Stereoselective synthesis of (2R,5R)- and (2S,5R)-5-hydroxylysine

Article abstract of DOI:10.1002/1099-0690(200011)2000:22<3683::AID-EJOC3683>3.0.CO;2-U

A stereoselective synthesis of (2S,5R)-5-hydroxylysine (1) and (2R,5R)-5-hydroxylysine (17), based on a concept involving Williams glycine template methodology and (R)-hydroxynitrile lyase for the introduction of chirality at the α-position and the side-chain, respectively, is described. This strategy offers an expeditious route towards orthogonally protected 5-hydroxylysines.

Full text of DOI:10.1002/1099-0690(200011)2000:22<3683::AID-EJOC3683>3.0.CO;2-U

FULL PAPER
Stereoselective Synthesis of (2R,5R)- and (2S,5R)-5-Hydroxylysine
Adrianus M. C. H. van den Nieuwendijk,[a] Nicole M. A. J. Kriek,[a] Johannes Brussee,*[a]
Jacques H. van Boom,[a] and Arne van der Gen[a]
Keywords: Asymmetric synthesis / Natural products / Cyanohydrins / Template synthesis / Amino acids
S
R
1
R
R
17
R
α
Introduction
Results and Discussion
Collagen is the major structural protein in mammals and
is a key molecule in relation to the mechanical strength of
tissues such as bone, cartilage, skin, and tendon.[1] One of
the amino acids found in collagen is (2S,5R)-5-hydroxylys-
ine (1). It was first discovered by Van Slyke et al. as a con-
stituent of protein hydrosylates.[2] Its structure was elucid-
ated in 1950[3] and, shortly thereafter, Sheehan and Bol-
hofer presented the first synthesis of ,-5-hydroxylysine.[4a]
Since then, numerous syntheses have been published, all of
them giving mixtures of stereoisomers.[4bϪ4g] Separation of
the four stereoisomers has been achieved by fractional crys-
tallization of 5-hydroxylysine derivatives.[5]
Recently, there has been renewed interest in the stereose-
lective synthesis of 5-hydroxylysine. Adamczyk et al.[6]
started from a derivative of (S)-glutamic acid and used a
diastereomeric separation to obtain a (2S,5R)-5-hydroxylys-
ine derivative. Kunz et al.[7] reported an interesting ap-
proach, combining the Schöllkopf method[8] to create the
α-stereogenic centre, and a Sharpless asymmetric aminohy-
droxylation[9] to generate the β-ethanolamine moiety of 5-
hydroxylysine. This strategy provided a stereoselective route
for the synthesis of (2S,5S)-5-hydroxylysine, but was found
to be less suitable for preparation of the naturally occurring
(2S,5R)-isomer.[7]
The retrosynthesis, depicted in Scheme 1, shows how the
orthogonally protected (2S,5R)-5-hydroxylysine derivatives
2 can be obtained from the enolate of the Williams glycine
template 3 through alkylation by electrophiles of type 4.
The latter already contain, in protected form, the β-eth-
anolamine moiety present in (2S,5R)-5-hydroxylysine. Tem-
plate 3 has proved to be an excellent enantioselective re-
agent for the synthesis of α-amino acids[10Ϫ12] and is both
commercially available[13] and readily accessible from (R)-
mandelonitrile (5) on a multigram scale.[14] Chiral iodides
of type 4 can be synthesized from (R)-cyanohydrin 6, which,
in turn, may be obtained through (R)-hydroxynitrile ly-
ase[15] mediated addition of HCN[16] to (3E)-3-hexenal.
In our research on the synthesis of collagen cross-
links,[10] we employed the Williams glycine template[11] for
the introduction of the α-stereogenic centres in the synthesis
of 5-hydroxylysylnorleucine (HLNL). However, at that
time, we were unable to introduce the 5-hydroxyl function
of HLNL in a stereoselective manner.[10]
As a result of our continuing research in this area, we
report herein the first fully stereoselective synthesis of
(2S,5R)-5-hydroxylysine (1) as well as that of a number of
orthogonally protected 5-hydroxylysine derivatives. A con-
vergent strategy, similar to that reported previously for
HLNL, has been followed.[10]
Scheme 1. Retrosynthetic analysis for the synthesis of (2S,5R)-5-hy-
droxylysine
In the first step, (3E)-3-hexenal was converted into its
(R)-cyanohydrin 6 (ee Ͼ 98%, determined as the TBDPS
ether) with the aid of purified (R)-hydroxynitrile lyase[15]
in an aqueous/organic two-phase solvent system.[17] Upon
treatment of 6 with TBSCl, O-protected cyanohydrin 7a
was obtained (Scheme 2). Conversion into O,N-protected
[a]
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden
University,
P. O. Box 9502, 2300 RA Leiden, The Netherlands
Eur. J. Org. Chem. 2000, 3683Ϫ3691
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
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3683

J. Brussee et al.
FULL PAPER
ethanolamine 8 was accomplished by a three-step, one-pot,
DIBAL reduction/transimination/NaBH4 reduction pro-
cedure,[18] using p-methoxybenzylamine (pMBn-NH2) for
the transimination with subsequent Boc-protection of the
secondary amine. Compound 8 was subjected to ozonolysis,
followed by reductive work-up, to afford a primary alcohol.
This was then converted to iodide 9 using Garegg’s
method.[19]
Scheme 3. Synthesis of protected (2S,5R)-5-hydroxylysines 2c؊f;
reagents: (a) DIBAL, (b) MeOH, (c) NaBH4, (d) Boc2O or Cbz-
Cl, (e) TBAF, (f) 2-methoxypropene, (g) O3, (h) Ts-Cl, (i) NaI, (j)
NaHMDS, 3a or 3b
Scheme 2. Synthesis of protected (2S,5R)-5-hydroxylysine em-
ploying the Williams glycine template; reagents: (a) DIBAL, (b)
MeOH, (c) pMBn-NH2, (d) NaBH4, (e) Boc2O, (f) O3, (g) triiodo-
imidazole, (h) NaHMDS
Characterization of compounds 2c؊f was achieved by
means of 300 MHz 2D H NMR techniques. Only a single
diastereoisomer was observed in each case. This indicates a
diastereoselectivity of Ͼ96% for the alkylation of the Willi-
ams glycine templates.
The versatility of the building blocks 2 is illustrated in
Scheme 4. Compound 14, a suitable intermediate for pep-
tide synthesis, was obtained in 84% yield following reduc-
tive deprotection of 2e. After removal of the isopropylidene
moiety in 70% HOAc, O-deprotected 5-hydroxylysine 15
was isolated in 89% yield. This compound may well serve as
a valuable building block in the synthesis of O-glycosylated
biologically active compounds.
1
In this way, iodide 9 was obtained from cyanohydrin 7a
in 58% overall yield. Alkylation of the Williams glycine
template was achieved using a slight modification of Bald-
win’s method.[12b] Pilot experiments indicated that optimal
alkylation results were achieved at temperatures between
Ϫ50 and Ϫ35 °C. The yields, however, were unsatisfactory
(29Ϫ43%), most probably due to steric factors concerning
iodide 9.[20] It was therefore decided to use a more rigid
compound instead of 9. This demanded several adjustments
to the synthesis, as illustrated in Scheme 3. Thus, the
TBDPS-protected cyanohydrin 7b was converted into the
O,N-protected primary amines 10a,b. Subsequent removal
of the TBDPS moiety, followed by acid-catalyzed reaction
with 2-methoxypropene,[21] afforded oxazolidines 11a,b in
excellent yields. Ozonolysis and reductive work-up gave the
primary alcohols 12a,b almost quantitatively. When conver-
sion of compounds 12a,b into the corresponding iodides
was attempted using triiodoimidazole, no reaction oc-
curred. Alternatively, 12a,b could be converted into their
tosylates. After substitution with excess NaI in refluxing
acetone, iodides 13a,b were obtained in good overall yields.
Iodides 13a and 13b gave much better yields in the al-
kylation of Williams glycine templates 3a and 3b. In accord-
ance with the literature,[12b] the Boc-protected template 3a
gave higher yields (71Ϫ80%) than the Cbz-protected tem-
plate 3b (34Ϫ58%).
Scheme 4. Selective deprotection of (2S,5R)-5-hydroxylysine; re-
agents: (a) H2/Pd/C, (b) 70% HOAc, (c) 1.5  HCl
3684
Eur. J. Org. Chem. 2000, 3683Ϫ3691

Stereoselective Synthesis of (2R,5R)- and (2S,5R)-5-Hydroxylysine
FULL PAPER
heating to 150 °C, 5% (w/v) aqueous KMnO4, or Merck ninhydrin
spray for TLC followed by heating to 150 °C. Column chromato-
graphy was performed on Baker silica gel (0.063Ϫ0.200 mm). Solv-
ents for chromatography were distilled before use. Diethyl ether was
dried over sodium wire. THF was distilled from LiAlH4. Methanol
In order to verify the stereochemistry, compound 14 was
deprotected with 1.5  HCl to obtain 1 (Scheme 4). Both
chiral HPLC and H NMR analyses of the crude product
revealed that the synthesized (2S,5R)-5-hydroxylysine (1)
was identical to a commercial sample.[22] By chiral HPLC
on a CROWNPACK CR(ϩ) column, we were able to separ-
ate (5R,S)-hydroxy-,-lysine (normal and allo forms, ratio
40:60 according to HPLC) into its four stereoisomers. By
analysis of a commercial sample,[22] the (2S,5R)-5-hy-
1
˚
was dried over molecular sieves (3 A). Toluene was distilled from
˚
and stored over molecular sieves (3 A). Commercial chemicals were
used as received. All reactions were carried out under an inert at-
mosphere. Ϫ Melting points are uncorrected. Ϫ 1H and 13C NMR
spectra were recorded on a Bruker AC-200 instrument, except in
droxylysine peak could be assigned and, by comparison of the case of compounds 2a؊f, the spectra of which were recorded
on a Bruker WM-300 instrument. The latter experiments were per-
formed at elevated temperatures to obtain well-resolved spectra.[25]
Unless otherwise stated, samples were examined in CDCl3 solution
using TMS as an internal standard for 1H NMR and CDCl3 as
internal standard for 13C NMR. Spectra recorded in [D4]methanol
were referenced to residual MeOH/MeOD (δH ϭ 4.78, δC ϭ 49.0)
as internal standard. Spectra recorded in [D6]DMSO were refer-
enced to (residual protons in) DMSO (δH ϭ 2.49, δC ϭ 39.5) as
internal standard. Enantiomeric excesses (eeЈs) were determined by
HPLC employing a Daicel CHIRALCEL OD column, eluting with
the peak areas, that of its enantiomer (2R,5S)-5-hydroxylys-
ine as well. In order to assign the two peaks due to the allo
isomers, we alkylated the enantiomer of 3b, i.e. template 16
(Scheme 5), with iodide 13a. After deprotection according
to the procedure described above, we obtained (2R,5R)-5-
hydroxylysine (17), which was eluted as the second peak in
the chromatogram of the four isomers. Thus, we were able
to establish the order of elution of the four stereoisomers
of 5-hydroxylysine on a CROWNPACK CR(ϩ) column as
being 2R,5S Ǟ 2R,5R Ǟ 2S,5R Ǟ 2S,5S. For compounds hexane (HEX)/2-propanol (IPA) mixtures, or a Daicel CROWN-
PACK CR(ϩ) column, eluting with aqueous HClO4 solutions. Elu-
ents are specified in each case. Ϫ Optical rotations were measured
on a Propol automatic polarimeter (Na D line, λ ϭ 589 nm). Ϫ
ESI-MS was performed on a PerkinϪElmer SCIEX API 165 in-
strument. ESI-HRMS was performed on a Finnigan MAT 900 in-
strument.
