A straightforward synthesis of both enantiomers of allo-norcoronamic acids and allo-coronamic acids, by asymmetric Strecker reaction from alkylcyclopropanone acetals

Article abstract of DOI:10.1016/S0957-4166(97)00633-2

Methylcyclopropanone hemiacetal (2S)-3a underwent the asymmetric Strecker reaction induced by a chiral amine to provide a useful synthesis of enantiomerically pure (1R,2S)-(+)-allo-norcoronamic acid 1 in good yield and high enantiomeric excess. From racem

Full text of DOI:10.1016/S0957-4166(97)00633-2

Pergamon
Tetrahedron: Asymmetry 9 (1998) 305–320
A straightforward synthesis of both enantiomers of
allo-norcoronamic acids and allo-coronamic acids, by
asymmetric Strecker reaction from alkylcyclopropanone acetals†
Antoine Fadel ∗ and Aballache Khesrani
Laboratoire des Carbocycles (Associé au CNRS), Institut de Chimie Moléculaire d’Orsay, Bât. 420, Université de Paris-Sud,
91405 Orsay, France
Received 14 November 1997; accepted 15 December 1997
Abstract
Methylcyclopropanone hemiacetal (2S)-3a underwent the asymmetric Strecker reaction induced by a chiral
amine to provide a useful synthesis of enantiomerically pure (1R,2S)-(+)-allo-norcoronamic acid 1 in good yield
and high enantiomeric excess. From racemic alkyl hemiacetal (ꢀ)-3, the same methodology also constituted a
useful way to prepare both (+)-1 and (−)-1 and (+)-allo-coronamic acid 2 and its antipode (−)-2 with good yield
and high enantiomeric excess. © 1998 Elsevier Science Ltd. All rights reserved.
The preparation of derivatives of 1-aminocyclopropanecarboxylic acid (ACC) has been the subject of
numerous synthetic efforts in recent years. This interest stems from their diverse documented biological
activities,1 and potential use in conformationally restricted peptides.2 The allo-norcoronamic acid 1 is a
substrate and the strongest known competitive inhibitor of the ethylene-forming enzyme (EFE) in mung
bean hypocotyls.3a Another cyclopropylamino acid ‘allo-coronamic acid 2’ is converted into 1-butene
by plant tissues and promises the control of enzymatic processes for plant growth and fruit ripening.3
Most of the reported pure enantiomers of cyclopropaneamino acids especially for allo-norcoronamic
acids 14 and allo-coronamic acids 25 have been produced by resolution of racemic mixtures, or by
asymmetric synthesis. Many of the starting materials used in these processes are not readily available or
are quite expensive. Furthermore, several of these syntheses suffer from low yield, unresolved mixture,
and moderate enantiomeric excess.
We have recently reported a simple and convenient synthesis of 1-aminocyclopropanecarboxylic
acid (ACC) from 1-methoxycyclopropanol 3 (R=H), which underwent a one-pot Strecker reaction in
good overall yield.6 The same methodology was also adopted to prepare (S) and (R)-1-amino-2,2-
∗
†
Corresponding author. Fax: +33(1)69156278; e-mail: antfadel@icmo.u-psud.fr
Dedicated to Professor Dr. Dieter Seebach in honour of the occasion of his 60th birthday.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(97)00633-2

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dimethylcyclopropanecarboxylic acids (methanovalines), using an asymmetric Strecker7 reaction from
dimethylcyclopropanone hemiacetal.8
This strategy appeared to be a promising approach for asymmetric synthesis of allo-norcoronamic
acids 1 and allo-coronamic acids 2. These are provided from a chiral or racemic alkylcyclopropanone
hemiacetal 3a,b by a Strecker reaction induced by a chiral amine leading to the nitrile 5 via iminium 4.
1. Synthesis of (1R,2S)-allo-norcoronamic acid 1 from chiral hemiacetal 3a
Acetal 3a was obtained in three steps from commercially available (S)-methyl 3-hydroxy-2-
methylpropionate 6a. The corresponding bromide (+)-6b, obtained by reaction with Ph3P/CBr4,9
underwent a sodium induced cyclisation, in the presence of Me3SiCl and sonication at room
temperature, to lead to the desired acetal 7a. Simple methanolysis of the latter afforded the hemiacetal
3a with 85% yield.10
The mixture of cyclopropanone hemiacetal (2S)-3a, NaCN and a chiral amine underwent a Strecker
reaction to form, under various conditions, the aminonitriles 8 and 9. Our results are reported in Table 1.
At 55°C in MeOH in the presence of (S)-phenylethylamine 10 or (R)-11,11a the hemiacetal (S)-3a
gave the aminonitrile in 82% yield as a mixture of diastereoisomers 8a:9a in 88:12 and 90:10 ratios,
respectively (entries 1 and 3). On the other hand, reaction with amine (R)-10 did not modify the selectivity
(entry 2). In the presence of the non-aryl amine 12,11b the major product (54%) was the amide 12d,
formed by ring opening of the hydroxy amine intermediate (entry 4). Other conditions such as utilisation
of the chlorohydrate of the amine 10 in the presence of silica gel8 or under sonication conditions did not
improve the yield nor the diastereoselectivity.
After separation, the α-aminocyanocyclopropanes 8a,b were hydrolysed in the presence of concen-
trated H2SO4 in CH2Cl2 at 0°C to rt for 10 h, to afford the amides (1R,2S)-13a,b in 81–84% yield.
Hydrolysis of the cyanocyclopropane 8c under the same conditions, gave a mixture of the desired amide
13c (68%), and the azalactone 14 (24% yield).

A. Fadel, A. Khesrani / Tetrahedron: Asymmetry 9 (1998) 305–320
307
Table 1
Asymmetric Strecker reaction from chiral hemiacetal (2S)-3
Subsequent hydrogenolysis of the amides 13a–c in the presence of a catalytic amount of 20% Pd(OH)2
on activated carbon (w/w, 20%) in AcOH under hydrogen (1 atm, 10 h) gave after chromatography the
amino amide 15 in 90% yield ([α]D20=+95 (c=0.6, CHCl3)). The enantiomeric excesses of 15 from
13a–c, determined from chiral GC (cydex B, 105°C, 1 bar), were over 97%.
The usual hydrolysis of amide 15 with 6 N HCl at reflux (3 h) led, after treatment with ion-exchange
resin (activated Dowex 50 WX.8.100), to (1R,2S)-1-amino-2-methylcyclopropanecarboxylic acid 1 ((+)-
allo-norcoronamic acid) in 85% yield ([α]D20=+76 (c=0.97, H2O), lit.3a ([α]D20=+75.5 (c=0.24, H2O)).
On the other hand, the hydrogenolysis (H2, Pd(OH)2/C) of lactone 14 followed by hydrolysis (6 N
HCl) then treatment on Dowex H+, gave the same amino acid 1 in 77% yield.
The specific rotation of (+)-1 was in agreement with the values previously reported,3a and confirmed
the structure (1R,2S) of (+)-1. Its enantiomeric excess, determined by 19F NMR analysis of the corre-
sponding Mosher amide,12 was found to be >97% ee in agreement with the value given above (GC,
Cydex B, 105°C, 1 bar) of the corresponding amide 15.
This stereochemistry showed that the nucleophilic attack of the cyanide anion on the iminium
intermediate 4a, took place from the less hindered face (si-face) opposite the methyl group on the
cyclopropane with a relative like approach,13 to give 8a as the major product. Modification of the
configuration of the amine did not affect this induction as shown in Table 1 (entries 1 and 2).

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Table 2
Asymmetric Strecker reaction from racemic hemiacetal (ꢀ)-3
2. Synthesis of amino acid 1 and 2 from racemic hemiacetal 3
The successful synthesis of allo-norcoronamic acid (+)-1 from the hemiacetal (2S)-3a described above,
prompts us to adopt the same methodology, starting from the inexpensive and readily available racemic
hemiacetal (ꢀ)-3.
Effectively, the β-chloroesters 16a,b, readily available from the corresponding α,β-unsaturated acids
17a,b,14 gave, by sodium induced cyclisation in the presence of Me3SiCl under sonication10 followed by
methanolysis, the corresponding racemic hemiacetals (ꢀ)-3 in 86% yield.
The mixture of cyclopropanone acetal (ꢀ)-3, NaCN and a chiral amine underwent a Strecker reaction
to form, via the iminium intermediates, the aminocyanocyclopropanes 18 and 19 as a mixture of
diastereoisomers in 78–82% yield (see Table 2).
The major products (1R,2S)-18 and (1S,2R)-19 were obtained in 47% and 38–42% ratios respectively.
From the nucleophilic attack of cyanide on the iminium intermediates 4S and 4R (obtained from (ꢀ)-3),
we could expect one main diastereoisomer (path a or d in Scheme 1) on the four possible isomers.15
However, the results obtained in Table 2 show that there is no large difference of cyanide attack on
the iminium intermediates 4S and 4R (see paths a and d). Moreover, the diastereoselectivities of each
intermediate are roughly the same (compare 18 or 19 in Table 2, entries 1–3).
Scheme 1.
The major aminonitriles 18a–c and 19a–c were easily isolated by flash chromatography in enantiomer-
ically and diastereoisomerically pure forms.

