Iodolactonization of 3-amino-4-pentenoic acid: a stereoselective synthesis of syn-γ-hydroxy-β-amino acids

Article abstract of DOI:10.1016/S0957-4166(00)00033-1

The reaction of (S)-3-N-Cbz-4-pentenoic acid with iodine in acetonitrile in the presence of AgOTf gave the cis-iodo-lactone 6 in excellent yield and in a highly diastereoselective manner. The substitutions of the iodine in 6 by different Grignard reagents in the presence of CuI and the subsequent conversions into the functionalized syn-γ-hydroxy-β-amino acids have been investigated. By the above reaction sequence, (3S,4S)-3-amino-4-hydroxy-5-cyclohexyl pentanoic acid was synthesized with high enantioselectivity.

Full text of DOI:10.1016/S0957-4166(00)00033-1

Tetrahedron: Asymmetry 11 (2000) 1137±1149
Iodolactonization of 3-amino-4-pentenoic acid:
a stereoselective synthesis of syn-g-hydroxy-b-amino acids
Giuliano Delle Monache,a Domenico Misiti,b Patrizia Salvatoreb and
Giovanni Zappiab,*
aCentro di Studio per la Chimica dei Recettori e delle Molecole Biologicamente Attive-Istituto di Chimica,
Á
Universita Cattolica del S. Cuore, Largo F. Vito 1, 00168 Roma, Italy
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Universita `La Sapienza',
P. le A. Moro 5, 00185 Roma, Italy
b
Á
Received 17 December 1999; accepted 19 January 2000
Abstract
The reaction of (S)-3-N-Cbz-4-pentenoic acid with iodine in acetonitrile in the presence of AgOTf gave
the cis-iodo-lactone 6 in excellent yield and in a highly diastereoselective manner. The substitutions of the
iodine in 6 by di€erent Grignard reagents in the presence of CuI and the subsequent conversions into the
functionalized syn-g-hydroxy-b-amino acids have been investigated. By the above reaction sequence,
(3S,4S)-3-amino-4-hydroxy-5-cyclohexyl pentanoic acid was synthesized with high enantioselectivity.
# 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
b-Amino acids are emerging as an important topic in organic chemistry and as an interesting
class of compounds in medicinal chemistry. They are found in humans, animals, micro-organisms
and plants, either in the free form or as components of peptides or depsipeptides,1 with anti-
biotic,1 antifungal,2 cytotoxic,3 anticancer4 etc. activities. Natural or synthetic enzyme inhibitors,
such as bestatin and amastatin, contain b-amino acids as key components.1 Peptides that contain
b-amino acids are generally more stable to enzymatic hydrolysis, because the enzyme is not able
to recognize the amide bonds.1,5 Moreover, the ability of short b-peptide oligomers to form well
de®ned, remarkably stable secondary structures6 has enhanced the potential of these compounds
as mimics of a-peptides.
In view of the importance and utility of b-amino acids a number of synthetic methods,7 based
mainly on the stereoselective formation of the C±N bond or on the transformation of a-amino
acids, have been developed.
* Corresponding author. E-mail: g.zappia@caspur.it
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00033-1

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G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 1137±1149
The Michael addition of `chiral ammonia' equivalent to achiral a,b-unsaturated esters8 or
amines to chiral a,b-unsaturated esters,9 as well as the stereoselective addition of metal acetate to
chiral imines,10 have been extensively studied. The stereoselective formation of 6-substituted per-
hydropyrimidin-4-ones,11 the C-4 alkylation and arylation of enantiomerically pure dihydropyr-
imidones12 and the use of b-lactams as acylating agents13 in b-peptide synthesis have also been
considered.
The Arndt±Eistert homologation of a-amino acids14 is a versatile method for the preparation
of enantiomerically pure b-amino acids with the same substituent as the proteinogenic a-amino
acids. Moreover, in a di€erent approach, the carboxylic group at C-1 of l-aspartic acid and l-
asparagine has been transformed into the desired alkyl or aryl substituent15 without altering the
b-amino acid backbone. By contrast, insucient consideration has been given to the synthesis of
functionalized a-unsubstituted g-hydroxy-b-amino acids, although they are components of anti-
biotic peptides, such as tuberactinomycins A and N,16 or gastroprotective natural products such
as Amicoumacin C and AI-77-B.17 On the other hand, electrophilic mediated lactonization18 of 4-
pentenoic acid is a powerful method to introduce a g-hydroxy function, and in the case of chiral
3-substituted 4-pentenoic acids, high levels of 1,2 stereochemical induction have been observed.
However, whereas 3-hydroxy-, 3-alkoxy- and 3-alkyl-4-pentenoic acids have been extensively studied,
little attention has been paid to 3-amino-4-pentenoic acid, in spite of its electronic characteristics.
Following our studies19 on the stereoselective synthesis of non-proteinaceous amino acids via
electrophilic functionalization of chiral allyl amines, we report here our results on the stereo-
selective, iodine mediated, lactonization reaction of (S)-3-N-benzyloxycarbonyl-4-pentenoic acid,
as the key step for the preparation of g-substituted syn-b-amino-g-hydroxy acids.
2. Results and discussion
The (S)-3-N-benzyloxycarbonyl-4-pentenoic acid 5 was prepared in line with the two synthetic
pathways depicted in Scheme 1.
Scheme 1.
In the ®rst approach, N-Cbz g-tert-butyl l-aspartic acid20 1 was converted into the amino
alcohol15a,21 2 by activation (EtOCOCl, Et3N, THF, 15ꢀC) of the acid function as a mixed
anhydride followed by reduction with NaBH4/MeOH, according to Kokotos.22 The amino
alcohol 2 was obtained in 89% yield and converted under Swern conditions (COCl2/DMSO,
63ꢀC, then DIPEA) into the corresponding a-amino aldehyde, which in turn, by Wittig methyl-
ation (Ph3P+CH3 Br /KHMDS, 78ꢀC!rt), gave 3 in 80% yield. In the second pathway, the

