Synthesis of Fmoc-protected (2S,3S)-2-hydroxy-3-amino acids from a furyl substituted chiral cyanohydrin

Article abstract of DOI:10.1016/S0957-4166(03)00218-0

A stereoselective chemoenzymatic synthesis of Fmoc-protected (2S,3S)-2-hydroxy-3-amino acids 6 is described. After the formation of cyanohydrin 2 from 2-furaldehyde in the presence of R-oxynitrilase and subsequent protection, 3 was transformed into fully protected ethanolamines 5. Ozonolysis provided the target compounds in good yields.

Full text of DOI:10.1016/S0957-4166(03)00218-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1645–1652
Synthesis of Fmoc-protected (2S,3S)-2-hydroxy-3-amino acids
from a furyl substituted chiral cyanohydrin
Reynier A. Tromp, Michael van der Hoeven, Alessia Amore, Johannes Brussee,* Mark Overhand,
Gijs A. van der Marel and Arne van der Gen
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA, Leiden, The Netherlands
Received 21 February 2003; accepted 5 March 2003
Abstract—A stereoselective chemoenzymatic synthesis of Fmoc-protected (2S,3S)-2-hydroxy-3-amino acids 6 is described. After
the formation of cyanohydrin 2 from 2-furaldehyde in the presence of R-oxynitrilase and subsequent protection, 3 was
transformed into fully protected ethanolamines 5. Ozonolysis provided the target compounds in good yields. © 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction1
Here we describe a stereoselective chemoenzymatic syn-
thesis of Fmoc-protected (2S,3S)-2-hydroxy-3-amino
acids starting from 2-furaldehyde,12 which were used in
the solid phase synthesis of a completely a-hydroxyl-
ated b-hexapeptide.1 So far, only two Fmoc-protected
2-hydroxy-3-amino acids have been described:13 a-
hydroxy-b-glycine14 and 2-hydroxy-3-amino-pentanoic
acid.15
Although less abundant than a-amino acids, b-amino
acids are also present in nature. While only a few occur
in mammals, e.g. b-alanine and b-valine as catabolites
of the cytosine or the thymine metabolism,2 an increas-
ing number is found in bacteria, sponges, tunicates and
plants.3 In the latter cases, the b-amino acids are not
only catabolites, but also constituents of a variety of
compounds that exhibit interesting biological proper-
ties. Among these is the anti-tumour active paclitaxel,
first isolated from the bark of the pacific yew Taxus
brevifolia.4 Other examples are scytonemyn A from the
blue-green alga Scytonema sp. with potential calcium
antagonistic properties,5 aminopeptidase B inhibitor
bestatin, isolated from Streptomyces olivoreticuli,6
To obtain the Fmoc-protected (2S,3S)-2-hydroxy-3-
amino acids,
a
chemoenzymatic route described
earlier16 was further developed. The a-hydroxy-b-ana-
logues of glycine, alanine, valine, leucine, phenyl-
glycine, and phenylalanine (R%=H, Me, iso-Pr, iso-Bu,
Ph, and Bn, respectively) have been prepared.
aminopeptidase
M
inhibitor microginin 51-A,
a
hexapeptide from the cyanobacterium Microcystis
aeruginosa,7 and antimicrobially and insecticidally
active jasplakinolide or jaspamide.8
2. Results and discussion
First, 2-furaldehyde was converted into (S)-
cyanohydrin17 2 by an enzymatic reaction using R-
oxynitrilase (E.C. 4.1.2.10) as present in ground,
defatted almond meal18 with high conversion and with
high enantiomeric excess (99%) (Scheme 1). Subse-
quently, the crude cyanohydrin was protected at its
hydroxyl function by means of tert-butyldimethylsi-
lylchloride (TBS-Cl) and imidazole in DMF19 to yield 3
in high yield after distillation (89% from 1).
Apart from this, b-peptides have attracted considerable
attention since it was found that these compounds can
fold to give stable secondary structures similar to those
found in a-peptides.9 Importantly, they are stable
against enzymatic degradation.10 Several biologically
active b-peptides have been described.11
Next, the amine function and the amino acid side chain
were introduced by either a two-step reduction20 for 4a
or a Grignard addition–reduction sequence21 4b–f.
* Corresponding author. E-mail: brussee@chem.leidenuniv.nl
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00218-0

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R. A. Tromp et al. / Tetrahedron: Asymmetry 14 (2003) 1645–1652
3) was good (Table 1). Introduction of the iso-propyl
side chain followed by imine reduction and amine
protection was problematic, with yields of 20–25% for
5c. Yields were improved to 48% by adding a catalytic
amount of copper(I) bromide and using THF as the
solvent, as described by Weiberth and Hall23 for steri-
cally demanding Grignard reagents and by Fmoc-pro-
tection in the absence of water, using dry
dichloromethane and DIPEA.24
Finally, the furan ring was readily oxidised by ozonoly-
sis to obtain the carboxylic acid.25 Taking advantage of
the b-amide proton present,26 a one-pot oxidation/silyl–
deprotection step was foreseen to obtain the desired
Fmoc-protected a-hydroxy-b-amino acids. Thus, a
solution of the fully protected (2%-furyl)-ethanolamine 5
in methanol was cooled to −70°C. A mixture of oxygen
and ozone was bubbled through until no more starting
material could be observed (TLC). The mixture was left
to warm to room temperature, while oxygen was passed
through to remove all remaining ozone from the solu-
tion. To obtain complete deprotection by migration of
the silyl group, the methanol was first evaporated, and
the resulting yellow oil was dissolved in a mixture of
THF, acetonitrile, and water (3/1/1, v/v/v), which was
stirred for 2 h at 40°C. After work-up, the Fmoc-pro-
tected 2-hydroxy-3-amino acids 6 were obtained from
the resulting yellow oil as white solids by crystallisation
from EtOAc/pentane or, in the case of 6a, simply by
washing with diethyl ether (Table 2).
Scheme 1. Reagents: (i) R-Oxynitrilase, HCN, MTBE, pH
5.5; (ii) TBS-Cl, imidazole, DMF; (iii) 1. DibalH or R%MgX,
Et2O, 2. MeOH, 3. NaBH4; (iv) Fmoc-Cl, CH2Cl2, NaHCO3
(aq.); (v) 1. O3, MeOH, 2. THF/MeCN/H2O, 40°C.
To a solution of 3 in dry diethyl ether (−70°C) was
added 1.2 equiv. of DIBALH in hexanes. The reaction
was allowed to warm to −20°C before it was cooled
again to −70°C. After addition of methanol and NaBH4
at −70°C, the mixture was allowed to warm slowly to
room temperature overnight, providing crude 4a after
work-up, which was used as such for Fmoc-protection.
For the introduction of the amino acid side chains R%
the appropriate Grignard reagent was added dropwise
to a solution of 3 in diethyl ether. The reaction mixture
was refluxed for 1 h, cooled to −20°C, and methanol
was added. Subsequent stereoselective sodium borohy-
dride reduction of the resulting imine provided the
crude TBS protected ethanolamines 4b–f, with the
(1S,2S)-diastereoisomer as the major product (Table 1).
