Synthesis of the γ-amino-β-hydroxy acid of hapalosin via an asymmetric dihydroxylation route

Article abstract of DOI:10.1016/S0040-4020(99)01052-2

Starting from the allylic alcohol 3, the epoxide 7 was prepared by asymmetric dihydroxylation of the allylic chloride followed by subsequent protection of the secondary hydroxy group. Opening of the oxirane with phenyl cuprate gave the triol 8 with a free hydroxy group. Mitsunobu reaction of 8 with diphenylphosphoryl azide led to the azide 9. Simple functional group manipulations delivered the acid 2 in further five steps. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(99)01052-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 557–561
Synthesis of the g-Amino-b-hydroxy Acid of Hapalosin via an
Asymmetric Dihydroxylation Route
*
Martin E. Maier and Christoph Hermann
¨
¨
¨
¨
Institut fur Organische Chemie, Universitat Tubingen, Auf der Morgenstelle 18, D-72076 Tubingen, Germany
Received 29 October 1999; accepted 3 December 1999
Abstract—Starting from the allylic alcohol 3, the epoxide 7 was prepared by asymmetric dihydroxylation of the allylic chloride followed by
subsequent protection of the secondary hydroxy group. Opening of the oxirane with phenyl cuprate gave the triol 8 with a free hydroxy group.
Mitsunobu reaction of 8 with diphenylphosphoryl azide led to the azide 9. Simple functional group manipulations delivered the acid 2 in
further five steps. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
droxy-5-phenylpentanoic acid requires a higher synthetic
effort. Typically, amino acid C is prepared by elongation
of N-protected phenylalanine in a sequence of about four to
seven steps. Moreover, we recently disclosed the synthesis
of acid 2 using the tactical combination of an aldol reaction
and a Curtius rearrangement as key steps.12 However, this
and the other known syntheses do not allow for an easy
modification or replacement of the aryl group. We therefore
devised another route towards 2 that introduces the aryl
group through the opening of an epoxide. The stereo-
chemical information was established by a Sharpless
asymmetric dihydroxylation reaction (ADH).13
The cyclic depsipeptide hapalosin (1) was found to reverse
multidrug resistance1,2 (MDR) in tumor cells.3 Common
MDR is caused by overexpression of the MDR1 gene that
encodes for
a 170 kDa P-glycoprotein. Structurally,
hapalosin consists of three subunits, a b-hydroxy acid A,
an a-hydroxy acid B, and a g-amino-b-hydroxy acid C.
With the modular structure, this molecule presents itself
for analog synthesis in a parallel fashion.4 Due to the bio-
logical activity, syntheses of the natural product5–10 and of
some analogs10,11 have been reported.
Results
The synthesis started from the allylic alcohol 3, which is
available from benzyloxypropanol by an oxidation, Wittig–
Horner and reduction sequence.14–16 Chlorination17 with
N-chlorosuccinimide and dimethyl sulfide provided allyl
chloride 4 in high yield (Scheme 1). The asymmetric
dihydroxylation was performed under standard conditions18
While the synthesis and availability of subunits of type A
and B are no problem, the (3R,4S)-4-N-methylamino-3-hy-
Scheme 1.
Keywords: hapalosin; amino acid; epoxides; hydroxylation.
* Corresponding author. Fax: ϩ49-7071-29-5137; e-mail: martin.e.maier@uni-tuebingen.de
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01052-2

558
M. E. Maier, C. Hermann / Tetrahedron 56 (2000) 557–561
Scheme 2.
using (DHQD)2PHAL as chiral ligand, which furnished the
(2S,3R)-diol 5. Treatment of the chlorodiol 5 with pulver-
ized sodium hydroxide led to the epoxy alcohol 6. Despite
the presence of the epoxide, protection of the hydroxyl
group as its MOM ether proceeded uneventually to give
the key building block 7.
DMAP, THF) and then by methylation (1.3 equiv. NaH,
2.0 equiv. MeI, DMF) to the protected amino alcohol 13.