G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 1137±1149
1139
conversion of the partially protected l-aspartic acid 1 into the Weinreb amide23 4 (MeNHOMe,
EDC, 90%) was followed by treatment with LiAlH4 (1 M THF, 5ꢀC) to give the corre-
24
sponding a-amino aldehyde, which was then subjected to the Wittig ole®nation reaction as above.
The allyl amine 3 was obtained in 78% yield from 4 and in 70% yield from 1. Although com-
parable yields were obtained by the two methods, the second was chosen because it requires less
technically demanding transformations. The tert-butyl ester 3 was converted into the free acid 5
in quantitative yield by treatment with CF3COOH in CH2Cl2.
The iodine mediated lactonization reaction of (S)-3-N-Cbz-4-pentenoic acid 5 (Scheme 2) was
then studied under di€erent conditions, and the results are reported in Table 1. Diastereomeric
1
ratios were determined on the crude mixture by integration of non-overlapping signals in the H
NMR spectra and of chromatographic peaks in HPLC pro®les. Under all conditions the major
product was the cis-lactone 6, although with di€erent chemical yields and stereoselectivities.
Scheme 2.
Table 1
Iodonium ion promoted lactonization of (S)-3-benzyloxycarbonylamino-4-pentenoic acid
Initial attempts to achieve the iodolactonization reaction18 of 5, in a biphasic system H2O/Et2O
(entry 1) in the presence of sat. aqueous NaHCO3 at 5ꢀC, gave the two iodo-lactones 6 and 7 in
good chemical yield (84%) but in a moderate ratio (8:1). On the other hand, reactions carried out
in CH2Cl2 or CCl4 (entries 2, 3) gave a mixture of products, where compounds 6 and 7 occurred
in low yields and poor ratios. A cleaner reaction occurred in acetonitrile (entries 4 and 5) at 5ꢀC,
to give the diastereomeric mixture of iodo-lactones 6/7 in 65±70% overall yield and 11:1 ratio. A
better diastereoselectivity (15:1, entry 6) was observed when the reaction was performed at
40ꢀC25 in CH3CN, but with lower yields. A prolonged reaction time (entry 7) did not improve

1140
G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 1137±1149
the yield. The use of bases (NaHCO3, pyridine, entries 8 and 9), in the same solvent, was also
investigated, but the results were no better. However, a dramatic rate enhancement was observed
when the reaction was carried out in the presence (1.0 equiv., entry 10) of AgOTf.26 Within 3.5 h
the starting material was consumed to give the iodo-lactones 6/7 in 97% yield and 15:1 ratio. The
1H and 13C NMR spectral data of diastereoisomers 6 and 7 are reported in Table 2.
Table 2
1H and 13C NMR spectroscopic dataa for the iodo-lactones 6 and 7
1
In the H NMR spectra of compound 7 the signal of the H-2 proton appeared at higher ®eld
than that of compound 6, as required for trans isomers.27 On the other hand, in the 13C NMR
spectra the signals attributed to C-2, C-3 (82.18, 50.25 ppm) and CH2I ( 0.88 ppm) for the cis
isomer 6 were up®eld27 from the corresponding signals (83.60, 52.76 and 5.68 ppm, respectively)
of the trans isomer 7. Finally, a DIFNOE (3.5%) between the NH and CH2I con®rmed the cis-
relationship between the two groups. A single crystallization gave 6 in 73% yield and 97.5% d.e.28
The stereochemical outcome may be rationalized on the basis of electronic and steric e€ects
(Scheme 3).
The trans-product 7 is expected to arise from the transition state D, since the conformer C is
sterically less hindered than the conformer A. On the other hand, electronic e€ects29 activate the
double bond in the conformer A for electrophilic addition towards the transition state B to give
the predominant cis-form 6.
Given that the iodo-lactone 6 can be considered equivalent, from a synthetic point of view, to
the electrophilic synthon 8 (Scheme 4), the nucleophilic substitution of the iodine was investigated
to obtain g-functionalized syn-b-amino-g-hydroxy acids.

