Stereoselective synthesis of β-amino-γ-butyrolactones

Article abstract of DOI:10.1016/S0957-4166(02)00437-8

A novel synthesis of optically active β-amino-γ-butyrolactones is described. O-Silylated (R)-cyanohydrins (R)-3 (derived from aldehydes 1 by (R)-hydroxynitrile lyase ((R)-PaHNL)-catalyzed addition of HCN) were reacted with allyl Grignard to give amino alc

Full text of DOI:10.1016/S0957-4166(02)00437-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1855–1862
Stereoselective synthesis of b-amino-g-butyrolactones†
Ju¨rgen Roos‡ and Franz Effenberger*
Institut fu¨r Organische Chemie der Universita¨t Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Received 19 June 2002; accepted 25 July 2002
Abstract—A novel synthesis of optically active b-amino-g-butyrolactones is described. O-Silylated (R)-cyanohydrins (R)-3
(derived from aldehydes 1 by (R)-hydroxynitrile lyase ((R)-PaHNL)-catalyzed addition of HCN) were reacted with allyl Grignard
to give amino alcohols (4R,5S)-5 after reduction. In the addition of crotyl Grignard reagent, workup conditions are decisive for
the formation of amino alcohol 8, which was isolated as a diastereoisomeric mixture; the acetylated main diastereoisomer
(3S,4R,5R)-10 was separated. Ozonolysis of the acetylated amino alcohols (4S,5R)-7a,b and (3S,4S,5R)-10 affords the aldehydes
12a–c, which were directly oxidized with CrO3 in dilute H2SO4 to yield the b-acetamido-g-acetoxycarboxylic acids (3S,4R)-13a,b
and (2R,3S,4R)-13c. Compounds 13 cyclized spontaneously under acidic conditions to afford b-acetamido-g-butyrolactones
(4S,5R)-14a,b and (3R,4S,5R)-14c. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Optically active cyanohydrins, which are readily avail-
able using enzymes as catalysts,12 offer an access to
b-amino-g-butyrolactones independent of the limited
compounds of the ‘chiral pool’. A methodology already
developed13 involves Reformatsky reaction of O-pro-
tected cyanohydrins to enamino esters, subsequent
reduction with NaBH3CN to b-amino-g-hydroxycar-
boxylates and acid-catalyzed ring closure to give 2-sub-
stituted b-amino-g-butyrolactones in relatively good
yields. Although the reduction of optically active enam-
ino esters to b-amino-g-hydroxycarboxylates occurs
without racemization, the achieved diastereomeric
ratios for the hydroxycarboxylates were not satisfy-
ing.13 Therefore the reaction of optically active O-silyl-
ated cyanohydrins with allyl Grignard reagent has been
investigated in this respect. The resultant addition
products—unsaturated amino alcohols—should be con-
verted to the corresponding b-amino-g-hydroxycar-
b-Amino-g-butyrolactones and the corresponding open-
chain b-amino-g-hydroxycarboxylic acids, respectively,
are known as components of many biologically active
natural products and pharmaceuticals. Thus, this struc-
tural unit has been found in antifungal or antibiotic
peptides,2,3 in antimalarial alkaloids,4 gastroprotective
drugs,5 as well as in new inhibitors of
phosphodiesterase6 and HIV-1 protease.7 Furthermore,
b-amino-g-butyrolactones are important intermediates
in the preparation of a variety of interesting b-amino
acids8 and b-lactam antibiotics.9
Only few generally applicable stereoselective syntheses
for b-amino-g-butyrolactones have been described in
the literature until now. In general, optically active
compounds derived from the ‘chiral pool’ serve as
starting materials. For example, optically active 2-sub-
stituted b-amino-g-lactones have been prepared from
aspartic acid with relatively high diastereoselectivity
and conservation of the configuration at the stereogenic
a-C center of aspartic acid.8,9a,c,10 Further approaches
to specially substituted b-amino-g-lactones start from
a,b-unsaturated g-hydroxycarboxylates or lactones
derived from carbohydrates.9d,11
boxylic acids, affording
a
generally applicable,
stereoselective synthetic route to b-amino-g-butyro-
lactones.
2. Results and discussion
2.1. Addition of Grignard reagents to O-silylated
cyanohydrins (R)-3
* Corresponding
po.uni-stuttgart.de
† See Ref. 1.
author.
E-mail:
franz.effenberger@
The synthesis of chiral b-amino-g-butyrolactones 14
starting from optically active cyanohydrins (R)-2 is
outlined in Scheme 1.
‡ Part of dissertation, Universita¨t Stuttgart, 2000.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00437-8

1856
J. Roos, F. Effenberger / Tetrahedron: Asymmetry 13 (2002) 1855–1862
Scheme 1.
