 64.35 (t, CH2OH), 52.55 (d,
CHN), 26.24, 24.99 (q each, 2×Me). Anal. calcd for C15H21NO5: C 61.00, H 7.17, N 4.74. Found: C
60.83, H 7.18, N 4.72.

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3.5. Methyl (4S,5R,Z)-3-N-benzyloxycarbonyl-5,6-isopropylidendioxy-2-hexenoate 8
Oxalyl chloride (3 ml, 33 mmol) was dissolved in dry CH2Cl2 (50 ml), the mixture was cooled to
−63°C, and a solution of dry DMSO (5.61 ml, 66 mmol) in CH2Cl2 (10 ml) was then added dropwise
during 15 min. The aminoalcohol 7 (6.0 g, 20.0 mmol) in CH2Cl2 (20 ml) was added dropwise during
10 min, the resulting slightly cloudy solution was stirred for 10 min at −63°C, and a solution of N,N-
diisopropylethyl amine (20.9 ml, 0.12 mol) in CH2Cl2 (50 ml) was added dropwise during 15 min. After
15 min, the reaction was quenched by adding water (5.0 ml) to the stirred reaction mixture at −63°C. The
resulting slurry was poured into Et2O (300 ml) and washed with 20% aqueous KHSO4 (2×100 ml). The
layers were separated and the aqueous layer was back-extracted with Et2O (2×100 ml). The combined
organic layers were washed with brine solution (2×50 ml), dried over Na2SO4 and filtered. The solvent
was removed under vacuum to afford the crude aldehyde as an oil, which was immediately used in the
next reaction.
To a solution of 18-crown-6 (26.45 g, 0.1 mol) and methyl[bis(2,2,2-trifluoroethyl) (methoxycarbo-
nylmethyl) phosphonate (6.36 g, 20.0 mmol) in dry THF (400 ml) at −65°C was added under nitrogen
with stirring during 15 min a solution of KN(TMS)2 (0.5 M in THF, 40.0 ml). The mixture was stirred
for 20 min at the same temperature, cooled to −78°C and a solution of the above crude aldehyde in THF
(10 ml) was added dropwise. The solution was stirred at −78°C for 45 min, whereupon a satd solution
of NH4Cl (15 ml) was added cautiously. The mixture was diluted with EtOAc (100 ml), separated and
the aqueous layer was extracted with EtOAc (3×100 ml). The combined extracts were washed with
brine, H2O, dried over Na2SO4, filtered and concentrated under reduced pressure. Flash chromatography
(eluent hexane:EtOAc 75:25) of the residue gave pure α,β-unsaturated ester 8 (6.49 g, 93%) as a solid;
mp 48–49°C; [α]D=−30.9 (c=0.33, CHCl3); 1H NMR δ: 7.35 (5H, br s, C6H5), 6.17 (1H, dd, J=11.5 and
8.0 Hz, CH_CHCO), 5.91 (1H, br d, J=11.5 Hz, CH_CHCO), 5.42 (1H, br t, J=8.5 Hz, CHN), 5.31
(1H, br d, J=9.0 Hz, NH), 5.12, 5.08 (1H each, d, J=12.0 Hz, COOCH2), 4.38 (1H, br t, J=6.5 Hz, CHO),
4.11 (1H, dd, J=11.0 and 6.5 Hz, CHAHBO), 3.80 (1H, dd, J=11.0 and 6.0 Hz, CHAHBO), 3.73 (3H, br
s, OMe), 1.46, 1.32 (3H each, s, 2×Me); 13C NMR δ: 174.75 (s, COOMe), 154.17 (s, CON), 148.08 (d,
CH_CHCO), 137.15, 128.54, 128.22, 128.19 (s, d×2, d, d×2, C6H5), 120.49 (d, CH_CHCO), 109.91
(s, COO), 77.67 (d, CHO), 67.01 (t, CH2O), 66.31 (t, CH2OCO), 51.52 (d, CHN), 50.23 (q, OMe), 26.28,
24.62 (q each, 2×Me). Anal. calcd for C18H23NO6: C 61.88, H 6.64, N 4.01. Found: C 61.71, H 6.65, N
4.00.
