Stereoselective synthesis of (5S,6S)- and (5S,6R)-aza-muricatacin from an L-glutamic acid derivative

Article abstract of DOI:10.1016/S0957-4166(01)00251-8

A stereodivergent synthesis of threo and erythro aza-muricatacin, a non-natural aza-analogue of the bioactive annonaceous acetogenin muricatacin, is presented. The configuration of the C(5) stereocenter is controlled by diastereoselective alkylation of α-

Full text of DOI:10.1016/S0957-4166(01)00251-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1503–1509
Stereoselective synthesis of (5S,6S)- and
(5S,6R)-aza-muricatacin from an -glutamic acid derivative
L
Jose´ M. Andre´s, Noem´ı de Elena, Rafael Pedrosa* and Alfonso Pe´rez-Encabo
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Valladolid, Doctor Mergelina s/n,
47011 Valladolid, Spain
Received 17 May 2001; accepted 30 May 2001
Abstract—A stereodivergent synthesis of threo and erythro aza-muricatacin, a non-natural aza-analogue of the bioactive
annonaceous acetogenin muricatacin, is presented. The configuration of the C(5) stereocenter is controlled by diastereoselective
alkylation of a-dibenzylamino aldehyde 1 or diastereoselective reduction of a-dibenzylamino ketone 3. © 2001 Elsevier Science
Ltd. All rights reserved.
1. Introduction
stereoselective addition of different organometallic
reagents to the chiral a-amino aldehyde structure previ-
ously described7 to vic-amino alcohols 2 and further
elaboration to the final 5-substituted pyrrolidin-2-one
10.
Threo and erythro aza-muricatacin (Fig. 1) are 5-(a-
hydroxy)-substituted pyrrolidin-2-ones with interesting
cytotoxic activity;1 they are related to muricatacin, a
hydroxy lactone, isolated from Annona muricata which
also has physiological activity.2 (+)-Aza-muricatacin is
also a component of the aza-solamine isolated from
some species of Annonaceae with related cytotoxic
activity.3 As a consequence, the synthesis of different
diastereoisomers of aza-muricatacin has attracted much
attention. In this way, (+)-syn- and (−)-anti-aza-muri-
catacins have been prepared by diastereoselective reduc-
tion of a ketone obtained from a pyroglutamic acid
derivative or diastereoselective condensation of tridec-
anal with a silyloxypyrrole derivative.1a N-Boc-tert-
butyldimethylsilyloxypyrrole readily reacted with
tridecanal enantioselectively to (+)-aza-muricatacin in
the presence of (R)-Binol as catalyst4 and the same
The reaction of N,N-dibenzylamino aldehyde 1 with
dodecylmagnesium bromide for 1.5 h at 0°C in diethyl
Figure 1.
pyrrole derivative has been used in
a different
diastereoselective approach to aza-muricatacin by con-
densation with a chiral a-hydroxy aldehyde.5
2. Results and discussion
Herein we report on the stereoselective preparation of
enantiopure syn-(5S,6S)- and anti-(5S,6R)-aza-muri-
catacin starting from a common a-amino-d-hydroxy-
pentanal derivative obtained from
L
-glutamic acid.6
The retrosynthetic approach (Scheme 1) used the
Scheme 1. Retrosynthetic analysis of (S,S)- and (S,R)-aza-
muricatacin.
* Corresponding author.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00251-8

1504
J. M. Andre´s et al. / Tetrahedron: Asymmetry 12 (2001) 1503–1509
The transformation of anti-2 and syn-2 into the corre-
sponding enantiopure aza-muricatacins is summarized
in Scheme 3. To this end, anti- and syn-2 were trans-
formed into the MEM derivatives anti- and syn-5 in 90
and 78% yield, respectively, by reaction with MEM
chloride in the presence of N-ethyldi-iso-propylamine
in methylene chloride at rt for 4 h, then the primary
hydroxy group was quantitatively deprotected to anti-6
and syn-6 by treatment with tetrabutylammonium
fluoride in THF at 0°C for 10 h. Oxidation of the
primary hydroxyl group to give the corresponding car-
boxylic acid was carried out in two steps. First, anti-6
and syn-6 were subjected to Swern oxidation leading to
aldehydes anti-7 and syn-7 in 94 and 98% yield, respec-
tively. Treatment of these aldehydes with sodium
chlorite11 gave anti-8 and syn-8 in 67 and 58% yield,
respectively. These amino acids were quantitatively
debenzylated by hydrogenolysis with palladium hydrox-
ide on carbon and, without purification, the resulting
ether lead to the expected Felkin–Ahn anti-2 addition
compound8 in 70% yield as a single diastereomer as
1
demonstrated by the H NMR analysis of the reaction
mixture. Compound 1 was also treated with the zinc
reagent derived from dodecyl bromide attempting to
prepare syn-2 but this compound was obtained in only
low yield, probably due to the difficult formation of the
zinc reagent, and very low stereoselection (a 6:4 mixture
of syn and anti products was observed). Thus syn-2 was
prepared from anti-2 in two steps. Swern oxidation of
anti-2 gave amino ketone 3 in 86% yield, which was
transformed stereoselectively into syn-2 (93:7 mixture,
86% d.e.) by reduction with sodium borohydride in
methanol;9 enantiopure syn-2 was obtained in 76%
yield from 3 after purification by flash chromatography
on silica gel and hexane/ethyl acetate as eluent.
The stereochemistry of both anti-2 and syn-2 was
assigned on the basis of previously published results,7
and confirmed by transformation into the oxazolidin-
ones cis-4 and trans-4, respectively, by debenzylation
and reaction with triphosgene (Scheme 2). The vicinal
coupling constants between the protons at C(3) and
C(4) in the rings were higher for cis-4 (J=7.2 Hz) than
for trans-4 (J=5.8 Hz) and were consistent with previ-
ously reported data.10
Scheme 3. Reagents and conditions: (i) MEMCl, iPr2NEt,
CH2Cl2, rt; (ii) TBAF, THF, 0°C; (iii) (COCl)2, DMSO,
Et3N, CH2Cl2, −78°C; (iv) NaClO2, NaH2PO4, 2-methyl-2-
butene, tBuOH/CH3CN, 0°C; (v) (1) H2, Pd(OH)2–C, MeOH,
rt; (2) DCC, 4-PPY, CH2Cl2, 20°C; (vi) TiCl4, CH2Cl2, 0°C.
Scheme 2. Reagents and conditions: (i) BrMg(CH2)11CH3,
Et2O, 0°C; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, −78°C; (iii)
NaBH4, MeOH/THF, −20°C; (iv) (1) H2, Pd(OH)2–C,
MeOH, rt; (2) (CCl3O)2CO, iPr2NEt, CH2Cl2.