The (R)-cyanohydrins (R)-2a–c, easily accessible by
(R)-PaHNL-catalyzed addition of HCN to aldehydes
1a–c, were silylated with trimethylchlorosilane in the
presence of pyridine14 to give the O-trimethylsilylated
cyanohydrins (R)-3a–c with 90–99% ee (Table 1). As
described in a recent publication,15 the ‘CH2CHO’ moi-
ety was introduced by reacting compounds (R)-3a–c
with allyl Grignard. The resulting imino intermediates
were hydrogenated in situ with NaBH4 giving the
amino alcohols (4R,5S)-5a–c with diastereomeric
excesses of 75–99% (Table 1). Compounds (4R,5S)-5a–
c were converted without further purification by treat-
ment with acetic anhydride and catalytic amounts of
DMAP in pyridine to yield the 4-acetamido-5-ace-
toxyalkenes (4S,5R)-7a–c. The diastereomeric excess of
(4S,5R)-7a and (4S,5R)-7b could be improved from 89
and 70%, respectively, to 94 and 96% by recrystalliza-
tion (Table 1). Because the Grignard reagent prepared
from allyl bromide is very reactive,15,16 a second mole
of Grignard reagent reacted with the imino intermedi-
Table 1. Addition of allyl Grignard to silylated cyanohydrins (R)-3, reduction of the imino intermediates to amino alcohols
(4R,5S)-5 and subsequent acetylation to give 4-acetamido-5-acetoxyalkenes (4S,5R)-7
(R)-3
ee (%)
R.-time
(h)
Amino alcohols (4R,5S)-5
Acetamido-acetoxyalkenes (4S,5R)-7
Crude yield (%)
de (%)
Yield (%)
de (%)
[h]2D0 (c in CHCl3)
3a
3b
3c
90
94
99
3
4
1.5
5a
5b
5c
81a
70
87
89
75
99
7a
7b
7c
78b
79
58
94c
96d
99
+27.4 (1.0)
+14.0 (1.67)
−49.6 (0.5)
a As a mixture with (R)-4a.
b Acetylated carbinamine derivative (R)-6a was separated in 15% yield.
c After recrystallization from diisopropyl ether; 90% ee, [h]D20=+10.5 (c 1.3, CHCl3).
d After recrystallization from diisopropyl ether/petroleum ether.

J. Roos, F. Effenberger / Tetrahedron: Asymmetry 13 (2002) 1855–1862
1857
ate derived of (R)-3a15,17 to give the carbinamine
derivative (R)-4a as a by-product in 15% yield. (R)-4a
could be separated after acetylation to (R)-6a by recrys-
tallization from diisopropyl ether (Table 1).
Although crotyl Grignard reagent, resembling the allyl
Grignard in reactivity, exists in an equilibrium in favor
of form A18 (Scheme 2), the a-methylallyl product,
resulting from reaction of isomer B, is formed almost
exclusively in the addition to carbonyl compounds.16,19
The addition of the crotyl Grignard reagent to (R)-3a
follows that of allyl Grignard, giving the corresponding
imino intermediate (Scheme 1). The formation of amino
alcohols 8 or (4R,5S)-9 after diastereoselective reduc-
tion with NaBH4 depends on the workup conditions.
Under acidic conditions the terminal double bond iso-
merizes to give compound (4R,5S)-9 exclusively in 79%
yield. Acetylation and recrystallization afforded
diastereomerically pure (4S,5R)-11. In basic medium,
however, the amino alcohol (4R,5RS,6RS)-8 was iso-
lated in 81% yield as a diastereoisomeric mixture in a
ratio of 62:21:11:6. After acetylation of 8, the main
diastereoisomer of 10 could be separated by chro-
matography on silica gel. The newly generated stereo-
genic center at C-3 was determined by X-ray
crystallographic analysis20 to be (S)-configured (Fig. 1).
The main diastereoisomer therefore is (3S,4S,5R)-10.
Figure 1. ORTEP view of the main diastereoisomer
(3S,4S,5R)-10.
2.2. Ozonolysis, oxidation and cyclization of 4-acetam-
ido-5-acetoxyalkenes 7a,b and 10 to b-acetamido-g-
butyrolactones 14
Thus, the diastereoisomers could be assigned as
follows:
(3S,4S,5R)-10:(3R,4S,5R)-10:(3S,4R,5R)-
10:(3R,4R,5R)-10=62:21:11:6. Surprisingly, the (S)-
configuration at C-3 is generated with relatively high
selectivity21 of 73:27, indicating an influence of the
cyanohydrin configuration on the addition of the Grig-
nard reagent. A prerequisite for an asymmetric induc-
tion is the coordination of magnesium to both the N-
and O-atom, resulting in four possible transition
states,19b,21,22 from which the sterically favored state
affords the two major diastereoisomers.
Oxidative cleavage of the terminal double bond in
(4S,5R)-7a,b and (3S,4S,5R)-10 was performed by
ozonolysis to give the corresponding aldehydes
(3S,4R)-12a,b and (2R,3S,4R)-12c. Crude aldehydes
12—with the exception of (3S,4R)-12a, which was iso-
lated in 87% yield—were oxidized without further
purification with CrO3 in dilute H2SO4,23 yielding the
b-acetamido-g-acetoxycarboxylic acids (3S,4R)-13a,b
and (2R,3S,4R)-13c (Scheme 1, Table 2). Other oxi-
dants such as H2O2/formic acid24 or KMnO4 afforded
25
either product mixtures or the oxidation reaction pro-
ceeded very slowly.
Selective cleavage of the ester function in the b-acetam-
ido-g-acetoxycarboxylic acids 13 with a solution of
NaOMe/MeOH followed by spontaneous cyclization
Scheme 2.
Table 2. Oxidation of (4S,5R)-7a,b and (3S,4S,5R)-10 to g-acetoxycarboxylic acids (3S,4R)-13a,b and (2R,3S,4R)-13c fol-
lowed by cyclization to b-acetamido-g-butyrolactones (4S,5R)-14a,b and (3R,4S,5R)-14c
7, 10
(3S,4R)- and (2R,3S,4R)-Carboxylic acids 13
(4S,5R)- and (3R,4S,5R)-Butyrolactones 14
de (%)
Yield (%)
54b
de (%)a
[h]2D0 (c in solvent)
Yield (%)
61
de (%)a
[h]2D0 (c in
CHCl3)
7a
95
13a
95c
+11.1 (0.36,
14a
\95c
−14.4 (0.93)
CHCl3)
7b
10
75
\99
13b
13c
67
28
75
+15.0 (0.5, CHCl3) 14b
−7.25 (0.4, MeOH) 14c
84
83
75
–
\95c
\95c
+31.5 (0.4)
a Determined from 1H NMR spectra.
b Referred to aldehyde (3S,4R)-12a, isolated in 87% yield.
c Only one diastereoisomer was detected by 1H NMR and gas chromatography.

