Stereoselective total synthesis of (-)-deoxoprosophylline

Article abstract of DOI:10.1016/S0040-4020(00)01113-3

An efficient synthesis of the prosopis alkaloid (-)-deoxoprosophylline has been developed, utilizing the easily available amino acid L-serine as a chiral pool starting material.

Full text of DOI:10.1016/S0040-4020(00)01113-3

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1169±1173
Stereoselective total synthesis of (2)-deoxoprosophylline
Apurba Datta,a,b,p Jalluri S. Ravi Kumarb and Subho Roya
aDepartment of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045-2506, USA
bOrganic Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 16 October 2000; accepted 21 November 2000
AbstractÐAn ef®cient synthesis of the prosopis alkaloid (2)-deoxoprosophylline has been developed, utilizing the easily available amino
acid l-serine as a chiral pool starting material. q 2001 Elsevier Science Ltd. All rights reserved.
Alkaloids containing multifunctionalized piperidine rings
are found abundantly in nature.1 Prosopis alkaloids, belong-
ing to such a subgroup of alkaloid lipids have been isolated
from the leaves, stems and roots of Prosopis afrikana and
were found to contain a 2,3,6-trisubstituted piperidine
framework (Fig. 1).2 Besides the interesting structural
features, these compounds and their synthetic analogs are
also of considerable pharmaceutical interest, exhibiting
antibiotic, anesthetic and CNS stimulating properties.1,3
Consequently, several approaches have been developed
for the synthesis of these classes of compounds.4 Described
herein is an ef®cient chiral pool approach for the synthesis
of (2)-deoxoprosophylline, starting from the natural amino
acid l-serine.
homoallylic ketone 2 (Scheme 1) as a key intermediate in
the proposed synthesis, wherein, stereoselective reduction
of the keto carbonyl will afford the 3R secondary hydroxy
group, while the terminal alkene can be utilized as a
convenient handle towards (i) introduction of the C12 side
chain, and (ii) forming the piperidine framework. The
ketone 2 can in turn be prepared via addition of 3-butenyl-
magnesium bromide to the known serine-derived Weinreb
amide 3.5
1. Results and discussion
In a three-step sequence, the readily available amino acid
l-serine was converted to the corresponding N,O-protected
Weinreb amide 3, following a reported procedure.5
Our retrosynthetic strategy envisions the l-serine-derived
Figure 1. Structures of some prosopis alkaloids and synthetic analogs.
Scheme 1.
Keywords: piperidine alkaloid; chiral pool; chelation control; stereoselection.
Corresponding author. Tel.: 1785-864-4117; fax: 785-864-5836; e-mail: adutta@rx.pharm.ukans.edu
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01113-3

1170
A. Datta et al. / Tetrahedron 57 (2001) 1169±1173
Scheme 2.
Grignard reaction of the amide 3 with 3-butenylmagnesium
bromide uneventfully afforded the pivotal ketone derivative
2 (Scheme 2) in 76% yield.
Having obtained the a-aminoketone 2, stereoselective
reduction of the keto group was then undertaken. Thus,
zinc borohydride [Zn(BH4)2]-mediated chelation-controlled
reduction of the ketone 2 was found to form the required
amino alcohol derivative 5 (Scheme 3) with good anti-
selectivity.6 Interestingly, reduction of the ketone 2 with
sodium borohydride (NaBH4) resulted in the exclusive
formation of the corresponding 1,2-syn-amino alcohol 6 in
near-quantitative yield. [The assigned stereochemistry of
compounds 5 and 6 were con®rmed via their corresponding
oxazolidinone derivatives 5A and 6A in which the coupling
constants between the ring protons (H4±H5) were in good
agreement with the assigned structures.]
The observed syn-selectivity in this reaction is precedented
in the literature and has been explained via a non-chelated
Felkin±Anh transition state.7
Introduction of the dodecyl side chain via functionalization
of the terminal ole®n was next investigated. Thus, pro-
tection of the free hydroxy group of the anti-amino alcohol
5 as its benzyl ether derivative 7 (Scheme 4), followed by
oxidative degradation of the double bond under standard
conditions cleanly afforded the aldehyde 8 in high overall
Scheme 3.