A. Fadel, A. Khesrani / Tetrahedron: Asymmetry 9 (1998) 305–320
309
The major nitriles (1R,2S)-18a,b (R=Me), as the precedent nitriles 8a,c, were transformed into amides
20, by reaction with H2SO4. After hydrogenolysis into 15, then hydrolysis, we obtained the allo-
norcoronamic acid (1R,2S)-1 with ee >97% as measured by chiral GC.
Similarly, the aminonitrile (−)-19a was transformed via the corresponding amides (+)-21 then (−)-
15 (ee >96%, from GC Cydex B), into allo-norcoronamic acid (1S,2R)-(−)-1 (70% overall yield),
([α]D20=−72 (c=0.7, H2O), lit.4f ([α]D20=−74 (c=0.3, H2O)). Its enantiomeric excess, confirmed by
19F NMR analysis of the corresponding Mosher amide,12 was found to be 96% in agreement with the
value given above by gas chromatography.
2.1. Syntheses of (+)- and (−)-allo-coronamic acid 2
The major nitrile 18c, separated and hydrolysed (H2SO4, CH2Cl2), gave the corresponding amide 22
(70%), as a mixture with the lactone 23 (20%). Similarly, the major nitrile 19c reacted with sulphuric
acid to give a mixture of the amide 24 (68%), with the lactone 25 (20%).
Subsequent hydrogenolysis of (1R,2S)-22 and (1S,2R)-24 gave the free amines (1R,2S)-26 and (1S,2R)-
26 respectively in 85% yield. Their enantiomeric excesses, determined by chiral GC (Cydex B, 110°C,
0.8 bar) were >97% and 96% respectively.
Finally, acidic hydrolysis and treatment over Dowex, H+, of (+)-26 and (−)-26 separately, furnished
the (1R,2S)-(+)-allo-coronamic acid 2 and its antipode (1S,2R)-216 in 92% and 90% yields, respectively,
([α]D20=+67.2 (c=0.6, H2O) for the (1R,2S)-2, lit.4a [α]D20=+65 (c=1.3, H2O) lit.5g [α]D20=+67.3
(c=1.52, H2O). Their enantiomeric excesses, determined by 19F NMR analysis of the corresponding
Mosher amides,12 were found to be >97% for (+)-2 and 96% for (−)-2. Moreover, the hydrolysis of 23

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and 25 followed by hydrogenolysis and treatment on Dowex, H+, gave separately the amino acid (+)-2
and (−)-2 respectively.
In conclusion, methylcyclopropanone hemiacetal (2S)-3a10 underwent the asymmetric Strecker re-
action induced by a chiral amine and provided a useful synthesis of enantiomerically pure (1R,2S)-
(+)-allo-norcoronamic acid 1 in good yield and high enantiomeric excess. Furthermore, from racemic
alkyl hemiacetal (ꢀ)-3 the same methodology17 also constituted a useful way to prepare both (+)-1
and (−)-1 (R=CH3) and (+)-allo-coronamic acid 2 and its antipode (−)-2 (R=Et) with good yield and
high enantiomeric excess. The synthesis of other cyclic amino acids, e.g., optically active substituted
derivatives of ACC, and the improvement of the diastereoselective Strecker reaction, are currently under
investigation.
3. Experimental section
All reactions were monitored by thin layer chromatography (TLC) using 0.25 mm E. Merck precoated
silica gel plates. Flash chromatography was performed with silica gel 60 (particle size 0.040–0.063 mm).
Proton and carbon-13 NMR spectra were recorded on a Bruker AM250 spectrometer in deuteriochloro-
form or deuterium oxide using the solvent signal as an internal standard, 7.27 and 4.80 ppm respectively.
Chemical shifts (δ) are expressed in parts per million and the coupling constants (J) are given in hertz.
IR spectra we recorded on a Perkin–Elmer 682 spectrophotometer. Melting points were determined on
a Mettler FP51 capillary melting point apparatus and are uncorrected. Specific rotations were obtained
at 20°C using a Perkin–Elmer 341 polarimeter. Enantiomeric excesses were performed on a GC (Fisons
9130) chiral column Cydex B (SGE) (25 m, 110°C, 0.8 bar).
3.1. (2S)-1-Methoxy-2-methyl-1-trimethylsiloxycyclopropane 7a
This procedure has been described previously.10 To 2.87 g of Na (125 mmol), cut into small cubic
pieces (5 mm) in 45 mL of ether was added successively at 0°C, 17.75 mL (15.19 g, 140 mmol) of
ClSiMe3 and (dropwise) a solution of 9.05 g (50 mmol) of β-bromoester 6b9 in 10 mL of ether. The
reaction flask kept under argon was immersed in an ultrasonic cleaning bath.18 The reaction was complete
within 4 h as shown by GC. The mixture was filtered on Celite, and washed with ether (20 mL). The
solvent was removed by distillation (T<67°C) and the residue distilled at 50–55°C (20 mmHg) to yield
1
7.3 g of chiral acetal 7a (84%) in a 6:4 diastereoisomeric mixture (cis:trans). H NMR (CDCl3) δ: (6:4
mixture of cis:trans): 3.35/3.40 (s, 3H), 1.20–0.84 (m, 2H), 1.06 (m, 3H), 0.50–0.30 (m, 1H), 0.21/0.19
(s, 9H).
3.2. (1R,2S,10S)-2-Methyl-1-[(10-methylbenzyl)amino]cyclopropanecarbonitrile 8a
To a solution of 870 mg (5 mmol) of chiral acetal 7a in 4 mL of MeOH was added one drop of
TMSCl. After 5 min of stirring (formation of (2S)-3a), were added successively, 1.1 g (10 mmol) of
(S)-methylbenzylamine 10, 1.2 mL (4 equiv.) of AcOH, 10 mL of MeOH and 500 mg (10 mmol) of
NaCN. The reaction mixture was stirred and heated at 55°C for 3.5 days. The reaction evolution was
followed by thin layer chromatography (TLC). The reaction mixture was concentrated, then eluted with
ether (100 mL) and stirred in the presence of 300 mg of K2CO3 for 10 min. After filtration over Celite
and concentration, 1.4 g of crude nitriles 8a and 9a were obtained as two diastereoisomers in 88:12 ratio.