1858
J. Roos, F. Effenberger / Tetrahedron: Asymmetry 13 (2002) 1855–1862
under acidic workup conditions afforded the b-acetam-
ido-g-butyrolactones (4S,5R)-14a,b and (3R,4S,5R)-14c
(Scheme 1, Table 2). The configuration of the butyro-
lactones 14 could be confirmed by X-ray crystallo-
graphic analysis20 of (4S,5R)-14a (Fig. 2).
3b: yield: 68%; bp 65°C/13 torr; [h]2D0=+60.5 (c 1.1,
1
CHCl3), 94% ee. H NMR (250 MHz): l 0.21 (s, 9H,
(CH3)3Si), 0.94 (d, J=6.3 Hz, 3H, CH3), 0.96 (d, J=6.4
Hz, 3H, CH3), 1.58–1.92 (m, 3H, CH2, 4-CH), 4.43 (dd,
J1=6.3 Hz, J2=7.8 Hz, 1H, 2-CH). 13C NMR (63
MHz): l −0.36 (Si(CH3)3), 21.93, 22.53 (CH3), 24.12
(C-4), 44.96 (C-3), 59.98 (C-2), 120.33 (CN). Anal.
calcd for C9H19NOSi (185.3): C, 58.32; H, 10.33; N,
7.56. Found: C, 57.90; H, 10.17; N, 7.33%.
3. Experimental
3.1. Materials and methods
3.4. Preparation of (4R,5S)-amino alcohols, (4R,5S)-5;
general procedure
Melting points were determined on a Bu¨chi SMP-20
and are uncorrected. Unless otherwise stated, H and
1
13C NMR spectra were recorded on a Bruker AC 250 F
(250 MHz) and ARX 500 (500 MHz) in CDCl3 with
TMS as internal standard. Optical rotations were mea-
sured with a Perkin–Elmer polarimeter 241 LC in a
thermostated glass cuvette (l=10 cm). Chromatography
was performed using silica gel S (Riedel-de Haen), grain
size 0.032–0.063 mm. Diastereomeric excess: GC sepa-
rations were conducted using (a) capillary glass
columns (20 m) with OV 1701 or PS086 with 10%
permethylated b-cyclodextrin or Bondex-un-5,5-Et-105,
carrier gas 0.4–0.5 bar hydrogen; (b) a Chiraldex B-TA
(ICT) column (30 m×0.32 mm), carrier gas hydrogen.
All solvents were dried and distilled.
According to the method of Effenberger et al.15 to a
solution of allyl Grignard reagent in diethyl ether [pre-
pared by slow addition of allyl bromide (59.1 mmol for
3a, 61.5 mmol for 3b, 81.8 mmol for 3c) to equimolar
amounts of Mg in diethyl ether] was added dropwise
compound 3a–c (27.3–30.2 mmol) over 15 min. After
stirring for the time given in Table 1 (TLC control), the
reaction mixture was cooled to −78°C. Methanol (40
mL for 3b,c, 90 mL for 3a) was added followed by
NaBH4 (ca. 2 equiv. referred to 3a,c, 1 equiv. referred
to 3b) in three portions. The reaction mixture was
allowed to warm to room temperature (12 h), and
hydrolyzed with water (50 mL). The aqueous layer was
adjusted to pH 2 with 1 M HCl and separated. The
organic layer was extracted with dilute HCl (pH 2,
2×20 mL). The combined aqueous layers were adjusted
to pH 10 with NaOH, and extracted with ethyl acetate
(3×50 mL). The combined extracts were dried
(Na2SO4), and concentrated.
3.2. Preparation of (R)-cyanohydrins, (R)-2
(R)-Cyanohydrins (R)-2 were prepared according to
Effenberger et al.,26 but citrate buffer (pH 3.3) was
used, and stirring at 4°C for 5–13 h.
3.3. Silylation of (R)-2 to (R)-3
3.4.1. (4R,5S)-5-Amino-7-octen-4-ol, (4R,5S)-5a. Mp
1
67–69°C; [h]2D0=+24.3 (c 1.0, CHCl3). H NMR (250
Silylation was performed according to Effenberger et
al.14 (R)-4-methyl-2-trimethylsilyloxypentanenitrile (R)-
MHz): l 0.95 (t, J=6.9 Hz, 3H, CH3), 1.25–2.35 (m,
9H, (CH2)2, 6-CH2, OH, NH2), 2.84 (dt, J=3.7 Hz, 1H,
5-CH), 3.53 (dt, J1=7.9 Hz, J2=4.0 Hz, 1H, 4-CH),
5.13–5.16 (m, 2H, ꢀCH2), 5.71–5.88 (m, 1H, CHꢀ). 13C
NMR (63 MHz): l 14.18 (CH3), 19.36 (C-2), 34.26
(C-3), 36.22 (C-6), 54.35 (C-5), 73.79 (C-4), 117.63
(ꢀCH2), 136.03 (CHꢀ).
