Synthesis of the C-analog of 2-acetylamino-2-deoxy-β-D-glucopyranosyl L- and D-serine

Article abstract of DOI:10.1055/s-1998-4490

Glucosamine was transformed into N-tetrachlorophthaloyl-protected fluoride 5 which gave with allyltrimethylsilane as C-nucleophile in the presence of BF₃·OEt₂ as catalyst β-C-allyl derivative 6 in good yield. Removal of the TCP group

Full text of DOI:10.1055/s-1998-4490

May 1998
SYNTHESIS
753
b
Synthesis of the C-Analog of 2-Acetylamino-2-deoxy- -D-glucopyranosyl L- and D-
Serine
Thomas Fuchss, Richard R. Schmidt*
Fakultät Chemie, Universität Konstanz, Fach M 725, D-78357 Konstanz, Germany
Fax +49(7531)883135
Received 9 October 1997
Abstract: Glucosamine was transformed into N-tetrachlorophtha- 5 as glycosyl donor. Reaction of 5 with allyltrimethylsi-
loyl-protected fluoride 5 which gave with allyltrimethylsilane as
C-nucleophile in the presence of BF3·OEt2 as catalyst b-C-allyl
derivative 6 in good yield. Removal of the TCP group, introduc-
lane in the presence of BF3· OEt2 as catalyst afforded C-
allyl glycoside 6 in a b-selective reaction (Scheme 3). Re-
moval of the TCP group with ethylenediamine in butanol
at 90°C and then acetylation with acetic anhydride in py-
tion of the N-acetyl group, and then ozonolysis afforded C-glyco-
syl acetaldehyde derivative 8 which gave with a glycine derived
phosphonate in a Wittig–Horner reaction a-acylaminoacrylate 10. ridine furnished known N-acetyl derivative 7,7 a useful in-
Hydrogenolysis and removal of the protective groups furnished
termediate for the synthesis of 1b and various other C-
glycosyl amino acids, such as, for example 2b.
target molecule L-1b and also the corresponding D-isomer (D-1b).
The configuration of these compounds was assigned.
Key words: glucosamine, glycopeptides, synthesis, C-analog of
glycosyl serine derivatives
Intracellular posttranslational protein glycosylation,
through which N-acetylglucosamine (GlcNAc) residues
are b-glycosidically linked to the hydroxy group of serine
and/or threonine, has been observed for some time.1 The
specific functions of O-GlcNAc attachment to proteins
have not yet been fully elucidated. Indirect evidence led to
the hypothesis that the O-GlcNAc linkage may have a re-
ciprocal relationship to the regulatory effect of protein
phosphorylation and dephosphorylation.2 Therefore, ac-
cess to glycopeptides carrying hydrolytically stable
GlcNAc residues is of great interest. Hydrolytic stability
without largely affecting the glycopeptide structure can
best be accommodated by the C-glycosyl analog3 of O-(2-
Scheme 2
acetamido-2-deoxy-b-D-glucopyranosyl)serine (Scheme
1, 1a,b) as glycopeptide building block. An efficient syn-
For the synthesis of the amino acid moiety, construction
of an a-acylamino acrylate moiety using a Wittig–Horner
reaction with glycine phosphonate derivative 9b was en-
visaged. To this aim, N-Cbz-protected a-methoxyglycine
methyl ester 8 was transformed under standard conditions
into phosphonate 9a (Scheme 3).8, 9 For the replacement
of the Cbz group by the Boc group hydrogenation with
Pearlman’s catalyst [Pd(OH)2/C] in the presence of triflu-
oroacetic acid and then treatment with di-tert-butyl dicar-
bonate was performed leading to 9b. Ozonolysis of 7 at
–78°C furnished aldehyde 8, which gave with 9b in the
presence of lithium diisopropylamide as base a-acylami-
noacrylate derivative (E/Z)-10 in good yield (73%, E/Z
1:2).
thesis of L- and D-1b is reported in this paper. A synthesis
of the corresponding homolog derived from homoserine
(L-2a,b) (regarded in the literature as analog of N-glu-
coasparagine) based on demanding carbanion chemistry
has been recently reported.4
Scheme 1
Hydrogenation of (E/Z)-10 was performed with Pearl-
man’s catalyst in order to obtain both potential diastere-
omers L-11 and D-11 (Scheme 4); the yield was practically
N-Tetrachlorophthaloyl (TCP) protection of glucosamine
provides excellent glycosyl donors for b-selective glyco-
side bond formation; for example, O-, S-, N-, and C-nu- quantitative and after separation the L/D ratio was 5:4. Lat-
cleophiles have been already successfully employed in er it was found that none of the common chiral hydroge-
this reaction.5, 6 To this aim, known TCP-protected glu- nation catalysts for the selective synthesis of either L-11
cosamine derivative 35 (Scheme 2) was transformed with or D-11 worked well in this case; this is presumably due to
the presence of the additional acetylamino group in the
p-toluenethiol in the presence of FeCl3 into thioglycoside
4 which gave with NBS/DAST the corresponding fluoride
sugar residue.10 In order to obtain the target molecules the

754
Papers
SYNTHESIS
romethyl)acetyl chloride (MTPA-Cl)12 in the presence of
Hünig’s base (i-Pr2NEt) was carried out affording diaste-
reoisomers (L,S)-, (L,R)-14 and (D,S)-, (D,R)-14, respec-
tively. The 1H NMR downfield shift of 0.20 ppm of the O-
methyl group in the MTPA moiety of (L,S)-14 compared
with (L,R)-14 due to interaction with the ester moiety in-
dicates L-configuration for the amino acid residue.10 In ac-
cordance with this assignment (D,R)-14 exhibits a 0.17
ppm downfield shift of the corresponding O-methyl group
in comparison with (D,S)-14, thus confirming D-configu-
ration for the amino acid residue (Scheme 5).
Scheme 3
Scheme 5
O-acetyl groups in L- and D-11 were removed with
NaOMe/MeOH (L- and D-12), then the ester moiety was
hydrolyzed with NaOH (L- and D-13) and finally the Boc
group was cleaved by treatment with TFA in water, thus
furnishing L-1b and D-1b, respectively, in good overall
yield.
In conclusion, an efficient synthesis of target molecule L-
1b and the corresponding D-isomer can be based on readi-
ly available allyl C-glycosides 6 and 7, respectively.
Reagents and solvents were obtained from commercial suppliers. Sol-
vents were purified by distillation and dried as usual, except for dis-
tilled CH2Cl2 and toluene which were passed through columns of
commercially available neutral alumina (ICN Alumina N, activity
grade super I) as an alternative drying procedure. All nonhydrolytic
reactions were conducted in oven-dried glassware and under dry ar-
gon. Analytical TLC was performed on silica gel Merck Kieselgel 60
F254 plates (0.2 mm). The plates were visualized by immersion in mo-
stain [200 mL 10% H2SO4, 10 g (NH4)6Mo7O24·4H2O, 200 mg
Ce(SO4)2] or ninhydrin solution (1% in EtOH) followed by heating
(165°C). Flash chromatography was carried out on Mallinck-
rodt–Baker 7024-02 silica gel 40 m. MPLC was performed by using
columns of silica gel LiChrep 60 with approx. 4600 plates and solvent
pressures of 0.7 to 0.8 MPa. FAB-MS were recorded on a modified
Finnigan MAT 312/AMD 5000. 1H NMR and 13C NMR spectra were
recorded on a BrukerAC 250 Cryospec and a Bruker DRX 600 instru-
ment. Proton chemical shifts are reported in ppm relative to the cor-
responding solvent peak, as are carbon chemical shifts. Assignments
of proton and carbons were carried out with the aid of 600 MHz spec-
tra: COSY, HMBC, HMQC, DEPT, ROESY [strength of observed in-
teractions (ROE): classification into strong (s), medium (m), and
weak (w)]. Measurements of optical rotations were performed on a
Perkin–Elmer polarimeter 241 MC (1 dm cell).