Reducitve removal of the benzyl group gave the known
primary alcohol 14.12 The measured optical rotation of 14
25
25
‰aŠ ˆϪ16:0 (cˆ0.9 in CHCl3) {Ref. 12 ‰aŠ ˆϪ17:8
D
D
(cˆ0.9 in CHCl3)} was proof of the high enantioselectivity
in the ADH reaction. To complete the synthesis, the primary
alcohol 14 was oxidized to the acid 2 with sodium
hypochlorite and TEMPO as described.12
The stage was now set for the introduction of the phenyl
group. Thus, the higher order cyanocuprate,19 prepared from
phenyllithium (2 equiv.) and copper cyanide added
smoothly to the terminal carbon of the epoxide 7 affording
the di-protected triol 8 in good yield (Scheme 2). The
alcohol 8 was used to determine the enantioselectivity of
the dihydroxylation reaction. It was converted to the corre-
sponding Mosher esters using both Mosher acids.20,21 An
equimolar mixture of the Mosher esters could be separated
on a DAICEL ODH column [250×4.6 mm, 2% iPrOH in
heptane, flow 0.9 ml minϪ1, retention times 11.99 and
13.40 min, 254 nm]. Injecting the Mosher ester derived
from the (S)-acid (8MS) gave basically only one peak
(13.40 min). The ratio from integration indicated an
ee-value of 96%.
In summary, we prepared the chiral oxirane 7 by an asym-
metric dihydroxylation of the allylic chloride 4 and
illustrated the use of this polyfunctional C-5 building
block by its conversion to the 4-amino-3-hydroxy-5-phenyl-
pentanoic acid 2.
Experimental
General
1H and 13C NMR: Bruker AC 250; all spectra were recorded
in CDCl3. Optical rotations: JASCO P-1020 polarimeter. IR:
JASCO FT/IR-430 spectrometer, EI-MS: AMD Intectra
GmbH AMD 402. HPLC: Hewlett Packard HP 1100.
Flash chromatography: J. T. Baker silica gel 30–60 mm.
Thin-layer chromatography: Merck Si 60 F254. Solvents
were distilled prior to use; petroleum ether with a boiling
range of 35–65ЊC was used.
In the next step the nitrogen function was introduced
through a Mitsunobu reaction22 with diphenyl-phosphoryl
azide10 in the presence of triphenylphosphine and diethyl
azodicarboxylate to furnish the azide 9. This substitution
reaction went in high yield but was accompanied by
the elimination product 10, which could be separated by
chromatography.
Benzyl (3E)-5-chloro-3-pentenyl ether (4). To a solution
of NCS (15.4 g, 115 mmol) in dry CH2Cl2 (300 ml) was
added DMS (8.5 ml, 115 mmol) at 0ЊC. After stirring for
1 h at 0ЊC the mixture was cooled to Ϫ20ЊC and a solution
After reduction of the azide with LiAlH4 the amine 11 was
obtained (Scheme 3). The free amine could be converted to
the corresponding N-Boc derivative 12 (Boc2O, NEt3, trace
Scheme 3.

M. E. Maier, C. Hermann / Tetrahedron 56 (2000) 557–561
559
of the allylic alcohol 3 (11.1 g, 57.7 mmol) in CH2Cl2
(100 ml) was added dropwise over a period of 30 min.