G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 1137±1149
1141
Scheme 3.
Scheme 4.
Therefore, the nucleophilic displacement of the iodine in 6 by di€erent Grignard reagents in the
presence of CuI salts30 was considered. Reactions were performed by addition of compound 6 in
THF to a mixture of the Grignard reagent and CuI in dry THF at 50ꢀC for 1.5 h. Fair results
(Table 3) were obtained when both primary and secondary alkyl Grignard reagents were
employed, whereas phenyl failed to give the substitution product in acceptable yield under all
conditions tested.
Table 3
CuI mediated cross-coupling of iodo-lactone 6 with di€erent Grignard reagents

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G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 1137±1149
The synthesis of (3S,4S)-5-cyclohexyl 4-hydroxy 3-amino pentanoic acid, an isomeric analogue
of the biologically relevant (3S,4S)-cyclohexylstatine,31 was then carried out (Scheme 5). First, we
chose to open the lactone moiety under basic conditions and then to remove, by hydrogenolysis,
the Cbz protecting group. However, treatment of 12 under alkaline conditions (K2CO3, NaOH)
either in MeOH/H2O or acetone/H2O gave a mixture of products. The major product was
1
assigned the structure 1,3-oxazinane-2,6 dione derivative 14, based on H and 13C NMR and
mass spectral data. Notably, the reaction performed with KOH (3 equiv.) in MeOH at 40ꢀC
a€orded 14 in almost quantitative yield within 30 min. Ring opening of the lactone might have
occurred by intramolecular attack of the carbamate followed by elimination of the benzyl group
as benzyl alcohol, which was actually present in the reaction mixture. To circumvent this
unwanted result we changed the sequence of reactions. The free amine 15 was thus obtained by
hydrogenolysis (1 atm, 10% Pd/C, AcOEt) of the N-protected lactone 12 in quantitative yield,
and was converted into the free amino acid 16 under alkaline conditions (0.1N NaOH, pH 9) in
74% yield.
Scheme 5.
In conclusion we have developed a convenient route to a-unsubstituted g-functionalized syn-b-
amino-g-hydroxy amino acids by the combination of the stereoselective iodolactonization of (S)-
3-N-benzyloxycarbonyl 4-pentenoic acid, and the replacement of the iodide in the compound 6 by
CuI mediated cross-coupling addition of Grignard reagents. The feasibility of this approach was
demonstrated by the synthesis of the (3S,4S)-3-amino-4-hydroxy-5-cyclohexyl pentanoic acid.
Further use of the iodo-lactone 6 as a key intermediate for the total synthesis of biologically
active natural products is at present under investigation.
3. Experimental
Melting points were determined in open capillaries using a Buchi apparatus and are uncor-
1
rected. H and 13C NMR spectra were run on a Varian Gemini 300 spectrometer at 300 and 75
MHz, respectively, in CDCl3, unless otherwise reported. Chemical shifts (ꢀ scale) are relative to
1
TMS as internal reference. The proton chemical-shifts in H NMR spectra were con®rmed by
COSY and HETCOR experiments. MS spectra for 14 were recorded with a Hewlett±Packard HP
5980A spectrometer equipped with a Data System 5934 A. Optical rotations were determined on

