Asymmetric synthesis of 1-aminopentadecane-3,5,7,9,11,13,15-heptols and of 1,15-diaminopentadecane-3,5,7,9,11,13-hexols and derivatives

Article abstract of DOI:10.1055/s-2002-34381

Starting from 2,2′-methylenedifuran, enantiomerically enriched (98%) (3R,5S,7R,9S,11R,13R)- and (3R,5S,7S,9R, 11R,13R)-15-amino-5,7,9,11-tetrahydroxy-3,13-bis-(4-methoxybenzoyloxy) pentadec-1-yl) pivalate were prepared as well as (3R,5R,7R,9R,11S,13S)-1,1

Full text of DOI:10.1055/s-2002-34381

PAPER
1979
Asymmetric Synthesis of 1-Aminopentadecane-3,5,7,9,11,13,15-heptols and of
1,15-Diaminopentadecane-3,5,7,9,11,13-hexols and Derivatives
Asymmetric
S
a
ynthesis of
n
A
minopenta
d
decanealcoh
r
ols and D
i
erivati
n
ves e Gerber-Lemaire,* Florence Popowycz, Cécile Glanzmann, Pierre Vogel
Institut de chimie moléculaire et biologique, Ecole Polytechnique Fédérale, Lausanne, Switzerland
Fax + 41(21)6939375; E-mail: pierre.vogel@epfl.ch
Received 7 June 2002
placement with NaN3 in DMF providing diazide (+)-6
Abstract: Starting from 2,2 -methylenedifuran, enantiomeri-
cally enriched (98%) (3R,5S,7R,9S,11R,13R)- and
(3R,5S,7S,9R,11R,13R)-15-amino-5,7,9,11-tetrahydroxy-3,13-bis-
(60%). Hydrogenation (H2, Pd/C, MeOH) followed by
acidic hydrolysis (CF3COOH/H2O) gave the semi-pro-
tected diamine (+)-7 (60%). The completely deprotected
(4-methoxybenzoyloxy)pentadec-1-yl) pivalate were prepared as
well as (3R,5R,7R,9R,11S,13S)-1,15-diamino-5,7,9,11-tetra- 1,15-diaminopenta-3,5,7,9,11,13-hexol (+)-8 was ob-
hydroxypentadeca-3,13-diyl
(3R,5S,7S,9S,11R,13S)-1,15-diaminopentadecane-3,5,7,9,11,13-
hexol.
bis(4-methoxybenzoate)
and
tained in 88% yield by reduction of diester (+)-7 with
(iBu)2AlH in THF (Scheme 1).
To illustrate the flexibility of our method, we describe
the preparation of two semi-protected stereomeric 1-ami-
no-pentadecane-3,5,7,9,11,13,15-heptols. Cycloheptene
(–)-2 was esterified selectively on its primary alcoholic
moiety with pivaloyl chloride (pyridine/CH2Cl2) giving
pivalate (–)-9. Oxidative cleavage of the alkene moiety of
(–)-9 as above provided pyranose (+)-10 in 83% yield
(Scheme 2). Reduction under Evans’ conditions provided
the corresponding anti-4 ,6 -diol that was not isolated
but directly protected as an acetonide under standard con-
ditions.8 This afforded (–)-11 in 40% yield. Esterification
of primary alcohol (–)-11 with CH3SO2Cl/Et3N followed
by treatment with NaN3 in DMF gave azide (–)-12 in 63%
yield. Reduction by catalytic hydrogenation and subse-
quent acidic hydrolysis furnished monoamine (–)-13 in
70% yield. Migration of the p-methoxybenzoyl group was
not observed, as was confirmed by the spectral data for
(–)-13.
Starting from (–)-14 derived from 1,6 the 7,9-diepimer of
(–)-13, (–)-20 has been prepared in a similar way
(Scheme 3). Oxidative cleavage of the cycloheptene dou-
ble bond of (–)-14 was achieved by dihydroxylation
(NMO, OsO4 cat.), then subsequent treatment with
Pb(OAc)4 in MeOH, to provide pyranose (–)-15 in 83%
yield. Its reduction under Nasaraka’s conditions7 gave the
expected syn-3,5-diol (–)-16 (67%) which was protected
as acetonide (–)-17 under standard conditions (82%). Es-
terification of the primary alcohol (–)-17 with CH3SO2Cl/
Et3N, followed by displacement of the intermediate mesy-
late with NaN3 gave azide (+)-18 (60%).
Key words: aminopolyketide, asymmetric synthesis, diamino-
polyketide, long-chain aminopolyols, 2,2 -methylenedifuran
Long-chain polyketides with amino groups are rare natu-
ral compounds that show interesting biological properties.
For instance Linearmycin A and B have been described as
having antifungal and anti-bacterial activities.1 Zwitter-
mycin A produced by Bacillus cereus UW85 is a 4,8-di-
amino-2,3,5,7,9-pentahydroxy
carboxamide
which
suppresses certain plant diseases and which is highly ac-
tive against Oomycetes and algal protists. It has also a
moderate activity against Gram-negative and Gram-posi-
tive bacteria and pathogenic fungi.2 Biogenic polyamines
are essentially derived from 1,3-diaminopropane and 1,4-
diaminobutane. These systems and diamines derived from
poly(ethylene)glycols are used as tethers for the linkage of
biomolecules.3 Recently, our group has developed a new,
non-iterative synthetic approach to long-chain
polyketides.4 Our method allows the preparation of all
possible pentadecan-1,3,5,7,9,11,13,15-octols and deriva-
tives.5,6 We decided to exploit the method to generate a
new class of long-chain aminopolyols to be tested, both
for their biological properties, and as ligation tools. We
disclose here our first efforts toward these goals.
Starting from 2,2 -methylenedifuran 1 we prepared enan-
tiomerically enriched (ee: 98.4%) cycloheptene deriva-
tives (–)-2.6 Dihydroxylation of (–)-2 [4-methyl-
morpholine-4-oxide (NMO), OsO4 cat.] followed by Mal-
aprade cleavage (NaIO4) afforded pyranose (–)-3 in 60%
yield. Reduction of (–)-3 under Nasaraka’s conditions7
provided the expected syn-5,7-diol (+)-4 (75%). Protec-
tion of the 3,5-diol as an acetonide [Me2C(OMe)2,
pyrH+TsO–] gave (+)-5 (72%) that was esterified by MsCl
(NEt3, CH2Cl2) giving the corresponding bismesylate that
was not isolated but directly submitted to the double dis-
Quantitative hydrogenation of the azide [H2, Pd(OH)2/C,
MeOH] provided the corresponding primary amine
(–)-19. Acidic hydrolysis (HCl–THF–H2O) resulted in
the cleavage of the acetonides to afford the semi-protected
amino-polyol (–)-20.
The method presented here should be applicable to the
preparation of all stereomeric 15-amino-pentadecan-
1,3,5,7,9,11,13-heptols and 1,15-diamino-pentadecane-
3,5,7,9,11,13-hexols in both their enantiomerically pure
forms. The possibility to readily and selectively obtain
Synthesis 2002, No. 14, Print: 07 10 2002.
Art Id.1437-210X,E;2002,0,14,1979,1986,ftx,en;C02602SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1980
S. Gerber-Lemaire et al.
PAPER
1. NMO, OsO4 cat.
acetone/H2O
ref. 6
OR
O
O
OH OR
O
O
2. NaIO4 2 equiv,
dioxane/H2O
1
OH
R = 4-MeOC6H4CO
(-)-2
(60 %)
1
O
5
3
1
Et2BOMe 3 equiv,
OR
OH
OH OR
O
O
O
NaBH4 4 equiv
HO
OR
O
O
OR′ OR′′ OR OH
THF/MeOH 0 °C
Me2C(OMe)2
acetone
(75%)
(+)-4 R′ = H
(-)-3
pyrH+TsO–
(+)-5 R′, R′′ = CMe2
(72%)
1. MsCl 2 equiv, NEt3
4 equiv, CH2Cl2, 0 °C
1. H2, Pd/C, MeOH
N3
OR
O
1
O
O
O
OR N3
2. CF3COOH/H2O
(60%)
2. NaN3, DMF, 60 °C
(60%)
(+)-6
13
11
9
7
5
3
NH2 OR OH OH OH OH OR NH2
(i-Bu)2AlH
THF
(+)-7 R = 4-MeOC6H4CO
(+)-8 R = H
(88%)
Scheme 1
semi-protected derivatives should allow the synthesis of
more complicated systems with secondary alcoholic moi-
eties substituted by other functions including amines.