3.6. Methyl (4R,5R,10R)-α-iodo-4-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-5-oxazolidineacetate 9
and methyl (4R,5R,10S)-α-iodo-4-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-5-oxazolidineacetate 10
To a solution of the α,β-unsaturated ester 8 (5.25 g, 15 mmol), AgOTf (7.8 g, 30 mmol) and NaHCO3
5.06 g, 60 mmol) in dry CH3CN (90 ml), I2 (9.53 g, 37.5 mmol) was added in one portion at room
temperature. The reaction mixture was stirred at the same temperature for 2 h, then diluted with CHCl3
(200 ml) and extracted with an aqueous solution of Na2S2O3 (0.3 M, 2×150 ml). The aqueous layers
were extracted with CHCl3 (2×50 ml) and the combined extracted were dried over Na2SO4, filtered and
1
evaporated to dryness under vacuum. The H NMR spectra of the crude mixture showed the presence
of 9 and 10 in a ratio 92:8 by integration. The residue was passed through a short silica gel column
(EtOAc:n-hexane 7:3) to give an inseparable mixture of 9 and 10 (3.75 g, 81% based on the recovery of
20% of 8).
9: 1H NMR δ: 5.52 (1H, br s, NH), 4.69 (1H, dd, J=7.0, and 3.5 Hz, CHOCO), 4.61 (1H, d, J=7.0 Hz,
CHI), 4.22 (1H, dt, J=7.0 and 4.5 Hz, CHO), 4.11 (1H, dd, J=9.0 and 7.0 Hz, CHAHBO), 3.87 (1H, dd,

G. Delle Monache et al. / Tetrahedron: Asymmetry 10 (1999) 2961–2973
2969
J=9.0 and 4.5 Hz, CHAHBO), 3.79 (3H, s, OMe), 3.78 (1H, br d, J=4.0 Hz, CHN), 1.44, 1.35 (3H each,
s, 2×Me); 13C NMR δ: 169.07 (s, COOMe), 158.01 (s, NCO), 110.31 (s, COO), 77.98 (d, CHOCO),
76.07 (d, CHO), 65.65 (t, CH2O), 58.05 (d, CHN), 53.40 (q, OMe), 26.21, 24.87 (q each, 2×Me), 19.82
(d, CHI).
10: 1H NMR δ: 5.46 (1H, br s, NH), 4.66 (1H, dd, J=8.0, and 3.5 Hz, CHOCO), 4.55 (1H, d, J=8.0 Hz,
CHI), 4.22 (1H, dt, J=7.0 and 4.5 Hz, CHO), 4.11 (1H, dd, J=9.0 and 7.0 Hz, CHAHBO), 3.85 (1H, dd,
J=9.0 and 4.5 Hz, CHAHBO), 3.82 (1H, br t, J=4.0 Hz, CHN), 3.79 (3H, s, OMe), 1.44, 1.35 (3H each,
s, 2×Me); 13C NMR δ: 169.13 (s, COOMe), 157.87 (s, NCO), 110.34 (s, COO), 77.62 (d, CHOCO),
75.91 (d, CHO), 68.51 (t, CH2O), 59.00 (d, CHN), 53.34 (q, OMe), 27.79, 24.96 (q each, 2×Me), 19.71
(d, CHI).
3.7. Methyl (4R,5R)-4-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-5-oxazolidineacetate 11
Tributyltin hydride (4.68 ml, 17.66 mmol) was added to a solution of AIBN (0.164 g, 1 mmol) in dry
toluene (55 ml) under nitrogen and the clear solution brought to reflux. A solution of iodo ester 9 and 10
(3.4 g, 8.83 mmol) in toluene (80 ml) was added and the solution was refluxed for 3 h and concentrated
under vacuum. The residue was purified by silica gel column chromatography (n-hexane:EtOAc 30:70)
to give 11 (2.13 g, 93%) as a white solid; mp 137°C; [α]D=49.7 (c=1.61, CHCl3); 1H NMR δ: 5.50 (1H,
br s, NH), 4.70 (1H, ddd, J=8.0, 5.5 and 3.5 Hz, CHOCO), 4.20 (1H, ddd, J=6.5, 6.0 and 4.5 Hz, CHO),
4.11 (1H, dd, J=9.0 and 6.5 Hz, CHAHBO), 3.83 (1H, dd, J=9.0 and 4.5 Hz, CHAHBO), 3.73 (3H, s,
OMe), 3.58 (1H, dd, J=6.0 and 3.5 Hz, CHN), 2.86 (1H, dd, J=16.5 and 5.5 Hz, CHCHDCO), 2.75 (1H,
dd, J=16.5 and 8.0 Hz, CHCHDCO), 1.45, 1.35 (3H each, s, 2×Me). 13C NMR δ: 169.40 (s, COOMe),
157.96 (s, NCO), 110.32 (s, COO), 76.34 (d, CHO), 74.20 (d, CHOCO), 65.70 (t, CH2O), 59.69 (d,
CHN), 52.15 (q, OMe), 38.81 (t, CH2CO), 26.48, 24.51 (q each, 2×Me). Anal. calcd for C11H17NO6: C
50.96, H 6.61, N 5.40. Found: C 50.85, H 6.59, N 5.39.