G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 1137±1149
1143
a Perkin±Elmer 243 polarimeter at 23ꢀC (concentration g/100 ml). All solvents were dried prior to
use.32 Thin layer chromatography was performed on Merck silica gel 60 F254 glass plates.
3.1. tert-Butyl-(3S)-3-{[(benzyloxy)carbonyl]amino}-4-hydroxy-butanoate 2
To a stirred solution of Z-l-aspartic 4-tert-butyl ester 120 (6.47 g, 20 mmol) in THF (100 ml) at
15ꢀC (ice+NaCl), N-methylmorpholine (2.2 ml, 20 mmol) was added followed by ethyl chloro-
formate (1.91 ml, 20 mmol). The reaction mixture was stirred at the same temperature for 15 min,
and NaBH4 (2.26 g, 60 mmol) was added followed by addition of MeOH (200 ml) over a period
of 30 min at 15ꢀC. The solution was stirred for 15 min and neutralized with 1N HCl. The
organic solvents were evaporated under reduced pressure and the residue was extracted with
EtOAc (3Â150 ml). The combined organic phase was washed with 1N HCl (100 ml), H2O (2Â100
ml), 5% aqueous NaHCO3 (2Â100 ml), dried over Na2SO4 and evaporated under reduced pres-
sure. The residue was puri®ed by silica gel chromatography (EtOAc:n-hexane 1:1) to give the
amino alcohol 2 (5.51 g, 89%) as an oil; [ꢁ]D= 19.6 (c=1.2, CHCl3); [ꢁ]D15a= 19.3 (c=2.03,
1
CHCl3); H NMR spectra as reported.15a,21
3.2. tert-Butyl-(3S)-3-{[(benzyloxy)carbonyl]amino}-4-pentenoate 3
Oxalyl chloride (3 ml, 33 mmol) was dissolved in CH2Cl2 (50 ml), the mixture was cooled to
63ꢀC and a solution of dry DMSO (5.61 ml, 66 mmol) in CH2Cl2 (10 ml) was added dropwise
during 15 min.
The amino alcohol 2 (6.18 g, 20.0 mmol) in CH2Cl2 (20 ml) was added dropwise during 10 min,
the resulting solution was stirred for 10 min at 63ꢀC, and a solution of N,N-diisopropyl ethyl
amine (20.9 g, 0.12 mol) in CH2Cl2 (50 ml) was added dropwise during 15 min. After 20 min
water (5.0 ml) was added to the vigorously stirred solution at 63ꢀC. The resulting slurry was
poured in Et2O (300 ml) and washed with 20% aqueous KHSO4 (2Â100 ml), the layers were
separated and the aqueous layer was back-extracted with Et2O (2Â100 ml). The combined
organic layers were washed with brine solution (2Â50 ml), dried over Na2SO4 and the solvent was
removed under reduced pressure (T=20ꢀC) to a€ord the crude aldehyde, which was immediately
used in the next reaction without any further puri®cation.
Methyl triphenylphosphonium bromide (12.52 g, 35 mmol) was suspended in dry THF (300
ml) at room temperature and KHMDS (0.5 M in toluene, 67.2 ml, 33.6 mmol) was added. The
resultant yellow solution was stirred at room temperature for 1 h, then cooled to 78ꢀC and a
solution of the above aldehyde in dry THF (20 ml) was added dropwise. The temperature of the
cooling bath was slowly increased to room temperature over 1 h and then stirred for a further 2 h.
The reaction was quenched with MeOH (30 ml) and the resulting mixture was poured into a
mixture of sat. potassium sodium tartrate and water (1:1, 500 ml). Extraction with Et2O
(3Â250 ml), drying over Na2SO4 and evaporation under reduced pressure gave the crude ole®n.
The residue was puri®ed by silica gel chromatography using EtOAc:n-hexane (20:80) as eluent to
1
give 3 (4.9 g, 80%) as an oil; [ꢁ]D=+26.8 (c=3.3, CHCl3); H NMR ꢀ: 7.35 (5H, s, C6H5), 5.85
(1H, ddd, J=17.0, 10.0 and 5.0 Hz, CHˆ), 5.54 (1H, br d, J=8.0 Hz, NH), 5.22 (1H, br
d, J=17.0 Hz, ˆCHAHB), 5.14 (1H, br d, J=10.0 Hz, ˆCHAHB), 5.11 (1H, s, OCH2), 4.55
(1H, dq, J=8.0 and 6.0 Hz, CHN), 2.56 (1H, dd, J=15.0 and 6.0 Hz, CHCHD), 2.50 (1H, dd,
J=15.0 and 6.0 Hz, CHCHD), 1.43 [9H, s, (CH3)3C]; 13C NMR ꢀ: 170.31 (s, COO), 155.61 (s,