After stirring for 30 min at 0ЊC the mixture was allowed
to warm slowly to room temperature and stirred at this
temperature for 1 h. Water (150 ml) was added, the two
layers were separated, and the CH2Cl2 layer was washed
with brine ꢀ2×150 ml†; dried (Na2SO4), filtered and concen-
trated in vacuo. Purification of the residue by flash chroma-
tography on silica gel (petroleum ether/ethyl acetate 96:4
and 90:10) gave 4 (11.5 g, 94%) as a colorless oil. TLC
(petroleum ether/ethyl acetate, 95:5): Rfˆ0.48; IR (neat):
1495, 1453, 1363, 1252, 1204, 1102, 1028, 967, 738,
4,5-Anhydro-1-O-benzyl-2-deoxy-3-O-(methoxymethyl)-
d-threo-pentitol (7). To a cooled (0ЊC) solution of epoxy
alcohol 6 (4.60 g, 22.3 mmol) and diisopropylethylamine
(11.4 ml, 66.8 mmol) in dry CH2Cl2 (6 ml) was added drop-
wise chloromethyl methylether (3.9 ml, 44.6 mmol). The
reaction mixture was stirred at 0ЊC for 1 h and then at
room temperature for 2 h. Water (60 ml) and CH2Cl2
(100 ml) were added, the two layers separated, and the
aqueous layer was extracted with CH2Cl2 ꢀ2×60 ml†: The
combined CH2Cl2 layers were washed with 1 N HCl
(40 ml), water (80 ml), dried (Na2SO4), filtered and concen-
trated in vacuo. Purification of the residue by flash chroma-
tography on silica gel (petroleum ether/ethyl acetate, 80:20
and 75:25) gave 7 (5.0 g, 89%) as a colorless oil.
698 cmϪ1
;
1H NMR (250 MHz, CDCl3):dˆ2.39 (dt,
Jˆ6.5, 6.5 Hz, 2H), 3.50 (t, Jˆ6.6 Hz, 2H, CH2OBn),
4.04 (d, Jˆ6.7 Hz, 2H, CH2Cl), 4.50 (s, 2H, CH2Ph),
5.60–5.90 (m, 2H, olefinic), 7.26–7.35 (m, 5H); 13C NMR
(62.9 MHz, CDCl3):dˆ32.6, 45.2, 69.3, 73.0, 127.7, 128.4,
132.3, 138.0; HRMS (EI) calcd for C12H15ClO 210.08113,
found 210.07991.
28
‰aŠ ˆϩ40:9 (c 1.0, CH2Cl2); TLC (petroleum ether/ethyl
aceDtate, 8:2): Rfˆ0.38; IR (neat); 1496, 1454, 1404, 1364,
1242, 1208, 1155, 1102, 1032, 919, 851, 813, 740, 699,
1
610 cmϪ1; H NMR (250 MHz, CDCl3):dˆ1.86–1.94 (m,
2H), 2.51–2.55, 2.75–2.77 (2m, 2H, CH2O), 2.99–3.04 (m,
1H, CH), 3.37 (s, 3H, CH3), 3.44–3.52 (m, 1H, CH) 3.60 (t,
Jˆ6.2 Hz, 2H, CH2OBn), 4.49 (s, 2H, CH2Ph), 4.66, 4.84 (2
5-O-Benzyl-1-chloro-1,4-dideoxy-d-threo-pentitol (5). A
solution of (DHQD)2PHAL (370 mg, 1 mol%), K2OsO2
(OH)4 (87 mg, 0.5 mol%), K3[Fe(CN)6] (47.0 g, 142 mmol),
K2CO3 (20.0 g, 142 mmol), NaHCO3 (12 g, 142 mmol) and
CH3SO2NH2 (4.50 g, 47.5 mmol) in t-BuOH/H2O (1:1,
500 ml) was cooled to 0ЊC and treated with the allylic halide
4 (10.0 g, 47.5 mmol). The mixture was stirred vigorously
for 24 h at 0ЊC. Na2S2O5 (45 g, 237 mmol) was added care-
fully, and stirring was continued for 1 h at room tempera-
ture. The layers were separated and the aqueous layer was
extracted with ethyl acetate (150 ml). The combined organic
layers were washed with a 1N KOH (150 ml), 5% aqueous
HCl (150 ml) and brine (150 ml), dried (MgSO4), filtered
and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate, 1:1 and 2:3) to give 5 (11.1 g, 95%) as a
d, Jˆ6.25 Hz, 1H each, CH2OMe), 7.27–7.37 (m, 5H); 13
C
NMR (62.9 MHz, CDCl3): dˆ32.6, 43.9, 54.6, 55.7,
66.2, 73.1, 75.5, 95.8, 127.7, 128.4, 138.3; HRMS (EI)
calcd for C12H15O3 (MϪCH2OCH3) 207.10211, found
207.10007.
