Chemoenzymatic synthesis of enantiomerically enriched aminoalkenols and glycosides thereof

Article abstract of DOI:10.1016/S0957-4166(00)00294-9

1-t-Butoxycarbonylamido-3-pentene-1-ol 3 and 2-azido-4-phenyl-3-butene-1-ol 4 were enantiomerically enriched by enzymatic acetylation using various lipases and esterases (CHIRAZYM) to give acetylated compounds 5 and 7, respectively. Compound 3 gave the be

Full text of DOI:10.1016/S0957-4166(00)00294-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3403–3418
Chemoenzymatic synthesis of enantiomerically enriched
aminoalkenols and glycosides thereof†
Thomas Ziegler* and Claus Jurisch
Institute of Organic Chemistry, University of Cologne, Greinstraße 4, D-50939 Cologne, Germany
Received 11 July 2000; accepted 25 July 2000
Abstract
1-t-Butoxycarbonylamido-3-pentene-1-ol 3 and 2-azido-4-phenyl-3-butene-1-ol 4 were enantiomerically
enriched by enzymatic acetylation using various lipases and esterases (CHIRAZYM) to give acetylated
compounds 5 and 7, respectively. Compound 3 gave the best results (E=94) with Candida antarctica A
lipase (CHIRAZYM L-5), whereas 4 could not be separated into the enantiomers with satisfactory E
values. The absolute configurations were proven for both compounds via independently prepared
derivatives. Both enantiomers of 5, as well as racemic 7, were N-deblocked and condensed with octonic
acid derivatives 14 to give the corresponding C-glycosides 17 and 22 after deprotection of the intermedi-
ates in good overall yield. Compound 4 was similarly condensed with glucose imidate 11 to give the
diastereomeric O-glycosides 13 after deprotection. The latter glycosides were prepared as precursors for
the generation of the corresponding aldehydes as substrates for aldolase catalyzed reactions. © 2000
Published by Elsevier Science Ltd.
1. Introduction
As part of a project towards the synthesis of enantiomerically pure alkenyl glycosides, we
recently prepared a series of optically active alkene diol derivatives by lipase and esterase
catalyzed saponification and esterification reactions, respectively, of racemic precursors 1 and 2.1
These enantiomerically pure alkene diols were subsequently glycosylated to afford the corre-
sponding alkenyl glycosides after deblocking of the protected intermediates.1 The diastereomer-
ically pure alkenyl glycosides obtained were useful precursors for the generation of glycosylated
aldehydes, which in turn were substrates for aldolase catalyzed syntheses of unnatural
oligosaccharides.2
* Corresponding author. Fax: +49 (0) 221 470 5057; e-mail: thomas.ziegler@uni-koeln.de
†
Dedicated to James Reed Harris.
0957-4166/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0957-4166(00)00294-9

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T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
In continuation of this project we extended the enzymatic resolution of alkenols to 1-t-
butoxycarbamido-3-pentene-2-ol 3 and 2-azido-4-phenyl-3-butene-1-ol 4 in order to prepare the
corresponding glycosides as useful precursors for substrates for aldolase catalyzed reactions.
Furthermore, optically active aminoalkenols of type 3 and 4 are important building blocks for
the synthesis of pyrrolidine and indolicine alkaloids,3,4 (+)-galantinic acid,5 polyamino acids,6
and acromelinic acid derivatives.7
2. Results and discussion
Both racemic aminoalkenol derivatives 3 and 4 that were used in this study were prepared
according to known procedures8–11 from crotonaldehyde and cinnamaldehyde, respectively, as
follows. First, trimethylsilyl cyanide was quantitatively added to crotonaldehyde using a
catalytic amount of ZnCl2.8 Next, the intermediate silylated cyanohydrin was reduced with
LiAlH4 without further purification9 to afford 1-amino-3-pentene-2-ol, which was condensed
with Boc2O in dichloromethane according to a slightly modified literature procedure9 to give
racemic aminoalkenol 3 in a 95% yield. Starting from cinnamaldehyde, condensation with
trimethyl sulfonium iodide according to Ma¨rkl10 gave first styryl oxirane, which was regioselec-
tively opened11 with NaN3 to afford aminoalkenol derivative 4 (82%). Both racemic
aminoalkenol derivatives 3 and 4 were subsequently used as substrates for enzymatic acetyl-
ations with various lipases and esterases.
First, 3 was used as the substrate for enzymatic esterification using some CHIRAZYM lipases
and esterases (Table 1) in combination with vinyl acetate in t-butylmethylether as the solvent
(Scheme 1). Although several racemic saturated 1-amino-2-alkanols have been previously
resolved by enzymatic esterification and saponification of acylated derivatives,12 to the best of
our knowledge no resolution of aminoalkenol 3 or similar 1-amino-3-alkene-2-ol derivatives
have been previously described. Only 1-t-butoxycarbamido-4-pentene-3-ol has been previously
enzymatically acylated with lipases in good enantiomeric excess.13
Scheme 1. i: Lipase or esterase, vinyl acetate, t-butyl methyl ether (Table 1). ii: Cat. NaOMe in MeOH. iii: Acetic
anhydride in pyridine. iv: (a) Crotonaldehyde, HCN, almond oxynitrilase, Ref. 14 (“(R)-6); (b) LiAlH4, Ref. 15; (c)
Boc2O, Et3N, Ref. 9

T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
3405
For our study of the enzymatic resolution of aminoalkenols we used the Boc protecting group
in 3 for the amino function, because the latter can be easily cleaved after the resolution of the
enantiomers without affecting the double bond. As shown in Scheme 1, enzymatic esterifications
of 3 led to the acetylated aminoalkenol (R)-5 and the non-acetylated enantiomer (S)-3,
respectively, or vice versa. Both products could be separated by simple column chromatography.
Furthermore, (S)-3 was conventionally acetylated to give (S)-5 and (R)-5 was saponified without
any loss of enantiomeric excess to afford (R)-3. Thus, both enantiomers of 3 and 5 could be
prepared this way and their enantiomeric purity determined by gas chromatography of acetates
5 on chiral stationary phases (see Section 3). The absolute configuration of (R)-3 and (R)-5 was
also proven by an independent preparation via oxynitrilase catalyzed addition14 of HCN to
crotonaldehyde followed by subsequent reduction15 and N-protection9 of the intermediate
cyanohydrin (R)-6.
The various Pseudomonas species lipases (Table 1, entries 1–3, 6, and 10), which previously gave
excellent results for the resolution of alkene diols,1 resulted in poor resolutions of compound 3
in this case. Similarly, other lipases and esterses could not be used efficiently for the resolution
of aminoalcohol 3. Only the Candida antarctica A lipase (CHIRAZYM L-5, entry 7) gave good
results, which could be improved further by immobilisation of the lipase on Celite (entries 8 and
9).16 Interestingly, all Pseudomonas species lipases, as well as some Candida lipases and the porcine
Table 1
Enzymatic resolution of 3 using various lipases under esterification conditionsa
Entry
Enzyme (mg)
Time
Yield of products (ee)
E value
Alcohol 3
Ester 5
1
2
3
4
5
6
7
8
9
Pseudomonas speciesb (40)
Pseudomonas speciesb,c (40)
Pseudomonas speciesd (10)
Candida antarctica Be (3)
Candida cyclindraceaf (20)
Pseudomonas speciesg (10)
Candida antarctica Ah (10)
Candida antarctica Ah,i (40)
Candida antarctica Ah,j (440)
Pseudomonas speciesk (10)
Porcine pancreasl (20)
66 h
27 h
26 h
30 d
15 d
5.5 h
96 h
29 h
29 h
8.5 h
15 d
30 d
48% (R)-3 (64%)
48% (R)-3 (53%)
34% (R)-3 (66%)
–
42% (S)-5 (71%)
44% (S)-5 (58%)
62% (S)-5 (36%)
Traces (S)-5 (96%)
Traces (S)-5 (69%)
46% (S)-5 (37%)
46% (R)-5 (86%)
48% (R)-5 (92%)
49% (R)-5 (93%)
34% (S)-5 (73%)
Traces (S)-5 (77%)
–
11
6
4
–
–
–
46% (R)-3 (41%)
44% (S)-3 (93%)
44% (S)-3 (96%)
44% (S)-3 (99%)
60% (R)-3a (46%)
–
3
45
94
94
10
–
10
11
12
Humicola speciesm (10)
–
–
a 3 (100 mg, 497 mmol) was treated with the respective lipase and vinyl acetate (5 ml) in t-butyl methyl ether (9 ml)
until ca. 50% conversion was obtained, followed by chromatographic separation of the products.
b
Amano PS lipase immobilized on Celite.
In n-pentane as the solvent.
CHIRAZYM L-1, similar to Burkholderia cepacia.
CHIRAZYM L-2
CHIRAZYM L-3.
CHIRAZYM L-4, cholesterine esterase.
CHIRAZYM L-5.
Immobilized on Celite.
3a (1.5 g, 7.46 mmol).
CHIRAZYM L-6.
CHIRAZYM L-7.
CHIRAZYM L-8.
c
d
e
f
g
h
i
j
k
l
m