CaH2. Light petroleum ether used refers to the boiling fraction 40–
60 °C. After reactions and extractions solutions were evaporated in
a rotatory evaporator under reduced pressure. Liquid/solid flash
chromatography (FC): columns of silica gel (0.040–0.63 mm,
Merck No.9385 silica gel 60, 240–400 mesh). TLC for reaction
monitoring: Merck silica gel 60F254 plates; detection by UV light;
Pancaldi reagent [(NH4)6MoO4, Ce(SO4)2, H2SO4, H2O] or KMnO4.
Commercial reagents (Fluka, Aldrich) were used without purifica-
tion. Solvents were distilled prior to use: THF from Na and ben-
zophenone; MeOH from Mg and I2; DMF from P2O5; CH2Cl2 from
1. NMO, OsO4 cat.,
acetone/H2O
OR
PivCl 1.5 equiv,
(–)-2
OPiv OR
O
O
Pyr/CH2Cl2, 0 °C
(75%)
2.NaIO4 2 equiv,
dioxane/H2O
OH
(–)-9
R = 4-MeOC6H4CO
(83 %)
1
OH
O
6''
4''
O
1. (Me4N)BH(OAc)3
2. Me2C(OMe)2
7
OR
5
PivO
OR
O
O
O
OR
X
OPiv OR
O
O
O
acetone pyrH+TsO–
(–)-11 X = OH
(–)-12 X = N3 (63%)
(+)-10
(40%)
1. MsCl
2. NaN3
1''
1'
11
9
7
5
3
1
2''
1. H2, Pd/C, MeOH
2'
PivO
OR OH OH OH OH OR NH2
2. CF3COOH/H2O
(60%)
(–)-13
Scheme 2
Synthesis 2002, No. 14, 1979–1986 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Aminopentadecanealcohols and Derivatives
1981
1. NMO, OsO4 cat.,
acetone/H2O
O
OR
OR
OH
OPiv OR
O
O
OPiv OR
O
O
O
2. Pb(OAc)4, MeOH
(83%)
OH
(–)-14
(–)-15
R = 4-MeOC6H4CO
1. MsCl 2equiv, NEt3
4 equiv, CH2Cl2 , 0 °C
5
3
1
Et2BOMe 3 equiv
PivO
OR
O
O
OR′ OR′ OR OH
2. NaN3, DMF, 50 °C
(60%)
NaBH4 4 equiv
THF/MeOH, 0 °C
Me2C(OMe)2
acetone
(67%)
(–)-16 R′ = H
pyrH+TsO–
(–)-17 R′, R′′ = CMe2
(82%)
1'''
6''
2
1'
6''''
4''''
O
4''
O
1
3
H2, Pd(OH)2/C, MeOH
PivO
OR
O
O
OR N3
(100%)
(+)-18
PivO
OR
O
9
O
O
O
3
OR NH2
HCl/THF/H2O
(–)-19
1''
1'
5
11
7
1
2''
2'
PivO
OR
OH OH OH OH OR NH2
(–)-20
Scheme 3
IR spectra: Perkin–Elmer-1420 spectrometer. 1H NMR spectra:
Bruker-ARX-400 spectrometer (400 MHz); (H) in ppm relative to
the solvent’s residual H signal [CHCl3, (H) 7.27; CH3OD, (H)
3 equiv) was added and the solution was stirred at r.t. for 1 h. The
mixture was cooled to 0 °C and anhyd MeOH (4 mL) and NaBH4
(281 mg, 7.44 mmol, 4 equiv) were added. After stirring at 0 °C for
1 h, the mixture was poured into a sat. aq solution of NaHCO3 (60
mL) and extracted with EtOAc (3 60 mL). The combined organic
extracts were dried (MgSO4) and concentrated under reduced pres-
sure. The residue was taken up in MeOH (10 mL) and concentrated
under reduced pressure. The operation was repeated twice. Purifica-
tion by FC (CH2Cl2–MeOH, 9:1; Rf 0.46) afforded a colorless oil
(75%).
1
3.31] as internal reference; all 1H assigments were confirmed by 2
D-COSY-45 and 2 D-NOESY spectra. 13C NMR spectra: same in-
strument as above (100.6 MHz); (C) in ppm relative to solvent's C-
signal [CDCl3, (C) 77.0; CD3OD, (H) 49.2] as internal reference;
coupling constants J in Hz. MS: Nermag R-10-10C, chemical ion-
ization (NH3) mode m/z (amu) [% relative base peak (100%)]. Ele-
mental analyses: Ilse Beetz, 96301 Kronach, Germany.
[ ]58920 +11, [ ]57720 +21, [ ]54620 +36, [ ]43520 +50, [ ]40520 +59
(c 0.7, CH2Cl2).
(1R,3R,5R)-6-{(4R,6S)-6-{(2S)-4-Hydroxy-2-[(4-methoxybenz-
oyl)oxy]butyl}-2,2-dimethyl-1,3-dioxan-4-yl}-3,5-dihydroxy-1-
(2-hydroxyethyl)hexyl 4-methoxybenzoate [(+)-4]
IR (film): 3420, 2945, 1700, 1610, 1580, 1510, 1455, 1420, 1385,
1315, 1260, 1225, 1165, 1100, 1050, 1030, 900, 845, 770 cm–1.
1H NMR (400 MHz, CDCl3): = 7.98 and 6.90 (2 m, 8 Harom),
5.44 (m, 2 H, H-1, H-2 ), 4.06 (m, 2 H, H-3, H-5), 3.92 (m, 2 H, H-
4 , H-6 ), 3.88 and 3.86 (2 s, 6 H, 2 CH3), 3.75–3.58 (m, 4 H, 2
H-4 , 2 H-2 ), 2.09–1.55 (m, 14 H, 2 H-2, 2 H-4, 2 H-6,
To a solution of (–)-2 (1.9 g, 3.10 mmol) in acetone–H2O (8:1, 45
mL), NMO (630 mg, 4.65 mmol, 1.5 equiv) and OsO4 (0.1 M in
CCl4, 3.1 mL, 0.310 mmol, 0.1 equiv) were added. The mixture was
stirred at r.t. for 11 h. The solution was then diluted with EtOAc
(100 mL), and Na2S2O5 (3.75 g) was added. After stirring for 30 min
at r.t., the mixture was poured into H2O (100 mL) and extracted with
EtOAc (3 100 mL). The combined organic layers were dried
(MgSO4)and concentrated under reduced pressure to afford a color-
less oil. The crude diol (2.0 g, 3.10 mmol) was dissolved in diox-
ane–H2O (4:1, 50 mL) with NaIO4 (1.35 g, 6.20 mmol) and stirred
at r.t. for 12 h. The mixture was poured into H2O (80 mL) and ex-
tracted with EtOAc (3 80 mL). The combined organic extracts
were dried (MgSO4)and concentrated under reduced pressure to af-
ford a white foam (1.2 g, 60%), which was directly taken up in
anhyd THF (40 mL). Et2BOMe (1 M in THF, 5.6 mL, 5.58 mmol,
2
2
H-5 , 2 H-1 , 2 H-3 , 2 H-1 ), 1.31 and 1.12 (2 s, 6 H,
Me-C2 ).
13C NMR (100.6 MHz, CDCl3): = 166.2, 167.1 (2 s, 2 Carom),
162.2, 162.0 (2 s, 2 C=O), 132.0, 131.9 [2 d, 1J(C,H) = 162, 161,
4
Carom], 122.3, 122.0 (2 s, 2
Carom), 113.6, 113.5 [2 d,
1J(C,H) = 162, 161, 4 Carom], 100.8 (s, C2 ), 69.5, 68.4 [2 d,
1J(C,H) = 146, 148, C1, C2 ], 67.9, 67.3 [2 d, 1J(C,H) = 142, 144,
C3, C5], 64.9, 64.2 [2 d, 1J(C,H) = 143, C4 , C6 ], 58.8 [t,
1J(C,H) = 142, C4 , C2 ], 55.5, 55.4 [2 q, 1J(C,H) = 145, 2 CH3],
44.1, 43.6, 43.0, 42.1, 40.8, 38.8, 38.0 [7 t, 1J(C,H) = 125, C2, C4,
Synthesis 2002, No. 14, 1979–1986 ISSN 0039-7881 © Thieme Stuttgart · New York

1982
S. Gerber-Lemaire et al.
PAPER
C6, C5 , C1 , C3 , C1 ], 24.7, 24.1 [2 q, 1J(C,H) = 126, 125, 2
Me-C2 ].
IR (film): 2985, 2940, 2100, 1710, 1605, 1580, 1510, 1460, 1380,
1315, 1255, 1225, 1170, 1100, 1030, 940, 850, 770, 665 cm–1.