The presence of the furan ring had a large positive
influence on the stereoselectivity of the ethanolimine
reduction by sodium borohydride compared to the
synthesis starting from crotonaldehyde. In the latter
case d.e.’s were found to be lower than 20% in the
presence of hindered side groups like iso-propyl and
iso-butyl.22
Table 2. Yield and (2S,3S)/(2S,3R)-ratio of 6 after
ozonolysis–desilylation
R=
(2S,3S)/(2S,3R)a
Yieldb
a
b
c
d
e
f
H
Me
iso-Propyl
iso-Butyl
Phenyl
Benzyl
–
80
61
52
61
69
52
95/5
88/12
80/20
95/5
80/20
a (2S,3S)/(2S,3R)-Ratio determined by NMR.
b Yields after purification from 5.
Table 1. Stereoselectivity of the addition–reduction
sequence and yield after Fmoc-protection
2.1. Confirmation of the stereochemistry in 4
For the addition–reduction sequence discussed above,
only formation of the anti diastereoisomer as the major
isomer is described in literature, but all examples deal
with sterically less demanding side chains (R%). Thus, in
order to confirm the formation of sterically demanding
(1S,2S)-ethanolamines crude ethanolamines 4c and 4f
were converted into their respective oxazolidinones
(Scheme 2). Protection with the tert-butyloxocarbonyl
(Boc) function, using Boc-anhydride in dichloro-
methane and a saturated aqueous sodium hydrogencar-
bonate solution, yielded fully protected 7 and 8. The
alcohol function was desilylated with tetrabutyl-
ammonium fluoride (TBAF) in THF to yield 9 and 10
as white solids. Formation of the required oxazolidi-
nones 9 and 10 was accomplished by sodium hydride
assisted ring closure in a DMF/THF mixture.27 Cou-
R=
(1S,2S)/(1S,2R)-4a
Yield 5b
a
b
c
d
e
f
H
Me
iso-Propyl
iso-Butyl
Phenyl
Benzyl
–
56
80
48c
61
79
43
95/5
90/10
80/20
95/5
80/20
a (1S,2S)/(1S,2R)-Ratio determined by NMR.
b Yields after purification from 3.
c See text.
At this stage, the crude O-protected ethanolamines 4
were N-protected using Fmoc-Cl in CH2Cl2/H2O. Gen-
erally, the yield for the protected ethanolamines (from

R. A. Tromp et al. / Tetrahedron: Asymmetry 14 (2003) 1645–1652
1647
pling constants of the vicinal protons (J=7.7 Hz for 11
and 8.0 Hz for 12) were in accordance with those
reported in literature for syn orientated protons in
oxazolidinones,27,28 thus confirming the formation of
the anti-diastereoisomers of the sterically hindered
ethanolamines 4c and 4f.
cm−1, res. 4 cm−1). Melting points were determined with
a Bu¨chi melting point apparatus and are uncorrected.
The enantiomeric purity was determined by HPLC
using a Daicel Chiralcel OD column; with hexane/2-
propyl alcohol (99.75/0.25, v/v) as eluent. Optical rota-
tions were measured with
a
Propol automatic
polarimeter, at the sodium D line (u=589 nm). Ozone
was generated with a Fisher Ozon-Generator 500. Ana-
lytical samples of 6b–f were prepared by recrystallisa-
tion from EtOAc/hexane.
4.1.1. (S)-2-(2%-Furyl)-2-hydroxy-acetonitrile 2. A sus-
pension of 30 g almond meal in 45 mL of 0.10 M citric
acid buffer pH 5.5, 19.2 g of freshly distilled 2-furalde-
hyde 1 (200 mmol) and 50 mL of MTBE was stirred at
4°C. Meanwhile a fresh solution of HCN in MTBE was
prepared: a solution of 440 mmol of NaCN (2.1 equiv.)
in 400 mL of H2O was acidified to pH 5.5 with AcOH
(CAUTION: toxic hydrogen cyanide gas may evolve.
Work in a well ventilated hood.). The hydrogen cyanide
solution was extracted three times with 175 mL of
MTBE. The combined MTBE layers were transferred
into a dropping funnel. After 1 h at 4°C the HCN
solution was added dropwise to the enzyme mixture.
The whole was allowed to stir over the weekend,
filtered, and dried with MgSO4. The solvent was evapo-
rated to yield the crude product (26.1 g). E.e. 98.6%
(HPLC; determined as TBDPS ether).—Yellow oil.—
1H NMR (CDCl3) l=3.54 (br s, 1H, OH), 5.55 (s, 1H,
H-2), 6.44 (dd, 1H, J=1.8, J=3.3, H-4%), 6.61 (d, 1H,
J=3.3, H-3%), 7.49 (d, 1H, J=1.8, H-5%).—13C NMR
(CDCl3) l=56.4 (C-2), 109.8, 110.6 (C-3%, C-4%), 116.9
(C-1), 143.9 (C-5%), 147.3 (C-2%).
Scheme 2. Reagents: (i) Boc2O, CH2Cl2, NaHCO3 (aq.); (ii)
TBAF, THF; (iii) NaH, DMF, THF.
3. Concluding remarks
A direct chemoenzymatic route towards Fmoc-pro-
tected (2S,3S)-2-hydroxy-3-amino acids has been devel-
oped. 2-Furaldehyde was readily converted into its
corresponding (S)-cyanohydrin with high enantioselec-
tivity by R-oxynitrilase as present in defatted almond
meal. Protection with the tert-butyldimethylsilyl group
proceeded in high yield. Subsequent introduction of the
amino acid side chain by a Grignard addition-reduction
sequence, or by a two-step reduction (in the case of
a-hydroxy-b-glycine), followed by Fmoc-protection of
the crude ethanolamine gave in general good results,
both with regard to yield and to diastereoselectivity.
Introduction of the sterically demanding iso-propyl
group was greatly facilitated by addition of a catalytic
amount of copper(I) bromide to the Grignard reaction
and by altering conditions for Fmoc-protection. Taking
advantage of the tendency of the silyl-protecting group
to migrate, both oxidation of the furan ring and desilyl-
ation could be achieved in one step to yield the
required Fmoc-protected (2S,3S)-2-hydroxy-3-amino
acids after crystallisation.
4.1.2. (S)-2-(2%-Furyl)-2-O-(tert-butyldimethylsilyl)-acet-
onitrile 3. To a solution of 36 g of tert-butyldimethylsi-
lylchloride (240 mmol; 1.2 equiv.) in 250 mL of DMF
(0°C) was added 32.7 g of imidazole (480 mmol; 2.4
equiv.). After 15 min the crude cyanohydrin 2 was
added and the mixture was allowed to warm to rt
overnight. Water and diethyl ether were added and the
layers separated. The organic phase was washed with
water and brine, dried (MgSO4) and the solvent was
evaporated. The product was obtained by distillation
under reduced pressure (96°C, 150 Pa) from the result-
ing oil. Yield: 88%.—Colourless oil.—IR: w (cm−1):
1500, 1473, 1464, 1254, 1146, 1070, 1014, 1006, 834,
779, 740.—1H NMR (CDCl3) l=0.14, 0.16 (2×s, 2×3H,
2×CH3Si), 0.92 (s, 9H, (CH3)3C), 5.56 (s, 1H, H-2),
6.40 (dd, 1H, J=1.8, J=3.3, H-4%), 6.61 (d, 1H, J=0.7,
J=3.3, H-3%), 7.49 (d, 1H, J=0.7, J=1.8, H-5%).—13C
NMR (CDCl3) l=−5.4 (CH3Si), 18.0 ((CH3)3C), 25.3
((CH3)3C), 57.9 (C-2), 109.3, 110.6 (C-3%, C-4%), 117.1
(C-1), 143.6 (C-5%), 148.3 (C-2%).—[h]2D0=18.9 (c 5,
CHCl3).