3406
T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
pancreas lipase acetylated the (S)-enantiomer of 3, whereas the Candida antarctica A lipase showed
an inverted enantioselectivity and consumed the (R)-isomer faster. A similar observation was
recently made by Oshida et al.17 for the enantioselective acylation of a cholesterine derivative. This
significant deviation from the Katzlauskas rule18 for the preferred reaction of one enantiomer
during enzymatic acylations with Pseudomonas and Candida lipases may be interpreted in terms
of a similar bulkiness of the two substituents in compound 3 (i.e. the (E)-propenyl residue vs.
the t-butoxycarbamidomethyl residue). Obviously, Candida antarctica A lipase recognizes the
t-butoxycarbamidomethyl residue as the larger residue, whereas all other enzymes recognize the
(E)-propenyl residue as the larger one. However, since the E values in the second case are
significantly lower, this finding may not be interpreted as an exception from the Katzlauskas rule.2
Next, (E)-2-azido-4-phenyl-3-butene-1-ol 4 was used as a substrate for the enzymatic resolution
of the enantiomers. All attempts to kinetically resolve the enantiomers of racemic 7 by
saponification with various Pseudomonas species lipases failed. In all cases, 100% conversion was
found for enzymatic deacetylation without any discrimination of enantiomers (no details are shown
in Section 3). Thus, the enzymatic acetylation was used next for separation of the enantiomers.
Although many examples of the resolution of 1-azido-alkane-2-ols by enzymatic esterification are
in the literature12f no examples of 2-azido-alkane-1-ols are described. Only for (E)-1-amino-2-
azido-4-phenyl-3-butene has it been shown that enzymatic esterification with Amano PS lipase
in ethyl acetate led to the corresponding (S)-enantiomer in 80% ee.19 Therefore, compound 4 was
used as a substrate for several lipases as similarly performed above for aminoalcohol 3 (Table
2). The enantiomeric excess of the formed acetates 7 and the recovered alcohols 4 was determined
by HPLC after derivatisation with Moshers acid20 to give compounds 8 because a direct separation
of enantiomers of 7 or 4 on chiral stationary phases was not possible. For the determination of
the absolute configuration of the obtained esters (R)-7 and of the remaining alcohols (S)-4, the
latter was first reduced to the corresponding aminoalcohol by a variation of the Staudinger
reaction,11 followed by condensation of the intermediate with phosgene to afford oxazolidinone
(S)-9. The specific rotation of the latter was compared to the one of the enantiomer, which was
independently prepared from
-serine (Scheme 2).21
L
Scheme 2. i: Lipase or esterase, vinyl acetate, t-butyl methyl ether (Table 2). ii: Cat. NaOMe in MeOH. iii:
(R)-2-Methoxy-2-phenyl-2-trifluoromethyl-acetyl chloride, pyridine. iv: (a) PPh3, THF, 2 days then H2O, 1 day, Ref.
11; (b) COCl2 in toluene, pyridine, −30°C, 2.5 h

T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
3407
In sharp contrast to the results of the enzymatic acylation of compound 3, the azidoalcohol
4 gave only useless E values with various enzymes (Table 2). The best results (ee values of ca.
20%) were solely obtained from acylations of 4 with Candida cyclindracea (CHIRAZYM L-3,
entry 4) and Humicola species (CHIRAZYM L-8, entry 10). Candida antarctica A lipase
(CHIRAZYM L-5, entries 5–7) gave (S)-4 and (R)-7 up to 16% ee. Thus, due to the low E
values in these cases no further optimizations were performed22 and racemic 4 was used for
glycosylations (see below).
Previously, 1-azido-3-butene-2-yl b- -glucopyranoside has been prepared from the corre-
D
sponding benzoylated 1-p-toluenesulfonyloxy-3-butene-2-yl glucoside by nucleophilic substitu-
tion with sodium azide, followed by debenzoylation of the intermediate and was found to be
unstable at room temperature.1a Here, we glycosylated racemic 4 with 2,3,4,6-tetra-O-benzoyl-
b-
D
-glucopyranosyl trichloroacetimidate 11, prepared from 2,3,4,6-tetra-O-benzoyl- -
D
glucopyranose23 10 in 86% yield, to give glucoside 12 (86%) as a 1:1 mixture of diastereomers,
Table 2
Enzymatic resolution of 4 using various lipases under esterification conditionsa
Entry
Enzyme (mg)
Time
Yield of products (ee)
E value
Alcohol 4
Ester 7
1
2
3
4
5
6
7
8
9
Pseudomonas speciesb (40)
Pseudomonas speciesc (10)
Candida antarctica Bd (5)
Candida cyclindraceae (100)
Candida antarctica Af (50)
Candida antarctica Af,g (40)
Candida antarctica Af,g,h (200)
Pseudomonas speciesi (25)
Pocine pancreasj (100)
24 h
5.5 h
4.5 h
51 h
100 h
10 h
62 h
1.2 h
3.3 h
42 h
17.5 h
4 h
–
–
100% rac-7 (0%)
–
–
100% rac-7 (0%)
51% (R)-7 (12%)
40% (R)-7 (20%)
47% (R)-7 (10%)
42% (R)-7 (B5%)
45% (R)-7 (16%)
49% (S)-7 (8%)
59% (S)-7 (B5%)
49% (S)-7 (20%)
53% (R)-7 (5%)
100% rac-7 (0%)
42% (S)-4 (18%)
47% (S)-4 (20%)
42% (S)-4 (13%)
57% (S)-4 (B5%)
52% (S)-4 (16%)
45% (R)-4 (B5%)
28% (R)-4 (B5%)
38% (R)-4 (21%)
44% (S)-4 (10%)
–
1.5
1.8
1.4
–
1.0
1.2
–
1.8
1.2
–
10
11
12
Humicola speciesk (100)
Mucor mieheil (9)
Alcaligines speciesm (50)
a 4 (100 mg, 528 mmol) was treated with the respective lipase and vinyl acetate (5 ml) in t-butyl methyl ether (9 ml)
until ca. 50% conversion was obtained, followed by chromatographic separation of the products and derivatisation
with Mosher’s acid.
b
Amano PS lipase immobilized on Celite.
CHIRAZYM L-1, similar to Burkholderia cepacia.
CHIRAZYM L-2.
CHIRAZYM L-3.
CHIRAZYM L-5.
Immobilized on Celite.
4 (1.0 g, 5.28 mmol).
CHIRAZYM L-6.
c
d
e
f
g
h
i
j
CHIRAZYM L-7.
CHIRAZYM L-8.
CHIRAZYM L-9.
k
l
m CHIRAZYM L-10.