3
MS (CI; NH3): m/z (%) = 666 (40) [M + 18+], 649 (20), [M + H+],
1H NMR (400 MHz, CDCl3): = 7.99 and 6.94 (2 d, J = 8.9, 8
591 (56), 152 (22), 135 (100).
Harom), 5.38 (m, 2 H, H-1, H-2 ), 4.06–3.92 (m, 4 H, H-4 , H-6 ,
H-4 , H-6 ), 3.89 and 3.88 (2 s, 6 H, 2 CH3), 3.39 (t, 4 H,
UV (MeCN): max ( ) = 255 (8100), 197 nm (11100).
3J = 7.5, 2 H-3, 2 H-4 ), 2.07–2.03 (m, 4 H, 2 H-2, 2 H-
Anal. Calcd for C34H48O12 (648.74): C, 62.95; H, 7.46. Found: C,
62.99; H, 7.39.
3
2
), 2.02–1.71 (m, 4 H, 2 H-1 , 2 H-1 ), 1.63–1.38 (m, 6 H,
H-5 , 2 H-1 , 2 H-5 ), 1.36, 1.29, 1.28, 1.18 (4s, 12 H, 2
Me-C2 , 2 Me-C2 ).
(1R)-3-Hydroxy-1-{[(4R,6R)-6-({(4R,6S)-6-(2S)-4-hydroxy-2-
[(4-methoxybenzoyl)oxy]butyl-2,2-dimethyl-1,3-dioxan-4-
yl}methyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}propyl 4-
methoxybenzoate [(+)-5]
A solution of (+)-4 (0.5 g, 0.771 mmol) and pyridinium toluene-4-
sulfonate (50 mg) in acetone–2,2-dimethoxypropane (9:1, 40 mL)
was stirred at 0 °C for 5 h. The mixture was neutralized by
NaHCO3, filtered and concentrated under reduced pressure. Purifi-
cation by FC (CH2Cl2–MeOH, 96:4, Rf 0.31) afforded a pale yellow
oil (382 mg, 72%).
13C NMR (100.6 MHz, CDCl3): = 165.6, 165.5 (2 s, 2 Carom),
163.4 (s, 2 C=O), 131.5 [2 d, 1J(C,H) = 163, 4 Carom], 122.5 (s,
2
Carom), 113.6 [d, 1J(C,H) = 165, 4 Carom], 100.6, 98.6 (2 s, C2 ,
C2 ), 68.9, 68.7 [2 d, 1J(C,H) = 148, 146, C1, C2 ], 65.6, 64.9,
1
63.1, 62.1 [4 d, J(C,H) = 142, 143, 142, 144, C4 , C6 , C4
,
C6 ], 55.4 [q, 1J(C,H) = 145, 2 CH3], 47.8 [t, 1J(C,H) = 142, C3,
1
C4 ], 42.0, 41.3, 40.7, 38.9, 37.5 [5 t, J(C,H) = 127, C1 , C5 ,
C1 , C5 , C1 ], 30.1 [t, 1J(C,H) = 125, C2, C3 ], 29.4, 24.3,
24.1, 19.5 [4 q, 1J(C,H) = 126, 2 Me-C2 , 2 Me-C2 ].
MS (CI; NH3): m/z (%) = 739 (2), [M + H+], 723 (11), [M – Me+],
681 (39), 559 (10), 304 (6), 135 (100).
[ ]58920 +8.0, [ ]57720 +9.5, [ ]54620 +16, [ ]43520 +20, [ ]40520 +34
(c 1.1, CH2Cl2).
UV (MeCN): max ( ) = 263 (18480), 253 (15540), 210 nm
(15540).
IR (film): 3480, 2940, 1715, 1605, 1510, 1380, 1260, 1165, 1030,
970, 860 cm–1.
Anal. Calcd for C37H50O10N6 (738.84): C, 60.15; H, 6.82; N, 11.37.
Found: C, 59.92; H, 6.80; N, 11.14.
1H NMR (400 MHz, CDCl3): = 7.97 and 6.91 (2 m, 8 Harom),
5.47 (m, 2 H, H-1, H-2 ), 4.01–3.90 (m, 4 H, H-4 , H-6 , H-4
H-6 ), 3.87 and 3.86 (2 s, 6 H, 2 CH3), 3.75–3.58 (m, 4 H, 2
H-3, 2 H-4 ), 1.97–1.70 (m, 8 H, 2 H-2, 2 H-1 , 2 H-1
,
(1R,3R,5R,7R,9S,11S)-1,11-bis(2-Aminoethyl)-3,5,7,9-tetrahy-
droxyundecane-1,11-diyl Bis(4-methoxybenzoate) [(+)-7]
A solution of (+)-6 (80 mg, 0.108 mmol) and 10% Pd/C (20 mg) in
anhyd MeOH (10 mL) was stirred at r.t. under 1 atm of hydrogen
for 90 min. The mixture was filtered through a pad of Celite and
concentrated under reduced pressure to afford a pale yellow oil. The
crude diamine was treated in CF3COOH–H2O (4:1, 3.75 mL) for 45
min at r.t. The solution produced was concentrated under reduced
pressure and the residue purified by FC (MeCN–25% aq NH3, 4:1,
Rf 0.44) to produce a white foam (39 mg, 60%).
,
2
H-3 ), 1.60–1.37 (m, 6 H, 2 H-5 , 2 H-1 , 2 H-5 ),
1.31, 1.23, 1.14 and 1.12 (4s, 12 H, 2 Me-C2 , 2 Me-C2 ).
13C NMR (100.6 MHz, CDCl3): = 166.9, 165.6 (2 s, 2 Carom),
163.2, 163.0 (2 s, 2 C=O), 132.0, 131.7 [2 d, 1J(C,H) = 162, 160,
4
Carom], 122.7, 122.2 (2 s, 2
Carom), 113.7, 113.5 [2 d,
1J(C,H) = 162, 161, 4 Carom], 100.8, 100.5 (2 s, C2 , C2 ), 68.5,
68.2 [2 d, 1J(C,H) = 147, 146, C1, C2 ], 65.6, 65.3, 64.4, 64.0 [4d,
1J(C,H) = 142, 144, 140, 141, C4 , C6 , C4 , C6 ], 58.8, 58.3 [2
t, 1J(C,H) = 142, C3, C4 ], 55.3, 55.4 [2 q, 1J(C,H) = 145, 2 CH3],
44.0, 43.4, 43.0, 40.1, 40.0, 38.7, 38.0 [7 t, 1J(C,H) = 125, C2, C1 ,
C5 , C1 , C5 , C1 , C3 ], 30.1, 19.5 [2 q, 1J(C,H) = 125, 2
Me-C2 ], 24.7, 24.1 [2 q, 1J(C,H) = 126, 125, 2 Me-C2 ].
[ ]58920 +2.4, [ ]57720 +7.4, [ ]54620 +24, [ ]43520 +51, [ ]40520 +80
(c 0.12, H2O).
IR (film): 3500-2900, 1670, 1450, 1260, 1195, 1130, 1030, 845,
805, 775, 725 cm–1.
MS (CI; NH3): m/z (%) = 702 (20), [M + 18+], 689 (45), [M + H+],
495 (7), 387 (8), 135 (100).
3
1H NMR (400 MHz, CDCl3): = 8.03 and 7.03 (2 d, J = 9.0, 8
H
arom), 5.41 (m, 2 H, H-1, H-11), 4.08–4.03 (m, 4 H, H-3, H-5, H-7,
UV (MeCN): max ( ) = 251 (60000), 206 nm (45000).
H-9), 3.90 (s, 6 H, 2 CH3), 3.06 (t, 4 H, 3J = 7.3, 2 H-2 , 2 H-
2 ), 2.13–1.96, 1.78–1.56 (2m, 14 H, 2 H-2, 2 H-4, 2 H-6, 2
H-8, 2 H-10, 2 H-1 , 2 H-1 ).
(1R)-3-Azido-1-{[(4R,6R)-6-({(4R,6S)-6-(2S)-4-azido-2-[(4-
methoxybenzoyl)oxy]butyl}-2,2-dimethyl-1,3-dioxan-4-yl}me-
thyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}propyl 4-methoxy-
benzoate [(+)-6]
13C NMR (100.6 MHz, CDCl3): = 170.5 (s, 2 Carom), 168.0 (s,
2
C=O), 135.3, 119.3, 117.4 (3 d, 8
Carom), 122.2 (s, 2 Carom),
Et3N (152 L, 1.09 mmol, 5 equiv) and methanesulfonyl chloride
(MsCl; 42 L, 0.654 mmol, 3 equiv) were added to a cooled solution
(0 °C) of (+)-5 (150 mg, 0.218 mmol) in anhyd CH2Cl2 (4.5 mL).
