A practical synthesis of protected β-homolysine

Article abstract of DOI:10.1016/S0957-4166(00)00173-7

Protected β-homolysine of high enantiomeric purity (ee>99.5%) is prepared utilizing the stereoselective conjugate addition of lithiated (S)-(α-methylbenzyl)benzylamide to (E)-7-(tosyloxy)hept-2-enoic acid tert-butyl ester, followed by subsequent ammonia s

Full text of DOI:10.1016/S0957-4166(00)00173-7

Tetrahedron: Asymmetry 11 (2000) 2231±2237
A practical synthesis of protected b-homolysine
Markus Baenziger, Luca Gobbi, Bernard P. Riss,* Frank Schaefer and Andrea Vaupel
Chemical & Analytical Development, NOVARTIS Pharma AG, CH-4002 Basel, Switzerland
Received 13 April 2000; accepted 5 May 2000
Abstract
Protected b-homolysine of high enantiomeric purity (ee>99.5%) is prepared utilizing the stereoselective
conjugate addition of lithiated (S)-(a-methylbenzyl)benzylamide to (E)-7-(tosyloxy)hept-2-enoic acid tert-
butyl ester, followed by subsequent ammonia substitution, Boc protection and removal of the auxiliary.
# 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
b-Homolysine is an important constituent of a new interesting drug substance GPI-562.1
Although it could be readily obtained through Arndt±Eistert2 homologation of l-lysine, this
method is not suitable for large scale production in standard multipurpose equipment due to the
high risk potential of diazomethane. A more practical way consists in reduction of the carboxyl
group of o-Z-lysine methyl ester, activation of the resulting hydroxyl group as a mesylate,
substitution with cyanide and ®nal solvolysis to the desired acid derivative.3 In order to ®nd an
alternative to this long pathway we studied the application of the well-documented4 stereo-
selective Michael addition of a homochiral amine to a suitable a,b-unsaturated ester. After several
attempts5 we achieved a practical and ecient synthesis of (S)-o-Boc-b-homolysine tert-butyl
ester 6 as shown in Scheme 1.
2. Results and discussion
Starting from readily available 3,4-dihydropyran and tert-butyl diethylphosphonoacetate we
obtained directly the acrylate 1 via a Wittig±Horner reaction6 as a 9:1 E:Z mixture. Subsequent
tosylation of the crude product with tosylanhydride, triethylamine and catalytic amount of
4-(dimethylamino)pyridine (DMAP) in THF gave compound 26 also as a 9:1 E:Z mixture
(use of tosylchloride gave about 10% chloro substituted by-product). The selective addition of
(S)-(a-methylbenzyl)benzylamine to the crude acrylate 2 in DME was achieved easily by adding
* Corresponding author.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00173-7

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M. Baenziger et al. / Tetrahedron: Asymmetry 11 (2000) 2231±2237
Scheme 1. (a) Catalytic amount of HCl, water; (b) tert-butyl diethylphosphonoacetate/K2CO3/DMSO; (c) tosylanhydride/
triethylamine/DMAP/THF; (d) (i) (S)-(a-methylbenzyl)benzylamine, hexyllithium/DME, ^60ꢀC, (ii) AcOH; (e) ammonia/
ethanol; (f) BOC2O/AcOEt/K2CO3, water; (g) Pd/C, EtOH, AcOEt, oxalic acid
hexyllithium at ^60ꢀC to the mixture of the two substrates. The reaction can be monitored by on-line
FT-IR, which shows nicely the disappearance of the absorption at 1656 cm^1 attributed to the CˆC
stretching as well that of the carbonyl at 1711 cm^1. After an acidic quench at ^60ꢀC and an
aqueous work-up we obtained adduct 3 as the main product. At this stage it was not possible to
determine the diastereomeric purity by NMR or HPLC. Intermediate 3 was contaminated with
about 10% starting material 2, but it was free of the cyclohexane derivative 7 which may occur
through cyclization of the intermediate anion by displacement of the tosylate.7 Compound 7 was
only obtained when the reaction mixture was slowly warmed up to 0ꢀC before aqueous quench8
(Scheme 2). Transformation of 3 to the amine 4 proved to be quite dicult, as compound 3
did not react under Gabriel conditions9 (potassium salt of phthalimide, hexamethyldisilylazane,
di-tert-butyl imidodicarbonate/dimethylformamide at 100ꢀC) nor with sodium azide. However,
the tosylate reacted slowly with benzylamine in toluene at re¯ux or with excess ammonia in ethanol
at 50ꢀC in a closed vessel. Under these conditions it was possible to transform smoothly the
tosylate 3 to the primary amine 4. With an acidic work up, it was possible to get rid of the main
by-product accumulated in the previous steps.