4-Methylphenyl 3,4,6-Tri-O-acetyl-2-deoxy-2-(tetrachlo-
rophthalimido)-1-thio-b-D-glucopyranoside (4):
Scheme 4
Compound 35 (15.2 g, 24.71 mmol) was dissolved in anhyd CH2Cl2
(213 mL) under dry Ar. Subsequently, p-thiocresol (6.44 g,
51.88 mmol) was added and the solution was stirred for 15 min at r.t.
Anhyd FeCl3 (4.81 g, 29.65 mmol) was added and the mixture was
stirred for 2.5 h. For workup it was diluted with CH2Cl2 (220 mL) and
the brown mixture filtered through a Celite pad which was washed
The structural assignment of L- and D-1b was based on the
method of Dale and Mosher.11 To this aim, the Boc group
in L- and D-12 was removed with TFA/H2O and the reac-
tion with (R)- and (S)-a-methoxy-a-phenyl-a-(trifluo-

May 1998
SYNTHESIS
755
with the solvent. The filtrate was extracted with sat. NaHCO3 to give a 14 h. The solution was concentrated in vacuo and again coevaporated
light yellow organic layer which was dried (MgSO4) and concentrated with toluene to remove pyridine. The residue was purified by flash
to dryness. The residue was purified by flash chromatography (toluene/ chromatography (toluene/EtOAc, gradient: 1:1 ® 1:2; amount of sil-
EtOAc, gradient: 10:1 ® 2:1) to afford 4 as a yellow oil (16.78 g, quan- ica gel: 10 fold excess of the crude product is sufficient) to afford 7
titative);TLC (toluene/EtOAc 8:1): Rƒ 0.27; [a]D –8 (c = 1.0, CH2Cl2). (440 mg, 6l%) as a white solid; TLC (toluene/EtOAc 1:3): Rƒ 0.20.
1H NMR (250 MHz, CDCl3): d = 1.84, 1.99, 2.08 (3 s, 9 H, 3 OAc), The reported analytic and spectroscopic data7 are in accordance with
2.28 (s, 3 H, Me), 3.82 (ddd, 3J4,5 = 10.1, 3J5,6 = 4.8, 3J5,6¢ = 2.5 Hz, l our results.
2
H, 5-H), 4.16 (dd, Jgem = 12.4,3J5,6¢ = 2.5 Hz, 1 H, 6¢-H), 4.26 (dd,
2Jgem = 12.4, 3J5,6 = 4.8 Hz, 1 H, 6-H), 4.28 (dd, 3J1,2 = 3J2,3 = 10.1 Hz,
4-Acetamido-5,6,8-tri-O-acetyl-3,7-anhydro-2,3,4-trideoxy-D-
1 H, 2-H), 5.10 (dd, 3J3,4 = 3J4,5 = 10.1 Hz, 1 H, 4-H), 5.58 (d, 3J1,2
10.1 Hz, 1 H, l-H), 5.67 (dd, J2,3
=
glycero-D-gulo-octose (8):
3
=
3J3,4 = 10.1 Hz, 1 H, 3-H),
A solution of 7 (100 mg, 270 mmol) in anhyd MeOH (10 mL) was cooled
to –78°C. Ozone was then passed through the solution under vigorous
stirring. The maximum time for the ozone treatment was 5 min (flow: ap-
prox. 60 L O2/h generating 3 L O3/h). This resulted in the formation of a
bluish solution. Dry Ar was passed through the cold solution in order to
remove excess ozone. Ph3P (70.6 mg, 270 mmol) and CH2Cl2 (4 mL)
were added and the solution was allowed to warm up to r.t. while stirring
was continued for 1.5 h. The clear solution was concentrated to dryness
and purified by flash chromatography (CH2Cl2/MeOH 30:1) to yield 8
(84.4 mg, 84%) as a colorless oil; TLC (CH2Cl2/MeOH 10:1): Rƒ 0.38;
[a]D –26 (c = 1.0, CH2Cl2).
7.02–7.06, 7.23–7.27 (2 m, 4 H, phenyl).
13C NMR (62.9 MHz, CDCl3): d = 20.4, 20.5, 20.7, 21.1 [4 C,
OC(O) CH3, SPhCH3], 54.6, 62.0, 68.4, 71.6, 76.0 (5 C, 2-, 3-, 4-, 5-,
6-C), 82.3 (1 C, 1-C), 126.5–140.5 (12 C, Ph), 162.1, 163.2 {2 C,
N[C(O)]2}, 169.3, 170.4, 170.5 [3 C, OC(O)CH3].
Anal. calcd for C27H23Cl4NO9S (679.36): C 47.74, H 3.41, N 2.06;
found: C 47.64, H 3.46, N 2.01.
3,4,6-Tri-O-acetyl-2-deoxy-2-(tetrachlorophthalimido)-a-D-glu-
copyranosyl Fluoride (5):
Compound 4 (1.0 g, 1.47 mmol) was dissolved in anhyd CH2Cl2 1H NMR (250 MHz, CDCl3): d = 1.89 (s, 3 H, NHAc), 2.01 (s, 6 H, 2
(14 mL) under dry Ar and was cooled to –15°C. Then DAST OAc), 2.05 (s, 3 H, OAc), 2.71 (ddd, 3J1,2¢ < 1.0, 2Jgem = 18.0, 3J2¢,3
=
(292 mL, 2.21 mmol) was added and, after stirring for 5 min, NBS 7.4 Hz, 1 H, 2¢-H), 2.81 (ddd, 3J1,2 <1.0, 2Jgem = 18.0, 3J2,3 = 4.5 Hz,
(341 mg, 1.91 mmol) was added and stirring was continued for 10 1 H, 2-H), 3.61 (ddd, 3J6,7 = 9.8, 3J7,8¢ = 2.2, 3J7,8 = 4.8 Hz, 1 H, 7-H),
min. Thereafter, the red mixture was allowed to warm up to r.t. TLC 3.89 (ddd, 3J3,4 = 9.8, 3J2,3 = 4.5, 3J2¢,3 = 7.4 Hz, 1 H, 3-H), 4.03 (dd,
(toluene/EtOAc 8:1) indicated complete fluorination after 5 h. The 3J7,8¢ = 2.2, 3Jgem = 12.4 Hz, 1 H, 8¢-H), 4.08 (dd, 3J3,4 = 3J4,5 = 9.8 Hz,
solution was diluted with CH2Cl2 and extracted with sat. NaHCO3 1 H, 4-H), 4.99 (dd, 3J4,5 = 3J5,6 = 9.8 Hz, 1 H, 5-H), 5.06 (dd, 3J5,6
=
and NaS2O3. The organic layer was dried (MgSO4) and concentrated
in vacuo. The residue was purified by flash chromatography (toluene/ (dd, 3J1,2 = 3J1,2¢ < 1 Hz, 1 H, 1-H).