4. Experimental
4.1. General
Column chromatography was performed on Baker sil-
ica gel (0.063–0.200 mm). For TLC analysis, Schleicher
and Schuell F1500/LS 254 silica plates were used. Spots
were visualised with ultraviolet light, potassium per-
manganate spray [solution of KMnO4 (5%) and
NaHCO3 (0.5%) in water] or by molybdene spray [solu-
tion of conc. sulfuric acid (10 mL) and
(NH4)6Mo7O24·4H2O (2.5 g) in 90 mL of water] and
4.1.3. (1S)-1-(2%-Furyl)-1-O-(tert-butyldimethylsilyl)-2-
ethylamine 4a. To a solution (−70°C) of 4.74 g of 3 (20
mmol) in 150 mL of dry diethyl ether was added 24
mmol of DibalH (24 mL of 1 M in hexanes; 1.2 equiv.).
The temperature was allowed to rise to −20°C, lowered
to −70°C and 60 mL of MeOH was added, followed by
1.51 g of NaBH4 (40 mmol; 2 equiv.). The mixture was
1
heating. H and 13C NMR were recorded with a Bruker
AC 200 instrument. Tetramethylsilane was used as
internal standard; l in ppm, J in Hz. Infrared spectra
were obtained with a Perkin–Elmer FT-IR Paragon
1000 spectrometer equipped with a Golden Gate Dia-
mond ATR, using reflectance technique (neat, 4000–300

1648
R. A. Tromp et al. / Tetrahedron: Asymmetry 14 (2003) 1645–1652
allowed to warm slowly to rt, diethyl ether was added
and the organic layer was washed with 2N NaOH,
water and brine, dried (MgSO4) and the solvent evapo-
rated. The resulting crude compound was used without
purification in the next reaction.—Yellow oil.—1H
NMR (CDCl3) l=−0.05, 0.07 (2×s, 2×3H, 2×CH3Si),
0.89 (s, 9H, (CH3)3C), 1.37 (br s, 2H, NH2), 2.90 (dd,
1H, J=4.9, J=13.2, H-2), 2.99 (dd, 1H, J=5.9, J=
13.2, H-2), 4.6–4.71 (m, 1H, H-1), 6.21 (dd, 1H, J=
0.9, J=3.3, H-3%), 6.32 (dd, 1H, J=1.8, J=3.3, H-4%),
7.35 (dd, 1H, J=0.9, J=1.8, H-5%).—13C NMR
(CDCl3) l=−5.5, −5.3 (2×CH3Si), 17.8 ((CH3)3C), 18.6
(C-3), 25.5 ((CH3)3C), 51.5 (C-2), 73.8 (C-1), 107.3,
109.7 (C-3%, C-4%), 141.3 (C-5%), 154.7 (C-2%).
J=1.8, J=3.3, H-4%), 7.37 (dd, 1H, J=0.7, J=1.8,
H-5%).—13C NMR (CDCl3) l=−5.4 (s, 2×CH3Si), 16.7,
20.2 ((CH3)2CH), 17.8 ((CH3)3C), 25.5 ((CH3)3C), 28.4
(C-3), 61.0 (C-2), 70.4 (C-1), 107.8, 110.0 (C-3%, C-4%),
141.4 (C-5%), 154.7 (C-2%).
4.2.3. (1S,2S)-1-(2%-Furyl)-1-O-(tert-butyldimethylsilyl)-
4-methyl-2-pentylamine 4d. Dark brown oil.—1H NMR
(CDCl3) l=−0.12, 0.03 (s, 3H, CH3Si), 0.78–1.15 (m,
16H, (CH3)3C, (CH3)2CH, (CH3)2CH), 1.41–1.86 (m,
4H, NH2, H-3), 3.03 (ddd, 1H, J=4.4, J=5.1, J=9.3,
H-2), 4.47 (d, 1H, J=5.1, H-1), 6.21 (dd, 1H, J=0.7,
J=3.3, H-3%), 6.33 (dd, 1H, J=1.8, J=3.3, H-4%), 7.40
(dd, 1H, J=0.7, J=1.8, H-5%).—13C NMR (CDCl3)
l=−5.5, −5.3 (2×CH3Si), 17.8 ((CH3)3C), 21.8, 23.3
((CH3)2CH), 24.5 (C-4), 25.5 ((CH3)3C), 41.9 (C-3),
54.0 (C-2), 72.7 (C-1), 107.6, 109.7 (C-3%, C-4%), 141.4
(C-5%), 154.4 (C-2%).
4.2. General procedure for the Grignard reaction
(except for 4.2.2)
Per mmol of 3 in 3 mL of dry diethyl ether was added
dropwise 1.2 mmol of Grignard reagent in a total
volume of 3 mL of dry diethyl ether. The mixture was
refluxed for 1 h, cooled to −70°C and 2 mL of MeOH
was added dropwise followed by 2 mmol of NaBH4 (78
mg, 2 equiv.) and allowed to warm to rt overnight.
Diethyl ether and water were added. The water layer
was extracted three times with diethyl ether, the com-
bined organic layers dried (MgSO4), and the solvent
was evaporated. The crude products were used without
purification in the next step.
4.2.4. (1S,2S)-1-(2%-Furyl)-1-O-(tert-butyldimethylsilyl)-
2-phenyl-2-ethylamine 4e. Dark yellow oil.—1H NMR
(CDCl3) l=−0.27, −0.24 (2×s, 2×3H, 2×CH3Si), 0.71
(s, 9H, (CH3)3C), 1.51 (br s, 2H, NH2), 4.21 (d, 1H,
J=7.3, H-2), 4.65 (d, 1H, J=7.3, H-1), 6.22 (dd, 1H,
J=0.7, J=3.3, H-3%), 6.32 (dd, 1H, J=1.8, J=3.3,
H-4%), 7.32 (m, 6H, CH Ph, H-5%).—13C NMR (CDCl3)
l=−5.7, −5.5 (2×CH3Si), 17.8 ((CH3)3C), 25.5
((CH3)3C), 60.5 (C-2), 73.8 (C-1), 107.9, 110.0 (C-3%,
C-4%), 127.1, 127.6, 127.8 (CH Ph), 141.7 (C-5%), 142.4
(Cq Ph), 154.8 (C-2%).