3408
T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
which could not separated by preparative chromatography. Final debenzoylation of the latter
afforded glucoside 13 (88%), which was completely stable at room temperature and thus was
useful for generation of the corresponding glycosylated aldehyde for aldolase catalyzed prepara-
tion of disaccharides (Scheme 3).2
Scheme 3. i: Cl3CCN, K2CO3, CH2Cl2, 20°C, 6 days, 86%. ii: 4, cat. TMSOTf, CH2Cl2, −30°C, 3.5 h, 86%. iii: Cat.
NaOMe, MeOH, 20°C, 1 day, 88%
4,5,6,8-Tetra-O-acetyl-3,7-anhydro-2-deoxy-
D
-glycero- -gulo-octonic acid 14a was chosen as
D
the glycon fragment for aminoalcohols 5. The latter can be prepared by condensation of
acetobromoglucose and dibenzyl malonate using Hanessian’s procedure,24 by oxidation of an
allyl C-glycoside25 or by Mata’s procedure26 via condensation of 2,3,4,6-tetra-O-acetyl-
-gluco-
D
pyranose with Meldrum’s acid. The latter procedure worked best in our hands for the
preparation of larger amounts of 14a. Direct condensation of 14a with intermediately N-
deblocked racemic 5 (treatment of 5 with trifluoacetic acid in dichloromethane at 20°C for 1 h,
followed by concentration of the solution) and dicyclohexyl carbodiimide (DCC) afforded only
racemic 15. Therefore, crude chloride 14b, which was prepared from 14a by treatment with
thionyl chloride25,27 was used. Reaction of the latter with N-deblocked (R)-5 afforded 16a (57%)
and (R)-15 (20%) as a byproduct formed by condensation of the intermediate trifluoroacetic
acid salt derived in situ from (R)-5. No such byproduct was found when 14b was condensed
with in situ N-deblocked 20 obtained from racemic 4 by subsequent Staudinger reaction,11
N-protection with Boc2O, and O-acetylation (see Scheme 4). Here, the corresponding octonic
amide 21 was obtained in 84% yield as an inseparable 1:1 mixture of diastereomers.
Next, pentafluorophenyl ester 14c was used as the glycosyl donor, which was prepared from
14a by condensation with trifluorophenol and DCC in 91% yield. Reaction of 14c with both
enantiomers of in situ N-deblocked 5 proceeded smoothly at 80°C and afforded 16a (72%) and
16b (68%) without formation of undesired 15. Finally, all three glycosides 16a, 16b and 21 were
deacetylated to give the free C-glycosides 17a, 17b, and 22, respectively, which are in turn
precursors for the generation of aldehydes as substrates for aldolase catalyzed reactions as
previously described.2

T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
3409
Scheme 4. i: (a) F3CCOOH, CH2Cl2, 20°C, 1.5 h; (b) (R)-5+14b“16a (57%)+(R)-15 (20%), (R)-5+14c“16a (72%),
(S)-5+14c“16b (68%), 20+14b“21 (84%). ii: Cat. NaOMe, MeOH, 1–2 days, 17a (87%), 17b (96%), 22 (94%). iii:
Ref. 11. iv: Boc2O, CH2Cl2, 20°C, 31 h (73%). v: Ac2O, pyridine, CH2Cl2, 20°C, 1.5 days (97%)
3. Experimental
3.1. General
The NMR data were obtained from spectra measured in CDCl3 solutions (with Me4Si as the
1
internal standard) at 25°C with a Bruker AMX 300 spectrometer. H NMR signal assignments
were made by first-order analysis of the spectra and by HH-COSY spectra. Of the two
magnetically non-equivalent geminal protons at C-6 of the sugar residues of compounds 12, 13,
16, 17, 21, and 22, the one resonating at lower field was allocated H-6a and the one resonating
at higher field H-6b. 13C NMR assignments were made by mutual comparison of the spectra by
DEPT spectra and CH-COSY spectra. Proton and carbon signals of diastereomers of com-
pounds 12, 13, 21, and 22 were allocated non-italic and italic, respectively. Optical rotations
were measured at 25°C with a Perkin–Elmer automatic polarimeter, Model 241. TLC was
performed on precoated plastic sheets, Polygram SIL UV254, 40×80 mm (Macherey–Nagel) using
appropriately adjusted mixtures of toluene/acetone and n-hexane/ethyl acetate. Detection was
affected by UV light, where applicable, and by charring with 5% H2SO4 in ethanol. CC was

3410
T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
performed by eluting from columns of silica gel 60 (Merck) with appropriately adjusted mixtures
of toluene/acetone, n-hexane/ethyl acetate, and CCl4/acetone, respectively. Solutions in organic
solvents were dried with anhydrous Na2SO4 and concentrated at 2 kPa, <40°C. The enan-
tiomeric excess (ee) of compounds 5 were determined with a Hewlett–Packard HP 6890 series
gas chromatograph with a FID detector at 200°C and a split injector at 150°C using H2 at 105
Pa and a 23 m glass capillar column with a diameter of 0.25 mm packed with heptakis-(2,6-di-
O-methyl-3-O-pentyl)-b-cyclodextrin as the stationary phase. Compound 3 was acetylated (see
below) to give 5 prior to the determination of the ee value, as described above. The ee values
of compound 4 were determined by esterification with (−)-Mosher’s acid (see below) and
separation of the formed diastereomers 8 by HPLC using a Sykam S1100 pump with a Linear
Instruments UV–vis 206 multiple wavelength detector, a 200 mm Macherey–Nagel column with
a diameter of 4 mm packed with Nucleosil 100-5 (Macherey–Nagel) and 50:1 n-hexane/ethyl
acetate at a flow rate of 0.4 ml/min for elution. Compound 7 was deacetylated (see below) to
give 4 prior to the determination of the ee value, as described above.
3.2. (E)-1-t-Butoxycarbonylamido-3-pentene-2-ol 3
A solution of (E)-1-amino-3-pentene-2-ol9 (5.76 g, 56.9 mmol), Boc2O (13.66 g, 62.6 mmol)
and Et3N (25 ml) in CH2Cl2 (100 ml) was stirred for 16 h at 0°C, while the temperature was
brought to room temp. Concentration of the solution and recrystallisation of the residue from
aq. MeOH afforded 3 (10.88 g, 95%). The physical data were in accordance to the literature
data.9
3.3. Analytic kinetic resolution of 3
A mixture of racemic 3 (150 mg, 0.745 mmol), vinyl acetate (5 ml) and enzyme (see Table 1)
in t-butylmethylether (9 ml) was stirred at room temp. until TLC showed about 50% conversion.
The mixture was filtered and the filtrate was concentrated. Chromatography of the residue with
2:1 n-hexane/ethyl acetate afforded first (R)-5 or (S)-5, the ee value of which was determined by
GC (see above).
Eluted next was (R)-3 or (S)-3, the ee value of which was determined by GC (see above), as
described above for compound 5 after treatment of the sample of 3 with pyridine (10 ml) and
Ac2O (1 ml) at room temp. for 24 h, followed by concentration and filtration of the residue with
CH2Cl2 over a short column of silica gel.
3.4. Preparative kinetic resolution of 3
A mixture of racemic 3 (1.50 g, 7.45 mmol), vinyl acetate (55 ml) and Candida antarctica A
lipase (440 mg, CHIRAZYM L-5, immobilized on Celite16) in t-butylmethylether (120 ml) was
stirred at room temp. for 24 h. The mixture was filtered and the filtrate was concentrated.
Chromatography of the residue with 2:1 n-hexane:ethyl acetate afforded first (R)-5 (895 mg,
1
49%, ee=93%); [h]D=−22.0 (c=1.8, CHCl3); H NMR (300 MHz): l=5.80 (m, 1H, H-4,
J3,4=15.3 Hz, J4,5=6.5 Hz, J2,3=0.9 Hz), 5.40 (ddd, 1H, H-3, J2,3=7.2 Hz, J3,5=1.6 Hz), 5.25
(dd, 1H, H-2, J1,2=11.6 Hz), 4.68 (s, 1H, NH), 3.39–3.21 (m, 2H, H-1), 2.06 (s, 2H, COCH3),
1.72–1.69 (m, 3H, H-5), 1.44 (s, 9H, C(CH3)3); 13C NMR (75.5 MHz): l=170.2 (CO), 155.7
(CONH), 130.8 (C-4), 126.5 (C-3), 79.5 (C(CH3)3), 73.8 (C-2), 43.8 (C-1), 28.3 (C(CH3)3), 21.2