A. Fadel, A. Khesrani / Tetrahedron: Asymmetry 9 (1998) 305–320
311
Purification by flash chromatography (35 g of SiO2, elution with ether:petroleum ether=10:90) afforded
720 mg (72% yield, 98% ee) of nitrile (1R,2S)-8a and 100 mg (10% yield) of isomer (1S,2S)-9a.
Data for (1R,2S)-8a: Rf=0.7 (EtOAc:petroleum ether=3:7); [α]D20=−60 (c=1.1, CHCl3); IR (neat) ν
1
(cm−1): 3334, 2240 (νCN); H NMR (CDCl3) δ: 7.42–7.20 (m, 5H), 4.20 (q, J=6.7 Hz, 1H), 1.84 (s,
NH), 1.45 (d, J=6.7 Hz, 3H), 1.50–1.20 (m, 2H), 0.96 (d, J=6.3 Hz, 3H), 0.75 (dd, J=4.2 and 6.3 Hz, 1H);
13C NMR (CDCl3) δ: [6 arom. C: 144.4 (s), 128.4 (2d), 127.5 (d), 127.1 (2d)], 122.2 (s, CN), 56.8 (d),
30.1 (s, C1), 23.2 (d, C2), 22.7 (q), 22.1 (t, C3), 11.7 (q); MS (EI) (rel. int.): 200 (M+, 2.2), 106 (12), 105
(100), 79 (10), 77 (15). Anal. calcd for C13H16N2: C, 77.96; H, 8.05; N, 13.99. Found: C, 77.72; H, 8.22;
N, 14.09.
Data for (1S,2S,10S)-2-Methyl-1-[(10-methylbenzyl)amino]cyclopropanecarbonitrile 9a: Rf=0.63
(EtOAc:petroleum ether=3:7); [α]D20=−99 (c=1, CHCl3); H NMR (CDCl3) δ: 7.40–7.20 (m, 5H),
1
4.20 (q, J=6.7 Hz, 1H), 2.25 (br, s, NH), 1.38 (d, J=6.7 Hz, 3H), 1.50–1.20 (m, 1Hcycle and 3H), 0.90
(dd, J=5.2 and 8.4 Hz, 1H), 0.69 (dd, J=6.3 and 5.2 Hz, 1H).
3.3. (1R,2S,10S)-2-Methyl-1-[(10-methylbenzyl)amino]cyclopropanecarbonitrile 8b
Following the procedure given above: 870 mg (5 mmol) of chiral acetal 7a, 1.1 g (10 mmol) of (R)-
methylbenzylamine 10, 1.2 mL (4 equiv.) of AcOH, 10 mL of MeOH and 500 mg (10 mmol) of NaCN,
gave after heating at 50–55°C for 3 days and the usual work-up 1.1 g of crude nitriles as a mixture of 8b
and 9b in an 87:13 ratio. Purification by flash chromatography afforded 710 mg (71%) of (1R,2S)-8b as
the major nitrile and 90 mg (9%) of (1S,2S)-9b.
Data for (1R,2S)-8b major: Rf=0.7 (EtOAc:petroleum ether=1:3); [α]D20=+168 (c=1, CHCl3); IR
1
(neat) ν (cm−1): 3600, 3330, 2225; H NMR (CDCl3) δ: 7.40–7.20 (m, 5H), 4.19 (q, J=6.7 Hz, 1H),
1.90 (br, s, NH), 1.39 (d, J=6.7 Hz, 3H), 1.45–1.25 (m, 1Hcycle), 1.21 (d, J=6.8 Hz, 3H), 1.05 (dd, J=5.3
and 9.4 Hz, 1Hcycle), 0.29 (dd, J=5.3 and 6.8 Hz, 1Hcycle); 13C NMR (CDCl3) δ: [6 arom. C: 144.4 (s),
128.1 (2d), 127.1 (d), 126.9 (2d)], 122.0 (s, CN), 56.4 (d), 30.1 (s, C1), 23.5 (d, C2), 21.7 (q), 21.5 (t,
C3), 11.7 (q); MS (EI) (rel. int.): 201 (M++1, 1.3), 200 (M+, 6.5), 171 (5), 106 (10), 105 (100), 79 (18),
77 (21); HRMS calcd for C13H16N2: 200.1313. Found: 200.1308.
Data for (1R,2S)-9b minor: Rf=0.63 (EtOAc:petroleum ether=1:3); IR (neat) ν (cm−1): 3600, 3330,
1
2225; H NMR (CDCl3) δ: 7.45–7.20 (m, 5H), 4.20 (q, J=6.7 Hz, 1H), 2.30 (br, s, NH), 1.40 (d, J=6.7
Hz, 3H), 1.27 (dd, J=8.4 and 6.3 Hz, 1Hcycle), 1.15 (dd, J=5.1 and 8.4 Hz, 1Hcycle), 1.00–0.63 (m, 1Hcycle),
0.84 (d, J=6.3 Hz, 3H).
3.4. (1R,2S,10R)-1-[(10-Methoxymethylbenzyl)amino]-2-methylcyclopropanecarbonitrile 8c
Following the procedure given above: 870 mg (5 mmol) of chiral acetal 7a, 980 mg (6.5 mmol, 1.3
equiv.) of (R)-methoxymethylbenzylamine 11, 1.2 mL (4 equiv.) of AcOH, 10 mL of MeOH and 500 mg
(10 mmol) of NaCN gave, after heating at 50–55°C for 36 h and the usual workup, 1.2 g of crude nitriles
as a mixture of 8c and 9c in a 90:10 ratio. Purification by flash chromatography as above afforded 815
mg (71%) of (1R,2S)-8c as the major nitrile and 80 mg (7%) of (1S,2S)-9c.
Data for (1R,2S)-8c major: Rf=0.56 (EtOAc:petroleum ether=1:3); [α]D20=−106.5 (c=1, CHCl3); IR
(neat) ν (cm−1): 3600, 3330, 2225; 1H NMR (CDCl3) δ: 7.45–7.20 (m, 5H), 4.23 (dd, J=8.6 and 4.5 Hz,
1H), 3.72–3.45 (m, 2H), 3.41 (s, 3H), 2.64 (br, s, NH), 1.38 (dd, J=9.5 and 4.7 Hz, 1Hcycle), 1.34–1.10
(m, 2Hcycle), 0.66 (d, J=6.2 Hz, 3H); 13C NMR (CDCl3) δ: [6 arom. C: 139.3 (s), 128.4 (2d), 128.2 (2d),
127.9 (d)], 122.1 (s, CN), 75.6 (q), 60.5 (d), 58.6 (t), 30.9 (s, C1), 23.4 (d, C2), 21.5 (t, C3), 11.9 (q); MS

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(EI) (rel. int.): 230 (M+, 0.7), 185 (53), 135 (17), 105 (22), 104 (27), 103 (72), 92 (10), 91 (100), 78 (11),
77 (30). Anal. calcd for C14H18N2O: C, 73.01; H, 7.88; N, 12.16. Found: C, 72.84; H, 7.88; N, 12.01.
Data for (1R,2S)-9c minor: Rf=0.51 (EtOAc:petroleum ether=1:3); IR (neat) ν (cm−1): 3600, 3330,
2225; 1H NMR (CDCl3) δ: 7.45–7.20 (m, 5H), 4.33 (dd, J=8.7 and 4.4 Hz, 1H), 3.60–3.40 (m, 2H), 3.42
(s, 3H), 2.89 (br, s, NH), 1.40–1.05 (m, 1Hcycle), 1.22 (d, J=6.3 Hz, 3H), 0.73 (dd, J=8.2 and 5.5 Hz,
1Hcycle), 0.52 (dd, J=5.5 and 6.8 Hz, 1Hcycle); MS (EI) (rel. int.): 231 (M++1, 0.5), 230 (M+, 1), 186 (19),
185 (100), 135 (11), 105 (10), 104 (14), 103 (35), 91 (62), 77 (26).
3.5. (1R,2S,20R,30S)-1-[(20-Hydroxybornan-30 -yl)amino-2-methylcyclopropanecarbonitrile 8d
Following the procedure given above: 175 mg (1 mmol) of chiral acetal 7a, 225 mg (1.3 mmol) of
amine 12, 0.25 mL of AcOH, 3 mL of MeOH and 100 mg (2 mmol) of NaCN, gave after heating at
50–55°C for 48 h and the usual workup, 300 mg of crude residue. Purification by flash chromatography
afforded 22 mg (9%) of (1R,2S)-8d and 130 mg (54%) of opening ring amide 12d as a major product.
Data for aminonitrile 8d: Rf=0.67 (EtOAc:petroleum ether=3:7); IR (neat) ν (cm−1): 3600, 3440,
3340, 2230; 1H NMR (CDCl3) δ: 3.60 (m, 1H), 3.00 (m, 1H), 2.07 (br, s, NH), 1.95 (m, 1H), 1.37–1.15
(m, 1H), 1.58–1.33 (m, 3H), 1.25 (m, 1Hcycle), 1.17 (d, J=6.3 Hz, 3H), 1.18–1.00 (m, 1Hcycle), 1.05–0.80
(m, OH), 1.04 (s, 3H), 0.95 (s, 3H), 0.82 (s, 3H), 0.80 (m, 1Hcycle).
Data for amine 12d: Rf=0.4 (EtOAc:petroleum ether=3:7); IR (neat) ν (cm−1): 3600, 3320, 1670; 1H
NMR (CDCl3) δ: 6.50 (m, Hamide), 4.20 (d, J=8.5 Hz, 1H), 3.93 (d, J=8.5 Hz, 1H), 2.44 (sept., J=6.8 Hz,
1H), 2.04 (m, 1H), 1.80–1.57 (m, 2H), 1.57–1.35 (m, 1H), 1.35–1.15 (m, 1H), 1.30–1.00 (m, OH), 1.15
(d, J=6.8 Hz, 6H), 1.03 (s, 3H), 0.91 (s, 3H), 0.84 (s, 3H); 13C NMR (CDCl3) δ: 172.8 (s), 91.2 (d), 75.6
(d), 48.4 (d), 48.3 (s), 46.8 (s), 32.1 (d), 28.3 (t), 25.9 (t), 23.4 (q), 19.0 (q), 18.95 (q), 18.7 (q), 11.2 (q).
3.6. (1R,2S,10S)-2-Methyl-1-[(10-methylbenzyl)amino]cyclopropanecarboxamide 13a
A solution of nitrile (1R,2S)-8a (600 mg, 3 mmol) in CH2Cl2 (12 mL) was cooled to 0°C and
concentrated sulphuric acid (5 mL) was added very slowly with efficient stirring. The reaction mixture
was allowed to warm to room temperature and stirred for 5 h. The aqueous layer was separated, washed
with CH2Cl2 (2 mL), then poured onto crushed ice (10 g), and was slowly basified with conc. NH4OH.
The mixture extracted with EtOAc (4×50 mL), dried over MgSO4 and concentrated to give, after flash
chromatography (SiO2, 30 g, eluent EtOAc:petroleum ether=4:6 to 100%), the title amide (1R,2S)-13a
(535 mg, 82%).
Data for (1R,2S)-13a: Rf=0.45 (EtOAc); [α]D20=−63.7 (c=1, CHCl3); IR (neat) ν (cm−1): 3470, 3330,
1675 (νamide); 1H NMR (CDCl3) δ: 7.42–7.20 (m, 5H), 7.14 (br, s, 1Hamide), 5.12 (br, s, 1Hamide), 3.75
(q, J=6.7 Hz, 1H), 1.69–1.48 (m, 2H), 1.38 (d, J=6.7 Hz, 3H), 1.15 (d, J=6.3 Hz, 3H), 0.77 (m, 1H); 13
C
NMR (CDCl3) δ: 178.6 (s), [6 arom. C: 144.95 (s), 128.5 (2d), 127.1 (d), 126.7 (2d)], 56.8 (d), 43.5 (s,
C1), 24.0 (q), 23.2 (d, C2), 20.6 (t, C3), 13.0 (q); MS (EI) (rel. int.): 218 (M+, 0.4), 113 (71), 106 (11),
105 (100), 104 (12), 103 (18), 96 (22), 91 (11), 79 (23), 77 (27), 68 (15); HRMS calcd for C13H18N2O:
218.1419. Found: 218.1415.
3.7. (1R,2S,10R)-2-Methyl-1-[(10-methylbenzyl)amino]cyclopropanecarboxamide 13b
Following the procedure given above: nitrile (1R,2S,10R)-8b (600 mg, 3 mmol), 12 mL of CH2Cl2 and
5 mL of conc. H2SO4, gave after chromatography 530 mg (81%) of amide (1R,2S)-13b.