4.2.1. (1S,2S)-1-(2%-Furyl)-1-O-(tert-butyldimethylsilyl)-
2-propylamine 4b. Yellow oil.—1H NMR (CDCl3) l=
−0.13, 0.03 (2×s, 2×3H, 2×CH3Si), 0.86 (s, 9H,
(CH3)3C), 1.03 (d, 3H, J=6.6, H-3), 1.50 (br s, 2H,
NH2), 3.12 (dq, 1H, J=5.9, J=6.6, H-2), 4.41 (d, 1H,
J=5.9, H-1), 6.21 (dd, 1H, J=0.7, J=3.1, H-3%), 6.31
(dd, 1H, J=1.8, J=3.1, H-4%), 7.36 (dd, 1H, J=0.7,
J=1.8, H-5%).—13C NMR (CDCl3) l=−5.5, −5.3 (2×
CH3Si), 17.8 ((CH3)3C), 18.6 (C-3), 25.5 ((CH3)3C),
51.5 (C-2), 73.8 (C-1), 107.3, 109.7 (C-3%, C-4%), 141.3
(C-5%), 154.7 (C-2%).
4.2.5. (1S,2S)-1-(2%-Furyl)-1-O-(tert-butyldimethylsilyl)-
3-phenyl-2-propylamine 4f. Brown oil.—1H NMR
(CDCl3) l=−0.14, 0.04 (2×s, 2×3H, 2×CH3Si), 0.89 (s,
9H, (CH3)3C), 1.26 (br s, 2H, NH2), 2.45 (dd, 1H,
J=9.3, J=13.5, H-3a), 3.04 (dd, 1H, J=4.4, J=13.5,
H-3b), 3.31 (ddd, 1H, J=4.4, J=6.0, J=9.3, H-2),
4.54 (d, 1H, J=6.0, H-1), 6.28 (d, 1H, J=3.1, H-3%),
6.36 (dd, 1H, J=1.8, J=3.1, H-4%), 7.25 (m, 6H, CH
Ph, H-5%).—13C NMR (CDCl3) l=−5.6, −5.4 (2×
CH3Si), 17.7 ((CH3)3C), 25.4 ((CH3)3C), 38.8 (C-3),
57.1 (C-2), 71.7 (C-1), 107.8, 109.8 (C-3%, C-4%), 125.9,
127.9, 128.9 (CH Ph), 138.7 (Cq Ph), 141.5 (C-5%), 154.0
(C-2%).
4.2.2. (1S,2S)-1-(2%-Furyl)-1-O-(tert-butyldimethylsilyl)-
3-methyl-2-butylamine 4c. Compound 3 (20 mmol) was
dissolved in 40 mL of dry THF and the mixture was
cooled to −35°C. Iso-propylmagnesiumchloride (2 M in
diethyl ether, 11 mL, 1.1 equiv.) was added dropwise,
followed by 0.34 mmol of Cu(I)Br (50 mg, 1.7 mol%).
The mixture was allowed to slowly warm to rt. When
the reaction had come to completion (TLC), the solu-
tion was cooled to −20°C and 20 mL of dry MeOH was
added. After stirring for 5 min it was further cooled to
−70°C and 1.52 g of NaBH4 (40 mmol, 2 equiv.) was
added. The mixture was allowed to warm to rt
overnight. Diethyl ether, water and brine were added,
the layers separated and the water layer extracted twice
with diethyl ether. The combined organic layers were
washed with brine, dried (MgSO4), and the solvent
evaporated.—Dark brown oil.—1H NMR (CDCl3) l=
0.03, 0.10 (2×s, 2×3H, 2×CH3Si), 0.74–0.98 (m, 15H,
(CH3)3C, (CH3)2C), 1.61–1.92 (m, 3H, H-3, NH2), 2.82
(dd, 1H, J=5.5, J=6.6, H-2), 4.59 (d, 1H, J=6.6,
H-1), 6.32 (dd, 1H, J=0.7, J=3.3, H-3%), 6.24 (dd, 1H,
4.3. General procedure for Fmoc-protection (except
4.3.3)
To
a vigorously stirred mixture of 3 mL of
dichloromethane and 6 mL of saturated NaHCO3 (aq.)
per mmol of 4 was added 1.4 equiv. of Fmoc-Cl. After
the reaction had come to completion (TLC), 6 mL of
dichloromethane and 3 mL of water were added, and
the layers separated. The organic phase was washed
once with brine, dried (MgSO4), and the solvent evapo-
rated. The crude compound was purified by column
chromatography (pet. ether 40–60/EtOAc 95/5, v/v).
Yields from 3.
4.3.1. (1S)-2-N-(9H-Fluorenylmethoxycarbonyl)-1-(2%-
furyl)-1-O-(tert-butyldimethylsilyl)-ethane 5a. Yield:
56%.—Yellowish oil.—IR: w (cm−1) 3346, 1706, 1508,
1472, 1463, 1450, 1250, 1148, 1083, 1005, 835, 777, 758,

R. A. Tromp et al. / Tetrahedron: Asymmetry 14 (2003) 1645–1652
1649
735.—1H NMR (CDCl3) l=−0.05, 0.07 (2×s, 2×3H,
2×CH3Si), 0.89 (s, 9H, (CH3)3C), 3.39–3.65 (m, 2H,
H-2), 4.17–4.27 (m, 1H, CH Fmoc), 4.34–4.41 (m, 2H,
CH2 Fmoc), 4.82 (dd, 1H, J=5.1, J=7.0, H-1), 5.08 (t,
1H, J=5.7, NH), 6.24 (d, 1H, J=3.1, H-3%), 6.32 (dd,
1H, J=1.8, J=3.1, H-4%), 7.34 (m, 5H, CH Ph Fmoc,
H-5%), 7.58 (d, 2H, J=7.3, CH Ph Fmoc), 7.76 (d, 2H,
J=7.0, CH Ph Fmoc).—13C NMR (CDCl3) l=−5.6,
−5.5 (2×CH3Si), 17.7 ((CH3)3C), 25.3 ((CH3)3C), 45.7
(C-2), 46.7 (CH Fmoc), 66.2 (CH2 Fmoc), 66.8 (C-1),
106.5, 109.7 (C-3%, C-4%), 119.5, 124.6, 126.5, 127.2 (CH
Ph Fmoc), 140.8, 143.5 (2×Cq Fmoc), 141.5 (C-5%),
154.1 (C-2%), 155.9 (NCO).—HRMS (ESI) m/z Found:
486.2124 [M+Na]+, calcd: 486.2077.—[h]2D0=−21.6 (c 1,
CHCl3).
154.4 (C-2%), 156.3 (NCO).—HRMS (ESI) m/z Found:
528.2490 [M+Na]+, calcd: 528.2546.—[h]2D0=−41.6 (c 1,
CHCl3).