After stirring for 15 min at 0 °C, the mixture was poured into H2O
(30 mL) and extracted with EtOAc (3 30 mL). The combined or-
ganic extracts were dried (MgSO4) and concentrated under reduced
pressure to afford a pale yellow oil. To a solution of the crude bis-
mesylate (185 mg, 0.218 mmol) in DMF (5 mL), sodium azide (85
mg, 1.308 mmol, 6 equiv) was added and the mixture stirred at
60 °C for 2 h. The solution was poured into a sat. aq solution of
NaHCO3 (20 mL) and extracted with EtOAc (3 20 mL). The com-
bined organic extracts were dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by FC (CH2Cl2–MeOH,
98:2, Rf 0.4) to afford a colorless oil (97 mg, 60%).
72.9, 72.8 (2 d, C1, C11), 70.3, 70.0, 68.3, 68.1 (4 d, C3, C5, C7,
C9), 58.6 (q, 2 CH3), 49.2, 48.9, 48.8, 46.1, 45.5 (5 t, C2, C4, C6,
C8, C10), 40.0 (t, C2 , C2 ), 36.6 (t, C1 , C1 ).
MS (CI; NH3): m/z (%) = 607 (6), [M + H+], 536 (1), 451 (1), 208
(23), 152 (100), 135 (48).
UV (MeCN): max ( ) = 256 (4400), 200 nm (1500).
Anal. Calcd for C31H46O10N2 (606.71): C, 61.37; H, 7.64; N, 4.62.
Found: C, 61.22; H, 7.40; N, 4.90.
(3R,5R,7R,9R,11S,13S)-1,15-Diaminopentadecane-
3,5,7,9,11,13-hexol [(+)-8]
DIBAL-H (1 M in CH2Cl2, 230 L, 0.230 mmol, 4 equiv) was add-
ed dropwise to a cooled solution (–78 °C) of (+)-7 (35 mg, 0.058
mmol) in anhyd CH2Cl2 (2 mL). After stirring for 1 h at -78 °C, the
mixture was concentrated under reduced pressure. Purification by
FC (MeCN–25% aq NH3, 1:1) afforded a white foam (17 mg, 88%).
20
[ ]58920 +1.4, [ ]57720 +5.1, [ ]546 +19, [ ]43520 +57, [ ]40520 +63
(c 0.65, CH2Cl2).
Synthesis 2002, No. 14, 1979–1986 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Aminopentadecanealcohols and Derivatives
1983
[ ]58920 +6, [ ]57720 +5, [ ]54620 +25, [ ]43520 +33, [ ]40520 +40
Anal. Calcd for C39H52O11 (696.83): C, 67.22; H, 7.52. Found: C,
(c 0.10, H2O).
67.23; H, 7.49.
IR (film): 3500–3050, 2940, 1415, 1135, 1080, 940, 895, 820, 800
cm–1.
1H NMR (400 MHz, D2O): = 4.12–3.98 (m, 6 H, H-3, H-5, H-7,
H-9, H-11, H-13), 3.06 (t, 4 H, 3J = 6.6, 2 H-1, 2 H-15), 1.77–
1.70 (m, 4 H, 2 H-2, 2 H-14), 1.69–1.55 (m, 10 H, 2 H-4, 2
H-6, 2 H-8, 2 H-10, 2 H-12).
(1R)-3-Hydroxy-1-{[(4R,6S)-6-{[(4R,6S)-6-[(2S)-4-(2,2-dimeth-
yl-1-oxopropoxy)-2-[(4-methoxybenzoyl)oxy]butyl]-2,2-dime-
thyl-1,3-dioxan-4-yl]methyl}-2,2- dimethyl-1,3-dioxan-4-
yl]methyl}propyl 4-methoxybenzoate [(–)-11]
NMO (157 mg, 1.162 mmol, 1.5 equiv) and OsO4 (0.1 M in CCl4,
470 L, 0.047 mmol, 0.06 equiv) were added to a solution of (–)-9
(540 mg, 0.775 mmol) in acetone–H2O (5:1, 12 mL). The mixture
was stirred at r.t. for 11 h, then diluted with EtOAc (40 mL), and
Na2S2O5 (990 mg) added. After stirring for 30 min at r.t., the mix-
ture was poured into H2O (40 mL) and extracted with EtOAc
(3 40 mL). The combined organic layers were dried (MgSO4)and
concentrated under reduced pressure to afford a colorless oil. The
crude diol was dissolved in dioxane–H2O (4:1, 25 mL) with NaIO4
(331 mg, 1.550 mmol) and stirred at r.t. for 12 h. The mixture pro-
duced was poured into H2O (40 mL) and extracted with EtOAc
(3 40 mL). The combined organic extracts were dried (MgSO4)
and concentrated under reduced pressure to afford a white foam
(468 mg, 83%), which was directly taken up in acetic acid (20 mL).
(Me4N) BH(OAc)3 (2.53 g, 9.63 mmol, 15 equiv) was added and the
solution was stirred at r.t. for 2 h. The solvent was evaporated under
reduced pressure and the residue poured into cold water (35 mL).
After neutralization with NaHCO3, the mixture was extracted with
EtOAc (3 35 mL) and the combined organic extracts dried
(MgSO4) and concentrated under reduced pressure. The residual oil
(300 mg, 0.409 mmol) was stirred at 0 °C, for 2 h, in a mixture of
acetone (16 mL) and 2,2-dimethoxypropane (4 mL) in the presence
of pyridinium toluene-4-sulfonate (20 mg). The solution was then
neutralized with NaHCO3, filtered and concentrated under reduced
pressure. Purification by FC (CH2Cl2–MeOH, 98:2) afforded a col-
orless oil (127 mg, 40%).
13C NMR (100.6 MHz, D2O): = 68.4, 68.3, 67.3, 67.1, 66.6 (5 d,
1J(C,H) = 144, 142, 143, 145, 141, C3, C5, C7, C9, C11, C13), 47.3,
1
47.1, 45.9, 44.5, 44.2 (5 t, J(C,H) = 125, 127, 124, 123, 126, C4,
C6, C8, C10, C12), 41.0 [t, 1J(C,H) = 126, C1, C15], 37.2, 37.1 [2
t, 1J(C,H) = 127, C2, C14].
UV (MeCN): max ( ) = 202 nm (5100).
Anal. Calcd for C15H34O6N2 (338.44): C, 53.23; H, 10.13; N, 8.28.
Found: C, 52.98; H, 10.01; N, 8.11.
(1R,6R)-6-Hydroxy-4-{(4R,6S)-6-[(2S)-4-(2,2-dimethyl-1-oxo-
propoxy)-2-[(4-methoxybenzoyl)oxy]butyl-2,2-dimethyl-1,3-di-
oxan-4-yl]methyl}cyclohept-3-en-1-yl 4-methoxybenzoate
[(–)-9]
A cooled solution (0 °C) of (–)-2 (640 mg, 1.045 mmol) in anhyd
CH2Cl2 (12 mL), was treated with pyridine (2 mL) and pivaloyl
chloride (206 mL, 1.671 mmol, 1.6 equiv). After stirring for 12 h at
0 °C, the mixture was poured into a sat. aq solution of NaHCO3 (50
mL) and extracted with EtOAc (3 50 mL). The combined organic
extracts were washed with 1 M aqueous HCl (30 mL), brine (30
mL) and concentrated under reduced pressure. The residual oil was
purified by FC (CH2Cl2–MeOH, 98:2, Rf 0.3) to afford a colorless
oil (551 mg, 75%).
[ ]58920 –34, [ ]57720 –35, [ ]54620 –41, [ ]43520 –74, [ ]40520 –93
(c 0.86, CH2Cl2).
[ ]58920 –10, [ ]57720 –11, [ ]54620 –14, [ ]43520 –25, [ ]40520 –31
(c 1.0, CH2Cl2).
IR (film): 2940, 1710, 1605, 1510, 1460, 1365, 1260, 1170, 1100,
1030, 850, 770, 735, 700 cm–1.
IR (film): 3475, 2940, 1710, 1605, 1510, 1380, 1260, 1225, 1170,
1100, 1030, 850, 770 cm–1.