A. Fadel, A. Khesrani / Tetrahedron: Asymmetry 9 (1998) 305–320
313
Data for 13b: Rf=0.51 (EtOAc); [α]D20=−5 (c=1, CHCl3); IR (neat) ν (cm−1): 3460, 3330, 1675; 1H
NMR (CDCl3) δ: 7.75 (br, s, Hamide), 7.46–7.20 (m, 5H), 3.67 (q, J=6.7 Hz, 1H), 1.78–1.49 (m, 2Hcycle),
1.35 (d, J=6.7 Hz, 3H), 1.04 (d, J=6.3 Hz, 3H), 0.69 (dd, J=5.3 and 4.1 Hz, 1Hcycle); 13C NMR (CDCl3)
δ: 179.7 (s), [6 arom. C: 145.2 (s), 128.4 (2d), 127.2 (d), 126.5 (2d)], 56.6 (s, C1), 23.4 (d, C2), 22.4 (t,
C3), 18.6 (q), 12.9 (q); MS (EI) (rel. int.): 219 (M++1, 0.5), 218 (M+, 0.7), 173 (11), 113 (64), 106 (10),
105 (100), 104 (11), 103 (17), 96 (19), 91 (10), 79 (22), 77 (27), 68 (16); HRMS calcd for C13H18N2O:
218.1419. Found: 218.1416.
3.8. (1R,2S,10R)-1-[(10-Methoxymethylbenzyl)amino]-2-methylcyclopropanecarboxamide 13c
Following the procedure given above: 690 mg (3 mmol) of nitrile (1S,2R)-8c, 12 mL of CH2Cl2 and
5 mL of conc. H2SO4, gave after chromatography 520 mg (70%) of amide 13c, and 140 mg (22%) of
lactone 14.
Data for amide (1R,2S)-13c major: Rf=0.34 (EtOAc); [α]D20=−100 (c=0.6, CHCl3); H NMR
1
(CDCl3) δ: 7.45–7.10 (m, 5H), 5.35 (br, s, Hamide), 3.82 (dd, J=9 and 4.5 Hz, 1H), 3.60–3.37 (m, 2H),
3.38 (s, 3H), 2.63 (br, s, 1H), 1.65–1.43 (m, 2Hcycle), 1.14 (d, J=6 Hz, 3H), 0.75 (dd, J=4.5 and 6 Hz,
1Hcycle); HRMS calcd for C14H20N2O2: 248.1524. Found: 248.1529.
Data for lactone (1R,2S)-14 minor: Rf=0.76 (EtOAc); [α]D20=−23.7 (c=0.6, CHCl3); IR (neat) ν
1
(cm−1): 3600, 3330, 1730; H NMR (CDCl3) δ: 7.50–7.15 (m, 5H), 4.74 (dd, J=11.3 and 4 Hz, 1H),
4.49 (dd, J=11.3 and 11.3 Hz, 1H), 4.21 (dd, J=11.3 and 4.0 Hz, 1H), 2.00 (br, s, NH), 1.80 (dd, J=9.6
and 4.6 Hz, 1Hcycle), 1.74–1.47 (m, 1Hcycle), 1.24 (d, J=6.0 Hz, 3H), 0.71 (dd, J=7.2 and 4.6 Hz, 1Hcycle);
13C NMR (CDCl3) δ: 172.4 (s), [6 arom. C: 137.4 (s), 128.8 (2d), 128.3 (d), 126.3 (2d)], 75.1 (t), 55.5
(d), 41.0 (s, C1), 26.5 (d, C2), 23.6 (t, C3), 11.5 (q); MS (EI) (rel. int.): 218 (M++1, 2), 217 (M+, 8),
105 (11), 104 (100), 103 (12), 91 (11), 78 (15), 77 (14); HRMS calcd for C13H15NO2: 217.1102. Found:
217.1099.
3.9. (1R,2S)-1-Amino-2-methylcyclopropanecarboxamide 15
A solution of amide (1R,2S)-13a (525 mg, 2 mmol) in glacial acetic acid (8 mL) was hydrogenated
in the presence of 20% palladium hydroxide on activated charcoal as catalyst (100 mg, w/w: 20%) at
room temperature under hydrogen (1 atm) for 16 h (as shown by TLC). After purging with argon, the
resulting mixture was filtered over Celite and washed with MeOH (15 mL). The combined washings were
concentrated and the crude product was dissolved in CHCl3 (20 mL), basified with aqueous NaHCO3
solution to pH=9 and extracted with CHCl3 (3×20 mL). The organic layer was dried, concentrated, and
the residue purified by chromatography (MeOH:CH2Cl2=1:4) to afford the title free amine (1R,2S)-15
(210 mg, 91% yield).
N.B. The amide 13b under the same conditions gave the same amine 15 in the same yield.
Data for (1R,2S)-15: Rf=0.54 (MeOH:CH2Cl2=1:4); RT (1R,2S)=19.19 min (chiral Cydex B, 105°C,
1 bar); [α]D20=+95 (c=0.6, CHCl3); IR (neat) ν (cm−1): 3460, 3340, 1670 (νamide); 1H NMR (CDCl3)
δ: 7.63 (br, s, 1Hamide), 6.13 (br, s, 1Hamide), 2.88 (br, s, 2Hamide), 1.80–1.55 (m, 2H), 1.18 (d, J=6.3 Hz,
3H), 0.41 (dd, J=5.8 and 3.3 Hz, 1H); 13C NMR (CDCl3) δ: 179.2 (s), 38.5 (s), 26.3 (d), 21.4 (t), 12.9
(q); MS (EI) (rel. int.): 115 (M++1, 1), 114 (M+, 8.7), 99 (10), 97 (22), 82 (20), 70 (27), 69 (100), 68 (26),
54 (40), 44 (25), 43 (24), 42 (30), 41 (29); HRMS calcd for C5H10N2O: 114.0793. Found: 114.0796.