3.8. (4R,5R)-4-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-5-(2-hydroxyethyl)-2-oxo-oxazolidine 12
To a well stirred and cooled (−15°C) solution of the ester 11 (1.8 g, 6.95 mmol) in dry THF (30 ml)
was added dropwise LiAlH4 (1 M in THF, 6.95 ml), and the solution was stirred at the same temperature
for 3 h. After that time EtOAc (60 ml) was added and the mixture was stirred at the same temperature for
10 min, before adding cautiously H2O. The solution was diluted with EtOAc (100 ml), filtered through a
short pad of Celite, and concentrated under reduced pressure. The crude alcohol was purified by silica gel
column chromatography (CHCl3:MeOH 93:7) to give 12 (1.52 g, 95%); mp 107°C; [α]D=93.0 (c=1.1,
MeOH); 1H NMR δ: 5.64 (1H, br s, NH), 4.54 (1H, dt, J=8.0 and 5.0 Hz, CHOCO), 4.14 (1H, dt, J=6.5
and 5.0 Hz, CHO), 4.08 (1H, dd, J=9.0 and 6.5 Hz, CHAHBO), 3.83 (2H, t, J=6.0 Hz, CH2OH), 3.75
(1H, dd, J=9.0 and 6.5 Hz, CHAHBO), 3.60 (1H, t, J=6.0 Hz, CHN), 1.97 (1H, ddt, J=15.0, 8.0 and 6.0
Hz, CHCHD), 1.88 (1H, dtd, J=15.0, 6.0 and 5.0 Hz, CHCHD), 1.44, 1.34 (3H each, s 2×Me); 13C NMR
δ: 158.46 (s, NCO), 110.30 (s, COO), 76.67 (d, CHOCO), 76.14 (d, CHO), 65.64 (t, CH2O), 59.92 (d,
CHN), 58.41 (q, CH2OH), 37.64 (t, CH2O), 26.46, 24.87 (q each, 2×Me). Anal. calcd for C10H17NO5:
C 51.94, H 7.41, N 6.06. Found: C 52.03, H 7.39, N 6.03.
3.9. (4R,5R)-4-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-5-(2-chloroethyl)-2-oxo-oxazolidine 13
To a solution containing the alcohol 12 (1.45 g, 6.3 mmol) in dry pyridine (90 ml), was added at room
temperature triphenylphosphine (6.68 g, 25.2 mmol) followed by carbon tetrachloride (1.015 ml, 12.6

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G. Delle Monache et al. / Tetrahedron: Asymmetry 10 (1999) 2961–2973
mmol). The mixture was protected by moisture and stirred at 45°C for 15 h then cooled at 0°C and abs.
ethanol (60 ml) was added. The mixture was stirred for 15 min and concentrated at reduced pressure. The
residue was purified by flash chromatography (eluent CHCl3:MeOH 97:3) to give the compound 13 (1.47
g, 98% yield) as a white solid; mp 94°C; [α]D=61.2 (c=0.59, CHCl3); 1H NMR δ: 6.18 (1H, br s, NH),
4.61 (1H, dt, J=9.5 and 4.0 Hz, CHOCO), 4.18 (1H, dt, J=7.0 and 5.0 Hz, CHO), 4.12 (1H, dd, J=9.0
and 7.0 Hz, CHAHBO), 3.77 (1H, dd, J=9.0 and 5.0 Hz, CHAHBO), 3.73 (1H, ddd, J=11.0, 6.5 and 5.0
Hz, CHCHDCl), 3.69 (1H, ddd, J=11.0, 9.0 and 5.0 Hz, CHCHDCl) 3.54 (1H, t, J=5.0 Hz, CHN), 2.10
(1H, ddt, J=15.0, 9.5 and 5.0 Hz, CHEHF), 2.01 (1H, dddd, J=15.0, 9.0, 6.5 and 4.0 Hz, CHEHF), 1.45,
1.35 (3H each, s, 2×Me); 13C NMR δ: 158.46 (s, NCO), 110.37 (s, COO), 76.21 (d, CHO), 75.04 (d,
CHO), 65.40 (t, CH2O), 59.50 (d, CHN), 38.89 (t, CH2Cl), 38.12 (t, CH2), 26.40, 24.74 (q each, 2×Me).