5-O-Benzyl-1,4-dideoxy-3-O-(methoxymethyl)-1-phenyl-
d-threo-pentitol (8). To a cooled (Ϫ78ЊC) suspension of
copper cyanide (2.44 g, 27.2 mmol) in dry THF (60 ml)
was added dropwise phenyllithium [30.2 ml, 1.8 M solution
in diethylether/(30%) cyclohexane, 54.4 mmol]. The
mixture was allowed to warm to Ϫ20ЊC for complete disso-
lution and was then recooled to Ϫ78ЊC. Now the epoxide 7
(4.90 g, 19.4 mmol) was added neat slowly via syringe.
After warming to Ϫ20ЊC stirring was continued at this
temperature for 8 h. The reaction was quenched with a
mixture of 10% concentrated aqueous NH3 in saturated
aqueous NH4Cl (60 ml) and allowed to warm to room
temperature. Ether (60 ml) was added, the layers were sepa-
rated followed by extracting the aqueous layer with ether
ꢀ2×100 ml†: The combined organic layers were washed with
brine, dried (Na2SO4) and filtered. The solvent was removed
in vacuo and the residue purified by flash chromatography
(petroleum ether/ethyl acetate, gradient: 8:2, 7:3 and 6:4) to
29
D
colorless solid. ‰aŠ ˆϪ13:0 (c 2.0, CH2Cl2); TLC (petro-
leum ether/ethyl acetate, 6:4): Rfˆ0.44; IR (neat): 1453,
1
1366, 1252, 1094, 849, 742, 6999, 612 cmϪ1; H NMR
(250 MHz, CDCl3): dˆ1.73–1.82, 1.91–2,08 (2 m, 2H),
2.9 (br s, 1H, OH), 3.30 (br s, 1H, OH), 3.56–3.77 (m,
5H, CH2Cl, CH2OBn, CH) 3.97–4.02 (m, 1H, CH), 4.53
(s, 2H, CH2Ph), 7.26–7.40 (m, 5H); 13C NMR (62.9 MHz,
CDCl3): dˆ33.2, 45.9, 68.5, 70.6, 73.5, 74.0, 127.8, 128.6,
137.6.
25
D
give 8 (6.04 g, 94%) as a light yellow oil. ‰aŠ ˆϩ15:3 (c
4,5-Anhydro-1-O-benzyl-2-deoxy-d-threo-pentitol (6). To
a cooled (0ЊC) solution of chlorodiol 5 (5.0 g, 20.5 mmol) in
THF (30 ml) was added pulverized NaOH (1.64 g,
41.0 mmol). After stirring for 2 h at 0ЊC the mixture was
diluted with diethyl ether (100 ml). Water (40 ml) was
added, the layers were separated, and the organic layer
was washed with saturated aqueous NH4Cl (50 ml), brine
0.51, CH2Cl2); TLC (petroleum ether/ethyl acetate, 8:2):
Rfˆ0.17; IR (neat): 1603, 1495, 1454, 1364, 1208, 1100,
1030, 918, 743, 699, 606 cmϪ1 1H NMR (250 MHz,
;
CDCl3): dˆ1.82–1.92, 1.97–2.04 (2m, 2H), 2.70–2.91
(m, 3H, CH2Ph, OH), 2.85–2.92 (m, 2H, CH2Ph), 3.40 (s,
3H, CH3), 3.58–3.70 (m, 3H, CH2OBn, CH), 3.76–3.83 (m,
1H, CH), 4.48 (d, Jˆ1.9 Hz, 2H,CH2Ph), 4.68–4.69 (m, 2H,
CH2OMe), 7.18–7.27, 7.28–7.38 (2m, 10H); 13C NMR
(62.9 MHz, CDCl3); dˆ31.6 39.6, 56.0, 56.0, 66.4, 73.1,
74.1, 76.6, 97.3, 126.3, 127.7, 128.5, 138.2, 139.0; HRMS
(EI) calcd for C19H23O3 (MϪOCH3) 299.16471, found 299.