H NMR (400 MHz, CDCl3): = 7.96 and 6.90 (2 m, 8 Harom), 5.63
3
1H NMR (400 MHz, CDCl3): = 7.98 and 6.91 (2 m, 8 Harom),
(dd, 1 H, J = 6.7, H-3), 5.40 (m, 1 H, H-2 ), 5.16 (dddd, 1 H,
3J = 8.0, 3J = 7.9, 3J = 4.0, 3J = 4.0, H-1), 4.15 (ddd, 1 H, 2J = 17.5,
3J = 11.2, 3J = 6.3, H-4 ), 4.13 (ddd, 1 H, 2J = 17.5, 3J = 11.2,
3J = 6.9, H-4 ), 4.06 (m, 1 H, H-6), 3.99 (m, 1 H, H-4 ), 3.91 (m,
1 H, H-6 ), 3.85 and 3.83 (2 s, 6 H, 2 CH3), 2.48 (m, 4 H, 2 H-
2, 2 H-5), 2.26–2.08 (m, 4 H, 2 H-7, 2 H-1 ), 2.04 (m, 2 H, 2
5.47 (m, 1 H, H-1), 5.38 (m, 1 H, H-2 ), 4.14 (ddd, 1 H, 2J = 17.5,
3
2
3
3J = 11.2, J = 6.5, H-4 ), 4.12 (ddd, 1 H, J = 17.5, J = 11.3,
3J = 6.9, H-4 ), 3.91 (m, 4 H, H-4 , H-6 , H-4 , H-6 ), 3.87
and 3.86 (2 s, 6 H, 2 CH3), 3.65 and 3.60 (2m, 2 H, 2 H-3), 2.10–
1.70 (m, 9 H, 2 H-2, 2 H-1 , H-1 , 2 H-1 , 2 H-3 ), 1.60
(m, 4 H, 2 H-5 , 2 H-5 ), 1.44 (m, 1 H, H-1 ), 1.27, 1.18 and
1.11 (3 s, 12 H, 2 Me-C2 , 2 Me-C2 ), 1.17 (s, 9 H, tBu).
2
3
H-3 ), 1.87 (ddd, 1 H, J = 14.2, 3J = 9.0, J = 3.2, H-1 ), 1.78
(ddd, 1 H, 2J = 14.2, 3J = 9.5, 3J = 3.9, H-1 ), 1.62 (m, 2 H, 2 H-
5 ), 1.31 and 1.21 (2 s, 6 H, 2 Me-C2 ), 1.18 (s, 9 H, tBu).
13C NMR (100.6 MHz, CDCl3): = 178.4 (s, tBuCOO), 166.9,
13C NMR (100.6 MHz, CDCl3): = 178.3 (s, tBuCOO), 165.4,
165.4 (2 s, 2
Carom), 163.6, 163.2 (2 s, 2 C=O), 131.9, 131.8 [2
d, 1J(C,H) = 163, 161, 4 Carom], 122.8, 122.2 (2 s, 2 Carom), 113.6,
113.5 [2 d, 1J(C,H) = 162, 161, 4 Carom], 100.5, 100.4 (2 s, C2 ,
C2 ), 68.5, 68.4 [2 d, 1J(C,H) = 146, 148, C1, C2 ], 63.0, 62.8
[2 d, 1J(C,H) = 146, 144, C4 , C6 , C4 , C6 ], 60.8 [t,
1J(C,H) = 150, C4 ], 58.4 [t, 1J(C,H) = 142, C3], 55.5 [2 q,
1J(C,H) = 145, 2 °CH3], 41.5 [t, 1J(C,H) = 128, C1 ], 41.1, 40.5 [2
t, 1J(C,H) = 127, 126, C1 , C1 ], 38.8 [s, C(Me)3], 38.6 [t,
1J(C,H) = 125, C5 , C5 ], 37.7, 33.8 [2 t, 1J(C,H) = 125, 126, C2,
165.2 (2 s, 2
Carom), 163.3, 163.1 (2 s, 2 C=O), 137.4 (s, C4),
1
131.4 [d, J(C, H) = 164, 4 Carom], 123.7 [d, 1J(C,H) = 170, C3],
123.0, 122.8 (2 s, 2
C
arom), 113.5, 113.2 [2 d, 1J(C,H) = 162, 161,
1
4
Carom], 100.6 (s, C2 ), 68.8 [d, J(C,H) = 148, C1], 68.4 [d,
1J(C,H) = 149, C2 ], 66.7 [d, 1J(C,H) = 142, C4 ], 65.8 [d,
1J(C,H) = 145, C6], 62.9 [d, 1J(C,H) = 144, C6 ], 60.5 [t,
1J(C,H) = 146, C4 ], 55.5 [q, J(C,H) = 142, 2 CH3], 45.9 [t,
1
1J(C,H) = 128, C1 ], 44.5 [t, J(C,H) = 129, C7], 40.5, 40.4 [2 t,
1
1J(C,H) = 127, C5, C1 ], 38.5 [s, C(Me)3], 38.4, 33.7 [2 t,
1
C3 ], 27.2 [q, J(C,H) = 125, tBu], 24.5, 24.4, 24.3, 24.1 [4q,
1J(C,H) = 127, C5 , C3 ], 32.9 [t, J(C,H) = 128, C2], 27.1 [q,
1
1J(C,H) = 127, 2 Me-C2 , 2 Me-C2 ].
1J(C,H) = 128, tBu], 24.5 [q, 1J(C,H) = 125, 2 Me-C2 ].
MS (CI; NH3): m/z (%) = 757 (14), [M – Me+], 715 (14), 657 (4),
486 (4), 334 (4), 135 (100), 81 (24).
MS (CI; NH3): m/z (%) = 714 (66), [M + 18+], 697 (20), [M + H+],
639 (100), 487 (4), 363 (61), 317 (8), 135 (87), 109 (44), 83 (79).
UV (MeCN): max ( ) = 255 (74500), 197 nm (91500).
UV (MeCN): max ( ) = 253 (79100), 199 (90400), 194 nm
(88700).
Anal. Calcd for C42H60O13 (772.93): C, 65.27; H, 7.82. Found: C,
65.16; H, 7.75.
Synthesis 2002, No. 14, 1979–1986 ISSN 0039-7881 © Thieme Stuttgart · New York

1984
S. Gerber-Lemaire et al.
PAPER
(1R)-3-Azido-1-{[(4R,6S)-6-{[(4R,6S)-6-{(2S)-4-(2,2-dimethyl-
1-oxopropoxy)-2-[(4-methoxybenzoyl)oxy]butyl}-2,2-dimethyl-
1,3-dioxan-4-yl]methyl}-2,2- dimethyl-1,3-dioxan-4-yl]meth-
yl}propyl 4-methoxybenzoate [(–)-12]
2 ), 3.91-3.85 (m, 4 H, H-3, H-5, H-7, H-9), 3.88 (s, 6 H, 2 CH3),
3.06 (t, 2 H, 3J = 7.0, 2 H-2), 2.08–2.01 (4 H, m, 2 H-1 , 2 H-
1 ), 1.90-1.49 (m, 10 H, 2 H-2, 2 H-4, 2 H-6, 2 H-8, 2 H-
10), 1.18 (s, 9 H, tBu).
Et3N (54 L, 0.388 mmol, 3 equiv) and MsCl (15 L, 0.194 mmol,
1.5 equiv) were added to a cooled solution (0 °C) of (–)-11 (100 mg,
0.129 mmol) in anhyd CH2Cl2 (4 mL). After stirring for 1 h at 0 °C,
the mixture was poured into H2O (12 mL) and extracted with
CH2Cl2 (3 15 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. The residual oil
was taken up in anhyd DMF (2 mL) and treated with sodium azide
(42 mg, 0.645 mmol, 5 equiv) for 5 h at 60 °C. The solution was
poured into a sat. aq solution of NaHCO3 (10 mL) and extracted
with EtOAc (3 10 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. Purification by
FC (CH2Cl2–MeOH, 99:1) afforded a colorless oil (65 mg, 63%).
13C NMR (100.6 MHz, CD3OD: = 172.9 (s, tBuCOO), 166.1 (s,
2
C
C
arom), 163.1, 162.8 (2 s, 2 C=O), 133.6 [d, 1J(C,H) = 162, 4
1
arom], 124.5, 124.4 (2 s, 2 Carom), 155.7 [d, J(C,H) = 165, 4
Carom], 71.2 [d, 1J(C,H) = 144, C1, C11], 68.2, 66.7, 66.4, 65.9 [4 d,
1J(C,H) = 142, 144, 141, 145, C3, C5, C7, C9], 63.0 [t,
1J(C,H) = 142, C2 ], 56.9 [q, 1J(C,H) = 142, 2 CH3], 47.2, 46.8 [2
t, 1J(C,H) = 128, 125, C2, C10], 45.0, 44.8, 43.2, 43.0 [4 t,
1J(C,H) = 125, C4, C6, C8, C1 ], 41.1 [t, 1J(C,H) = 126, C2 ], 39.8
1
1
[s, C(Me)3], 35.9 [t, J(C,H) = 125, C1 ], 28.4 [q, J(C,H) = 126,
tBu].