CON), 136.99 (d, CHˆ), 136.49 (s, C6H5), 128.48 (4Âd, C6H5), 128.06 (d, C6H5), 115.44

1144
G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 1137±1149
(d, ˆCH2), 81.33 [s, (CH3)3CO], 66.72 (t, OCH2), 50.01 (d, CHN), 40.09 (t, CH2), 28.03 [q, (CH3)3C].
Anal. calcd for C17H23NO4: C=66.86, H=7.59, N=4.59; found: C=66.90, H=7.60, N=4.57.
3.3. tert-Butyl-(3S)-3-{[(benzyloxy)carbonyl]amino}-4-[methoxy(methyl)amino]-4-oxobutanoate 4
A solution of acid 120 (1.94 g, 6 mmol) in CH2Cl2 (25 ml) was cooled to 15ꢀC and N,O-
dimethyl hydroxyl amine hydrochloride (0.6 g, 6.15 mmol), N-methylmorpholine (0.68 ml, 6.15
mmol) were added, followed by N-(3-dimethylamino propyl)-N-ethylcarbodiimide hydrochloride
(1.18 g, 6.15 mmol) in small portions. The reaction was stirred for 1 h at room temperature and
then ice cooled 1 M HCl (8 ml) was added. The aqueous layer was extracted with CH2Cl2 (2Â25
ml) and the combined organic layers were washed with H2O (50 ml), sat. NaHCO3 (25 ml) dried
over Na2SO4 and concentrated under reduced pressure to give 4 as a colourless solid (1.98 g,
90%), which was used without any further puri®cation. An analytical sample of hydroxamate
was obtained by crystallization in an EtOAc/n-hexane mixture; m.p. 75ꢀC; [ꢁ]D= 19.4 (c=2.27,
MeOH); 1H NMR ꢀ: 7.34 (5H, s, C6H5), 5.54 (1H, br d, J=8.0 Hz, NH), 5.13 (1H, d, J=12.0 Hz,
OCHAHB) 5.08 (1H, d, J=12.0 Hz, OCHAHB), 5.03 (1H, ddd, J=9.0, 7.0 and 5.0 Hz, CHN),
3.78 (3H, s, OCH3), 3.22 (s, NCH3), 2.71 (1H, dd, J=15.0 and 5.0 Hz, CHCHDCO), 2.55 (1H, dd,
J=15.0 and 7.0 Hz, CHCHDCO), 1.42 [9H, s, (CH3)3C]; 13C NMR ꢀ: 169.20 (s, COO), 155.70 (s,
CON), 136.32 (s, C6H5) 128.45 (2Âd, C6H5), 128.07 (2Âd, C6H5), 127.99 (d, C6H5), 81.38 [s,
(CH3)3CO], 66.89 (t, OCH2), 61.59 (q, OCH3), 48.44 (d, CHN), 38.35 (t, CH2CO), 32.38 (q,
NCH3), 27.97 [q, (CH3)3C]. Anal. calcd for C18H26NO6: C=61.35, H=7.44, N=3.97; found:
C=61.38, H=7.45, N=3.97.
3.4. Preparation of (3S)-tert-Butyl-3(S)-{[(benzyloxy)carbonyl]amino}-4-pentenoate 3 from the
hydroxamate 4
Hydroxamate 4 (1.83 g, 5 mmol), in dry THF (20 ml), was cooled ( 5ꢀC, ice+NaCl) and a
solution of LiAlH4 (1.0 M in THF, 2.5 ml, 2.5 mmol) was added dropwise over 10 min. The
mixture was stirred for 30 min at the same temperature, then the reaction was cooled to 15ꢀC
and sat. aqueous KHSO4 (15 ml) was added carefully followed by addition of Et2O (50 ml). The
mixture was stirred for additional 15 min and the organic layer separated, dried over Na2SO4 and
concentrated under vacuum to give the corresponding a-amino aldehyde, which was immediately
used without any further puri®cation. The amino aldehyde was subjected to the Wittig methyl-
ation reaction following the above procedure to give 3 (1.3 g, 78%) as an oil.
3.5. (3S)-3-{[(Benzyloxy)carbonyl]amino}-4-pentenoic acid 5
To a solution of the tert-butyl ester 3 (3.97 g, 13 mmol) in CH2Cl2 (80 ml) at 0ꢀC was added
CF3COOH (6.5 ml) and the reaction mixture was stirred at room temperature until the starting
material was consumed. The mixture was then concentrated under reduced pressure, the residue
was treated with Et2O (50 ml) and concentrated under vacuum to give the acid 5 (3.23 ꢀg, 99%) as
ꢀ
1
a colourless solid. M.p. 108±109 C; [ꢁ]D=+12.0 (c=1.7, MeOH). H NMR (T=55 C) ꢀ: 7.33
(5H, s, C6H5), 5.85 (1H, ddd, J=17.0, 10.0 and 5.5 Hz, CHˆ), 5.48 (1H, br d, J=8.0 Hz, NH),
5.22 (1H, br d, J=17.0 Hz, ˆCHAHB), 5.14 (1H, br d, J=10.0 Hz, ˆCHAHB), 5.11 (2H, s,
OCH2), 4.57 (1H, dq, J=8.0 and 5.5 Hz, CHN), 2.66 (2H, dd, J=5.5 Hz, CH2); 13C NMR ꢀ:
175.83 (s, COO), 155.83 (s, CON), 136.53 (d, CHˆ), 136.23 (s, C6H5) 128.53 (2Âd, C6H5), 128.18