T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
3411
(COCH3), 17.8 (C-5); anal. calcd for C12H21NO4 (243.3): C, 59.24; H, 8.70; N, 5.76; found: C,
59.34; H, 8.83; N, 5.74.
Eluted next was (S)-3 (661 mg, 44%, ee=99%); [h]D=+13.9 (c=1.1, CHCl3); physical data
were in accordance with the data of the racemate.
3.5. (R)-1-t-Butoxycarbonylamido-3-pentene-2-ol (R)-3
(a) A solution of (R)-5 (0.20 g, 0.822 mmol, ee=89%) and a catalytic amount of NaOMe in
MeOH (5 ml) was stirred at room temp. for 16 h. The mixture was neutralized by addition of
Dowex 1X8 H+ resin and filtered. Concentration of the filtrate afforded (R)-3 (161 mg, 97%,
ee=89%); [h]D=−7.8 (c=0.6, CHCl3); physical data were in accordance with the data of the
racemate.
(b) A mixture of (R)-2-hydroxy-3-pentenenitrile14 (R)-6 (1.94 g, 20.0 mmol, ee=94%) and
LiAlH4 (0.84 g, 22.0 mmol) in Et2O (20 ml) was refluxed for 2 h. Workup as described28
afforded crude (R)-1-amino-3-pentene-1-ol (1.14 g), which was treated with Boc2O as described
under Section 3.2 to give (R)-3 (107 mg, 27%, ee=74%); [h]D=−9.5 (c=1.5, CHCl3); physical
data were in accordance with the data of the racemate.
3.6. (R)-2-Acetoxy-1-t-butoxycarbonylamido-3-pentene (R)-5
A solution of (R)-3 (0.20 g, 0.994 mmol, ee=74%), pyridine (2 ml) and Ac2O (1.5 ml) in
CH2Cl2 (10 ml) was stirred at room temp. for 16 h, washed subsequently with aq. HCl and aq.
NaHCO3 solution, dried and concentrated. Chromatography of the residue with 3:2 n-hexane:
ethyl acetate afforded (R)-5 (0.22 g, 90%, ee=74%).
3.7. (S)-2-Acetoxy-1-t-butoxycarbonylamido-3-pentene (S)-5
A solution of (S)-3 (0.71 g, 3.53 mmol, ee=93%), pyridine (4 ml) and Ac2O (3 ml) in CH2Cl2
(15 ml) was treated as described under Section 3.6 to give (S)-5 (0.62 g, 73%, ee=93%).
3.8. Analytic kinetic resolution of 4
A mixture of racemic 410,11 (100 mg, 0.528 mmol), vinyl acetate (5 ml) and enzyme (see Table
2) in t-butylmethylether (9 ml) was stirred at room temp. until TLC showed about 50%
conversion. The mixture was filtered and the filtrate was concentrated. Chromatography of the
residue with 3:1 n-hexane:ethyl acetate afforded first (R)-7 or (S)-7, the ee value of which was
determined by treatment of a sample (2–3 mg) with a catalytic amount of NaOMe in MeOH (5
ml) at room temp. for 16 h, neutralisation with Dowex H+ resin, filtration and concentration,
followed by redissolving the residue (2–3 mg) in CH2Cl2 (1 ml) and treatment with pyridine (10
ml) and (R)-(−)-2-methoxy-2-trifluoromethyl-2-phenyl acetyl chloride20 (3 ml) at room temp. for
16 h, filtration of the mixture with CH2Cl2 over a short column of silica gel and determination
of the diastereomers by HPLC (see above).
Eluted next was (R)-4 or (S)-4, the ee value of which was determined as described above for
compound 7.

3412
T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
3.9. Preparative kinetic resolution of 4
A mixture of racemic 410,11 (1.0 g, 5.28 mmol), vinyl acetate (55 ml) and Candida antarctica
A lipase (200 mg, CHIRAZYM L-5, immobilized on Celite16) in t-butylmethylether (90 ml) was
stirred at room temp. for 62 h. The mixture was filtered and the filtrate was concentrated.
Chromatography of the residue with 6:1 n-hexane:ethyl acetate afforded first (R)-7 (543 mg,
1
45%, ee=16%); [h]D=−13.6 (c=1.1, CHCl3); H NMR (300 MHz): l=7.42–7.25 (m, 5H,
HꢀPh), 6.73 (d, 1H, H-4, J3,4=15.9 Hz), 6.09 (dd, 1H, H-3, J2,3=7.6 Hz), 4.35 (dt, 1H, H-2,
J
1a,2=4.4 Hz, J1b,2=7.6 Hz), 4.26 (dd, 1H, H-1a, J1a,1b=−11.4 Hz), 4.11 (dd, 1H, H-1b), 2.11 (s,
3H, COCH3); 13C NMR (75.5 MHz): l=170.6 (CO), 135.5–126.7 (Ph), 135.4 (C-4), 122.3 (C-3),
65.7 (C-2), 62.5 (C-1), 20.7 (COCH3); anal. calcd for C12H13N3O2 (231.3): C, 62.33; H, 5.67; N,
18.17; found: C, 62.61; H, 5.63; N, 17.98.
Eluted next was (S)-4 (516 mg, 52%, ee=16%); [h]D=+22.5 (c=1.0, CHCl3); physical data
were in accordance with the data of the racemate.11
3.10. (R)-2-Azido-4-phenyl-3-butene-1-ol (R)-4
A solution of (R)-7 (170 mg, 0.735 mmol, ee=16%) in MeOH (5 ml) was treated with a
catalytic amount of NaOMe as described in Section 3.5 (a). Chromatography of the residue with
4:1 n-hexane:ethyl acetate afforded (R)-4 (131 mg, 94%, ee=16%); [h]D=−27.0 (c=1.0, CHCl3);
physical data were in accordance with the data of the racemate.11
3.11. (S)-4-(2-Phenyethenyl)-2-oxazolidinone (S)-9
A solution of Ph3P (253 mg, 0.97 mmol) in THF (6 ml) was added at room temp. to a solution
of (S)-4 (166 mg, 0.88 mmol, ee=16%) in THF (10 ml) and the mixture was stirred for 2 d.
Water (1 ml) was added and stirring was continued for 1 day. The mixture was concentrated,
redissolved in Et2O (6 ml) and extracted three times with a 5% aq. HCl solution (5 ml). The
combined aq. extracts were brought to pH 13 by addition of a 1 M aq. NaOH solution and
extracted with CH2Cl2. Pyridine (2 ml) and a 20% solution of phosgene (2 ml) were added at
−30°C to the dried extracts and the solution was stirred for 2.5 h at 5°C. Water (2 ml) was
added, the mixture was diluted with CH2Cl2, washed subsequently with aq. HCl and aq.
NaHCO3 solution, dried and concentrated. Chromatography of the residue with 2:1 n-hexane:
ethyl acetate afforded (S)-9 (79 mg, 55%); mp=110°C (n-hexane); [h]D=+1.3 (c=1.5, EtOH);
1
Ref. 21 [h]D=−6.5 (c=2.4, EtOH) for (R)-9; H NMR (300 MHz): l=7.40–7.29 (m, 5H,
HꢀPh), 6.61 (d, 1H, H-2%, J1%,2%=15.8 Hz), 6.13 (dd, 1H, H-1%, J1%,4=7.6 Hz), 5.74 (s, 1H, NH),
4.63–4.52 (m, 2H, H-5), 4.20–4.10 (m, 1H, H-4); 13C NMR (75.5 MHz): l=159.4 (C-2),
135.3–126.7 (Ph), 133.9 (C-2%), 126.3 (C-1%), 70.2 (C-5), 55.1 (C-4; anal. calcd for C11H11NO2
(189.2): C, 69.83; H, 5.86; N, 7.40; found: C, 69.68; H, 5.72; N, 7.27.
3.12. 2,3,4,6-Tetra-O-benzoyl-h- -glucopyranosyl trichloroacetimidate 11
D
K2CO3 (8.43 g, 60.9 mmol) was added to a solution of 2,3,4,6-tetra-O-benzoyl- -
D
glucopyranose23 10 (7.29 g, 12.2 mmol), CCl3CN (7.4 ml, 73.45 mmol) in CH2Cl2 (100 ml), the
mixture was stirred at room temp. for 6 days, filtered and concentrated. Chromatography of the
1
residue with 20:1 CCl4:acetone afforded 11 (7.78 g, 86%); [h]D=+82.0 (c=1.0, CHCl3); H