MS (Electrospray): m/z (%) = 646 (100, [M + H+]).
[ ]58920 –26, [ ]57720 –32, [ ]54620 –35, [ ]43520 –59, [ ]40520 –69
UV (MeCN): max ( ) = 260 (13300), 200 nm (17600).
(c 0.25, CH2Cl2).
Anal. Calcd for C35H51NO10 (645.79): C, 65.10; H, 7.96. Found: C,
64.83; H, 8.04.
IR (film): 2965, 2925, 2100, 1720, 1710, 1605, 1510, 1460, 1255,
1100, 1030 cm–1.
(1R,3R,5S)-6-[(4S,6S)-6-{(2S)-4-(2,2-Dimethyl-1-oxopropoxy)-
2-[(4-methoxybenzoyl)oxy]butyl}-2,2-dimethyl-1,3-dioxan-4-
yl]-3,5-dihydroxy-1-(2-hydroxyethyl)hexyl 4-methoxybenzoate
[(–)-16]
1H NMR (400 MHz, CDCl3): = 7.98 (d, 3J = 8.8, 4 Harom), 6.91
(2 m, 4
Harom), 5.38 (m, 1 H, H-2 ), 5.21 (m, 1 H, H-1), 4.23 (m,
2 H, 2 H-4 ), 3.90 (m, 4 H, H-4 , H-6 , H-4 , H-6 ), 3.88 and
3.87 (2 s, 6 H, 2 CH3), 3.38 (t, 2 H, 3J = 7.2, 2 H-3), 2.10–1.81
(m, 10 H, 2 H-2, 2 H-1 , 2 H-1 , 2 H-1 , 2 H-3 ), 1.65–
1.30 (m, 4 H, 2 H-5 , 2 H-5 ), 1.27, 1.17 (2 s, 12 H, 2 Me-
C2 , 2 Me-C2 ), 1.13 (s, 9 H, tBu).
13C NMR (100.6 MHz, CDCl3): = 178.2 (s, tBuCOO), 165.7,
165.5 (2 s, 2 Carom), 162.3, 159.9 (2 s, 2 C=O), 131.7, 131.6 [2
d, 1J(C,H) = 162, 163, 4 Carom], 123.5, 122.8 (2 s, 2 Carom), 113.7
NMO (74 mg, 0.55 mmol, 1.5 equiv) and OsO4 (0.1 M in CCl4, 370
L, 0.037 mmol, 0.1 equiv) were added to a solution of (–)-14 (256
mg, 0.37 mmol) in acetone–H2O (25:1, 5.2 mL). The mixture was
stirred at r.t. for 2 h, then diluted with AcOEt (14 mL), and Na2S2O5
(480 mg) added. After stirring for 30 min at r.t., the mixture was
poured into H2O (10 mL) and extracted with EtOAc (3 30 mL).
The combined organic layers were dried (MgSO4)and concentrated
under reduced pressure to afford a colorless oil. The crude diol (284
mg, 0.39 mmol) was dissolved in anhyd MeOH (10 mL) with
Pb(OAc)4 (346 mg, 0.78 mmol) and stirred at r.t. for 20 min. The
mixture was poured into a sat. aq solution of NaHCO3 (15 mL) and
extracted with EtOAc (3 30 mL). The combined organic extracts
were dried (MgSO4)and concentrated under reduced pressure to af-
ford a white foam (233 mg, 83%), which was directly taken up in
anhyd THF (5 mL). Et2BOMe (1 M in THF, 0.96 mL, 0.96 mmol,
3 equiv) was added and the solution stirred at r.t. for 1 h. The mix-
ture was cooled to 0 °C and anhyd MeOH (0.4 mL) and NaBH4 (48
mg, 1.28 mmol, 4 equiv) were added. After stirring at 0 °C for 1 h,
NaBH4 (48 mg, 1.28 mmol, 4 equiv) was added again. After stirring
at 0 °C for an additional hour, AcOH (0.2 mL) was added to the
mixture, that was then poured into a sat. aq solution of NaHCO3 (10
mL) and extracted with EtOAc (3 30 mL). The combined organic
extracts were dried (MgSO4) and concentrated under reduced pres-
sure. Purification by FC (CH2Cl2–MeOH, 97:3; Rf 0.18) afforded a
colorless oil (75%).
[d, 1J(C,H) = 161, 4
Carom], 100.8 (s, C2 , C2 ), 68.8 [d,
1J(C,H) = 143, C1], 68.1 [d, 1J(C,H) = 145, C2 ], 66.5, 63.1 [2 d,
1J(C,H) = 143, 145, C4 , C6 , C4 , C6 ], 62.8 [t, 1J(C,H) = 148,
C4 ], 55.5 [2 q, 1J(C,H) = 143, 2 CH3], 49.0 [t, 1J(C,H) = 138,
C3], 47.8 [t, 1J(C,H) = 128, C1 , C1 ], 40.6, 38.7, 38.3, 34.2, 34.0
[5 t, 1J(C,H) = 126, 125, 123, 127, 122, C2, C5 , C1 ,
1
C5 ,C3 ], 39.3 [s, C(Me)3], 27.0 [q, J(C,H) = 127, tBu], 24.4,
24.2 [2 q, 1J(C,H) = 125, 2 Me-C2 , 2 Me-C2 ].
MS (CI; NH3): m/z (%) = 663 (5), [M – PMBz+], 648 (3), 622 (2),
575 (2), 524 (1), 135 (100).
UV (MeCN): max ( ) = 271 (21900), 254 (42100), 207 nm
(33800).
Anal. Calcd for C42H60O13 (797.94): C, 63.22; H, 7.45; N, 5.27.
Found: C, 62.98; H, 7.40; N, 5.12.
(1R,3R,5S,7R,9S,11S)-1-(2-Aminoethyl)-11-[2-(2,2-dimethyl-1-
oxopropoxy)ethyl]undecane-1,11-diyl bis(4-methoxybenzoate)
[(–)-13]
[ ]58920 –1, [ ]57720 –3.4, [ ]54620 –4, [ ]43520 –7, [ ]40520 –7.4 (c 0.5,
A solution of (–)-12 (60 mg, 0.061 mmol) and 10% Pd/C (10 mg) in
anhyd MeOH (5 mL) was stirred at r.t. under 1 atm of hydrogen for
1 h. The mixture was filtered through a pad of Celite and concen-
trated under reduced pressure to afford a pale yellow oil. The crude
amine was treated in CF3COOH–H2O (4:1, 2.5 mL) for 45 min at
r.t., then the solution was concentrated under reduced pressure. The
residue was purified by FC (MeCN–25% sat. aq NH3, 5:1, Rf 0.38)
to produce a pale yellow oil (28 mg, 70%).
CH2Cl2).
IR (film): 3420, 2935, 1715, 1695, 1605, 1515, 1455, 1260, 1170,
1100, 850, 770, 665 cm–1.
1H NMR (400 MHz, CDCl3): = 7.98 and 6.93 (2 m, 8 Harom),
5.46 (m, 2 H, H-1, H-2 ), 4.19–4.09 (m, 4 H, 2 H-4 , H-4 , H-5),
3.96–3.89 (m, 2 H, H-3, H-6 ), 3.86 (2 s, 6 H, 2 OCH3), 3.71–
3.65 (m, 2 H, 2 H-2 ), 2.04–2.01 (m, 2 H, 2 H-3 ), 1.95–1.92
(m, 2 H, 2 H-1 ), 1.81–1.73 (m, 4 H, 2 H-1 , 2 H-2), 1.66–
1.53 (m, 6 H, 2 H-5 , 2 H-6, 2 H-4), 1.32 (s, 3 H, Me-C2 ), 1.29
(s, 3 H, Me-C2 ), 1.17 (s, 9 H, tBu).
[ ]58920 –14, [ ]57720 –23, [ ]54620 –30, [ ]43520 –34, [ ]40520 –40
(c 0.75, CH2Cl2).
IR (film): 3500–3100, 2970, 1785, 1710, 1605, 1580, 1515, 1480,
1420, 1365, 1315, 1260, 1170, 1105, 1030, 850, 770, 735, 690, 665
cm–1.