In contrast to the low reactivity of tosylate 3, it is rapidly transformed under hydrogenolysis to
the cyclization product 8 by an intramolecular displacement (Scheme 2).
Scheme 2. (a) (S)-(a-Methylbenzyl)benzylamine, hexyllithium/DME, ^60 to 0ꢀC; (b) H2, Pd/C, EtOH

M. Baenziger et al. / Tetrahedron: Asymmetry 11 (2000) 2231±2237
2233
After Boc protection of 4 under the usual conditions, the subsequent removal of the benzyl
groups of 5 by hydrogenolysis with palladium on charcoal failed in the ®rst attempt. However, we
observed a dramatic increase in reactivity by adding oxalic acid to the hydrogenation mixture, the
t-butyl groups remained untouched. After aqueous work up the target molecule 6 was obtained as
the crystalline oxalate salt in pure form. The enantiomeric excess was determined by HPLC after
derivatisation with Marfey's reagent,10 and proved to be about 96% for the crude base and
>99.5% for the oxalate salt. The absolute con®guration has been con®rmed after hydrolysis with
6N HCl and compared with an authentic sample of S-(+)-homolysine dihydrochloride derived
from l-lysine.3 In conclusion, we have achieved a new synthesis of the b-homolysine derivative 6
in about 20% overall yield, using inexpensive and readily available starting materials.
3. Experimental
All chemicals and solvents were purchased by Fluka as synthetic grade and used without further
puri®cation. Hexyllithium was obtained from Chemetall GmBH in bulk and titrated11 before use.
Reactions with hexyllithium were performed under argon. Melting points were determined on a
Buchi 535 in open capillary tubes and are uncorrected. Optical rotations were measured on a
Perkin±Elmer 241 polarimeter with a 1.0 dm cell and are given in units of 10^1 deg cm2 g^1. NMR
spectra were recorded on a Bruker±Spectrospin DPX-300 instrument (1H spectra at 300 MHz,
13C spectra at 75 MHz) in CDCl3 solutions, unless otherwise speci®ed. Chemical shifts are given
in ppm down®eld from TMS internal standard; coupling constants are given in hertz. IR spectra
were recorded on a Bruker IFS66 FT-IR spectrophotometer. HPLC analysis were performed on
a Merck±Hitachi instrument equipped with a UVD-L 4000, using reversed-phase (Macherey±
Nagel) RP-18, 125/4 mm columns, eluted with a gradient of diammoniumhydrogenphosphate at
pH 2 and acetonitrile.
3.1. tert-Butyl (E)-7-Hydroxyhept-2-enoate 1
3,4-Dihydropyran [84.1 g (799 mmol)], 270 ml water and 1.7 ml concd HCl were stirred for
about 3 h at 0ꢀC; then, 133 g of potassium carbonate, 670 ml dimethylsulfoxide and 100.0 g (340
mmol) tert-butyl diethylphosphonoacetate were added and the resultant mixture stirred overnight
at 50ꢀC. After dilution with water and extraction with isopropyl acetate, the organic phase was
dried (MgSO4) and evaporated to give 78.4 g of 1 as a colorless oil (crude yield >100% as a 9:1
E:Z mixture). 1H NMR: 1.48 (9H, s, C(CH3)3), 1.43±1.65 (4H, m, H2C(5), H2C(6)), 1.74 (1H, `s',
CH2OH), 2.21 (2H, m, H2C(4)), 3.65 (2H, m, H2C(7)), 5.75 (1H, dt, J=15.6, 1.5, HC(2)), 6.85
(1H, dt, J=15.6, 6.9, HC(3)).
3.2. tert-Butyl (E)-7-[[(4-methylphenyl)sulfonyl]oxy]hept-2-enoate 2
To a mixture of 30.5 g (122 mmol) of 1, 47.8 g (146 mmol) tosylanhydride and 40 ml triethyl-
amine in 250 ml tetrahydrofuran was added a catalytic amount of 4-(dimethylamino)pyridine.