1 and 17, only a single isomer could be detected by HPLC.
(3E)-3-Hexenal:
A solution of 95% (3E)-3-hexenol (2.94 g,
27.93 mmol) in CH2Cl2 (20 mL) was added dropwise to a suspen-
sion of DessϪMartin periodinane[26] (12.90 g, 30.42 mmol) in
CH2Cl2 (60 mL). After a few minutes, the reaction mixture started
to boil and was allowed to do so for about five minutes. The sus-
pension thus obtained was stirred for a further 3 h at room temper-
ature. It was then filtered through a glass frit and the filtrate was
washed with saturated aqueous NaHCO3 solution (100 mL) con-
taining Na2S2O3 (25 g). The resulting clear solution was dried over
MgSO4 and filtered, and the CH2Cl2 was removed by distillation
(waterbath, max. temp. 60 °C) under argon using a 10 cm Vigreux
Scheme 5. Synthesis of (2R,5R)-5-hydroxylysine; reagents: (a)
NaHMDS, (b) iodide 13a, (c) H2/Pd/C, (d) 1.5  HCl
Conclusion
The synthetic strategy described in this paper offers two
expeditious and stereoselective routes towards the synthesis
of orthogonally protected 5-hydroxylysines. The first route,
leading to TBS-protected 5-hydroxylysines 2a,b, is short,
but gives only moderate yields in the final alkylation. The
route to 2c؊f is more laborious but offers higher efficiency.
As the Williams glycine template is available in both enanti-
omeric forms and the (S)-enantiomers of cyanohydrins 7a,b
are also available, either by using an (S)-hydroxynitrile ly-
ase[23] in the cyanohydrin synthesis or by inversion of the
configuration of (2R)-hydroxy-4E-heptenenitrile (6),[24] all
possible stereoisomers of 5-hydroxylysine have become syn-
thetically accessible by this stereoselective route. Protected
hydroxylysine 14 is now available for peptide synthesis,
while 15 should represent an excellent starting material for
O-glycosylation reactions.
1
column. According to H NMR spectroscopy, the residue (8.80 g)
consisted of a mixture of CH2Cl2, diethyl ether, and (3E)-3-hexenal
in the molar ratio 1.0:1.2:1.2 (estimated 30% w/w (3E)-3-hexenal, ഠ
26.94 mmol). Ϫ 1H NMR: δ ϭ 0.97 (t, J ϭ 7.3 Hz, 3 H, CH3),
2.10 (m, 2 H, CH3CH2), 3.12 (dd, J ϭ 6.6, 2.2 Hz, 2 H, CH2CHO),
5.58 (m, 2 H, CHϭCH), 9.66 (t, J ϭ 2.2 Hz, 1 H, CHO). Ϫ 13C
NMR: δ ϭ 13.1 (CH3), 25.4 (CH3CH2), 46.9 (CH2CHO), 118.0,
130.6 (CϭC), 199.9 (CHO).
(2R,4E)-2-Hydroxy-4-heptenenitrile (6): NaCN (4.50 g, 91.83
mmol) was dissolved in cold water (45 mL) and the pH was ad-
justed to 5.2 with citric acid. Ϫ (Caution! Toxic HCN is formed;
this operation should be performed in a well-ventilated hood!). Ϫ This
HCN buffer was extracted with tert-butyl methyl ether (3 ϫ 15 mL)
and the combined HCN extracts were placed in a reaction flask.
Purified (R)-hydroxynitrile lyase[15] (30 mg) was dissolved in 0.1 
citrate buffer (6 mL, pH 5.1) and then added to the HCN extract.
At 4 °C, the (3E)-3-hexenal solution (vide supra) was added and
the reaction mixture was stirred overnight at 4 °C. Stirring was
then stopped, the aqueous layer was discarded, and the organic
layer was dried over MgSO4. After filtration and evaporation of the
solvent in vacuo (max. temp. 35 °C), the crude (2R,4E)-hydroxy-4-
Experimental Section
General Remarks: TLC analyses were performed on Merck plastic-
backed silica gel 60 F254 plates. Detection by UV (λ ϭ 254 nm) or
by developing with ammonium molybdate (50 g dmϪ3
)
and
heptenenitrile (3.30 g, 94%) was obtained as an orange oil. [α]2D0
ϩ22 (c ϭ 1, CH2Cl2). Ϫ H NMR: δ ϭ 1.02 (t, J ϭ 7.3 Hz, 3 H,
ϭ
1
cerium(IV) sulfate (1 g dmϪ3) in aqueous 10% H2SO4 followed by
Eur. J. Org. Chem. 2000, 3683Ϫ3691
3685

J. Brussee et al.
FULL PAPER
CH3), 2.07 (m, 2 H, CH3CH2), 2.55 (m, 2 H, CH2CHO), 4.48 (t, CH2Cl2). Ϫ ESI-MS: m/z ϭ 364.4 [M ϩ H]ϩ. Ϫ 1H NMR: δ ϭ
J ϭ 5.8 Hz, 1 H, CHOH), 5.49 (m, 1 H, CHϭCH), 5.82 (m, 1 H, 0.12 (s, 3 H, CH3Si), 0.13 (s, 3 H, CH3Si), 0.98 [s, 9 H, (CH3)3CSi],
CHϭCH). Ϫ 13C NMR: δ ϭ 13.1 (CH3), 25.3 (CH3CH2), 37.9 1.03 (t, J ϭ 7.3 Hz, 3 H, CH3), 2.06 (m, 2 H, CH3CH2), 2.27 (m,
(CH2CHϭ), 61.0 (CHOH), 119.6 (CN), 120.6, 137.9 (CϭC).
2 H, ϭCHCH2), 2.68 (m, 2 H, CH2N), 3.45 (m, 1 H, CHOSi), 3.72
(m, 2 H, PhCH2), 3.87 (s, 3 H, OCH3), 5.49 (m, 2 H, CHϭCH),
6.93 (d, J ϭ 8.8 Hz, 2 H, arom.), 7.33 (d, J ϭ 3.7 Hz, 2 H, arom.).
(2R,4E)-2-(tert-Butyldimethylsilyl)oxy-4-heptenenitrile (7a): To an
ice-cold solution of 97% tert-butyldimethylsilyl chloride (2.41 g,
15.51 mmol) and imidazole (1.90 g, 27.94 mmol) in DMF (30 mL)
was added crude (2R,4E)-hydroxy-4-heptenenitrile (1.25 g,
10.00 mmol). After stirring overnight at room temperature, the
mixture was poured into water (60 mL) and extracted with diethyl
Ϫ
13C NMR: δ ϭ Ϫ5.3 [(CH3)2Si], 13.4 (CH3), 17.8 [(CH3)3CSi],
25.4 (CH3CH2), 25.6 [(CH3)3CSi], 38.9 (ϭCHCH2), 53.0 (CH2N),
54.2 (PhCH2), 54.8 (OCH3), 71.6 (CHOSi), 113.4, 113.6, 128.8,
132.3, 158.3 (arom.), 124.8, 134.3 (CϭC).
ether (3 ϫ 20 mL). The combined ethereal extracts were washed (2R,4E)-2-(tert-Butyldimethylsilyl)oxy-1-[(tert-butyloxycarbonyl)(p-
with water (20 mL) and brine (20 mL). After drying (MgSO4) and
evaporation of the solvent, the protected cyanohydrin 7a was ob-
tained. Purification by column chromatography [silica gel, light pet-
roleum/ethyl acetate, 97.5:2.5) afforded 1.74 g of 7a (64% based on
methoxybenzyl)]amino-4-heptene (8): Crude (2R,4E)-2-(tert-butyldi-
methylsilyl)oxy-1-(p-methoxybenzyl)amino-4-heptene (6.90 mmol)
was dissolved in CH2Cl2 (35 mL). Diisopropylethylamine (3.50 mL,
20.13 mmol) and di-tert-butyl dicarbonate (3.00 g, 13.76 mmol)
were added and the reaction mixture was stirred for 16 h at room
(3E)-3-hexenol] as a colorless oil. [α]2D0 ϭ ϩ29 (c ϭ 1, CH2Cl2). Ϫ
1
ESI-MS: m/z ϭ 262.1 [M ϩ Na]ϩ. Ϫ H NMR: δ ϭ 0.13 (s, 3 H, temperature. After evaporation of the solvent, the residual oil was
CH3Si), 0.17 (s, 3 H, CH3Si), 0.89 [s, 9 H, (CH3)3CSi], 0.99 (t, J ϭ subjected to silica gel chromatography (0 Ǟ10% diethyl ether/light
7.3 Hz, 3 H, CH3), 2.05 (m, 2 H, CH3CH2), 2.46 (t, J ϭ 6.6 Hz, 2
petroleum) to afford 2.65 g (83%) of compound 8. [α]2D0 ϭ Ϫ23 (c ϭ
1
H, ϭCHCH2), 4.37 (t, J ϭ 6.6 Hz, 1 H, CHOSi), 5.39 (m, 1 H, 1, CH2Cl2). Ϫ ESI-MS: m/z ϭ 464.4 [M ϩ H]ϩ. Ϫ H NMR: δ ϭ
CHϭCH), 5.67 (m, 1 H, CHϭCH). Ϫ 13C NMR: δ ϭ Ϫ5.63,
0.01 (s, 3 H, CH3Si), 0.05 (s, 3 H, CH3Si), 0.91 [s, 9 H, (CH3)3CSi],
Ϫ5.48 [(CH3)2Si], 13.2 (CH3), 17.8 [(CH3)3C], 25.2 [(CH3)3CSi], 1.12 (t, J ϭ 8.7 Hz, 3 H, CH3), 1.53 [s, 9 H, (CH3)3CO], 1.98 (m,
25.6 (CH3CH2), 39.4 (ϭCHCH2), 62.1 (CHOSi), 119.4 (CN), 2 H, CH3CH2), 2.11 (t, J ϭ 6.6 Hz, 2 H, ϭCHCH2), 2.85 (m, 2 H,
121.2, 137.6 (CϭC).