G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 1137±1149
1145
(2Âd, C6H5), 128.08 (d, C6H5), 116.03 (t, ˆCH2), 67.03 (t, OCH2), 49.68 (d, CHN), 38.82 (t, CH2).
Anal. calcd for C13H15NO4: C=62.64, H=6.07, N=5.62; found: C=62.67, H=6.09, N=5.61.
3.6. Benzyl (2R,3S)-2-(iodomethyl)-5-oxotetrahydrofuran-3-ylcarbamate 6
A solution of the unsaturated acid 5 (1.25 g, 5 mmol) and AgOTf (1.29 g, 5 mmol) in dry
CH3CN (18 ml) was cooled to 40 ꢀC and I2 (4.75 g, 15 mmol) was added in small portions. The
reaction mixture was stirred at the same temperature for 3.5 h in the dark, then diluted with
CHCl3 (100 ml) and extracted with aqueous Na2S2O3 (0.25 M, 3Â50 ml). The aqueous solution
was extracted with CHCl3 (2Â50 ml) and the combined organic extracts were washed with H2O
(2Â100 ml), sat. aqueous NaHCO3 (2Â50 ml), H2O (100 ml), dried over Na2SO4 and con-
centrated under reduced pressure to give 6 and 7 (1.82 g, 97%) as a 15:1 diastereomeric mixture,
1
as judged by H NMR and HPLC [column: SiO2 LiChrosorb Si 60, 250Â4 mm ID; eluent:
CHCl3:n-hexane 60:40+0.3% MeOH; T=30ꢀC, tR (min) 6=7.3, K06=2.32; tR (min) 7=8.3,
K07=2.77]. A single crystallization (AcOEt:n-hexane 1:2.5) gave compound 6 (73% yield from 5)
as a colourless solid in a d.e.=97.5% as judged by HPLC. M.p. 131±132ꢀC; [ꢁ]D= 43.6 (c=1.3,
CHCl3); 1H NMR and 13C NMR are reported in the text. Anal. calcd for C13H14NO4I: C=41.62,
H=3.76, N=3.73; found: C=41.61, H=3.76, N=3.74.
3.7. General procedure for nucleophilic displacement using Grignard reagents/CuI
CuI (1.5 mmol) was placed in a ¯ame dried, round-bottomed ¯ask which was ¯ushed with
nitrogen and charged with dry THF (10 ml). The suspension was cooled to 50ꢀC (CO2+ace-
tone) and the Grignard reagent (3 mmol) was added over 10 min. The mixture was stirred at the
same temperature for 1 h then iodo-lactone 6 (0.376 g, 1 mmol) in THF (4 ml) was added dropwise
over 5 min. The mixture was stirred at 50ꢀC for 1.5 h, quenched by adding satd. NH4Cl, stirred
for additional 10 min and extracted with AcOEt (3Â50 ml). The combined extracts were dried
over Na2SO4, ®ltered and concentrated under reduced pressure. The residue was puri®ed by silica
gel chromatography using AcOEt:n-hexane (7:3) as solvent.
3.8. Benzyl (2S,3S)-2-propyl-5-oxotetrahydrofuran-3-ylcarbamate 9
M.p. 97±98ꢀC; [ꢁ]D= 47.1 (c=1.2, CHCl3); 1H NMR ꢀ: 7.35 (5H, s, C6H5), 5.23 (1H, br d, J=8.0
Hz, NH), 5.12 (2H, s, OCH2), 4.67 (1H, tdd, J=8.0, 4.5 and 3.0 Hz, CHN), 4.50 (1H, dt, J=9.0 and
4.5 Hz, CHO), 2.89 (1H, dd, J=17.0 and 8.0 Hz, CHAHBCO), 2.47 (1H, dd, J=17.0 and 3.0 Hz,
CHAHBCO), 1.73±1.35 (4H, m, 2ÂCH2), 0.94 (3H, t, J=7.0 Hz, CH3); 13C NMR ꢀ: 174.75 (s,
COO), 155.79 (s, NCO), 135.99 (s, C6H5), 128.61, 128.38, 128.14 (2Âd, 2Âd, d, C6H5), 83.15 (d, CHO),
67.27 (t, OCH2), 50.64 (d, CHN), 36.85 (t, CH2CO), 31.21 (t, CH2), 18.94 (t, CH2), 13.81 (q, CH3).
Anal. calcd. for C15H19NO4: C=64.97, H=6.91, N=5.05; found: C=65.00, H=6.93, N=5.04.
3.9. Benzyl (2S,3S)-2-tridecyl-5-oxotetrahydrofuran-3-ylcarbamate 10
M.p. 83±84ꢀC; [ꢁ]D= 25 (c=1.7, CHCl3); H NMR ꢀ: 7.35 (5H, s, C6H5), 5.22 (1H, br d,
1
J=8.0 Hz, NH), 5.11 (2H, s, OCH2), 4.57 (1H, m, J=23.0 Hz, CHN), 4.50 (1H, dt, J=8.0 and
4.5 Hz, CHO), 2.89 (1H, dd, J=17.5 and 7.5 Hz, CHAHBCO), 2.47 (1H, dd, J=17.0 and 2.5 Hz,
CHAHBCO), 1.64±1.26 (24H, m, 12ÂCH2), 0.88 (3H, t, J=7.0 Hz, CH3); 13C NMR ꢀ: 174.76 (s,