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3.10. (1R,2S)-1-Amino-2-methylcyclopropanecarboxamide 15 from 13c
Following the same procedure developed above: from 248 mg (1 mmol) of amide (1R,2S)-13c, AcOH
(5 mL), 20% Pd(OH)2/C 50 mg, we obtained after flash chromatography 105 mg (92%) of free amine
(1R,2S)-15. [α]D20=+92 (c=0.8, CHCl3).
The spectral data are identical with those reported above for the (1R,2S)-15 and the enantiomeric
excess was >97% ee as shown by chiral GC (RT (1R,2S)=19.19 min and 17.51 min for antipode; Cydex
B, 25 m, 105°C, 1 bar).
3.11. (1R,2S)-1-Amino-2-methylcyclopropanecarboxylic acid 1 (allo-norcoronamic acid 1)
A mixture of (1R,2S)-amide 15 (114 mg, 1 mmol) and 6 N HCl (6 mL) was gently heated to
reflux. The reaction was complete within 10 h as shown by TLC. The solution reaction was cooled
to room temperature, and extracted with ether (5 mL) to remove coloured ether-soluble material. The
hydrochloric acid was evaporated to dryness under reduced pressure to give 150 mg of 1·HCl as a
white solid. Recrystallisation from MeOH–Et2O furnished pure crystalline (1R,2S)-allo-norcoronamic
acid hydrochloride 1·HCl (140 mg, 92%).
Data for 1·HCl: m.p. 215°C decomposition; [α]D20=+53 (c=1, H2O); H NMR (D2O; HOD, 4.80
1
ppm) δ: 1.95–1.72 (m, 1H), 1.65 (dd, J=9.6 and 6.1 Hz, 1H), 1.20 (d, J=6.3 Hz, 3H), 1.07 (dd, J=7.2 and
6.1 Hz, 1H); 13C NMR (D2O)19 δ: 173.3 (s), 38.1 (s), 20.6 (d), 20.3 (t), 11.3 (q); [lit.4f for (1S,2R) 13
NMR (75.5 MHz, D2O) δ: 175.8, 40.6, 23.1, 22.8, 13.7].
C
The amino acid hydrochloride (1R,2S)-1·HCl (140 mg) was diluted with distilled water (10 mL) and
+
applied to a Dowex 50WX.8.100 ion-exchange (10 g) column in the activated form (NH4 ). The column
was washed with distilled water until neutral, and then the free amino acid was eluted with 1.3 N aq. NH3
(120 mL). The eluant was concentrated under vacuum. Complete removal of NH3 was accomplished by
redissolving the substance in H2O and concentrating in a rotary evaporator. Finally, drying for 2 h (20°C,
0.02 mmHg) provided pure crystalline (1R,2S)-allo-norcoronamic acid 1 (105 mg, quantitative yield).
Data for 1: m.p. 212°C (dec) [lit.4d m.p. 215°C (dec) for its antipode]; [α]D20=+76 (c=1, H2O), lit.3a
[α]D20=+75.5 (c=0.24, H2O); H NMR (D2O; HOD, 4.80 ppm) δ: 1.74–1.60 (m, 1H), 1.46 (dd, J=9.4
1
and 6.3 Hz, 1H), 1.22 (d, J=6.4 Hz, 3H), 0.91 (dd, J=6.5 and 6.3 Hz, 1H); [lit.4a 1H NMR (D2O; HOD,
4.63 ppm) δ: 1.52–1.40 (m, 1H), 1.24 (dd, J=9.5 and 6.0 Hz, 1H), 0.99 (d, J=6.5 Hz, 3H), 0.68 (dd, J=6.0
and 7.5 Hz, 1H)]; 13C NMR (D2O)19 δ: 178.7 (s), 42.4 (s), 21.6 (d), 20.9 (t), 14.2 (q); [lit.4f for (1S,2R)
13C NMR (75.5 MHz, D2O) δ: 178.7, 42.3, 21.6, 20.9, 14.2].
3.12. General procedure for the Mosher amide preparation of amino acids 1 and 2
To a stirred suspension of 1 (4 mg, 0.0348 mmol) in THF (1 mL) was added (S)-(+)-Mosher’s acid
chloride (8 µl, 0.035 mmol), 1 equiv.) and propylene oxide (10 µl, 0.14 mmol, 4 equiv.). The resulting
mixture was heated to reflux for 1 h, cooled to room temperature, and thoroughly evaporated to provide a
crude oil (12 mg, 100%). Racemic amino acid 1 was transformed in a similar manner (1 h at reflux)
to provide the diastereoisomeric reference signals of the CF3 groups. The enantiomeric excess was
determined by 19F NMR analysis of the MTPA amide (δ CF3CH2OH as a reference, −80 ppm): −69.97
(98.5%) for (1R,2S)-(+)-allo-norcoronamic acid 1, −70.05 (1.5%) for (1S,2R)-antipode. Moreover the
1H NMR spectra of the MTPA amide of racemic 1 showed two distinguished doublets at 1.16 ppm for
the (1S,2R)-1 and at 1.04 ppm for its antipode (1R,2S)-1.

A. Fadel, A. Khesrani / Tetrahedron: Asymmetry 9 (1998) 305–320
315
3.13. (ꢀ)-1-Methoxy-2-methyl-1-trimethylsiloxycyclopropane 3a
Following the same procedure described above: from 2.87 g of Na (125 mmol), 17.75 mL of ClSiMe3
(140 mmol) and 6.825 g (50 mmol) of (ꢀ)-β-chloroester 17a under sonication for 4 h to afford after
distillation 7.4 g (85%) of acetal (ꢀ)-7a into a 3:7 (cis:trans) diastereoisomeric mixture. The spectral
data are identical with those of chiral 7a.
To the acetal (ꢀ)-7a dissolved in MeOH (10 mL) was added one drop (20 µl) of TMSCl. After stirring
for 5 min, the residue was distilled at 60–65°C/18 mmHg to give 4.3 g (quantitative) of hemiacetal (ꢀ)-
3a.
Data for (ꢀ)-3a: 1H NMR (CDCl3) δ: (6:4 cis:trans mixture) 3.48/3.42 (s, 3H), 2.82/2.69 (br, s, OH),
1.34–1.19 (m, 1H), 1.11/1.15 (d, J=6.3 Hz, 3H), 1.13–0.90 (m, 1H), 0.45 (m, 1H).
3.14. (ꢀ)-2-Ethyl-1-hydroxy-1-methoxycyclopropane (ꢀ)-7b
Following the same procedure described above for chiral 7a: from 2.87 g of Na (125 mmol), 17.75
mL of ClSiMe3 (140 mmol) and 7.53 g (50 mmol) of (ꢀ)-methyl 3-chloropentanoate 17b14 under
sonication for 3 h were afforded after distillation (65°C/15 mmHg) 8.18 g (87%) of 2-ethyl-1-methoxy-
1-trimethylsiloxycyclopropane (ꢀ)-7b in a 3:7 (cis:trans) diastereoisomeric mixture.
1
Data for (ꢀ)-7b: IR (neat) ν (cm−1): 3100, 1285, 1260, 1165, 875, 850; H NMR (CDCl3) δ (3:7
cis/trans mixture): 3.38/3.32 (s, 3H), 1.73–1.50/1.50–1.35 (m, 1H), 1.35–1.06 (m, 2H), 0.99/0.98 (t,
J=7.2 Hz, 3H), 0.87 (dd, J=10 and 5.2 Hz, 1H), 0.53–0.34 (m, 1H), 0.16 (s, 9H); 13C NMR (CDCl3) δ
(3:7 cis/trans mixture): 90.1/89.8 (s, C1), 53.1/53.6 (q), 25.6/28.6 (d, C2), 21.7/21.5 (t, C3), 19.6 (t), 13.6
(q), 0.6 (3q).
3.15. (1S,2R,10S)-2-Methyl-1-[(10-methylbenzyl)amino]cyclopropanecarbonitrile 19a and isomer 18a
To a solution of 870 mg (5 mmol) of acetal (ꢀ)-7a in 4 mL of methanol was added one drop of TMSCl.
After 5 min of stirring, were added successively, 1.1 g (10 mmol) of (S)-methylbenzylamine 10, 1.2 mL
(4 equiv.) of AcOH, 10 mL of MeOH and 500 mg (10 mmol) of NaCN. The reaction mixture was stirred
and heated at 50°C for 48 h. The reaction was complete as shown by TLC.
The usual workup as reported above gave 1.3 g of crude nitriles as a mixture of four diastereoisomers in
47.5:40.5:5.5:6.5 ratio (determined by chiral GC). Purification by flash chromatography (Et2O:petroleum
ether=10:90) gave 370 mg (37%) of nitrile (1R,2S)-18a and 315 mg (31.5%) of nitrile (1S,2R)-19a
as major products and 30 mg (3%) of (1S,2S)-18a and 45 mg (4.5%) of nitrile (1R,2R)-19a as minor
products (76% overall). Data for (1R,2S)-18a are identical with those reported above for the nitrile
(1R,2S)-8a.
Data for (1S,2R)-19a: Rf=0.65 (EtOAc:petroleum ether=3:7); [α]D20=−155 (c=1.1, CHCl3); IR (neat)
ν (cm−1): 3335, 2240 (νCN); 1H NMR (CDCl3) δ: 7.40–7.20 (m, 5H), 4.20 (q, J=6.7 Hz, 1H), 2.25 (br,
s, NH), 1.38 (d, J=6.7 Hz, 3H), 1.40–1.20 (m, 1H), 1.25 (d, m, J=6.2 Hz, 3H), 0.90 (dd, J=5.2 and 8.4
Hz, 1H), 0.69 (dd, J=5.7 and 6.3 Hz, 1H); 13C NMR (CDCl3) δ: [6 arom. C: 144.6 (s), 128.3 (2d), 127.3
(d), 127.1 (2d)], 122.3 (s, CN), 56.6 (d), 30.3 (s, C1), 23.7 (t, C2), 21.9 (d), 21.7 (q, C3), 11.9 (q); HRMS
calcd for C13H16N2: 200.1313. Found: 200.1309.
Data for (1S,2S)-18a are identical with those reported above for the nitrile (1S,2S)-9a.
Data for (1R,2R)-19a minor: Rf=0.58 (EtOAc:petroleum ether=3:7); [α]D20=−164 (c=1, CHCl3); 1H
NMR (CDCl3) δ: 7.40–7.20 (m, 5H), 4.00 (q, J=6.7 Hz, 1H), 2.27 (br, s, NH), 1.41 (d, J=6.7 Hz, 3H),
1.33 (dd, J=8.4 and 6.3 Hz, 1Hcycle), 1.14 (dd, J=8.4 and 5.2 Hz, 1Hcycle), 0.90–0.68 (m, 1Hcycle), 0.85

