A stereoselective synthesis of nonracemic (+)-desoxoprosophylline by a tandem Wittig [2+3]-cycloaddition reaction

Article abstract of DOI:10.1002/(SICI)1099-0690(199906)1999:6<1407::AID-EJOC1407>3.0.CO;2-T

L-Ascorbic acid serves as chiral starting material for the synthesis of (+)-desoxoprosophylline. The synthetic pathway includes the formation of an O-protected 5-azido-2,3-dideoxysugar which is subjected to a tandem Wittig [2+3] cycloaddition reaction, le

Full text of DOI:10.1002/(SICI)1099-0690(199906)1999:6<1407::AID-EJOC1407>3.0.CO;2-T

FULL PAPER
A Stereoselective Synthesis of Nonracemic (؉)-Desoxoprosophylline by a
Tandem Wittig [2؉3]-Cycloaddition Reaction
Claus Herdeis*[a] Joachim Telser[a]
Keywords: -Ascorbic acid / (ϩ)-Desoxoprosophylline / Lactones / Alkaloids / Domino reactions
L
-Ascorbic acid serves as chiral starting material for the
cycloaddition reaction, leading to the heterocyclic core unit
of (+)-prosophylline. Stereoselective hydrogenation and
chain elongation yields the desired alkaloid.
synthesis of (+)-desoxoprosophylline. The synthetic pathway
includes the formation of an O-protected 5-azido-2,3-
dideoxysugar which is subjected to a tandem Wittig [2+3]-
2,3,6-Substituted chiral piperidine alkaloids such as (ϩ)- sures that our reaction sequence for the (ϩ)-enantiomer of
prosopine (1), (ϩ)-prosopinine (2), (±)-prosophylline (3), desoxprosophylline and its derivatives also offers the pos-
and micropine (4) can be isolated from various Prosopis sibility of synthesizing their optical antipodes.
species[1] or, in the case of micropine from Microcos philip-
The general strategy of the synthesis is outlined in
pinensis.[2] These compounds have recently been targets of Scheme 1. The heterocyclic ring system should be accessible
increasing interest for total synthesis. Some 6-alkyl-3- by a tandem Wittig [2ϩ3]-cycloaddition, a reaction se-
hydroxy-2-(hydroxymethyl)piperidines have been synthe- quence previously used by us in the synthesis of chiral, non-
sized in racemic form,[3] but during the last few years a racemic piperidine derivatives.[8] The introduction of the
growing number of enantioselective syntheses of Prosopis[4] side chain should be accomplished by standard procedures
and Microcos alkaloids[5] and their derivatives have been published by Cook, Beholz, and Stille.[3d,3e]
published.
Scheme 1. Retrosythetic analysis
Figure 1
A key intermediate in our reaction sequence is the 5-azi-
dolactole 7 that should be obtainable by diastereoselective
synthesis from -gulonolactone 5. To this end, -gulonolac-
tone 5 is protected as its 5,6-isopropylidene derivative 8 ac-
These compounds display some significant pharmaco-
logical activities, e.g. local anaesthetic, antibiotic, and hypo-
tensive activities have been described for prosopine.[6] Fur-
thermore, extracts from Prosopis juliflora used in indigen-
cording to a procedure described by Vekemans and Chit-
ous medicine show activity against gonorrhea.[7]
tenden.[10] In the literature two pathways for deoxygenation
of 8 are described.[10][11] Since neither method is suitable
for scaling up, we developed an alternative method for the
large-scale synthesis of 9. Compound 8 should be treated
according to the CoreyϪWinter reductive elimination pro-
cedure.[12] Unfortunately, the reaction of 8 with thiocarbon-
yldiimidazole (TCDI) failed to give a cyclic thionocarbon-
ate. Instead, decomposition of starting material and TCDI
occurred and an untractable mixture was isolated.
In our continuing studies of chiral, nonracemic piperi-
dine derivatives,[8] we now report a chiral-pool synthesis of
(ϩ)-desoxoprosophylline starting from -gulonolactone 5,
which is a cheap chiral starting material that can be ob-
tained by the catalytic hydrogenation of -ascorbic acid.[9]
Furthermore, its enantiomer, namely -gulonolactone 6 is
also commercially available at a reasonable price. This en-
[a]
Institut für Pharmazie und Lebensmittelchemie der Julius-Maxi-
The synthesis of the 9 was therefore carried out as out-
lined in Scheme 2. Deoxygenation of the α- and β-positions
of 8 was accomplished by a 4-step procedure, which in-
milians-Universität Würzburg,
Am Hubland, D-97074 Würzburg, Germany
E-mail: herdeis@pharmazie.uni-wuerzburg.de
Eur. J. Org. Chem. 1999, 1407Ϫ1414
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0606Ϫ1407 $ 17.50ϩ.50/0
1407

C. Herdeis, J. Telser
FULL PAPER
volved two steps already described by Vekemans and Chit-
tenden leading to the α-mesylated lactone 10.[13] Nucleo-
philic substitution of the α-mesyl group by iodine lead to
the crystalline light-sensitive α-iodolactone 11. In this reac-
tion acetone was the solvent of choice because cleavage of
the isopropylidene-protecting group occurred when the re-
action was run in acetonitrile. The α-iodolactone could then
be converted into lactone 9 by catalytic hydrogenation in
the presence of a palladium catalyst and an excess of tri-
ethylamine. This reaction sequence turned out to be su-
perior to the known methods on a large scale.
Scheme 3. a) concd. HCl, iPrOH, 48 h, 96%; b) excess TBDMSCl,
Et3N, DMAP, DMF, 12 min, 99%; c) MsCl, Et3N, CH2Cl2, 20 min,
79%; d) NaN3, DMPU, 70°C, 24 h, 65%; e) DIBAlH, THF,
Ϫ78°C, 4Ϫ6 h, 69%
and completely characterized. A trans configuration was as-
signed to the double bond. At Ϫ20°C this compound can
be stored for weeks without undergoing a remarkable con-
version into the triazolines.
Scheme 2. a) NaI, acetone, reflux, 92%. Ϫ b) H2, Et3N, 10% Pd/
C, 20Ϫ30 h, 82%.
The isopropylidene-protecting groups were then re-
moved, giving the unprotected lactone 12. NMR spectra of
this molecule revealed the presence of an equilibrium mix-
ture of γ- and δ- lactones 12a and 12b, but this did not
cause serious problems because similar mixtures had been
completely converted into the butanolide form by blocking
the primary alcohol function with a sterically demanding
protecting group.[14] For this transformation we chose the
TBDMS group because of its stability towards bases and
dilute acids, and its facile deprotection with ethanolic hy-
drogen chloride solution. Introduction of the silyl group
with TBDMS chloride in DMF with an excess of imidazole
proved troublesome at first because of the long reaction
times and unacceptable yields. It therefore proved advan-
Scheme 4. a) Ph3PCHCOOEt, toluene, room temp., 1 d; b) toluene,
room temp, 4 d, 98%
When 16 was left at ambient temperature, two dia-
tageous to carry out the reaction in the presence of a cata- stereomeric triazolines 17 and 18 resulted. Assignment of
lytic amount of DMAP.[15] It must be noted that an excess the stereochemistry was achieved by 1H-NMR spectroscopy
of base was needed and TBDMS chloride had to be added and by assuming that the triazoline ring is orientated in
in separate portions in order to obtain the primary silyl an equatorial position. The remaining substituents are then
ether 13 in quantitative yield.
either both axially or both equatorially disposed. The ob-
1
3
Mesylation of the secondary alcohol function, followed served H-NMR coupling constants J2Ј,3 of 9.1 Hz for the
by introduction of azide by stereoselective nucleophilic sub- major product 17 revealed that in fact, only equatorially
stitution, gave rise to lactone 14 and the 5-azidolactone 15, orientated substituents are present, whereas in the minor
respectively. The lactole 7 could then be synthesized by re- product 18 this coupling constant was smaller than 1 Hz
duction of 15 with DIBAlH in THF at Ϫ78°C.
which indicates that both substituents, namely the hydroxy
The next task was to carry out the tandem Wittig [2ϩ3]- and the CH2OTBDMS group, occupy axially orientated po-
cycloaddition reaction (Scheme 4). This was achieved by sitions.
treating 7 with (ethoxycarbonylmethylene)triphenylphos-
The cycloaddition shows moderate diastereoselectivity.
phorane in dry toluene. To our surprise, the Wittig reaction The major product 17 is formed with a d.e. of 34% (deter-
led to complete conversion after 80 minutes. In contrast a mined by HPLC). Change of solvent did not cause substan-
reaction time of 4 days was required for the cycloaddition tial improvements of diastereoselectivity. We suspect that
step. The α,β-unsaturated azido ester 16 could be isolated conformational constraints caused by the OTBDMS group
1408
Eur. J. Org. Chem. 1999, 1407Ϫ1414

Nonracemic (ϩ)-Desoxoprosophylline by a Tandem Wittig [2ϩ3]-Cycloaddition Reaction
FULL PAPER
must prevent the double bond of the α,β-unsaturated ester 19 and 20 was submitted to RhII-mediated extrusion of ni-
moiety from attaining the proper alignment with the 1,3- trogen,[16] the vinylogous urethane 21 was formed under
dipolar azide functionality, so the activation barriers for very mild conditions in quantitative yield.
both chair-like conformers A and B (Scheme 5) are rather
The introduction of the aliphatic side chain was at-
high. In fact, when the CH2OTBDMS group is replaced by tempted in two ways. First we alkylated the α-position of
a methyl group, quantitative conversion into the triazolines the anion of the vinylogous urethane 21 according to a
could be observed within 48 h, and the α,β-unsaturated modified procedure by Lhommet,[17] by deprotonating the
azido ester could not be isolated.[8b]
NϪH group with butyllithium in THF at Ϫ40°C and ad-
ding undecyl bromide. A small amount of alkylation prod-
uct was obtained, but the yield did not exceed 16%. It must
be noted that extensive decomposition occurred. Alkylation
at the unprotected hydroxy function at C-5Ј was not ob-
served.
Scheme 5. Stereochemical outcome of the cycloaddition reaction
These observations suggest that conformer A is, despite
the steric repulsion of the hydroxy and the silyloxymethyl
group, the major conformer which is involved in the cyclo-
addition step leading to 17 (Scheme 5). Electronic effects,
like the attractive gauche interaction between the azido
group, and the hydroxy group might favour the formation
of B, but on the other hand, the axial orientation of the
bulky silyloxymethyl group destabilises this conformation.
In summary, both chair-like conformers are not ideally
suited to cycloaddition, and the reaction rate is severely re-
tarded.
Scheme 7. a) TBDMSCl, imidazole, DMF, 84%; b) DiBAlH, n-
pentane, Ϫ78°C, 25 min, 66%; c) Ph3P(CH2)9CH3Br, NaN[-
Si(CH3)3]2, THF, (i) Ϫ40°C, 60 min, (ii) room temp, 160 min, 79%;
d) H2, 10% Pd/C, EtOH, 12 h, 93%; e) HCl, EtOH, 15 min, then
6  KOH, 87%
Alternatively, in order to introduce the side chain, we hy-
drogenated the vinylogous urethane 21 in the presence of
palladium on charcoal. This reaction proved to be com-
pletely diastereoselective as can be shown by 1H-NMR
analysis, and provided the 2,6-cis-substituted product 22.
The unprotected hydroxy group was blocked with another
TBDMS group, and the ester 23 was selectively reduced to
the aldehyde 24 with DIBAlH in pentane. Subsequent Wit-
tig reaction with decylphosphonium bromide under salt-
free conditions led to the olefin 25, which was then hydro-
genated .The resulting compound 26 was finally depro-
tected to yield (ϩ)-desoxoprosophylline 27, which exhibited
an optical rotation identical in magnitude, but opposite in
sign, to the rotation of (Ϫ)-desoxoprosophylline.[4b] Spec-
Scheme 6. a) i. Et3N, CH2Cl2, 12 h, 96%, b) Rh2(OAc)4, 12 h, 97%;
c) H2, 10% Pd/C, EtOH, 48 h, 71%
Rearrangement of the triazolines to the corresponding troscopic and physical data were in accordance with those
diazo esters could be achieved by addition of triethylamine, reported in literature for (ϩ)-desoxoprosophylline.[4i]
and afforded compounds 19 and 20 in nearly quantitative
yields. The diazo esters are remarkably stable towards dilute
acid. Treatment of 19 with 1  hydrochloric acid lead to the
formation of a hydrochloride of 19 which could be isolated
Experimental Section
1
General: H, HH-COSY, and 13C NMR: Bruker AC 200, chemical
and characterized as its monohydrate. When a mixture of shifts relative to the solvent as internal standard. Ϫ IR: Perki-
Eur. J. Org. Chem. 1999, 1407Ϫ1414 1409

C. Herdeis, J. Telser
FULL PAPER
nϪElmer 681. Ϫ MS: Finnigan MAT 8200 (70 eV). Ϫ Gas chroma-
tography: Carlo Erba HRGC 5160 Mega Series, MachereyϪNagel
solved in a mixture of 2-propanol (30 mL) and HCl (concd.) (5.0
mL). The mixture was stirred for 48 h at ambient temperature, and
SE 54 column (25 m ϫ 0.2 mm ID, 0.1 µm film thickness), helium then the solvent was removed in vacuo and the product dried at
at 27 cm/s. Ϫ Retention indices RIp were determined according to
the method of van den Dool and Kratz[18] at 5°C/min relative to a
standard of n-paraffins. Ϫ TLC: Merck silica gel 60 F254 plates. Ϫ
Optical rotation: PerkinϪElmer 241. Ϫ Melting points are uncor-
0.1 mbar for several days. Yield 2.17 g (14.85 mmol, 96%) of an
equilibrium mixture of 12a and 12b, as a pale yellow hygroscopic
1
oil. Ϫ IR (neat): ν˜ ϭ 3500Ϫ3300 cmϪ1 (OH), 1750 (CϭO). Ϫ H
NMR (200 MHz, [D6]acetone): δ ϭ 2.25Ϫ2.53 (4 H, m, 2-H, 3-H),
rected. Ϫ Column chromatography: silica gel 60 (0.063Ϫ0.2 mm). 3.79 (1 H, dd, J5,6A ϭ 6.6, JAB ϭ 8.3 Hz, 6A-H), 4.07 (1 H, dd,
Ϫ All reactions were carried out under nitrogen. Ϫ THF and ether
were distilled from potassium sodium couple, acetone from calcium
chloride, DMF, dichloromethane, and triethylamine from calcium
hydride.
J5,6B ϭ 6.8, JAB ϭ 8.3 Hz, 6B-H), 4.22 (1 H, ddd., J4,5 ϭ 3.8,
5,6A ϭ 6.6, J5,6B ϭ 6.8 Hz, 5-H), 4.57 (1 H, ddd, J4,5 ϭ 3.8, J3A,4 ϭ
J
5.6, J3B,4 ϭ 7.7 Hz, 4-H), 7.99Ϫ8.03 (2 H, m, OϪH). Ϫ 13C NMR
(50.3 MHz, [D6]acetone) DEPT: for 12a: δ ϭ 23.4 (CH2, C-3), 27.8
(CH2, C-2), 62.6 (CH2, C-6), 73.4 (CH, C-5), 79.6 (CH, C-4), 177.0
(C-1); for 12b: δ ϭ 28.0 (CH2, C-3, 29.9 (CH2, C-2), 63.4 (CH2, C-
6), 70.4 (CH, C-4), 73.9 (CH, C-5), 173.5 (C-1). Ϫ MS (EI); m/z
(%): 129.1 (5.1) [Mϩ Ϫ OH], 115.1 (14.61) [Mϩ Ϫ CH3O], 85.1
(100) [Mϩ Ϫ C2H5O2], 61.1 (3.14) [Mϩ Ϫ C4H5O2].
2,3-Dideoxy-2-iodo-5,6-isopropylidene-L-talo-hexono-1,4-lactone
(11): 3-Deoxy-5,6-isopropylidene-2-mesyloxy--gulo-hexono-1,4-
lactone (10) (15.61 g, 55.69 mmol) and sodium iodide (10.85 g,
72.40 mmol, 1.3 equivalents) were dissolved in 160 mL of acetone
(abs.) and heated to reflux for 1 h. The solvent was removed in
vacuo, and the oily yellow residue was taken up in ethyl acetate.
The organic solution was washed with satd. sodium hydrogen car-
bonate solution, 0.1  sodium thiosulfate solution, and brine. The
solvent was distilled and 16.04 g (51.40 mmol, 92%) of the crude
product was obtained. This material was sufficiently pure for
further reaction, for analytical purposes it was chromatographed
(EtOAc, Rf ϭ 0.70) and recrystallized from tBuOMe. The product
is light-sensitive and should not be stored in solution. Ϫ Colourless
6-(tert-Butyldimethylsilyloxy)-2,3-dideoxy-L-threo-hexono-1,4-
lactone (13): 1.64 g (11.22 mmol) of 12, DMAP (68 mg, 0.56 mmol,
0.05 equivalents) and tert-butyl(chloro)dimethylsilane (1.86 g,
12.32 mmol, 1.1 equivalents) were dissolved in (abs.) DMF (20
mL). Triethylamine (6.2 mL, 4.54 g, 45 mmol, 4 equivalents) was
added. An exothermic reaction occurred, and the immediate for-
mation of a colourless precipitate was observed. Within 10 min
another three portions (each consisting of 844 mg, 5.6 mmol, 0.5
equivalents) of tert-butyl(chloro)dimethylsilane were added, then
the mixture was stirred for 2 min, followed by addition of water
(40 mL). The reaction mixture was extracted with two portions of
ether. The combined organic extracts were washed with 1  HCl
and conc. NaHCO3 solution, and dried over anhydrous Na2SO4.
20
crystals, m.p. 99°C. Ϫ RIp ϭ 1755. Ϫ [α]D ϭ Ϫ2 (c ϭ 0.7,
MeOH). Ϫ IR (KBr): ν˜ ϭ 1760 cmϪ1 (CϭO), 1370, 1165, 1060,
1075. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.24 (3 H, s, CH3), 1.27
(3 H, s, CH3), 2.39 (1 H, ddd, J2,3A ϭ 4.2, J3A,4 ϭ 6.7, JAB
14.5 Hz, 3A-H), 2.61 (1 H, ddd, J3B,4 ϭ 7.0, J2,3B ϭ 7.8, JAB
ϭ
ϭ
Column chromatography (Et2O, Rf
ϭ 0.51) yielded 2.90 g,
14.5 Hz, 3B-H), 3.81 (1 H, dd, J5,6A ϭ 6.4, JAB ϭ 8.4 Hz, 6A-H),
4.00 (1 H, dd, J5,6B ϭ 6.8, JAB ϭ 8.4 Hz, 6B-H), 4.14 (1 H, ddd,
(11.14 mmol, 99%) of 13 as a colourless opaque oil that crystallized
20
at Ϫ20°C within days. Ϫ m.p. 52°C. Ϫ RIp ϭ 1775. Ϫ [α]D
ϭ
J4,5 ϭ 3.1, J5,6A ϭ 6.4, J5,6B ϭ 6.8 Hz, 5-H), 4.54 (1 H, ddd, J4,5 ϭ
ϩ60 (c ϭ 1.1, MeOH). Ϫ IR (neat): ν˜ ϭ 2950 cmϪ1, 2920, 2850,
1780 (CϭO), 1460, 1250, 1115, 1080. Ϫ 1H NMR (200 MHz,
CDCl3): δ ϭ 0.01 [6 H, s, Si(CH3)2], 0.82 [9 H, s, SiC(CH3)3],
2.13Ϫ2.66 (4 H, m, 2-H, 3-H), 3.03 (1 H, s, OϪH), 3.59Ϫ3.65 (3
3.1, J3A,4 ϭ 6.7, J3B,4 ϭ 7.0 Hz, 4-H), 4.60 (1 H, dd, J2,3A ϭ 4.2,
J2,3B ϭ 7.8 Hz, 2-H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 10.7
(C-2), 26.0 (CH3), 26.5 (CH3), 38.0 (C-3), 65.8 (C-6), 76.5 (C-5),
79.8 (C-4), 111.0 [C(CH3)2], 174.2 (C-1). Ϫ C9H13IO4 (312.12):
calcd. C 34.63, H 4.20; found C 34.92, H 4.20.
H, m, 5-H, 6-H), 4.55 (1 H, m, J4,5 ϭ 2.5, J3A,4 ϭ 6.9, J3B,4
ϭ
7.0 Hz, 4-H). Ϫ 13C NMR (50.3 MHz, CDCl3) DEPT: δ ϭ Ϫ5.7
[CH3, Si(CH3)2], 18.0 [SiC(CH3)3], 23.6 (CH2, C-3), 26.6 [CH3,
SiC(CH3)3], 28.2 (CH2, C-2), 63.4 (CH2, C-6), 73.2 (CH, C-5), 79.4
(CH, C-4), 177.7 (C-1). Ϫ C12H24O4Si (260.41): calcd. C 55.35, H
9.29; found C 54.99, H 9.14.
2,3-Dideoxy-5,6-isopropylidene-L-threo-hexono-1,4-lactone
(9):
7.00 g (22.43 mmol) of 11 were dissolved in ethyl acetate (200 mL),
triethylamine (6.20 mL, 4.54 g, 44.85 mmol, 2 equivalents) and Pd/
C (700 mg) were added, and the mixture was hydrogenated at 70
bar at ambient temperature (average reaction times: 20Ϫ36 h). The
catalyst was removed by filtration, the filtrate was washed with 1 
HCl and brine, dried with anhydrous sodium sulfate and concen-
trated to dryness in vacuo. The residue was purified by chromatog-
raphy (EtOAc, Rf ϭ 0.47), to yield a colourless oil: 3.43 g
(18.40 mmol, 82%), RIp ϭ 1426. Ϫ [α]D20 ϭ ϩ30 (c ϭ 1.3, MeOH).
Ϫ IR (neat): ν˜ ϭ 1775 cmϪ1 (CϭO), 1380, 1160, 1060. Ϫ 1H NMR
(200 MHz, CDCl3): δ ϭ 1.38 (3 H, s, CH3), 1.40 (3 H, s, CH3),
6-(tert-Butyldimethylsilyloxy)-2,3-dideoxy-5-mesyloxy-L-threo-
hexono-1,4-lactone (14): To a cold (Ϫ20°C) solution 13 (2.97 g,
11.39 mmol) and triethylamine (4.7 mL 34 mmol, 3 equivalents) in
dichloromethane (abs.) (50 mL) was added methanesulfonyl chlo-
ride (1.1 mL, 13.66 mmol, 1.2 equivalents). The mixture was stirred
for 20 min and then was allowed to warm to room temperature.
After addition of water, the mixture was extracted with 4 portions
of dichloromethane. The combined organic extracts were washed
with 1  HCl and concd. NaHCO3 solution and dried with anhy-
drous Na2SO4. The solvent was then removed by distillation, and
the colourless crystalline residue was recrystallized from tBuOMe
to yield colourless crystals: 3.05 g (9.0 mmol, 79%), m.p. 58°C. Ϫ
2.06Ϫ2.35 (2 H, m, 3-H), 2.48 (1 H, ddd, J2A,3A ϭ 6.1, J2A,3B
ϭ
9.3, JAB ϭ 17.4 Hz, 2A-H), 2.61 (1 H, ddd, J2B,3 ϭ 6.7, J2B,3 ϭ 7.3,
JAB ϭ 17.4 Hz, 2B-H), 3.85 (1 H, dd, J5,6A ϭ 6.9, JAB ϭ 8.2 Hz,
6A-H), 4.02 (1 H, dd, J5,6B ϭ 6.7, JAB ϭ 8.2 Hz, 6B-H), 4.11 (1 H,
ddd, J4,5 ϭ 2.9, J5,6B ϭ 6.7, J5,6A ϭ 6.9 Hz, 5-H), 4.44 (1 H, ddd,
J4,5 ϭ 2.9, J3A,4 ϭ 5.2, J3B,4 ϭ 7.9 Hz, 4-H). Ϫ 13C NMR
(50.3 MHz, CDCl3) DEPT: δ ϭ 24.1 (CH2, C-3), 25.3 (CH3, CH3),
25.8 (CH3, CH3), 27.8, (CH2, C-2), 65.1 (CH2, C-6), 77.5 (CH, C-
5), 78.0 (CH, C-4), 109.9 [CCH3)2], 177.0 (C-1). Ϫ C9H14O4
(186.23): calcd. C 58.05, H 7.58; found C 57.82, H 7.20.
20
RIp ϭ 2149. Ϫ [α]D ϭ ϩ16 (c ϭ 1.1, CHCl3). Ϫ IR (KBr): ν˜ ϭ
1780 cmϪ1 (CϭO), 1350, 1170, 825. Ϫ 1H NMR (200 MHz,
CDCl3): δ ϭ 0.65 (3 H, s, SiCH3), 0.80 (3 H, s, SiCH3), 0.89 [9 H,
s, SiC(CH3)3], 2.17Ϫ2.46 (2 H, m, 3-H), 2.50Ϫ2.78 (2 H, m, 2-H),
3.12 (3 H, s, SOCH3), 3.86 (1 H, dd, J5,6A ϭ 5.0, JAB ϭ 11.2 Hz,
6A-H), 3.95 (1 H, dd, J5,6B ϭ 6.0, JAB ϭ 11.2 Hz, 6B-H), 4.68 (1 H,
ddd, J4,5 ϭ 3.6, J5,6A ϭ 5.0, J5,6 B ϭ 6.0 Hz, 5-H), 4.76 (1 H, ddd,
2,3-Dideoxy-L-threo-hexono-1,4-lactone (12a) and 2,3-Dideoxy-L-
threo-hexono-1,5-lactone (12b): 2.82 g (15.15 mmol) of 9 was dis- J4,5 ϭ 3.6, J3A,4 ϭ 6.1, J3B,4 ϭ 7.6 Hz, 4-H). Ϫ 13C NMR
1410 Eur. J. Org. Chem. 1999, 1407Ϫ1414

Nonracemic (ϩ)-Desoxoprosophylline by a Tandem Wittig [2ϩ3]-Cycloaddition Reaction
(50.3 MHz, CDCl3) DEPT: δ ϭ Ϫ5.7 [CH3, Si(CH3)2], 18.0 1 equivalent) was added. The mixture was stirred at room tempera-
FULL PAPER
[SiC(CH3)3], 23.6 (CH2, C-3), 25.6 [CH3, SiC(CH3)3], 27.5 (CH2, ture for 48 h, the solvent was evaporated at ambient temperature in
C-2), 38.6 (CH3, SO2CH3), 62.2 (CH2, C-6), 77.4 (CH, C-5), 83.0 vacuo into a cooling trap and the residue was subjected to column
(CH, C-4), 176.1 (C-1). Ϫ C13H26O6SSi (338.50): calcd. C 46.13, H
7.74, S 9.47; found C 45.75, H 7.86, S 9.98.
chromatography (EtOAc) to give a mixture of all three products
(1.49 g, 4.16 mmol, 98%). If the reaction mixture was stirred at
room temperature for 5 d instead of 48 h, 98% of the dia-
stereomeric triazolines were obtained, and no α,β-unsaturated ester
16 could be detected. Ϫ C16H31N3O4Si (357.53) calcd. C 53.75, H
8.74, N 11.75; found C 53.70, H 8.69, N 11.44. Ϫ For spectroscopic
purposes, pure samples of all three products could be obtained by
column chromatography (EtOAc).
5-Azido-6-(tert-butyldimethylsilyloxy)-2,3,5-dideoxy-D-erythro-
hexono-1,4-lactone (15): A mixture of 14 (2.77 g, 8.18 mmol) and
NaN3 (883 mg, 13.58 mmol, 1.7 equivalents) dissolved in DMPU
(5 mL) was stirred at 70°C for 24 h. Water was then added, and
the mixture extracted with ether. The organic phase was washed
with 1  HCl, and concd. NaHCO3 solution, dried with anhydrous
Na2SO4, the solvent was evaporated and the yellow oily residue Ethyl (6S,7R)-7-Azido-8-(tert-butyldimethylsilyloxy)-6-hydroxyoct-
was purified by chromatography (Et2O, Rf ϭ 0.70). Ϫ Yield 1.51 g
2-enoate (16): Rf ϭ 0.73 (EtOAc). Ϫ [α]D20 ϭ ϩ1 (c ϭ 0.8, MeOH).
Ϫ IR (neat): ν˜ ϭ 3450 cmϪ1 (OH), 2095 (NϭNϭN), 1715 (CϭO),
20
(5.28 mmol, 65%) as a colourless oil. Ϫ RIp ϭ 1857. Ϫ [α]D
ϭ
Ϫ3 (c ϭ 0.88, MeOH). Ϫ IR (neat): ν˜ ϭ 2100 cmϪ1 (N3), 1780 1650 (CϭC), 1460, 1250, 1100. Ϫ 1H NMR (200 MHz, CDCl3):
1
(CϭO), 1250, 1110. Ϫ H NMR (200 MHz, CDCl3): δ ϭ 0.72 [6 δ ϭ Ϫ0.01 [6 H, s, Si(CH3)2], 0.80 [9 H, s, SiC(CH3)3], 1.16 (3 H,
H, s, Si(CH3)2], 0.88 [9 H, s, SiC(CH3)3], 2.09Ϫ2.29 (2 H, m, 3-H),
2.48Ϫ2.59 (2 H, m, 2-H), 3.63 (1 H, ddd, J5,6A ϭ 4.7, J4,5 ϭ 5.9,
t, J ϭ 7.1 Hz, OCH2CH3), 1.48Ϫ1.62 (2 H, m, 5-H), 2.16Ϫ2.37 (2
H, m, 4-H), 3.22Ϫ3.32 (1 H, m, 7-H), 3.52Ϫ3.58 (1 H, m, 6-H),
J5,6B ϭ 6.1 Hz, 5-H), 3.75 (1 H, dd, J5,6B ϭ 6.1, JAB ϭ 10.5 Hz, 4.06 (2 H, q, J ϭ 7.1, OCH2CH3), 5.74 (1 H, d, J2,3 ϭ 15.6 Hz, 2-
6B-H), 3.84 (1 H, dd, J5,6A ϭ 4.7, JAB ϭ 10.5 Hz, 6A-H), 4.51 (1
H, dt, J4,5 ϭ 5.9, J3,4 ϭ 6.9 Hz, 4-H); homodecoupling: HD set to
H), 6.86 (1 H, dd, J3,4 ϭ 7.0, J2,3 ϭ 15.6 Hz, 3-H). Ϫ 13C NMR
(50.3 MHz, CDCl3) DEPT: δ ϭ Ϫ5.9 [CH3, Si(CH3)2], 13.9 (CH3,
3.63 ppm: J3,4 ϭ 6.9 Hz, HD set to 2.19 ppm: J4,5 ϭ 5.9 Hz. Ϫ 13C OCH2CH3), 17.8 [SiC(CH3)3], 25.4 [CH3, SiC(CH3)3], 27.9 and
NMR (50.3 MHz, CDCl3) DEPT: δ ϭ Ϫ5.7 [CH3, Si(CH3)2], 18.1
31.4 (CH2, C-4 and C-5), 59.9 (CH2, OCH2CH3), 63.4 (CH2, C-8),
[SiC(CH3)3], 23.7 (CH2, C-3), 25.7 [CH3, SiC(CH3)3], 27.9 (CH2, 66.8 (CH, C-7), 70.3 (CH, C-6), 121.4 (CH, C-2), 148.2 (CH, C-3),
C-2), 63.0 (CH2, C-6), 65.1 (CH, C-5), 77.7 (CH, C-4), 176.3 (C-
1). Ϫ C12H23N3O3Si (285.42): calcd. C 50.50, H 8.12, N 14.72;
found C 50.11, H 7.88, N 15.06.
166.3 (C-1).
Ethyl (2R,3S,6R,7R)-2-(tert-Butyldimethylsilyloxymethyl)-3-hydroxy-
1,8,9-triazabicyclo[4.3.0]non-8-ene-7-carboxylate (17): Rf ϭ 0.62
20
5-Azido-6-(tert-butyldimethylsilyloxy)-2,3,5-trideoxy-
D
-erythro-
(EtOAc), [α]D ϭ ϩ213 (c ϭ 0.74, MeOH). Ϫ IR (neat): ν˜ ϭ
furanose (7): A solution of 15 (1.35 g, 4.73 mmol) in THF (abs.)
3500Ϫ3350 cmϪ1 (OH), 1730 (CϭO), 1460, 1250, 830. Ϫ 1H NMR
(25 mL) was cooled to Ϫ78°C. DIBAlH (6.30 mL, 6.30 mmol, 1.3 (200 MHz, CDCl3): δ ϭ 0.05 [6 H, s, Si(CH3)2], 0.89 [9 H, s,
equivalents of a 1  solution in heptane) was added under vigorous
stirring. The reaction mixture was stirred at Ϫ78°C for 2 h, then
another portion (2.40 mL, 2.40 mmol, 0.5 equivalents) of DIBAlH
solution was carefully added. The stirring was continued until no
SiC(CH3)3], 1.31 (3 H, t, J ϭ 7.1 Hz, OCH2CH3), 1.38Ϫ2.16 (4 H,
m, 4-H, 5-H), 3.41 (1 H, ddd, J1ЈB,2 ϭ 4.1, J2,3 ϭ 9.1, J1ЈA,2
9.1 Hz, 2-H), 3.59Ϫ3.76 (2 H, m, 3-H, 6-H), 4.21 (3 H, t, J ϭ
7.1 Hz, OCH2CH3), 4.34 (1 H, dd, J1ЈA,2 ϭ 9.1, JAB ϭ 10.3 Hz,
ϭ
more starting material could be detected by GC. Average reaction 1ЈA-H), 4.51 (1 H, d, J6,7 ϭ 8.2 Hz, 7-H), 4.55 (1 H, dd, J1ЈB,2
times ranged from 4 to 6 h. After carefully controlled addition of 4.1, JAB ϭ 10.3 Hz, 1ЈB-H); homodecoupling: HD set to 1.45 ppm:
water (10 mL) so that the temperature of the reaction mixture did 4.21 (2 H, s, OCH2CH3), 4.34 (1 H, dd, J1ЈA,2 ϭ 9.2, JAB ϭ 9.7 Hz,
ϭ
not exceed Ϫ60°C, 1  HCl (20 mL) was added. When the mixture
had reached room temperature, brine was added and the product
was isolated by extraction with four portions of dichloromethane.
The combined organic layers were washed with conc. NaHCO3,
dried with Na2SO4 and filtered through Celite. The crude product
1ЈA-H), HD set to 4.52 ppm: 3.40 (1 H, dd, J1ЈB,2 ϭ 3.4, J2,3 ϭ
9.1 Hz, 2-H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ Ϫ5.7 [CH3,
Si(CH3)2], 14.0 (CH3, OCH2CH3), 17.9 [SiC(CH3)3], 25.6 [CH3,
SiC(CH3)3], 26.4 and 31.3 (CH2, C-4 and C-5), 58.4 (CH, C-2),
62.6 (CH2, OCH2CH3), 63.6, (CH, C-6), 65.5 (CH2, C-1Ј), 72.9
was purified by column chromatography (Et2O, Rf ϭ 0.70). Ϫ Yield (CH, C-3), 80.8 (CH, C-7), 167.9 (COOEt).
941 mg (3.27 mmol, 69%) as a mixture of both anomeric lactols. Ϫ
Ethyl (2R,3S,6S,7S)-2-(tert-Butyldimethylsilyloxymethyl)-3-hydroxy-
RIp ϭ 1767. Ϫ IR (neat): ν˜ ϭ 2095 cmϪ1 (N3), 1470, 1460, 1255.
Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ Ϫ5.6 [12 H, s, Si(CH3)2], 0.89
[18 H, s, SiC(CH3)3], 1.78Ϫ2.06 (8 H, m, 2-H and 3-H), 3.44Ϫ3.89
1,8,9-triazabicyclo[4.3.0]non-8-ene-7-carboxylate (18): Rf ϭ 0.51
20
(EtOAc), [α]D ϭ Ϫ206 (c ϭ 1.96, MeOH). Ϫ IR (neat): ν˜ ϭ
3400Ϫ3300 cmϪ1 (OH), 1730 (CϭO), 1460, 1100, 830. Ϫ 1H NMR
(200 MHz, CDCl3): δ ϭ 0.05 [6 H, s, Si(CH3)2], 0.87 [9 H, s,
SiC(CH3)3], 1.28 (3 H, t, J ϭ 7.1 Hz, OCH2CH3), 1.40Ϫ1.48 (1 H,
m, 5A-H), 1.60Ϫ1.95 (3 H, 5B-H, 4-H), 2.26 (1 H, s, OϪH), 3.80
(2 H, d, J1Ј,2 ϭ 5.7, 1Ј-H), 3.96 (1 H, ddd, J5A,6 ϭ 4.6, J6,7 ϭ 6.5,
J5B,6 ϭ 11.6 Hz, 6-H), 4.20 (2 H, q, J ϭ 7.1, OCH2CH3), 4.34 (1
H, m,, 2-H), 4.69 (1 H, d, J6,7 ϭ 6.5 Hz, 7-H); homodecoupling:
HD set to 3.96 ppm: 1.44 (ddd, J4,5 < 2, JAB ϭ 12.4 Hz, 5A-H),
HD set to 1.27 ppm: 4.20 (2 H, s, OCH2CH3), 4.15 (1 H, m, 3-H),
HD set to 4.34 ppm: 3.79 (2 H, s, 1Ј-H), HD set to 4.70 ppm: 3.96
(1 H, dd, J5A,6 ϭ 4.4, J5B,6 ϭ 11.6 Hz, 6-H). Ϫ 13C NMR
(50.3 MHz, CDCl3) DEPT: δ ϭ Ϫ5.6 [CH3, Si(CH3)2], 14.1 (CH3,
OCH2CH3), 18.1 [SiC(CH3)3], 22.7 and 26.6 (CH2, C-4 and C-5),
(8 H, m, 4-H, 5-H and 8-H), 5.44 (1 H, dd, J1,2A ϭ 1.5, J1,2B
3.7 Hz, 1-H) and 5.55 (1 H, dd, J1,2A ϭ 1.6, J1,2B ϭ 4.5 Hz, 1-H).
13C NMR (50.3 MHz, CDCl3) DEPT: δ ϭ Ϫ5.6 [CH3,
Si(CH3)2], 18.1 [SiC(CH3)3], 25.2 and 25.4 (CH2, C-3), 25.7 [CH3,
SiC(CH3)3], 32.6 and 33.7 (CH2, C-2), 63.7 and 63.9 (CH2, C-6),
66.0 and 66.9 (CH, C-5), 77.0 and 78.7 (CH, C-4), 98.5 and 98.6
(CH, C-1). Ϫ C12H25N3O3Si (287.43): calcd. C 50.15, H 8.77, N
14.62; found C 50.01, H 8.88, N 14.31.
ϭ
Ϫ
Ethyl (6S,7R)-7-Azido-8-(tert-butyldimethylsilyloxy)-6-hydroxyoct-
2-enoate (16), Ethyl (2R,3S,6R,7R)-2-(tert-Butyldimethylsilyloxy-
methyl)-3-hydroxy-1,8,9-triazabicyclo[4.3.0]non-8-ene-7-carboxylate
(17), and Ethyl (2R,3S,6S,7S)-2-(tert-Butyldimethylsilyloxymethyl)-
3-hydroxy-1,8,9-triazabicyclo[4.3.0]non-8-ene-7-carboxylate
(18): 25.8 [CH3, SiC(CH3)3], 54.9 (CH, C-2), 61.8 (CH2, OCH2CH3),
1.22 g (4.24 mmol) of 7 was dissolved in dry toluene (15 mL) and
(ethoxycarbonylmethylene)triphenylphosphorane (1.48 g, 4.24 mmol,
62.8 (CH2, C-1Ј), 63.0 and 65.9 (CH, C-3 and C-6), 82.2 (CH, C-
2), 168.4 (COOEt).
Eur. J. Org. Chem. 1999, 1407Ϫ1414
1411

C. Herdeis, J. Telser
FULL PAPER
Ethyl (2ЈR,3ЈS,6ЈR)-2-Diazo-2-[2Ј-(tert-butyldimethylsilyloxymeth-
Ethyl (2ЈR,3ЈS)-2-[2Ј-(tert-Butyldimethylsilyloxymethyl)-3Ј-hydroxy-
yl)-3Ј-hydroxypiperid-6Ј-yl]acetate (19) and Ethyl (2ЈR,3ЈS,6ЈS)-2- piperidyliden-6Ј-yl]acetate (21): 1.43 g (4.00 mmol) of diazo esters
Diazo-2-[2Ј-(tert-butyldimethylsilyloxymethyl)-3Ј-hydroxypiperid- 19 and 20 was dissolved in dichloromethane (20 mL) and rho-
6Ј-yl]acetate (20): A mixture of diastereomeric triazolines (1.49 g, dium(II) acetate dimer (9 mg, 0.02 mmol, 5·10Ϫ3 equivalents) was
4.17 mmol) and triethylamine (0.64 mL, 4.6 mmol, 1.1 equivalents) suspended in the solution. The solution was stirred for 24 h at room
was dissolved in dichloromethane (20 mL). The mixture was stirred temperature. It was then twice extracted with brine, dried with
and left to stand overnight. Removal of the solvent and triethyl- Na2SO4 and the solvent evaporated to yield 1.28 g (3.88 mmol,
20
amine in vacuo followed by filtration through silica gel with ethyl 97%), of a pale yellow oil, [α]D ϭ Ϫ30 (c ϭ 1.1, MeOH). Ϫ IR
acetate afforded 1.43 g of a mixture of diastereomeric diazo esters
19 and 20 (4.00 mmol, 96%). Ϫ C16H31N3O4Si (357.53): calcd. C
(neat): ν˜ ϭ 3420 cmϪ1 (OH), 1740, 1650, 1600 (CϭO, CϭC), 1460,
1250. Ϫ H NMR (200 MHz, CDCl3): δ ϭ 0.05 [6 H, s, Si(CH3)2],
1
53.75, H 8.74, N 11.75; found C 53.56, H 8.51, N 11.90. Ϫ For 0.88 [9 H, s, SiC(CH3)3], 1.18 (3 H, t, J ϭ 7.1 Hz, OCH2CH3),
spectroscopic purposes pure samples of both diastereomers could
be obtained by column chromatography (EtOAc).
1.50Ϫ2.46 (4 H, m, 4Ј-H, 5Ј-H), 3.20 (1 H, ddd, J1ЈЈA,2Ј ϭ J1ЈЈB,2Ј ϭ
J2Ј,3Ј ϭ 6.7 Hz, 2Ј-H), 3.38 (1 H, s, OϪH), 3.64Ϫ3.78 (3 H, m, 3Ј-
H, 1ЈЈ-H), 4.02 (2 H, q, J ϭ 7.1, OCH2CH3), 4.38 (1 H, s, 2-H),
8.45 (1 H, s, NϪH). Ϫ 13C NMR (50.3 MHz, CDCl3) DEPT: δ ϭ
Ϫ5.6 [CH3, Si(CH3)2], 14.5 (CH3, OCH2CH3), 18.0 [SiC(CH3)3],
27.2, 27.8 (CH2, C-4Ј, C-5Ј), 58.3 (CH2, OCH2CH3), 58.5 (CH, C-
2Ј), 66.6 (CH2, C-1ЈЈ), 69.1 (CH, C-3Ј), 81.3 (CH, C-2), 160.6 (C-
6Ј), 170.4 (C-1). Ϫ C16H31NO4Si (329.52): calcd. C 58.32, H 9.48,
N 4.25; found C 57.89, H 9.75, N 4.11.
Ethyl (2ЈR,3ЈS,6ЈR)-2-Diazo-2-[2Ј-(tert-butyldimethylsilyloxymeth-
yl)-3Ј-hydroxypiperid-6Ј-yl]acetate (19): Rf
ϭ 0.55 (EtOAc),
[α]D20 ϭ ϩ44 (c ϭ 1.1, MeOH). Ϫ IR (neat): ν˜ ϭ 3400Ϫ3300 cmϪ1
(OH), 2080 (NϭN), 1690 (CϭO), 830. Ϫ 1H NMR (200 MHz,
CDCl3): δ ϭ 0.08 [6 H, s, Si(CH3)2], 0.89 [9 H, s, SiC(CH3)3], 1.27
(3 H, t, J ϭ 7.1 Hz, OCH2CH3), 1.35Ϫ1.59 (2 H, m, 4Ј-H),
1.78Ϫ2.16 (2 H, m, 5Ј-H), 2.71 (1 H, ddd, J1ЈЈA,2Ј ϭ 6.4, J1ЈЈB,2Ј
ϭ
6.7, J2Ј,3Ј ϭ 8.8 Hz, 2Ј-H), 3.38Ϫ3.53 (1 H, m, 3Ј-H), 3.45Ϫ3.70 (2
H, m, 1ЈЈA-H, 6Ј-H), 3.85 (1 H, dd, J1ЈЈB,2Ј ϭ 6.7, JAB ϭ 9.7 Hz,
1ЈЈB-H), 4.22 (3 H, t, J ϭ 7.1 Hz, OCH2CH3). Ϫ 13C NMR
(50.3 MHz, CDCl3) DEPT: δ ϭ Ϫ5.5 [CH3, Si(CH3)2], 14.5 (CH3,
OCH2CH3), 18.1 [SiC(CH3)3], 25.8 [CH3, SiC(CH3)3], 28.1 (CH2,
C-5Ј), 33.0 (CH2, C-4Ј), 50.3 (CH, C-2Ј), 60.1 (CH2, OCH2CH3),
62.4 (CH, C-6Ј), 66.8 (CH2, C-1ЈЈ), 71.1 (CH, C-3Ј), 166.5 (C-1).
Ethyl (2ЈR,3ЈS,6ЈR)-2-[2Ј-(tert-Butyldimethylsilyloxymethyl)-3Ј-hy-
droxypiperid-6Ј-yl]acetate (22): 1.42 g (4.30 mmol) of 21 was dis-
solved in ethanol (60 mL) (p.a.), 10% Pd/C (750 mg) was added
and the mixture was hydrogenated at 50 bar for 48 h. The catalyst
was removed by filtration and the solvent evaporated in vacuo.
After column chromatography (EtOAc/MeOH, 9:1), 22 was ob-
tained as colourless oil, Rf ϭ 0.22, yield 1.02 g (3.06 mmol, 71%),
[α]D20 ϭ ϩ20 (c ϭ 1.4, MeOH). Ϫ IR (neat): ν˜ ϭ 3600Ϫ3300 cmϪ1
Ethyl
(2ЈR,3ЈS,6ЈS)-2-Diazo-2-[2Ј-(tert-butyldimethylsilyloxy-
1
(NH, OH), 1750 (CϭO), 1480, 1205, 900. Ϫ H NMR (200 MHz,
methyl)-3Ј-hydroxypiperid-6Ј-yl]acetate (20): Rf ϭ 0.35 (EtOAc),
20
CDCl3): δ ϭ 0.03 [6 H, s, Si(CH3)2], 1.12 [9 H, s, SiC(CH3)3], 1.44
(3 H, t, J ϭ 7.1 Hz, OCH2CH3), 1.32Ϫ1.69 (2 H, m, 4Ј-H),
1.80Ϫ1.93 (1 H, m, 5ЈA-H), 2.15Ϫ2.25 (1 H, m, 5ЈB-H), 2.52 (1 H,
dd, J2A,6Ј ϭ 9.1, JAB ϭ 16.3 Hz, 2A-H), 2.69 (1 H, dd, J2B,6Ј ϭ 4.0,
JAB ϭ 16.3 Hz, 2B-H), 2.67Ϫ2.77 (1 H, m, 2Ј-H), 3.03Ϫ3.16 (1 H,
m, 6Ј-H), 3.40 (1 H, ddd, J3ЈA,4Ј ϭ 4.5, J ϭ 9.6, J ϭ 10.6, 3Ј-H),
3.70 (1 H, dd, J2Ј,1ЈЈA ϭ 8.9, JAB ϭ 9.9 Hz, 1ЈЈA-H), 4.25 (1 H, dd,
J2Ј,1ЈЈB ϭ 3.3, JAB ϭ 9.9 Hz, 1ЈЈB-H), 4.32 (3 H, t, J ϭ 7.1 Hz,
OCH2CH3). Ϫ 13C NMR (50.3 MHz, CDCl3) DEPT: δ ϭ Ϫ5.3,
Ϫ5.2 [CH3, Si(CH3)2], 14.6 (CH3, OCH2CH3), 19.1 [SiC(CH3)3],
26.4 [CH3, SiC(CH3)3], 31.7 (CH2, C-5Ј), 34.5 (CH2, C-4Ј), 41.0
(CH2, C-2), 53.5 (CH, C-6Ј), 61.6 (CH3, OCH2CH3), 65.0 (CH, C-
[α]D ϭ Ϫ36 (c ϭ 1.39, MeOH). Ϫ IR (neat): ν˜ ϭ 3400Ϫ3300
cmϪ1 (OH), 2075 (NϭN), 1685 (CϭO), 830. Ϫ1H NMR
(200 MHz, CDCl3) δ ϭ 0.07 [6 H, s, Si(CH3)2], 0.89 [9 H, s,
SiC(CH3)3], 1.28 (3 H, t, J ϭ 7.1 Hz, OCH2CH3), 1.20Ϫ2.04 (4 H,
m, 4Ј-H, 3Ј-H), 2.70 (1 H, ddd, J2Ј,3Ј ϭ J1ЈЈA,2Ј ϭ J1ЈЈB,2Ј ϭ 6.6 Hz,
2Ј-H), 3.54 (1 H, ddd, J3Ј,4Ј ϭ 4.6, J2Ј,3Ј ϭ 6.6, J3Ј,4Ј ϭ 9.9 Hz, 3Ј-
H), 3.59 (1 H, dd, J1ЈЈ,2Ј ϭ 6.6, JAB ϭ 9.7 Hz, 1ЈЈA-H), 3.82 (1 H,
dd, J1ЈЈ, 2Ј ϭ 6.6, JAB ϭ 9.7 Hz, 1ЈЈB-H), 4.19 (1 H, m, 6Ј-H), 4.23
(2 H, q, J ϭ 7.1, OCH2CH3). Ϫ 13C NMR (50.3 MHz, CDCl3):
δ ϭ Ϫ5.8 [Si(CH3)2], 14.3 (OCH2CH3), 17.9 [SiC(CH3)3], 24.6 (C-
5Ј), 25.6 [SiC(CH3)3], 29.1 (C-4Ј), 46.5 (C-2Ј), 57.8 (OCH2CH3),
60.4 (C-6Ј), 65.1 (C-1ЈЈ), 69.7 (C-3Ј), 166.9 (C-1).
2Ј), 65.3 (CH2, C-1ЈЈ), 69.5 (CH, C-3Ј), 173.5 (C-1).
Ϫ
Ethyl (2ЈR,3ЈS,6ЈR)-2-Diazo-2-[2Ј-(tert-butyldimethylsilyloxymeth-
yl)-3Ј-hydroxypiperid-6Ј-yl]acetate Hydrochloride Monohydrate: A
solution of 17 (396 mg, 1.11 mmol) and triethylamine (150 µL,
110 mg, 1.11 mmol, 1 equivalent) in chloroform (15 mL) was left
to stand overnight until the diazo ester was formed quantitatively.
The mixture was then washed with 1  HCl. The intense yellow
colour of the diazo ester immediately changed to pale yellow. The
organic phase was dried with Na2SO4 and the solvent was evapo-
rated to yield the product as a pale yellow solid (366 mg,
C16H33NO4Si (331.53): calcd. C 57.97, H 10.03, N 4.22; found C
57.82, H 9.84, N 4.14.
Ethyl (2ЈR,3ЈS,6ЈR)-2-[2Ј-(tert-Butyldimethylsilyloxymethyl)-3Ј-(tert-
butyldimethylsilyloxy)piperid-6Ј-yl]acetate (23): Imidazole (817 mg,
12.00 mmol, 4 equivalents) and tert-butyl(chloro)dimethylsilane
(905 mg, 6.00 mmol, 2 equivalents) were added to a solution of 22
(1.0 g, 3.02 mmol) in 10 mL of DMF (abs.). The reaction mixture
was stirred at 60°C for 24 h; another portion of imidazole (905 mg,
0.89 mmol, 80%), m.p. 55°C (decomposition). Ϫ [α]D20 ϭ ϩ11 (c ϭ 6.00 mmol,
1.36, MeOH). Ϫ IR (KBr): ν˜ ϭ 3300 cmϪ1 (OH, NH), 2100 (Nϭ
(817 mg, 12.00 mmol, 4 equivalents) was added. The mixture was
N), 1670 (CϭO), 1580, 1530, 1250, 830.
1H NMR stirred at 60°C until no more starting material could be detected
(200 MHz,CDCl3): δ ϭ 0.08 [6 H, s, Si(CH3)2], 0.89 [9 H, s, by TLC. Water was then added and the mixture extracted with 4
2 equivalents) and tert-butyl(chloro)dimethylsilane
Ϫ
SiC(CH3)3], 1.28 (3 H, t, J ϭ 7.2 Hz, OCH2CH3), 1.60Ϫ2.49 (4 H, portions of ether, the combined organic layers were dried with
m, 4Ј-H, 5Ј-H), 3.05Ϫ3.23 (1 H, m, 2Ј-H), 4.04Ϫ4.18 (3 H, m, Na2SO4, the solvent was distilled, and the residue was purified by
3Ј-H, 1ЈЈ-H), 4.24 (3 H, t, J ϭ 7.2 Hz, OCH2CH3). Ϫ 13C NMR column chromatography (Et2O/petroleum ether, 2:1, Rf ϭ 0.64).
(50.3 MHz, CDCl3) DEPT: δ ϭ Ϫ5.5 [CH3, Si(CH3)2], 14.2 (CH3, The product was dried at 0.1 mbar for 3 d to yield 1.13 g
20
OCH2CH3), 18.0 [SiC(CH3)3], 23.9 (CH2, C-5Ј), 25.7 [CH3, (2.54 mmol, 84%) of a colourless oil. Ϫ [α]D ϭ ϩ33 (c ϭ 0.9,
SiC(CH3)3], 31.9 (CH2, C-4Ј), 53.1 (CH, C-2Ј), 60.2 (CH2, C-1ЈЈ), tBuOMe). Ϫ IR (neat): ν˜ ϭ 3380 cmϪ1 (NH), 1760 (CϭO), 1480,
1
63.0 (CH, C-6Ј), 64.1 (CH, C-3Ј), 166.1 (C-1). Ϫ C16H34ClN3O5Si 1270, 1100. Ϫ H NMR (200 MHz, CDCl3): δ ϭ 0.00, 0.01, 0.02,
(412.01): calcd. C 46.64, H 8.32, N 10.12; found C 46.48, H 8.36,
N 10.11.
0.03 [12 H, 4 s, Si(CH3)2], 0.84 [9 H, s, SiC(CH3)3], 0.86 [9 H, s,
SiC(CH3)3], 1.22 (3 H, t, J ϭ 7.1 Hz, OCH2CH3), 1.15Ϫ1.48 (2 H,
1412
Eur. J. Org. Chem. 1999, 1407Ϫ1414

Nonracemic (ϩ)-Desoxoprosophylline by a Tandem Wittig [2ϩ3]-Cycloaddition Reaction
m, 4ЈA-H, 5ЈA-H), 1.59Ϫ1.69 (1 H, m, 5ЈB-H), 1.84Ϫ1.92 (1 H, m, (1 H, ddd, J3,4 ϭ 4.6, J ϭ 8.8, J ϭ 10.4 Hz, 3-H), 3.43 (1 H, dd,
FULL PAPER
4ЈB-H), 2.32Ϫ2.40 (2 H, m, 2-H), 2.43 (1 H, s, NϪH), 2.54 (1 H, J1ЈA,2 ϭ 8.9, JAB ϭ 9.4 Hz, 1ЈA-H), 4.00 (1 H, dd, J1ЈB, 2 ϭ 2.9,
ddd, J1ЈЈB,2Ј ϭ 3.0, J1ЈЈA,2Ј ϭ 9.0, J2Ј,3Ј ϭ 9.0 Hz, 2Ј-H), 2.85Ϫ2.95 JAB ϭ 9.4 Hz, 1ЈB-H), 5.27Ϫ5.55 (2 H, m, 2ЈЈ-H, 3ЈЈ-H). Ϫ 13C
(1 H, m, 6Ј-H), 3.24 (1 H, ddd, J3Ј,4Ј ϭ 4.5, J2Ј,3Ј ϭ 9.0, J3Ј,4Ј
10.0 Hz, 3Ј-H), 3.39 (1 H, dd, J1ЈЈA,2Ј ϭ 9.0, JAB ϭ 9.5 Hz, 1ЈЈA-
ϭ
NMR (50.3 MHz, [D6]acetone) DEPT: δ ϭ Ϫ5.5, Ϫ5.1, Ϫ4.2
[CH3, Si(CH3)2], 14.0 (CH3, C-12ЈЈ), 18.1 [SiC(CH3)3], 18.5
H), 3.95 (1 H, dd, J1ЈЈB,2Ј ϭ 3.0, JAB ϭ 9.5 Hz, 1ЈЈB-H), 4.01 (2 H, [SiC(CH3)3], 23.0 (CH2), 25.8 [CH3, SiC(CH3)3], 25.9 [CH3,
q, J ϭ 7.1, OCH2CH3). Ϫ 13C NMR (50.3 MHz, CDCl3) DEPT:
SiC(CH3)3], 27.7 (CH2), 28.3 (CH2), 28.7 (CH2), 29.7 (CH2), 29.9
Ϫ5.5, Ϫ5.0, Ϫ4.1, Ϫ3.0 [CH3, Si(CH3)2], 14.1 (CH3, (CH2), 30.2 (CH2), 31.9 (CH2), 32.3 (CH2), 34.8 (CH2), 56.1 (CH,
OCH2CH3), 17.8, 18.2 [SiC(CH3)3], 25.6, 25.7 [CH3, SiC(CH3)3], C-6), 65.1 (CH, C-2), 65.5 (CH2, C-1Ј), 70.9 (CH, C-3), 127.0 and
31.0 (CH2, C-5Ј), 34.1 (CH2, C-4Ј), 41.0 (CH2, C-2), 52.1 (CH, C- 132.5 (CH, C-2ЈЈand C-3ЈЈ). Ϫ C30H63NO2Si2 (526.01): calcd. C
δ
ϭ
6Ј), 60.3 (CH2, OCH2CH3), 63.9 (CH, C-2Ј), 64.5 (CH2, C-1ЈЈ), 68.50, H 12.07, N 2.66; found C 68.51, H 11.78, N 2.41.
69.9 (CH, C-3Ј), 171.9 (C-1). Ϫ C22H47NO4Si2 (445.80): calcd. C
59.27, H 10.63, N 3.10; found C 58.95, H 10.38, N 3.14.
(2R,3S,6S)-3-(tert-Butyldimethylsilyloxy)-2-(tert-butyldimeth-
ylsilyloxymethyl)-6-(n-dodecyl)piperidine (26): 10% Pd/C (80 mg)
was added to a solution of 25 (392 mg, 0.75 mmol) in of ethanol
(p.a.) (15 mL) and the mixture was hydrogenated at 50 bar over-
night. The catalyst was then removed by filtration, the filtrate was
concentrated to dryness, and the residue was purified by column
chromatography (Et2O/petroleum ether, 1:6, Rf ϭ 0.54). Yield
(2ЈR,3ЈS,6ЈR)-2-[3Ј-(tert-Butyldimethylsilyloxy)-2Ј-(tert-butyldi-
methylsilyloxymethyl)piperid-6Ј-yl]ethanal (24): A solution of 23
(850 mg, 1.91 mmol) in of pentane (abs.) (10 mL) was cooled to
Ϫ78°C. DIBAlH (2.30 mL, 2.30 mmol, 1.2 equivalents of a 1 
solution in hexane) was slowly added, and the reaction stirred at
Ϫ78°C for 25 min. Then, 10 mL of a methanol/water (1:1) mixture
was cautiously added, while avoiding warming of the reaction
above Ϫ60°C. When the evolution of gas had stopped and the
water was entirely frozen, the mixture was warmed to room tem-
perature and diluted with brine. It was extracted with four portions
of dichloromethane, the combined organic extracts were dried with
Na2SO4, filtered through a layer of Celite, and the solvent was eva-
porated. The crude product was purified by column chromatogra-
20
369 mg (0.70 mmol, 93%) as a colourless oil. Ϫ [α]D ϭ ϩ39 (c ϭ
1.3, tBuOMe). Ϫ IR (neat): ν˜ ϭ 1440 cmϪ1, 1230, 1070, 820. Ϫ 1H
NMR (200 MHz, CDCl3): δ ϭ 0.02, 0.03, 0.05 [12 H, 3 s, Si(CH3)2],
0.87 [9 H, s, SiC(CH3)3], 0.89 [9 H, s, SiC(CH3)3], 0.90Ϫ1.70 (25
H, m, (CH2)11CH3), 1.58Ϫ1.94 (4 H, m, 4-H, 5-H), 2.43Ϫ2.50 (1
H, m, 6-H), 2.51 (1 H, ddd, J1ЈB,2 ϭ 3.1, J1ЈA,2 ϭ 9.1, J2,3 ϭ 9.3 Hz,
2-H), 3.28 (1 H, ddd, J3,4 ϭ 4.5, J2,3 ϭ 9.3, J3,4 ϭ 10.4 Hz, 3-H),
3.43 (1 H, dd, J1ЈA,2 ϭ 9.1, JAB ϭ 9.5 Hz, 1ЈA-H), 3.97 (1 H, dd,
J1ЈB,2 ϭ 3.1, JAB ϭ 9.5 Hz, 1ЈB-H). Ϫ 13C NMR (50.3 MHz,
CDCl3): δ ϭ Ϫ5.4, Ϫ4.9, Ϫ4.1 [CH3, Si(CH3)2], 14.1 [CH3,
(CH2)11CH3], 18.0 [SiC(CH3)3], 18.2 [SiC(CH3)3], 22.7 (CH2), 25.8
[CH3, SiC(CH3)3], 25.9 [CH3, SiC(CH3)3], 26.1 (CH2), 29.6 (CH2),
31.6 (CH2), 31.9 (CH2), 34.5 (CH2), 36.6 (CH2), 55.5 (CH, C-6),
64.3 (CH, C-2), 64.8 (CH2, C-1Ј), 70.6 (CH, C-3). Ϫ C30H65NO2Si2
(528.03): calcd. C 68.24, H 12.41, N 2.65; found C 68.57, H 12.57,
N 2.74.
phy through silica gel (Et2O, Rf
ϭ 0.45) to yield 504 mg
(1.25 mmol, 66%) of a colourless oil. The aldehyde could not be
stored for more than a few hours because even at Ϫ20°C the com-
pound decomposed rapidly. Immediate conversion into 25 is
strongly recommended. Ϫ IR (neat): ν˜ ϭ 1740 cmϪ1 (CϭO), 1480,
1
1270, 1110, 850. Ϫ H NMR (200 MHz, CDCl3): δ ϭ 0.02, 0.03,
0.04, 0.05 [12 H, 4 s, Si(CH3)2], 0.87 [9 H, s, SiC(CH3)3], 0.93 [9 H,
s, SiC(CH3)3], 1.18Ϫ1.96 (4 H, m, 4Ј-H, 5Ј-H), 2.47Ϫ2.53 (2 H, m,
2-H), 2.51Ϫ2.60 (1 H, m, 2Ј-H), 3.03Ϫ3.08 (1 H, m, 6Ј-H), 3.28 (1
H, ddd, J3Ј,4Ј ϭ 4.5, J3Ј,4Ј ϭ 9.2, J2Ј,3Ј ϭ 9.2 Hz, 3Ј-H), 3.42 (1 H,
(2R,3S,6S)-6-(n-Dodecyl)-3-hydroxy-2-(hydroxymethyl)piperidine
[(؉)-Desoxoprosophylline, 27]: 369 mg (0.70 mmol) of 26 was dis-
solved in 30 mL of freshly prepared ethanolic HCl. The solution
was stirred at ambient temperature for 1 h, and the solvent was
removed by distillation in vacuo. The residue was dissolved in 50
mL of 6  aqueous KOH, and extracted with four portions of di-
chloromethane. The combined organic extracts were concentrated
to dryness and the residue was purified by column chromatography
(CH2Cl2/MeOH, 9:1, Rf ϭ 0.16) and recrystallized from acetone to
give 27 (182 mg 0.61 mmol, 87%) as colourless crystals, m.p. 83°C.
dd, J1ЈЈA,2Ј ϭ 8.5, JAB ϭ 9.5 Hz, 1ЈЈA-H), 3.93 (1 H, dd, J1ЈЈB,2Ј
ϭ
3.0, JAB ϭ 9.5 Hz, 1ЈЈB-H), 9.79 (1 H, t, J ϭ 1.6 Hz, 1-H). Ϫ 13C
NMR (50.3 MHz, CDCl3) DEPT: δ ϭ Ϫ5.4, Ϫ4.9, Ϫ4.1 [CH3,
Si(CH3)2], 17.9 [SiC(CH3)3], 18.3 [SiC(CH3)3], 25.7 [CH3,
SiC(CH3)3], 25.9 [CH3, SiC(CH3)3], 31.8 (CH2, C-5Ј), 34.2 (CH2,
C-4Ј), 50.4 (CH2, C-2), 50.5 (CH, C-6Ј), 63.4 (CH, C-2Ј), 64.4
(CH2, C-1ЈЈ), 69.9 (CH, C-3Ј), 201.3 (CH, C-1).
(2R,3S,6R)-3-(tert-Butyldimethylsilyloxy)-2-(tert-butyldimeth-
ylsilyloxymethyl)-6-(n-dodec-2-enyl)piperidine (25): A solution of n-
decylphosphonium bromide (904 mg, 1.87 mmol, 1.5 equivalents)
in THF (abs.) (20 mL) was cooled to Ϫ40°C, followed by slow
addition of sodium bis(trimethylsilyl)amide (1  in THF, 3.70 mL,
3.7 mmol, 3 equivalents). Immediately after the addition, the mix-
ture turned to an intense orange colour. After stirring the Wittig
reagent at Ϫ40°C for 1 h, a previously cooled solution of 24
(500 mg, 1.24 mmol) in THF (abs.) (10 mL) was added. The reac-
tion mixture was left at Ϫ40°C for 40 min, and then it was warmed
to room temperature and stirred for 2 h. The solvent was evapo-
rated and the residue treated with Et2O/petroleum ether (1:6) which
led to immediate precipitation of triphenylphosphane oxide. The
product was purified by column chromatography (Et2O/petroleum
ether, 1:6, Rf ϭ 0.52), yield 515 mg (0.98 mmol, 79%) as a colour-
less oil. Ϫ [α]D20 ϭ ϩ57 (c ϭ 2.0, tBuOMe). Ϫ IR (neat): ν˜ ϭ 1480
cmϪ1, 1270, 1100. Ϫ 1H NMR (200 MHz, [D6]acetone): δ ϭ
0.04Ϫ0.08 [12 H, m, Si(CH3)2], 0.85Ϫ0.95 [18 H, m, SiC(CH3)3],
20
20
Ϫ [α]D ϭ ϩ13 (c ϭ 0.22, CHCl3) {ref.[4b]: [α]D ϭ Ϫ14.0 (c ϭ
0.24, CHCl3)}. Ϫ IR (KBr): ν˜ ϭ 2980 cmϪ1, 2880, 1490, 1480,
1280, 1080. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 0.87 [3 H, t, J ϭ
6.7 Hz, (CH2)11CH3], 1.0Ϫ1.4 [22 H, m, CH2)11], 1.65Ϫ1.80 (2 H,
m, 5-H), 1.96Ϫ2.09 (2 H, m, 4-H), 2.42Ϫ2.61 (2 H, m, 2-H, 6-H),
2.93 (3 H, br s, NϪH, OϪH), 3.45 (1 H, ddd, J3,4 ϭ 4.5, J ϭ 8.6,
J ϭ 9.2 Hz, 3-H), 3.70 (1 H, dd, J1ЈA,2 ϭ 5.3, JAB ϭ 10.7 Hz, 1ЈA-
H), 3.82 (1 H, dd, J1ЈB,2 ϭ 4.4, JAB ϭ 10.7 Hz, 1ЈB-H). Ϫ 13C NMR
(50.3 MHz, CDCl3) DEPT: δ ϭ 14.1 [CH3, (CH2)11CH3], 22.7
(CH2), 26.2 (CH2), 29.3 (CH2), 29.6 (CH2), 29.8 (CH2), 31.0 (CH2),
33.8 (CH2), 36.4 (CH2), 56.1 (CH, C-6), 63.2 (CH, C-2), 64.2 (CH2,
C-1Ј), 70.2 (CH, C-3). Ϫ C18H37NO2 (299.50): calcd. C 72.19, H
12.45, N 4.68; found C 71.94, H 12.17, N 4.72.
Acknowledgments
We thank the Deutsche Forschungsgemeinschaft and the Fonds der
1.03Ϫ1.46 [17 H, m, (CH2)7CH3], 1.56Ϫ1.69 (2 H, m), 1.88Ϫ2.18 Chemischen Industrie for financial support and the Merck KG
(6 H, m), 2.41Ϫ2.56 (2 H, m, 2-H, 6-H), 2.81 (1 H, s, NϪH), 3.35 Darmstadt for donating chemicals.
Eur. J. Org. Chem. 1999, 1407Ϫ1414
1413

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1414
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