T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
3413
NMR (300 MHz): l=8.64 (s, 1H, NH), 8.06–7.25 (m, 20H, Ph), 6.85 (d, 1H, H-1, J1,2=3.7 Hz),
6.29 (t, 1H, H-3, J2,3=J3,4=10.0 Hz), 5.83 (t, 1H, H-4, J4,5=9.8 Hz), 5.63 (dd, 1H, H-2), 4.65
(dd, 1H, H-6a, J5,6a=2.6 Hz, J6a,6b=−12.9 Hz), 4.69–4.62 (m, 1H, H-5), 4.49 (dd, 1H, H-6b,
J
5,6b=5.5 Hz); 13C NMR (75.5 MHz): l=166.0, 165.6, 165.4, 165.2 (4 CO), 160.5 (CNH),
133.6–128.4 (4 Ph), 93.1 (C-1), 90.7 (CCl3), 70.7 (2C, C-3,5), 70.2 (C-2), 68.6 (C-4), 62.5 (C-6);
anal. calcd for C36H28NO10Cl3 (741.0): C, 58.36; H, 3.81; N, 1.89; Cl, 14.35; found: C, 58.22; H,
3.83; N, 1.83; Cl, 14.00.
3.13. 2-Azido-4-phenyl-3-butene-1-yl 2,3,4,6-tetra-O-benzoyl-i- -glucopyranoside 12
D
TMSOTf (29 ml, 0.16 mmol) was added at −30°C to a solution of racemic 410,11 (0.29 g, 1.50
mmol) and 11 (1.19 g, 1.61 mmol) in CH2Cl2 (20 ml), the mixture was stirred for 3 h and
neutralized by addition of pyridine. The mixture was washed with aq. HCl and aq. NaHCO3
solutions, dried and concentrated. Chromatography of the residue with a gradient of 60:1 to
50:1 toluene:ethyl acetate afforded 12 (0.99 g, 86%) as a 1:1 mixture of diastereomers; [h]D=+5.4
1
(c=1.5, CHCl3); H NMR (300 MHz): l=8.04–7.16 (m, 50H, Ph, Ph), 6.58 (d, 1H, H-4%,
J3%,4%=15.9 Hz), 6.57 (d, 1H, H-4%, J3%,4%=15.3 Hz), 6.03 (dd, 1H, H-3%, J3%,4%=15.9 Hz, J2%,3%=7.8
Hz), 5.96 (dd, 1H, H-3%, J3%,4%=16.0 Hz, J2%,3%=7.6 Hz), 5.93 (t, 1H, H-3, J2,3=J3,4=9.6 Hz), 5.92
(t, 1H, H-3, J2,3=J3,4=9.6 Hz), 5.70 (t, 1H, H-4, J3,4=J4,5=9.6 Hz), 5.69 (t, 1H, H-4,
J3,4=J4,5=9.7 Hz), 5.58 (dd, 1H, H-2, J2,3=9.7 Hz, J1,2=7.8 Hz), 5.57 (dd, 1H, H-2, J2,3=9.7
Hz, J1,2=7.8 Hz), 4.98 (d, 1H, H-1, J1,2=7.8 Hz), 4.97 (d, 1H, H-1, J1,2=7.8 Hz), 4.67 (dd, 1H,
H-6a, J6a,6b=−12.1 Hz, J5,6a=2.9 Hz), 4.66 (dd, 1H, H-6a, J6a,6b=−12.1 Hz, J5,6a=2.8 Hz), 4.52
(dd, 2H, H-6b, H-6b, J6a,6b=−12.2 Hz, J5,6b=5.2 Hz), 4.29–4.15 (m, 4H, H-2%, H-5, H-2%, H-5),
4.02 (dd, 1H, H-1%a, J1%a,1%b=−10.7 Hz, J1%a,2%=3.8 Hz), 3.98 (dd, 1H, H-1%a, J1%a,1%b=−10.7 Hz,
J1%a,2%=5.9 Hz), 3.73 (dd, 1H, H-1%b, J1%a,1%b=−10.4 Hz, J1%b,2%=5.1 Hz), 3.63 (dd, 1H, H-1%b,
J1%a,1%b=−10.6 Hz, J1%b,2%=8.1 Hz); 13C NMR (75.5 MHz): l=166.1–165.0 (Ph), 135.6–125.3 (Ph),
134.9 (C-4%), 134.5 (C-4%), 123.0 (C-3%), 122.7 (C-3%), 101.5 (C-1), 101.2 (C-1), 72.8 (C-3,3), 72.4
(C-5,5), 71.9 (C-1%), 71.71 (C-2), 71.66 (C-2), 71.0 (C-1%), 69.6 (C-4,4), 63.6 (C-2%), 63.2 (C-2%),
63.0 (C-6,6); anal. calcd for C44H37N3O10 (767.8): C, 68.83; H, 4.86; N, 5.47; found: C, 68.61; H,
5.01; N, 5.41.
3.14. 2-Azido-4-phenyl-3-butene-1-yl i- -glucopyranoside 13
D
A solution of 12 (0.50 g, 0.64 mmol) and a catalytic amount of NaOMe in MeOH (10 ml) and
toluene (2 ml) was stirred at room temp. for 24 h, neutralized with Dowex H+ resin, filtered and
concentrated. Chromatography of the residue with 20:1 CH2Cl2:MeOH, followed by filtration
with water over a column of Biogel P2 and lyophilisation afforded 13 (0.20 g, 88%) as a 1:1
1
mixture of diastereomers; [h]D=−16.3 (c=1.5, MeOH); H NMR (300 MHz, CD3OD): l=
7.38–7.15 (m, 10H, Ph, Ph), 6.68 (d, 2H, H-4%,4%, J3%,4%=15.9 Hz), 6.18 (dd, 1H, H-3%, J3%,4%=15.8
Hz, J2%,3%=7.5 Hz), 6.17 (dd, 1H, H-3%, J3%,4%=15.9 Hz, J2%,3%=7.6 Hz), 4.39–4.31 (m, 2H, H-2%,2%),
4.29 (d, 1H, H-1, J1,2=7.7 Hz), 4.28 (d, 1H, H-1, J1,2=7.7 Hz), 3.94 (dd, 1H, H-1%a,
J1%a,1%b=−10.7 Hz, J1%a,2%=4.2 Hz), 3.90 (dd, 1H, H-1%a, J1%a,1%b=−10.8 Hz, J1%a,2%=7.5 Hz), 3.82 (d,
2H, H-6a,6a, J6a,6b=−12.0 Hz), 3.69–3.57 (m, 4H, H-1%b,6b,1%b,6b), 3.34–3.14 (m, 8H, H-
2,3,4,5,2,3,4,5); 13C NMR (75.5 MHz, CD3OD): l=137.5–127.7 (Ph, Ph), 135.5 (C-4%,4%), 124.9
(C-3%), 124.8 (C-3%), 104.9 (C-1), 104.3 (C-1), 78.0 (C-3,5,3,5), 75.1 (C-2), 75.0 (C-2), 73.0 (C-1%),
72.5 (C-1%), 71.6 (C-4), 71.5 (C-4), 65.3 (C-2%), 64.7 (C-2%), 62.8 (C-6), 62.7 (C-6); FAB-MS
calcd for C16H21N3O6 (m/z=351.143); found: 352.150 ([M+H]+).