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(d, J=6.3 Hz, 3H); MS (EI) (rel. int.): 201 (M++1, 0.4), 200 (M+, 2), 171 (2), 106 (10), 105 (100), 103
(8), 79 (10), 77 (14).
3.16. (1S,2R,10S)-2-Methyl-[(10-methylbenzyl)amino]cyclopropanecarboxamide 21
Following the procedure given above: 600 mg (3 mmol) of nitrile (1S,2R)-19a, 12 mL of CH2Cl2 and
5 mL of conc. H2SO4, gave after chromatography 560 mg (85%) of amide (1S,2R)-21.
Data for 21: Rf=0.46 (EtOAc); [α]D20=+4.1 (c=1, CHCl3); IR (neat) ν (cm−1): 3440, 3320, 1675
(νamide); 1H NMR (CDCl3) δ: 7.75 (br, s, Hamide), 7.40–7.30 (m, 5H), 5.62 (br, s, Hamide), 3.68 (q, J=6.6
Hz, 1H), 1.75–1.45 (m, 2H), 1.38 (d, J=6.6 Hz, 3H), 1.05 (d, J=6.3 Hz, 3H), 0.74 (m, 1H); 13C NMR
(CDCl3) δ: 179.8 (s), [6 arom. C: 145.2 (s), 128.5 (2d), 127.3 (d), 126.5 (2d)], 56.7 (d), 42.4 (s, C1),
23.5 (q), 22.4 (d, C2), 18.6 (t, C3), 13.0 (q); MS (EI) (rel. int.): 219 (M++1, 0.4), 218 (M+, 0.6), 113
(58), 105 (100), 104 (12), 103 (19), 96 (22), 91 (13), 79 (28), 78 (11), 77 (32), 68 (18); HRMS calcd for
C13H18N2O: 218.1419. Found: 218.1420.
3.17. (1S,2R)-1-Amino-2-methylcyclopropanecarboxamide 15
Following the same procedure developed above: from 536 mg of amide (1S,2R)-21 (2 mmol), AcOH (8
mL), 20% Pd(OH)2/C (100 mg), we obtained after flash chromatography 205 mg of free amine (1S,2R)-
15 (89%). Rf=0.54 (MeOH:CH2Cl2=1:4); [α]D20=−91 (c=0.7, CHCl3); RT (1S,2R)=17.51 min (chiral
Cydex B, 105°C, 1 bar).
The spectral data are identical with those reported above for the antipode (1R,2S)-15.
3.18. (1S,2R)-1-Amino-2-methylcyclopropanecarboxylic acid 1 ((1S,2R)-allo-norcoronamic acid)
Following the same procedure developed above: 114 mg of amide (1S,2R)-15 and 5 mL of 6 N
HCl, gave after treatment over Dowex (50WX8.100) 106 mg (92%) of pure crystalline (1S,2R)-allo-
norcoronamic acid 1. [α]D20=−72 (c=0.5, H2O); [lit.4f [α]D20=−74 (c=0.3, H2O)]. The spectral data are
identical with those reported above for its antipode (1R,2S)-1.
The enantiomeric excess determined from 19F NMR analysis of the MTPA amide (δ CF3CH2OH as
reference, −80 ppm): −69.97 (2%) for (1R,2S)-1, and −70.05 (98%) for (1S,2R)-1, ee=96%.
3.19. (1S,2R,10R)-2-Methyl-1-[(10-methoxymethylbenzyl)amino]cyclopropanecarbonitrile 19b and iso-
mer 18b
Following the same procedure noted above: 870 mg (5 mmol) of acetal (ꢀ)-7a, 980 mg (6.5 mmol, 1.3
equiv.) of (R)-methoxymethylbenzylamine 11,11 1.2 mL (4 equiv.) of AcOH, 10 mL of MeOH and 500
mg (10 mmol) of NaCN, gave after heating at 55°C for 48 h and the usual workup, 1.3 g of crude nitriles
as a mixture of 4 diastereoisomers in a 47:42.5:4.5:7 ratio determined by chiral GC. Purification by flash
chromatography (Et2O:petroleum ether=10:90) furnished 415 mg (36%) of nitrile (1R,2S)-18b and 370
mg (32%) of nitrile (1S,2R)-19b as major products and 35 mg (3%) of (1S,2S)-18b and 45 mg (4%) of
nitrile (1R,2R)-19b as minor products (75% overall).
Data for (1R,2S)-18b are identical with those reported above for the nitrile (1R,2S)-8c.
Data for (1S,2R)-19b: Rf=0.65 (EtOAc:petroleum ether=3:7); [α]D20=−187 (c=1, CHCl3); IR (neat)
ν (cm−1): 3600, 3330, 2222, 1612; 1H NMR (CDCl3) δ: 7.60–7.44 (m, 5H), 4.58 (dd, J=9.6 and 4.2 Hz,
1H), 3.80–3.58 (m, 2H), 3.64 (s, 3H), 2.86 (br, s, NH), 1.65–1.45 (m, 1Hcycle), 1.44 (d, J=6.3 Hz, 3H),