4.3.4. (1S,2S)-2-N-(9H-Fluorenylmethoxycarbonyl)-1-
(2%-furyl)-1-O-(tert-butyldimethylsilyl)-4-methyl-pentane
5d. Yield: 61%.—Colourless oil.—IR: w (cm−1) 3339,
1710, 1505, 1471, 1450, 1250, 1076, 1005, 836, 777, 758,
736.—1H NMR (CDCl3) l=−0.08, 0.03 (2×s, 2×3H,
2×CH3Si), 0.81–0.96 (m, 16H, (CH3)3C, CH3CH, H-4),
1.12–1.33 (m, 2H, H-3), 3.96–4.09 (m, 1H, H-2), 4.18–
4.26 (m, 1H, CH Fmoc), 4.36–4.45 (m, 2H, CH2 Fmoc),
4.76 (br s, 1H, NH), 4.81 (d, 1H, J=3.5, H-1), 6.22 (d,
1H, J=3.1, H-3%), 6.31 (dd, 1H, J=1.8, J=3.1, H-4%),
7.29–7.33 (m, 5H, CH Ph Fmoc, H-5%), 7.61 (d, 2H,
J=7.3, CH Ph Fmoc), 7.64 (d, 2H, J=8.2, CH Ph
Fmoc), 7.77 (d, 2H, J=7.1, CH Ph Fmoc).—13C NMR
(CDCl3) l=−5.3, −5.2 (2×CH3Si), 18.1 ((CH3)3C), 21.5,
23.6 ((CH3)2C-4), 24.6 (C-4), 25.7 ((CH3)3C), 38.6 (C-
3), 47.2 (CH Fmoc), 53.8 (C-2), 66.5 (CH2 Fmoc), 71.3
(C-1), 107.2, 110.0 (C-3%, C-4%), 119.8, 125.0, 126.9,
127.5 (CH Ph Fmoc), 141.5, 143.8 (Cq Fmoc), 141.6
(C-5%), 154.5 (C-2%), 156.0 (NCO).—HRMS (ESI) m/z
Found: 542.2672 [M+Na]+, calcd: 542.2703.—[h]D20=
−34.9 (c 1, CHCl3).
4.3.2. (1S,2S)-2-N-(9H-Fluorenylmethoxycarbonyl)-1-
(2%-furyl)-1-O-(tert-butyldimethylsilyl)-propane
5b.
Yield: 80%.—Colourless oil.—IR: w (cm−1) 3337, 17.8,
1505, 1472, 1463, 1450, 1241, 1073, 1053, 1006, 835,
777, 758, 735.—1H NMR (CDCl3) l=−0.08, 0.03 (2×s,
2×3H, 2×CH3Si), 0.91 (s, 9H, (CH3)3C), 1.15 (d, 3H,
J=6.8, H-3), 4.01–4.14 (m, 1H, H-2), 4.26 (t, 1H,
J=6.8, CH Fmoc), 4.34–4.42 (m, 2H, CH2 Fmoc), 4.90
(d, 1H, J=3.7, H-1), 5.10 (d, 1H, J=8.8, NH), 6.28 (d,
1H, J=3.3, H-3%), 6.35 (dd, 1H, J=1.8, J=3.3, H-4%),
7.27–7.44 (m, 5H, CH Ph Fmoc, H-5%), 7.65 (d, 2H,
J=7.1, CH Ph Fmoc), 7.86 (d, 2H, J=7.1, CH Ph
Fmoc).—13C NMR (CDCl3) l=−5.4, −5.1 (2×CH3Si),
15.0 (C-3), 18.0 ((CH3)3C), 25.7 ((CH3)3C), 47.1 (CH
Fmoc), 51.2 (C-2), 66.5 (CH2 Fmoc), 71.0 (C-1), 107.0,
110.0 (C-3%, C-4%), 119.8, 125.0, 126.9, 127.5 (CH Ph
Fmoc), 141.2, 143.9 (Cq Fmoc), 141.6 (C-5%), 154.5
(C-2%), 155.6 (NCO).—HRMS (ESI) m/z Found:
500.2287 [M+Na]+, calcd: 500.2233.—[h]2D0=−28.4 (c 1,
CHCl3).
4.3.5. (1S,2S)-2-N-(9H-Fluorenylmethoxycarbonyl)-1-
(2%-furyl)-1-O-(tert-butyldimethylsilyl)-2-phenyl-ethane
5e. Yield: 79%.—White solid, mp 88°C.—IR w (cm−1)
3320, 1690, 1542, 1472, 1450, 1258, 1241, 1087, 1027,
1009, 836, 778, 756, 731, 698.—1H NMR (CDCl3)
l=−0.13, −0.02 (2×s, 2×3H, 2×CH3Si), 0.82 (m, 9H,
(CH3)3C), 4.25 (m, 2H, CH2 Fmoc), 4.40 (m, 1H, CH
Fmoc), 5.01 (m, 2H, H-1, H-2), 5.63 (d, 1H, J=6.8,
NH), 5.95 (d, 1H, J=3.1, H-3%), 6.23 (dd, 1H, J=1.8,
J=3.1, H-4%), 7.30 (m, 10H, CH Ph Fmoc, CH Ph,
H-5%), 7.57 (m, 2H, CH Ph Fmoc), 7.76 (d, 2H, J=7.3,
CH Ph Fmoc).—13C NMR (CDCl3) l=−5.7, −5.4 (2×
CH3Si), 17.8 ((CH3)3C), 25.4 ((CH3)3C), 46.9 (CH
Fmoc), 59.7 (C-2), 66.6 (CH2 Fmoc), 72.5 (C-1), 107.8,
109.9 (C-3%, C-4%), 119.7, 124.8, 126.8, 127.3, 127.4,
127.9 (CH Ph, Fmoc), 138.9 (Cq Ph), 141.0, 143.7,
143.8 (Cq Fmoc), 141.5 (C-5%), 153.6 (C-2%), 155.5
(NCO).—HRMS (ESI) m/z Found: 562.2296 [M+Na]+,
calcd: 562.2390.—[h]2D0=−26.1 (c 1, CHCl3).