3414
T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
3.15. 4,5,6,8-Tetra-O-acetyl-3,7-anhydro-2-deoxy-
D
-glycero-
D
-gulo-octonoyl chloride 14b
-gulo-octonic acid26 14a
A solution of 4,5,6,8-tetra-O-acetyl-3,7-anhydro-2-deoxy-
D
-glycero-
D
(0.3 g, 0.77 mmol) in thionyl chloride (10 ml) was stirred for 2 h at 80°C. Concentration of the
solution afforded crude 14b,25,27 which was used without further purification.
3.16. Pentafluorophenyl 4,5,6,8-tetra-O-acetyl-3,7-anhydro-2-deoxy-
D
-glycero- -gulo-octonoate
D
14c
DCC (88 mg, 0.43 mmol) was added at 0°C to a solution of 4,5,6,8-tetra-O-acetyl-3,7-anhy-
dro-2-deoxy- -glycero-
-gulo-octonic acid26 14a (0.15 g, 0.38 mmol) and pentafluorophenol (78
D
D
mg, 0.42 mmol) in ethyl acetate (3 ml), the mixture was stirred for 2 h, filtered and the filtrate
was concentrated. Chromatography of the residue with 3:1 n-hexane:ethyl acetate afforded 14c
1
(194 mg, 91%); mp=115–116°C; [h]D=−3.6 (c=1.3, CHCl3); H NMR (300 MHz): l=5.25 (t,
1H, H-5, J4,5=J5,6=9.3 Hz), 5.09 (t, 1H, H-6, J5,6=J6,7=9.7 Hz), 4.99 (t, 1H, H-4, J3,4=J4,5=
9.7 Hz), 4.27 (dd, 1H, H-8a, J8a,8b=−12.3 Hz, J7,8a=5.1 Hz), 4.08 (dd, 1H, H-8b, J8a,8b=−12.5
Hz, J7,8b=2.2 Hz), 4.08–4.01 (m, 1H, H-3), 3.75 (ddd, 1H, H-7, J6,7=10.0 Hz, J7,8a=5.0 Hz,
J
7,8b=2.2 Hz), 2.90–2.87 (m, 2H, H-2), 2.08, 2.07, 2.04, 2.02 (12H, COCH3); 13C NMR (75.5
MHz): l=170.7, 170.2, 169.7, 169.4 (4 CO), 166.0 (C-1), 165.9, 149.4, 149.2, 139.3, 134.5, 123.9
(C6F5), 76.0 (C-7), 74.2, 73.9 (C-3,5), 71.3 (C-4), 68.3 (C-6), 62.0 (C-8), 36.6 (C-2), 20.6 (4 CH3);
FAB-MS calcd for C22H21F5O11 (m/z=556.100); found: 557.110 ([M+H]+).
3.17. N-[(R)-2-Acetoxy-3-pentene-1-yl] 4,5,6,8-tetra-O-acetyl-3,7-anhydro-2-deoxy-
D
-glycero-
D
-gulo-octo-noyl amide 16a
(a) A solution of (R)-5 (173 mg, 0.71 mmol) and CF3COOH (1 ml) in CH2Cl2 (10 ml) was
stirred at room temp. for 1 h, concentrated and redissolved in CH2Cl2 (20 ml). The solution was
cooled to 0°C, pyridine (2 ml) and a solution of crude 14b (freshly prepared from 0.3 g of 14a
as described in Section 3.15) in CH2Cl2 (20 ml) was added and the mixture was stirred at room
temp. for 40 h. The solution was washed subsequently with aq. HCl and aq. NaHCO3 solutions,
dried and concentrated. Chromatography of the residue with 3:1 n-hexane:ethyl acetate afforded
1
first (R)-15 (33 mg, 20%); [h]D=−15.3 (c=0.8, CHCl3); H NMR (300 MHz): l=6.60 (s, 1H,
NH), 5.85 (dq, 1H, H-4, J3,4=15.4 Hz, J4,5=6.6 Hz), 5.46–5.31 (m, 2H, H-2,3), 3.60 (dd, 1H,
H-1a, J1a,1b=−14.4 Hz, J1a,2=4.7 Hz), 3.52 (dd, 1H, H-1b, J1a,1b=−14.2 Hz, J1b,2=6.3 Hz), 2.09
(s, 3H, COCH3), 1.73 (ddd, 3H, H-5, J4,5=6.5 Hz, J3,5=1.6 Hz, J2,5=0.6 Hz); 13C NMR (75.5
MHz): l=170.6 (CO), 157.3 (q, JC,F=37 Hz, COCF3), 131.9 (C-4), 125.4 (C-3), 115.7 (q,
JC,F=288 Hz, COCF3), 72.5 (C-2), 43.1 (C-1), 21.0 (COCH3) 17.7 (C-5); anal. calcd for
C9H12F3NO3 (239.2): C, 45.19; H, 5.06; N, 5.86; found: C, 45.08; H, 5.09; N, 5.83.
1
Eluted next was 16a (209 mg, 57%); [h]D=−17.6 (c=1.4, CHCl3); H NMR (300 MHz):
l=6.15 (bt, 1H, NH, J1%,NH=5.6 Hz), 5.78 (dd, 1H, H-4%, J3%,4%=15.1 Hz, J4%,5%=6.6 Hz), 5.37
(ddd, 1H, H-3%, J3%,4%=15.3 Hz, J2%,3%=7.1 Hz, J3%,5%=1.6 Hz), 5.29–5.23 (m, 1H, H-2%), 5.16 (t, 1H,
H-5, J4,5=J5,6=9.3 Hz), 5.02 (t, 1H, H-6, J5,6=J6,7=9.7 Hz), 4.84 (t, 1H, H-4, J3,4=J4,5=9.6
Hz), 4.17, 4.16 (2 s, 2H, H-8a,8b), 3.83 (td, 1H, H-3, J3,4=J2b,3=9.4 Hz, J2a,3=2.9 Hz), 3.67
(ddd, 1H, H-7, J6,7=10.0 Hz, J7,8a=3.9 Hz, J7,8b=2.9 Hz), 3.46 (ddd, 1H, H-1%a, J1%a,1%b=−14.1
Hz, J1%a,NH=5.7 Hz J1%a,2%=4.4 Hz), 3.41–3.32 (m, 1H, H-1%b), 2.38 (dd, 1H, H-2a, J2a,2b=−15.1
Hz, J2a,3=2.9 Hz), 2.29 (dd, 1H, H-2b, J2a,2b=−15.2 Hz, J2b,3=8.9 Hz), 2.05, 2.03, 2.00, 1.99,