EtOAc 10:1) to yield 5 (610 mg, 72%) as a yellow foam; TLC (tolu- 1 3C NMR (62.9 MHz, CDCl3): d = 20.5, 20.6, 20.7 [3 C, OC(O)CH3],
3J6,7 = 9.8 Hz, 1 H, 6-H), 5.59 (d, 3JNH,4 = 9.1 Hz, 1 H, NHAc), 9.72
ene/EtOAc 8:1): Rƒ 0.25; [a]D +55 (c = 1.0, CH2Cl2).
23.0 [1 C, NHC(O)CH3], 37.2, 46.0, 53.4, 62.2, 68.3, 74.0, 75.7 (7 C,
1H NMR (250 MHz, CDCl3): d = 1.89, 2.02, 2.11 (3 s, 9 H, 3 OAc), 2-, 3-, 4-, 5-, 6-, 7-, 8-C), 169.3–173.2 [4 C, 3 OC(O)CH3,
3.95 (ddd, 3J5,6 = 4.8, 3J5,6¢ = 2.0, 3J4,5 = 9.2 Hz, 1 H, 5-H), 4.18 (dd, NHC(O)CH3], 199.5 (1 C, 1-C).
3J5,6¢ = 2.0, 2Jgem = 12.5 Hz, 1 H, 6¢-H), 4.28–4.45 (m, 2 H, 2-, 6-H), FAB-MS (positive mode, matrix: 3-nitrobenzyl alcohol): m/z (%) =
5.19 (dd, 3J3,4 = 10.0, 3J4,5 = 9.5 Hz, 1 H, 4-H), 5.71 (dd, 3J2,3 = 9.5, 747 (5) [(M2H]+, 374 (89) [MH]+.
3J3,4 = 10.0 Hz, 1 H, 3-H), 6.02 (dd, 3J1,2 = 7.7, 2J1,F = 52.2 Hz, 1 H, Anal. calcd for C16H23NO9 (373.36): C 51.47, H 6.21, N 3.75; found
1-H).
C 51.36, H 6.34, N 3.60.
FAB-MS (positive mode, matrix: CH2Cl2/3-nitrobenzyl alcohol 1:1,
NA1): m/z (%) = 748 (4) [(M + NA1)Na]+, 598 (37) [MNa]+.
Anal. calcd for C20H16Cl4FNO9 (575.16): C 41.77, H 2.80, N 2.44;
found C 41.64, H 2.91, N 2.32.
Methyl 2-(Benzyloxycarbonylamino)-2-(diethoxyphosphoryl)ac-
etate (9a):
2-(Benzyloxycarbonylamino)-2-methoxyacetic acid9 (8) (12 g,
47.38 mmol) was dissolved in anhyd toluene (72 mL) at 50°C under
dry Ar. The solution was cooled to r.t. and PCl3 (5.17 mL, 59.22
mmol) was added. The solution was stirred for 18 h at 70°C, then it
1,3,4-Tri-O-acetyl-2,6-anhydro-5,7,8,9-tetradeoxy-5-(tetrachlo-
rophthalimido)-L-glycero-L-gulo-non-8-enitol (6):
Compound 5 (2.5 g, 4.38 mmol) was dissolved in anhyd CH2Cl2 was cooled again to r.t., (EtO)3P (8.53 mL, 49.75 mmol) was added
(42 mL) and allyltrimethylsilane (6.94 mL, 43.47 mmol) was added and then it was heated to 70°C for 3 h. For workup the mixture was
under dry Ar. The solution was cooled to –10°C. A catalytic amount concentrated in vacuo and the residue was partitioned between Et2O
of BF3·Et2O (273 mL, 2.17 mmol) was added dropwise and stirring and sat. NaHCO3. The organic layer was dried (MgSO4) and concen-
was continued at –5°C for 14 h. During this time a cloudy precipitate trated to dryness. Flash silica gel chromatography eluting with a gra-
was formed. Thereafter, the mixture was diluted with CH2Cl2, ex- dient of toluene/EtOAc (2:1 ® 1:1) afforded 9a (10.83 g, 64%) as a
tracted with sat. NaHCO3, dried (MgSO4) and concentrated to dry- white, waxy solid; TLC (toluene/EtOAc 1:1): Rƒ 0.18.
ness. The remaining residue was purified by flash chromatography 1H NMR (250 MHz, CDCl3): d = 1.23–1.30 (m, 6 H, 2 OCH2CH3),
(toluene/EtOAc, 6:1) to afford 6 (1.89 g, 73%) as a yellow foam; TLC 3.77 (s, 3 H, CO2Me), 4.05–4.16 (m, 4 H, 2 OCH2CH3), 4.85 (dd, 2J2,P
(toluene/EtOAc 6:1): Rƒ 0.37.
The reported analytic and spectroscopic data7 are in accordance to our d, 3J2,NH ~9.2 Hz, 1 H, NH), 7.24–7.30 (m, 5 H, phenyl).
= 22.3, 3J2,NH = 9.2 Hz, 1 H, 2-H), 5.09 [m, 2 H, CH2 (Cbz)], 5.63 (br.
results.
1 3C NMR (62.9 MHz, CDCl3): d = 16.1, 16.2 (2 C, 2 OCH2CH3), 52.5
(d, 1J2,P = 146.9 Hz, 1 C, 2-C), 53.1 (1 C, CO2Me), 63.6–63.8 (2 C, 2
OCH2CH3), 67.4 [1 C, CH2 (Cbz)], 128.0–128.4, 135.8 (6 C, phenyl),
155.5–155.6 [1 C, NHC(O)O], 167.3–167.4 (1 C, CO2Me).
Anal. calcd for C15H22NO7P (359.31): C 50.14, H 6.17, N 3.90; found
C 50.11, H 6.19, N 3.97.
5-Acetamido-1,3,4-tri-O-acetyl-2,6-anhydro-5,7,8,9-tetradeoxy-
L-glycero-L-gulo-non-8-enito1 (7):
Compound 6 (1.16 g, 1.94 mmol) was dissolved in BuOH (10 mL)
under dry Ar. Ethane-1,2-diamine (1.94 mL 28.89 mmol) was added
and the solution heated to 90°C for 22 h. The resulting reddish solu-
tion was concentrated in vacuo and coevaporated with toluene. The Methyl 2-(tert-Butoxycarbonylamino)-2-(diethoxyphosphoryl)ac-
red oil was dissolved in anhyd pyridine (40 mL) and Ac2O (30 mL) etate (9b):
after removal of all volatile residues (high vacuum). A catalytic Compound 9a (200 mg, 557 mmol) was dissolved in EtOAc (23 mL).
amount of DMAP was added and stirring was continued at r.t. for To this solution was subsequently added TFA (52 mL, 670 mmol), wa-

756
Papers
SYNTHESIS
ter (0.2 mL) and Pearlman’ s catalyst Pd(OH)2/C (60 mg). The mix-
ture was treated with hydrogen for 2 h at normal pressure and r.t.
Thereafter, the black suspension was filtered through a Celite pad
which was washed with MeOH. The clear filtrate was concentrated in
vacuo to a volume of approx. 6 mL to remove MeOH. Then it was
again diluted with EtOAc (4 mL) and NaHCO3 (47 mg) was added
followed by vigorous stirring in order to neutralize TFA. After 10 min
Boc2O (244 mg, 1.12 mmol) was added. When this was completely
dissolved, Et3N (39 mL) was added and stirring was continued for
l4 h at r.t. For workup the mixture was concentrated to dryness and
the remaining residue was purified by flash chromatography (toluene/
EtOAc 1:2) to afford 9b (151 mg, 83%) as an amorphous, white solid;
TLC (toluene/EtOAc 1:3): Rƒ 0.37 (ninhydrin).