4.3.3. (1S,2S)-2-N-(9H-Fluorenylmethoxycarbonyl)-1-
(2%-furyl)-1-O-(tert-butyldimethylsilyl)-3-methyl-butane
5c. To a well stirred solution of crude 4c in CH2Cl2 (10
mL per mmol) were added 2 mmol of Fmoc-Cl (0.52 g)
and 1 mmol of DIPEA. When the reaction had come to
completion (TLC), the mixture was washed with water
and brine. The organic layer was dried (MgSO4), the
solvent evaporated and the crude compound purified by
column chromatography. Yield: 48%.—Colourless
oil.—IR: w (cm−1) 3330, 1699, 1506, 1473, 1464, 1450,
1239, 1087, 1004, 836, 776, 757, 734.—1H NMR
(CDCl3) l=−0.15, 0.03 (2×s, 2×3H, 2×CH3Si), 0.86 (s,
9H, (CH3)3C), 0.90 (d, 3H, J=7.3, CH3CH), 0.95 (d,
3H, J=6.8, CH3CH), 1.72–1.91 (m, 1H, H-3), 3.91
(ddd, 1H, J=6.0, J=10.4, J=10.8, H-2), 4.09–4.36 (m,
2H, CH2 Fmoc), 4.37–4.50 (m, 1H, CH Fmoc), 4.77 (d,
1H, J=6.0, H-1), 4.85 (d, 1H, J=10.8, NH), 6.26 (d,
1H, J=3.1, H-3%), 6.31 (dd, 1H, J=1.8, J=3.1, H-4%),
7.25–7.46 (m, 5H, CH Ph Fmoc, H-5%), 7.56 (d, 1H,
J=5.1, CH Ph Fmoc), 7.64 (d, 1H, J=8.2, CH Ph
Fmoc), 7.77 (d, 2H, J=6.9, CH Ph Fmoc).—13C NMR
(CDCl3) l=−5.6, −5.4 (2×CH3Si), 16.8, 20.2 ((CH3)2C-
3), 17.8 ((CH3)3C), 25.4 ((CH3)3C), 28.1 (C-3), 47.0
(CH Fmoc), 59.7 (C-2), 66.4 (CH2 Fmoc), 69.0 (C-1),
107.4, 110.0 (C-3%, C-4%), 119.6, 124.8, 126.7, 127.3 (CH
Ph Fmoc), 141.0, 143.7, 144.0 (Cq Fmoc), 141.5 (C-5%),
4.3.6. (1S,2S)-2-N-(9H-Fluorenylmethoxycarbonyl)-1-
(2%-furyl)-1-O-(tert-butyldimethylsilyl)-3-phenyl-propane
5f. Yield: 43%.—Yellowish, viscous oil.—IR: w (cm−1)
3336, 1710, 1504, 1471, 1465, 1450, 1250, 1074, 1041,
1005, 835, 777, 756, 734, 699.—1H NMR (CDCl3)
l=−0.10, 0.04 (2×s, 2×3H, 2×CH3Si), 0.92 (m, 9H,
(CH3)3C), 2.81 (dd, 1H, J=9.1, J=14.4, H-3), 2.87
(dd, 1H, J=5.1, J=14.4, H-3), 4.15 (t, 1H, J=7.3, CH
Fmoc), 4.25 (m, 3H, CH2 Fmoc, H-2), 4.86 (d, 1H,
J=9.0, NH), 4.89 (d, 1H, J=4.5, H-1), 6.29 (d, 1H,
J=3.1, H-3%), 6.36 (dd, 1H, J=1.8, J=3.1, H-4%), 7.29
(m, 10H, CH Ph Fmoc, CH Ph, H-5%), 7.49 (m, 2H,
CH Ph Fmoc), 7.76 (d, 2H, J=7.1, CH Ph Fmoc).—
13C NMR (CDCl3) l=−5.7, −5.4 (2×CH3Si), 17.8
((CH3)3C), 25.5 ((CH3)3C), 35.4 (C-3), 46.8 (CH
Fmoc), 56.5 (C-2), 66.3 (CH2 Fmoc), 69.9 (C-1), 107.5,
109.9 (C-3%, C-4%), 119.6, 125.0, 126.2, 127.8, 127.4,

1650
R. A. Tromp et al. / Tetrahedron: Asymmetry 14 (2003) 1645–1652
128.2, 129.0 (CH Ph, Fmoc), 138.0 (Cq Ph), 141.0,
143.8 (Cq Fmoc), 141.8 (C-5%), 154.0 (C-2%), 155.6
(NCO).—HRMS (ESI) m/z Found: 576.2349 [M+Na]+,
calcd: 576.2546.—[h]2D0=−17.6 (c 1,CHCl3).
7.43 (m, 4H, CH Ph Fmoc), 7.60–7.71 (m, 2H, CH Ph
Fmoc), 7.78 (d, 2H, J=7.1, CH Ph Fmoc).—13C NMR
(MeOD/CDCl3 9/1, v/v) l=18.1, 20.6 (CH3CH), 29.5
(C-4), 48.3 (CH Fmoc), 59.8 (C-3), 67.7 (CH2 Fmoc),
73.0 (C-2), 120.7, 126.1, 128.0, 128.6 (CH Ph Fmoc),
142.4, 145.0, 145.2 (Cq Ph Fmoc), 158.7 (NCO), 176.2
(C-1).—HRMS (ESI) m/z Found: 370.1652 [M+H]+,
calcd: 370.1654.—[h]2D0=−5.9 (c 0.1, MeOH).
4.4. General procedure for ozonolysis-deprotection
Compound 5 was dissolved in 10 mL of MeOH (5e was
dissolved in 10 mL of MeOH/CH2Cl2, 1/1, v/v) per
mmol and cooled to −70°C. A gas stream of O3/O2 was
bubbled through until no starting material could be
detected (TLC). To remove excess ozone, oxygen was
bubbled through for 30 min, after which the mixture
was allowed to warm to rt. The solvent was evaporated
and the resulting oil stirred for 2 h in a mixture of
THF/CH3CN/H2O (3/1/1, v/v/v), 5 mL per mmol 5, at
40°C. EtOAc was added and the layers were separated.
The water layer was extracted three times with EtOAc.
The combined organic layers were dried (MgSO4) and
the solvent evaporated to yield a thick yellow oil. The
crude product was purified by crystallisation from
EtOAc/pentane or by washing with diethyl ether 6a.
4.4.4. (2S,3S)-3-N-(9H-Fluorenylmethoxycarbonyl)-2-
hydroxyl-5-methyl-hexanoic acid 6d. Yield: 61%.—
White solid, mp 154–155°C (dec.).—IR: w (cm−1) 3379,
1715, 1696, 1520, 1452, 1245, 1224, 1105, 1082, 1048,
758, 735.—1H NMR (MeOD/CDCl3 5/1, v/v) l=0.87
(d, 3H, J=6.4, CH3CH), 0.92 (d, 3H, J=6.6, CH3CH),
1.01–1.19 (m, 1H, CH3CH), 1.48–1.72 (m, 2H, H-4),
3.94–4.13 (m, 1H, H-3), 4.15–4.45 (m, 4H, H-2, CH-,
CH2 Fmoc), 7.02 (d, 1H, J=8.8, NH), 7.22–7.44 (m,
4H, CH Ph Fmoc), 7.66 (d, 2H, J=6.8, CH Ph Fmoc),
7.79 (d, 2H, J=6.9, CH Ph Fmoc).—13C NMR
(MeOD/CDCl3 5/1, v/v) l=21.7 (CH3CH), 24.0
(CH3CH), 24.4 (C-5), 38.5 (C-4), 48.2 (CH Fmoc),
52.9 (C-3), 67.5 (CH2 Fmoc), 74.2 (C-1), 120.7, 126.0,
127.9, 128.5 (CH Ph Fmoc), 142.3, 144.9, 145.1 (Cq Ph
Fmoc), 158.1 (NCO), 175.4 (C-1).—HRMS (ESI) m/z
Found: 384.1795 [M+H]+, calcd: 384.1811.—[h]D20=
−19.2 (c 0.1, MeOH).
4.4.1.
(2S)-3-N-(9H-Fluorenylmethoxycarbonyl)-2-
hydroxylpropanoic acid 6a. Yield: 80%.—White solid,
mp 162–164°C (dec.) (lit.: 168°C).14—IR: w (cm−1) 3407,
3264, 1750, 1681, 1557, 1452, 1270, 1119, 761, 736.—1H
NMR (MeOD) l=3.35 (dd, 1H, J=6.6, J=13.9, H-3),
3.52 (dd, 1H, J=4.4, J=13.9, H-3), 4.15–4.40 (m, 4H,
H-2, CH, CH2 Fmoc), 7.22–7.45 (m, 4H, CH Ph
Fmoc), 7.65 (d, 2H, J=6.9, CH Ph Fmoc), 7.79 (d, 2H,
J=6.6, CH Ph Fmoc).—13C NMR (MeOD) l=45.5
(C-3), 48.4 (CH Fmoc), 68.0 (CH2 Fmoc), 71.0, (C-2),
120.9, 126.2, 128.2, 128.8 (CH Fmoc), 142.6, 145.3 (Cq
Fmoc), 159.0 (NCO), 175.8 (C-1).—HRMS (ESI) m/z
Found: 328.1156 [M+H]+, calcd: 328.1184.—[h]D20=
−17.8 (c 0.1, MeOH).