1146
G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 1137±1149
COO), 155.76 (s, NCO), 135.98 (s, C6H5), 128.58, 128.36, 128.12 (2Âd, 2Âd, d, C6H5), 83.36 (d,
CHO), 67.27 (t, OCH2), 50.61 (d, CHN), 36.88 (t, CH2CO), 31.92, 29.68, 29.64, 29.61, 29.52,
29.38, 29.34, 29.18, 25.57, 22.67 (t, t, 2Ât, t, t, t, 2Ât, t, t, t, 12ÂCH2), 14.10 (t, CH3). Anal. calcd
for C25H39NO4: C=71.91, H=9.41, N=3.35; found: C=71.90, H=9.40, N=3.33.
3.10. Benzyl (2S,3S)-2-isobutyl-5-oxotetrahydrofuran-3-ylcarbamate 11
M.p. 90ꢀC; [ꢁ]D= 59.7 (c=0.72, CHCl3); 1H NMR (CD3COCD3) ꢀ: 7.39±7.29 (5H, s, C6H5),
7.01 (1H, br s, NH), 5.13 (1H, d, J=12 Hz, CHAHBOCO), 5.07 (1H, d, J=12 Hz, CHAHBOCO),
4.69 (1H, dt, J=8.0 and 5.0 Hz, CHO), 4.56 (1H, tdd, J=8.0, 5.0 and 3.0 Hz, CHN), 3.01 (1H,
dd, J=17.0 and 8.0 Hz, CHCHDCO), 2.42 (1H, dd, J=17.0 and 3.0 Hz, CHCHDCO), 1.77 (1H,
m, ÆJ=56 Hz, CH), 1.62 (1H, ddd, J=14.0, 9.0 and 5.0 Hz, CHEHF), 1.43 (1H, ddd, J=14.0,
8.0 and 4.0 Hz, CHEHF), 0.93 (3H, J=6.5, CH3), 0.91 (3H, d, J=6.5 Hz, CH3); 13C NMR ꢀ:
175.59 (s, COO), 155.93 (s, NCO), 136.98 (s, C6H5), 129.19, 128.65, 128.53 (2Âd, 2Âd, d, C6H5),
82.02 (d, CHO), 66.72 (t, OCH2), 51.57 (d, CHN), 38.72 (t, CH2CO), 36.38 (t, CH2), 25.63 (q,
CH3), 23.47 (d, CH), 22.26 (q, CH3). Anal. calcd for C16H21NO4: C=65.96, H=7.27, N=4.81;
found: C=65.98, H=7.28, N=4.80.
3.11. Benzyl (2S,3S)-2-cyclohexylmethyl-5-oxotetrahydrofuran-3-ylcarbamate 12
M.p. 112ꢀC; [ꢁ]D= 46.9 (c=3.1, CHCl3); H NMR ꢀ: 7.35 (5H, s, C6H5), 5.37 (1H, br d,
1
J=8.0 Hz, NH), 5.13 (H, d, J=12 Hz OCHAHB), 5.08 (H, d, J=12.0 Hz OCHAHB), 4.62 (1H,
td, J=7.0 and 4.0 Hz, CHO), 4.54 (1H, tt, J=8.0 and 3.5 Hz, CHN), 2.87 (1H, dd, J=17.0 and
8.0 Hz, CHCHDCO), 2.47 (1H, dd, J=17.0 and 3.0 Hz, CHCHDCO), 1.61, 1.39 (1H each, m,
CH2), 1.41 (1H, m, CH), 1.69, 1.62, 0.86, 0.79 (1H each, m, 2Âa-CH2), 1.54, 1.28 (1H each, m, g-
CH2), 1.65, 1.60, 1.17, 1.09 (1H each, m, 2Âb-CH2); 13C NMR ꢀ: 175.07 (s, COO), 155.82 (s,
NCO), 136.04 (s,C6H5), 128.57, 128.31, 128.08 (2Âd, 2Âd, d, C6H5), 81.25 (d, CHO), 67.16 (t,
OCH2), 50.93 (d, CHN), 36.83 (t, CH2CO), 36.54 (t, CH2), 34.09 (d, CH), 33.90, 32.56 (t each,
2Âa-CH2), 26.33 (t, g-CH2), 26.10, 25.97 (t each, 2Âb-CH2). Anal. calcd for C19H25NO4:
C=68.86, H=7.60, N=4.23; found: C=68.87, H=7.62, N=4.21.
3.12. Benzyl (2S,3S)-2-benzyl-5-oxotetrahydrofuran-3-ylcarbamate 13
M.p.=54±55ꢀC; [a]d= 56.2 (c=0.3, CHCl3); H NMR ꢀ: 7.97±7.33 (10H, m, 2ÂC6H5), 5.52
1
(1H, br d, J=8.0 Hz, NH), 5.10 (1H, d, J=12 Hz, OCHAHB), 5.07 (1H, d, J=12 Hz, OCHAHB),
4.43 (1H, dt, J=8.0 and 3.5 Hz, CHO), 3.97 (1H, m, CHN), 2.97 (1H, dd, J=17.0 and 8.0 Hz,
CHAHBCO), 2.85 (1H dd, J=14.0 and 9.0 Hz, CHCHDC6H5), 2.68 (1H, dd, J=14.0 and 5.0 Hz,
CHCHDC6H5), 2.35 (1H, dd, J=17.0 and 3.0 Hz, CHAHBCO); 13C NMR ꢀ: 175.80 (s, OCO),
155.11 (s, NCO), 137.62, 136.84 (s each, 2ÂC6H5), 128.76, 128.58, 128.28, 128.21, 128.06 (2Âd each,
2ÂC6H5), 82.37 (d, CHO), 67.25 (t, OCH2), 50.72 (d, CHN), 40.78 (t, CH2CO), 32.83 (t, CH2C6H5).
Anal. calcd for C19H19NO4: C=70.14, H=5.89, N=4.30; found: C=70.20, H=5.92, N=4.31.
3.13. (4S)-4-[(1S)-2-Cyclohexyl-1-hydroxyethyl]1,3-oxazinane-2,6-dione 14
To a stirred solution of lactone 12 (0.124 g, 0.38 mmol) in methanol (6 ml) was added solid
KOH (64 mg, 1.14 mmol) and the mixture was stirred at 40ꢀC for 30 min. The solvent was