NHC(O)CH3], 28.1–28.2 (3 C, CMe3), 68.6 (1 C, 169.3–171.4 [4 C,
3 OC(O)CH3, NHC(O)CH3]. (E)-10: d = 31.1 (1 C, 4-C), 52.2 (1 C,
CO2Me), 53.9 (1 C, 6-C), 62.4 (1 C, 10-C), 68.5 (1 C, 8-C), 74.4 (1 C,
7-C), 75.6 (1 C, 9-C), 79.3 (1 C, 5-C), 124.5 (1 C, 3-C), 128.8 (1 C,
2-C), 153.0 [1 C, NHC(O)O], 164.3 (1 C, 1-C). (Z)-10: d = 30.5 (1 C,
4-C), 52.3 (1 C, CO2Me), 53.7 (1 C, 6-C), 62.3 (1 C, 10-C), 68.5 (1 C,
8-C), 74.1 (1 C, 7-C), 75.5 (1 C, 9-C), 78.1 (1 C, 5-C), 125.5 (1 C, 3-
C), 129.3 (1 C, 2-C), 153.5 [1 C, NHC(O)O], 165.1 (1 C, 1-C).
ROESY (600 MHz, CDCl3, characteristic ROE): (E)-10: d = 2.92,
3.76 (4-H, CO2Me; m). (Z)-10: d = 3.74, 6.49 (3-H, CO2Me; m).
FAB-MS (positive mode, matrix: 3-nitrobenzyl alcohol, NaI): m/z
(%) = 717 (6) [(M + NaI)Na]+, 567 (100) [MNa]+, 467 (9) [(M – C4H8
– CO2)Na]+.
1H NMR (250 MHz, CDCl3): d = 1.27–1.33 (m, 6 H, 2 OCH2CH3),
1.41 [br. s, 9 H, CMe3 (Boc)], 3.78 (s, 3 H, CO2Me), 4.08–4.20 (m, 4
Anal. calcd for C24H36N2O12 (544.55): C 52.94, H 6.66, N 5.14; found
C 52.95, H 6.65, N 5.26.
3
H, 2 OCH2CH3), 4.80 (dd, 2J2,P = 22.5, J2,NH = 9.3 Hz, 1 H, 2-H),
5.30 (br. d, 3J2,NH ~9.3 Hz, 1 H, NH).
Methyl (2S)-6-Acetamido-7,8,10-tri-O-acetyl-5,9-anhydro-2-(tert-
butoxycarbonylamino)-2,3,4,6-tetradeoxy-D-glycero-D-gulo-de-
conate (L-11), Methyl (2R)-6-Acetamido-7,8,10-tri-O-acetyl-5,9-
anhydro-2-(tert-butoxycarbonylamino)-2,3,4,6-tetradeoxy-D-
glycero-D-gulo-deconate (D-11):
1 3C NMR (62.9 MHz, CDCl3): d = 16.2–16.3 (2 C, 2 OCH2CH3), 28.2
(3 C, CMe3), 52.1 (d, 1J2,P = 147.0 Hz, 1 C, 2-C), 53.0 (1 C, CO2Me),
63.6–63.7 (2 C, 2 OCH2CH3), 80.7 (1 C, CMe3), 154.8–154.9 [1 C,
NHC(O)O], 167.6–167.7 (1 C, CO2Me).
Anal. calcd for CM2H24NO7P(325.30): C 44.31, H 7.44, N 4.31; found
C 44.10, H 7.46, N 4.31.
Compound (E/Z)-10 (100 mg, 184 mmol) was dissolved in EtOAc
(7.4 mL). To this solution was subsequently added MeOH (0.4 mL),
water (0.1 mL), HOAc (10 mL, 89 mmol) and Pearlman’s catalyst
Pd(OH)2/C (30 mg). The mixture was treated with hydrogen for 24 h
under normal conditions. Thereafter, the black suspension was fil-
tered through a Celite pad which was washed with MeOH. The clear
filtrate was concentrated to dryness to afford a mixture of the pure
compounds L-11 and D-11 (98.4 mg, 98%). Separation of the com-
pound mixture was performed by MPLC eluting with toluene/acetone
(3:2) to yield L-11 (54.2 mg, 54%) as a colorless, waxy solid and D-
11 (44.2 mg, 44%) as an amorphous, white solid; TLC (toluene/ace-
tone 2:1): Rƒ L-11 0.25; Rƒ D-11 0.19; [a]D L-11 –27 (c = 1.0, CH2Cl2);
[a]D D-11 –32 (c = 1.0, CH2Cl2).
Methyl (E and Z)-6-Acetamido-7,8,10-tri-O-acetyl-5,9-anhydro-
2-(tert-butoxycarbonylamino)-2,3,4,6-tetradeoxy-D-glycero-D-
gulo-dec-2-enonate (E/Z-10):
i-Pr2NH (58 mL, 411 mmol) was added under dry Ar to a two-necked
50-mL flask charged with anhyd THF (2 mL). The solution was
cooled to –30°C, BuLi (257 mL, 411 mmol) was added and stirring
was continued for 20 min. 9b (134 mg, 411 mmol) was dissolved in
anhyd THF (5 mL) and was added to the mixture at –40°C. Over the
course of 20 min, the solution was allowed to warm up to –10 °C.
Then the solution was cooled to –60°C and 8 (128 mg, 343 mmol, dis-
solved in 5 mL of anhyd THF) was added dropwise. The cooling was
stopped after 10 min and the solution warmed up to r.t. while stirring
was continued for an additional 3 h. The appearance of a light yellow
color after addition of 8 indicates that the reaction is proceeding. For
workup the mixture was diluted with Et2O and extracted with sat.
NH4Cl. The aqueous layer was washed with additional Et2O. The
combined organic layers were dried (MgSO4), filtered, concentrated
to dryness and the remaining residue was purified by flash chroma-
tography (CH2Cl2/MeOH 40:1) to afford (E/Z)-10 (135 mg, 73%) as
a white foam comprising an inseparable mixture (MPLC) of the E-
and Z-isomers (E/Z 1:2 as determined by peak integration of 1H
NMR); TLC (CH2Cl2/MeOH 10:1): Rƒ 0.61–0.63.
1H NMR (250 MHz, CDCl3): L-11: d = 1.39 (br. s, 9 H, CMe3),
1.42–1.79 (m, 4 H, 3-, 3¢-, 4-, 4¢-H), 1.89 (s, 3 H, NHAc), 1.98 (br. s,
6 H, 2 OAc), 2.05 (s, 3 H, OAc), 3.36 (m, 1 H, 5-H), 3.55 (m, 1 H, 9-
H), 3.69 (s, 3 H, CO2Me), 3.99 (ddd, 3J5,6 = 3J6,7 = 3JNH,6 = 9.6 Hz, 1
H, 6-H), 4.05 (dd, 2Jgem = 12.3, 3J9,10¢ = 2.6 Hz, 1 H, 10¢-H), 4.17 (dd,
2Jgem = 12.3, 3J9,10 = 5.5 Hz, 1 H, 10-H), 4.14 (br. m, 1 H, 2-H), 4.96
(dd, 3J6,7 = 3J7,8 = 9.5 Hz, 1 H, 7-H), 5.01 (dd, 3J7,8 = 3J8,9 = 9.5 Hz, 1
H, 8-H), 5.17 (d, 3JNH,6 = 9.6 Hz, 1 H, NHAc), 5.60 (br. d, 3JNH,2 ~9.0
Hz, 1 H, NHBoc).
1H NMR (250 MHz, CDCl3): D-11: d = 1.41 (br. s, 9 H, CMe3),
1.54–1.73, 1.81–2.04 (2 m, 4 H, 3-, 3¢-, 4-, 4¢-H), 1.91 (s, 3 H, NHAc),
2.00 (br. s, 6 H, 2 OAc), 2.07 (s, 3 H, OAc), 3.29 (m, 1 H, 5-H), 3.52
(ddd, 3J8,9 = 9.7, 3J9,10 = 5.2, 3J9,10¢ = 2.4 Hz, 1 H, 9-H), 3.70 (s, 3 H,
CO2Me), 3.97 (ddd, 3J5,6 = 3J6,7 = 3JNH,6 = 9.8 Hz, 1 H, 6-H), 4.06 (dd,
2Jgem = 12.4, 3J9,10¢ = 2.4 Hz, 1 H, 10¢-H), 4.16 (dd, 2Jgem = 12.4, 3J9,10
1H NMR (250 MHz, CDCl3): (E)-10 and (Z)-10 (unassigned signals):
d = 1.42 (br. s, 9 H, CMe3), 1.89 (s, 3 H, NHAc), 1.99 (br. s, 6 H, 2
OAc), 2.07 (s, 3 H, OAc). (E)-10: d = 2.68 (ddd, 2Jgem = 16.1, 3J3,4¢
3J4¢,5 = 7.6 Hz, 1 H, 4¢-H), 2.92 (ddd, 2Jgem = 16.1, 3J3,4 = 7.8, 3J4,5
=
=
= 5.2 Hz, 1 H, 10-H), 4.18 (br. m, 1 H, 2-H), 4.92 (dd, 3J6,7 = 3J7,8
=
9.8 Hz, 1 H, 7-H), 5.02 (dd, 3J7,8 = 3J8,9 = 9.8 Hz, 1 H, 8-H), 5.16 (br.
d, 3JNH,2 ~9.5 Hz, 1 H, NHAc), 5.47 (d, 3JNH,2 = 9.5 Hz, 1 H, NHBoc).
13C NMR (62.9 MHz, CDCl3): L-11: d = 20.5–20.6 [3 C, 3
OC(O)CH3], 27.0, 27.7 (2 C, 3-, 4-C), 28.3 (3 C, CMe3), 52.2, 52.6 (2
C, 2-, 6-C), 53.2 (1 C, CO2Me), 68.6 (1 C, CMe3), 62.5, 74.5, 75.7,
77.7, 79.8 (5 C, 5-, 7-, 8-, 9-, 10-C), 155.8 [1 C, NC(O)O], 169.3,
3.7 Hz, 1 H, 4-H), 3.40 (ddd, 3J4,5 = 3.7, 3J4¢,5 = 7.6, 3J5,6 = 10.0 Hz, 1
H, 5-H), 3.60 (m, 1 H, 9-H), 3.76 (s, 3 H, CO2Me), 4.00 (dd, 3J5,6
=
3J6,7 = 10.0 Hz, 1 H, 6-H), 4.04 (dd, 2Jgem = 12.2, 3J9,10¢ = 2.3 Hz, 1 H,
10¢-H), 4.19 (dd, 2Jgem – 12.2, 3J9,10 = 5.6 Hz, 1 H, 10-H), 5.01 (dd,
3J6,7 = 10.0, 3J7,8 = 9.5 Hz, 1 H, 7-H), 5.02 (dd, 3J7,8 = 3J8,9 = 9.5 Hz,
1 H, 8-H), 5.62 (d, 3J6,NH = 9.3 Hz, 1 H, NHAc), 6.59 (br. s, 1 H, NH-
Boc), 6.68 (br. dd, 3J3,4 = 3J3,4¢ ~7.7 Hz, 1 H, 3-H). (Z)-10: d = 2.36
(ddd, 2Jgem = 16.1, 3J3,4¢ = 3J4¢,5 = 7.6 Hz, 1 H, 4¢-H), 2.54 (ddd, 2Jgem
= 16.1, 3J3,4 = 7.8, 3J4,5 = 3.7 Hz, 1 H, 4-H), 3.53 (m, 1 H, 5-H), 3.60
(m, 1 H, 9-H), 3.74 (s, 3 H, CO2Me), 3.96 (dd, 3J5,6 = 3J6,7 = 10.0 Hz,
1 H, 6-H), 4.08 (dd, 2Jgem = 12.2, 3J9,10¢ = 2.3 Hz, 1 H, 10¢-H), 4.17
170.2, 170.7, 171.5, 173.1 [5 C, NHC(O)CH3, CO2Me,
OC(O)CH3].
3
Anal. calcd for C24H38N2O12 (546.58): C 52.74, H 7.01, N 5.13; found
C 52.94, H 7.10, N 5.14.
(dd, 2Jgem = 12.2, 3J9,10 = 5.5 Hz, 1 H, 10-H), 5.02 (dd, 3J7,8 = 3J8,9
=
Methyl (2S)-6-Acetamido-5,9-anhydro-2-(tert-butoxycarbonyl-
amino)-2,3,4,6-tetradeoxy-D-glycero-D-gulo-deconate (L-12):
Compound L-11 (108 mg, 197.6 mmol) was dissolved in anhyd
MeOH (2.4 mL). 0.173 M NaOMe in MeOH (36 mL, 5.93 mmol) was
added and the reaction solution (8.0 < pH ≤ 8.5) was stirred at r.t. for
2 h. Subsequently, the solution was diluted with MeOH, and Amber-
9.5 Hz, 1 H, 8-H), 5.04 (dd, 3J6,7 = 10.0, 3J7,8 = 9.5 Hz, 1 H, 7-H), 5.67
(d, 3JNH,6 = 9.3 Hz, 1 H, NHAc), 6.39 (br. s, 1 H, NHBoc), 6.49 (br.
dd, 3J3,4 = 3J3,4¢ ~7.7 Hz, 1 H, 3-H).
13C NMR (62.9 MHz, CDCl3): (E)-10 and (Z)-10 (not assigned sig-
nals):
d = 20.620.7 [3 C, 3 OC(O)CH3], 23.1–23.2 [1 C,

May 1998
SYNTHESIS
757
lite IR-120 [H+] (8.0 mg) was added and stirring was continued for
15 min (pH neutral). The mixture was filtered and concentrated to
dryness to afford L-12 (70.6 mg, 85%) as a colorless solid; TLC
(CH2Cl2/MeOH 3:1): Rƒ 0.67; [a]D –19 (c = 1.0, MeOH).
(2R)-6-Acetamido-5,9-anhydro-2-(tert-butoxycarbonylamino)-
2,3,4,6-tetradeoxy-D-glycero-D-gulo-deconic Acid (D-13):
For the preparation see L-13. To a solution of D-12 (66.2 mg,
157.4 mmol) in MeOH (6 mL) and water (4 mL) was added a solution
of 1.0 M NaOH in MeOH (0.47 mL, 470 mmol). The workup afforded
D-13 (46.1 mg, 72%) as a colorless oil; TLC (CH2Cl2/MeOH 1:1): Rƒ
0.32; [a]D –20 (c = 1.0, MeOH).
1H NMR (250 MHz, MeOH-d4): d = 1.48 (br. s, 9 H, CMe3), 1.54–1.77
(m, 2 H, 4-, 4¢-H), 1.87–1.98 (m, 2 H, 3-, 3¢-H), 2.03 (s, 3 H, NHAc),
3.21–3.31 (m, 2 H, 5-, 9-H), 3.32 (dd, 3J7,8 = 3J8,9 = 8.6 Hz, 1 H, 8-H),
3.41 (dd, 3J6,7 =3J7,8 = 8.6 Hz, 1 H, 7-H), 3.66 (dd, 3J5,6 =3J6,7 = 8.6 Hz,
1 H, 6-H), 3.69 (dd, 2Jgem = 12.0, 3J9,10¢ = 5.8 Hz, 1 H, 10¢-H), 3.75 (s, 3
H, CO2Me), 3.89 (dd, 2Jgem = 12.0, 3J9,10 = 2.3 Hz, 1 H, 10-H), 4.11 (dd,
3J2,3 = 4.3, 3J2,3¢ = 8.7 Hz, 1 H, 2-H), 4.93 (s, 5 H, 3 OH, 2 NH).
FAB-MS (positive mode, matrix: MeOH/3-nitrobenzyl alcohol 1:1):
m/z (%) = 421 (17) [MH]+, 365 (34) [(M – C4H8)H]+, 321 (100) [(M
– C4H8 – CO2)H]+.
1H NMR (250 MHz, MeOH-d4): d = 1.40–2.09 (m, 4 H, 3-, 3¢-, 4-, 4¢-
H), 1.48 (br. s, 9 H, CMe3), 2.02 (s, 3 H, NHAc), 3.21–3.36 (m, 3 H,
5-, 8-, 9-H), 3.40 (dd, 3J6,7 = 3J7,8 = 9.3 Hz, 1 H, 7-H), 3.62 (dd, 3J5,6
= 3J6,7 = 9.3 Hz, 1 H, 6-H), 3.66 (dd, 2Jgem = 12.6, 3J9,10¢ = 5.6 Hz, 1
H, 10,-H), 3.89 (dd, 2Jgem = 12.6, 3J9,10¢ = 2.0 Hz, 1 H, 10-H), 4.15 (m,
1 H, 2-H), 4.92 (br. s, 6 H, 4 OH, 2 NH).
FAB-MS (positive mode, matrix: MeOH/3-nitrobenzyl alcohol 1:1):
m/z (%) = 429 (18) [MNa]+, 407 (32) [MH]+, 351 (52) [(M –
C4H8)H]+, 307 (100) [(M – C4H8 – CO2)H]+.
(2S)-6-Acetamido-5,9-anhydro-2-(tert-butoxycarbonylamino)-
2,3,4,6-tetradeoxy-D-glycero-D-gulo-deconic Acid (L-13):
To a solution of L-12 (70 mg, 166.4 mmoL) in MeOH (6 mL) and wa-
ter (4 mL) was added 1.0 M NaOH (0.5 mL, 500 mmoL). The solution
was stirred for 14 h at r.t. Subsequently, Amberlite IR-120 [H+]
(ca. 450 mg) was added and after stirring for 30 min, the pH dropped
to 7. The mixture was filtered and concentrated to dryness to give L-
13 (51.4 mg, 76%) as a colorless oil; TLC (CH2Cl2/MeOH 1:1): Rƒ
0.32; [a]D –16 (c = 1.0, MeOH).
(2R)-6-Acetamido-2-amino-5,9-anhydro-2,3,4,6-tetradeoxy-D-
glycero-D-gulo-deconic Acid (D-1b):
For the preparation see L-1b. Compound D-13 (45.7 mg, 112.4 mmol)
was dissolved in TFA (2 mL) and water (0.2 mL) was added. D-1b
(33.1 mg, 96%) was obtained as a colorless solid; TLC (CHCl3/
MeOH/H2O 60:35:8): Rƒ 0.1; [a]D –9 (c = 0.66, MeOH).
1H NMR (250 MHz, MeOH-d4): d = 1.55–1.67, 1.78–1.88 (2 m, 2 H,
4-, 4¢-H), 2.02 (s, 3 H, NHAc), 1.92–2.25 (m, 2 H, 3-, 3¢-H), 3.28–3.48
(m, 4 H, 5-, 7-, 8-, 9-H), 3.64 (dd, 3J5,6 = 3J6,7 = 9.2 Hz, 1 H, 6-H),
3.67 (m, 1 H, 10¢-H), 3.92 (dd, 2Jgem = 11.9, 3J9,10 < 2 Hz, 1 H, 10-H),
4.06 (dd, 3J2,3 = 4.6, 3J2,3¢ = 9.2 Hz, 1 H, 2-H), 4.97 (br. s, 7 H, 3 OH,
4 NH).
1H NMR (250 MHz, MeOH-d4): d = 1.41–1.95 (m, 4 H, 3-, 3¢-, 4-, 4¢-
H), 1.48 (br. s, 9 H, CMe3), 2.03 (s, 3 H, NHAc), 3.21–3.34 (m, 3 H,
5-, 8-, 9-H), 3.41 (dd, 3J6,7 = 3J7,8 = 9.0 Hz, 1 H, 7-H), 3.67 (dd, 3J5,6
= 3J6,7 = 9.0 Hz, 1 H, 6-H), 3.69 (dd, 2Jgem = 12.0, 3J9,10¢ = 5.7 Hz, 1
H, 10¢-H), 3.90 (dd, 2Jgem = 12.0, 3J9,10¢ = 2.4 Hz, 1 H, 10-H), 4.08 (dd,
3J2,3 = 4.9, 3J2,3¢ = 9.0 Hz, 1 H, 2-H), 4.93 (br. s, 6 H, 4 OH, 2 NH).
Anal. calcd for: C17H30N2O9·1.3 H2O (429.86): C 47.50, H 7.64, N
6.52; found C 47.61, H 7.79, N 6.33.
1 3C NMR (150.8 MHz, MeOH-d4): d = 22.9 [1 C, NHC(O)CH3], 27.9
(1 C, 3-C), 28.0 (1 C, 4-C), 53.7 (1 C, 2-C), 56.4 (1 C, 6-C), 62.9 (1
C, 10-C), 72.3 (1 C, 8-C), 77.0 (1 C, 7-C), 79.4 (1 C, 5-C), 81.7 (1 C,
9-C), 171.8 (1 C, NHC(O)CH3), 173.9 (1 C, 1-C).
FAB-MS (positive mode, matrix: MeOH/3-nitrobenzyl alcohol 1:1):
(2S)-6-Acetamido-2-amino-5,9-anhydro-2,3,4,6-tetradeoxy-D-
glycero-D-gulo-deconic Acid (L-1b):
m/z (%) = 329 (9) [MNa]+, 307 (68) [MH]+.
Anal. calcd for: C12H22N2O7·0.5 H2O (315.33): C 45.71, H 7.35, N
8.88; found C 45.79, H 7.41, N 8.90.
Compound L-13 (46 mg, 113.2 mmol) was dissolved in TFA (2 mL).
Water (0.2 mL) was added and the solution was stirred for 2.5 h at r.t.
Then the solution was concentrated in vacuo and coevaporated with
water. After drying under high vacuum pure L-1b (33.6 mg, 97%)
could be obtained as a colorless solid; TLC (CHCl3/MeOH/H2O
60:35:8): Rƒ 0.1; [a]D –5 (c = 0.66, MeOH).
General Procedure for the Synthesis of the MTPA-Amides (L,S)-,
(L,R)-14, (D,S)-, (D,R)-14:
The compounds L- and D-11 were dissolved in TFA (2 mL) then water
(0.1 mL) was added. After stirring for approx. 2.5 h at r.t. the solution
was concentrated to dryness in vacuo. The remaining oily residue was
dissolved in CH2Cl2 (30 mL) and then washed with 43.5 mM aq
K2CO3 (10 mL). The organic layer was dried (MgSO4), filtered and
evaporated to dryness. The oily residue was dissolved either in anhyd
MeCN (2 mL) and in CH2Cl2 (1.5 mL; starting from L-11) or in
CH2Cl2 only (2.5 mL; starting from D-11). Subsequently, i-Pr2NEt
(1.1 equiv) and the appropriate a-methoxy-a-trifluoromethyl-a-phe-
nylacetyl chloride12 (MTPA-Cl, 1.3 equiv) were added and stirring
was continued for 2 h. Thereafter, the mixture was diluted with
CH2Cl2, extracted with sat. NaHCO3 and dried (MgSO4). The suspen-
sion was filtered and concentrated in vacuo. The residue was purified
by flash chromatography (CH2Cl2/MeOH 40:1) to afford the corre-
sponding MTPA-amides as colorless oils.
1H NMR (250 MHz, D2O): d = 1.31–1.45 (m, 1 H, 4¢-H), 1.60–1.74
(m, 1 H, 4-H), 1.89 (s, 3 H, NHAc), 1.90–1.98 (m, 2 H, 3-, 3¢-H),
3.21–3.29 (m, 3 H, 5-, 8-, 9-H), 3.32 (dd, 3J6,7 = 3J7,8 = 9.3 Hz, 1 H,
7-H), 3.48 (dd, 3J5,6 = 3J6,7 = 9.3 Hz, 1 H, 6-H), 3.54 (dd, 2Jgem = 12.2,
3J9,10¢ = 5.4 Hz, 1 H, 10¢-H), 3.74 (dd, 2Jgem = 12.2, 3J9,10 = 2.0 Hz, 1
H, 10-H), 3.86 (dd, 3J2,3 = 3J2,3¢ = 6.3 Hz, 1 H, 2-H), 4.63 (br. s, 7 H,
3 OH, 4 NH).
Anal. calcd for: C12H22N2O7·0.75 H2O (319.83): C 45.06, H 7.41, N
8.76; found C 45.17, H 7.39, N 8.80.
Methyl (2R)-6-Acetamido-5,9-anhydro-2-(tert-butoxycarbonyl-
amino)-2,3,4,6-tetradeoxy-D-glycero-D-gulo-deconate (D-12):
For the preparation see L-12. Compound D-11 (103 mg, 188.4 mmol)
was dissolved in anhyd MeOH (2.3 mL). 0.173 M NaOMe in MeOH
(34 mL, 5.66 mmol) was added. D-12 (68.1 mg, 86%) was obtained as
a colorless solid; TLC (CH2Cl2/MeOH 3:1): Rƒ 0.67; [a]D –25 (c =
1.0, MeOH).
Methyl (2S)-6-Acetamido-7,8,10-tri-O-acetyl-5,9-anhydro-2-
{[(R)-(a-trifluoromethyl-a-methoxy-a-phenyl)methylcarbon-
yl]amino}-2,3,4,6-tetradeoxy-D-glycero-D-gulo-deconate [(L,R)-
14]:
For the preparation see General Procedure. Compound L-11 (50 mg,
91.5 mmol), i-Pr2NEt (9.5 mL, 104 mmol) and (S)-(+)-MTPA-Cl (22.5
mL, 119.2 mmol) were employed to afford (L,R)-14 (45 mg, 74%);
TLC (CH2Cl2/MeOH, 10:1): Rƒ 0.70; [a]D –27 (c = 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 1.53–1.87 (m, 2 H, 4-, 4¢-H),
2.14–2.23 (m, 2 H, 3-, 3¢-H), 1.90 (s, 3 H, NHAc), 1.99 (s, 6 H, 2
OAc), 2.05 (s, 3 H, OAc), 3.30 (s, 3 H, OMe), 3.45 (ddd, 3J4,5 = 3.0,
1H NMR (250 MHz, MeOH-d4): d = 1.37 (br. s, 9 H, CMe3),
1.42–1.69 (m, 4 H, 3-, 3¢-, 4-, 4¢-H), 1.92 (s, 3 H, NHAc), 3.13–3.24
(m, 3 H, 5-, 8-, 9-H), 3.29 (dd, 3J6,7 = 3J7,8 = 9.0 Hz, 1 H, 7-H), 3.51
(dd, 3J5,6 = 3J6,7 = 9.0 Hz, 1 H, 6-H), 3.60 (m, 1 H, 10¢-H), 3.64 (s, 3
2
H, CO2Me), 3.79 (dd, Jgem = 12.0, 3J9,10 ~2.5 Hz, 1 H, 10-H), 4.09
(br. m, 1 H, 2-H), 4.93 (s, 5 H, 3 OH, 2 NH).
FAB-MS (positive mode, matrix: MeOH/3-nitrobenzyl alcohol 1:1):
m/z (%) = 421 (12) [MH]+, 365 (22) [(M – C4H8)H]+, 321 (100) [(M
– C4H8 – CO2)H]+.

758
Papers
SYNTHESIS
Methyl (2R)-6-Acetamido-7,8,10-tri-O-acetyl-5,9-anhydro-2-
{[(S)-(a-trifluoromethyl-a-methoxy-a-phenyl)methylcarbon-
yl]amino}-2,3,4,6-tetradeoxy-D-glycero-D-gulo-deconate [(D,S)-
14]:
3J4¢,5 = 9.0, 3J5,6 = 9.4 Hz, 1 H, 5-H), 3.55 (ddd, 3J9,10 = 6.0, 3J9,10¢
2.7, 3J8,9 = 9.1 Hz, 1 H, 9-H), 3.74 (s, 3 H, CO2Me), 3.98 (ddd, 3J5,6
3J6,7 = 9.1, 3JNH,6 = 9.7 Hz, 1 H, 6-H), 4.07 (dd, 2Jgem = 12.1, 3J9,10¢
=
=
=
2.7 Hz, 1 H, 10¢-H), 4.19 (dd, 2Jgem = 12.1, 3J9,10 = 6.0 Hz, 1 H, 10-H),
4.56 (ddd, 3J2,3 = 3.3, 3J2,3¢ = 7.6, 3JNH,2 = 9.0 Hz, 1 H, 2-H), 4.93 (dd,
3J7,8 = 3J8,9 = 9.1 Hz, 1 H, 8-H), 5.01 (dd, 3J6,7 = 3J7,8 = 9.1 Hz, 1 H,
7-H), 5.51 (d, 3JNH,6 = 9.7 Hz, 1 H, NHAc), 7.38–7.41, 7.49–7.52 (2
m, 5 H, phenyl), 7.61 (d, 3JNH,2 = 9.0 Hz, 1 H, NH-MTPA).
FAB-MS (positive mode, matrix: MeOH/3-nitrobenzyl alcohol 1:1):
m/z (%) = 663 (100) [MH]+, 321 (22) [(M – C2H2O)H]+, 603 (25) [(M
– C2H4O2)H]+.
For the preparation see General Procedure. Compound D-11 (61 mg,
111.6 mmol), i-Pr2NEt (11.6 mL, 126.9 mmol) and (R)-(–)-MTPA-Cl
(28 mL, 148.3 mmol) were used to afford (D,S)-14 (56.2 mg, 76%);
TLC (CH2Cl2/MeOH 10:1): Rƒ 0.69; [a]D –46 (c = 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 1.54–2.15 (m, 4 H, 3-, 3¢-, 4-, 4¢-H),
1.88 (s, 3 H, NHAc), 2.00 (s, 6 H, 2 OAc), 2.06 (s, 3 H, OAc), 3.32
(m, 1 H, 5-H), 3.33 (s, 3 H, OMe), 3.54 (m, 1 H, 9-H), 3.71 (s, 3 H,
CO2Me), 3.92 (ddd, 3J5,6 = 3J6,7 = 3JNH,6 = 9.5 Hz, 1 H, 6-H), 4.06 (dd,
2Jgem = 11.8, 3J9,10¢ = 2.4 Hz, 1 H, 10¢-H), 4.20 (dd, 2Jgem = 11.8, 3J9,10
Methyl (2S)-6-Acetamido-7,8,10-tri-O-acetyl-5,9-anhydro-2-
{[(S)-(a-trifluoromethyl-a-methoxy-a-phenyl)methylcarbon-
yl]amino}-2,3,4,6-tetradeoxy-D-glycero-D-gulo-deconate [(L,S)-
14]:
3
= 5.6 Hz, 1 H, 10-H), 4.52 (ddd, 3J2,3 = 5.6, 3J2,3¢ = 9.3, JNH,2
=
9.3 Hz, 1 H, 2-H), 4.98 (dd, 3J6,7 = 3J7,8 = 9.5 Hz, 1 H, 7-H), 5.13 (dd,
3J7,8 = 3J8,9 = 9.5 Hz, 1 H, 8-H), 5.49 (d, 3JNH,6 = 9.5 Hz, 1 H, NHAc),
7.24–7.54 (m, 6 H, NH-MTPA, phenyl).
For the preparation see General Procedure. Compound L-11 (52 mg,
95.2 mmol), i-Pr2NEt (9.8 mL, 108.1 mmol) and (R)-(–)-MTPA-Cl
(23.4 mL, 124 mmol) were used to yield (L,S)-14 (48.7 mg, 77%); TLC
(CH2Cl2/MeOH, 10:1): Rƒ 0.69; [a]D –42 (c = 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 1.32–1.49, 1.56–1.83, 1.90–2.15 (3
m, 4 H, 3-, 3¢-, 4-, 4¢-H), 1.53 (s, 3 H, NHAc), 1.96, 1.99, 2.05 (3 s, 9
H, 3 OAc), 3.34 (ddd, 3J4,5 = 3.0, 3J4¢,5 =3J5,6 = 9.5 Hz, 1 H, 5-H), 3.50
(s, 3 H, OMe), 3.54 (m, 1 H, 9-H), 3.75 (s, 3 H, CO2Me), 3.87 (ddd,
3J5,6 = 3J6,7 = 3JNH,6 = 9.5 Hz, 1 H, 6-H), 4.64 (dd, 2Jgem = 12.7, 3J9,10¢
= 2.4 Hz, 1 H, 10¢-H), 4.17 (dd, 2Jgem = 12.7, 3J9,10 = 5.7 Hz, 1 H, 10-
H), 4.55 (ddd, 3J2,3 = 3.5, 3J2,3¢ = 7.8, 3JNH,2 = 9.7 Hz, 1 H, 2-H), 4.89
(dd, 3J7,8 = 3J8,9 = 9.5 Hz, 1 H, 8-H), 4.97 (dd, 3J6,7 = 3J7,8 = 9.5 Hz, 1
H, 7-H), 5.46 (d, JNH,6 = 9.2 Hz, 1 H, NHAc), 7.24–7.52 (m, 6 H,
NH-MTPA, phenyl).
FAB-MS (positive mode, matrix: MeOH/3-nitrobenzyl alcohol 1:1):
m/z (%) = 663 (100) [MH]+, 321 (31) [(M– C2H2O)H]+, 603 (12) [(M
– C2H4O2)H]+.
FAB-MS (positive mode, matrix: MeOH/3-nitrobenzyl alcohol, 1:1):
m/z (%) = 663 (100) [MH]+, 321 (17) [(M – C2H2O)H]+, 603 (29) [(M
– C2H4O2)H]+.
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie.
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3
Methyl (2R)-6-Acetamido-7,8,10-tri-O-acetyl-5,9-anhydro-2-
{[(R)-(a-trifluoromethyl-a-methoxy-a-phenyl)methylcarbon-
yl]amino}-2,3,4,6-tetradeoxy-D-glycero-D-gulo-deconate [(D,R)-
14]:
Dullenkopf, W.; Castro-Palomino, J. C.; Manzoni, L.; Schmidt,
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Castro-Palomino, J. C.; Schmidt R. R. Liebigs Ann. Chem.
1996, 1623.
For the preparation see General Procedure. Compound D-11 (51 mg,
93.3 mmol), i-Pr2NEt (9.7 mL, 106.1 mmol) and (S)-(+)-MTPA-Cl
(23 mL, 121.6 mmol) were employed to afford (D,R)-14 (45.1 mg,
73%); TLC (CH2Cl2/MeOH 10:1): Rƒ 0.71; [a]D –32 (c = 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 1.49–1.65 (m, 2 H, 4-, 4¢-H),
1.72–1.91 (m, 2 H, 3-, 3¢-H), 1.87 (s, 3 H, NHAc), 1.99 (s, 6 H, 2
OAc), 2.01 (s, 3 H, OAc), 3.12 (ddd, 3J4,5 = 2.9, 3J4¢,5 = 7.4, 3J5,6 = 9.7
Hz, 1 H, 5-H), 3.31 (m, 1 H, 9-H), 3.50 (s, 3 H, OMe), 3.72 (s, 3 H,
CO2Me), 3.87 (ddd, 3J5,6 =3J6,7 = 3JNH,6 = 9.5 Hz, 1 H, 6-H), 4.03 (dd,
2Jgem = 12.7, 3J9,10¢ = 2.8 Hz, 1 H, 10¢-H), 4.11 (dd, 2Jgem = 12.7, 3J9,10
= 5.2 Hz, 1 H, 10-H), 4.49 (ddd, 3J2,3 = 4.6, 3J2,3¢ = 8.4, 3JNH,2 = 9.4
Hz, 1 H, 2-H), 4.84 (dd, 3J6,7 = 3J7,8 = 9.5 Hz, 1 H, 7-H), 4.96 (dd, 3J7,8
= 3J8,9 = 9.5 Hz, 1 H, 8-H), 5.44 (d, 3JNH,6 = 9.5 Hz, 1 H, NHAc), 7.16
(d, 3JNH,2 = 8.0 Hz, 1 H, NH-MTPA, 7.36–7.42, 7.52–7.56 (2 m, 5 H,
phenyl).
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(10) For an alternative route for the preparation of 9a see:
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(11) Yamaguchi, S. In Asymmetric Synthesis (Analytical Methods);
Morrison, J. D., Ed.; Academic: New York, 1983; p 128.
(12) Commercially available material (Aldrich) was used.
FAB-MS (positive mode, matrix: MeOH/3-nitrobenzyl alcohol, 1:1):
m/z (%) = 663 (100) [MH]+, 321 (31) [(M – C2H2O)H]+.