Scheme 4. a. NaH, BnBr; b. i) OsO4, ii) NalO4 (on silica gel); c. C12H25MgBr; d. 2-Iodoxybenzoic acid; e. 80% AcOH in H2O; f. BnBr, Ag2O; g. HCO2H;
h. Palladium hydroxide, H2, EtOH-HCI.

A. Datta et al. / Tetrahedron 57 (2001) 1169±1173
1171
yield. Grignard reaction of the aldehyde 8 with dodecyl-
magnesium bromide to form the adduct 9 and subsequent
oxidation of the resulting hydroxy group afforded the corre-
sponding ketone 10 in good yield. Towards constructing the
target piperidine framework, selective hydrolysis of the
acetonide linkage and benzyl protection of the primary
hydroxy group yielded the open chain ketone 12. Treatment
of this d-amino ketone with 96% formic acid resulted in
simultaneous N-Boc-deprotection and cyclodehydration to
form the expected D1-piperidine derivative 13 in 78%
yield.8 Finally, in a one-pot reaction, hydrogenation of the
imine double bond and reductive removal of the benzyl
protecting groups under standard conditions completed the
intended synthesis of (2)-deoxyprosophylline (1). The
speci®c rotation and spectral data of 1 were in good agree-
ment with the reported values thereby con®rming the struc-
ture and the assigned stereochemistry of the product. The
observed stereoselectivity in the reduction of the imine can
be ascribed to the benzyloxymethyl substituent at the
2-position, directing hydrogenation to occur from the less
hindered a-face.
ether (15 mL) and stirred at the same temperature for 3 h.
The reaction was quenched by careful addition of an
aqueous 10% HCl solution (25 mL) and stirred for 5 min.
The resulting solution was extracted with ethyl acetate
(3£30 mL), the combined extract washed sequentially
with water and brine, dried over anhydrous Na2SO4 and
concentrated under vacuum. Puri®cation of the oily residue
by column chromatography (ethyl acetate±hexaneˆ1:15)
afforded the pure product 2 (0.9 g, 76%) as a colorless oil:
 Ã
22
a
ˆ264 (cˆ1.3, CHCl3); IR (neat) 1725, 1702 cm21; 1H
D
NMR d 1.41 and 1.52 (2s, 12H), 1.74 (s, 3H), 2.34 (m, 2H),
2.59 (m, 2H), 3.86 (m, 1H), 4.11 (m, 1H), 4.32 (m,1H), 5.0
(m, 2H), 5.79 (m, 1H); MS (FAB1) 284 (MH1); Anal.
Calcd for C15H25NO4 (283.18): C, 63.58; H, 8.89; N, 4.94.
Found: C, 63.37; H, 8.90; N, 5.28.
1.1.2. tert-Butyl (4S,10R)-2,2-dimethyl-4-(10-hydroxy-40-
pentenyl)oxazolidine-3-carboxylate (5). To a stirred solu-
tion of the ketone 2 (2.3 g, 8.1 mmol) in anhydrous ether
(15 mL) and benzene (5 mL) at room temperature was
added dropwise a solution of freshly prepared zinc borohy-
dride (0.66 M solution in THF, 6.2 mL, 4.06 mmol) and
stirred for 10 min. The reaction was quenched by addition
of saturated NH4Cl solution and extracted with ethyl acetate
(3£50 mL). The combined organic extracts were washed
with brine, dried (Na2SO4), solvent was removed under
vacuum and the residue puri®ed by column chromatography
In conclusion, the present synthesis compares well with the
earlier reported syntheses of enantiopure deoxoprosophyl-
line and offers an ef®cient alternative route to this important
class of piperidine alkaloids. The strategy and the approach
described is of general applicability and lends itself well to
the preparation of various possible stereoisomers by choice
of the starting amino acid (d- or l-serine) and through selec-
tive formation of either the syn- or anti-1,2-amino alcohol
fragment as shown above. Moreover, the side chain at C-6
can be easily modi®ed through introduction of alkyl or aryl
groups of choice by using the respective alkyl/aryl Grignard
reagent. The described method can thus be easily extended
towards synthesizing various prosopis alkaloids and other
related compounds of structural and biological importance.
(ethyl acetate±hexaneˆ1:10) to yield the anti-amino alco-
 Ã
22
hol 5 (1.6 g, 70%) as a viscous liquid: a ˆ23.2 (cˆ1,
D
1
CHCl3); IR (neat) 3456, 1696 cm21; H NMR d 1.51 (s,
15H), 1.78 (br s, 2H), 2.19 (m, 1H), 2.42 (m, 1H), 3.74±
4.11 (m, 5H), 5.05 (m, 2H), 5.84 (m, 1H); MS (FAB1) 286
(MH1); Anal. Calcd for C15H27NO4 (285.19): C, 63.13; H,
9.54; N, 4.91. Found: C, 63.07; H, 9.70; N, 5.28.
1.1.3. tert-Butyl (4S,10S)-2,2-dimethyl-4-(10-hydroxy-40-
pentenyl)oxazolidine-3-carboxylate (6). To a stirred solu-
tion of the ketone 2 (1.1 g, 3.9 mmol) in dry methanol
(35 mL) at 2208C was added sodium borohydride (0.3 g,
8 mmol) in one lot and stirring continued at the same
temperature for another 2 h. The reaction was then
quenched by addition of water (5 mL), concentrated under
vacuum, the residue taken up in ethyl acetate (50 mL) and
washed sequentially with water and brine. After drying over
anhydrous Na2SO4 and removal of solvent the residual oil
was puri®ed by column chromatography (ethyl acetate±
1. Experimental
1.1. General
Reagents and solvents were obtained from commercial
suppliers and used as received, unless otherwise noted.
Moisture- or air-sensitive reactions were conducted under
a nitrogen atmosphere in oven dried (1208C) glass appara-
tus. Diethyl ether and THF were distilled from sodium
benzophenone ketyl prior to use. All yields reported refer
to isolated material judged to be homogeneous by TLC and
NMR spectroscopy. Column chromatography was
performed on silica gel 60 (60±120 mesh), using ethyl
acetate/hexane mixture as eluent, unless speci®ed other-
wise. The NMR spectra were recorded in CDCl3 on a
200 MHz spectrometer with TMS as the internal standard.
Elemental analyses were carried out at the Indian Associa-
tion for the Cultivation of Science, Jadavpur, Calcutta.
hexaneˆ1:10) to yield the syn-amino alcohol 6 (1 g, 97%)
 Ã
22
as a viscous liquid:
a
ˆ241.5 (cˆ0.95, CHCl3); IR
D
1
(neat) 3458, 1692 cm21; H NMR d 1.45 (br s, 15H), 1.53
(br s, 2H), 2.13 (m, 2H), 3.60±4.28 (m, 5H), 4.97 (m, 2H),
5.72 (m, 1H); MS (FAB1) 286 (MH1).
1.1.4. tert-Butyl (4S,10R)-4-(10-benzyloxy-40-pentenyl)-
2,2-dimethyloxazolidine-3-carboxylate (7). To a well-
stirred solution of the alcohol 5 (2.6 g, 9.1 mmol) in dry
DMF (25 mL) was added tetrabutylammonium iodide
(6.7 g, 18.2 mmol) followed by benzyl bromide (2.2 mL,
18.2 mmol). The solution was cooled to 08C and sodium
hydride (95%, 0.33 g, 13.6 mmol) added to it. The solution
was allowed to warm to room temperature and stirred for
2 h. The reaction was quenched by addition of saturated
NH4Cl solution and extracted thoroughly with diethyl
ether (5£50 mL). The combined organic extracts were
1.1.1. tert-Butyl (4S)-2,2-dimethyl-4-(10-oxo-40-pentenyl)-
oxazolidine-3-carboxylate (2). To an ice-cold solution of
the Weinreb amide 35 (1.2 g, 4 mmol) in 10 mL of
anhydrous THF was added dropwise a solution of 3-butenyl-
magnesium bromide (10 mmol) [prepared from Mg (0.48 g,
0.02 g atom) and 4-bromo-1-butene (1.35 g, 10 mmol)] in

1172
A. Datta et al. / Tetrahedron 57 (2001) 1169±1173
washed sequentially with water and brine, dried (Na2SO4),
solvent was removed under vacuum and the residue puri®ed
by column chromatography (ethyl acetate±hexaneˆ1:24) to
5.4 mmol)10 in anhydrous DMSO (5 mL) was added a solu-
tion of the secondary alcohol 9 (1 g, 1.8 mmol) in THF
(10 mL) and stirred for 4 h. The reaction was quenched by
addition of water (10 mL), the precipitated solid was
®ltered, ®ltrate extracted with ether (3£50 mL) and the
combined extracts dried over Na2SO4. Evaporation of
solvent and puri®cation of the crude product by column
chromatography (ethyl acetate±hexaneˆ1:12) afforded the
yield the benzyl ether derivative 7 (3.32 g, 97%) as a pale
 Ã
22
yellow liquid: a ˆ236.2 (cˆ1.04, CHCl3); IR (neat)
D
1
1697 cm21; H NMR d 1.54 (br s, 17H), 2.18 (m, 2H),
3.71±4.18 (m, 4H), 4.57 (br s, 2H), 5.0 (m, 2H), 5.76 (m,
1H), 7.30 (s, 5H); MS (FAB1) 376 (MH1); Anal. Calcd for
C22H33NO4 (375.24): C, 70.37; H, 8.86; N, 3.73. Found: C,
70.07; H, 8.40; N, 3.88.
pure ketone 10 (0.9 g, 91%) as a colorless oily liquid:
 Ã
22
a
ˆ221.3 (cˆ1.05, CHCl3); IR (neat) 1795,
D
1694 cm21; H NMR d 0.90 (br t, Jˆ7.4 Hz, 3H), 1.29 (br
s, 20H), 1.43±1.68 (m, 17H), 2.21±2.52 (m, 4H), 3.58±4.70
(m, 6H), 7.31 (br s, 5H); MS (FAB1) 546 (MH1); Anal.
Calcd for C33H55NO5 (545.41): C, 72.62; H, 10.16; N, 2.57.
Found: C, 72.85; H, 10.37; N, 2.88.
1
1.1.5. tert-Butyl (4S,10R)-4-(10-benzyloxy-40-oxo-butyl)-
2,2-dimethyl-oxazolidine-3-carboxylate (8). To a room
temperature solution of the pentenyl oxazolidine derivative
7 (1.65 g, 4.4 mmol) and N-methylmorpholine-N-oxide
(60% aq. solution, 5 mL, 51.2 mmol) in acetone (10 mL)
and water (2 mL) was added a catalytic amount of OsO4
solution in toluene (5% solution, 5 mol%) and stirred for
8 h. A saturated aqueous solution of Na2SO3 (10 mL) was
then added to the mixture and extracted with ethyl acetate
(3£50 mL). The combined extracts were dried over Na2SO4
and solvent removed under vacuum affording the crude
dihydroxylated compound (1.7 g) which was dissolved in
CH2Cl2 (15 mL) and added in one lot to a vigorously stirred
suspension of NaIO4 supported in silica gel (7 g, 20%
NaIO4)9 in CH2Cl2 (30 mL) maintained at 08C. After stirring
at the same temperature for 1 h, the solid was removed by
®ltration, washed with CHCl3 (3£25 mL), combined ®ltrate
concentrated under vacuum and the residue ®ltered through
a pad of silica gel column (ethyl acetate±hexaneˆ1:12)
1.1.8. (2S,3R)-3-Benzyloxy-2-(tert-butoxycarbonylamino)-
1-hydroxyoctadecane-6-one (11). A solution of the ketone
10 (0.82 g, 1.5 mmol) in 80% aqueous acetic acid (10 mL)
was stirred at room temperature for 12 h. The reaction
mixture was concentrated, residue dissolved in CHCl3
(40 mL), neutralized to pH 7 by careful addition of saturated
NaHCO3 solution, organic layer separated, aqueous layer
extracted once with CHCl3, combined organic extracts
washed with brine and dried (Na2SO4). Removal of solvent
under vacuum and puri®cation of the residue by column
chromatography (ethyl acetate±hexaneˆ1:4) afforded the
keto alcohol 11 (630 mg, 83%) as a viscous liquid:
 Ã
22
D
a
ˆ24.03 (cˆ1, CHCl3); IR (neat) 3451, 1725,
1701 cm21; H NMR d 89 (br t, Jˆ7.7 Hz, 3H), 1.30 (s,
20H), 1.41 (br s, 9H), 1.84 (m, 2H), 2.31±2.60 (m, 4H),
3.64 (m, 3H), 3.94 (m, 1H), 4.55 (q, Jˆ6.9 Hz, 2H), 5.15
(br s, 1H), 7.32 (s, 5H); MS (FAB1) 506 (MH1); Anal.
Calcd for C30H51NO5 (505.38): C, 71.25; H, 10.16; N,
2.77. Found: C, 71.52; H, 10.40; N, 2.72.
1
yielding the aldehyde 8 (1.53 g, 92% two steps) as a viscous
 Ã
22
liquid:
a
ˆ232 (cˆ3.2, CHCl3); IR (neat) 1726,
D
1
1697 cm21; H NMR d 1.51 (br s, 15H), 1.78 (m, 2H),
2.46 (m, 2H), 3.81 (m, 3H), 4.15 (br s, 1H), 4.53 (m, 2H),
7.3 (s, 5H), 9.70 (s, 1H); MS (FAB1) 378 (MH1). This
aldehyde was found to decompose slowly on storage and
was used immediately for the next reaction.
1.1.9. (2S,3R)-2-(tert-Butoxycarbonylamino)-1,3-diben-
zyloxy-octadecane-6-one (12). To a vigorously stirred
solution of the alcohol 11 (605 mg, 1.2 mmol) in CH2Cl2
(8 mL), at 08C was added Ag2O (556 mg, 2.4 mmol)
followed by benzyl bromide (0.6 mL, 5 mmol). After stir-
ring at room temperature for 24 h the reaction mixture was
®ltered, the residual solid washed with CH2Cl2 (3£10 mL)
and the combined ®ltrate was concentrated. Puri®cation of
the residue by column chromatography (ethyl acetate±hex-
1.1.6. tert-Butyl (4S,10R)-4-(10-benzyloxy-40-hydroxyhex-
adecyl)-2,2-dimethyl-oxazolidine-3-carboxylate (9). To
an ice-cooled solution of dodecylmagnesium bromide
(12 mmol) [prepared from Mg (0.6 g, 0.025 g atom) and
dodecyl bromide (3 g, 12 mmol)] in anhydrous ether
(30 mL) was added dropwise over 15 min, a solution of
the oxazolidine aldehyde 8 (1.5 g, 4 mmol) in ether
(20 mL). The mixture was then allowed to warm to room
temperature and stirred for another 4 h. The reaction
mixture was poured into a saturated aqueous NH4Cl solution
(50 mL). The organic layer was separated, aqueous layer
extracted with ethyl acetate (3£50 mL), combined extracts
washed with brine, dried (Na2SO4) and solvent removed
under vacuum. The residue on column chromatography
(ethyl acetate±hexaneˆ1:7) afforded the adduct carbinol 9
aneˆ1:9) afforded the benzylated derivative 12 (607 mg,
 Ã
22
85%) as a colorless liquid: a ˆ16.8 (cˆ1.2, CHCl3);
D
IR (neat) 1724, 1702 cm21
;
1H NMR d 0.88 (br t,
Jˆ7.4 Hz, 3H), 1.28 (s, 20H), 1.44 (br s, 9H), 1.71 and
1.92 (2m, 2H), 2.35 (m, 4H), 3.41 (m, 2H), 3.64 (m, 1H),
3.87 (m, 1H), 4.35±4.65 (m, 4H), 4.79 (d, Jˆ9.2 Hz, 1H),
7.27 (s, 10H); MS (FAB1) 596 (MH1); Anal. Calcd for
C37H57NO5 (595.42): C, 74.58; H, 9.64; N, 2.35. Found:
C, 74.28; H, 10.01; N, 2.69.
(1.7 g, 76%) as a colorless oil: IR (neat) 3482, 1694 cm21
;
1H NMR d 0.88 (br t, Jˆ7.4 Hz, 3H), 1.20 and 1.47 (2s,
41H), 3.48 (m, 1H), 3.67±4.0 (m, 4H), 4.08 (m, 1H), 4.51
(br s, 2H), 7.29 (s, 5H); MS (FAB1) 548 (MH1). Anal.
Calcd for C33H57NO5 (547.42): C, 72.35; H, 10.49; N,
2.56. Found: C, 72.67; H, 10.40; N, 2.91.
1.1.10. (2S,3R)-3-Benzyloxy-2-benzyloxymethyl-6-dode-
cyl-2,3,4,5-tetrahydropyridine (13). A solution of the
ketone 12 (500 mg, 0.84 mmol) in CH2Cl2 (8 mL) was
treated with 98% formic acid (12 mL) at 08C, followed by
stirring at room temperature for 6 h. Excess acid was
removed under vacuum, the residue diluted with CH2Cl2
(25 mL), cooled to 08C and neutralized to pH 7 by adding
aqueous saturated NaHCO3 solution. The layers were then
1.1.7. tert-Butyl (4S,10R)-4-(10-benzyloxy-40-oxo-hexade-
cyl)-2,2-dimethyl-oxazolidine-3-carboxylate (10). To a
room temperature solution of 2-iodoxybenzoic acid (1.5 g,

A. Datta et al. / Tetrahedron 57 (2001) 1169±1173
1173
Chemical and Biological Perspectives, Pelletier, S. W., Ed.;
Wiley-Interscience: New York, 1985; Vol. 3, pp 1±90.
(b) Schneider, M. J. Pyridine and Piperidine Alkaloids:
An Update. In Alkaloids: Chemical and Biological Perspec-
tives, Pelletier, S. W., Ed.; Pergamon: Oxford, 1996; Vol. 10,
pp 155±299.
separated, aqueous layer extracted with CH2Cl2 (2£25 mL)
and the combined organic extracts were washed with brine.
Drying over Na2SO4 and removal of solvent under vacuum
afforded the crude D1-piperidine derivative 13 (315 mg,
78%) and was used as such for the next reaction. IR (neat)
1645 cm21; 1H NMR d 0.9 (br t, Jˆ7.1 Hz, 3H), 1.25 (br s,
20H), 1.57 (br s, 2H), 1.98±2.51 (m, 4H), 3.72 (m, 2H), 3.91
(br s, 2H), 4.55 (m, 4H), 7.30 (s, 10H).
2. (a) Ratle, G.; Monseur, X.; Das, B.; Yassi, J.; Khuong-Huu,
Q.; Goutrarel, R. Bull. Soc. Chim. Fr. 1966, 2945±2947.
(b) Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutrarel, R.
Bull. Soc. Chim. Belg. 1972, 81, 425±458.
1.1.11. (2)-Deoxoprosophylline (1). To a room tempera-
ture solution of the imine 13 (300 mg, 0.63 mmol) in EtOH
(10 mL) and conc. HCl (0.5 mL) was added Pearlman's
catalyst (40 mg) and the suspension stirred vigorously
under an atmosphere of hydrogen for 24 h. The reaction
mixture was then ®ltered, the catalyst washed with EtOH
(3£10 mL) and the combined ®ltrate concentrated under
vacuum. The residue was dissolved in water (5 mL) and
extracted once with ether (10 mL). The aqueous layer was
made alkaline by addition of 1N NaOH solution and
extracted thoroughly with CHCl3 (5£15 mL). The combined
extracts were dried over Na2SO4 and solvent removed under
vacuum. The residual solid was crystallized from acetone to
3. (a) Bourinet, P.; Quevauviller, A. Compt. Rend. Soc. Biol.
1968, 162, 1138±1140 [Chem. Abstr. 70: 95233k].
(b) Bourinet, P.; Quevauviller, A. Ann. Pharm. Fr. 1968, 26,
787±796 [Chem. Abstr. 71: 29012g].
4. For some recent syntheses of deoxoprosophylline, see: (a)
Koulocheri, S. D.; Haroutounian, S. A. Tetrahedron Lett.
1999, 40, 6869±6870. (b) Yang, C.; Liao, L.; Xu, Y.;
Zhang, H.; Xia, P.; Zhou, W. Tetrahedron: Asymmetry 1999,
10, 2311±2318. (c) Ojima, I.; Vidal, E. S. J. Org. Chem. 1998,
63, 7999±8003. (d) Yang, C.-F.; Xu, Y.-M.; Liao, L.-X.;
Zhou, W.-S. Tetrahedron Lett. 1998, 39, 9227±9228.
(e) Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem.
1997, 62, 3592±3596. For the ®rst stereoselective synthesis of
deoxoprosophylline, see: (f) Saitoh, Y.; Moriyama, Y.;
Takahashi, T.; Khuong-Huu, Q. Tetrahedron Lett. 1980, 21,
75±78. (g) Saitoh, Y.; Moriyama, Y.; Hirota, H.; Takahashi,
T.; Khuong-Huu, Q. Bull. Chem. Soc. Jpn. 1981, 54, 488±492.
5. Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis
1998, 1707±1709.
yield (2)-deoxoprosophylline (1) as a white solid (135 mg,
 Ã
22
D
72%): mpˆ85±868C (lit.4f mp 89.5±908C); a ˆ215.2
 Ã
22
D
(cˆ0.55, CHCl3) {lit.4f
a
ˆ214.7 (cˆ0.3, CHCl3)}; IR
(KBr) 3341, 3247 cm21; H NMR d 0.88 (t, Jˆ7 Hz, 3H),
1.28 (br s, 24H), 1.75 (m, 3H, 2H exchangeable with D2O),
2.05 (m, 1H), 2.53(m, 2H), 3.45 (ddd, Jˆ10.5, 8.9,
4.5 Hz,1H), 3.71 (dd, Jˆ10.7, 5.5 Hz,1H), 3.86 (dd,
Jˆ11.0, 5.6 Hz,1H); 13C NMR d 69.7, 63.7, 63.2, 56.1,
38.4, 33.7, 31.8, 30.9, 29.7, 29.6, 29.3, 26.2, 22.6, 14.0;
HRMS (FAB1) calcd for C18H38NO2 300.2902 (MH1);
found 300.2914; Anal. Calcd for C18H37NO2 (299.28): C,
72.19; H, 12.45; N, 4.68. Found: C, 72.47; H, 12.80; N, 4.92.
1
6. (a) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338±344.
(b) Doi, Y.; Ishibashi, M.; Kobayashi, J. Tetrahedron 1996,
52, 4573±4580.
7. Hanessian, S.; Park, H.; Yang, R. Y. Synlett 1997, 353±354.
8. For similar cyclization, see: Kumar, K. K.; Datta, A. Tetra-
hedron 1999, 55, 13899±13906.
9. Zhang, Y. L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622±
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