3.4.2. (4R,5S)-5-Amino-2-methyl-7-octen-4-ol, (4R,5S)-
1
5b. [h]2D0=+28.6 (c 1.0, CHCl3). H NMR (250 MHz): l
0.92 (d, J=6.6 Hz, 3H, CH3), 0.96 (d, J=6.7 Hz, 3H,
CH3), 1.09–1.46 (m, 2H, 3-CH2), 1.74–1.90 (m, 1H,
2-CH), 1.94–2.33 (m, 5H, 6-CH2, OH, NH2), 2.85 (dt,
J=3.7 Hz, J=9.6 Hz, 1H, 5-CH), 3.64 (dt, J=3.3 Hz,
1H, 4-CH), 5.09–5.16 (m, 2H, ꢀCH2), 5.70–5.87 (m, 1H,
CHꢀ). 13C NMR (63 MHz): l 21.83, 23.81 (CH3), 24.72
(C-2), 36.13 (C-6), 41.04 (C-3), 54.77 (C-5), 71.72 (C-4),
117.75 (ꢀCH2), 135.83 (CHꢀ).
3.5. Acetylation of amino alcohols (R)-4a and (4R,5S)-
5 to (R)-6a and (4S,5R)-7; general procedure
According to Effenberger et al.,15 but purification either
by chromatography on silica gel with ethyl acetate (7c)
or recrystallization from diisopropyl ether (7a) or diiso-
propyl ether/petroleum ether (7b).
Figure 2. ORTEP view of 4-acetamido-5-propyltetrahydro-2-
furanone (4S,5R)-14a.

J. Roos, F. Effenberger / Tetrahedron: Asymmetry 13 (2002) 1855–1862
1859
3.5.1. (R)-4-Acetamido-4-(2-acetoxybutyl)-1,6-heptadi-
0.01 torr; 79% de. 1H NMR (250 MHz): l 0.93 (t,
J=7.0 Hz, 3H, CH3), 1.18–1.73 (m, 13H, (CH2)2, 6,8-
CH3, OH, NH2), 3.20 (d, J=6.1 Hz, 1H, 5-CH), 3.51–
3.58 (m, 1H, 4-CH), 5.42–5.51 (m, 1H, CHꢀ). 13C
NMR (63 MHz): l 12.70, 13.16, 14.19 (CH3), 19.19
(C-2), 34.69 (C-3), 63.41 (C-5), 72.32 (C-4), 121.71
(CHꢀ), 136.56 (C-6).
1
ene, (R)-6. H NMR (500 MHz): l 0.91 (t, J=7.3 Hz,
3H, 4%-CH3), 1.20–1.38 (m, 2H, 3%-CH2), 1.56–1.61 (m,
2H, 2%-CH2), 1.92 (s, 3H, CH3CON), 2.08 (s, 3H,
CH3COO), 2.49–2.73 (m, 4H, 3,5-CH2), 5.08–5.15 (m,
4H, ꢀCH2), 5.24–5.26 (m, 1H, 1%-CH), 5.59 (s, 1H, NH),
5.75–5.89 (m, 2H, CHꢀ). 13C NMR (126 MHz): l 13.85
(4%-CH3), 19.29 (3%-CH3), 21.07, 24.40 (CH3CO), 31.40
(C-2%), 38.15, 38.77 (C-3,5), 61.03 (C-4), 77.22 (C-1%),
118.35, 118.94 (ꢀCH2), 133.16, 133.92 (CHꢀ), 169.76,
171.37 (CO). Anal. calcd for C15H25NO3 (267.4): C,
67.38; H, 9.43; N, 5.24. Found: C, 66.98; H, 9.46; N,
5.06%.
3.6.2.
(4S,5R)-4-Acetamido-5-acetoxy-3-methyl-2-
octene, (4S,5R)-11. As described in Section 3.5, from
(4R,5S)-9 (0.7 g, 4.45 mmol), acetic anhydride (1.3 mL,
13.75 mmol), DMAP (40 mg, 0.33 mmol) in pyridine (5
mL); yield: 77%, mp 83°C (diisopropyl ether); [h]2D0=
1
+29.5 (c 0.6, CHCl3), >99% de. H NMR (500 MHz): l
3.5.2.
(4S,5R)-4-Acetamido-5-acetoxy-1-octene,
0.90 (t, J=7.3 Hz, 3H, CH3), 1.24–1.44 (m, 2H, 7-
CH2), 1.45–1.58 (m, 2H, 6-CH2), 1.61 (d, J=5.8 Hz,
3H, 1-CH3), 1.61 (s, 3H, 6-CH3), 2.00 (s, 3H,
CH3CON), 2.04 (s, 3H, CH3COO), 4.52 (dd, J=5.1 Hz,
1H, 4-CH), 4.94–4.98 (m, 1H, 5-CH), 5.45–5.47 (m, 1H,
CHꢀ), 5.97 (d, J=8.6 Hz, 1H, NH). 13C NMR (63
MHz): l 13.26, 13.46, 13.84 (CH3), 18.89 (C-7), 21.08,
23.51 (CH3CO), 32.88 (C-6), 58.42 (C-4), 74.65 (C-5),
123.24 (CHꢀ), 131.63 (C-3), 169.30, 171.16 (CO). Anal.
calcd for C13H23NO3 (241.3): C, 64.70; H, 9.61; N, 5.80.
Found: C, 64.88; H, 9.56; N, 5.66%.