This was stirred overnight at room temperature, then diluted with water and extracted with iso-
propyl acetate; the organic phase was dried (MgSO4) and evaporated to give 50.6 g of 2 as a
1
brown liquid (yield 93.7%, as a 9:1 E:Z mixture). H NMR: 1.48 (9H, s, C(CH3)3), 1.40±1.54
(2H, m, H2C), 1.62±1.71 (2H, m, H2C), 2.12 (2H, m, H2C(4)), 2.45 (3H, s, CH3 of TsO), 4.03 (2H,

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M. Baenziger et al. / Tetrahedron: Asymmetry 11 (2000) 2231±2237
t, J=6.2, H2C(7)), 5.69 (1H, dt, J=15.6, 1.5, HC(2)), 6.76 (1H, dt, J=15.6, 6.9, HC(3)), 7.35
(2H, d, J=8.1, TsO), 7.79 (2H, d, J=8.3, TsO). 13C NMR: 21.6 (CH3 of TsO), 23.9 (CH2), 28.1
(OC(CH3)3), 28.3 (CH2), 31.1 (CH2), 70.0 (CH2), 80.2 (OC(CH3)3), 123.7 (CH), 127.9 (CH), 129.9
(CH), 133.1 (C of TsO), 144.8 (C of TsO), 146.6 (CH), 165.9 (COOtBu).
3.3. tert-Butyl (3S,ꢀS)-3-(N-benzyl-N-ꢀ-methylbenzylamino)-7-[[(4-methylphenyl)sulfonyl]oxy]-
heptanoate 3
To a stirred mixture of 10.0 g (28.2 mmol) crude 2, 5.96 g (28.2 mmol) of (S)-(a-methylbenzyl)-
benzylamine in 280 ml anhydrous dimethoxyethane at ^60ꢀC was added dropwise 18.5 ml (42.3
mmol) of a 2.3 M solution of hexyllithium in hexane. The reaction was quenched after 15 min by
addition of 3.2 ml (56.4 mmol) acetic acid, followed by dilution with water, acidi®cation to pH 2
and extraction with isopropyl acetate. After treatment with aqueous potassium carbonate, the
organic phase was dried over MgSO4. Subsequent evaporation of the solvent yielded 12.1 g of 3
as a yellow oil (yield: 75%). Unreacted amine (1.54 g, 25%) can be recovered from the ®rst water
phase upon treatment with potassium carbonate and extraction with isopropyl acetate. 1H NMR:
1.27 (3H, d, J=7.0, PhCH(CH3)N), 1.13±1.65 (6H, m, H2C(4), H2C(5), H2C(6)), 1.37 (9H, s,
C(CH3)3), 1.82 (1H, dd, J=14.8, 9.5, HC(2)), 1.94 (1H, dd, J=14.8, 3.3, HC(2)), 2.40 (3H, s, CH3
of TsO), 3.22 (1H, m, HC(3)), 3.45 (1H, d, J=15.0, PhCH2N), 3.72 (1H, d, J=14.9, PhCH2N),
3.78 (1H, q, J=7.0, PhCH(CH3)N), 3.99 (2H, m, H2C(7)), 7.19±7.39 (12H arom.), 7.77 (2H, d,
J=8.3, TsO). 13C NMR: 20.6 (PhCH(CH3)N), 21.6 (CH3 of TsO), 22.7 (CH2), 28.1 (OC(CH3)3),
28.7 (CH2), 32.8 (CH2), 37.4 (C(2)), 50.1 (PhCH2N), 53.5 (C(3)), 58.4 (PhCH(CH3)N), 70.6
(TsOCH2), 80.1 (OC(CH3)3), 126.7±128.5 (CH arom.), 129.8 (CH arom.), 133.4 (C TsO), 141.8 (C
Ph), 143.0 (C Ph), 144.6 (C TsO), 172.0 (COOtBu).