Anal. calcd for C10H16ClNO4: C 48.10, H 6.46, N 5.61. Found: C 48.19, H 6.48, N 5.61.
3.10. (2S,3R)-1-(Benzyloxycarbonyl)-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-hydroxy-pyrrolidine
14
To a solution of chloride 13 (1.02 g, 4.06 mmol) in 50 ml of MeOH:H2O (3:1) was added NaOH (0.48
g, 12.0 mmol) and the solution was heated at 75°C overnight. The solvents were evaporated under reduced
pressure and the residue was dissolved in CHCl3 (100 ml), filtered and concentrated. The residue was
dissolved in dry THF (10 ml) followed by addition of Et3N (0.21 ml, 1.5 mmol) and dibenzyl dicarbonate
(0.43 g, 1.5 mmol). The mixture was stirred overnight, concentrated under reduced pressure and purified
by silica gel column chromatography (EtOAc:n-hexane 6:4) to give 14 (0.873 g, 68%) as a colorless oil;
1
[α]D=−40.9 (c=1.53, CHCl3); H NMR δ: 7.35 (5H, br s, C6H5), 5.14, 5.11 (1H each, d, J=12.5 Hz,
OCH2C6H5), 4.44 (1H, p, J=7.5 Hz, CH2CH2CHO), 4.35 (1H, t, J=7.0 Hz, CHO), 4.08 (1H, br t J=8.0
Hz, CHAHBO), 4.05 (1H, br d, J=8.0 Hz, CHAHBO), 3.97 (1H, br d, J=7.0 Hz, OH), 3.74 (1H, J=8.0
Hz, CHN), 3.58 (1H, ddd, J=9.5, 6.0 and 5.0 Hz, CHCHDN), 3.50 (1H, dt, J=9.5 and 5.0 Hz, CHCHDN),
2.06 (1H, dq, J=12.0 and 8.0 Hz, CHEHF), 1.81 (1H, m, CHEHF), 1.40, 1.35 (3H each, s, 2×Me); 13C
NMR δ: 157.01 (s, CO), 136.42, 128.50, 128.08, 127.85 (s, d×2, d, d×2, C6H5), 108.87 (s, COO), 75.13
(d, CHO), 71.45 (d, CHN), 66.94, 66.16 (t each, 2×CH2O), 58.78 (d, CHN), 44.35 (t, CH2N), 33.38 (t,
CH2), 26.21, 25.28 (q each, 2×Me). Anal. calcd for C17H23NO5: C 63.53, H 7.21, N 4.36. Found: C
63.41, H 7.22, N 4.35.
3.11. (2S,3R)-1-(Benzyloxycarbonyl)-2-[(1R)-1,2-dihydroxyethyl]-3-hydroxy-pyrrolidine 15
To a solution of the acetonide 14 (0.777 g, 2.42 mmol) in 5:1 THF:H2O (12 ml) at 0°C was added
trifluoroacetic acid (0.4 ml). The resulting mixture was allowed to warm to room temperature and left
overnight. The solvent was removed under reduced pressure and the residue purified by silica gel column
chromatography (CHCl3:MeOH 9:1) to give the triol 15 (0.606 g, 92%) as a white solid; mp 30–31°C;
[α]D=−38.1 (c=1.16, MeOH); 1H NMR δ: 7.29 (5H, br s, C6H5), 5.07 (2H, s, COOCH2), 4.44 (1H, q,
J=6.5 Hz, CH2CH2CHO), 4.04 (1H, m, CHOH), 3.91 (1H, dd, J=6.5 and 2.5 Hz, CHN), 3.62 (1H, dt,
J=12.0 and 7.0 Hz, CHAHBO), 3.54 (1H, m, CHAHBO), 3.53 (1H, m, CHCHDN), 3.48 (1H, dt, J=11.0
and 7.0 Hz, CHCHDN), 2.03, 1.95 (1H each, br p, J=7.0 Hz, CH2); 13C NMR δ: 157.61 (s, NCO), 136.14,
128.57, 128.23, 127.92 (s, 2×d, 2×d, d, C6H5), 71.56, 71.14 (d each, 2×CHOH), 67.64 (t, COOCH2),
63.65 (t, CH2O), 62.17 (d, CHN), 44.90 (t, CH2N), 33.01 (t, CH2). Anal. calcd for C14H19NO5: C 59.78,
H 6.81, N 4.98. Found: C 59.90, H 6.79, N 4.99.