1
(4S,5R)-7a. Mp 75°C. H NMR (250 MHz): l 0.91 (t,
J=7.2 Hz, 3H, CH3), 1.22–1.62 (m, 4H, (CH2)2), 1.97
(s, 3H, CH3CON), 1.99–2.39 (m, 2H, 3-CH2), 2.08 (s,
3H, CH3COO), 4.17–4.27 (m, 1H, 4-CH), 4.89 (dt,
J1=4.4 Hz, J2=8.5 Hz, 1H, 5-CH), 5.04–5.17 (m, 2H,
ꢀCH2), 5.62 (d, J=9.1 Hz, 1H, NH), 5.68–5.84 (m, 1H,
CHꢀ). 13C NMR (63 MHz): l 13.85 (CH3), 18.79 (C-7),
21.11, 23.39 (CH3CO), 33.08 (C-6), 34.45 (C-3), 50.61
(C-4), 75.61 (C-5), 117.79 (ꢀCH2), 134.25 (CHꢀ),
169.69, 171.07 (CO). Anal. calcd for C12H21NO3
(227.3): C, 63.41; H, 9.31; N, 6.16. Found: C, 63.33; H,
9.35; N, 6.08%.
3.6.3. 5-Amino-6-methyl-7-octen-4-ol, 8. As described in
Section 3.4, from (R)-3a (5 g, 29.2 mmol), but modified
workup: after reduction with NaBH4, the reaction mix-
ture was hydrolyzed with water. The organic layer was
separated and the aqueous layer was extracted with
diethyl ether (3×65 mL). The combined organic layers
were dried (Na2SO4) and concentrated. The residue was
taken up in methanol (2×70 mL) and again concen-
trated to give 3.72 g (81%) of 8 as a diastereoisomeric
mixture of 62:21:11:6.
3.5.3.
(4S,5R)-4-Acetamido-5-acetoxy-7-methyl-1-
1
octene, (4S,5R)-7b. Mp 63–64°C. H NMR (250 MHz):
l 0.89, 0.93 (d each, J=6.5 Hz, 3H, CH3), 1.25–1.67
(m, 3H, CH2, 7-CH), 1.97 (s, 3H, CH3CON), 2.07 (s,
3H, CH3COO), 2.08–2.38 (m, 2H, 3-CH2), 4.16–4.26
(m, 1H, 4-CH), 4.98 (dt, J1=3.9 Hz, J2=9.6 Hz, 1H,
5-CH), 5.04–5.11 (m, 2H, ꢀCH2), 5.57 (d, J=9.0 Hz,
1H, NH), 5.68–5.84 (m, 1H, CHꢀ). 13C NMR (63
MHz): l 21.14 (CH3CO), 21.88, 23.26 (CH3), 23.41
(CH3CO), 24.62 (C-7), 34.47 (C-3), 39.73 (C-6), 50.89
(C-4), 74.19 (C-5), 117.75 (ꢀCH2), 134.27 (CHꢀ),
169.66, 171.06 (CO). Anal. calcd for C13H23NO3
(241.3): C, 64.70; H, 9.61; N, 5.80. Found: C, 64.47; H,
9.71; N, 5.72%.
3.6.4.
(3S,4S,5R)-4-Acetamido-5-acetoxy-3-methyl-1-
octene, (3S,4S,5R)-10. The diastereoisomeric mixture of
8 was acetylated as described in Section 3.5. Chro-
matography on silica gel with petroleum ether:ethyl
acetate (2:1) gave 1.9 g (33%) of (3S,4S,5R)-10; mp
83°C (diisopropyl ether); [h]2D0=+16.4 (c 2.3, CHCl3).
1H NMR (250 MHz): l 0.90 (t, J=7.2 Hz, 3H, CH3),
1.05 (d, J=6.9 Hz, 3H, 3-CH3), 1.23–1.64 (m, 4H,
(CH2)2), 2.00 (s, 3H, CH3CON), 2.07 (s, 3H,
CH3COO), 2.44–2.52 (m, 1H, 3-CH), 4.08–4.17 (m, 1H,
4-CH), 4.84–4.91 (m, 1H, 5-CH), 5.02–5.17 (m, 2H,
ꢀCH2), 5.30 (d, J=9.8 Hz, 1H, NH), 5.76–5.90 (m, 1H,
CHꢀ). 13C NMR (63 MHz): l 13.86, 16.64 (CH3), 18.53
(C-7), 21.03, 23.33 (CH3CO), 32.95 (C-6), 36.91 (C-3),
54.55 (C-4), 73.81 (C-5), 116.50 (ꢀCH2), 138.47 (CHꢀ),
169.95, 170.75 (CO). Anal. calcd for C13H23NO3
(241.3): C, 64.70; H, 9.61; N, 5.80. Found: C, 64.84; H,
9.54; N, 5.80%.
3.5.4. (4S,5R)-4-Acetamido-5-acetoxy-5-phenyl-1-pen-
tene, (4S,5R)-7c. Mp 93°C. 1H NMR (500 MHz): l
1.93 (s, 3H, CH3CON), 2.04–2.32 (m, 2H, 3-CH2), 2.13
(s, 3H, CH3COO), 4.47–4.52 (m, 1H, 4-CH), 5.04–5.08
(m, 2H, ꢀCH2), 5.31 (d, J=9.2 Hz, 1H, NH), 5.68–5.76
(m, 1H, CHꢀ), 5.88 (d, J=4.4 Hz, 1H, 5-CH), 7.29–
7.38 (m, 5H, Ph). 13C NMR (63 MHz): l 21.15, 23.34
(CH3CO), 34.35 (C-3), 51.73 (C-4), 76.56 (C-5), 118.05
(ꢀCH2), 126.69, 128.25, 128.50, 136.82 (Ph), 134.02
(CHꢀ), 169.62, 170.05 (CO). Anal. calcd for C15H19NO3
(261.3): C, 68.94; H, 7.33; N, 5.36. Found: C, 69.11; H,
7.43; N, 5.30%.