15907.
(50 ml), dried (MgSO4), filtered and concentrated in vacuo
28
to give 6 (3.8 g, 89%) as a colorless oil. ‰aŠ ˆϪ2:8 (c 1.0,
CH2Cl2); TLC (petroleum ether/ethyl Dacetate, 6:4):
1
Rfˆ0.44; H NMR (250 MHz, CDCl3):dˆ1.82–1.93 (m,
2H), 2.59–2.61 (m, 1H, OH), 2.70–2.73, 2.75–2.79 (2m,
2H, CH2O), 2.98–3.02 (m, 1H, CH), 3.63–3.79 (m, 3H,
CH, CH2OBn), 4.51 (d, Jˆ1.5 Hz, 2H, CH2Ph), 7.26–7.37
(m, 5H); 13C NMR (62.9 MHz, CDCl3):dˆ33.9, 44.6, 55.1,
67.6, 69.9, 73.3, 127.7, 128.5, 138.0; HRMS (EI) calcd for
C12H16O3 208.10993, found 208. 10051.
Preparation of the Mosher esters from the alcohol 8. To a
solution of (S)-MTPA (24 mg, 0.10 mmol) and DMF (7 mg,
0.1 mmol) in hexane (4 ml) was added dropwise (COCl)2
(54.6 mg, 0.43 mmol) at room temperature. A white

560
M. E. Maier, C. Hermann / Tetrahedron 56 (2000) 557–561
precipitate formed immediately. After stirring for 1 h the
precipitate had disappeared and some oily drops resulted.
The hexane solution was separated and concentrated under
reduced pressure. A solution of the di-protected triol 8
(25 mg, 0.076 mmol), DMAP (5 mg, 0.04 mmol) and NEt3
(23 mg, 0.23 mmol) in CHCl3 (1 ml) was added to the resi-
due at room temperature. After 2 h CH2Cl2 (5 ml) was added
and the solution washed with 1 M KHSO4 (5 ml) and brine
(5 ml), dried (MgSO4), filtered and concentrated in vacuo.
The residue was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate, 8:2) to give the Mosher
ester (33 mg, 80%) as a colorless oil. TLC (petroleum ether/
ethyl acetate, 8:2); Rfˆ0.61.
Mosher ester derived from the (S)-acid: 1H NMR (250 MHz,
CDCl3):dˆ1.64–1.75 (m, 2H, CH2), 2.75 (dd, Jˆ14.4,
10.3 Hz, 1H, CH2Ph), 3.11 (dd, Jˆ14.4, 3.3 Hz, 1H,
CH2Ph), 3.19 (d, Jˆ1.2 Hz, 3H, OCH3), 3.34 (s, 3H, CH3
(MOM)), 3.38–3.53 (m, 2H, CH2OBn), 3.81–3.88 (m, 1H,
CHOMOM), 4.39 (d, Jˆ1.5 Hz, 2H, CH2Ph), 4.57–4.63 (m,
2H, CH2OMe), 5.49–5.54 (m, 1H, CH), 7.02–7.61 (m,
15H); 13C NMR (62.9 MHz. CDCl3):dˆ30.2, 34.6, 55.3,
56.1, 66.4, 73.0, 75.5, 78.1, 97.6, 125.6, 126.7, 127.7,
128.3, 128.6, 129.4, 132.3, 137.3, 138.4, 166.2.