T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
3415
1.96 (5 s, 15H, COCH3), 1.67 (d, 3H, H-5%, J4%,5%=6.5 Hz); 13C NMR (75.5 MHz): l=170.6,
170.4, 170.2, 169.8, 169.5, 169.1 (COCH3, C-1), 131.0 (C-4%), 126.4 (C-3%), 75.8 (C-7), 74.7 (C-3),
73.9 (C-5), 73.3 (C-2%), 71.3 (C-4), 68.2 (C-6), 61.9 (C-8), 42.9 (C-1%), 38.9 (C-2), 21.2, 20.7, 20.6,
20.5 (COCH3), 17.8 (C-5%); anal. calcd for C23H33NO12 (515.5): C, 53.59; H, 6.45; N, 2.72; found:
C, 53.34; H, 6.60; N, 2.66.
(b) A solution of (R)-5 (243 mg, 1.0 mmol) and CF3COOH (1.5 ml) in CH2Cl2 (10 ml) was
stirred at room temp. for 1 h, concentrated and redissolved in DMF (8 ml). Et3N (0.153 ml, 1.1
mmol) and a solution of crude 14c (0.56 g, 1.0 mmol) in DMF (5 ml) was added and the
solution was stirred for 6 h at 80°C. The mixture was concentrated, the residue redissolved in
CH2Cl2, washed subsequently with aq. HCl and aq. NaHCO3 solutions, dried and concentrated.
Chromatography of the residue with 1:3 n-hexane:ethyl acetate afforded 16a (373 mg, 72%).
3.18. N-[(S)-2-Acetoxy-3-pentene-1-yl] 4,5,6,8-tetra-O-acetyl-3,7-anhydro-2-deoxy-
-gulo-octo-noyl amide 16b
D
-glycero-
D
Treatment of (S)-5 (243 mg, 1.0 mmol) as described in Section 3.17 (b) afforded 16b (352 mg,
1
68%); [h]D=0.0 (c=1.4, CHCl3); mp=123°C; H NMR (300 MHz): l=6.16 (bt, 1H, NH,
1%,NH=5.7 Hz), 5.81 (dd, 1H, H-4%, J3%,4%=15.1 Hz, J4%,5%=6.5 Hz), 5.41 (ddd, 1H, H-3%,
J
J3%,4%=15.2 Hz, J2%,3%=7.0 Hz, J3%,5%=1.6 Hz), 5.33–5.27 (m, 1H, H-2%), 5.20 (t, 1H, H-5,
J4,5=J5,6=9.3 Hz), 5.06 (t, 1H, H-6, J5,6=J6,7=9.7 Hz), 4.89 (t, 1H, H-4, J3,4=J4,5=9.7 Hz),
4.24 (dd, 1H, H-8a, J8a,8b=−12.4 Hz, J7,8a=4.9 Hz), 4.12 (dd, 1H, H-8b, J8a,8b=−12.4 Hz,
J7,8b=2.2 Hz), 3.90 (ddd, 1H, H-3, J3,4=9.9 Hz, J2b,3=8.5 Hz, J2a,3=3.3 Hz), 3.68 (ddd, 1H,
H-7, J6,7=10.0 Hz, J7,8a=4.8 Hz, J7,8b=2.2 Hz), 3.50 (ddd, 1H, H-1%a, J1%a,1%b=−14.1 Hz,
J
1%a,NH=5.7 Hz J1%a,2%=4.3 Hz), 3.44–3.35 (m, 1H, H-1%b), 2.43 (dd, 1H, H-2a, J2a,2b=−15.0 Hz,
2a,3=3.3 Hz), 2.34 (dd, 1H, H-2b, J2a,2b=−15.1 Hz, J2b,3=8.6 Hz), 2.09, 2.07, 2.04, 2.03, 2.00
J
(5 s, 15H, COCH3), 1.71 (dd, 3H, H-5%, J4%,5%=6.3 Hz, J3%,5%=1.2 Hz); 13C NMR (75.5 MHz):
l=170.5, 170.3, 170.1, 169.8, 169.4, 169.1 (COCH3, C-1), 131.0 (C-4%), 126.4 (C-3%), 75.8 (C-7),
74.7 (C-3), 73.9 (C-5), 73.3 (C-2%), 71.2 (C-4), 68.3 (C-6), 61.9 (C-8), 42.9 (C-1%), 39.0 (C-2), 21.1,
20.7, 20.6, 20.5 (COCH3), 17.8 (C-5%); anal. calcd for C23H33NO12 (515.5): C, 53.59; H, 6.45; N,
2.72; found: C, 53.75; H, 6.58; N, 2.82.
3.19. N-[(R)-2-Hydroxy-3-pentene-1-yl] 3,7-anhydro-2-deoxy-
17a
D
-glycero- -gulo-octonoyl amide
D
Treatment of 16a (281 mg, 0.545 mmol) as described in Section 3.14 afforded 17a (144 mg,
1
87%); [h]D=−9.5 (c=1.0, MeOH); H NMR (300 MHz, CD3OD): l=5.66 (dqd, 1H, H-4%,
J3%,4%=15.4 Hz, J4%,5%=6.5 Hz, J2%,4%=1.0 Hz), 5.39 (ddd, 1H, H-3%, J3%,4%=15.3 Hz, J2%,3%=6.7 Hz,
J3%,5%=1.6 Hz), 4.02 (dd, 1H, H-2%, J1%,2%=12.4 Hz, J2%,3%=6.5 Hz), 3.75 (dd, 1H, H-8a, J8a,8b
−12.0 Hz, J7,8a=2.0 Hz), 3.57 (dd, 1H, H-8b, J8a,8b=−11.9 Hz, J7,8b=5.0 Hz), 3.46 (dt, 1H, H-3,
J3,4=J2b,3=9.2 Hz, J2a,3=2.8 Hz), 3.29–3.16 (m, 4H, H-1%a,5,6,7), 3.07 (dd, 1H, H-1%b, J1%a,1%b
=
=
−13.5 Hz, J1%b,2%=7.3 Hz), 3.01 (t, 1H, H-4, J3,4=J4,5=9.0 Hz), 2.66 (dd, 1H, H-2a, J2a,2b=−14.7
Hz, J2a,3=2.8 Hz), 2.28 (dd, 1H, H-2b, J2a,2b=−14.8 Hz, J2b,3=9.0 Hz), 1.63 (d, 3H, H-5%,
J4%,5%=6.5 Hz); 13C NMR (75.5 MHz): l=174.1 (C-1), 132.7 (C-3%), 128.7 (C-4%), 81.6, 79.6
(C-5,7), 78.0 (C-3), 75.0 (C-4), 72.1, 71.6 (C-2%,6), 62.8 (C-8), 46.4 (C-1%), 40.1 (C-2), 18.0 (C-5%);
FAB-MS calcd for C13H23NO7 (m/z=305.147); found: 306.150 ([M+H]+).

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T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
3.20. N-[(S)-2-Hydroxy-3-pentene-1-yl] 3,7-anhydro-2-deoxy-
D
-glycero- -gulo-octonoyl amide
D
17b
Treatment of 16b (187 mg, 0.363 mmol) as described in Section 3.14 afforded 17b (106 mg,
1
96%); [h]D=−11.8 (c=1.0, MeOH); H NMR (300 MHz, CD3OD): l=5.66 (dqd, 1H, H-4%,
J3%,4%=15.4 Hz, J4%,5%=6.5 Hz, J2%,4%=1.0 Hz), 5.39 (ddd, 1H, H-3%, J3%,4%=15.4 Hz, J2%,3%=6.7 Hz,
J3%,5%=1.6 Hz), 4.03 (dd, 1H, H-2%, J1%,2%=12.3 Hz, J2%,3%=6.6 Hz), 3.76 (d, 1H, H-8a, J8a,8b=−12.6
Hz), 3.55 (dd, 1H, H-8b, J8a,8b=−12.0 Hz, J7,8b=5.1 Hz), 3.46 (dt, 1H, H-3, J3,4=J2b,3=9.3 Hz,
J2a,3=2.8 Hz), 3.30–3.11 (m, 4H, H-1%a,5,6,7), 3.06 (dd, 1H, H-1%b, J1%a,1%b=−13.5 Hz, J1%b,2%=7.4
Hz), 3.01 (t, 1H, H-4, J3,4=J4,5=9.0 Hz), 2.66 (dd, 1H, H-2a, J2a,2b=−14.7 Hz, J2a,3=2.8 Hz),
2.27 (dd, 1H, H-2b, J2a,2b=−14.7 Hz, J2b,3=9.1 Hz), 1.63 (d, 3H, H-5%, J4%,5%=6.5 Hz); 13C NMR
(75.5 MHz): l=174.1 (C-1), 132.7 (C-3%), 128.7 (C-4%), 81.7, 79.5 (C-5,7), 78.0 (C-3), 75.1 (C-4),
72.0, 71.7 (C-2%,6), 62.9 (C-8), 46.5 (C-1%), 40.1 (C-2), 18.0 (C-5%); FAB-MS calcd for C13H23NO7
(m/z=305.147); found: 306.150 ([M+H]+).
3.21. (E)-2-t-Butoxycarbonylamido-4-phenyl-3-butene-1-ol 19
A solution of (E)-2-amino-4-phenyl-3-butene-1-ol11 18 (0.3 g, 1.37 mmol), Boc2O (0.33 g, 1.5
mmol) and Et3N (0.38 ml) in CH2Cl2 (15 ml) was stirred at room temp. for 3 h. Concentration
of the solution and chromatography of the residue with 2:1 n-hexane:ethyl acetate afforded 19
(0.37 g, 73%). The physical data were in accordance with the literature data.29
3.22. (E)-1-Acetoxy-2-t-butoxycarbonylamido-4-phenyl-3-butene 20
Treatment of 19 (0.8 g, 3.1 mmol) with pyridine (4 ml) and Ac2O (2 ml) in CH2Cl2 (15 ml)
at room temp. for 1.5 h and workup as described in Section 3.6 afforded 20 (0.9 g, 97%);
1
mp=78–79°C; H NMR (300 MHz): l=7.38–7.22 (m, 5H, Ph), 6.59 (dd, 1H, H-4, J3,4=15.9
Hz, J2,4=1.4 Hz), 6.10 (dd, 1H, H-3, J3,4=16.0 Hz, J2,3=5.9 Hz), 4.81 (bs, 1H, H-2), 4.60 (bs,
1H, NH), 4.25–4.15 (m, 1H, H-1a), 4.18 (dd, 1H, H-1b, J1a,1b=−11.2 Hz, J1b,2=5.0 Hz), 2.07 (s,
3H, COCH3), 1.47 (s, 9H, C(CH3)3); 13C NMR (75.5 MHz): l=170.9 (CO), 155.2
(COOC(CH3)3), 136.3–126.5 (Ph), 131.9 (C-4), 126.1 (C-3), 79.9 (C(CH3)3), 66.1 (C-1), 51.5
(C-2), 28.4 (C(CH3)3), 20.8 (COCH3); anal. calcd for C17H23NO4 (305.4): C, 66.86; H, 7.59; N,
4.59; found: C, 66.78; H, 7.54; N, 4.51.
3.23. N-[1-Acetoxy-4-phenyl-3-butene-2-yl] 4,5,6,8-tetra-O-acetyl-3,7-anhydro-2-deoxy-
D
-
glycero- -gulo-octonoyl amide 21
D
A solution of 20 (218 mg, 0.72 mmol) and CF3COOH (1.5 ml) in CH2Cl2 (10 ml) was stirred
at room temp. for 1.5 h, concentrated and redissolved in CH2Cl2 (15 ml). The solution was
cooled to 0°C, pyridine (2 ml) and a solution of crude 14b (freshly prepared from 0.31 g of 14a)
as described in Section 3.15 in CH2Cl2 (15 ml) was added and the mixture was stirred at room
temp. for 24 h. The solution was washed subsequently with aq. HCl and aq. NaHCO3 solutions,
dried and concentrated. Chromatography of the residue with 5:1 toluene:acetone afforded 21
1
(347 mg, 84%) as a 1:1 mixture of diastereomers; H NMR (300 MHz): l=7.38–7.16 (m, 10H,
Ph, Ph), 6.59 (dd, 1H, H-4%, J3%,4%=16.0 Hz, J2%,4%=1.2 Hz), 6.58 (dd, 1H, H-4%, J3%,4%=16.0 Hz,
J2%,4%=1.5 Hz), 6.34 (d, 1H, NH, J2%,NH=8.7 Hz), 6.29 (d, 1H, NH, J2%,NH=8.6 Hz), 6.13 (dd, 1H,