3.6. Addition of the crotyl Grignard reagent to (R)-3a
3.7. Ozonolysis of 4-acetamido-5-acetoxy-1-octenes
(4S,5R)-7a,b and (3S,4S,5R)-10 and subsequent
oxidation with CrO3; general procedure
3.6.1. (4R,5S)-5-Amino-6-methyl-6-octen-4-ol, (4R,5S)-
9. As described in Section 3.4, from (R)-3a (5 g, 29.2
mmol), Mg (1.42 g, 58.4 mmol), crotyl bromide (6 mL,
59.6 mmol), diethyl ether (130 mL), methanol (90 mL)
and NaBH4 (2.2 g, 58.2 mmol); yield: 61%, bp 69°C/
(a) Ozone (40 L/h) was passed through a solution of 7
(1 mmol 7a, 12.4 mmol 7b) or 10 (3.1 mmol) in
methanol (20 mL for 7a, 150 mL for 7b, 35 mL for 10)

1860
J. Roos, F. Effenberger / Tetrahedron: Asymmetry 13 (2002) 1855–1862
at −78°C over 10 min, and subsequently O2 was passed
through for 5 min to remove excess O3. Then dimethyl-
sulfide (ca. 3 equiv. referred to 7, 10) was added, and
the reaction mixture was allowed to warm to room
temperature (12 h). The reaction mixture was concen-
trated, and crude aldehydes 12 were dried under high
vacuum.
3.7.4. (2R,3S,4R)-3-Acetamido-4-acetoxy-2-methylhep-
1
tanoic acid, (2R,3S,4R)-13c. Mp 156–157°C. H NMR
(500 MHz, acetone): l 0.87 (t, J=7.4 Hz, 3H, CH3),
1.16 (d, J=7.2 Hz, 3H, 2-CH3), 1.19–1.65 (m, 4H,
(CH2)2), 1.94 (s, 3H, CH3CON), 1.97 (s, 3H,
CH3COO), 2.77 (dq, J=4.1 Hz, 1H, 2-CH), 4.32 (ddd,
J1=7.8 Hz, J2=10.0 Hz, 1H, 3-CH), 4.96–5.00 (m, 1H,
4-CH), 7.07 (d, 1H, NH), 10.92 (br s, 1H, CO2H). 13C
NMR (126 MHz, acetone): l 14.60, 15.01 (CH3), 19.36
(C-6), 21.26, 23.41 (CH3CO), 34.40 (C-5), 39.87 (C-2),
54.28 (C-3), 74.14 (C-4), 170.51, 170.98 (CO), 176.92
(CO2H). Anal. calcd for C12H21NO5 (259.3): C, 55.58;
H, 8.16; N, 5.40. Found: C, 55.61; H, 8.20; N, 5.27%.
(b) To a solution of crude 12 (3.1–12.4 mmol) in
acetone (40 mL for 12a, 100 mL for 12b, 25 mL for
12c) at 0°C was added dropwise a solution of CrO3 in
H2SO4 [prepared by dissolving CrO3 (22 g, 0.22 mol) in
dilute H2SO4 (65 mL)] (20 mL for 7a, 65 mL for 7b, 15
mL for 10) over 30 min, and the reaction mixture was
stirred at 0°C for a further 30 min. Then isopropanol
(12–50 mL) was added followed by addition of water
(25–100 mL) after 1 h. The reaction mixture was
extracted with CHCl3 (3×65 mL). The combined
organic layers were extracted with a solution of
NaHCO3 (10%) (2×70 mL). The combined aqueous
layers were adjusted to pH 2 with conc. HCl and
extracted with CHCl3 (3×50 mL). The combined
extracts were dried (Na2SO4), and concentrated.
Recrystallization from diethyl ether gave acids 13.
3.8. Cyclization of heptanoic acids (3S,4R)-13a,b and
(2R,3S,4R)-13c to the corresponding lactones (4S,5R)-
14a,b and (3R,4S,5R)-14c; general procedure
Acid 13 (0.8–3.7 mmol) in a 0.5 M solution of NaOMe
in methanol (20 mL for 13a,c, 10 mL for 13b) was
stirred for
2
h
at room temperature. Then
dichloromethane (50 mL) and a 1.5-fold volume of HCl
(10%) (referred to NaOMe/MeOH) were added, and
the reaction mixture was stirred for a further 5 min.
The organic layer was separated and the aqueous layer
was extracted with dichloromethane (3×25 mL). The
combined organic layers were dried (Na2SO4), and con-
centrated. The residue was recrystallized from diethyl
ether to give lactones 14.
3.7.1. (3S,4R)-3-Acetamido-4-acetoxyheptanal, (3S,4R)-
12a. Yield: 87%, mp 63–64°C; [h]2D0=+42.6 (c 1.0,
CHCl3), 94% de. 1H NMR (250 MHz): l 0.92 (t, J=7.2
Hz, 3H, CH3), 1.22–1.62 (m, 4H, (CH2)2), 1.98 (s, 3H,
CH3CON), 2.08 (s, 3H, CH3COO), 2.51–2.63 (m, 2H,
CH2), 4.49–4.59 (m, 1H, 3-CH), 4.94–5.06 (m, 1H,
4-CH), 6.41 (d, J=8.5 Hz, 1H, NH), 9.73 (t, J=2.0 Hz,
1H, CHO). 13C NMR (63 MHz): l 13.77 (CH3), 18.65
(C-6), 21.02, 23.26 (CH3CO), 33.57 (C-5), 43.64 (C-2),
47.91 (C-3), 75.30 (C-4), 169.99, 171.23 (CO), 200.59
(CHO). Anal. calcd for C11H19NO4 (229.3): C, 57.63;
H, 8.35; N, 6.11. Found: C, 57.54; H, 8.38; N, 5.92%.
