Asymmetric synthesis of (-)-deoxoprosophylline

Article abstract of DOI:10.1016/S0957-4166(03)00275-1

Michael addition of γ-amino alcohol 2 to alkynone 3 affords enamine 4, which is converted into cyclic enamine 6 through its bromide 5. Diastereoselective hydrogenation of 6 followed by protection and epimerization provides piperidine 8. Baeyer-Villiger ox

Full text of DOI:10.1016/S0957-4166(03)00275-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1403–1406
Asymmetric synthesis of (−)-deoxoprosophylline
Nan Maa and Dawei Mab,*
aDepartment of Chemistry, Fudan University, Shanghai 200433, China
bState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 3 March 2003; accepted 24 March 2003
Abstract—Michael addition of g-amino alcohol 2 to alkynone 3 affords enamine 4, which is converted into cyclic enamine 6
through its bromide 5. Diastereoselective hydrogenation of 6 followed by protection and epimerization provides piperidine 8.
Baeyer–Villiger oxidation of 8 and the subsequent deprotection give (−)-deoxoprosophylline. © 2003 Elsevier Science Ltd. All
rights reserved.
1. Introduction
to employ either sugars5g or amino acids5b–f as the
chiral pool starting material. Herein we wish to report
A number of alkaloids possessing the 2,6-disubstituted
piperidin-3-ol skeleton have been isolated from the
leaves of Prosopis africana, which have been used in
Africa for the treatment of toothache.1,2 Two represen-
tative compounds are (−)-prosophylline and (+)-
prosopinine (Scheme 1), which have been found to have
noteworthy antibiotic and anaesthetic activities.1,2 Fur-
ther studies indicated that their reduction analogues
such as (−)-deoxoprosophylline also display similar bio-
logical properties.1,2b Given these facts it is not surpris-
ing that these compounds have been the targets for
numerous synthetic efforts and have served as ideal test
cases for newly developed synthetic strategies over the
past decades.3–5 Among the synthetic routes reported
for (−)-deoxoprosophylline,5 the strategy often used is
a
short and effective protocol to (−)-deoxopro-
sophylline.
2. Results and discussion
As outlined in Scheme 1, (−)-deoxoprosophylline is
envisioned to be obtainable through the intermediate A
via a diastereoselective hydrogenation and subsequent
conversions. The cyclic enamine A may be assembled
by Michael addition too and subsequent intramolecular
cyclization of alkynone 3 and an enantiopure g-amino
alcohol 2, which can be prepared from an enantiopure
b-amino ester.6
Scheme 1.
* Corresponding author. E-mail: madw@pub.sioc.ac.cn
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00275-1

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N. Ma, D. Ma / Tetrahedron: Asymmetry 14 (2003) 1403–1406
The detailed synthesis was illustrated in Scheme 2.
After the b-amino ester 1 was obtained using Davies’
procedure,7 LAH reduction was carried out to convert
the ester to the corresponding alcohol, which on
hydrogenolysis provided the desired g-amino alcohol 2.
The Michael addition of 2 to the alkynone 3 worked
well in DMF at room temperature to give the enamine
4 in 82% yield. It is notable that the reaction in
refluxing ethanol8 gave 4 in lower yield (ꢀ40%). Treat-
ment of 4 with triphenylphosphine and carbon tetra-
bromide assisted by triethylamine produced the
bromide 5, which was refluxed in acetonitrile to afford
the cyclic enamine 6.
methanol to remove all protecting groups and afford
(−)-deoxoprosophylline, the analytical data of which
were all identical with those reported.5b
In summary, we have developed a short and effective
protocol to 2,6-disubstituted piperidin-3-ol type alka-
loids illustrated by the synthesis of (−)-deoxoproso-
phylline. It is obvious that this route should allow
synthesis of natural (−)-prosophylline and (+)-
prosopinine by changing the side chain and the stereo-
chemistry of the hydrogenation step. Further studies
are in progress and will be reported in due course.
PtO2-catalyzed hydrogenation of 6 was carried out in
acetic acid at 70 atm to afford the corresponding
saturated piperidine, which was protected with tri-
3. Experimental
3.1. (R)-3-Aminopentadecan-1-ol 2
1
fluoroacetic anhydride to provide the amide 7. The H
NMR spectra of 7 indicated that no other isomers were
present at this stage. Epimerization of the 3-acetyl
group of 7 under the action of DBU produced a
mixture of 7 and its thermodynamically more stable
A solution of the b-amino ester 1 (20 g, 42 mmol) in
THF was added dropwise into a suspension solution of
LAH in THF under 0°C. After the addition, the resul-
tant mixture was allowed to warm to rt. Stirring was
continued until the starting material was consumed
monitored by TLC. The reaction was quenched by
adding water, 15% sodium hydroxide and water in turn.