2-Amino-5-O-benzyl-1,2,4-trideoxy-3-O-(methoxymethyl)-
1-phenyl-d-threo-pentitol (11). To a suspension of LiAlH4
(1.1 g, 28.8 mmol) in dry diethyl ether (80 ml) was added
dropwise a solution of the azide 9 (5.1 g, 14.4 mmol) in dry
diethyl ether (10 ml) at room temperature. The reaction
mixture was stirred for 3 h at room temperature. After cool-
ing to 0ЊC wet diethyl ether (80 ml) was added followed by
the dropwise addition of water (60 ml). The aqueous layer
was removed and then extracted with ether (300 ml). The
combined ether layers were washed with brine ꢀ2×100 ml†;
dried (MgSO4), filtered and evaporated in vacuo. The resi-
due was purified by flash chromatography on silica gel (50%
petroleum ether in ethyl acetate and 20% methyl alcohol in
ethyl acetate as eluents) to give 11 (4.1 g, 86%) as a color-
25
less oil. ‰aŠ ˆϩ9:7 (c 0.45, CH2Cl2); TLC (petroleum
D
ether/ethyl acetate, 1:1): Rfˆ0.1; IR (neat): 3377 (w),
1603, 1495, 1454, 1364, 1207, 1151, 1098, 10.35, 917,
;
839, 740, 700, 607, 536 cmϪ1 1H NMR (250 MHz,
CDCl3): dˆ1.43 (br s, 2H, NH2), 1.90–1.97 (m, 2H),
2.40–2.49, 2.83–2.89 (2m, 2H, CH2Ph), 3.10–3.24 (m,
1H, CH), 3.37 (s, 3H, CH3), 3.59–3.70 (m, 2H, CH2OBn),
3.71–3.76 (m, 1H, CHOMOM), 4.51 (s, 2H, CH2Ph), 4.63–
4.70 (m, 2H, CH2OMe), 7.17–7.26, 7.27–7.37 (2m, 10H);
13C NMR (62.9 MHz, CDCl3):dˆ30.2, 39.7 55.6, 55.8,
66.9, 73.1, 79.6, 96.8, 126.3, 127.6, 128.4, 129.2, 138.5,
139.6; HRMS (EI) calcd for C20H27NO3 329.19908, found
329.20495.
Mosher ester derived from the (R)-acid: 1H NMR
(250 MHz, CDCl3): dˆ1.73–1.82, 1.83–1.91 (2m, 2H,
CH2), 2.73 (dd, Jˆ14.4, 9.9 Hz, 1H, CH2Ph), 3.04 (dd,
Jˆ14.4, 3.4 Hz, 1H, CH2Ph), 3.23 (d, Jˆ1.1 Hz, 3H,
OCH3), 3.34 (s, 3H, CH3 (MOM)), 3.45–3.56 (m, 2H,
CH2OBn), 3.82–3.89 (m, 1H, CHOMOM), 4.41 (d,
Jˆ1.3 Hz, 2H, CH2Ph), 4.60–4.64 (m, 2H, CH2OMe),
5.46–5.53 (m, 1H, CH), 7.00–7.03, 7.07–7.12, 7.15–7.43
(3m, 15H); 13C NMR (62.9 MHz, CDCl3): dˆ30.8, 35.1
55.4, 56.0, 66.2, 73.1, 75.7, 77.8, 97.5, 125.6, 126.6.
127.5, 127.7, 128.3, 128.5, 129.3, 132.0, 137.1, 138.4,
166.1.