3.8.1. (4S,5R)-4-Acetamido-5-propyltetrahydro-2-fura-
none, (4S,5R)-14a. Mp 104–105°C. 1H NMR (500
MHz, acetone): l 0.94 (t, J=7.4 Hz, 3H, CH3), 1.38–
1.76 (m, 4H, (CH2)2), 1.89 (s, 3H, CH3CON), 2.44 (dd,
J1=5.7 Hz, J2=17.7 Hz, 1H, 3-CH2), 2.90 (dd, J=8.3
Hz, 1H, 3-CH2), 4.27–4.36 (m, 2H, 4,5-CH), 7.57 (br s,
1H, NH). 13C NMR (126 MHz, acetone): l 14.45
(CH3), 19.71 (CH2), 23.23 (CH3CO), 35.28 (CH2), 36.85
(C-3), 51.80 (C-4), 86.32 (C-5), 170.52 (CO), 175.38
(C-2). Anal. calcd for C9H15NO3 (185.2): C, 58.36; H,
8.16; N, 7.56. Found: C, 58.48; H, 8.21; N, 7.52%.
3.7.2. (3S,4R)-3-Acetamido-4-acetoxyheptanoic acid,
1
(3S,4R)-13a. Mp 129°C. H NMR (500 MHz): l 0.83
(t, J=7.3 Hz, 3H, CH3), 1.13–1.54 (m, 4H, (CH2)2),
1.93 (s, 3H, CH3CON), 2.00 (s, 3H, CH3COO), 2.41–
2.53 (m, 2H, CH2), 4.35–4.40 (m, 1H, 3-CH), 4.94 (ddd,
J1=5.1 Hz, J2=8.2 Hz, 1H, 4-CH), 6.74 (d, J=9.0 Hz,
1H, NH), 8.74 (br s, 1H, CO2H). 13C NMR (126 MHz):
l 13.80 (CH3), 18.58 (C-6), 20.94, 23.11 (CH3CO),
33.45 (C-5), 34.32 (C-2), 48.93 (C-3), 74.84 (C-4),
170.93, 171.21 (CO), 175.01 (CO2H). Anal. calcd for
C11H19NO5 (245.3): C, 53.87; H, 7.81; N, 5.71. Found:
C, 53.63; H, 7.83; N, 5.62%.
3.8.2.
(4S,5R)-4-Acetamido-5-(2-methylpropyl)tetra-
hydro-2-furanone, (4S,5R)-14b. Mp 91°C. 1H NMR
(500 MHz, acetone): l 0.93 (d, J=6.8 Hz, 3H, CH3),
0.95 (d, J=6.8 Hz, 3H, CH3), 1.54–1.59 (m, 2H, CH2),
1.77–1.84 (m, 1H, CH), 1.90 (s, 3H, CH3CON), 2.44
(dd, J1=5.8 Hz, J2=17.7 Hz, 1H, 3-CH2), 2.90 (dd,
J=8.3 Hz, 1H, 3-CH2), 4.28–4.33 (m, 1H, 4-CH), 4.36–
4.39 (m, 1H, 5-CH), 7.59 (br s, 1H, NH). 13C NMR
(126 MHz, acetone): l 22.16 (CH3), 22.84 (CH3CO),
23.35 (CH3), 25.66 (CH), 34.78 (CH2), 43.38 (C-3),
51.91 (C-4), 84.48 (C-5), 170.25 (CO), 174.97 (C-2).
Anal. calcd for C10H17NO3 (199.3): C, 60.28; H, 8.60;
N, 7.03. Found: C, 60.28; H, 8.63; N, 6.95%.
3.7.3. (3S,4R)-3-Acetamido-4-acetoxy-6-methylheptanoic
acid, (3S,4R)-13b. Mp 122–125°C. 1H NMR (500
MHz): l 0.90, 0.93 (d each, J=6.4 Hz, 3H, CH3),
1.32–1.63 (m, 3H, CH2, 6-CH), 2.00 (s, 3H, CH3CON),
2.07 (s, 3H, CH3COO), 2.47–2.59 (m, 2H, CH2), 4.39–
4.43 (m, 1H, 3-CH), 5.08–5.11 (m, 1H, 4-CH), 6.78 (d,
J=8.8 Hz, 1H, NH), 9.45 (br s, 1H, CO2H). 13C NMR
(126 MHz): l 20.97, 23.15 (CH3CO), 21.89, 23.17
(CH3), 24.60 (C-6), 34.21, 40.37 (C-2,5), 49.43 (C-3),
73.61 (C-4), 170.88, 171.25 (CO), 175.08 (CO2H). Anal.
calcd for C12H21NO5 (259.3): C, 55.58; H, 8.16; N, 5.40.
Found: C, 55.62; H, 8.12; N, 5.30%.
3.8.3. (3R,4S,5R)-4-Acetamido-3-methyl-5-propyltetra-
1
hydro-2-furanone, (3R,4S,5R)-14c. Mp 119–120°C. H
NMR (500 MHz, acetone): l 0.95 (t, J=7.4 Hz, 3H,
CH3), 1.09 (d, J=7.5 Hz, 3H, 3-CH3), 1.39–1.70 (m,
4H, (CH2)2), 1.93 (s, 3H, CH3CON), 2.94 (dq, J=7.6
Hz, 1H, 3-CH), 4.21–4.25 (m, 1H, 4-CH), 4.45–4.49 (m,

J. Roos, F. Effenberger / Tetrahedron: Asymmetry 13 (2002) 1855–1862
1861
1H, 5-CH), 7.47 (s, 1H, NH). 13C NMR (126 MHz,
acetone): l 9.71, 14.00 (CH3), 19.49 (CH2), 22.69
(CH3CO), 36.20 (CH2), 37.43 (C-3), 53.90 (C-4), 84.29
(C-5), 170.14 (CO), 178.09 (C-2). Anal. calcd for
C10H17NO3 (199.3): C, 60.28; H, 8.60; N, 7.03. Found:
C, 60.51; H, 8.68; N, 7.01%.