4.4.5. (2S,3S)-3-N-(9H-Fluorenylmethoxycarbonyl)-2-
hydroxyl-3-phenyl-propanoic acid 6e. Yield: 69%.—
White
solid,
mp
134–135°C
(dec.).—IR:
w
(cm−1)=3351, 1697, 1523, 1450, 1244, 1229, 1117, 1084,
1033, 738, 701.—1H NMR (MeOD) l=4.14–4.24 (m,
1H, CH Fmoc), 4.25–4.40 (m, 2H, CH2 Fmoc), 4.46 (d,
1H, J=4.8, H-2), 5.05 (d, 1H, J=4.8, H-3), 7.16–7.44
(m, 9H, CH Ph Fmoc, Ph), 7.63 (d, 2H, J=7.3, CH Ph
Fmoc), 7.77 (d, 2H, J=7.3, CH Ph Fmoc).—13C NMR
(MeOD) l=48.1 (CH Fmoc), 58.5 (C-3), 67.8 (CH2
Fmoc), 74.2 (C-2), 120.7, 126.0, 128.0, 128.6, 129.0
(CH Ph Fmoc, Ph), 139.1 (Cq Ph), 142.2, 144.9 (Cq Ph
Fmoc), 157.7 (NCO), 174.8 (C-1).—HRMS (ESI) m/z
Found: 404.1506 [M+H]+, calcd: 404.1497.—[h]2D0=−6.0
(c 0.1, MeOH).
4.4.2. (2S,3S)-3-N-(9H-Fluorenylmethoxycarbonyl)-2-
hydroxyl-butanoic acid 6b. Yield: 61%.—White solid,
mp 152–153°C (dec.).—IR: w (cm−1) 3330, 1734, 1689,
1532, 1450, 1251, 1116, 1053, 736.—1H NMR (MeOD)
l=1.10 (d, 3H, J=6.8, H-4), 3.94–4.12 (m, 1H, H-3),
4.15–4.27 (m, 2H, H-2, CH Fmoc), 4.28–4.39 (m, 2H,
CH2 Fmoc), 7.04 (d, 1H, J=8.4, NH), 7.24–7.43 (m,
4H, CH Ph Fmoc), 7.66 (d, 2H, J=7.1, CH Ph Fmoc),
7.79 (d, 2H, J=7.7, CH Ph Fmoc).—13C NMR
(MeOD) l=14.4 (C-4), 48.4 (CH Fmoc), 50.3 (C-3),
67.6 (CH2 Fmoc), 73.5, (C-2), 120.7, 126.0, 127.9,
128.5 (CH Fmoc), 140.8, 144.9 (Cq Fmoc), 157.7
(NCO), 175.4 (C-1).—HRMS (ESI) m/z Found:
364.1177 [M+H]+, calcd: 364.1160.—[h]2D0=−11.8 (c 0.1,
MeOH).
4.4.6. (2S,3S)-3-N-(9H-Fluorenylmethoxycarbonyl)-2-
hydroxyl-4-phenyl-butanoic acid 6f. Yield: 52%.—White
solid, mp 170–172°C (dec.).—IR: w (cm−1)=3329, 1690,
1532, 1428, 1247, 1110, 1034, 733, 702.—1H NMR
(MeOD) l=2.75–2.86 (m, 2H, H-4), 4.02–4.29 (m, 5H,
CH, CH2 Fmoc, H-2, H-3), 7.07–7.42 (m, 9H, CH Ph,
Fmoc), 7.54 (d, 2H, J=7.3, CH Ph Fmoc), 7.76 (d, 2H,
J=6.9, CH Ph Fmoc).—13C NMR (MeOD/CDCl3 1/1,
v/v) l=35.5 (C-4), 47.5 (CH Fmoc), 55.6 (C-3), 67.2
(CH2 Fmoc), 73.1 (C-2), 120.3, 125.4, 126.8, 127.4,
128.0, 128.7, 128.9, 129.7 (CH Ph Fmoc, Ph), 138.3 (Cq
Ph), 141.6, 144.3 (Cq Ph Fmoc), 157.2 (NCO), 174.8
(C-1).—HRMS (ESI) m/z Found: 418.1655 [M+H]+,
calcd: 418.1654.—[h]2D0=−36.0 (c 0.1, MeOH).
4.4.3. (2S,3S)-3-N-(9H-Fluorenylmethoxycarbonyl)-2-
hydroxyl-4-methyl-pentanoic acid 6c. Yield: 52%.—
White solid, mp 153–155°C (dec.).—IR: w (cm−1) 3339,
1695, 1532, 1452, 1240, 1103, 1027, 758, 735.—1H
NMR (MeOD/CDCl3 9/1, v/v) l=0.90 (d, 3H, J=
5.11, CH3CH), 0.94 (d, 3H, J=4.4, CH3CH), 1.96–2.16
(m, 1H, H-4), 3.71–3.89 (m, 1H, H-3), 4.12 (d, 1H,
J=6.2, H-2), 4.22 (d, 1H, J=5.8, CH Fmoc), 4.26–4.38
(m, 2H, CH2 Fmoc), 6.97 (d, 1H, J=9.7, NH), 7.21–
4.5. General procedure for Boc-protection
To a vigorously stirred mixture of crude ethanolamine
4 (1 mmol), 5 mL of dichloromethane, and saturated
NaHCO3 (aq.) was added 3 mmol of Boc-anhydride.

R. A. Tromp et al. / Tetrahedron: Asymmetry 14 (2003) 1645–1652
1651
After stirring overnight, 10 mL of dichloromethane and
5 mL of water were added. The organic layer was dried
(MgSO4) and the solvent was evaporated. The crude
product was purified by column chromatography (pet.
ether 40–60/EtOAc 99/1–95/5, v/v). Yields from 3.
J=6.9, H-3), 3.49 (d, 1H, J=4.5, OH), 4.23–4.31 (m,
1H, H-2), 4.69–4.79 (m, 2H, H-1, NH), 6.33 (d, 1H,
J=3.3, H-3%), 6.38 (dd, 1H, J=1.8, J=3.3, H-4%),
7.18–7.34 (m, 5H, CH Ph), 7.43 (s, 1H, J=0.7, J=1.8,
H-5%).—13C NMR (CDCl3) l=28.2 ((CH3)3CO), 36.5
(C-3), 56.4 (C-2), 69.9 (C-1), 79.9 ((CH3)3CO), 107.7,
110.2 (C-3%, C-4%), 126.4, 128.4, 129.2 (CH Ph), 137.4
(Cq Ph), 142.1 (C-5%), 154.0 (C-2%).