T. Ziegler, C. Jurisch / Tetrahedron: Asymmetry 11 (2000) 3403–3418
3417
H-3%, J3%,4%=16.0 Hz, J2%,3%=5.8 Hz), 6.11 (dd, 1H, H-3%, J3%,4%=16.0 Hz, J2%,3%=6.3 Hz), 5.22 (t,
1H, H-5, J4,5=J5,6=9.3 Hz), 5.21 (t, 1H, H-5, J4,5=J5,6=9.3 Hz), 5.08 (t, 1H, H-6, J5,6=J6,7=
9.7 Hz), 5.07 (t, 1H, H-6, J5,6=J6,7=9.7 Hz), 5.01–4.87 (m, 2H, H-2%,2%), 4.94 (t, 1H, H-4,
J3,4=J4,5=9.5 Hz), 4.91 (t, 1H, H-4, J3,4=J4,5=9.5 Hz), 4.36–4.08 (m, 8H, H-
1%a,1%b,8%a,8%b,1%a,1%b,8%a,8%b), 3.99–3.88 (m, 2H, H-3,3), 3.74 (ddd, 1H, H-7, J6,7=9.9 Hz,
J
7,8a=4.3 Hz, J7,8b=2.5 Hz), 3.70 (ddd, 1H, H-7, J6,7=9.9 Hz, J7,8a=4.5 Hz, J7,8b=2.3 Hz),
2.55–2.37 (m, 4H, H-2a,2b,2a,2b), 2.09–1.97 (m, 30H, COCH3); 13C NMR (75.5 MHz):
l=171.0–168.6 (10 CO, C-1,1), 136.1–126.4 (Ph, Ph) 132.5 (C-4%), 132.2 (C-4%) 125.3 (C-3%),
125.2 (C-3%), 76.0 (C-7), 75.9 (C-7) 74.9 (C-3), 74.7 (C-3), 73.9 (C-5,5), 71.4 (C-4), 71.1 (C-4),
68.2 (C-6,6), 65.6 (C-1%), 65.5 (C-1%), 61.8 (C-8,8), 50.5 (C-2%), 50.3 (C-2%), 39.1 (C-2,2),
20.8–20.6 (10 COCH3); anal. calcd for C28H35NO12 (577.6): C, 58.23; H, 6.11; N, 2.43; found:
C, 58.03; H, 6.06; N, 2.30.
3.24. N-[1-Hydroxy-4-phenyl-3-butene-2-yl] 3,7-anhydro-2-deoxy-
D
-glycero- -gulo-octonoyl
D
amide 22
Treatment of 21 (150 mg, 0.267 mmol) as described Section 3.14 afforded 22 (91 mg, 94%) as
1
a 1:1 mixture of diastereomers; H NMR (300 MHz, CD3OD): l=7.35–7.10 (m, 10H, Ph, Ph),
6.52 (d, 2H, H-4%,4%, J3%,4%=16.0 Hz), 6.17 (dd, 1H, H-3%, J3%,4%=16.0 Hz, J2%,3%=6.0 Hz), 6.16 (dd,
1H, H-3%, J3%,4%=16.0 Hz, J2%,3%=6.2 Hz), 4.58–4.52 (m, 2H, H-2%,2%), 3.76 (dd, 1H, H-8a,
J8a,8b=−12.0 Hz, J7,8a=1.5 Hz), 3.72 (dd, 1H, H-8a, J8a,8b=−12.1 Hz, J7,8a=2.1 Hz), 3.63–3.48
(m, 8H, H-1%a,1%b,3,8b,1%a,1%b,3,8b), 3.32–3.16 (m, 6H, H-5,6,7,5,6,7), 3.05 (t, 2H, H-4,4,
J3,4=J4,5=9.1 Hz), 2.73 (dd, 1H, H-2a, J2a,2b=−14.6 Hz, J2a,3=2.7 Hz), 2.72 (dd, 1H, H-2a,
J2a,2b=−14.4 Hz, J2a,3=2.5 Hz), 2.36 (dd, 1H, H-2b, J2a,2b=−14.6 Hz, J2b,3=9.0 Hz), 2.35 (dd,
1H, H-2b, J2a,2b=−14.4 Hz, J2b,3=9.1 Hz); 13C NMR (75.5 MHz): l=173.6 (C-1), 173.5 (C-1),
138.3–127.4 (Ph, Ph), 132.6 (C-4%), 132.3 (C-4%), 127.9 (C-3%), 127.9 (C-3%), 81.7, 81.5, 79.6
(C-5,7,5,7), 78.1 (C-3), 78.0 (C-3), 75.2 (C-4), 75.1 (C-4), 71.8 (C-6), 71.5 (C-6), 65.1 (C-1%,1%),
63.0 (C-8), 62.6 (C-8), 54.8 (C-2%,2%), 40.4 (C-2), 40.3 (C-2); FAB-MS calcd for C18H25NO7
(m/z=367.163); found: 368.170 ([M+H]+).
Acknowledgements
We thank Dr. H. Schmickler, and C. Schmitz, University of Cologne for performing the
NMR spectra and elemental analyses. This work was financially supported by the Fonds der
Chemischen Industrie and the BMBF. CHIRAZYME was a gift from Hofmann La Roche
(former Boehringer Mannheim).
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