6. Hoff, H.; Drautz, H.; Fiedler, H.-P.; Za¨hner, H.; Schultz,
J. E.; Keller-Schierlein, W.; Philipps, S.; Ritzau, M.;
Zeeck, A. J. Antibiot. 1992, 45, 1096–1107.
7. Roggo, B. E.; Petersen, F.; Delmendo, R.; Jenny, H.-B.;
Peter, H. H.; Roesel, J. J. Antibiot. 1994, 47, 136–142.
8. Jefford, C. W.; Wang, J. Tetrahedron Lett. 1993, 34,
1111–1114.
3.9. Crystallography
9. (a) Takahashi, Y.; Hasegawa, S.; Izawa, T.; Kobayashi,
S.; Ohno, M. Chem. Pharm. Bull. 1986, 34, 3020–3024;
(b) Nitta, H.; Hatanaka, M.; Ueda, I. J. Chem. Soc.,
Perkin Trans. 1 1990, 432–433; (c) Nitta, H.; Hatanaka,
M.; Ishimaru, T. J. Chem. Soc., Chem. Commun. 1987,
51–52; (d) Collis, M. P.; Perlmutter, P. Tetrahedron:
Asymmetry 1996, 7, 2117–2134.
10. Seki, M.; Moriya, T.; Matsumoto, K. Agric. Biol. Chem.
1987, 51, 3033–3038.
11. (a) Dyong, I.; Hohenbrink, W. Chem. Ber. 1977, 110,
3655–3663; (b) Jones, J. B.; Barker, J. N. Can. J. Chem.
1970, 48, 1574–1578.
12. (a) Effenberger, F. Angew. Chem. 1994, 106, 1609–1619;
Angew. Chem., Int. Ed. Engl. 1994, 33, 1555–1564; (b)
Kruse, C. G. In Chirality in Industry; Collins, A. N.;
Sheldrake, G. N.; Crosby, J., Eds.; Wiley: New York,
1992; pp. 279–299; (c) Effenberger, F. In Stereoselective
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13. Syed, J.; Fo¨rster, S.; Effenberger, F. Tetrahedron: Asym-
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14. Effenberger, F.; Gutterer, B.; Ziegler, T. Liebigs Ann.
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Compound (3S,4S,5R)-10 was recrystallized from diiso-
propyl ether, compound (4S,5R)-14a from diethyl ether
to obtain single crystals for X-ray analysis. Intensity
data were collected on a Nicolet P3 diffractometer with
v-scan technique (graphite-monochromated Mo Ka
,
radiation, u=0.71073 A) at 293 K. The structures were
solved by direct methods and refined27 against F2.
Crystal data for 10: formula, C13H23NO3 (241.3); crys-
tal size, 1.0×1.0×0.6 mm; F(000)=1056; crystal system,
tetragonal, space group, P41; Z=4; a=9.3100(10), b=
3
,
,
9.3100(10), c=35.052(5) A; V=3038.2(6) A ; Dcalcd
=
1.055 g/cm3; number of reflections=2452; number of
independent reflections (with 2q in the range of 4.4–
46.0°)=2155; number of reflections having I>2|(I)=
1840; GooF=1.065; R1=0.0411; wR2=0.1031. Crystal
data for 14a: formula, C9H15NO3 (185.2); crystal size,
0.8×0.4×0.35 mm; F(000)=400; crystal system, tetra-
gonal, space group, P41; Z=4; a=7.3938(4), b=
3
,
,
7.3938(4), c=18.541(2) A; V=1013.58(13) A ;
D
calcd=1.214 g/cm3; number of reflections=1379; num-
ber of independent reflections (with 2q in the range of
5.5–50.0°)=1206; number of reflections having I>
2|(I)=1022; GooF=1.053; R1=0.0365; wR2=0.0776.
15. Effenberger, F.; Roos, J. Tetrahedron: Asymmetry 2000,
11, 1085–1095.
16. Benkeser, R. A. Synthesis 1971, 347–358.
17. (a) Allen, B. B.; Henze, H. R. J. Am. Chem. Soc. 1939,
61, 1790–1794; (b) Henze, H. R.; Thompson, T. R. J.
Am. Chem. Soc. 1943, 65, 1422–1425; (c) Henze, H. R.;
Allen, B. B.; Leslie, W. B. J. Am. Chem. Soc. 1943, 65,
87–89; (d) Horowitz, R. M.; Geissman, T. A. J. Am.
Chem. Soc. 1950, 72, 1518–1522; (e) Henze, H. R.;
Sutherland, G. L.; Edwards, G. D. J. Am. Chem. Soc.
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Chastrette, M. J. Organomet. Chem. 1977, 140, 245–255.
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(b) Nordlander, J. E.; Young, W. G.; Roberts, J. D. J.
Am. Chem. Soc. 1961, 83, 494–495.
Acknowledgements
We acknowledge the Fonds der Chemischen Industrie
and the Degussa AG for financial support of this work,
Dr. W. Frey for X-ray crystallographic analysis and
Dr. A. Baro for preparing the manuscript.
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