G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 1137±1149
1147
removed under reduced pressure, the residue was dissolved in H2O, extracted with CH2Cl2 (2Â5
ml) and acidi®ed at pH 4 with acetic acid. The aqueous solution was extracted with CH2Cl2
(3Â20 ml), washed with H2O (10 ml), sat. NaCl (20 ml), H2O (10 ml) and dried over Na2SO4.
Removal of the solvent under reduced pressure a€orded the 1,3-oxazinane-2,6-dione 14 (88 mg,
96%). M.p. 119±120ꢀC; [ꢁ]D= 82 (c=1.4, CHCl3); H NMR ꢀ: 4.32 (1H, p, J=5.0 Hz, CHO),
1
3.81 (1H, dt, J=9.0 and 5.0 Hz, CHN), 2.65 (1H, dd, J=17.0 and 5.0 Hz, CHAHBCO), 2.60 (1H,
dd, J=17.0 and 9.0 Hz, CHAHBCO), 1.62, 1.40 (1H each, m, CH2), 1.68, 1.57, 0.93, 0.84 (1H
each, m, 2Âa-CH2), 1.67, 1.63, 1.22, 1.10 (1H each, m, 2Âb-CH2), 1.42 (1H, m, CH), 1.40, 1.13
(1H each, m, g-CH2); 13C NMR ꢀ: 174.08 (s, OCO), 160.33 (s, NCO), 80.17 (d, CHO), 54.95 (d,
CHN), 42.12 (t, CH2), 39.17 (t, CH2CO), 33.82 (d, CH), 33.69, 32.72 (t, 2Âa-CH2), 26.32 (t, g-
CH2), 26.08, 25.97 (t each, 2Âb-CH2).
MS (CI, CH4) m/z (relative intensity): 242 [MH]+ (100), 198 [MH CO2] (52), 181 [198 NH3]+
(49), 163 [183 H2O]+ (44), 135 [163 CO] (17), 121 [M/2]2+ (72). Anal. calcd for C12H19NO4:
C=59.73, H=7.94, N=5.80; found: C=59.74, H=7.96, N=5.81.
3.14. (4S,5S)-4-Amino-5-(cyclohexylmethyl)-dihydrofuran-2(3H)-one 15
To a well stirred solution of the compound 12 (110 mg, 0.33 mmol) in dry AcOEt (4 ml) was
added 10% Pd/C (15 mg) and the solution was stirred under H2 (1 atm) until the TLC showed no
remaining starting material. The mixture was ®ltered through a short pad of Celite and con-
centrated under reduced pressure to give the amine 15 (64 mg, 98%) as a colourless solid. M.p.
ꢀ
1
39 C; [ꢁ]D= 86.9 (c=1.2, CHCl3); H NMR ꢀ: 4.59 (1H, dt, J=9.5 and 4.0 Hz, CHO), 3.71
(1H, ddd, J=6.0, 4.5 and 2.0 Hz, CHN), 2.80 (1H, dd, J=18.0 and 6.0 Hz, CHAHBCO), 2.34
(1H, dd, J=18.0 and 2.0 Hz, CHAHBCO), 1.63, 1.39 (1H each, m, CH2), 1.46 (1H, m, CH), 1.77,
1.60, 0.95, 0.85 (1H each, m, 2Âa-CH2), 1.45, 1.10 (1H, m, g-CH2), 1.66, 1.63, 1.23, 1.11 (1H
each, m, 2Âb-CH2); 13C NMR ꢀ: 175.96 (s, OCO), 81.90 (d, CHO), 50.90 (d, CHN), 39.57 (t,
CH2CO), 36.27 (t, CH2), 34.34 (d, CH), 33.99, 32.87 (t each, 2Âa-CH2), 26.38 (t, g-CH2), 26.17,
26.06 (t each, 2Âb-CH2). Anal. calcd for C11H19NO2: C=66.97, H=9.71, N=7.10; found:
C=66.96, H=9.71, N=7.11.
3.15. (3S,4S)-3-Amino-4-hydroxy-5-cyclohexyl pentanoic acid 16
A solution of the g-lactone 15 (50 mg, 0.255 mmol) in methanol (5 ml) was taken to pH 9 by
adding 0.1N NaOH solution. The mixture was stirred at this pH by addition of 0.1N NaOH
solution until TLC showed no remaining starting material (approx. 5 h). The mixture was then
acidi®ed to pH 6.5 with 0.1N HCl before removing the methanol. The aqueous solution was
puri®ed by passing through a column of Amberlite XAD-2 resin, eluting ®rst with water, followed
by methanol. Fractions containing the acid were combined and concentrated under reduced pressure
to give 16 (40 mg, 74%) as a colourless solid. M.p. 208±210ꢀC; [ꢁ]D= 51.1 (c=0.45, MeOH);1H
NMR (CD3OD, T=55ꢀC) ꢀ: 3.69 (1H, ddd, J=8.0, 6.0 and 5.0 Hz, CHO), 3.17 (1H, dt, J=9.0
and 5.0 Hz, CHN), 2.45 (1H, dd, J=16.0 and 5.0 Hz, CHAHBCO), 2.36 (1H, dd, J=16.0 and 9.0
Hz, CHAHBCO), 1.85, 1.67, 1.03, 0.91 (1H each, m, 2Âa-CH2), 1.75, 1.70, 1.28, 1.26 (1H each, m,
2Âb-CH2), 1.69, 1.35 (1H each, m, CH2), 1.54 (1H, m, CH), 1.34, 1.20 (1H each, m, g-CH2);
13CNMR ꢀ: 168.54 (s, COOH), 70.06 (d, CHO), 56.56 (d, CHN), 43.02 (t, CH2CO), 37.82 (t, CH2),
35.97, 34.01 (t each, 2Âa-CH2), 35.55 (d, CH), 28.13 (t, g-CH2), 27.92, 27.67 (t each, 2Âb-CH2).
Anal. calcd for C11H21NO3: C=61.37, H=9.83, N=6.51; found: C=61.36, H=9.81, N=6.50.

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G. Delle Monache et al. / Tetrahedron: Asymmetry 11 (2000) 1137±1149
Acknowledgements
This work was supported by MURST (Ministero dell'Universita e della Ricerca Scienti®ca,
Italy) and by CNR (Consiglio Nazionale delle Ricerche, Italy). The authors are greatly indebted
to Dr. Luciana Turchetto of the Istituto Superiore di Sanita for the mass spectra.
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