J. M. Andre´s et al. / Tetrahedron: Asymmetry 12 (2001) 1503–1509
1505
g-amino acids were directly ring closed12 to anti-9
and syn-9, in 74 and 55% yield, respectively, by treat-
ment with DCC and 4-pyrrolidinepyridine in methyl-
ene chloride at rt.
evaporated under vacuum. After flash chromatogra-
phy (silica gel: hexane/EtOAc: 50/1), anti-2 was
obtained as a colorless oil (16.3 g, 28 mmol, 70%);
[h]2D3=+8.6 (c 1.2, CHCl3); IR (film): 3400, 1600,
1
1490, 1450, 1090, 740, 695 cm−1; H NMR (CDCl3):
Finally, anti-9 and syn-9 were transformed into enan-
tiopure (5S,6R)-aza-muricatacin anti-10 and (5S,6S)-
aza-muricatacin syn-10, respectively, by removal of
the MEM protective group. To this end, compounds
anti-9 and syn-9 were treated with aqueous hydro-
chloric acid or zinc bromide as previously described13
but the reaction was very slow and only degradation
products were obtained. Attempts to cleave the ether
by reaction with B-bromo catecholborane14 were
more successful, but the hydroxy derivatives were iso-
lated in only 40% yield. Cleavage of the MEM group
was easily achieved by treatment of solutions of anti-
9 and syn-9 with 1 M TiCl4 in methylene chloride at
0°C for 4 h;13 under these conditions anti-10 and syn-
10 were obtained in 70 and 93% yield, respectively.
l 0.04 (s, 3H, CH
3H, J=6.4 Hz, CH
1.25 (m, 20H, (CH
TBDMSOCH2CH2, CHHCHOH, CH
(m, 2H, CHHCHOH, CHHCHN), 2.20 (br s, 1H,
OH), 2.64 (m, 1H, CHN), 3.58 (m, 2H, TBDM-
SOCH2), 3.67 (m, 4H, CH2Ph), 3.71 (m, 1H, CHOH),
7.20–7.40 (m, 10H, H
arom.); 13C NMR (CDCl3): l
−5.3 (CH3Si), 14.1 (CH3CH2), 18.3 (C(CH3)3), 21.3
(CH2CH3), 22.7 (CH2), 26.0 (C(CH3)3), 26.6 (CH2),
29.4 (CH2), 29.6 (several CH2), 30.6 (C
(CH2), 34.6 (CH2), 55.0 (CH2Ph), 60.7 (C
(TBDMSOCH2), 70.8 (C
(CHarom.), 140.0 (Carom.). Anal. calcd for
6
3Si), 0.05 (s, 3H, CH3
3CH2), 0.90 (s, 9H, C(CH3 3
2)10CH3), 1.46 (m, 4H,
HCHN), 1.73
6
Si), 0.89 (t,
6
6
) ),
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
H2), 31.9
6
6
6
6 HN), 63.0
6
6 HOH), 127.0, 128.3, 128.9
6
6
C37H63NO2Si: C, 76.36; H, 10.91; N, 2.41. Found: C,
76.06; H, 10.96; N, 2.44%.
The isolated (5S,6R)-aza-muricatacin anti-10 and
(5S,6S)-aza-muricatacin syn-10 had concordant physi-
cal and spectroscopic data with those previously
reported,1a,5 thus confirming the assigned stereochem-
istry for all compounds and that stereochemical
integrity was maintained during the transformations
of anti-2 to anti-10 and syn-2 to syn-10.
4.3. (4S)-4-(N,N-Dibenzylamino)-1-(tert-butyl-
dimethylsilyloxy)-5-heptadecanone 3
To a stirred solution of oxalyl chloride (1.95 mL,
22.35 mmol) in CH2Cl2 (50 mL) cooled to −78°C
under argon was added dropwise DMSO (3.3 mL,
46.5 mmol). After stirring the mixture for 15 min, a
solution of the amino alcohol anti-2 (9.6 g 16.5
mmol) in CH2Cl2 (50 mL) was added, and the mix-
ture was stirred for 30 min at −78°C before addition
of triethylamine (6.6 mL, 47.4 mmol). Then, the reac-
tion was allowed to warm to rt under stirring for 45
min and the mixture was quenched with water (50
mL). The aqueous phase was extracted with CH2Cl2
(45 mL), and the combined organic layers were
washed with saturated aqueous NaHCO3 and brine.
The organic phase was dried (MgSO4) and then con-
centrated to yield an oil which was purified by flash
chromatography (silica gel, hexane/EtOAc: 60/1) (8.23
g, 14.2 mmol, 86%); [h]2D3=−42.2 (c 1.1, CHCl3); IR
(film): 1700, 1595, 1485, 1445, 1090, 740, 690 cm−1;
3. Conclusion
In summary, the synthesis of two enantiopure
diastereoisomers of aza-muricatacin has been easily
carried out from a common N,N-dibenzylamino alde-
hyde derived from L-glutamic acid.
4. Experimental
4.1. General procedures
The reactions were carried out in oven-dried glass-
ware, under an argon atmosphere, and using anhy-
drous solvents. The 1H NMR (300 MHz) and 13C
NMR (75 MHz) spectra were recorded on a Bruker
AC 300 or Bruker AMX 300, using TMS as the
internal standard. IR spectra were recorded on a
Philips PU 9706 spectrometer, as a film or a KBr
dispersion. Optical rotations were measured on a
Perkin–Elmer 241 polarimeter in a 1 dm cell.
1H NMR (CDCl3): l 0.04 (s, 6H, CH3
3H, J=7.1 Hz, CH3CH2), 0.90 (s, 9H, C(CH3 3
(m, 18H, (CH2)9CH3), 1.42 (m, 4H, CH2CH2CO and
CH2CH2CHN), 1.74 (m, 2H, CH2CHN), 2.34 (dt, 1H,
J1=16.6 Hz, J2=7.3 Hz, CHHCO), 2.53 (dt, 1H,
J1=16.6 Hz, J2=7.2 Hz, CHHCO), 3.23 (dd, 1H,
J1=8.2 Hz, J2=5.4 Hz, CHN), 3.55 (m, 2H, TBDM-
SOCH2), 3.57 (d, 2H, J=13.7 Hz, CHHPh), 3.70 (d,
2H, J=13.7 Hz, CHHPh), 7.20–7.40 (m, 10H,
arom.); 13C NMR (CDCl3): l −5.3 (C
H3Si), 14.1
(CH3CH2), 18.3 (C(CH3)3), 19.7 (CH2CH3), 22.7
(CH2), 23.8 (CH2), 26.0 (C(CH3)3), 29.4 (CH2), 29.5
(CH2), 29.6 (several CH2), 30.3 (CH2), 31.9 (C
41.1 (CH2CO), 54.5 (CH2Ph), 62.7 (TBDMSOC
65.6 (CHN), 127.1, 128.3, 128.8 (C
(Carom.), 212.1 (CO). Anal. calcd for C37H61NO2Si:
6
Si), 0.88 (t,
) ), 1.38
6
6
6
6
6
6
6
6
6
6
6
4.2. (4S,5R)-4-(N,N-Dibenzylamino)-1-(tert-butyl-
dimethylsilyloxy)-5-heptadecanol anti-2
6
H
6
6
6
6
6
To a solution of CH3(CH2)11MgBr (60 mmol, 1.5
equiv.) in ether (60 mL) at 0°C was added dropwise a
solution of amino aldehyde 1 (16.46 g, 40 mmol) in
ether (150 mL). After stirring the mixture at this tem-
perature for 1.5 h, saturated NH4Cl (150 mL) was
added and the mixture was extracted with ether (3×
100 mL). The combined organic layers were washed
with brine, dried over Na2SO4 and the solvent was
6
6
6
6
6
6
6
6
H2),
H2),
6
6
6
6
6 Harom.), 139.6
6
6
C, 76.62; H, 10.60; N, 2.41. Found: C, 76.47; H,
10.48; N, 2.37%.

1506
J. M. Andre´s et al. / Tetrahedron: Asymmetry 12 (2001) 1503–1509
4.4. (4S,5S)-4-(N,N-Dibenzylamino)-1-(tert-butyl-
dimethylsilyloxy)-5-heptadecanol syn-2
67.39; H, 11.55; N, 3.27. Found: C, 67.47; H, 11.66;
N, 3.15%.
To a stirred solution of ketone 3 (10.62 g, 18.3 mmol)
in MeOH/THF (9:2, 110 mL), cooled to −20°C, was
added sodium borohydride (3.12 g, 82.4 mmol, 4.5
equiv.). After stirring the mixture for 2 h, the mixture
was quenched with H2O and extracted several times
with ether. The ethereal layer was washed with NaCl
solution and dried over MgSO4, the solvents were
removed, and the residue was purified by flash chro-
matography (silica gel, hexane/EtOAc: 50/1) to afford
a colorless oil (8.1 g, 13.9 mmol, 76%); [h]2D3=+15.2 (c
1.0, CHCl3); IR (film): 3410, 1600, 1495, 1455, 1100,
750, 700 cm−1; 1H NMR (CDCl3): l 0.09 (2s, 6H,
4.6. (4S,5S)-4-[3-(tert-Butyldimethylsilyloxy)propyl]-5-
dodecyloxazolidin-2-one trans-4
Oxazolidinone trans-4 was obtained from the amino
alcohol syn-2 (140 mg, 0.24 mmol) by the method
described for cis-4, and purified by flash chromatogra-
phy (silica gel, hexane/EtOAc: 8/1) to afford a color-
less oil (56 mg, 0.13 mmol, 55%); [h]2D3=−41.8 (c 1.0,
CHCl3); IR (film): 3260, 1740, 1245 cm−1; 1H NMR
(CDCl3): l 0.05 (s, 6H, (CH3 2
Hz, CH3CH2), 0.89 (s, 9H, C(CH3 3
CH2), 1.56 (m, 8H, CH2), 3.46 (m, 1H, CH
2H, J=5.2 Hz, TBDMSOCH2), 4.14 (m, 1H, CH
6.34 (br s, 1H, NH
); 13C NMR (CDCl3): l −5.4
(CH3Si), 14.1 (CH3CH2), 18.3 (C(CH3)3), 22.7
(CH2CH3), 24.8 (CH2), 25.9 (C(CH3)3), 28.7 (CH2),
29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (several
H2), 31.9 (CH2), 32.4 (CH2), 34.8 (CH2), 57.9
(CHN), 62.5 (TBDMSOCH2), 82.7 (CHO), 159.3
(C
6
) Si), 0.88 (t, 3H, J=7.1
) ), 1.26 (m, 18H,
N), 3.65 (t,
O),
6
6
6
6
6
(CH3 2
9H, C(CH
CH2CH2CHN), 1.47 (m, 1H, CH
2H, CHHCHN, CHHCHOH), 1.78 (m, 1H,
CHHCHOH), 2.40 (m, 1H, CHN), 3.43 (d, 2H, J=
13.2 Hz, CHHPh), 3.46 (m, 1H, CHOH), 3.63 (t, 2H,
J=6.1 Hz, TBDMSOCH2), 3.86 (d, 2H, J=13.2 Hz,
CHHPh), 4.47 (br s, 1H, OH), 7.20–7.35 (m, 10H,
arom.); 13C NMR (CDCl3): l −0.03 (C
H3Si), 14.1
(CH3CH2), 18.3 (C(CH3)3), 22.2 (CH2), 22.7 (CH2),
26.0 (C(CH3)3), 26.1 (CH2), 29.3 (CH2), 29.6 (several
H2), 29.8 (CH2), 31.9 (CH2), 32.5 (CH2), 34.2 (CH2),
54.0 (CH2Ph), 63.0 (CHN, TBDMSOCH2), 70.6
(CHOH), 127.2, 128.4, 129.1 (CHarom.), 139.0
(Carom.). Anal. calcd for C37H63NO2Si: C, 76.36; H,
6
) Si), 0.87 (t, 3H, J=6.6 Hz, CH3
3)3), 1.23 (m, 22H, (CH2 10
HCHN), 1.65 (m,
6
CH2), 0.94 (s,
6
6
6
6
) CH3,
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
C
6
6
6
6
6
6
6
6
6
6
6 ꢀO). Anal. calcd for C24H49NO3Si: C, 67.39; H,
H
6
6
11.55; N, 3.27. Found: C, 67.56; H, 11.67; N, 3.22%.
6
6
6
6
6
6
6
C6
6
6
6
6
6
6
6
4.7. (4S,5R)-4-(N,N-Dibenzylamino)-1-(tert-butyl-
dimethylsilyloxy)-5-[(2-methoxyethoxy)methoxy]-
heptadecane anti-5
6
6
6
10.91; N, 2.41. Found: C, 76.53; H, 10.80; N, 2.52%.
To a solution of anti-2 (6.75 g, 11.6 mmol) and di-iso-
propylethylamine (12.5 mL, 71.9 mmol) in CH2Cl2
(100 mL) at 0°C was added dropwise MEM chloride
(7.95 mL, 69.6 mmol). After stirring the mixture for 4
h at rt, the reaction was quenched with saturated
aqueous NH4Cl (150 mL). The aqueous phase was
extracted with CH2Cl2 (2×75 mL), and the combined
organic layers were washed with brine, dried
(Na2SO4), concentrated and chromatographed (silica
gel, hexane/EtOAc: 25/1) to give anti-5 as a colorless
oil (6.99 g 10.4 mmol, 90%); [h]2D3=−17.4 (c 1.8,
4.5. (4S,5R)-4-[3-(tert-Butyldimethylsilyloxy)propyl]-5-
dodecyloxazolidin-2-one cis-4
To a solution of anti-2 (140 mg, 0.24 mmol) in
methanol (4 mL) was added Pd(OH)2–C (28 mg) in
one portion. The mixture was stirred under hydrogen
for 3.5 h and the catalyst was removed by filtration
through Celite and washed with methanol. The filtrate
was evaporated under reduced pressure. The residue
was dissolved in CH2Cl2 (10 mL), and then di-iso-
propylethylamine (94 mL, 0.54 mmol) and triphosgene
(36 mg, 0.12 mmol) were added. The reaction solution
was allowed to warm to rt with stirring for 12 h, H2O
(2 mL) and EtOAc (30 mL) were added to the mix-
ture, and the organic phase was separated, dried over
MgSO4, concentrated under reduced pressure, and
purified by flash chromatography (silica gel, hexane/
EtOAc: 8/1) to afford a colorless oil (64 mg, 0.15
mmol, 64%); [h]2D3=−5.1 (c 1.0, CHCl3); IR (film):
CHCl3); IR (film): 1600, 1490, 1460, 1250, 740, 695
1
cm−1; H NMR (CDCl3): l 0.03 (s, 3H, SiCH3
6
), 0.04
CH2), 0.89
) ), 1.52 (m, 4H,
CH2CHN), 1.76 (m,
CHOMEM), 2.56 (m, 1H,
N), 3.38 (s, 3H, OCH3), 3.54 (m, 6H, OCH2CH2
and CHHPh), 3.70 (m, 2H, TBDMSOCH2), 3.77 (d,
2H, J=13.7 Hz, CHHPh), 3.82 (m, 1H, CHOMEM),
4.73 (d, 1H, J=7.0 Hz, OCHHO), 4.78 (d, 1H, J=7.0
Hz, OCHHO), 7.15–7.40 (m, 10H, H
arom.); 13C NMR
(CDCl3): −5.3 (CH3Si), 14.1 (CH3CH2), 18.3
(C(CH3)3), 21.9 (CH2CH3), 22.7 (CH2), 25.1 (CH2;
26.0 (C(CH3)3), 29.4 (CH2), 29.6 (CH2), 29.7 (several
H2), 29.9 (CH2), 31.3 (CH2), 31.9 (CH2), 32.5
(CH2), 54.3 (CH2Ph), 58.6 (CHN), 59.0 (OCH3),
63.2 (TBDMSOCH2), 67.4 (OCH2CH2O), 71.8
(OCH2CH2O), 78.1 (CHOMEM), 95.1 (OCH2O),
126.7, 128.0, 128.9 (CHarom.), 140.4 (Carom.). Anal.
(s, 3H, SiCH3
(s, 9H, C(CH3 3
CHHCHN, CHHCHOMEM, CH2
2H, CHHCHN, CHH
CH
6
), 0.88 (t, 3H, J=6.8 Hz, CH3
6
6
) ), 1.22 (m, 18H, (CH2 9
6
6
6
6
6
6
6
6
6
6 O
6
6
6
6
6
6
6
1
3250, 1740, 1240 cm−1; H NMR (CDCl3): l 0.06 (s,
l
6
6
6H, SiCH3
9H, C(CH3 3
2H, TBDMSOCH
CHO), 6.36 (br s, 1H, NH
−5.4 (CH3Si), 14.1 (CH3CH2), 18.2 (C
(CH2), 25.9 (C(CH3)3), 27.0 (CH2), 29.2 (C
(CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (several C
31.9 (CH2), 55.6 (CHN), 62.6 (TBDMSOCH2), 80.3
(CHO), 159.6 (CꢀO). Anal. calcd for C24H49NO3Si: C,
6
), 0.88 (t, 3H, J=7.1 Hz, CH3
) ), 1.26 (m, 19H), 1.63 (m, 7H), 3.65 (m,
2), 3.76 (m, 1H, CHN), 4.57 (m, 1H,
); 13C NMR (CDCl3): l
(CH3)3), 22.7
H2), 29.3
H2),
6
CH2), 0.89 (s,
6
6
6
6
6
6
6
6
6
6
C
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
calcd for C41H71NO4Si: C, 73.49; H, 10.68; N, 2.09.
Found: C, 73.27; H, 10.81; N, 2.07%.
6
6

J. M. Andre´s et al. / Tetrahedron: Asymmetry 12 (2001) 1503–1509
1507
4.8. (4S,5S)-4-(N,N-Dibenzylamino)-1-(tert-butyl-
4.10. (4S,5S)-4-(N,N-Dibenzylamino)-5-[(2-methoxy-
dimethylsilyloxy)-5-[(2-methoxyethoxy)methoxy]-
ethoxy)methoxy]-1-heptadecanol syn-6
heptadecane syn-5
The amino alcohol syn-6 was obtained from syn-5 (3.3
g, 4.9 mmol) by the method described for anti-6 and
purified by flash chromatography (silica gel, hexane/
EtOAc: 2/1) to afford a colorless oil (2.64 g, 4.7 mmol,
97%); [h]2D3=+40.7 (c 1.2, CHCl3); IR (film): 3420, 1600,
syn-5 was obtained from the amino alcohol syn-2 (3.80
g, 6.5 mmol) by the method described for anti-5, and
purified by flash chromatography (silica gel, hexane/
EtOAc: 30/1) to afford a colorless oil (3.40 g, 5.1 mmol,
78%); [h]2D3=+16.8 (c 1.1, CHCl3); IR (film): 1600, 1490,
1450, 1250, 745, 700 cm−1; 1H NMR (CDCl3): l 0.07 (s,
1
1490, 1450, 745, 700 cm−1; H NMR (CDCl3): l 0.60
(m, 1H, CH
Hz, CH3CH2), 1.11 (m, 4H, CH2
1.50 (m, 2H, CH2CH2CHN), 1.75 (m, 4H, CHH-
CHOMEM, CHHCHN), 2.25 (br s, 1H, OH), 2.52 (m,
1H, CHN), 3.39 (s, 3H, OCH3), 3.43 (d, 2H, J=13.4
Hz, CHHPh), 3.56 (m, 5H, OCH2CH2O, and
CHOMEM), 3.70 (m, 1H, CHHOH), 3.85 (m, 1H,
CHHOH), 3.99 (d, 2H, J=13.4 Hz, CHHPh), 4.62 (d,
1H, J=7.1 Hz, OCHHO), 4.71 (d, 1H, J=7.1 Hz,
OCHHO), 7.15–7.40 (m, 10H, H
arom.); 13C NMR
(CDCl3): l 14.1 (CH3CH2), 20.2 (CH2CH3), 22.7 (C
25.7 (CH2), 29.4 (CH2), 29.7 (several CH2), 29.9 (C
30.7 (CH2), 31.2 (CH2), 31.9 (CH2), 55.4 (C
(CHN), 59.1 (OCH3), 63.1 (CH2OH), 67.6
(OCH2CH2O), 72.0 (OCH2CH2O), 79.9 (CHOMEM),
95.1 (OCH2O), 126.7, 128.0, 129.2 (CHarom.), 140.9
(Carom.). Anal. calcd for C35H57NO4: C, 75.63; H,
6
H), 0.85 (m, 1H, CHH
6
), 0.89 (t, 3H, J=7.1
6
6
), 1.27 (m, 14H, CH2
6
),
6H, (CH3 2
(s, 9H, C(CH
CH2), 1.54 (m, 4H, CH
CH2CH2CHN), 1.77
CHHCHOMEM), 2.51 (m, 1H, CH
OCH3), 3.43 (d, 2H, J=13.4 Hz, CH
2H, TBDMSOCH2), 3.56 (m, 1H, CH
(m, 2H, OCH2CH2OCH3, CHOMEM), 3.68 (m, 2H,
OCH2CH2O), 3.96 (d, 2H, J=13.4 Hz, CHHPh), 4.63
(d, 1H, J=7.0 Hz, OCHHO), 4.70 (d, 1H, J=7.0 Hz,
OCHHO), 7.15–7.40 (m, 10H, H
arom.); 13C NMR
(CDCl3): −5.2 (CH3Si), 14.1 (CH3CH2), 18.4
(C(CH3)3), 20.1 (CH2CH3), 22.7 (CH2), 25.7 (CH2), 26.0
(C(CH3)3), 29.4 (CH2), 29.7 (several CH2), 29.9 (CH2),
30.7 (CH2), 31.4 (CH2), 31.9 (CH2), 55.4 (CH2Ph), 58.0
(CHN), 59.0 (CH3O), 63.2 (TBDMSOCH2), 67.2
(OCH2CH2O), 71.8 (OCH2CH2O), 80.0 (CHOMEM),
95.1 (OCH2O), 126.6, 128.0, 129.2 (CHarom.), 140.9
(Carom.). Anal. calcd for C41H71NO4Si: C, 73.49; H,
6
) Si), 0.89 (t, 3H, J=7.5 Hz, CH3
3)3), 1.11 (m, 4H, CH2), 1.27 (m, 16H,
HCHN, CHHCHOMEM,
(m, 2H, CHHCHN,
N), 3.37 (s, 3H,
HPh), 3.51 (m,
OMEM), 3.60
6
CH2), 0.93
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
H2),
H2),
6
6
6
6
6
6
6
6
6
6
6 H2Ph), 58.1
l
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
10.34; N, 2.52. Found: C, 75.49; H, 10.47; N, 2.66%.
6
6
6
6
6
4.11. (4S,5R)-4-(N,N-Dibenzylamino)-5-[(2-methoxy-
ethoxy)methoxy]heptadecanal anti-7
6
10.68; N, 2.09. Found: C, 73. 34; H, 10.64; N, 2.04%.
The amino aldehyde anti-7 was obtained from the
amino alcohol anti-6 (3.06 g, 5.5 mmol) by Swern
oxidation, as described for compound 3, as a colorless
oil (2.98 g, 5.4 mmol, 98%); [h]2D3=−37.4 (c 1.6, CHCl3);
4.9. (4S,5R)-4-(N,N-Dibenzylamino)-5-[(2-methoxy-
ethoxy)methoxy]-1-heptadecanol anti-6
1
IR (film): 1720, 1600, 1495, 1455, 750, 700 cm−1; H
To a solution of anti-5 (6.53 g, 9.7 mmol) in THF (90
mL) at 0°C was slowly added a solution of tetra-
butylammonium fluoride (4.61 g, 14.6 mmol) in THF
(45 mL). The mixture was stirred for 10 h at 0°C, and
the reaction was quenched by addition of water (90
mL). The aqueous phase was extracted with ether (2×75
mL), and the combined organic extracts were washed
with brine, dried (Na2SO4), concentrated and chro-
matographed (silica gel, AcOEt/hexane: 1/4) to yield
anti-6 as a colorless oil (5.36 g, 9.6 mmol, 99%);
[h]2D3=−33.7 (c 1.1, CHCl3); IR (film): 3420, 1600, 1490,
NMR (CDCl3): l 0.81 (t, 3H, J=7.0 Hz, CH3
0.94 (m, 2H, CH2), 1.16 (m, 18H, CH2), 1.40 (m, 1H,
CHHCHOMEM), 1.63 (m, 2H, CHHCHN,
CHHCHOMEM), 1.93 (m, 1H, CHHCHN), 2.45 (m,
2H, CHN and CHHCHO), 2.58 (m, 1H, CHHCHO),
3.30 (s, 3H, OCH3), 3.41 (d, 2H, J=13.8 Hz, CHHPh),
3.47 (m, 2H, OCH2CH2O), 3.64 (m, 2H, OCH2CH2O),
3.74 (d, 2H, J=13.8 Hz, CHHPh), 3.81 (m, 1H,
CHOMEM), 4.68 (d, 1H, J=7.0 Hz, OCHHO), 4.74
(d, 1H, J=7.0 Hz, OCHHO), 7.10–7.30 (m, 10H,
arom.), 9.60 (s, 1H, CH
O); 13C NMR (CDCl3): l 14.1
(CH3CH2), 18.2 (CH2CH3), 22.7 (CH2CHN), 25.1
(CH2), 29.3 (CH2), 29.6 (CH2), 29.7 (several CH2), 29.9
(CH2), 31.9 (CH2), 32.5 (CH2), 42.3 (CH2CHO), 54.1
(CH2Ph), 58.4 (CHN), 59.0 (OCH3), 67.6
(OCH2CH2O), 71.7 (OCH2CH2), 76.6 (CHOMEM),
95.0 (OCH2O), 126.9, 128.2, 128.9 (CHarom.), 140.0
(Carom.), 202.9 (CHO). Anal. calcd for C35H55NO4: C,
6 CH2),
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
H
6
6
1
1450, 745, 700 cm−1; H NMR (CDCl3): l 0.89 (t, 3H,
6
6
6
J=6.7 Hz, CH
5H), 1.80 (m, 3H), 2.60 (m, 1H, CH
OCH3), 3.54 (m, 6H, OCH2CH2O, CH
CH2OH), 3.72 (m, 2H, OCH2CH2O), 3.80 (d, 2H,
J=13.8 Hz, CHHPh), 3.86 (m, 1H, CHOMEM), 4.74
(d, 1H, J=7.0 Hz, OCHHO), 4.80 (d, 1H, J=7.0 Hz,
OCHHO), 7.20–7.40 (m, 10H, H
arom.); 13C NMR
(CDCl3): l 14.1 (CH3CH2), 22.2 (CH2CH3), 22.7 (C
25.1 (CH2), 29.4 (CH2), 29.6 (CH2), 29.7 (several C
29.9 (CH2), 31.3 (CH2), 31.9 (CH2), 32.5 (C
(CH2Ph), 58.8 (CHN), 59.0 (OCH3), 63.0 (C
67.6 (OCH2CH2O), 71.8 (OCH2CH2O),
(CHOMEM), 95.1 (OC
(CHarom.), 140.2 (C
6
3CH2), 1.24 (m, 18H, (CH2 9
N), 3.39 (s, 3H,
HPh and
6 ) ), 1.55 (m,
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
75.91; H, 10.01; N, 2.53. Found: C, 75.75; H, 10.19; N,
2.61%.
6
6
6
H2),
H2),
6
6
6
6
6
6
6
6 H2), 54.3
6
6
6
6
H2OH),
77.9
4.12. (4S,5S)-4-(N,N-Dibenzylamino)-5-[(2-methoxy-
ethoxy)methoxy]heptadecanal syn-7
6
6
6
6
H2O), 126.8, 128.1, 129.0
arom.). Anal. calcd for
6
6
The amino aldehyde syn-7 was obtained from the
amino alcohol syn-6 (5.38 g, 9.7 mmol) by Swern
oxidation, as described for compound 3, as a colorless
C35H57NO4: C, 75.63; H, 10.34; N, 2.52. Found: C,
75.76; H, 10.30; N, 2.45%.

1508
J. M. Andre´s et al. / Tetrahedron: Asymmetry 12 (2001) 1503–1509
oil (5.04 g, 9.1 mmol, 94%); [h]2D3=+14.6 (c 0.8,
CHCl3); IR (film): 1715, 1600, 1490, 1450, 745, 695
cm−1; 1H NMR (CDCl3): l 0.82 (t, 3H, J=6.7 Hz,
4.14. (4S,5S)-4-(N,N-Dibenzylamino)-5-[(2-methoxy-
ethoxy)methoxy]heptadecanoic acid syn-8
CH3
CHHCHOMEM), 1.68 (m, 1H, CH
2H, CHHCHOMEM, CHHCHN), 2.38 (m, 1H,
CHN), 2.47 (m, 2H, CH2CHO), 3.30 (s, 3H, OCH3),
3.46 (m, 5H, OCH2CH2O, CHOMEM and CHHPh),
3.57 (m, 1H, OCH2CHHO), 3.67 (m, 1H,
OCH2CHHO), 3.85 (d, 2H, J=13.4 Hz, CHHPh),
4.57 (d, 1H, J=7.1 Hz, OCHHO), 4.64 (d, 1H, J=7.1
Hz, OCHHO), 7.10–7.30 (m, 10H, Harom.), 9.67 (s,
1H, CH H3CH2), 16.9
O); 13C NMR (CDCl3): l 14.0 (C
(CH2CH3), 22.6 (CH2CHN), 25.4 (CH2), 29.3 (CH2),
29.6 (several CH2), 29.8 (CH2), 31.3 (CH2), 31.8
(CH2), 41.6 (CH2CHO), 55.0 (CH2Ph), 57.6 (C
58.9 (OCH3), 67.5 (OCH2CH2O), 71.6 (OCH2C
79.3 (CHOMEM), 94.9 (OC
(CHarom.), 140.4 (Carom.), 202.2 (C
6
CH2), 1.14 (m, 20H, CH2
6
), 1.47 (m, 1H,
The amino acid syn-8 was obtained from syn-7 (2.55
g, 4.6 mmol) by the procedure described for anti-8
and purified by flash chromatography (silica gel, hex-
ane/EtOAc: 4/1) to afford a colorless oil (1.52 g, 2.67
mmol, 58%); [h]2D3=+ 23.1 (c 0.6, CHCl3); IR (film):
6
6
HCHN), 1.88 (m,
6
6
6
6
6
6
6
6
1
6
3600–2400, 1720, 1600, 1490, 1450, 750, 700 cm−1; H
6
6
NMR (CDCl3): l 0.80 (m, 1H, CH
J=6.6 Hz, CH3CH2), 0.95 (m, 1H, CHH
18H, CH2), 1.52 (m, 1H, CHHCHOMEM), 1.78 (m,
1H, CHHCHOMEM), 1.90 (m, 1H, CH
(m, 1H, CHHCHN), 2.30 (m, 1H, CH
(m, 1H, CHHCHO), 2.65 (m, 1H, CH
OCH3), 3.54 (m, 2H, OCH2CH2O), 3.60 (d, 2H, J=
13.2 Hz, CHHPh), 3.63 (m, 1H, CHOMEM), 3.68 (m,
1H, OCH2CHHO), 3.77 (m, 1H, OCH2CHHOCH3),
3.94 (d, 2H, J=13.2 Hz, CHHPh), 4.68 (d, 1H, J=7.1
Hz, OCHHO), 4.74 (d, 1H, J=7.1 Hz, OCHHO),
7.20–7.40 (m, 10H, H
arom.); 13C NMR (CDCl3): l
14.1 (CH3CH2), 20.0 (CH2CH3), 22.7 (CH2CHN), 25.2
(CH2CO2H), 29.3 (CH2), 29.7 (several C
(CH2), 31.3 (CH2), 31.9 (CH2), 32.2 (C
(CH2Ph), 58.1 (CHN), 59.0 (OC
(OCH2CH2O), 71.7 (OCH2CH2O), 78.9 (C
94.9 (OCH2O), 127.0, 128.2, 129.4 (CHarom.), 139.6
(Carom.), 178.8 (CO2H). Anal. calcd for C35H55NO5:
6
H), 0.89 (t, 3H,
6
6
6
), 1.22 (m,
6
6
6
6
6
6
6
6
HCHN), 2.03
6 HCHO), 2.46
6
6
6
6
6
6
6
6
6
6 N), 3.38 (s, 3H,
6
6
6
6
HN),
H2O),
6
6
6
6
6
6
6
6
6
H2O), 126.7, 128.0, 129.0
HO). Anal. calcd
6
6
6
6
6
6
for C35H55NO4: C, 75.91; H, 10.01; N, 2.53. Found: C,
75.80; H, 10.13; N, 2.59%.
6
6
6
6
6
6
6
6
6
H2), 29.9
6
6
6
6 H2), 55.0
4.13. (4S,5R)-4-(N,N-Dibenzylamino)-5-[(2-methoxy-
ethoxy)methoxy]heptadecanoic acid anti-8
6
6
6
H3),
6 HOMEM),
67.6
6
6
6
6
To a solution of amino aldehyde anti-7 (5.0 g, 9
mmol) and 2-methyl-2-butene (11.4 mL, 108 mmol, 12
equiv.) in t-BuOH/CH3CN (5/3, 120 mL) was added
dropwise a solution containing 80% NaClO2 (6.1 g, 54
mmol, 6 equiv.) and NaH2PO4·2H2O (8.4 g, 54 mmol,
6 equiv.) in H2O (100 mL) at 0°C. The resulting solu-
tion was stirred at 0°C for 30 min and quenched by
addition of a 5% aqueous Na2S2O5 solution (100 mL).
The solution was adjusted to pH 6 and the mixture
was extracted with EtOAc (3×50 mL), the combined
organic phases were washed with brine, dried
(Na2SO4) and the solvent was evaporated. The
product was purified by flash chromatography (silica
gel, hexane/EtOAc: 4/1) yielding anti-8 as a colorless
oil (3.44 g, 6 mmol, 67%); [h]2D3=−17.3 (c 1.0, CHCl3);
IR (film): 3600–2400, 1740–1700, 1600, 1495, 1445,
745, 695 cm−1; 1H NMR (CDCl3): l 0.89 (t, 3H,
6
6
C, 73.78; H, 9.73; N, 2.46. Found: C, 73.99; H, 9.90;
N, 2.55%.
4.15. (5S,6R)-5-[1-(2-Methoxyethoxymethoxy)tridecyl]-
pyrrolidin-2-one anti-9
To a solution of N,N-dibenzylamino acid anti-8 (1.71
g, 3 mmol) in methanol (30 mL) was added 20%
Pd(OH)2–C (425 mg) in one portion. The mixture was
stirred under hydrogen at atmospheric pressure and
the reaction was monitored by TLC. After 2 h, when
reaction had reached completion, the catalyst was
removed by filtration through Celite and washed with
methanol. The filtrate was concentrated under reduced
pressure to afford the crude acid which was dissolved
in CH2Cl2 (30 mL) and stirred at rt during addition of
DCC (705 mg, 3.42 mmol) and 4-PPY (48 mg, 0.32
mmol). The resultant solution was stirred for 5 h at rt
(reaction complete by TLC) and the precipitated DCU
was filtered off. The filtrate was washed twice with
water, once with 5% aqueous acetic acid, and once
with water. The organic phase was dried over MgSO4
and then concentrated to yield a residue, which was
purified by flash chromatography (silica gel, EtOAc)
to afford a colorless oil (825 mg, 2.22 mmol, 74%);
[h]2D3=−10.0 (c 0.7, CHCl3); IR (film): 3200, 3060,
1685, 1035 cm−1; 1H NMR (CDCl3): l 0.86 (t, 3H,
J=6.7 Hz, CH3
18H, CH2), 1.46 (m, 1H, CH
1H, CHHCHOMEM), 1.82 (m, 1H, CH
(m, 1H, CHHCHN), 2.49 (t, 2H, J=7.2 Hz,
CH2CO2H), 2.67 (m, 1H, CHN), 3.38 (s, 3H, OCH3),
3.57 (m, 4H, OCH2CH2O and CHHPh), 3.72 (m, 2H,
OCH2CH2O), 3.93 (d, 2H, J=13.8 Hz, CHH
(m, 1H, CH
OCHHO), 4.84 (d, 1H, J=7.0 Hz, OCHH
7.40 (m, 10H, H
(CH3CH2), 20.5 (C
(CH2CO2H), 29.3 (C
H2), 29.8 (CH2), 31.9 (C
54.2 (CH2Ph), 59.0 (OC
(OCH2CH2O), 71.7 (OCH2C
94.8 (OCH2O), 127.3, 128.3, 129.3 (C
(Carom.), 179.0 (CO2H). Anal. calcd for C35H55NO5:
6
CH2), 1.02 (m, 2H, CH2
HCHOMEM), 1.65 (m,
HCHN), 2.08
6 ), 1.24 (m,
6
6
6
6
6
6
6
6
6
6
6
6
Ph), 3.98
6
OMEM), 4.77 (d, 1H, J=7.0 Hz,
6
6
O), 7.20–
6
arom.); 13C NMR (CDCl3): l 14.1
6
6
H2CH3), 22.7 (C
H2), 29.5 (CH2), 29.6 (several
H2), 32.5 (CH2), 32.9 (CH2),
H3), 59.4 (C
H2O), 76.3 (C
6 H2CHN), 25.2
6
6
6
J=6.7 Hz, CH3
2H), 2.27 (m, 2H, CH
3.58 (m, 4H, OCH2CH2O, OCH2CH
(m, 2H, CHOMEM, OCH2CHHO), 4.70 (d, 1H, J=
7.2 Hz, OCHHO), 4.74 (d, 1H, J=7.2 Hz, OCHHO),
6.31 (br s, 1H, NH
); 13C NMR (CDCl3): l 14.1
(CH3CH2), 21.4 (CH2CH3), 22.6 (CH2), 25.6 (CH2),
29.3 (CH2), 29.6 (several CH2), 29.7 (CH2), 30.0
6
CH2), 1.24 (m, 22H, CH2
2CONH), 3.38 (s, 3H, OCH3
H, CHN), 3.79
6
), 2.02 (m,
C
6
6
6
6
6
6
6
),
6
6
6
HN), 67.7
HOMEM),
6
6
6
6
6
6
6
6
6
6
Harom.), 138.5
6
6
6
6
6
C, 73.78; H, 9.73; N, 2.46. Found: C, 73.57; H, 9.78;
N, 2.30%.
6
6
6
6
6
6
6

J. M. Andre´s et al. / Tetrahedron: Asymmetry 12 (2001) 1503–1509
1509
(C
(OC
(CHOMEM), 94.7 (OC
calcd for C21H41NO4: C, 67.88; H, 11.12; N, 3.77.
Found: C, 67.96; H, 11.01; N, 3.90%.
6
H2), 30.3 (C
6
H2), 31.9 (C
H2CH2O), 71.7 (OCH2C
H2O), 178.4 (C6 ONH). Anal.
6
H2), 56.6 (C
6
HN), 59.0
colorless solid (53 mg, 0.19 mmol, 93%); mp 73–74°C
(from hexane); [h]D23=+9.3 (c 1.0, CHCl3); [Lit.5 mp
63–64°C; [h]2D3=+10.3 (c 0.4, CHCl3)]; IR (KBr): 3400,
6
H3), 67.1 (OC
6
6 H2O), 78.7
6
6
1
3200, 1670, 1370 cm−1; H NMR (CDCl3): l 0.88 (t,
3H, J=6.7 Hz, CH
1.47 (m, 2H, CH2), 1.78 (m, 1H, CH
1H, CHHCHN), 2.35 (m, 2H, CHHCONH), 3.34 (m,
1H, CHN), 3.53 (q, 1H, J=7.1 Hz, CHOH), 4.12 (bs,
1H, OH), 7.39 (br s, 1H, NH
); 13C NMR (CDCl3): l
14.1 (CH3CH2), 22.6 (CH2CH3), 23.7 (CH2), 25.5
(CH2), 29.3 (CH2), 29.6 (several CH2), 30.6 (CH2), 31.9
(CH2), 33.3 (CH2), 59.9 (CHN), 75.1 (CHOH), 179.1
(CONH). Anal. calcd for C17H33NO2: C, 72.04; H,
6
3CH2), 1.26 (m, 20H, (CH2 10
6 ) CH3),
6
6
HCHN), 2.13 (m,
4.16. (5S,6S)-5-[1-(2-Methoxyethoxymethoxy)tridecyl]-
pyrrolidin-2-one syn-9
6
6
6
6
6
The lactam syn-9 was obtained from syn-8 (1.42 g, 2.5
mmol) by debenzylation and cyclization as described
for compound anti-9. The product was purified by flash
chromatography (silica gel, EtOAc) to afford a color-
less solid (511 mg, 1.4 mmol, 55%); mp 38–40°C (from
hexane); [h]2D3=+38.1 (c 0.5, CHCl3); IR (Nujol): 3400,
6
6
6
6
6
6
6
6
6
6
6
6
11.73; N, 4.94. Found: C, 71.90; H, 11.59; N, 5.08%.
3160, 1690, 1450, 790 cm−1; H NMR (CDCl3): l 0.81
1
(t, 3H, J=6.7 Hz, CH
(CH2)11CH3), 1.63 (m, 1H, CH
CHHCHN), 2.28 (m, 2H, CHHCONH), 3.27 (m, 1H,
CHOMEM), 3.36 (s, 3H, OCH3), 3.51 (m, 2H,
OCHHCH2OCH3), 3.59 (m, 2H, OCH2CHHOCH3,
CHN), 3.74 (m, 1H, OCH2CHHOCH3), 4.67 (d, 1H,
J=7.3 Hz, OCHHO), 4.72 (d, 1H, J=7.3 Hz,
OCHHO), 6.70 (br s, 1H, NH
); 13C NMR (CDCl3): l
14.0 (CH3CH2), 22.6 (CH2CH3), 24.2 (CH2), 24.6
(CH2), 29.3 (CH2), 29.5 (CH2), 29.6 (several CH2), 30.6
(CH2), 30.8 (CH2), 31.8 (C
(OCH3), 67.7 (OCH2CH2O), 71.5 (OCH2C
(CHOMEM), 95.9 (OCH2O), 177.5 (C
6
3CH2), 1.12–1.50 (m, 22H,
Acknowledgements
6
6
HCHN), 2.05 (m, 1H,
6
6
6
The authors would like to thank the Spanish DGESYC
(Project PB98-0361) and Junta de Castilla y Leo´n (Pro-
ject VA67/99) for financial support.
6
6
6
6
6
6
6
6
6
6
6
6
6
References
6
6
6
H2), 57.6 (C
6
HN), 58.9
6
6
6
H2O), 84.1
6 ONH). Anal.
1. (a) Baussanne, I.; Schwardt, O.; Royer, J.; Pichon, M.;
Figade`re, B.; Cave´, A. Tetrahedron Lett. 1997, 38, 2259–
2262; (b) Cave´, A.; Chaboche, C.; Figade´re, B.; Har-
mange, J.-C.; Laurens, A.; Peyrat, J. F.; Pichon, M.;
Szlosek, M.; Cotte-Lafitte, J.; Que´ro, A. M. Eur. J. Med.
Chem. 1997, 32, 617–623.
2. Rieser, M. J.; Kozlowski, J. F.; Wood, K. V.; McLaugh-
lin, J. L. Tetrahedron Lett. 1991, 32, 1137–1140.
3. Pichon, M.; Hocquemiller, R.; Figade`re, B. Tetrahedron
Lett. 1999, 40, 8567–8570 and references cited therein.
4. Pichon, M.; Jullian, J.-C.; Figade`re, B.; Cave´, A. Tetra-
hedron Lett. 1998, 39, 1755–1758.
6
6
calcd for C21H41NO4: C, 67.88; H, 11.12; N, 3.77.
Found: C, 67.88; H, 10.96; N, 3.89%.
4.17. (5S,6R)-5-(1-Hydroxytridecyl)pyrrolidin-2-one,
erythro aza-muricatacin anti-101a
A cold solution (0°C) of lactam anti-9 (65 mg, 0.17
mmol) in CH2Cl2 (2 mL) was treated with a 1 M
solution of TiCl4 in CH2Cl2 (0.26 mL, 0.26 mmol) and
the resultant mixture stirred at 0°C for 4 h. After
hydrolysis with a saturated NaHCO3 solution, the mix-
ture was extracted with EtOAc (2×5 mL). The com-
bined organic layers were dried over MgSO4,
concentrated and the residue purified by flash chro-
matography (silica gel, EtOAc) to provide anti-10 as a
colorless solid (34 mg 0.12 mmol, 70%); mp 86–88°C
(from hexane/CH2Cl2); [h]2D3=+4.9 (c 0.9, CHCl3); IR
5. Rassu, G.; Pinna, L.; Spanu, P.; Zanardi, F.; Battistini,
L.; Casiraghi, G. J. Org. Chem. 1997, 62, 4513–4517.
6. Oestreich, M.; Fro¨hlich, R.; Hoppe, D. Tetrahedron Lett.
1998, 39, 1745–1748.
7. (a) Andre´s, J. M.; Barrio, R.; Mart´ınez, M. A.; Pedrosa,
R.; Pe´rez-Encabo, A. J. Org. Chem. 1996, 61, 4210–4213;
(b) Andre´s, J. M.; Pedrosa, R. Tetrahedron 1998, 54,
5607–5616; (c) Andre´s, J. M.; Pedrosa, R. Tetrahedron:
Asymmetry 1998, 9, 2493–2498; (d) Andre´s, J. M.; de
Elena, N.; Pedrosa, R. Tetrahedron 2000, 56, 1523–1531.
8. Reetz, M. T. Chem. Rev. 1999, 99, 1121–1162.
9. Reetz, M. T.; Drewes, M. W.; Lennick, K.; Schmitz, A.;
Holdgru¨n, X. Tetrahedron: Asymmetry 1990, 1, 375–378.
10. (a) Dufour, M. N.; Jouin, P.; Poncet, J.; Pantaloni, A.;
Castro, B. J. Chem. Soc., Perkin Trans. 1 1986, 1895–
1899; (b) Yamazaki, T.; Iwatsubo, H.; Kitazume, T.
Tetrahedron: Asymmetry 1994, 5, 1823–1830.
1
(KBr): 3600–3100, 1680, 1460 cm−1; H NMR (CDCl3):
l 0.88 (t, 3H, J=6.6 Hz, CH
(CH2)10CH3), 1.50 (m, 2H, CH2
CHHCHN), 2.33 (m, 2H, CH2CONH), 3.54 (br s, 1H,
OH), 3.66 (m, 2H, CHN, CHOH), 7.19 (br s, 1H, NH);
13C NMR (CDCl3): l 14.1 (C
H3CH2), 19.8 (CH2CH3),
22.7 (CH2), 26.1 (CH2), 29.3 (CH2), 29.6 (several CH2),
30.6 (CH2), 31.9 (CH2), 32.5 (CH2), 59.3 (CHN), 72.3
(CHOH), 180.0 (CONH). Anal. calcd for C17H33NO2:
6
3CH2), 1.26 (m, 20H,
6
6
), 2.06 (m, 2H,
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
C, 72.04; H, 11.73; N, 4.94. Found: C, 69.68; H, 10.66;
N, 6.61%.
11. Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron
1981, 37, 2091–2096.
4.18. (5S,6S)-5-(1-Hydroxytridecyl)pyrrolidin-2-one,
threo aza-muricatacin syn-10
12. Tanner, D.; Somfai, P. Tetrahedron 1988, 44, 619–624.
13. Corey, E. J.; Gras, J.-L.; Ulrich, P. Tetrahedron Lett.
1976, 11, 809–812.
This compound was obtained from syn-9 (74 mg, 0.2
14. Boeckman, R. K; Potenza, J. C. Tetrahedron Lett. 1985,
26, 1411–1414.
mmol) by the procedure described for anti-10 as a
.