A. Fadel, A. Khesrani / Tetrahedron: Asymmetry 9 (1998) 305–320
317
1.12 (dd, J=9.5 and 5.2 Hz, 1Hcycle), 0.41 (dd, J=7.9 and 5.2 Hz, 1Hcycle); 13C NMR (CDCl3) δ: [6 arom.
C: 139.8 (s), 128.2 (2d), 128.1 (2d), 127.8 (d)], 122.2 (s, CN), 76.3 (q), 60.3 (d), 58.4 (t), 30.2 (s, C1),
22.4 (d, C2), 20.6 (t, C3), 11.8 (q); MS (EI) (rel. int.): 231 (M++1, 0.4), 230 (M+, 1), 186 (14), 185 (100),
135 (13), 104 (12), 103 (30), 91 (60), 77 (27); HRMS calcd for C14H18N2O: 230.1419. Found: 230.1412.
Data for (1S,2S)-18b minor are identical with those reported above for the nitrile (1S,2S)-9c.
Data for (1R,2R)-19b minor: IR (neat) ν (cm−1): 3600, 3335, 2222; 1H NMR (CDCl3) δ: 7.50–7.15
(m, 5H), 4.17 (dd, J=8.8 and 5.5 Hz, 1H), 3.78–3.54 (m, 2H), 3.43 (s, 3H), 2.65 (br, s, NH), 1.50–1.18
(m, 1Hcycle), 1.28 (d, J=6.3 Hz, 3H), 1.19–1.05 (m, 1Hcycle), 1.05–0.84 (m, 1Hcycle); MS (EI) (rel. int.):
230 (M+, 1.6), 186 (15), 185 (100), 135 (13), 104 (10), 103 (25), 91 (41), 77 (19).
3.20. (1R,2S,10R)-2-Ethyl-1-[(10-methoxymethylbenzyl)amino]cyclopropanecarbonitrile 18c and iso-
mer (1S,2R,1R)-19c
To a solution of 665 mg (5 mmol) of acetal (ꢀ)-7b in 4 mL of methanol was added one drop
of TMSCl. After 5 min of stirring, were added successively 1.37 g (6.5 mmol, 1.3 equiv.) of (R)-
(methoxymethyl)benzylamine 11,11 1.2 mL (4 equiv.) of AcOH, 10 mL of MeOH and 500 mg (40
mmol) of NaCN. The reaction mixture was stirred and heated at 55°C for 4 days. The reaction was
complete as shown by TLC. Usual workup as reported above gave 1.4 g of crude nitriles as a mixture
of four diastereoisomers in a 47:42.5:4.5:7 ratio as determined by chiral GC. Purification by flash
chromatography (35 g of SiO2, elution with Et2O:petroleum ether=10:90) gave 440 mg (36%) of nitrile
(1R,2S)-18c and 380 mg (31%) of nitrile (1S,2R)-19c as major products and 35 mg (3%) of (1S,2S)-18c
and 60 mg (5%) of (1R,2R)-19c as minor products (77% overall).
Data for (1R,2S)-18c: Rf=0.60 (EtOAc:petroleum ether=3:7); [α]D20=−66.2 (c=1, CHCl3); IR (neat)
1
ν (cm−1): 3600, 3335, 2225; H NMR (CDCl3) δ: 7.45–7.25 (m, 5H), 4.17 (dd, J=8.1 and 5 Hz, 1H),
3.45 (m, ABC system, 2H), 3.39 (s, 3H), 2.49 (br, s, NH), 1.35 dd, J=9.4 and 5 Hz, 1Hcycle), 1.30–0.88
(m, 2H and 1Hcycle), 0.78 (t, J=7.2 Hz, 3H), 0.70 (dd, J=7.5 and 5 Hz, 1Hcycle); 13C NMR (CDCl3) δ: [6
arom. C: 139.5 (s), 128.1 (2d), 128.05 (2d), 127.7 (d)], 121.9 (s, CN), 75.5 (t), 60.5 (q), 58.5 (d), 30.9 (s,
C1), 30.5 (t), 20.3 (d, C2), 19.8 (t, C3), 13.0 (q); MS (EI) (rel. int.): 244 (M+, 1.9), 200 (15), 199 (100),
135 (17), 105 (8), 104 (10), 103 (18), 91 (31); HRMS calcd for C15H20N2O: 244.1575. Found: 244.1573.
Data for (1S,2R)-19c: Rf=0.67 (EtOAc:petroleum ether=3:7); [α]D20=−185 (c=1, CHCl3); IR (neat)
ν (cm−1): 3600, 3330, 2220 (νCN); 1H NMR (CDCl3) δ: 7.40–7.24 (m, 5H), 4.45 (dd, J=9.2 and 4.5 Hz,
1H), 3.06 (like AB system, ∆νAB=18,7 Hz, JAB=10 Hz, 2H), 3.43 (s, 3H), 2.68 (br, s, NH), 1.80–1.37
(m, 2H), 1.40–1.12 (m, 1Hcycle), 1.02 (t, J=8.5 Hz, 3H), 0.88 (dd, J=9.5 and 5.5 Hz, 1Hcycle), 0.22 (dd,
J=7.5 and 5.5 Hz, 1Hcycle); 13C NMR (CDCl3) δ: [6 arom. C: 139.7 (s), 128.1 (2d), 128.0 (2d), 127.7
(d)], 122.1 (s), 76.2 (t), 60.3 (q), 58.2 (d), 30.3 (s, C1), 27.7 (t), 21.1(d, C2), 20.3 (t, C3), 13.4 (q); MS
(EI) (rel. int.): 245 (M++1, 0.4), 244 (M+, 1.3), 200 (15), 199 (100), 135 (32), 105 (13), 104 (14), 103
(26), 91 (54), 77 (22), 65 (14); HRMS calcd for C15H20N2O: 244.1575. Found: 244.1577.
Data for (1S,2S)-18c (minor 3%): Rf=0.55 (EtOAc:petroleum ether=3:7); 1H NMR (CDCl3) δ:
7.50–7.15 (m, 5H), 4.31 (dd, J=8.6 and 4.6 Hz, 1H), 3.56–3.27 (m, 2H), 3.42 (s, 3H), 2.83 (br, s, NH),
1.45 (q, J=7.4 Hz, 2H), 1.35–1.12 (m, 1Hcycle), 1.05 (t, J=7.4 Hz, 3H), 0.70 (dd, J=5 and 9.1 Hz, 1Hcycle),
0.54 (dd, J=5 and 7.3 Hz, 1Hcycle).
1
Data for (1R,2R)-19c (minor 5%): Rf=0.52 (EtOAc:petroleum ether=3:7); H NMR (CDCl3) δ:
7.45–7.20 (m, 5H), 4.33 (dd, J=4.8 and 7.9 Hz, 1H), 3.55–3.75 (m, 2H), 3.41 (s, 3H), 2.91 (br, s, NH),
1.60–0.65 (m, 5H), 0.45 (t, J=7.2 Hz, 3H).

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3.21. (1R,2S,10R)-2-Ethyl-1-[(10-methoxymethylbenzyl)amino]cyclopropanecarboxamide 22
Following the procedure described above: 490 mg (2 mmol) of nitrile (1R,2S)-18c, 10 mL of CH2Cl2
and 4 mL of conc. H2SO4 gave after flash chromatography 370 mg (70%) of amide (1R,2S)-22 and 140
mg (20%) of lactone (1R,2S)-23.
Data for amide (1R,2S)-22: Rf=0.15 (EtOAc:petroleum ether=3:7); [α]D20=−48.5 (c=1, CHCl3); IR
(neat) ν (cm−1): 3460, 3360, 1675; 1H NMR (CDCl3) δ: 7.40 (m, 5H and 1Hamide), 5.44 (br, s, Hamide),
3.79 (dd, J=9.8 and 3.7 Hz, 1H), 3.52 (dd, J=9.8 and 9.8 Hz, 1H), 3.43 (dd, J=9.8 and 3.7 Hz, 1H), 3.37
(s, 3H), 2.74 (br, s, NH), 1.60–1.30 (m, 2H and 2Hcycle), 1.04 (t, J=7 Hz, 3H), 0.79 (d, J=1.5 Hz 1Hcycle);
13C NMR (CDCl3) δ: 178.65 (s), [6 arom. C: 140.2 (s), 128.2 (2d), 127.7 (2d), 127.6 (d)], 76.7 (t), 61.3
(q), 58.7 (d), 43.4 (s, C1), 31.6 (t), 21.2 (d, C2), 19.3 (t, C3), 13.5 (q); HRMS calcd for C15H22N2O2:
262.1681. Found: 262.1674.
Data for lactone (1R,2S)-23: Rf=0.47 (EtOAc:petroleum ether=1:3); [α]D20=−20.8 (c=0.9, CHCl3);
1
IR (neat) ν (cm−1): 3690, 3300, 1730, 1608; H NMR (CDCl3) δ: 7.60–7.20 (m, 5H), 4.75 (dd, J=3.5
and 9.8 Hz, 1H), 4.49 (dd, J=9.8 and 9.8 Hz, 1H), 4.25 (dd, J=3.5 and 9.8 Hz, 1H), 1.77 (dd, J=3.7 and
8.7 Hz, 1Hcycle), 1.68–1.40 (m, 2H and 1Hcycle), 1.05 (t, J=7 Hz, 3H), 0.75 (dd, J=3.7 and 6 Hz, 1Hcycle);
13C NMR (CDCl3) δ: 172.4 (s), [6 arom. C: 137.4 (s), 128.9 (2d), 128.3 (d), 126.3 (2d)], 75.1 (t), 55.6
(d), 41.2 (s, C1), 34.1 (t), 22.7 (d, C2), 20.0 (t, C3), 13.8 (q); HRMS calcd for C14H17NO2: 231.1259.
Found: 231.1250.
3.22. (1S,2R,10R)-2-Ethyl-1-[(10-methoxymethylbenzyl)amino]cyclopropanecarboxamide 24
Following the procedure described above: 365 mg (1.5 mmol) of nitrile (1S,2R)-19c, 10 mL of CH2Cl2
and 3 mL of conc. H2SO4 gave, after flash chromatography, 270 mg (69%) of amide (1S,2R)-24 and 70
mg (20%) of lactone (1S,2R)-25.
Data for amide (1S,2R)-24: Rf=0.47 (EtOAc:petroleum ether=3:7); [α]D20=−68 (c=0.72, CHCl3); IR
(neat) ν (cm−1): 3600, 3360, 1680; 1H NMR (CDCl3) δ: 8.06 (br, s, 1Hamide), 7.57–7.15 (m, 5H), 5.78
(br, s 1Hamide), 4.07 (dd, J=4.1 and 9.9 Hz, 1H), 3.55–3.25 (m, 2H), 3.44 (s, 3H), 1.78 (br, s, NH),
1.56–1.00 (m, 2H and 2Hcycle), 0.96 (t, J=7.2 Hz, 3H), 0.28 (dd, J=4 and 6.3 Hz, 1Hcycle); 13C NMR
(CDCl3) δ: 179.6 (s), [6 arom. C: 142.0 (s), 128.4 (2d), 127.5 (d), 127.2 (2d)], 77.2 (t), 61.8 (q), 59.0
(d), 44.6 (s, C1), 30.6 (t), 21.7 (d, C2), 19.9 (t, C3), 13.7 (q); HRMS calcd for C15H22N2O2: 262.1681.
Found: 262.1676.
Data for lactone (1S,2R)-25: Rf=0.64 (EtOAc:petroleum ether=1:3); [α]D20=−39 (c=0.3, CHCl3); IR
(neat) ν (cm−1): 3600, 3350, 1730. 1H NMR (CDCl3) δ: 7.55–7.25 (m, 5H), 4.65 (dd, J=1 and 8.2 Hz,
1H), 4.52–4.30 (m, like, AB system, 2H), 2.30 (br, s, NH), 1.90–1.45 (m, 2H and 2Hcycle), 1.08 (t, J=7.3
Hz, 3H), 0.70 (dd, J=4 and 7 Hz, 1Hcycle); 13C NMR (CDCl3) δ: 172.5 (s), [6 arom. C: 137.8 (s), 128.8
(2d), 128.3 (d), 126.5 (2d)], 74.6 (t), 55.6 (d), 41.2 (s, C1), 31.1 (t), 25.9 (d, C2), 20.8 (t, C3), 13.8 (q);
HRMS calcd for C14H17NO2: 231.1259. Found: 231.1258.
3.23. (1R,2S)-1-Amino-2-ethylcyclopropanecarboxamide 26
Following the same procedure developed above: from 265 mg of amide (1R,2S)-22 (1 mmol), AcOH
(5 mL), 20% Pd(OH)2/C (50 mg), we obtained after chromatography (MeOH:CH2Cl2=1:19), 110 mg of
free amine (1R,2S)-26 (86%).
Data for (1R,2S)-26: Rf=0.18 (MeOH:CH2Cl2=1:9); RT=27.65 min (chiral Cydex B, 110°C, 0.8 bar);
[α]D20=+80 (c=0.65, CHCl3); IR (neat) ν (cm−1): 3600, 3350, 3060, 1675; 1H NMR (CDCl3) δ: 7.60