4.5.1. (1S,2S)-1-(2%-Furyl)-1-O-(tert-butyldimethylsilyl)-
2-N-(tert-butyloxocarbonyl)-3-methyl-butane 7. Yield:
42%.—Colourless oil.—1H NMR (CDCl3) l: −0.14,
0.04 (2×s, 2×3H, 2×CH3Si), 0.85 (d, 3H, J=6.9,
(CH3CH), 0.87 (s, 9H, (CH3)3CSi), 0.91 (d, 3H, J=6.9,
CH3CH), 1.40 (s, 9H, (CH3)3CO), 1.65–1.81 (m, 1H,
H-3), 3.75–3.86 (m, 1H, H-2), 4.59 (d, 1H, J=10.6,
NH), 4.72 (d, 1H, J=5.9, H-1), 6.23 (d, 1H, J=3.3,
H-3%), 6.31 (dd, 1H, J=1.8, J=3.3, H-4%), 7.36 (dd,
1H, J=0.7, J=1.8, H-5%).—13C NMR (CDCl3) l: −5.6,
−5.3 (2×s, 2×3H, 2×CH3Si), 17.1, 20.4 ((CH3C)2CH),
18.0 ((CH3)3CSi), 28.3 ((CH3)3CO), 59.0 (C-2), 69.4
(C-1), 78.6 ((CH3)3CO), 107.3, 110.0 (C-3%, C-4%), 141.5
(C-5%), 154.8 (C-2%), 155.8 (NCO).
4.7. General procedure for oxazolidinone formation
The Boc-protected ethanolamine in DMF/THF (5 mL
per mmol) was added to a stirred suspension (0°C) of 2
equiv. NaH in DMF (7.5 mL per mmol). After 1 h the
reaction had come to completion and saturated NH4Cl
(aq.) was added. The title compound was extracted with
diethyl ether. The organic layer was washed once with
water, dried (MgSO4), and the solvent was evaporated.
4.7.1. (4S,5R)-5-(2%-Furyl)-4-(iso-propyl)-oxazolidinone
1
11. H NMR (CDCl3) l=0.73 (d, 3H, J=6.58, CH3),
4.5.2. (1S,2S)-1-(2%-Furyl)-1-O-(tert-butyldimethylsilyl)-
2-N-(tert-butyloxocarbonyl)-3-phenyl-propane 8. Yield:
28%.—Colourless oil.—1H NMR (CDCl3) l: −0.13,
0.06 (2×s, 2×3H, 2×CH3Si), 0.86 (s, 9H, (CH3)3CSi),
1.48 (s, 9H, (CH3)3CO), 2.61–2.94 (m, 2H, H-3), 4.03–
4.21 (m, 1H, H-2), 4.61 (d, 1H, J=8.8, NH), 4.92 (d,
1H, J=3.7, H-1), 6.25 (d, 1H, J=2.9, H-3%), 6.32 (br s,
1H, H-4%), 7.16–7.33 (m, 5H, CH Ph), 7.40 (s, 1H,
H-5%).—13C NMR (CDCl3) l: −5.4, −5.2 (2×s, 2×3H,
2×CH3Si), 18.1 ((CH3)3CSi), 25.7 ((CH3)3CSi), 28.2
((CH3)3CO), 35.4 (C-3), 56.0 (C-2), 70.0 (C-1), 79.0
((CH3)3CO), 107.5, 110.0 (C-3%, C-4%), 126.1, 128.2,
129.1 (CH Ph), 138.4 (Cq Ph), 141.8 (C-5%), 154.0
(C-2%), 155.2 (NCO).
0.95 (d, 3H, J=6.58, CH3), 1.48–1.74 (m, 1H,
CH(CH3)2), 3.78 (t, 1H, J=8.0, H-4), 5.59 (d, 1H,
J=7.7, H-5), 6.38 (dd, 1H, J=1.8, J=3.3, H-4%), 6.46
(d, 1H, J=3.3, H-3%), 7.44 (dd, 1H, J=0.7, J=1.8,
H-5%).—13C NMR (CDCl3) l=18.9, 19.5 (2×CH3),
28.6 (CH(CH3)2), 63.1 (C-4), 74.9 (C-5), 110.2, 110.3
(C-3%, C-4%), 142.9 (C-5%), 148.8 (C-2%), 159.8
(OCON).—MS (ESI) m/z found: [M+H]+: 218.2, calcd:
218.1.
4.7.2. (4S,5R)-5-(2%-Furyl)-4-benzyl-oxazolidinone 12. 1H
NMR (CDCl3) l=2.53 (dd, 1H, J=10.2, J=13.9,
CH2Ph), 2.63 (dd, 1H J=4.8, J=13.9, CH2Ph), 4.29
(ddd, 1H J=4.8, J=8.0, J=10.2, H-4), 5.72 (d, 1H,
J=8.0, H-5), 6.43 (dd, 1H, J=1.8, J=3.3, H-4%), 6.51
(d, 1H, J=3.3, H-3%), 7.44 (dd, 1H, J=0.7, J=1.8,
H-5%).—13C NMR (CDCl3) l=18.9, 19.5 (2×CH3),
28.6 (CH(CH3)2), 63.1 (C-4), 74.9 (C-5), 110.2, 110.3
(C-3%, C-4%), 142.9 (C-5%), 148.8 (C-2%), 159.8 (OCON).
MS (ESI) m/z found: 266.1 [M+Na]+, calcd: 266.1.
4.6. General procedure for silyl deprotection
Compound 7 and 8 were dissolved in THF (4 mL per
mmol) and 1.5 equiv. of TBAF·3H2O was added. After
the reaction had come to completion (TLC), ethyl
acetate was added. The organic layer was washed with
saturated NaHCO3 (aq.), dried (MgSO4), and the sol-
vent evaporated. The crude product was purified by
column chromatography (pet. ether 40–60/EtOAc 90/
10–70/30, v/v).
Acknowledgements
We like to thank Hans van der Elst for MS and Bertil
Hofte for HRMS spectroscopy.
4.6.1. (1S,2S)-1-(2%-Furyl)-2-N-(tert-butyloxocarbonyl)-
3-methyl-1-butanol 9. Yield: 60%.—White solid.—1H
NMR (CDCl3) l=0.89 (d, 3H, J=6.6, (CH3CH), 0.98
(d, 3H, J=6.6, CH3CH), 1.44 (s, 9H, (CH3)3CO),
1.50–1.68 (m, 1H, H-3), 3.08 (d, 1H, J=6.2, OH),
3.75–3.87 (m, 1H, H-2), 4.66 (d, 1H, J=9.9, NH), 4.85
(dd, 1H, J=5.9, J=5.9, H-1), 6.31 (d, 1H, J=2.9,
H-3%), 6.35 (dd, 1H, J=1.8, J=2.9, H-4%), 7.38 (dd,
1H, J=1.1, J=1.8, H-5%).—13C NMR (CDCl3) l=
18.4, 20.1 ((CH3C)2CH), 28.3 ((CH3)3CO), 29.4 (C-3),
60.2 (C-2), 68.5 (C-1), 79.6 ((CH3)3CO), 107.7, 110.1
(C-3%, C-4%), 142.0 (C-5%), 154.3 (C-2%), 157.0 (NCO).
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