3.4. tert-Butyl (3S,ꢀS)-7-amino-3-(N-benzyl-N-ꢀ-methylbenzylamino)heptanoate 4
Crude 3 [12.1 g (21.3 mmol)] and 110 ml ammonia in ethanol (10% w/v) were heated for 48 h
at 50ꢀC in a closed vessel. After evaporation of the solvent, the oily residue was diluted with
isopropyl acetate, water and acidi®ed to pH 2 with dilute HCl. The organic phase was then
separated, the pH of the aqueous phase was raised to 9 with potassium carbonate and the product
was extracted into isopropyl acetate. After drying over MgSO4, the organic phase was con-
1
centrated to give 3.94 g of the crude amine 4 in about 45% yield. H NMR: 1.17±1.65 (6H, m,
H2C(4), H2C(5), H2C(6)), 1.31 (3H, d, J=7.0, PhCH(CH3)N), 1.38 (9H, s, C(CH3)3), 1.85 (1H,
dd, J=14.8, 9.0, H2C(2)), 1.94 (1H, dd, J=14.8, 3.7, H2C(2)), 2.74 (2H, m, H2C(7)), 3.27 (1H, m,
HC(3)), 3.47 (1H, d, J=15.0, PhCH2N), 3.75 (1H, d, J=15.0, PhCH2N), 3.80 (1H, q, J=7.0,
PhCH(CH3)N), 4.31 (2H, s, NH2), 7.12±7.40 (10H, Ph). 13C NMR: 20.5 (PhCH(CH3)N), 24.1
(CH2), 28.1 (C(CH3)3), 31.3 (CH2), 33.1 (CH2), 37.6 (C(2)), 41.3 (C(7)), 50.1 (PhCH2N), 53.8
(C(3)), 58.3 (PhCH(CH3)N), 80.0 (OC(CH3)3), 126.5±128.3 (CH Ph), 141.8 (C Ph), 143.0 (C Ph),
172.1 (COOtBu). m/z (FAB): 411 ([MH]+, 100), 355 (13), 251 (46), 196 (14), 178 (30).
3.5. tert-Butyl (3S,ꢀS)-7-(tert-butyloxycarbonylamino)-3-(N-benzyl-N-ꢀ-methylbenzylamino)-
heptanoate 5
Compound 4 [3.94 g (9.60 mmol)], 2.2 g (10.1 mmol) di-tert-butyl dicarbonate and 2.0 g of
potassium carbonate were stirred for 30 min in 80 ml isopropyl acetate:water, 1:1. After the layers

M. Baenziger et al. / Tetrahedron: Asymmetry 11 (2000) 2231±2237
2235
were separated, the organic phase was evaporated to dryness to give 5.71 g of crude 5 (>100%).
1H NMR: 1.20±1.66 (6H, m, H2C(4), H2C(5), H2C(6)), 1.32 (3H, d, J=7.0, PhCH(CH3)N), 1.39
(9H, s, CH2COOC(CH3)3), 1.46 (9H, s, C(CH3)3 Boc), 1.86 (1H, dd, J=14.7, 9.4, H2C(2)), 1.97
(1H, dd, J=14.7, 3.4, H2C(2)), 3.07 (2H, m, H2C(7)), 3.27 (1H, m, HC(3)), 3.48 (1H, d, J=15.1,
PhCH2N), 3.79 (1H, d, J=13.3, PhCH2N), 3.80 (1H, q, J=7.0, PhCH(CH3)N), 4.46 (1H, `s',
BocNH), 7.21±7.42 (10H, Ph).
3.6. tert-Butyl (S)-3-amino-7-(tert-butyloxycarbonylamino)heptanoate 6
A mixture of 5.71 g crude 5 and 1 g oxalic acid was hydrogenated with 0.2 g palladium on
charcoal (10%) in 50 ml ethanol under 1 atm of hydrogen at 50ꢀC during 5 h. After removal of
the catalyst and solvent, the residue thus obtained was partitioned with water and isopropyl
acetate. After removal of the organic phase, the aqueous phase was treated with potassium
carbonate (2.0 g) and extracted with isopropyl acetate. Evaporation of the solvent yielded the
crude base as a colorless oil. Upon treatment with oxalic acid (0.8 g, 8.9 mmol) in ethyl acetate:
ethanol 4:1 (25 ml) we obtained: 2.42 g of the salt 6 as brilliant plates in 62% yield based on the
amine derivative 4. Mp: 134±135ꢀC. ‰ꢀŠD24=+7.62 (c 1.57, ethanol). MA: C: 52.94 (53.19), H: 8.15
1
(8.43), N: 6.87 (6.89), O: 31.81 (31.49). H NMR (d6-DMSO, 360 MHz): 1.24±1.59 (6H, m,
H2C(4), H2C(5), H2C(6)), 1.37 (9H, s, CH2COOC(CH3)3), 1.42 (9H, s, C(CH3)3 Boc), 2.49 (1H,
dd, J=16.7, 6.8, H2C(2)), 2.59 (1H, dd, J=16.7, 5.9, H2C(2)), 2.89 (2H, m, H2C(7)), 3.34 (1H, m,
HC(3)), 6.74 (1H, t (dd), J=5.4, BocNH), 8.48 (3H, NH3 ). 13C NMR (d6-DMSO, 75 MHz): 24.7
+
(H2C(5)), 30.7 (C(CH3)3), 31.3 (C(CH3)3), 32.0 (H2C(4)), 34.9 (H2C(6)), 40.8 (H2C(2)), 42.5
(H2C(7)), 50.2 (HC(3)), 78.2 (C(CH3)3), 81.7 (C(CH3)3), 165.5 (CˆO), 170.25 (CˆO). m/z (EI):
317 ([MH]+, 32), 261 ([MH^C4H8]+, 14), 205 ([MH^2ÂC4H8]+, 24), 88 (100), 57 ([C4H9]+, 97). IR
(KBr): 2978 (m), 2942 (m), 1730 (s), 1693 (s), 1597 (m), 1547 (m), 1518 (s), 1460 (m), 1398 (m),
1367 (m), 1250 (s), 1223 (m), 1155 (s), 720 (m) cm^1.
3.7. (S)-3,7-Diaminoheptanoic acid dihydrochloride
Compound 6 (free base) [250 mg (0.79 mmol)] were re¯uxed overnight in 3 ml of 6N HCl. After
concentration and dilution with ethanol, 137 mg of the amino acid salt (b-homolysine dihydro-
chloride) in 78% yield were obtained. Mp: 198±200ꢀC; ‰ꢀŠD24=+15.1 (c 2.00, water).12 A sample
obtained via homologation of l-lysine gave the following data: mp: 198±200ꢀC; ‰ꢀŠD24=+15.3 (c
1
2.00, water). MA: C: 35.87 (36.06), H: 7.49 (7.78), N: 11.88 (12.02), O: 13.69 (13.73). H NMR
(CD3OD, 360 MHz): 1.53 (2H, m, H2C(5)), 1.76 (4H, m, H2C(4), H2C(6)), 2.69 (1H, dd, J=17.6,
7.6, H2C(2)), 2.80 (1H, dd, J=17.5, 4.9, H2C(2)), 2.98 (2H, `t', J=7.4, H2C(7)), 3.58 (1H, m,
HC(3)). 13C NMR (CD3OD, 90 MHz): 23.3 (C(5)), 28.1 (C(4)), 33.1 (C(6)), 36.9 (C(2)), 40.4
(C(7)), 49.5 (C(3)), 173.6 (C(1)).
3.8. tert-Butyl (1S,2S,ꢀS)-2-(N-benzyl-N-ꢀ-methylbenzylamino)cyclohexanecarboxylate 7
A mixture of 5.00 g (14.1 mmol) of crude 2 and 3.28 g (15.5 mmol) of (S)-(a-methylbenzyl)-
benzylamine in 140 ml anhydrous dimethoxyethane was cooled to ^60ꢀC before adding 7.8 ml
(18.3 mmol) of a 2.36 M solution of hexyllithium in hexane. After stirring at ^60ꢀC for 30 min,
the temperature was allowed to rise slowly to 0ꢀC during 2.5 h and maintained at 0ꢀC for 1 h. The
reaction mixture was then quenched with 100 ml of water, acidi®ed to pH=1 with HCl (10%),

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M. Baenziger et al. / Tetrahedron: Asymmetry 11 (2000) 2231±2237
and extracted with 100 ml of isopropyl acetate. The organic phase was treated with 100 ml of a
10% aqueous potassium carbonate solution, dried over MgSO4 and evaporated to dryness leaving
2.95 g of crude product 7 as a yellow oil. Flash column chromatography over silica gel with
hexane:ethyl acetate (20:1) as eluent yielded 1.54 g (28%) of 7 as a colorless oil. ‰ꢀŠ2D4=+26.0 (c 1.25,
CHCl3); lit.:7 ‰ꢀŠD24=+30.4 (c 1.00, CHCl3). 1H NMR: 0.83±1.80 (8H, m, H2C(3,4,5,6)), 1.37 (3H,
d, J=7.0), 1.46 (9H, s, C(CH3)3), 2.22 (1H, ddd, `dt', J=11.4, 11.4, 3.7, HC(1)), 3.03 (1H, ddd,
`dt', J=11.4, 11.4, 3.3, HC(2)), 3.69 (1H, d, J=14.5, PhCH2N), 3.75 (1H, d, J=14.5, PhCH2N),
4.07 (1H, q, J=6.9, PhCH(CH3)N), 7.15±7.32 (10H, Ph). 13C NMR: 19.1 (PhCH(CH3)N), 25.2
(CH2), 25.7 (CH2), 28.0 (CH2), 28.1 (C(CH3)3), 30.7 (CH2), 49.5 (PhCH2N), 50.1 (CH), 60.0
(CH), 60.2 (CH), 79.4 (C(CH3)3), 125.9 (CH Ph), 126.3 (CH Ph), 126.4 (CH Ph), 127.7 (CH Ph),
128.0 (CH Ph), 128.9 (CH Ph), 141.9 (C Ph), 144.7 (C Ph), 175.0 (COOtBu). m/z (CI): 422
([M+C2H5]+, 6), 394 ([M+H]+, 94), 393 (M+, 97), 338 ([M^tBu+2H]+, 100), 288 ([M^PhMeCH]+,
38), 234 (62), 105 ([PhMeCH]+, 23), 91 ([Bn]+, 17).
3.9. tert-Butyl (S)-piperidine-2-acetate 8
Crude 3 [10.0 g (17.6 mmol)] in 200 ml ethanol were hydrogenated at 50ꢀC with 3 g palladium
on charcoal under 20 bar of hydrogen during 5 h. After removal of the catalyst, concentration of
the solution and addition of ether, the toluenesulfonic acid salt of 8 was obtained as white crystals
(3.20 g, 48.9%); mp: 112ꢀC, ‰ꢀŠD24=+11.7 (c 1.65, MeOH). MA: C: 57.35 (58.20), H: 7.48 (7.87),
N: 3.86 (3.77), O: 21.74 (21.53). Treatment of this salt in CH2Cl2 with 10% aqueous K2CO3 led to
the free base 8 as a colorless liquid. [ꢀ]D=+8.3 (c 1.35, CH2Cl2). MA: C: 65.60 (66.29), H: 10.58
1
(10.62), N: 6.90 (7.03), O: 16.25 (16.06). H NMR: 1.10±1.51 (3H, m, HaxC(3,4,5)), 1.44 (9H, s,
C(CH3)3), 1.55±1.81 (3H, m, HeqC(3,4,5)), 2.12 (1H, s, NH), 2.29 (2H, `d', J=6.5, CH2COOtBu),
2.66 (1H, m, HaxC(6)), 2.87 (1H, m, HC(2)), 3.05 (1H, m, HeqC(6)). 13C NMR: 24.4 (H2C), 25.8
(H2C), 27.9 (C(CH3)3), 32.2 (H2C), 42.5 (H2C), 46.6 (H2C), 53.3 (HC(2)), 80.3 (C(CH3)3), 171.6
(COOtBu). Hydrolysis with 6N HCl (overnight at 100ꢀC) and recrystallization from methanol±
ether gave piperidine-2-acetic acid hydrochloride in quantitative yield. Mp: 178±179ꢀC; ‰ꢀŠD24=+28.0
(c 1.10, water). Lit.:13 mp: 180±182ꢀC. The free amino acid was isolated over DOWEX 50 W X 4
(NH4) and recrystallized from methanol±ether. Mp: 229ꢀC; ‰ꢀŠD24=+41.7 (c 1.02, water). Lit.:14
24
ꢀ
1
mp: 234±235 C; ‰ꢀŠD =+33.5 (c 0.60, water). H NMR (D2O, 300 MHz): 1.32±1.50 (3H, m,
HaxC(3,4,5)), 1.71±1.79 (3H, m, HeqC(3,4,5)), 2.34 (2H, `d', J=6.6, CH2COOH), 2.85 (1H, m,
HaxC(6)), 3.19±3.28 (2H, m, HC(2) and HeqC(6)). 13C NMR (D2O, 75 MHz): 22.8 (H2C), 23.3
(H2C), 29.5 (H2C), 41.3 (H2C), 45.9 (H2C), 55.9 (HC(2)), 178.8 (COOH).
Acknowledgements
The author wishes to thank Dr. C. P. Mak, NOVARTIS AG, Basle, for providing graduate
student support (L. Gobbi, A. Vaupel) and helpful advice, also, Dr. W. Prikoszovich for infra-red
measurement and Dr. C. Spoendlin for analytical support.
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Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1993, 1375±1376. Davies, S. G.; Ichihara, O.; Walter, I. A. S.
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1994, 1129±1139. Bunnage, M. E.; Davies, S. G.; Goodwin, C. J.; Ischihara, O. Tetrahedron 1994, 50, 3975±3986.
Davies, S. G.; Bhalay, G. Tetrahedron: Asymmetry 1996, 7(6), 1595. Davies, S. G.; Ichihara, O. Tetrahedron:
Asymmetry 1996, 7(7), 1919. Davies, S. G.; Smyth, G. D.; Chippindale, A. M. J. Chem. Soc., Perkin Trans. 1 1999,
3089.
5. In a ®rst approach we applied the Davies chemistry to BOC protected 7-aminohept-2-enoic acid ethyl ester.
However, the success of this approach was limited by the diculty to prepare the BOC-protected aminopentanal
which rapidly cyclizes to N-Boc-1,2,3,4-dihydropyridine. Furthermore the Michael addition needs at least two
equivalents of the homochiral amine due to proton abstraction at the Boc-amide position. Replacement of the
BOC protection with the phthaloyl group did not give the desired addition product. Finally, the N-Boc-N-benzyl
protected derivative, which can be easily prepared, revealed to be resistant to the hydrogenolysis at the o-BOC-
position. This last approach was successful, but needed several more steps to obtain the desired molecule
(protection of the b-amino moiety, Boc cleavage, debenzylation, protection of the o-amino group and
deprotection of the b-amino position).
6. Stille, J. R.; Grubbs, R. H. J. Org. Chem. 1989, 54(2), 434±444.
7. An analogous synthesis of trans-2-aminocyclohexane-1-carboxylic acid starting from 7-iodohept-2-enoic acid, tert-
butyl ester through Michael addition of a lithiated chiral hydrazine has been recently reported, see: Enders, D.;
Wiedemann, J.; Bettray, W. Synlett 1995, 369±371. A synthesis of compound 7 and the enantiomer, through
Michael addition to cyclohexenecarboxylic acid tert-butyl ester, followed by a E/Z isomerisation is reported in the
literature, see: Davies, S. G.; Ichihara, O.; Walters, I. A. S. Synlett 1993, 461±462. Davies, S. G.; Ichihara, O.;
Lenoir, I.; Walters, J. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 1411±1415.
8. Under these conditions we obtained compound 7 in only 28% yield with an optical rotation of [ꢀ]D=+26.0 (c 1.25,
CHCl3). If the addition is performed at 0ꢀC, the yield rises to 47%, but the stereoselectivity is lower, as shown by
the optical rotation of only [ꢀ]D=+23.6 (c 0.46, CHCl3).
9. Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1991, 24(10), 285±289. Bestmann, H. S.; Wolfel, G. Chem. Ber. 1984,
117, 1250±1254. Ruhlmann, K. Chem. Ber. 1961, 94, 2311±2313.
10. Marfey, P. Carlsberg Res. Commun. 1984, 49, 591.
11. Winkler, M. R., et al. Chem. Commun. 1980, 87.
12. Kondo, S.; Iwasawa, H.; Ikeda, D.; Umeda, Y.; Ikeda, Y.; Iinuma, H.; Umezawa, H. J. Antibiot. 1981, 34(12),
1625±1627. The speci®c rotation of b-homolysine is strongly pH dependent. It varies between: ^1.18 under basic
conditions (0.5N NaOH), up to +20.8 in 1N HCl.
13. Marshall, W. D.; Nguyen, T. A. T.; MacLean, D. B.; Spenser, I. D. Can. J. Chem. 1975, 53, 41.
14. Morley, C.; Knight, D. W.; Share, A. C. J. Chem. Soc., Perkin Trans. 1 1994, 2903±2907.