G. Delle Monache et al. / Tetrahedron: Asymmetry 10 (1999) 2961–2973
2971
3.12. (1R,4R,5R)-N-(Benzyloxycarbonyl)-4-hydroxy-2-oxa-6-azabicyclo[3.3.0]octane 16
Freshly distilled pyridine (0.36 ml) and p-toluenesulfonyl chloride (0.509 g, 2.67 mmol) were added
to a solution of 15 (0.5 g, 1.78 mmol) in dry CH2Cl2 (5 ml) at −15°C under N2 atmosphere. The mixture
was stirred for 10 h at the same temperature, diluted with CH2Cl2 (10 ml) and then acidified (pH 3–4)
with 1N HCl. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:n-hexane 6:4)
to give the azabicyclo 16 (0.24 g, 61%) as an oil; [α]D=−37.9 (c=1.28, MeOH); 1H NMR δ: 7.40–7.30
(5H, m, C6H5), 5.17, 5.11 (1H each, d, J=12.0 Hz, COOCH2), 4.77 (1H, q, J=5.0 Hz, CH2CHOCH2),
4.45 (1H, br t, J=4.5 Hz, CHOH), 4.14 (1H, br d, J=5.0 Hz, CHN), 4.01 (1H, dd, J=9.5 and 4.5 Hz,
CHAHBO), 3.74 (1H, dd, J=9.5 and 4.0 Hz, CHAHBO), 3.71 (1H, m, CHCHDN), 3.33 (1H, dt, J=11.0
and 6.5 Hz, CHCHDN), 3.11 (1H, br s, OH), 2.07 (1H, br dd, J=13.0 and 6.5 Hz, CHEHF), 1.83 (1H,
ddd, J=13.0, 7.0 and 2.0 Hz, CHEHF); 13C NMR δ: 155.12 (s, NCO), 136.44, 128.54, 128.25, 127.90
(s, d×2, d, d×2, C6H5), 81.73 (d, CH2CHOCH2), 76.75 (d, CHOH), 74.31 (t, CH2O), 70.77 (d, CHN),
67.15 (t, COOCH2), 45.19 (t, CH2N), 31.64 (t, CH2). Anal. calcd for C14H17NO4: C 63.87, H 6.51, N
5.32. Found: C 63.67, H 6.50, N 5.32.
3.13. (2R,3R)-1-(Benzyloxycarbonyl)-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-tert-butyldiphenyl-
silyloxypyrrolidine 17
To a stirred solution of 14 (0.96 g, 3 mmol) and imidazole (0.51 g, 7.5 mmol) in dry THF (10 ml)
was added tert-butyldiphenylsilylchloride (0.917 ml, 3.5 mmol). The mixture was stirred overnight at
room temperature, then poured into 10 ml of satd brine and extracted with ethyl acetate (3×50 ml). The
combined extracts were washed with water, dried over Na2SO4 and concentrated under reduced pressure
to give crude silyl ether, which was purified by silica gel chromatography (EtOAc:n-hexane 5:95) to give
1
17 (1.65 g, 98%); [α]D=−7.3 (c=1.23, CHCl3); H NMR δ: 7.65 (4H, td, J=9.0 and 2.0 Hz, SiC6H5),
7.38 (6H, m, SiC6H5), 7.29 (5H, m, C6H5), 5.07, 5.03 (1H each, d, J=12.0 Hz, COOCH2), 4.50 (1H,
m, CHOSi), 4.33 (1H, dt, J=10.0 and 7.5 Hz, CHO), 3.93 (2H, m, CH2O), 3.38 (1H, td, J=10.0 and 2.0
Hz, CHAHBN), 3.26 (1H, br q, J=10.0 Hz, CHAHBN), 2.22 (1H, br p, J=10.0 Hz, CHCHD), 1.75 (1H,
br qd, J=10.0 and 2.0 Hz, CHCHD), 1.39, 1.31 (3H each, s, 2×Me), 1.08 (9H, s, Me3); 13C NMR δ:
153.24 (s, CO), 135.83, 135.64, 133.88, 133.60, 130.01, 129.95, 127.87, 127.73 (d×2, d×2, s, s, d, d,
d×2, d×2, 2×C6H5), 135.93, 128.46, 127.94, 127.91 (s, d×2, d×2, d, C6H5), 108.74 (s, COO), 74.52,
74.35 (d each, 2×CHO), 72.43 (t, CH2O), 67.09 (t, COOCH2), 58.79 (d, CHN), 44.06 (t, CH2N), 31.28
(t, CH2), 267.03 (q, Me3), 26.30, 26.05 (q each, 2×Me), 19.27 (s, SiC). Anal. calcd for C33H41NO5Si: C
70.81, H 7.38, N 2.50. Found: C 71.01, H 7.36, N 2.49.
3.14. (2R,3R)-1-(Benzyloxycarbonyl)-2-[(1R)-1,2-dihydroxyethyl]-3-tert-butyldiphenylsilyloxy-
pyrrolidine 18
A mixture of acetonide 17 (1.12 g, 2.0 mmol) and FeCl3/SiO221 (60 mg) in 15 ml of CHCl3 was stirred
at room temperature for 16 h. After that time, the mixture was filtered, the filtrate was concentrated under
reduced pressure and the residue was purified by silica gel chromatography (EtOAc:n-hexane 1:1) to give
18 (0.793 g, 93% based on recovery of 18% of 17); [α]D=−24.8 (c=1.7, MeOH); 1H NMR δ: 7.65 (4H,
td, J=7.0 and 1.5 Hz, SiC6H5), 7.41 (6H, m, SiC6H5), 7.31 (5H, br s, C6H5), 5.09 (2H, s, COOCH2),
4.43 (1H, dt, J=9.0 and 8.0 Hz, CHOSi), 4.32 (1H, ddd, J=7.5, 5.0 and 2.0 Hz, CHOH), 4.10 (1H, br
s, OH), 3.94 (1H, dd, J=8.0 and 2.0 Hz, CHN), 3.64 (1H, dd, J=11.5 and 7.5 Hz, CHAHBO), 3.55 (1H,

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G. Delle Monache et al. / Tetrahedron: Asymmetry 10 (1999) 2961–2973
dd, J=11.5 and 5.0 Hz, CHAHBO), 3.45 (1H, td, J=10.0 and 3.0 Hz, CHCHDN), 3.27 (1H, td, J=10.0
and 8.0 Hz, CHCHDN), 2.69 (1H, br s, OH), 2.11 (1H, dq, J=11.5 and 9.5 Hz, CHEHF), 1.82 (1H, dtd,
J=11.5, 8.0 and 3.0 Hz, CHEHF), 1.09 (9H, s, Me3); 13C NMR δ: 157.16 (s, CO), 136.20, 128.52, 128.17,
127.89 (s, d×2, d, d×2, C6H5), 135.71, 135.58, 133.09, 132.40, 130.23, 130.13, 128.01, 127.84 (d×2,
d×2, s, s, d, d, d×2, d×2, 2×SiC6H5), 72.51 (d, CHOSi), 70.66 (d, CHOH), 67.51 (t, COOCH2), 63.20
(t, CH2O), 60.0 (d, CHN), 44.08 (t, CH2N), 32.66 (t, CH2), 26.95 (q, 3×Me), 19.06 (s, SiC). Anal. calcd
for C30H37NO5Si: C 69.33, H 7.18, N 2.70. Found: C 69.30, H 7.19, N 2.69.
3.15. (2R,3R)-1-(Benzyloxycarbonyl)-2-[(1R)-2-p-toluenesulfonyloxy-ethyl-1-ol]-3-tert-butyldiphenyl-
silyloxypyrrolidine 19
To a solution of diol 18 (0.555 g, 1.065 mmol) in dry CH2Cl2 (3 ml) was added freshly distilled
pyridine (0.213 ml) and p-toluenesulfonyl chloride (0.406 g, 2.13 mmol) at −5°C. The mixture was
stirred at the same temperature for 10 h then diluted with CH2Cl2 (30 ml) and treated with 1N HCl
(2×15 ml), H2O, satd NaHCO3, brine and dried over Na2SO4. The residue was purified by silica gel
chromatography (EtOAc:n-hexane 3:7) to give 19 (0.618 g, 86%) as a colorless oil; [α]D=−20.4 (c=1.5,
MeOH); 1H NMR δ: 7.80 (2H, d J=8.0 Hz, SO2C6H4), 7.68 (4H, dd, J=7.5 and 1.5 Hz, SiC6H5), 7.62
(4H, td, J=7.5 and 1.5 Hz, SiC6H5), 7.48 (2H, m, SiC6H5), 7.48–7.28 (5H, m, C6H5), 7.31 (2H, d, J=8.0
Hz, SO2C6H4), 5.07 (2H, s, COOCH2), 4.74 (1H, q, J=4.0 Hz, CHOSi), 4.41 (1H, q, J=2.0 Hz, CHO),
4.35, 4.13 (1H each, dd, J=12.0 and 2.0 Hz, CH2O), 3.81 (1H, dt, J=11.0 and 8.5 Hz, CHAHBN), 3.56
(1H, dd, J=4.5 and 2.0 Hz, CHN), 3.43 (1H, dt J=11.0 and 6.0 Hz, CHAHBN), 2.42 (3H, s, Me), 2.05,
1.62 (1H each, tdd, J=9.0, 6.0 and 4.0 Hz, CH2), 1.06 (9H, s, 3×Me); 13C NMR δ: 152.44 (s, NCO),
136.10, 128.54, 128.16, 127.83 (s, d×2, d, d×2, C6H5), 134.79, 131.52, 129.82, 128.16 (s, s, d×2, d×2,
SiC6H5), 135.71, 133.29, 132.18, 130.62, 130.57, 128.21, 127.96 (d×4, s, s, d, d, d×2, d×2, SiC6H5),
76.86 (d, CHOSi), 71.88 (d, CHO), 67.13 (t, COOCH2), 62.77 (t, CH2O), 60.88 (d, CHN), 44.94 (t,
CH2N), 32.33 (t, CH2), 26.86 (q, Me3), 21.65 (q, Me3), 19.03 (s, SiC). Anal. calcd for C37H43NO7SSi:
C 65.95, H 6.43, N 2.08. Found: C 65.80, H 6.38, N 2.07.
3.16. (2R,3R)-1-(Benzyloxycarbonyl)-2-[(1R)-2-cyano-ethyl-1-ol]-3-tert-butyldiphenylsilyloxy-
pyrrolidine 20
A mixture of 19 (0.60 g, 0.9 mmol) and sodium cyanide (0.348 g, 7.2 mmol) in dry DMF (20 ml) was
stirred for 4 h at 45°C. Then the solvent was removed under reduced pressure and the residue was purified
by silica gel chromatography (EtOAc:n-hexane 4:6) to give the nitrile 20 (0.264 g, 83%); [α]D=−27.9
(c=0.76, MeOH); 1H NMR δ: 7.67 (4H, td, J=7.0 and 1.5 Hz, SiC6H5), 7.42 (6H, m, SiC6H5), 7.28 (5H,
br s, C6H5), 5.10 (2H, s, COOCH2), 4.49 (1H, dt, J=9.0 and 7.5 Hz, CHOSi), 4.33 (1H, m, CHOH), 4.11
(1H, dd, J=7.5 and 2.0 Hz, CHN), 3.57 (1H, br s, OH), 3.49 (1H, td, J=10.0 and 3.0 Hz, CHAHBN), 3.36
(1H, td, J=10.0 and 7.5 Hz, CHAHBN), 2.79 (1H, dd, J=11.0 and 7.0 Hz, CHCHDCN), 2.75 (1H, dd,
J=11.0 and 6.0 Hz, CHCHDCN), 2.11, 1.89 (1H each, m, CH2); 13C NMR δ: 157.44 (s, CO), 137.00,
128.45, 127.94, 127.78 (s, d×2, d, d×2, C6H5), 135.71, 135.48, 132.89, 132.42, 130.13, 128.09, 127.81
(d×2, d×2, s, s, d, d, d×2, d×2, 2×SiC6H5), 118.62 (s, CN), 74.26 (d, CHOSi), 70.55 (d, CHOH), 67.43
(t, COOCH2), 60.01 (d, CHN), 45.84 (t, CH2N), 32.88 (t, CH2), 27.89 (t, CH2CN), 26.91 (q, 3×Me),
19.07 (s, SiC). Anal. calcd for C31H36N2O4Si: C 70.42, H 6.86, N 5.30. Found: C 70.49, H 6.85, N 5.28.

G. Delle Monache et al. / Tetrahedron: Asymmetry 10 (1999) 2961–2973
2973
3.17. (−)-Detoxinine 2
A solution of 20 (0.2 g. 0.38 mmol) in dry EtOAc (4 ml) was hydrogenated (1 atm) in the presence
of catalytic 5% Pd/C for 5 h. After that time the mixture was filtered over Celite and concentrated
under reduced pressure. A solution of the above crude amine in 4N HCl was heated to 50°C and the
temperature was slowly increased to 75°C over 2.5 h. After 12 h the mixture was concentrated under
reduced pressure and the brown residue was purified by cation exchange chromatography (Dowex 50X8-
200), eluting with 1N NH4Cl. The residue was triturated with abs. EtOH to give (−)-2 (45 mg, 68%).
Mp 224–227°C; [α]D=−4.5 (c=0.4, H2O); (lit.7 mp 227–229°C; [α]20=−4.4 (c=0.5, H2O); lit.5c mp
D
225–228°C; [α]23=−4.8 (c=0.5, H2O); 1H and 13C NMR spectra as reported.7
D
Acknowledgements
This work was supported by MURST (Ministero dell’Università e della Ricerca Scientifica, Italy) and
by CNR (Consiglio Nazionale delle Ricerche, Italy).
References
1. Yonehara, H.; Seto, H.; Aizawa, S.; Hidaka, T.; Shimazu, A.; Otake, N. J. Antibiot. 1968, 21, 369.
2. For a comprehensive review see: Li, W.-R.; Han, S.-Y.; Joullie, M. M. Heterocycles 1993, 36, 359.
3. Yonehara, H.; Seto, H.; Shimazu, A.; Aizawa, S.; Hidaka, T.; Kakinuma, K.; Otake, N. Agric. Biol. Chem. 1973, 37, 2771.
4. Ogita, T.; Seto, H.; Otake, N.; Yonehara, H. Agric. Biol. Chem. 1981, 45, 2605.
5. Natural (−)-enantiomer syntheses see: (a) Kogen, H.; Kadokawa, H.; Kurabayahi, M. J. Chem. Soc., Chem. Commun. 1990,
1240. (b) Joullie, M. M.; Harris, B. D.; Bhat, K. L. Tetrahedron 1986, 42, 2421. (c) Ohfune, Y.; Nishio, H. Tetrahedron
Lett. 1984, 25, 4133. For a synthesis of (+)-detoxinine see: Mulzer, J.; Meier, A.; Buschmann, J.; Luger, P. J. Org. Chem.
1996, 61, 566.
6. Hausler, J. Liebigs Ann. Chem. 1983, 982.
7. Denmark, S. E.; Hurd, A. R.; Sacha, H. J. J. Org. Chem. 1997, 62, 1668.
8. For an account of our work in this field see: (a) Di Giovanni, M. C.; Misiti, D.; Zappia, G.; Delle Monache, G. Gazz. Chim.
Ital. 1997, 127, 475. (b) Di Giovanni, M. C.; Misiti, D.; Zappia, G.; Delle Monache, G. Tetrahedron 1993, 49, 11321.
(c) Di Giovanni, M. C.; Misiti, D.; Villlani, C.; Zappia, G. Tetrahedron: Asymmetry 1996, 7, 2277. (d) Misiti, D.; Delle
Monache, G.; Zappia, G. Liebigs Ann. Chem. 1996, 235. (e) Delle Monache, G.; Di Giovanni, M. C., Misiti, D.; Zappia,
G. Tetrahedron: Asymmetry 1997, 8, 231.
9. Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K.; Mikkileneni, A. B.; Wu, D. C.-J.; Saibaba, R.; Panzica, R. P. J.
Org. Chem. 1988, 53, 2598.
10. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
11. Ando, K. Tetrahedron Lett. 1995, 36, 4105. Ando, K. J. Org. Chem. 1997, 62, 1934.
12. Still, C. W.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
13. Koskinen, A. M. P.; Otsomaa, L. A. Tetrahedron 1997, 53, 6473.
14. For iodocyclocarbamation reactions of allylamines see: Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321; Ref. 8a and
references cited therein.
15. The nucleophilic ability of an acetonide oxygen has been well demonstrated in the total synthesis of nonensin by: Collum,
D. B.; McDonald III, J. H.; Still, W. C. J. Am. Chem. Soc. 1980, 102, 2118.
16. Futugawa, S.; Inui, T.; Shiba, T. Bull. Chem. Soc. Jpn. 1973, 46, 3308. Dhavale, D. D.; Gentilucci, L.; Piazza, M. G.;
Trombini, C. Liebigs Ann. Chem. 1992, 1289.
17. Hoffman, R. W. Chem. Rev. 1989, 89, 1841.
18. Alper, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801. Castro, B. R. Org. React. 1983, 29, 1.
19. St-Denis, Y.; Chan, T.-H. J. Org. Chem. 1992, 57, 3078.
20. Anisuzzaman, A. K. M.; Whistler, R. L. Carbohydr. Res. 1978, 61, 511.
21. For a similar reaction see: Li, G.; Shi, Z. Tetrahedron 1997, 53, 1369.
22. Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J. Org. Chem. 1986, 51, 404.
23. Perrin, D. D.; Armarego, W. L. Purification of Laboratory Chemicals; Pergamon Press: Oxford, 1988.