A. Fadel, A. Khesrani / Tetrahedron: Asymmetry 9 (1998) 305–320
319
(br, s, Hamide), 6.00 (br, s, Hamide), 1.87 (s, 2Hamine), 1.69–1.55 (m, 2H), 1.55–1.30 (m, 2H), 1.05 (t, J=7.7
Hz, 3H), 0.42 (dd, J=4.5 and 2.5 Hz, 1Hcycle); 13C NMR (CDCl3) δ: 179.3 (s), 38.8 (s, C1), 29.1 (d, C2),
25.3 (t, C3), 21.7 (t), 13.7 (q); HRMS calcd for C6H12N2O: 128.0949. Found: 128.0947.
3.24. (1S,2R)-1-Amino-2-ethylcyclopropanecarboxamide 26
Following the same procedure as above: from 265 mg of amide (1S,2R)-24 (1 mmol), AcOH (5 mL),
20% Pd(OH)2/C (50 mg), we obtained after chromatography (MeOH:CH2Cl2=1:19), 107 mg of free
amine (1S,2R)-26 (84%).
Data for (1S,2R)-26: Rf=0.18 (MeOH:CH2Cl2=1:9); RT=26.04 min (chiral Cydex B, 110°C, 0.8 bar);
[α]D20=−78 (c=0.6, CHCl3); HRMS calcd for C6H12N2O: 128.0949. Found: 128.0948. The spectral data
are identical with those reported above for the antipode (1R,2S)-26.
3.25. (1R,2S)-1-Amino-2-ethylcyclopropanecarboxylic acid 2 ((+)-allo-coronamic acid)
Following the same procedure described above, from 103 mg (0.8 mmol) of amide (1R,2S)-26, 3 mL
of 6 N HCl, we obtained 132 mg of (1R,2S)-allo-coronamic acid hydrochloride 2·HCl as a white solid.
Recrystallisation from ethanol–ether gave pure 2·HCl (127 mg, 96%).
1
Data for (1R,2S)-2·HCl: m.p.: 196°C decomp. [α]D20=+40.7 (c=O.85, H2O); H NMR (D2O) δ
(HOD, 4.8 ppm): 1.80 (ddd, J=9.5, 7.6 and 6.3 Hz, 1H-C2), 1.63 (dd, J=9.5 and 6 Hz, 1H-C3), 1.70–1.46
(m, 1H), 1.50–1.20 (m, 1H), 1.10 (dd, J=7.6 and 6.0 Hz, 1H-C3), 1.03 (t, J=7.3 Hz, 3H); 13C NMR (D2O)
(CDCl3 int. ref.) δ: 173.4 (s), 38.3 (s, C1), 27.7 (d, C2), 20.4 (t, C3), 19.2 (t), 12.7 (q).
The amino acid hydrochloride (1R,2S)-2·HCl, treated on Dowex 50WX8.100 ion exchange resin
provided pure crystalline (1R,2S)-allo-coronamic acid 2 (98 mg, 96% yield).
Data for (1R,2S)-2: m.p.: 185°C; [α]D20=+67.2 (c=0.6, H2O), lit.4a [α]D20=+65.0 (c=1.3, H2O); lit.5g
[α]D20=+67.3(c=1.52, H2O); H NMR (D2O) δ (HOD, 4.8 ppm): 1.58 (ddd, J=6.0, 7.6 and 9.7 Hz,
1
1Hcycle), 1.58–1.41 (m, 1H), 1.40 (dd, J=6.0 and 9.7 Hz, 1Hcycle), 1.42–1.20 (m, 1H), 1.01 (t, J=7.3 Hz,
3H), 0.87 (dd, J=6.0 and 7.6 Hz, 1Hcycle); [lit.4a 1H NMR (D2O) δ (HOD, 4.63 ppm): 1.45–1.07 (m,
4H, H-C2, H-C3,CH2CH3), 0.84 (t, J=7.0 Hz, CH2CH3), 0.70 (ca t, J=6.5 Hz, H-C3)]; 13C NMR (D2O)
(CDCl3 int. ref.) δ: 176.0 (s), 39.9 (s, C1), 25.8 (d, C2), 20.7 (t, C3), 17.9 (t), 13.0 (q). Anal. calcd for
C6H11NO2: C, 55.80; H, 8.58; N, 10.84. Found: C, 55.45; H, 8.28; N, 10.52.
The enantiomeric excess was determined by 19F NMR analysis of the MTPA amide (δ CF3CH2OH as
a reference, −80 ppm): −70.00 (98.6%) for (1R,2S)-(+)-allo-coronamic acid 2, and −70.14 (1.4%) for
(1S,2R)-antipode (>97% ee).
3.26. (1S,2R)-1-Amino-2-ethylcyclopropanecarboxylic acid 2 ((−)-allo-coronamic acid)
Following the same procedure noted above, from 103 mg (0.8 mmol) of amide (1S,2R)-26, 3 mL of
6 N HCl, we obtained 130 mg of (1S,2R)-2·HCl as a white solid. Recrystallisation from ethanol–ether
furnished pure (−)-2·HCl (125 mg, 95%). M.p.: 192°C dec.; [α]D20=−38 (c=0.5, H2O). After teatment
over Dowex, pure crystalline (1R,2S)-(+)-2 was obtained (95 mg, 95%). M.p.: 184°C dec; [α]D20=−65
(c=0.5, H2O).
Data for (1S,2R)-2·HCl are identical to those reported above for (1R,2S)-2·HCl. The enantiomeric
excess determined as above by 19F NMR analysis of the MTPA amide was 96% (ppm: −70.00 (2%) for
(1R,2S)-(+)-2, −70.14 (98%) for (1S,2R)-(−)-2.

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17. It is interesting to note that the Strecker reaction can also occur directly from the acetal 7a or (ꢀ)-7b.
18. Sonications were carried out in a Sonoclean TK 52 (Bransonic) cleaning bath at 60 KHz and 80–160 Wl−1
.
19. NMR spectra were recorded at 62.86 MHz in D2O solution using internal CDCl3=77.00 ppm as a reference.