13C NMR (100.6 MHz): = 178.4 (s, tBuCOO), 167.4, 165.5 (2 s,
2
C
arom), 163.9, 163.6 (2 s, 2
1J(C,H) = 163, 162, 4 Carom], 122.0, 121.5 (2 s, 2 Carom), 113.7
[d, 1J(C,H) = 161, 4
Carom], 98.9 (s, C2 ), 69.2, 68.8 [2 d,
1J(C,H) = 151, 142, C1, C2 ], 68.5, 68.2 [2 d, 1J(C,H) = 152, 151,
C=O), 131.8, 131.5 [2 d,
1H NMR (400 MHz, CD3OD): = 7.99 (m, 4 Harom), 7.00 (d,
3J = 7.8, 4 Harom), 5.46 (m, 2 H, H-1, H-11), 4.13 (m, 2 H, 2 H-
Synthesis 2002, No. 14, 1979–1986 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Aminopentadecanealcohols and Derivatives
1985
C4 , C5], 64.9 [d, 1J(C,H) = 146, C3], 62.7 [d, 1J(C,H) = 146, C6 ],
60.7 [t, 1J(C,H) = 150, C4 ], 58.6 (t, 1J(C,H) = 141, C2 ], 55.4 [q,
1J(C,H) = 144, OCH3], 43.8, 43.6, 43.1, 42.0, 38.7 [6 t,
1J(C,H) = 125, 125, 130, 129, 124, C6, C4, C2, C1 , C5 , C3 ], 38.6
[s, C(Me)3], 38.0 [t, J(C,H) = 125, C1 ], 33.9 [t, J(C,H) = 126,
C3 ], 30.1 [q, 1J(C,H) = 125, Me-C2 ], 27.1 [q, 1J(C,H) = 127,
tBu], 19.6 [q, 1J(C,H) = 125, Me-C2 ].
was added and the mixture was stirred at 60 °C overnight. The so-
lution was poured into a sat. aq solution of NaHCO3 (10 mL) and
extracted with EtOAc (3 30 mL). The combined organic extracts
were dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by FC (Et2O–light petroleum, 1:1, Rf 0.27) to
afford a colorless oil (39 mg, 65%).
[ ]58920 +9.4, [ ]57720 +8.4, [ ]54620 +9.5, [ ]43520 +10.5, [ ]40520 +11
(c 0.28, CH2Cl2).
1
1
MS (CI; NH3): m/z (%) = 733 (11), [M + H+], 675 (16), 565 (4), 523
(16), 407 (4), 334 (8), 232 (5), 135 (100), 81 (16).
IR (film): 3020, 2100, 1710, 1605, 1510, 1380, 1260, 1215, 1170,
1100, 1035, 935, 850, 760, 670 cm–1.
UV (MeCN): max ( ) = 267 (65500), 242 (76600), 216 nm
(60400).
1H NMR (400 MHz, toluene): = 8.10 and 6.65 (2 m, 8 Harom),
5.70 and 5.53 (m, 2 H, H-1, H-2 ), 4.18 (m, 2 H, 2 H-4 ),
4.18–3.95 (m, 4 H, H-4 , H-6 , H-4 , H-6 ), 3.23 (s, 6 H, 2
OCH3), 2.98 (t, 2 H, 3J = 7.4, 2 H-3), 1.93 (m, 2 H, 2 H-3 ),
1.69–1.35 (m, 12 H, 2 H-2, 2 H-1 , 2 H-1 , 2 H-1 , 2 H-
(1R)-3-Hydroxy-1-{[(4R,6S)-6-[{(4S,6S)-6-(2S)-4-(2,2-dimeth-
yl-1-oxopropoxy)-2-[(4-methoxybenzoyl)oxy]butyl-2,2-dimeth-
yl-1,3-dioxan-4-yl}methyl]-2,2-dimethyl-1,3-dioxan-4-
yl]methyl}propyl 4-methoxybenzoate ((–)-17)
A solution of (–)-16 (157 mg, 0.21 mmol) and pyridinium toluene-
4-sulfonate (10 mg) in acetone–2,2-dimethoxypropane (4:1, 10 mL)
was stirred at 0 °C for 2 h. The mixture was neutralized by
NaHCO3, filtered and concentrated under reduced pressure. Purifi-
cation by FC (CH2Cl2–MeOH, 97:3, Rf 0.21) afforded a colorless
oil (135 mg, 82%).
5
), 1.53, 1.38, 1.35 (3 s, 12 H, 2 Me-C2 , 2 Me-C2 ), 1.23 (s,
9 H, tBu).
13C NMR (100.6 MHz): = 178.5 (s, tBuCOO), 166. 1 (2 s, 2
C
2
arom), 164.4 (2 s, 2 Carom), 132.6 (d, 4 Carom), 125.6, 124.1 (2 s,
Carom), 114.6 (d, 4 Carom), 101.5, 99.5 (2 s, C2 , C2 ), 69.9,
69.1 (2 d, C1, C2 ), 66.7, 65.9, 64.1, 63.0, 61.6 (4d, 1t, C4 , C6 ,
C4 , C6 , C4 ), 55.4 (q, 2 CH3), 48.7 (t, C3), 43.5, 42.7, 41.9,
40.2, 38.8 (C1 , C1 , C1 , C5 , C5 ), 38.8 [s, C(Me)3], 35.3
(C2, C3 ), 31.2 and 25.4 (2 q, Me-C2 , Me-C2 ), 28.0 (q, tBu).
[ ]58920 –9, [ ]57720 –13, [ ]54620 –14, [ ]43520 –27, [ ]40520 –35
(c 0.48, CH2Cl2).
IR (film): 3500, 3055, 2990, 1710, 1605, 1510, 1460, 1380, 1315,
1265, 1170, 1105, 1030, 935, 850, 770, 740, 705, 665 cm–1.
1H NMR (400 MHz, CDCl3): = 7.98 and 6.92 (2m, 8 Harom), 5.44
(m, 2 H, H-1, H-2 ), 4.14 (m, 2 H, 2 H-4 ), 4.02–3.88 (m, 4 H,
H-4 , H-6 , H-4 , H-6 ), 3.87 (s, 3 H, OCH3), 3.86 (s, 3 H,
OCH3), 3.66–3.56 (m, 2 H, 2 H-3), 2.05–1.71 (m, 10 H, 2 H-2,
MS (CI; NH3): m/z (%) = 815 (3), [M + 18+], 798 (1), [M + H+], 758
(45), 718 (59), 538 (10), 407 (4), 281 (7), 135 (100), 96 (45).
UV (MeCN): max ( ) = 255 (39553), 210 nm (28564).
Anal. Calcd for C42H59N3O12 (797.98): C, 63.22; H, 7.45. Found: C,
62.98; H, 7.56.
2
H-1 , 2 H-1 , 2 H-1 , 2 H-3 ), 1.57–1.49 (m, 4 H, 2
(1R)-3-Amino-1-{[(4R,6S)-6-[{(4S,6S)-6-(2S)-4-(2,2-dimethyl-1-
oxopropoxy)-2-[(4-methoxybenzoyl)oxy]butyl-2,2-dimethyl-
1,3-dioxan-4-yl}methyl]-2,2-dimethyl-1,3-dioxan-4-yl]meth-
yl}propyl 4-methoxybenzoate [(–)-19]
A solution of (+)-18 (10 mg) and Pd(OH)2/C (2 mg) in anhyd
MeOH (1 mL) was stirred at r.t. under 1 atm of hydrogen for 1 h.
The mixture was filtered through a pad of Celite and concentrated
under reduced pressure. The residue was purified by FC (Et2O–light
petroleum, 2:1) to produce a pale oil (9 mg, quantitative yield).
H-5 , 2 H-5 ), 1.26, 1.24, 1.10 (3s, 12 H, 2 Me-C2 , 2 Me-
C2 ), 1.17 (s, 9 H, tBu).
13C NMR (100.6 MHz): = 178.5 (s, tBuCOO), 167.1, 165.5 (2 s,
2
Carom), 163.5, 163.3 (2 s, 2
C=O), 131.7, 131.5 [2 d,
1J(C,H) = 163, 163, 4 Carom], 122.7, 122.2 (2 s, 2 Carom), 113.6
1
[d, J(C,H) = 161, 4 Carom], 100.6, 98.6 (2 s, C2 , C2 ), 69.1,
68.3 [2 d, 1J(C,H) = 149, 148, C1, C2 ], 65.6-63.1 [4d,
1J(C,H) = 147, C4 , C6 , C4 , C6 ], 60.7 [t, 1J(C,H) = 151,
C4 ], 58.6 [t, 1J(C,H) = 142, C3], 55.4 [q, 1J(C,H) = 145, OCH3],
[ ]58920 –2, [ ]57720 –2.7, [ ]54620 –3.1, [ ]43520 –7.5, [ ]40520 –14
(c 0.26, MeOH).
1
1
42.6 [t, J(C,H) = 125, C1 ], 41.3-40.6 [2 t, J(C,H) = 127, 125,
C1 , C1 ], 38.7 [s, C(Me)3], 38.6 [t, 1J(C,H) = 125, C5 ], 38.3 [t,
1J(C,H) = 124, C5 ], 37.6 [t, 1J(C,H) = 125, C2], 33.9 [t,
1J(C,H) = 126, C3 ], 30.1, 19.5 [2 q, 1J(C,H) = 125, Me-C2 , Me-
C2 ], 27.2 [q, 1J(C,H) = 125, tBu].
MS (CI; NH3): m/z (%) = 773 (4), [M + H+], 772 (2), [M+], 757
(20), 715 (25), 657 (5), 486 (4), 279 (3), 135 (100), 83 (14).
IR (film): 3390, 3020, 1710, 1605, 1510, 1380, 1260, 1215, 1170,
1100, 1030, 935, 850, 760, 670 cm–1.
1H NMR (400 MHz, toluene): = 8.12 and 6.62 (2m, 8 Harom),
5.71 and 5.34 (m, 2 H, H-1, H-2 ), 4.18 (m, 2 H, 2 H-4 ),
4.18–3.25 (m, 6 H, H-4 , H-6 , H-4 , H-6 , 2 H-3), 3.22 and
3.20 (s, 6 H, 2 OCH3), 1.96 (m, 4 H, 2 H-2, 2 H-3 ), 1.68–
1.03 (m, 10 H, 2 H-1 , 2 H-1 , 2 H-1 , 2 H-5 , 2 H-5 ),
1.53, 1.38, 1.35, 1.32 (4 s, 12 H, 2 Me-C2 , 2 Me-C2 ), 1.24
(s, 9 H, Me3C).
UV (MeCN): max ( ) = 251 (26900), 212 nm (18100).
Anal. Calcd for C42H60O13 (772.97): C, 65.27; H, 7.82. Found: C,
65.38; H, 7.74.
13C NMR (100.6 MHz): = 177.0 (s, tBuCOO), 165.8, 165.5 (2 s,
(1R)-3-Azido-1-{[(4R,6S)-6-[{(4S,6S)-6-(2S)-4-(2,2-dimethyl-1-
oxopropoxy)-2-[(4-methoxybenzoyl)oxy]butyl-2,2-dimethyl-
1,3-dioxan-4-yl}methyl]-2,2-dimethyl-1,3-dioxan-4-yl]meth-
yl}propyl 4-methoxybenzoate [(+)-18]
Et3N (22 L, 0.168 mmol, 2 equiv) and MsCl (6 L, 0.084 mmol,
1 equiv) were added to a cooled solution (0 °C) of (–)-17 (65 mg,
0.084 mmol) in anhyd CH2Cl2 (1 mL). After stirring for 15 min at
0 °C, the mixture was poured into H2O (10 mL) and extracted with
EtOAc (3 15 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure to afford a pale
yellow oil. To a solution of the crude bismesylate (94 mg, 0.11
mmol) in DMF (1 mL), sodium azide (14 mg, 0.22 mmol, 2 equiv)
2
Carom), 164.3, 164.2 (2 s, 2 C=O), 132.9, 131.7 (2 d, 4 Carom),
126.1, 125.0 (2 s, 2 arom), 114.4, 114.0 (2 d, 4 Carom), 100.2,
C
99.0 (2 s, C2 , C2 ), 68.0, 66.7 (2 d, C1, C2 ), 66.5 (t, C4 ),
65.4, 63.6, 62.8, 61.4 (4 d, C4 , C6 , C4 , C6 ), 55.2 (q, 2
CH3), 43.2, 42.5, 40.0, 39.5 (4 t, C1 , C1 , C1 , C5 , C5 ), 38.5
(t, C3), 38.4 (s, C(Me)3), 35.1 (t, C2, C3 ), 30.0, 25.0 (2 q, Me-
C2 , Me-C2 ), 27.8 (q, tBu).
MS (Electrospray): m/z (%) = 772 (100), [M + H+].
UV (MeCN): max ( ) = 255 (15500), 207 (14000).
Synthesis 2002, No. 14, 1979–1986 ISSN 0039-7881 © Thieme Stuttgart · New York

1986
S. Gerber-Lemaire et al.
PAPER
(1R,3R,5R,7S,9S,11S)-1-(2-Aminoethyl)-11-[2-(2,2-dimethyl-1-
oxopropoxy)ethyl]undecane-1,11-diyl bis(4-methoxybenzoate)
[((–)-20]
A solution of (–)-19 (15 mg, 0.019 mmol) in THF–HCl (1 M)–H2O
(1mL) (1:0.1:1) was stirred at r.t. for 1 h. The mixture was concen-
trated under reduced pressure and the residue taken up in MeOH (1
mL) and then neutralized by addition of Na2CO3. This solution was
filtered, concentrated and finally purified by FC (CH2Cl2–MeOH,
95:5) to afford quantitatively (–)-20.
Acknowledgements
This project was supported by the Swiss National Science Founda-
tion (grant No. 20-63667.00 and 2100-063567.00). We thank Mr. F.
Sepúlveda, Mr. M. Rey and Prof M. Mutter (electrospray) for their
technical help. We are also grateful to the european COST D13/010/
00 program for encouragements.
References
[ ]58920 –2.5, [ ]57720 –2.5, [ ]54620 –5, [ ]43520 –9, [ ]40520 –12
(1) Sakuda, S.; Guce-Bigol, U.; Itoh, M.; Nishimura, T.;
Yamada, Y. J. Chem. Soc., Perkin Trans. 1 1996, 2315.
(2) (a) Silo-Suh, L. A.; Stabb, E. V.; Raffel, S. J.; Handelsman,
J. Curr. Microbiol. 1998, 37, 6. (b) Stohl, E. A.; Milner, J.
L.; Handelsman, J. Gene 1999, 237, 403.
(3) (a) Harris, J. M. Poly(ethylene glycol) Chemistry:
Biotechnical and Biomedical Applications; Harris, J. M.,
Ed.; Plenum Press: New York, 1992. (b) Bertozzi, C. R.;
Bednarski, M. D. J. Org. Chem. 1991, 56, 4326. (c) Cook,
R. M.; Adams, J. H.; Hudson, D. Tetrahedron Lett. 1994, 35,
6777. (d) Schwabacher, A. W.; Lane, J. W.; Schiesher, M.
W.; Leigh, K. M.; Johnson, C. W. J. Org. Chem. 1998, 63,
1727.
(4) Schwenter, M. E.; Vogel, P. Chem.–Eur. J. 2000, 6, 4091.
(5) Csákÿ, A. G.; Vogel, P. Tetrahedron: Asymmetry 2000, 11,
4935.
(6) Schwenter, M. E.; Vogel, P. J. Org. Chem. 2001, 66, 7869.
(7) (a) Nasaraka, K.; Pai, F. G. Tetrahedron Lett. 1984, 40,
2233. (b) Chen, K. N.; Hardtmann, G. E.; Prasad, K.; Repi,
O.; Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155.
(8) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
(c 0.2, MeOH).
IR (film): 3390, 2940, 1710, 1605, 1510, 1420, 1260, 1170, 1105,
1030, 850, 770, 695 cm–1.
1H NMR (400 MHz, CD3OD): = 8.02 and 7.01 (2m, 8 Harom),
5.45 (m, 2 H, H-1, H-11), 4.16 (m, 2 H, 2 H-2 ), 4.16–3.84 (m, 4
H, H-3, H-5, H-7, H-9), 3.88 (s, 6 H, 2 OCH3), 2.89 (m, 2 H, 2
H-2 ), 2.07 (m, 2 H, 2 H-1 ), 2.03–1.30 (m, 12 H, 2 H-1 , 2 H-
2, 2 H-4, 2 H-6, 2 H-8, 2 H-10), 1.18 (s, 9 H, tBu).
13C NMR (100.6 MHz): = 182.3 (s, tBuCOO), 170.3 (2 s, Carom),
167.8 (2 s, C=O), 135.2 (d, 4 Carom), 126.2 (2 s, 2 Carom), 117.4
(d, 4
Carom), 72.8 (2 d, C1, C11), 70.4, 70.0, 68.4, 68.2 (4 d, C3,
C5, C7, C9), 64.7 (t, C2 ), 58.5 (q, OCH3), 49.3-46.1 (5 t, C2, C4,
C6, C8, C10), 40.5 (t, C2 ), 39.0 [s, C(Me)3], 38.7, 37.7 (2 t, C1 ,
C1 ), 30.0 (tBu).
MS (CI; NH3): m/z (%) = 693 (60), [M + H+], 675 (52), [M + H –
H2O+], 559 (5), 407 (3), 337 (2), 243 (7), 152 (71), 135 (100), 77
(33).
UV (MeCN): max ( ) = 255 (31500), 209 (23900).
Synthesis 2002, No. 14, 1979–1986 ISSN 0039-7881 © Thieme Stuttgart · New York