The mixture was stirred until a white solid came out.
After the mixture was filtered on silica gel, the filtrate
was concentrated to dryness. The residual oil was dis-
solved in 100 mL of methanol before 10% Pd/C was
added. The resultant suspension solution was stirred
under hydrogen (50 atm) at 50°C for 20 h. After the
Pd/C was filtered off, the filtrate was concentrated to
afford 9.0 g (89%) of g-amino alcohol 2. [h]2D0=−5.6 (c
1
isomer 8. The ratio of 7 and 8 was about 1:10 by H
NMR and 8 was isolated pure by column chromatogra-
phy in 87% yield. Next, we planned to convert this
acetyl group to the corresponding acetic ester by a
Baeyer–Villiger oxidation.9 Initially, this reaction was
attempted using the oxidizing agents such as m-CPBA
or peracetic acid. However, no desired product was
detected in these cases. After some experimentation, we
found that treatment of 8 with trifluoroperacetic acid10
that was prepared in situ by mixing 95% hydrogen
peroxide and trifuoroacetic anhydride afforded the
Baeyer–Villiger oxidation product successfully. This
oxidation product was hydrolyzed with 6N HCl in
1
0.75, CHCl3); H NMR (300 MHz, CDCl3) l 0.88 (t,
J=6.8 Hz, 3H), 1.24 (m, 18H), 1.28 (m, 2H), 1.71 (m,
Scheme 2.

N. Ma, D. Ma / Tetrahedron: Asymmetry 14 (2003) 1403–1406
1405
1H), 1.87 (m, 1H), 2.00 (m, 1H), 3.46 (m, 1H), 4.06 (m,
3.5. 1-[(2R,3S,6R)-3-Acetyl-6-dodecyl-2-(tetrahydro-
pyran-2-yloxymethyl)-piperdin-1-yl]-2,2,2-trifluoro-
ethanone 7
2H), 7.82 (m, 2H); ESI-MS m/z 244.3 (M++H+);
HRMS calcd for C15H34NO (M++H+) 244.2562; found:
244.2634.
A mixture of 6 (1.9 g, 4.7 mmol) and 150 mg of PtO2 in
60 mL of acetic acid was hydrogenated under 1 atm
and rt until no more hydrogen was taken up. The
catalyst was filtered off and the filtrate was evaporated
under vacuum. The residue oil was dissolved in
dichloromethane before triethylamine (3.7 g, 37 mmol)
and 0.2 g of DMAP were added. To this stirring
solution was added trifluoroacetic anhydride (3.9 g,
18.5 mmol) with cooling by ice-water. The resultant
mixture was stirred at rt for 2 h, and then concentrated
in vacuo. The residue was separated by column chro-
matography eluting with 1/2 ethyl acetate/n-hexane to
3.2. (R)-4-[1-(2-Hydroxyethyl)-tridecylamino]-5-(tetra-
hydropyran-2-yloxy)-pent-3-en-2-one 4
To a stirring solution of 2 (2.8 g, 12 mmol) in 100 mL
of DMF was added alkynone 3 (3.2 g, 23 mmol) at rt.
The resultant solution was stirred at the same tempera-
ture until the starting material was consumed as moni-
tored by TLC. The mixture was concentrated in vacuo
and the residue was chromatographed eluting with 1/5
ethyl acetate/petroleum ether to afford 4.0 g (82%) of 4.
[h]2D0=+8.7 (c 0.36, CHCl3); 1H NMR (300 MHz,
CDCl3) l 0.88 (t, J=6.9 Hz, 3H), 1.26 (m, 21H),
1.40–1.78 (m, 10H), 2.00 (s, 3H), 2.50–2.90 (m, 5H),
4.11 (m, 2H), 4.66 (d, J=7.8 Hz, 1H), 5.12 (d, J=7.8
Hz, 1H), 10.18 (m, 1H); EIMS m/z: 425 (M+), 342, 341,
426, 343, 427, 310, 309; HRMS calcd for C25H47NO4
(M+) 425.3505; found 425.3491.
1
afford 1.8 g (76%) of 7. [h]2D0=+33 (c 0.8, EtOAc); H
NMR (300 MHz, CDCl3) l 0.88 (t, J=6.9 Hz, 3H),
1.28 (m, 22H), 1.63–1.80 (m, 4H), 1.90 (m, 4H), 2.25 (s,
3H), 2.28 (d, J=4.8 Hz, 2H), 2.66 (m, 1H), 3.46–3.75
(m, 3H), 3.93 (q, J=6.0 Hz, 1H,), 4.4–4.8 (m, 2H), 5.36
(m, 1H); ESI-MS m/z 528.4 (M++Na+); ESI-HRMS
calcd for C27H46F3NO4Na (M++Na+) 528.3277; found
528.3272.
3.3. (R)-4-[1-(2-Bromoethyl)-tridecylamino]-5-(tetra-
hydropyran-2-yloxy)-pent-3-en-2-one 5
3.6. 1-[(2R,3R,6R)-3-Acetyl-6-dodecyl-2-(tetrahydro-
pyran-2-lyoxymethyl)-piperdin-1-yl]-2,2,2-trifluoro-
ethanone 8
To a stirring solution of the enamine 4 (4.0 g, 9.4
mmol) in dichloromethane was added CBr4 (4.3 g, 13
mmol) at 0°C. After all CBr4 had dissolved, Ph3P (3.7
g, 14 mmol) in dichloromethane was added dropwise.
The resultant mixture was warmed to rt and the stirring
was continued until 4 disappeared monitored by TLC.
To this solution 1.3 mL of triethylamine was added and
the resultant solution was stirred for another hour.
After the solvent was removed in vacuum, the residue
was chromatographed eluting with 1/5 ethyl acetate/n-
hexane to afford 3.1 g (68%) of 5 as a yellow oil.
[h]2D0=+10 (c 0.06, CHCl3); 1H NMR (300 MHz,
CDCl3) l 0.88 (t, J=6.9 Hz, 3H), 1.26 (m, 21H),
1.40–1.78 (m, 10H), 2.01 (s, 3H), 2.50–2.90 (m, 5H),
3.28 (m, 2H), 4.66 (d, J=7.8 Hz, 1H), 5.12 (d, J=7.8
Hz, 1H), 10.18 (m, 1H); ESI-MS m/z 488.4 (M+);
ESI-HRMS calcd for C25H46NO3NaBr 510.2559 (M++
Na+); found 510.2553.
A solution of 7 (1.6 g, 3.2 mmol) and DBU (1.6 mmol)
in 20 mL of THF was stirred for 16 h at rt. The mixture
was partitioned between ethyl acetate and water. The
organic layer was separated and the aqueous layer was
extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over Na2SO4, and
concentrated. The residue was purified by column chro-
matography eluting with 1/2 ethyl acetate/n-hexane to
1
afford 1.4 g (87%) of 8. [h]2D0=−7.5 (c 1.1, CHCl3); H
NMR (500 MHz, CDCl3) l 0.88 (t, J=6.6 Hz, 3H),
1.25 (m, 22H), 1.57–1.78 (m, 10H), 2.20 (s, 3H), 2.84
(m, 1H), 3.56 (m, 2H), 3.63 (t, J=4.6 Hz, 1H), 3.77–
3.89 (m, 2H), 4.66 (m, 1H), 5.21 (m, 1H); ESIMS m/z
528.4
(M++Na+);
ESI-HRMS
calcd
for
C27H46NO4F3Na (M++Na+) 528.3277; found 528.3271.
3.4. (R)-1-[6-Dodecyl-2-(tetrahydropyran-2-yloxy-
methyl)-1,4,5,6-tetrahedropyridin-3-yl]ethanone 6
3.7. Synthesis of (−)-deoxoprosophylline
Trifluoroacetic anhydride (750 mg, 3.56 mmol) was
added dropwise to a solution of 95% H2O2 (110 mg,
3.97 mmol) in cold dichloromethane. After the addition
this solution was added dropwise to a mixture of 8 (1.0
g, 1.98 mmol) and Na2HPO4 (281 mg, 1.98 mmol) in
dichloromethane. The resultant mixture was heated at
reflux for 30 min before the cooled solution was
filtrated. After the filtrate had been washed with satu-
rated Na2S2O3, the organic layer was separated and the
aqueous layer was extracted with dichloromethane. The
combined organic layers were washed sequentially with
water and brine. The solution was dried over Na2SO4,
and concentrated. The residue was dissolved in
methanolic HCl and then the solution was heated at
65°C for 24 h. The solvent was removed and the residue
To a solution of compound 5 (3.0 g, 6.16 mmol) in 200
mL of anhydrous acetonitrile was added triethylamine
(677 mg, 6.8 mmol). The mixture was heated at 80–
85°C until the starting material disappeared monitored
by TLC. The solvent was evaporated in vacuo and the
residue was separated by column chromatography elut-
ing with 1/4 ethyl acetate/n-hexane to afford 1.9 g
(76%) of the cyclic enamine 6. [h]2D0=+57.6 (c 0.4,
1
CHCl3); H NMR (300 MHz, CDCl3) l 0.88 (t, J=6.3
Hz, 3H), 1.24 (m, 22H), 1.52 (m, 10H), 2.09 (s, 3H),
2.45 (m, 2H), 3.22 (m, 1H), 3.52 (m, 1H), 3.87 (m, 1H),
4.63 (s, 1H), 4.91 (m, 2H), 6.15 (s, 1H); EI-MS m/z 407
(M+), 323, 324, 136, 281, 306, 305, 85; HRMS calcd for
C25H45NO3 (M+) 407.3399; found 407.3382.

1406
N. Ma, D. Ma / Tetrahedron: Asymmetry 14 (2003) 1403–1406
was dissolved in MeOH. After 30% NaOH was added,
the mixture was extracted with chloroform. The com-
bined organic layers were dried over Na2SO4, and
concentrated. The column chromatography of the
residue afforded 199 mg (45%) of deoxoprosophylline.
[h]2D0=−13.6 (c 0.3, CHCl3); 1H NMR (500 MHz,
CDCl3) l 0.88 (t, J=6.6 Hz, 3H), 1.25–1.40 (m, 22H),
1.57–1.86 (m, 2H), 1.96–2.06 (m, 2H), 2.45–2.56 (m,
5H), 3.49 (m, 1H), 3.75 (dd, J=10.2, 5.5 Hz, 1H), 3.89
(dd, J=10.2, 4.7 Hz, 1H); ESI-MS m/z 300.3 (M++H+);
HRMS calcd for C18H38NO2 (M++H+) 300.2903, found
300.2879.
Liao, L.; Xu, Y.; Zhang, H.; Xia, P.; Zhou, W. Tetra-
hedron: Asymmetry 1999, 10, 2311; (d) Cossy, J. Cather-
ine, W.; Veronique, B.; BouzBouz, S. J. Org. Chem. 2002,
67, 1982.
4. For asymmetric synthesis of (+)-prosopinine, see: (a) Ref.
3b; (b) Ojima, I.; Vidal, E. S. J. Org. Chem. 1998, 63,
7999 and references cited therein.
5. For asymmetric synthesis of (−)-deoxoprosophylline, see:
(a) Saitoh, Y.; Moriyama, Y.; Takahashi, T.; Khuong-
Huu, Q. Tetrahedron Lett. 1980, 21, 75; (b) Takao, K.;
Nigawara, E.; Nishino, I.; Takagi, K.; Maeda, K.;
Tadano, K.; Ogawa, Tetrahedron 1994, 50, 5681; (c)
Kadota, I.; Kawada, M.; Muramatsu, Y.; Yamamoto, Y.
Tetrahedron: Asymmetry 1997, 8, 3887; (d) Ref. 4b; (e)
Herdeis, C.; Telser, J. Eur. J. Org. Chem. 1999, 1407; (f)
Jourdant, A.; Zhu, J. Tetrahedron Lett. 2001, 42, 3431;
(g) Dransfield, P. J.; Gore, P. M.; Shipman, M.; Slawin,
A. M. Z. Chem. Commun. 2002, 150.
6. For other efforts on the synthesis of natural alkaloids
from enantiopure b-amino esters from this group, see: (a)
Ma, D.; Pu, X.; Wang, J. Tetrahedron: Asymmetry 2002,
13, 2257; (b) Ma, D.; Zhu, W. Org. Lett. 2001, 3, 3927;
(c) Ma, D.; Xia, C.; Jiang, J.; Zhang, J. Org. Lett. 2001,
3, 2189; (d) Wang, Y.; Ma, D. Tetrahedron: Asymmetry
2001, 12, 725; (e) Ma, D.; Sun, H. J. Org. Chem. 2000,
65, 6009; (f) Ma, D.; Sun, H. Org. Lett. 2000, 2, 2503; (g)
Ma, D.; Sun, H. Tetrahedron Lett. 2000, 41, 1947; (h)
Ma, D.; Sun, H. Tetrahedron Lett. 1999, 40, 3609; (i) Ma,
D.; Zhang, J. Tetrahedron Lett. 1998, 39, 9067.
7. Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991,
2, 183.
Acknowledgements
The authors are grateful to the Chinese Academy of
Sciences and National Natural Science Foundation of
China (grant 29972049) for their financial support.
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