5-O-Benzyl-2-[(tert-butoxycarbonyl)amino]-1,2,4-
trideoxy-3-O-(methoxymethyl)-1-phenyl-d-threo-pentitol
(12). To a cooled (0ЊC) solution of the amine 11 (4.2 g,
12.4 mmol) in dry tetrahydrofuran (40 ml) were added
(Boc)2O (3.5 g, 16 mmol), triethylamine (1.5 g,
14.8 mmol) and dimethylaminopyridine (DMAP, 0.3 g,
2.5 mmol). The solution was stirred for 2 h at room
temperature, then diluted with ether (120 ml), washed
successively with a 1 M aqueous KHSO4 solution (40 ml),
water (40 ml), a saturated aqueous NaHCO3 solution
(40 ml), water (40 ml) and brine. The organic layer was
dried (Na2SO4), filtered and concentrated in vacuo. Purifi-
cation of the residue by flash chromatography on silica gel
2-Azido-5-O-benzyl-1,2,4-trideoxy-3-O-(methoxymethyl)-
1-phenyl-d-threo-pentitol (9). To a solution of the
di-protected triol 7 (6.90 g, 20.9 mmol) and triphenyl-
phosphine 6.0 g, 23 mmol) in dry THF (60 ml) at 0ЊC was
added dropwise diethyl azodicarboxylate (DEAD, 4.0 g,
23 mmol) and subsequently diphenylphosphoryl azide
(DPPA, 6.0 g, 21.8 mmol). After stirring for 20 min at 0ЊC
the solution was allowed to stir at room temperature for 3 h.
The reaction solution was partitioned between diethyl ether
(100 ml) and water (80 ml), the two layers were separated,
and the organic layer was washed with brine, dried
(MgSO4), filtered and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel (CH2Cl2
as eluent) to give 9 (6.54 g, 88%) as a colorless oil and the
(20% and 30% ethyl acetate in petroleum ether as eluents)
26
gave 12 (4.9 g, 92%). ‰aŠ ˆϪ18:0 (c 0.5, CH2Cl2); TLC
d
(petroleum ether/ethyl acetate, 8:2): Rfˆ0.43; IR (neat):
3364 (s), 1711 1604, 1498, 1454, 1365, 1245, 1171, 1100,
1034, 918, 851, 739, 699, 607, 463 cmϪ1 1H NMR
;
(250 MHz, CDCl3):dˆ1.31 (s, 9H), 1.83–1.91 (m, 2H),
2.61–2.70 (m, 1H, CH2Ph), 2.91 (dd, Jˆ13.9, 4.8 Hz, 1H,
CH2Ph), 3.40 (s, 3H, CH3), 3.51–3.65 (m, 2H, CH2OBn),
3.76–3.82 (m, 1H, CH), 3.91–4.00 (m, 1H, CH), 4.50 (m,
2H, CH2Ph), 4.53–4.61 (m, 2H, CH2OMe), 5.08 (br d,
Jˆ8.5, 1H, NH), 7.14–7.26, 7.27–7.41 (2m, 10H); 13C
NMR (62.9 MHz, CDCl3): dˆ28.3, 32.2, 36.2, 54.3, 55.9.
66.7, 73.1, 79.0, 97.3, 126.2, 127.8, 128.4, 129.3, 138.3,
138.6, 155.4.
29
by-product 10 (0.55 g, 8%). ‰aŠ ˆϩ18:5 (c 0.504,
CH2Cl2); TLC (CH2Cl2): Rfˆ0.53; IDR (neat): 2170, 2120,
1603, 1590, 1495, 1454, 1365, 1271, 1206, 1184, 1154,
1101, 1030, 965, 918, 739, 700, 618 cmϪ1 1H NMR
;
(250 MHz, CDCl3):dˆ1.89–1.96 (m, 2H), 2.64–2.85 (m,
2H, CH2Ph), 3.39 (s, 3H CH3), 3.59–3.66 (m, 2H,
CH2OBn), 3.81–3.91 (m, 2H, 2CH), 4.56–4.63 (m, 2H,
CH2Ph), 4.66 (q, 2H, CH2OMe), 7.20–7.27, 7.28–7.39
(2m, 10H); 13C NMR (62.9 MHz, CDCl3); dˆ30.5, 36.8,
56.0, 66.4, 67.2, 73.1, 97.0, 126.8, 127.7, 128.5, 129.2,
130.1, 138.0, 138.3.