CH2N), 3.33 (m, 1 H, CHOSi), 3.80 (s, 3 H, OCH3), 4.21 (d, J ϭ
14.7 Hz, 1 H, PhCH2), 4.63 (d, J ϭ 14.7 Hz, 1 H, PhCH2), 5.42
(m, 2 H, CHϭCH), 6.85 (d, J ϭ 8.1 Hz, 2 H, arom.), 7.17 (d, J ϭ
8.1 Hz, 2 H, arom.). Ϫ 13C NMR: δ ϭ Ϫ4.8 [(CH3)2Si], 13.5 (CH3),
17.8 [(CH3)3CSi], 25.4 (CH3CH2), 25.6 [(CH3)3CSi], 28.3
[(CH3)3CO], 39.0 (ϭCHCH2), 51.9 (CH2N), 54.9 (OCH3), 60.1
(PhCH2), 71.5 (CHOSi), 113.6, 128.8, 128.9, 130.6, 158.1 (arom.),
124.5, 134.6 (CϭC), 155.4 (CϭO).
(2R,4E)-2-(tert-Butyldiphenylsilyl)oxy-4-heptenenitrile (7b): To an
ice-cold solution of 97% tert-butyldiphenylsilyl chloride (5.92 g,
20.88 mmol) and imidazole (3.17 g, 46.62 mmol) in DMF (40 mL)
was added crude (2R,4E)-hydroxy-4-heptenenitrile (1.90 g,
15.20 mmol). After stirring overnight at room temperature, the
mixture was poured into water (100 mL) and extracted with diethyl
ether (3 ϫ 30 mL). The combined ethereal extracts were washed
with water (30 mL) and brine (30 mL). After drying over MgSO4
and evaporation of the solvent, the protected cyanohydrin 7b was
obtained. Purification by column chromatography afforded 4.41 g
[76% based on (3E)-3-hexenol] as a colorless oil. [α]2D0 ϭ ϩ19 (c ϭ
1, CH2Cl2). Ϫ HPLC: CHIRALCEL OD, eluent hexane/2-pro-
(2R)-2-(tert-Butyldimethylsilyl)oxy-1-[(tert-butyloxycarbonyl)(p-
methoxybenzyl)]amino-4-butanol: A solution of olefin 8 (2.04 g,
4.40 mmol) in CH2Cl2 (100 mL) and MeOH (5 mL) was cooled to
Ϫ70 °C and ozone was passed through it until a blue color per-
sisted. Stirring was continued for a further 30 min. at Ϫ70 °C and
panol, 99.75:0.25, 1.0 mL/min, UV 254 nm: (R)-10 tR ϭ 5.48 min, then a stream of oxygen was bubbled through the solution to re-
(S)-10 tR ϭ 8.21 min, ee Ͼ98%. Ϫ ESI-MS: m/z ϭ 364.2 [M ϩ
move the excess ozone. NaBH4 (0.28 g, 7.37 mmol) was added and,
after stirring overnight at room temperature, the reaction mixture
H]ϩ, 386.1 [M ϩ Na]ϩ. Ϫ 1H NMR: δ ϭ 0.95 (t, J ϭ 7.3 Hz, 3 H,
CH3), 1.09 [s, 9 H, (CH3)3CSi], 2.01 (m, 2 H, CH3CH2), 2.42 (m, was poured into water (60 mL). The layers were separated and the
2 H, ϭCHCH2), 4.30 (t, J ϭ 6.6 Hz, 1 H, CHOSi), 5.36 (m, 1 H, aqueous layer was extracted with diethyl ether (3 ϫ 50 mL). The
CHϭCH), 5.56 (m, 1 H, CHϭCH), 7.40 (m, 6 H, arom.), 7.67 (m, combined organic layers were dried (MgSO4), filtered, and concen-
4 H, arom.). Ϫ 13C NMR: δ ϭ 13.4 (CH3), 19.2 [(CH3)3CSi], 25.6 trated. Purification by silica gel column chromatography (0 Ǟ 20%
(CH3CH2), 26.7 [(CH3)3CSi], 39.4 (ϭCHCH2), 63.1 (CHOSi), ethyl acetate in light petroleum) yielded the title compound as a
119.0 (CN), 121.2, 137.9 (CϭC), 128.0, 130.4, 131.6, 132.0, 135.7, colorless oil (1.63 g, 84%). [α]2D0 ϭ Ϫ17 (c ϭ 1, CH2Cl2). Ϫ ESI-
1
135.8 (arom.).
MS: m/z ϭ 440.0 [M ϩ H]ϩ, 462.3 [M ϩ Na]ϩ. Ϫ H NMR: δ ϭ
0.07 (s, 3 H, CH3Si), 0.09 (s, 3 H, CH3Si), 0.91 [s, 9 H, (CH3)3CSi],
1.46 [s, 9 H, (CH3)3CO], 1.68 (m, 2 H, CH2), 1.78 (m, 1 H, CH2N),
3.09 (m, 1 H, CH2N), 3.49 (m, 1 H, CHOSi), 3.74 (t, J ϭ 7.3 Hz,
2 H, CH2OH), 3.80 (s, 3 H, OCH3), 4.10 (br. s, 1 H, OH), 4.26 (d,
J ϭ 16.1 Hz, 1 H, PhCH2), 4.61 (d, J ϭ 15.4 Hz, 1 H, PhCH2),
6.86 (d, J ϭ 8.0 Hz, 2 H, arom.), 7.14 (d, J ϭ 8.0 Hz, 2 H, arom.).
(2R,4E)-2-(tert-Butyldimethylsilyl)oxy-1-(p-methoxybenzyl)amino-
4-heptene: To a cooled (Ϫ80 °C) solution of nitrile 7a (1.65 g,
6.90 mmol) in dry diethyl ether (50 mL), DIBAL (11.7 mL, 1.0 
in hexane) was added dropwise and the mixture was allowed to
warm to Ϫ5 °C. After cooling to Ϫ95 °C, dry methanol (14 mL)
was added followed, after five minutes, by p-methoxybenzylamine
(3.80 mL, 29.12 mmol). The cooling bath was then removed and
the reaction mixture was stirred at room temperature for 2.5 hours.
After cooling to Ϫ3 °C, NaBH4 (0.69 g, 18.16 mmol) was added.
The resulting mixture was stirred overnight at room temperature
and then poured into 0.4  NaOH (75 mL). The layers were separ-
ated and the aqueous layer was extracted with diethyl ether (3 ϫ
50 mL). The combined organic layers were washed with aqueous
Ϫ
13C NMR: δ ϭ Ϫ5.3 [(CH3)2Si], 17.8 [(CH3)3CSi], 25.4
[(CH3)3CSi], 27.9 [(CH3)3CO], 37.5 (CH2), 51.7 (CH2N), 54.6
(OCH3), 58.4 (PhCH2), 59.8 (CH2OH), 68.6 (CHOSi), 79.3
[(CH3)3CO], 113.4, 127.9, 128.5, 130.0, 158.4 (arom.), 155.4 (Cϭ
O).
(2R)-2-(tert-Butyldimethylsilyl)oxy-1-[(tert-butyloxycarbonyl)(p-
methoxybenzyl)]amino-4-iodobutane (9): The aforementioned alco-
KHSO4 (1 , 50 mL), NaOH (0.8 , 40 mL), and brine (40 mL). hol (0.44 g, 1.00 mmol), imidazole (0.14 g, 2.06 mmol), and triiodo-
The organic phase was then dried (MgSO4), filtered, and concen-
imidazole (0.71 g, 1.58 mmol) were co-evaporated with dry toluene
(2 ϫ 5 mL). The residue was redissolved in toluene (15 mL) and
trated in vacuo to yield the crude amine. [α]2D0 ϭ Ϫ15 (c ϭ 1,
3686
Eur. J. Org. Chem. 2000, 3683Ϫ3691

Stereoselective Synthesis of (2R,5R)- and (2S,5R)-5-Hydroxylysine
FULL PAPER
triphenylphosphane (1.00 g, 3.81 mmol) was added. The reaction
mixture was refluxed for 15 min., after which TLC indicated com-
plete conversion of the starting material. At room temperature, the
obtained solids were dissolved by adding acetone (5 mL) and 10%
aqueous NaHCO3 (5 mL). The resulting mixture was diluted with
diethyl ether (20 mL) and washed with Na2S2O3 (10 mL, 1 ) and
tained in 29% yield. [α]2D0 ϭ Ϫ22 (c ϭ 1, CH2Cl2). Ϫ ESI-MS:
m/z ϭ 809.5 [M ϩ H]ϩ, 831.6 [M ϩ Na]ϩ. Ϫ 1H NMR
([D6]DMSO, 95 °C): δ ϭ 0.06 (s, 3 H, CH3Si), 0.09 (s, 3 H, CH3Si),
0.90 [s, 9 H, (CH3)3CSi], 1.41 [s, 9 H, (CH3)3CO], 1.69 (m, 2 H,
CH2), 2.17 (m, 2 H, CH2), 3.07 (dd, J ϭ 6.6, 14.6 Hz, 1 H, CH2N),
3.28 (dd, J ϭ 5.9, 14.6 Hz, 1 H, CH2N), 3.75 (s, 3 H, OCH3), 4.02
NaHCO3 (10 mL, 1 ). The ether layer was dried over MgSO4, (dd, J ϭ 5.8, 11.3 Hz, 1 H, CHOSi), 4.39 (AB, J ϭ 15.7 Hz, 2 H,
filtered, and concentrated under reduced pressure, and the residual
oil was subjected to silica gel chromatography. Elution with diethyl
ether/toluene (0 Ǟ 10%) afforded 0.99 g (83%) of iodide 9 as a
yellow oil. [α]2D0 ϭ ϩ4.4° (c ϭ 1, CH2Cl2). Ϫ ESI-MS: m/z ϭ 550.5
PhCH2), 4.80 (dd, J ϭ 6.2, 8.0 Hz, 1 H, CHN), 4.98 (s, 2 H,
PhCH2), 5.30 (d, J ϭ 2.9 Hz, 1 H, PhCHN), 6.14 (d, J ϭ 2.9 Hz,
1 H, PhCHO), 6.58 (s, 1 H, arom.), 6.61 (s, 1 H, arom.), 6.90 (d,
J ϭ 8.8 Hz, 2 H, arom.), 7.13 (m, 16 H, arom.). Ϫ 13C NMR
[M ϩ H]ϩ, 572.2 [M ϩ Na]ϩ. Ϫ 1H NMR: δ ϭ 0.04 (s, 3 H, ([D6]DMSO, 95 °C): δ ϭ Ϫ5.4, Ϫ5.3 [(CH3)2Si], 16.9 [(CH3)3CSi],
CH3Si), 0.09 (s, 3 H, CH3Si), 0.88 [s, 9 H, (CH3)3CSi], 1.48 [s, 9 H, 25.0 [(CH3)3CSi], 27.4 [(CH3)3CO], 28.8, 30.6 (CH2), 50.1 (CH2N),
(CH3)3CO], 1.99 (m, 2 H, CH2), 3.17 (m, 4 H, CH2, CH2I), 3.80 51.0 (OCH3), 56.8 (CϭOCHN), 59.7 (PhCHN), 66.2 (PhCH2), 69.4
(s, 3 H, OCH3), 3.94 (m, 1 H, CHOSi), 4.31 (d, J ϭ 15.4 Hz, 1 H,
(CHOSi), 77.7 (PhCHO), 78.5 [(CH3)3CO], 113.6, 125.7, 126.6,
PhCH2), 4.54 (d, J ϭ 15.4 Hz, 1 H, PhCH2), 6.86 (d, J ϭ 8.8 Hz, 126.8, 127.0, 127.3, 127.7, 129.9, 134.0, 135.6, 154.5 (arom.), 148.7,
2 H, arom.), 7.14 (m, 2 H, arom.). Ϫ 13C NMR: δ ϭ Ϫ4.8
[(CH3)2Si], 1.6 (CH2I), 17.6 [(CH3)3CSi], 25.5 [(CH3)3CSi], 28.1
[(CH3)3CO], 39.2 (CH2), 50.7 (CH2N), 51.1 (PhCH2), 54.6 (OCH3),
70.3 (CHOSi), 79.4 [(CH3)3CO], 113.6, 128.0, 128.6, 130.4, 158.6
(arom.), 155.2 (C؍O).
153.0 (NϪCϭO), 167.4 (OϪCϭO).
(2R,4E)-1-Amino-2-(tert-butyldiphenylsilyl)oxy-4-heptene: At Ϫ85
°C, DIBAL (20 mL, 1  in hexane) was added dropwise to a solu-
tion of O-protected nitrile 7b (4.29 g, 11.81 mmol) in dry diethyl
ether (100 mL). The solution was allowed to warm to Ϫ5 °C. After
cooling to Ϫ95 °C, dry methanol (25 mL) was quickly added, fol-
Alkylation of the Williams Template (General Procedure): The ap-
propriate Williams glycine template (1.50 mmol) and 15-crown-5 lowed by NaBH4 (1.30 g, 34.21 mmol). The cooling bath was then
(1.60 mL, 8.06 mmol) were co-evaporated twice with toluene and
removed and the mixture was stirred at room temperature for 1 h.
subsequently dissolved in dry THF (30 mL). At Ϫ78 °C, sodium
It was then poured into aqueous 0.6  NaOH (100 mL). The layers
bis(trimethylsilyl)amide (1.50 mL, 1.50 mmol, 1  in THF) was ad- were separated and the aqueous layer was extracted with diethyl
ded dropwise. After 5 min., a solution of the appropriate iodide
(1.20 mmol) in THF (10 mL) was added dropwise over a period of
ether (2 ϫ 50 mL). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo to yield 4.47 g
5 min. at Ϫ70 °C. The mixture was then stirred for 3 h at Ϫ50 Ǟ (103%) of the crude amine as a colorless oil. [α]2D0 ϭ Ϫ20 (c ϭ 1,
Ϫ35 °C. The reaction was subsequently quenched by adding a mix-
ture of EtOAc (20 mL) and water (5 mL) and the resulting mixture
was allowed to warm to room temperature. After dilution with
EtOAc (50 mL), washing with water (20 mL) and brine (20 mL),
drying over MgSO4, and evaporation of the solvent, the crude
product was obtained. Purification by column chromatography (sil-
CH2Cl2). Ϫ ESI-MS: m/z ϭ 368.2 [M ϩ H]ϩ. Ϫ 1H NMR: δ ϭ
0.90 (t, J ϭ 8.0 Hz, 3 H, CH3), 1.07 [s, 9 H, (CH3)3C], 1.93 (m, 2
H, CH3CH2), 2.17 (m, 2 H, ϭCHCH2), 2.65 (m, 2 H, CH2NH2),
3.67 (m, 1 H, CHOSi), 5.34 (m, 2 H, CHϭCH), 7.41 (m, 6 H,
arom.), 7.66 (m, 4 H, arom.). Ϫ 13C NMR: δ ϭ 13.5 (CH3), 19.1
[(CH3)3CSi], 25.4 (CH3CH2), 26.9 [(CH3)3CSi], 37.7 (ϭCHCH2),
ica gel, light petroleum/ethyl acetate mixtures) afforded the pure 46.6 (CH2NH2), 74.7 (CHOSi), 124.6, 134.4 (CϭC), 133.9 (ipso),
protected hydroxylysines 2.
127.4, 129.5, 135.6, 135.7 (arom.).
tert-Butyl (3ЈR,3S,5S,6R)-3-{3Ј-(tert-Butyldimethylsilyloxy)-4Ј-
[tert-butyloxycarbonyl(p-methoxybenzyl)amino]butyl}-2-oxo-5,6-
diphenylmorpholine-4-carboxylate (2a): From template 3a (0.54
(2R,4E)-2-(tert-Butyldiphenylsilyl)oxy-1-(tert-butyloxycarbonyl)-
amino-4-heptene (10a): The aforementioned crude amine (4.47 g)
was dissolved in a two-phase system consisting of CH2Cl2 (50 mL)
mmol) and iodide 9 (0.51 mmol), compound 2a (170 mg) was ob- and saturated aqueous NaHCO3 solution (100 mL). At 5 °C,
tained in 43% yield. [α]2D0 ϭ Ϫ13 (c ϭ 0.9, CH2Cl2). Ϫ ESI-HRMS:
m/z ϭ 775.43876 Ϯ 0.00294 [M ϩ H]ϩ; calcd. 775.43537. Ϫ 1H
NMR ([D6]DMSO, 120 °C): δ ϭ 0.06 (s, 3 H, CH3Si), 0.10 (s, 3
Boc2O (8.20 g, 37.61 mmol) was added and the mixture was stirred
vigorously overnight at room temperature. The layers were then
separated and the aqueous layer was extracted once with CH2Cl2.
H, CH3Si), 0.90 [s, 9 H, (CH3)3CSi], 1.17 [br. s, 9 H, (CH3)3CO], The combined organic layers were dried over MgSO4 and concen-
1.40 [s, 9 H, (CH3)3CO], 1.68 (m, 2 H, CH2), 2.13 (m, 2 H, CH2), trated in vacuo. The crude product was purified by column chroma-
3.08 (dd, J ϭ 6.7, 14.1 Hz, 1 H, CH2N), 3.28 (dd, J ϭ 5.9, 14.1 Hz,
tography (silica gel, light petroleum/ethyl acetate, 98:2 Ǟ 95:5) to
1 H, CH2N), 3.73 (s, 3 H, OCH3), 4.03 (m, 1 H, CHOSi), 4.39 (AB,
yield 4.58 g (83%, based on 7b) of urethane 10a. [α]2D0 ϭ Ϫ7.2 (c ϭ
J ϭ 15.4 Hz, 2 H, PhCH2), 4.76 (t, J ϭ 7.2 Hz, 1 H, CHN), 5.17 1, CH2Cl2). Ϫ ESI-MS: m/z ϭ 468.5 [M ϩ H]ϩ, 490.4 [M ϩ Na]ϩ.
(d, J ϭ 2.8 Hz, 1 H, PhCHN), 6.12 (d, J ϭ 2.8 Hz, 1 H, PhCHO),
6.56 (s, 1 H, arom.), 6.59 (s, 1 H, arom.), 6.88 (d, J ϭ 8.7 Hz, 2 H,
Ϫ
1H NMR: δ ϭ 0.90 (t, J ϭ 7.3 Hz, 3 H, CH3), 1.07 [s, 9 H,
(CH3)3CSi], 1.41 [s, 9 H, (CH3)3CO], 1.92 (m, 2 H, CH3CH2), 2.12
arom.), 7.16 (m, 10 H, arom.). Ϫ 13C NMR ([D6]DMSO, 95 °C): (t, J ϭ 6.2 Hz, 2 H, ϭCHCH2), 3.10 (m, 2 H, CH2N), 3.77 (m, 1
δ ϭ Ϫ5.3, Ϫ5.2 [(CH3)2Si], 17.0 [(CH3)3CSi] 25.2 [(CH3)3CSi], 27.0,
H, CHOSi), 4.66 (br. s, 1 H, NH), 5.32 (m, 2 H, CHϭCH), 7.41
27.5 [(CH3)3CO], 29.2, 30.7 (CH2), 50.2 (CH2N), 51.1 (OCH3), 56.3 (m, 6 H, arom.), 7.65 (m, 4 H, arom.). Ϫ 13C NMR: δ ϭ 13.5
(CϭOCHN), 59.9 (PhCHN), 69.5 (CHOSi), 77.8 (PhCHO), 78.6, (CH3), 19.2 [(CH3)3CSi], 25.5 (CH3CH2), 26.9 [(CH3)3CSi], 28.2
79.8 [(CH3)3CO], 113.6, 125.8, 126.7, 127.1, 127.5, 127.8, 130.0,
134.2, 136.4, 154.6 (arom), 152.4, 158.3 (NϪCϭO), 168.0
(OϪCϭO).
[(CH3)3CO], 38.3 (ϭCHCH2), 45.3 (CH2N), 72.6 (CHOSi), 78.5
[(CH3)3CO], 124.0, 135.1 (CϭC), 127.5, 127.6, 129.6, 133.8, 135.6,
135.7 (arom.), 155.6 (CϭO).
Benzyl (3ЈR,3S,5S,6R)-3-{3Ј-(tert-Butyldimethylsilyloxy)-4Ј-[tert-
butyloxycarbonyl(p-methoxybenzyl)amino]butyl}-2-oxo-5,6-di-
phenylmorpholine-4-carboxylate (2b): From template 3b (0.83
mmol) and iodide 9 (0.83 mmol), compound 2b (197 mg) was ob-
(2R,4E)-2-(tert-Butyldiphenylsilyl)oxy-1-(benzyloxycarbonyl)amino-
4-heptene (10b): The aforementioned crude amine (1.90 g,
5.18 mmol) was dissolved in CH2Cl2 (35 mL). Diisopropylethyl-
amine (1.10 g, 8.10 mmol) and N-(benzyloxycarbonyloxy)succinim-
Eur. J. Org. Chem. 2000, 3683Ϫ3691
3687

J. Brussee et al.
ine (2.01 g, 8.10 mmol) were added. After stirring overnight, the 36.0 (ϭCHCH2), 50.1 (CH2N), 73.1 (CHO), 79.0 [(CH3)3CO], 92.8
FULL PAPER
mixture was diluted with diethyl ether (50 mL), washed with water,
dried (MgSO4), filtered, and concentrated. The residue was applied
to a silica gel column and elution with light petroleum/ethyl acetate
(98:2 Ǟ 90:10) furnished 2.18 g of urethane 10b (81% yield based
on 7b). [α]2D0 ϭ Ϫ2.3 (c ϭ 1, CH2Cl2). Ϫ ESI-MS: m/z ϭ 502.3 [M
[(CH3)2C], 123.1, 134.9 (CϭC), 151.4 (CϭO).
(5R,2E)-3-(Benzyloxycarbonyl)-2,2-dimethyl-5-(pent-2-enyl)-
oxazolidine (11b): (2R,4E)-1-(Benzyloxycarbonyl)amino-4-hepten-
2-ol was dissolved in a mixture of acetone (10 mL) and 2,2-dime-
thoxypropane (30 mL). The pH was adjusted to 5.0 using p-tolu-
enesulfonic acid. After stirring overnight at room temperature, the
reaction mixture was neutralized with triethylamine and the solv-
ents were evaporated. Purification of the residue by silica gel col-
umn chromatography (light petroleum/ethyl acetate, 95:5 Ǟ 90:10)
1
ϩ H]ϩ, 524.4 [M ϩ Na]ϩ. Ϫ H NMR: δ ϭ 0.89 (t, J ϭ 7.3 Hz, 3
H, CH3), 1.05 [s, 9 H, (CH3)3CSi], 1.91 (m, 2 H, CH3CH2), 2.13
(m, 2 H, ϭCHCH2), 3.20 (m, 2 H, CH2N), 3.78 (m, 1 H, CHOSi),
5.04 (s, 2 H, PhCH2), 5.29 (m, 2 H, CHϭCH), 7.35 (m, 11 H,
arom.), 7.65 (m, 4 H, arom.). Ϫ 13C NMR: δ ϭ 13.2 (CH3), 18.9
[(CH3)3CSi], 25.2 (CH3CH2), 26.6 [(CH3)3CSi], 37.8 (ϭCHCH2),
48.0 (CH2N), 66.0 (PhCH2), 72.1 (CHOSi), 123.6, 135.4 (CϭC),
127.2, 127.3, 127.5, 128.0, 129.4, 133.4, 135.5, 136.4 (arom.), 155.9
(C؍O).
furnished oxazolidine 11b (1.20 g, 97%) as a colorless oil. [α]2D0
ϭ
Ϫ25 (c ϭ 1, CH2Cl2). Ϫ ESI-MS: m/z ϭ 304.1 [M ϩ H]ϩ, 326.1
[M ϩ Na]ϩ. Ϫ 1H NMR: δ ϭ 0.96 (t, J ϭ 7.3 Hz, 3 H, CH3), 1.53
(s, 3 H, CH3), 1.62 (s, 3 H, CH3), 2.01 (m, 2 H, CH3CH2), 2.22 (m,
1 H, ϭCHCH2), 2.41 (m, 1 H, ϭCHCH2), 3.14 (m, 1 H, CH2N),
3.70 (m, 1 H, CH2N), 4.07 (m, 1 H, CHO), 5.13 (s, 2 H, PhCH2),
5.36 (m, 1 H, CHϭCH), 5.58 (m, 1 H, CHϭCH), 7.36 (m, 5 H,
arom.). Ϫ 13C NMR: δ ϭ 13.3 (CH3), 24.3 (CH3), 25.2 (CH3CH2),
26.3 (CH3), 35.8 (ϭCHCH2), 50.1 (CH2N), 66.3 (PhCH2), 73.2
(CHO), 93.1 [(CH3)2C], 122.9, 135.1 (CϭC), 127.5, 128.0, 136.4
(arom.), 151.8 (C؍O).
(2R,4E)-1-(tert-Butyloxycarbonyl)amino-4-hepten-2-ol:
Urethane
10a (4.58 g, 9.81 mmol) was dissolved in THF (100 mL). At 5 °C,
TBAF (4.80 g, 15.24 mmol) was added. The mixture was stirred
overnight, after which TLC showed that the starting material had
been completely consumed. Evaporation of the solvent and puri-
fication of the residue by column chromatography (silica gel, light
petroleum/ethyl acetate, 95:5 for elution of Si compounds, 70:30 for
elution of the alcohol) yielded 1.85 g (83%) of the title alcohol. [α]
(5R)-3-(tert-Butyloxycarbonyl)-5-(1-hydroxyethyl)-2,2-dimethyl-
oxazolidine (12a): Alkene 11a (2.10 g, 7.80 mmol) was dissolved in
a mixture of CH2Cl2 (60 mL) and MeOH (8 mL). At Ϫ78 Ǟ Ϫ72
°C, ozone was passed through the solution until a blue color per-
sisted. The reaction mixture was stirred for a further 30 min. at
Ϫ75 °C and then oxygen was passed through it for 5 min. There-
after, NaBH4 (1.45 g, 38.16 mmol) was added and the resulting
mixture was allowed to warm slowly to room temperature and then
stirred for a further 2 h. Diethyl ether (100 mL) was added and the
solution was washed with water (30 mL) and brine (30 mL). After
drying (MgSO4) and evaporation of the solvent, column chromato-
graphy (silica gel, light petroleum/ethyl acetate, 1:1) of the residue
furnished alcohol 12a (1.85 g, 97%) as a colorless oil. [α]2D0 ϭ Ϫ19
(c ϭ 1, CH2Cl2). Ϫ ESI-MS: m/z ϭ 246.0 [M ϩ H]ϩ, 268.0 [M ϩ
Na]ϩ. Ϫ 1H NMR: δ ϭ 1.47 [s, 9 H, (CH3)3CO], 1.56 (s, 3 H,
CH3), 1.59 (s, 3 H, CH3), 1.87 (m, 2 H, CH2), 2.11 (t, J ϭ 5.1 Hz,
1 H, CH2N), 3.13 (t, J ϭ 9.5 Hz, 1 H, CH2N), 3.79 (m, 3 H,
CH2OH), 4.25 (m, 1 H, CHO). Ϫ 13C NMR: δ ϭ 24.2, 26.2
[(CH3)2C], 27.9 [(CH3)3CO], 35.5 (CH2), 50.6 (CH2N), 58.2
(CH2O), 71.1 (CHO), 79.1 [(CH3)3CO], 92.4 [(CH3)2C], 151.5
(CϭO).
ϭ Ϫ5.4 (c ϭ 1, CH2Cl2). Ϫ ESI-MS: m/z ϭ 252.1 [M ϩ Na]ϩ.
20
D
Ϫ
1H NMR: δ ϭ 0.98 (t, J ϭ 7.3 Hz, 3 H, CH3), 1.45 [s, 9 H,
(CH3)3CO], 2.04 (m, 2 H, CH3CH2), 2.17 (m, 2 H, ϭCHCH2), 2.32
(br. s, 1 H, OH), 3.02 (m, 1 H, CH2N), 3.30 (m, 1 H, CH2N), 3.69
(m, 1 H, CHOH), 4.91 (br. s, 1 H, NH), 5.42 (m, 1 H, CHϭCH),
5.57 (m, 1 H, CHϭCH). Ϫ 13C NMR: δ ϭ 13.3 (CH3), 25.1
(CH3CH2), 28.0 [(CH3)3CO], 37.7 (ϭCHCH2), 45.5 (CH2N), 70.4
(CHOH), 79.4 [(CH3)3CO], 123.9, 134.5 (CϭC), 156.4 (CϭO).
(2R,4E)-1-(Benzyloxycarbonyl)amino-4-hepten-2-ol: Prepared from
urethane 10b (2.18 g, 4.35 mmol) as described above. Purification
by silica gel column chromatography (light petroleum/ethyl acetate,
90:10 Ǟ 60:40) gave the title alcohol in 94% yield (1.08 g). [α]2D0
ϭ
Ϫ9.0 (c ϭ 1, CH2Cl2). Ϫ ESI-MS: m/z ϭ 263.9 [M ϩ H]ϩ, 285.9
[M ϩ Na]ϩ. Ϫ 1H NMR: δ ϭ 0.98 (t, J ϭ 7.3 Hz, 3 H, CH3), 2.11
(m, 5 H, CH3CH2, ϭCHCH2, OH), 3.09 (m, 1 H, CH2N), 3.37 (m,
1 H, CH2N), 3.71 (m, 1 H, CHOH), 5.11 (s, 2 H, PhCH2), 5.37
(m, 1 H, CHϭCH), 5.60 (m, 1 H, CHϭCH), 7.36 (s, 5 H, arom.).
Ϫ
13C NMR: δ ϭ 13.2 (CH3), 25.1 (CH3CH2), 37.5 (ϭCHCH2),
45.8 (CH2N), 60.0 (PhCH2), 70.1 (CHOH), 123.8, 135.0 (CϭC),
127.5, 127.9, 136.1 (arom.), 156.7 (C؍O).
(5R)-3-(Benzyloxycarbonyl)-5-(1-hydroxyethyl)-2,2-dimethyl-
oxazolidine (12b): Alcohol 12b was prepared from 11b as described
for 12a. Yield 1.06 g (95%). Ϫ [α]2D0 ϭ Ϫ15 (c ϭ 1, CH2Cl2). Ϫ
(5R,2E)-3-(tert-Butyloxycarbonyl)-2,2-dimethyl-5-(pent-2-enyl)-
oxazolidine (11a): (2R,4E)-1-(tert-Butyloxycarbonyl)amino-4-
hepten-2-ol (1.85 g, 8.14 mmol) was dissolved in a mixture of
CH2Cl2 (20 mL) and 2-methoxypropene (3 mL) and pyridinium p-
toluenesulfonate (58 mg, 0.23 mmol) was added. TLC analysis after
2.5 h showed that the reaction had reached completion. Saturated
aqueous NaHCO3 solution (5 mL) was then added and the mixture
was stirred for 10 min. The layers were separated and the organic
layer was concentrated. Purification of the residue by column chro-
matography (silica gel, light petroleum/ethyl acetate, 9:1 Ǟ 7:3) af-
ESI-MS: m/z ϭ 280.0 [M ϩ H]ϩ, 301.9 [M ϩ Na]ϩ. Ϫ H NMR:
1
δ ϭ 1.54 (s, 3 H, CH3), 1.63 (s, 3 H, CH3), 1.87 (m, 2 H, CH2),
2.15 (t, J ϭ 5.1 Hz, 1 H, CH2N), 3.18 (t, J ϭ 9.5 Hz, 1 H, CH2N),
3.70 (m, 3 H, CH2OH), 4.27 (m, 1 H, CHO), 5.13 (s, 2 H, PhCH2),
7.36 (m, 5 H, arom.). Ϫ 13C NMR: δ ϭ 24.3, 26.3 [(CH3)2C], 35.2
(CH2), 50.7 (CH2N), 58.9 (CH2O), 66.5 (PhCH2), 71.8 (CHO), 93.3
[(CH3)2C], 127.5, 128.1, 136.2 (arom.), 151.9 (C؍O).
(5R)-3-(tert-Butyloxycarbonyl)-2,2-dimethyl-5-(1-tosyloxy-
forded 11a (2.12 g, 97%) as a pale-yellow oil. [α]2D0 ϭ Ϫ30 (c ϭ 1, ethyl)oxazolidine: Alcohol 12a (1.11 g, 4.53 mmol) was dissolved in
CH2Cl2). Ϫ ESI-MS: m/z ϭ 270.0 [M ϩ H]ϩ, 291.9 [M ϩ Na]ϩ. CH2Cl2 (30 mL) containing dry triethylamine (1.80 mL,
Ϫ
1H NMR: δ ϭ 0.97 (t, J ϭ 7.3 Hz, 3 H, CH3), 1.47 [s, 9 H, 12.94 mmol). At Ϫ10 °C, TsCl (2.10 g, 11.01 mmol) was added and
(CH3)3CO], 1.54 (s, 3 H, CH3), 1.59 (s, 3 H, CH3), 2.02 (m, 2 H, the reaction mixture was stirred at this temperature for 30 min. and
CH3CH2), 2.25 (m, 1 H, ϭCHCH2), 2.37 (m, 1 H, ϭCHCH2), 3.09 then overnight at 4 °C. Thereafter, the solvent was evaporated and
(m, 1 H, CH2N), 3.62 (m, 1 H, CH2N), 4.07 (m, 1 H, CHO), 5.40 the residue was purified by column chromatography (silica gel, light
(m, 1 H, CHϭCH), 5.55 (m, 1 H, CHϭCH). Ϫ 13C NMR: δ ϭ petroleum/ethyl acetate, 9:1 Ǟ 3:1) to afford 1.75 g (97%) of the
13.3 (CH3), 24.3, 26.3 [(CH3)2C], 25.2 (CH3CH2), 28.0 [(CH3)3CO], pure tosylate. [α]2D0
ϭ
Ϫ4.9 (c
ϭ 1, CH2Cl2). Ϫ HPLC:
3688
Eur. J. Org. Chem. 2000, 3683Ϫ3691

Stereoselective Synthesis of (2R,5R)- and (2S,5R)-5-Hydroxylysine
FULL PAPER
CHIRALCEL OD, eluent hexane/2-propanol, 99:1, 1.2 mL/min, m.p. 69Ϫ71 °C. Ϫ [α]2D0 ϭ Ϫ35 (c ϭ 1, CH2Cl2). Ϫ ESI-HRMS:
1
UV 254 nm, (R)-tosylate tR ϭ 25.6 min, (S)-tosylate tR ϭ 21.4 min, m/z ϭ 581.3262 Ϯ 0.0008 [M ϩ H]ϩ, calcd. 581.3227. Ϫ H NMR
ee 99%. Ϫ ESI-MS: m/z ϭ 400.1 [M ϩ H]ϩ, 422.2 [M ϩ Na]ϩ. Ϫ
([D6]DMSO, 120 °C): δ ϭ 1.21 [br. s, 9 H, (CH3)3CO], 1.43 [s, 9
1H NMR: δ ϭ 1.41 [s, 6 H, (CH3)2C], 1.46 [s, 9 H, (CH3)3CO], H, (CH3)3CO], 1.45 (s, 3 H, CH3), 1.47 (s, 3 H, CH3), 1.81 (m, 2
1.93 (m, 2 H, CH2), 2.46 (s, 3 H, CH3Ph), 3.01 (t, J ϭ 9.5 Hz, 1 H, CH2), 2.21 (m, 2 H, CH2), 3.09 (dd, J ϭ 8.7, 10.0 Hz, 1 H,
H, CH2N), 3.63 (br. s, 1 H, CH2N), 4.08 (m, 1 H, CHO), 4.16 (t, CH2N), 3.68 (dd, J ϭ 6.0, 10.0 Hz, 1 H, CH2N), 4.17 (m, 1 H,
J ϭ 6.6 Hz, 2 H, CH2O), 7.35 (d, J ϭ 8.0 Hz, 2 H, arom.), 7.80
(d, J ϭ 8.8 Hz, 2 H, arom.). Ϫ 13C NMR: δ ϭ 21.2 (CH3Ph), 24.4,
26.4 [(CH3)2C], 28.0 [(CH3)3CO], 32.2 (CH2), 50.3 (CH2N), 66.8
CHO), 4.79 (dd, J ϭ 6.1, 9.1 Hz, 1 H, CHN), 5.17 (d, J ϭ 2.9 Hz,
1 H, PhCHN), 6.19 (d, J ϭ 2.9 Hz, 1 H, PhCHO), 6.57 (s, 1 H,
arom.), 6.59 (s, 1 H, arom.), 7.14 (m, 6 H, arom.), 7.27 (m, 2 H,
(CH2O), 69.7 (CHO), 79.2 [(CH3)3CO], 92.7 [(CH3)2C], 127.5, arom.). Ϫ 13C NMR ([D6]DMSO, 95 °C): δ ϭ 24.2, 26.0 [(CH3)2C],
129.6, 132.6, 144.5 (arom.), 151.5 (CϭO).
27.0, 27.5 [(CH3)3CO], 29.0, 29.5 (CH2), 49.7 (CH2N), 56.0 (Cϭ
OCHN), 59.7 (PhCHN), 72.1 (CHO), 77.6 (PhCHO), 78.3, 79.8
[(CH3)3CO], 92.0 [(CH3)2C], 125.7, 126.6, 127.0, 127.3, 134.2
(arom.), 150.8, 152.2 (NϪCϭO), 167.8 (OϪCϭO).
(5R)-3-(Benzyloxycarbonyl)-2,2-dimethyl-5-(1-tosyloxyethyl)-
oxazolidine: Prepared from 12b (1.03 g, 3.70 mmol) as described
above. Purification by column chromatography (silica gel, light pet-
roleum/ethyl acetate, 98:2 Ǟ 3:2) afforded 1.47 g (91%) of the pure
tosylate. [α]2D0 ϭ Ϫ3.8 (c ϭ 1, CH2Cl2). Ϫ ESI-MS: m/z ϭ 434.1
[M ϩ H]ϩ, 456.1 [M ϩ Na]ϩ. Ϫ 1H NMR: δ ϭ 1.45 (s, 3 H, CH3),
1.54 (s, 3 H, CH3), 1.95 (m, 2 H, CH2), 2.44 (s, 3 H, CH3Ph), 3.08
(m, 1 H, CH2N), 3.71 (m, 1 H, CH2N), 4.07 (m, 1 H, CHO), 4.16
(t, J ϭ 6.6 Hz, 2 H, CH2O), 5.10 (s, 2 H, PhCH2), 7.35 (m, 7 H,
arom.), 7.78 (d, J ϭ 8.0 Hz, 2 H, arom.) Ϫ 13C NMR: δ ϭ 21.0
(CH3Ph), 24.1, 26.1 [(CH3)2C], 31.9 (CH2), 50.1 (CH2N), 65.5
(CH2O), 67.1 (PhCH2), 69.7 (CHO), 93.2 [(CH3)2C], 127.3, 127.5,
128.0, 129.4, 132.3, 136.0, 144.4 (arom.), 151.5 (C؍O).
Benzyl (5ЈR,3S,5S,6R)-3-[2-(3Ј-Benzyloxycarbonyl-2Ј,2Ј-dimethyl-
oxazolidin-5Ј-yl)ethyl]-2-oxo-5,6-diphenylmorpholine-4-carboxylate
(2d): From template 3b (0.64 mmol) and iodide 13b (0.51 mmol),
compound 2d (111 mg) was obtained in 34% yield. [α]2D0 ϭ Ϫ17
(c ϭ 1.4, CH2Cl2). Ϫ ESI-MS: m/z ϭ 649.4 [M ϩ H]ϩ, 671.3 [M
ϩ Na]ϩ. Ϫ 1H NMR ([D6]DMSO, 95 °C): δ ϭ 1.47 (s, 3 H, CH3),
1.51 (s, 3 H, CH3), 1.82 (m, 2 H, CH2), 2.22 (m, 2 H, CH2), 3.14
(dd, J ϭ 8.8, 10.2 Hz, 1 H, CH2N), 3.66 (dd, J ϭ 5.8, 10.2 Hz, 1
H, CH2N), 4.17 (m, 1 H, CHO), 4.85 (dd, J ϭ 6.6, 8.0 Hz, 1 H,
CHN), 5.00 (AB, J ϭ 12.4 Hz, 2 H, PhCH2), 5.12 (s, 2 H, PhCH2),
5.29 (d, J ϭ 2.9 Hz, 1 H, PhCHN), 6.21 (d, J ϭ 2.9 Hz, 1 H,
PhCHO), 6.59 (s, 1 H, arom.), 6.62 (s, 1 H, arom.), 7.22 (m, 18 H,
arom.). Ϫ 13C NMR ([D6]DMSO, 95 °C): δ ϭ 23.9, 25.8 [(CH3)2C],
28.8, 29.4 (CH2), 49.5 (CH2N), 56.4 (CϭOCHN), 59.6 (PhCHN),
65.3, 66.3 (PhCH2), 72.4 (CHO), 77.6 (PhCHO), 92.4 [(CH3)2C],
125.7, 126.7, 127.0, 127.4, 134.1, 135.6 (arom.), 151.2, 159.8
(NϪCϭO), 167.5 (OϪCϭO).
(5R)-3-(tert-Butyloxycarbonyl)-5-(1-iodoethyl)-2,2-dimethyloxa-
zolidine (13a): (5R)-3-(tert-Butyloxycarbonyl)-2,2-dimethyl-5-(1-to-
syloxyethyl)oxazolidine (1.10 g, 2.76 mmol) was dissolved in acet-
one p.a. (40 mL). NaI (1.97 g, 13.13 mmol) was added and the solu-
tion was refluxed for 30 min. A white precipitate was formed. TLC
analysis revealed complete conversion of the tosylate. The mixture
was cooled in an ice bath and filtered. The filtrate was concentrated
to dryness and the white solid residue was triturated three times
with dry diethyl ether. Evaporation of the ether afforded 1.02 g of
a yellow oil, which was purified by column chromatography (silica
gel, light petroleum/ethyl acetate, 9:1) to yield 0.90 g (92%) of col-
orless iodide 13a. The compound solidified upon storage at Ϫ18
°C; m.p. 59Ϫ60 °C. Ϫ [α]2D0 ϭ Ϫ1.8 (c ϭ 1, CH2Cl2). Ϫ ESI-MS:
Benzyl (5ЈR,3S,5S,6R)-3-[2-(3Ј-tert-Butyloxycarbonyl-2Ј,2Ј-dimeth-
yloxazolidin-5Ј-yl)ethyl]-2-oxo-5,6-diphenylmorpholine-4-carboxy-
late (2e): From template 3b (0.65 mmol) and iodide 13a
(0.58 mmol), compound 2e (208 mg) was obtained in 58% yield;
m.p. 176Ϫ178 °C. Ϫ [α]2D0 ϭ Ϫ25 (c ϭ 1, CH2Cl2). Ϫ ESI-HRMS:
m/z ϭ 637.2902 Ϯ 0.0012 [M ϩ Na]ϩ, calcd. 637.2890. Ϫ 1H NMR
([D6]DMSO, 95 °C): δ ϭ 1.46 [s, 12 H, (CH3)3CO, CH3], 1.50 (s, 3
H, CH3), 1.81 (m, 2 H, CH2), 2.22 (m, 2 H, CH2), 3.06 (dd, J ϭ
8.8, 9.9 Hz, 1 H, CH2N), 3.66 (dd, J ϭ 5.8, 9.9 Hz, 1 H, CH2N),
4.13 (m, 1 H, CHO), 4.85 (dd, J ϭ 6.6, 7.7 Hz, 1 H, CHN), 5.01
(AB, J ϭ 12.4 Hz, 2 H, PhCH2), 5.30 (d, J ϭ 3.0 Hz, 1 H,
PhCHN), 6.22 (d, J ϭ 3.0 Hz, 1 H, PhCHO), 6.59 (s, 1 H, arom.),
6.62 (s, 1 H, arom.), 7.08 (m, 7 H, arom.), 7.23 (m, 6 H, arom.).
m/z ϭ 355.9 [M ϩ H]ϩ, 377.9 [M ϩ Na]ϩ. Ϫ H NMR: δ ϭ 1.47
1
[s, 9 H, (CH3)3CO], 1.53 (s, 3 H, CH3), 1.60 (s, 3 H, CH3), 2.11 (m,
2 H, CH2), 3.08 (m, 1 H, CH2N), 3.25 (t, J ϭ 6.3 Hz, 2 H, CH2I),
3.71 (m, 1 H, CH2N), 4.14 (m, 1 H, CHO). Ϫ 13C NMR: δ ϭ 0.68
(CH2I), 24.5, 26.5 [(CH3)2C], 28.2 [(CH3)3CO], 36.9 (CH2), 49.8
(CH2N), 73.1 (CHO), 79.2 [(CH3)3CO], 92.9 [(CH3)2C], 151.5
(CϭO).
Ϫ
13C NMR ([D6]DMSO, 95 °C): δ ϭ 24.1, 26.0 [(CH3)2C], 27.5
(5R)-3-(Benzyloxycarbonyl)-5-(1-iodoethyl)-2,2-dimethyloxazolidine
(13b): Prepared from (5R)-3-(benzyloxycarbonyl)-2,2-dimethyl-5-
(1-tosyloxyethyl)oxazolidine (1.44 g, 3.33 mmol) as described for
13a. Purification by column chromatography (silica gel, light petro-
leum/ethyl acetate, 9:1, afforded 1.28 g (96%) of pure iodide 13b.
[α]2D0 ϭ Ϫ1.8 (c ϭ 1, CH2Cl2). Ϫ ESI-MS: m/z ϭ 390.0 [M ϩ H]ϩ,
[(CH3)3CO], 28.9, 29.5 (CH2), 49.7 (CH2N), 56.4 (CϭOCHN), 59.7
(PhCHN), 66.3 (PhCH2), 72.1 (CHO), 77.7 (PhCHO), 78.4
[(CH3)3CO], 92.0 [(CH3)2C], 125.7, 126.6, 126.8, 127.0, 127.4,
134.0, 135.4, 135.6 (arom.), 150.8, 153.0 (NϪCϭO), 167.5
(OϪCϭO).
tert-Butyl (5ЈR,3S,5S,6R)-3-[2-(3Ј-Benzyloxycarbonyl-2Ј,2Ј-dimeth-
yloxazolidin-5Ј-yl)ethyl]-2-oxo-5,6-diphenylmorpholine-4-carboxy-
late (2f): From template 3a (1.30 mmol) and iodide 13b
(1.00 mmol), compound 2f (437 mg) was obtained in 71% yield;
m.p. 133Ϫ136 °C. Ϫ [α]2D0 ϭ Ϫ28 (c ϭ 1, CH2Cl2). Ϫ ESI-HRMS:
m/z ϭ 637.2905 Ϯ 0.0010 [M ϩ Na]ϩ, calcd. 637.2890. Ϫ 1H NMR
([D6]DMSO, 120 °C): δ ϭ 1.19 [br. s, 9 H, (CH3)3CO], 1.48 (s, 3
H, CH3), 1.53 (s, 3 H, CH3), 1.82 (m, 2 H, CH2), 2.19 (m, 2 H,
1
412.1 [M ϩ Na]ϩ. Ϫ H NMR: δ ϭ 1.54 (s, 3 H, CH3), 1.56 (s, 3
H, CH3), 2.11 (m, 2 H, CH2), 3.14 (m, 1 H, CH2N), 3.25 (t, J ϭ
6.9 Hz, 2 H, CH2I), 3.78 (m, 1 H, CH2N), 4.17 (m, 1 H, CHO),
5.11 (s, 2 H, PhCH2), 7.36 (m, 5 H, arom.). Ϫ 13C NMR: δ ϭ
0.52 (CH2I), 24.3, 26.3 [(CH3)2C], 36.4 (CH2), 49.7 (CH2N), 66.2
(PhCH2), 73.1 (CHO), 93.1 [(CH3)2C], 125.9, 127.3, 127.5, 128.0,
136.1 (arom.), 151.4 (C؍O).
tert-Butyl (5ЈR,3S,5S,6R)-3-[2-(3Ј-tert-Butyloxycarbonyl-2Ј,2Ј-di- CH2), 3.19 (dd, J ϭ 8.8, 9.9 Hz, 1 H, CH2N), 3.78 (dd, J ϭ 5.9,
methyloxazolidin-5Ј-yl)ethyl]-2-oxo-5,6-diphenylmorpholine-4-carb-
oxylate (2c): From template 3a (1.50 mmol) and iodide 13a
9.9 Hz, 1 H, CH2N), 4.21 (m, 1 H, CHO), 4.81 (m, 1 H, CHN),
5.11 (s, 2 H, PhCH2), 5.17 (d, J ϭ 2.9 Hz, 1 H, PhCHN), 6.19 (d,
(1.20 mmol), compound 2c (560 mg) was obtained in 80% yield; J ϭ 2.9 Hz, 1 H, PhCHO), 6.57 (s, 1 H, arom.), 6.59 (s, 1 H, arom.),
Eur. J. Org. Chem. 2000, 3683Ϫ3691 3689

J. Brussee et al.
FULL PAPER
7.24 (m, 13 H, arom.). Ϫ 13C NMR ([D6]DMSO, 95 °C): δ ϭ 24.0, (2S,5R)-5-Hydroxylysine (1): Protected (2S,5R)-5-hydroxylysine 14
25.9 [(CH3)2C], 27.0 [(CH3)3CO], 28.9, 29.5 (CH2), 49.6 (CH2N), (16 mg) was dissolved in 1.5  DCl (0.50 mL) and the resulting
56.1 (CϭOCHN), 59.8 (PhCHN), 65.3 (PhCH2), 72.5 (CHO), 74.6 solution was allowed to stand at room temperature for 2 h. 1H
(PhCHO), 79.9 [(CH3)3CO], 92.4 [(CH3)2C], 125.7, 126.1, 126.6,
127.0, 127.4, 134.2, 136.3 (arom.), 151.3, 152.3 (NϪCϭO), 167.9
(OϪCϭO).
NMR analysis gave a spectrum identical to that of a commercial
(2S,5R)-5-hydroxylysine sample. Ϫ HPLC: Daicel CROWNPACK
CR(ϩ), eluent HClO4 (pH 1.0), 0.50 mL/min at 8 °C, detection UV
200 nm: synthesized 1, tR ϭ 20.6 min, commercial 1, tR ϭ 20.7 min;
synthesized (2R,5R)-5-hydroxylysine (17) tR ϭ 16.5 min, commer-
cial ,-5-hydroxylysine (peak areas in parentheses): tR ϭ 11.9 min
(19%, 2R,5S); tR ϭ 16.2 min (29%, 2R,5R); tR ϭ 20.4 min (19%,
2S,5R); tR ϭ 22.3 min (30%, 2S,5S). Ϫ ESI-MS: m/z ϭ 163.2 [M
ϩ H]ϩ.
Benzyl (5ЈR,3R,5R,6S)-3-[2-(3Ј-tert-Butyloxycarbonyl-2Ј,2Ј-dimeth-
yloxazolidin-5Ј-yl)ethyl]-2-oxo-5,6-diphenylmorpholine-4-carboxy-
late: From template 16 (1.29 mmol) and iodide 13a (1.19 mmol),
the title compound (473 mg) was obtained in 65% yield. [α]2D0
ϭ
ϩ19 (c ϭ 1, CH2Cl2). Ϫ ESI-HRMS: m/z ϭ 637.2908 Ϯ 0.0007 [M
ϩ Na]ϩ, calcd. 637.2890. Ϫ 1H NMR ([D6]DMSO, 95 °C): δ ϭ
1.45 [s, 12 H, (CH3)3CO, CH3], 1.51 (s, 3 H, CH3), 1.82 (m, 2 H,
CH2), 2.22 (m, 2 H, CH2), 3.06 (dd, J ϭ 8.8, 9.9 Hz, 1 H, CH2N),
3.68 (dd, J ϭ 5.8, 9.9 Hz, 1 H, CH2N), 4.13 (m, 1 H, CHO), 4.86
(dd, J ϭ 5.1, 9.1 Hz, 1 H, CHN), 5.01 (AB, J ϭ 12.8 Hz, 2 H,
PhCH2), 5.30 (d, J ϭ 3.3 Hz, 1 H, PhCHN), 6.22 (d, J ϭ 3.3 Hz,
1 H, PhCHO), 6.58 (s, 1 H, arom.), 6.62 (s, 1 H, arom.), 7.08 (m,
7 H, arom.), 7.24 (m, 6 H, arom.). Ϫ 13C NMR ([D6]DMSO, 95
°C): δ ϭ 24.2, 26.0 [(CH3)2C], 27.5 [(CH3)3CO], 28.9, 29.6 (CH2),
49.7 (CH2N), 56.4 (CϭOCHN), 59.7 (PhCHN), 66.3 (PhCH2),
72.1 (CHO), 77.6 (PhCHO), 78.3 [(CH3)3CO], 92.0 [(CH3)2C],
125.7, 126.6, 126.8, 127.0, 127.4, 128.2, 134.1, 135.4, 135.6 (arom.),
150.8, 153.0 (NϪCϭO), 167.5 (OϪCϭO).
[1]
D. R. Eyre, M. A. Paz, P. M. Gallop, Ann. Rev. Biochem. 1984,
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[2a] D. D. Van Slyke, A. Hiller, Proc. Natl. Acad. Sci. USA 1921,
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J. Koeners, C. Schattenkerk, J. J. Verhoeven, J. H. van Boom,
Tetrahedron 1981, 37, 1763Ϫ1771.
Protected (2S,5R)-5-Hydroxylysine 14: In a hydrogenation flask,
compound 2e (208 mg, 0.34 mmol) was dissolved in a mixture of
THF (8 mL) and MeOH (24 mL). The flask was flushed with argon
and 10% Pd/C (0.19 g) was added. Hydrogenation was performed
at 4.2 bar H2 for 24 h. Thereafter, the solution was filtered through
Celite and the filtrate was concentrated to dryness to yield 183 mg
of a solid material. Purification by silica gel column chromato-
graphy (eluent light petroleum/ethyl acetate, 9:1 Ǟ MeOH/ethyl
acetate/triethylamine, 3:6:1) gave 86 mg (84%) of protected (2S,5R)-
5-hydroxylysine 14. [α]2D0 ϭ Ϫ6.4 (c ϭ 0.9, MeOH). Ϫ ESI-MS:
[5]
[6]
[5a] W. S. Fones, J. Am. Chem. Soc. 1953, 75, 4865Ϫ4866. Ϫ [5b]
W. S. Fones, Biochem. Prep. 1961, 8, 62Ϫ69.
M. Adamczyk, D. D. Johnson, R. E. Reddy, Tetrahedron 1999,
55, 63Ϫ88.
[7]
[8]
B. Löhr, S. Orlich, H. Kunz, Synlett 1999, 1139Ϫ1141.
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Engl. 1981, 20, 798Ϫ799.
G. Li, C. Han-Ting, K. B. Sharpless, Angew. Chem. Int. Ed.
Engl. 1996, 35, 451Ϫ454.
A. M. C. H. van den Nieuwendijk, J. C. J. Benningshof, V.
Wegmann, R. A. Bank, J. M. te Koppele, J. Brussee, A. van
der Gen, Bioorg. & Med. Chem. Lett. 1999, 9, 1673Ϫ1676.
R. M. Williams, M. N. Im, J. Am. Chem. Soc. 1991, 113,
9276Ϫ9286.
[9]
[10]
1
m/z ϭ 303.1 [M ϩ H]ϩ, 325.1 [M ϩ Na]ϩ. Ϫ H NMR (MeOD):
δ ϭ 1.34 [s, 9 H, (CH3)3CO], 1.37 (s, 3 H, CH3), 1.41 (s, 3 H, CH3),
1.61 (m, 2 H, CH2), 1.83 (m, 2 H, CH2), 2.92 (dd, J ϭ 9.4, 9.5 Hz,
1 H, CH2N), 3.48 (dd, J ϭ 5.1, 9.1 Hz, 1 H, CHN), 3.56 (dd, J ϭ
5.9, 9.5 Hz, 1 H, CH2N), 4.01 (m, 1 H, CHO). Ϫ 13C NMR
(MeOD): δ ϭ 24.9, 27.2 [(CH3)2C], 28.5 (CH2), 28.7 [(CH3)3CO],
29.8 (CH2), 51.9 (CH2N), 55.9 (CϭOCHN), 74.6 (CHO), 81.3
[(CH3)3CO], 94.5 [(CH3)2C], 153.7 (NϪCϭO), 174.2 (OϪCϭO).
[11]
[12] [12a]
D. M. Bender, R. M. Williams, J. Org. Chem. 1997, 62,
[12b]
6690Ϫ6691. Ϫ
lett 1992, 249Ϫ251. Ϫ
1992, 25, 11.
J. E. Baldwin, V. Lee, C. J. Schofield, Syn-
[12c]
R. M. Williams, Aldrichimica Acta
[13]
[14]
Both enantiomers are available from Aldrich as Cbz-protected
and as Boc-protected derivatives.
A. M. C. H. van den Nieuwendijk, E. G. J. C. Warmerdam, J.
Brussee, A. van der Gen, Tetrahedron: Asymmetry 1995, 6,
801Ϫ806.
Protected (2S,5R)-5-Hydroxylysine 15: A suspension of compound
2e (177 mg, 0.29 mmol) in acetic acid (7 mL) and water (3 mL) was
stirred at 30 °C. After 48 h, TLC showed that the conversion was
complete. The solvents were evaporated, the residue was suspended
in toluene, and the solvent was evaporated once more. This proced-
ure was repeated three times. The residue was then purified by col-
umn chromatography (silica gel, light petroleum/ethyl acetate, 9:1
Ǟ ethyl acetate/MeOH, 8:2) to yield compound 15 (147 mg, 89%).
[α]2D0 ϭ Ϫ23 (c ϭ 1, CH2Cl2). Ϫ ESI-MS: m/z ϭ 597.4 [M ϩ Na]ϩ.
[15]
E. Smitskamp-Wilms, J. Brussee, A. van der Gen, G. J. M. van
Scharrenburg, J. B. Sloothaak, Recl. Trav. Chim. Pays-Bas
1991, 110, 209Ϫ215.
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J. Brussee, A. C. A. Jansen, A. Kühn, Proc. Symp. Med.
[16b]
Chem., Acta Pharm. Suecica Suppl. 2:479, 1985. Ϫ
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[16c]
1987, 26, 458Ϫ459. Ϫ
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6.59 (s, 1 H, arom.), 6.62 (s, 1 H, arom.), 7.21 (m, 13 H, arom.). Ϫ
13C NMR (CDCl3): δ ϭ 28.3 [(CH3)3CO], 30.2, 30.6 (CH2), 46.4
(CH2N), 56.0 (CϭOCHN), 60.7 (PhCHN), 67.9 (PhCH2), 71.9
(CHO), 79.0 (PhCHO), 79.4 [(CH3)3CO], 126.4, 126.5, 127.3, 127.4,
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Eur. J. Org. Chem. 2000, 3683Ϫ3691

Stereoselective Synthesis of (2R,5R)- and (2S,5R)-5-Hydroxylysine
FULL PAPER
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Available from Fluka: (5R)-5-hydroxy--lysine dihydrochloride
monohydrate; -5-hydroxylysine hydrochloride (mixture of
-normal and -allo forms).
Received May 8, 2000
[O00226]
Eur. J. Org. Chem. 2000, 3683Ϫ3691
3691