5-O-Benzyl-2-[(tert-butoxycarbonyl)(methyl)amino]-
1,2,4-trideoxy-3-O-(methoxymethyl)-1-phenyl-d-threo-
pentitol (13). To a cooled (0ЊC) solution of 12 (4.6 g,
10.8 mmol) and MeI (3.1 g, 21.5 mmol) in dry DMF
(40 ml) was added NaH (0.56 g, 14 mmol, 60% in mineral
oil). After complete addition, the suspension was allowed to
warm to room temperature and stirred at this temperature for

M. E. Maier, C. Hermann / Tetrahedron 56 (2000) 557–561
561
18 h. The reaction was quenched at 0ЊC with saturated
aqueous NH4Cl (25 ml). The mixture was partitioned
between ethyl acetate (80 ml) and water (20 ml). The
aqueous layer was extracted with ethyl acetate ꢀ2×80 ml†:
Then the combined organic layers were washed with water
ꢀ3×40 ml†; dried (Na2SO4), filtered and concentrated in
vacuo. The residue was purified by flash chromatography
on silica gel (30% ethyl acetate in petroleum ether) to give
and the Fonds der Chemischen Industrie is gratefully
acknowledged.
References
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25
13 (4.38 g, 91%) as a colorless oil. ‰aŠ ˆϪ26:2 (c 0.578,
D
CH2Cl2); TLC (petroleum ether/ethyl acetate, 8:2);
Rfˆ0.43; IR (neat): 1738, 1693, 1604, 1585, 1496, 1479,
1454, 1391, 1365, 1321, 1244, 1169, 1151, 1034, 959, 919,
874, 824, 772, 738, 699, 607, 544, 520, 464 cmϪ1; 1H NMR
(250 MHz, CDCl3):d (two rotamers)ˆ1.19 (br, s, 9H,
minor), 1.29 (s, 9H, major), 1.69–1.82, 1.93–2.05 (2m,
2H), 2.53 (s, 3H, minor, NCH3), 2.68 (br s, 3H, major,
NCH3), 2.70–2.85 (m, 1H, CH2Ph), 3.11–3.21 (m, 1H,
CH), 4.18–4.22 (m, 1H, CH), 4.49 (s, 2H, CH2Ph), 4.65–
4.78 (m, 2H, CH2OMe), 7.12–7.26, 7.27–7.33 (2m, 10H);
13C NMR (62.9 MHz, CDCl3): dˆ28.3, 32.2, 32.4, 34.5,
56.4, 66.4, 66.8, 73.2, 79.3, 97.2, 126.1, 126.3, 127.7,
128.3, 129.2, 138.5, 139.2, 155.7; HRMS (EI) calcd for
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3-O-(methoxymethyl)-1-phenyl-d-threo-pentitol (14). A
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25
petroleum ether) to give 14 (3.3 g, 96%). ‰aŠ ˆϪ16:0 (c
0.9, CHCl3); TLC (petroleum ether/ethyl aDcetate, 3:7):
Rfˆ0.42; IR (neat): 1738, 1686, 1604, 1496, 1480, 1454,
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´
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´
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(250 MHz, CDCl3): d (two rotamers)ˆ1.16, 1.24 (2 s, 3H,
CH3), 1.52–1.66, 1.82–1.98 (2m, 2H), 2.25 (br s, 1H, OH),
2.49 (s, 3H, minor NCH3), 2.62 (s, 3H, major, NCH3), 2.70–
2.90 (complex, 1H, CH2Ph), 3.01–3.14 (m, 1H, CH2Ph),
3.38 (s, 3H, minor, CH3), 3.41 (s, 3H, major, CH3), 3.62–
3.84 (m, 3H, CH2(OH), CH), 4.20 (br s, 1H, CH), 4.64–4.76
(m, 2H, CH2OMe), 7.07–7.23 (m, 5H); 13C NMR
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34.3, 34.6, 56.2, 56.4, 58.8, 78.3, 79.6, 79.8, 97.4, 97.7,
126.1, 126.3, 128.9, 129.0, 138.8, 155.5, 156.0; HRMS
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354.23059. HRMS (EI) calcd for C19H32NO5 (Mϩ1)
354.22802, found 354.23059.
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Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft