Enantioselective allyltitanation and cross-metathesis. Synthesis of (-)-prosophylline

Article abstract of DOI:10.1055/s-2001-17461

An enantioselective synthesis of (-)-prosophylline has been accomplished in 15 steps from protected D-glyceraldehyde, with an overall yield of 9.2%, by using two enantioselective allyltitanations and a cross-metathesis reaction as the key-steps.

Full text of DOI:10.1055/s-2001-17461

1578
LETTER
Enantioselective Allyltitanation and Cross-Metathesis. Synthesis of (–)-
Prosophylline
S
ynthesis
a
of (-)-Proso
n
phylline ine Cossy,* Catherine Willis, Véronique Bellosta
Laboratoire de Chimie Organique associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05 - France.
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr
Received 28 June 2001
O
Abstract: An enantioselective synthesis of (–)-prosophylline has
been accomplished in 15 steps from protected D-glyceraldehyde,
with an overall yield of 9.2%, by using two enantioselective allylti-
tanations and a cross-metathesis reaction as the key-steps.
5
OH
O
cross-metathesis
2
OH
N
+
OR
Key words: enantioselective allylation, alkaloids, cross-metathe-
sis, piperidines, (–)-prosophylline
9
H
OR'
1
N
R''
A
Prosophylline 1, prosopinine, isoprosopinine A, isoproso-
pinine B and prosopine are prosopis alkaloids which con-
N3
OH
OH
OH
O
Mitsunobu
O
tain a 2,6-disubstituted-3-piperidinol skeleton (Figure).
These alkaloids are isolated from the leaves of Prosopis
africana1 and possess remarkable antibiotic and anesthet-
ic properties.2 Prosophylline was isolated and its structure
determined in 1972.1b Surprisingly, only one stereoselec-
tive synthesis of racemic prosophylline3 and two enantio-
selective syntheses of (-)-prosophylline4 have been report-
ed to date.
OR
OR
Allyltitanation
O
O
Allyltitanation
O
O
O
OR
OR
OH
OH
OH
OH
O
O
O
N
R
N
9
H
H
O
3
(-)-prosophylline 1
R = (CH2)9COEt
prosopinine
R = (CH2)6CO(CH2)4CH3 isoprosopinine A
R = (CH2)7CO(CH2)3CH3 isoprosopinine B
Scheme 1 Retrosynthetic scheme
R = (CH2)10CH(OH)Me
prosopine
tion of (+)-6, the aldehyde, obtained in quantitative yield,
was immediatly treated with the allyltitanium complex
(R,R)-I to give the homoallylic alcohol (+)-7 (81% yield)
with 98:2 diastereoselectivity.7 The next step was the
transformation of (+)-7 into azide 8 by a Mitsunobu reac-
tion. When homoallylic alcohol (+)-7 was treated with
diphenylphosphorylazide (DPPA)9 (DEAD, PPh3, DPPA,
THF, 0 °C to rt, 12h), the corresponding azide was formed
but it could not be separated from DPPA. However, after
treatment of 8 with a mixture of AcOH/H2O (80/20),
the diol was deprotected and the resulting hydroxy azide
(–)-9 could be purified and isolated in 76% yield (overall
yield from (+)-7). Protection of the primary alcohol of
(–)-9 as the tert-butyldiphenylsilyl ether (TBDPSCl, imi-
dazole, CH2Cl2) afforded (–)-10 (96% yield), which was
treated with methanesulfonyl chloride (MsCl, DMAP, py-
ridine) to produce (+)-11 in 98% yield. After reduction of
the azide (+)-11 to the amine (+)-12, (PPh3, H2O, THF;
89% yield), cyclization with Et3N in refluxing methanol
afforded the piperidine skeleton of prosophylline in 88%
yield.
Figure Prosopis alkaloids
Here, we describe the synthesis of (–)-prosophylline 1
from protected D-glyceraldehyde 3 according to the fol-
lowing retrosynthetic scheme (Scheme 1), by employing
two enantioselective allyltitanations, a Mitsunobu reac-
tion and a cross-metathesis reaction between olefin A and
the unsaturated ketone 2.
When protected D-glyceraldehyde 35 was treated with al-
lyltitanium complex (S,S)-I (Scheme 2) according to the
reported procedure,6 homoallylic alcohol (+)-4 was ob-
tained in 86% yield with 98:2 diastereoselectivity.7 Pro-
tection of (+)-4 with benzyl bromide (t-BuOK, BnBr,
THF) led to the benzyl ether (+)-5 (91% yield) which was
hydroborated (BH3 THF; NaOH, H2O2) to produce the
primary alcohol (+)-68 in 83% yield. After Swern oxida-
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1578,1580,ftx,en;G13201st.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Synthesis of (-)-Prosophylline
1579
The transformation of the piperidine (–)-13 to (–)-proso-
phylline was achieved in 4 steps (Scheme 3). The first
step led to the benzyl carbamate (+)-14 (quantitative
yield) by treatment of (–)13 with benzyl chloroformate in
the presence of aqueous Na2CO3 (CbzCl, Na2CO3,
CH2Cl2/H2O). To introduce the side chain of (–)-proso-
phylline, a cross-metathesis reaction10 was performed be-
tween compound (+)-14 and the unsaturated ketone 211 in
the presence of the “new generation” Grubbs' catalyst 1512
(10 mol%). After 5h, (+)-16 was isolated in 58% yield.
Hydrogenation of (+)-16 with a catalytic amount of Pd/C
in MeOH/HCl resulted in reduction of the double bond,
cleavage of the benzyloxycarbonyl group and deprotec-
tion of the secondary alcohol. The resulting hydroxylated
amine (–)-17 (60% yield) was then treated with tetrabuty-
lammonium fluoride in THF to afford ()prosophylline 1 in
90% yield. The spectral and physical data are in accor-
dance with the literature data1,3,4,13 {mp = 77-79 °C, lit.4a:
75–76 °C; [ ]D20 17.6 (c 1.5, MeOH), lit.4a: [ ]D20 -13.4 (c
1.5, MeOH)}.
O
O
OH
a)
c)
O
O
3
OR
(+)-4 (R=H)
OBn
(+)-6
b)
(+)-5 (R=Bn)
d), e)
OR2
OR1
N3
O
R1 R2
g)
O
OBn
OBn
(-)-9 (R1=R2=H)
h)
i)
(+)-7 (R1=OH, R2=H)
8 (R1=H, R2=N3)
f)
(-)-10 (R1=TBDPS, R2=H)
(+)-11 (R1=TBDPS, R2=Ms)
j)
OBn
OMs
NH2
k)
OTBDPS
OTBDPS
N
H
The application of a cross-metathesis reaction and two
enantioselective allyltitanation reactions to the synthesis
of (–)-prosophylline was efficient as this compound was
obtained in 15 steps with a diastereoselectivity up to 95%,
and an overall yield of 9.2%.
OBn
(+)-12
(-)-13
Cp
Ti
Cp
Ti
Ph
Ph
Ph
Ph
O
O
O
O
Ph
Ph
Acknowlegdments
O
Ph
O
Ph
O
O
C. W. thanks Rhodia for a grant.
(R,R)-I
(S,S)-I
References and Notes:
Scheme 2 Reagents and conditions: a) (S,S)-I, Et2O, -78 °C, 86%.
b) t-BuOK, BnBr, THF, 91%. c) (i) BH3 THF, (ii) H2O2, NaOH, H2O,
83%. d) DMSO, (COCl)2, Et3N, CH2Cl2, quantitative yield. e) (R,R)-
I, Et2O, -78 °C, 81%. f) PPh3, DEAD, DPPA, THF, 0 °C to r.t. g)
AcOH/H2O: 80/20, 76% for the two steps. h) TBDPSCl, imidazole,
CH2Cl2, 96%. i) MsCl, DMAP, pyridine, 98%. j) PPh3, THF/H2O,
89%. k) Et3N, MeOH, reflux, 88%.
(1) (a) Ratle, G.; Monseur, X.; Das, B. C.; Yassi, J.; Khuong-
Huu, Q.; Goutarel, R. Bull. Soc. Chim. Fr. 1966, 2945.
(b) Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R.
Bull. Soc. Chim. Belg. 1972, 81, 443.
(2) (a) Bourinet, P.; Quevauviller, A. Compt. Rend. Soc. Biol.
1968, 162, 1138. (b) Bourinet, P.; Quevauviller, A. Ann.
Pharm. Fr. 1968, 26, 787.
(3) Natsume, M.; Ogawa, M. Heterocycles 1981, 16, 973.
OBn
OBn
O
b)
OTBDPS
OTBDPS
N
N
R
5
Cbz
(-)-13 (R=H)
(+)-16
a)
(+)-14 (R=Cbz)
c)
OH
O
N
N
d)
OTBDPS
(-)-1
N
Cl
Cl
9
Ru
H
Ph
(-)-17
PCy3
15
Scheme 3
a) CbzCl, Na2CO3, CH2Cl2/H2O, quantitative yield. b) 2, 15, CH2Cl2, reflux, 58%. c) H2, Pd/C 10%, MeOH/HCl: 50/1, 60%.
d) TBAF, THF, 90%.
Synlett 2001, No. 10, 1578–1580 ISSN 0936-5214 © Thieme Stuttgart · New York

1580
J. Cossy et al.
LETTER
(4) (a) Koulocheri, S. D.; Haroutounian, S. A. Tetrahedron Lett.
1999, 40, 6869. (b) Toyooka, N.; Yoshida, Y.; Yotsui, Y.;
Momose, T. J. Org. Chem. 1999, 64, 4914.
(11) Compound 2 was prepared from ethyl vinyl ketone by 1,4-
addition of the Grignard reagent prepared from 6-bromo-1-
hexene in the presence of CuBr Me2S, in THF.
(5) Schmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6.
(6) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-
Streit, P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114,
2321.
(12) Scholl, M.; Ding, S.; Woo Lee, S.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
(13) 1H NMR (CDCl3, 300 MHz) (ppm)= 3.81 (m, 1 H), 3.70
(m, 1 H), 3.65-3.27 (m, 4 H), 2.58-2.45 (m, 2 H), 2.45-2.30
(m, 4 H), 2.01 (m, 1 H), 1.74 (m, 1 H), 1.62-1.46 (m, 2 H),
1.45-1.10 (m, 3 H), 1.25 (s, 13 H), 1.03 (t, 3 H, J = 7.4 Hz);
13C NMR (CDCl3, 75.5 MHz) (ppm) = 212.0 (s), 69.5 (d),
63.5 (t), 63.2 (d), 56.0 (d), 42.2 (t), 36.1 (t), 35.7 (t), 33.5 (t),
30.6 (t), 29.6 (t), 29.5 (t), 29.3 (t), 29.2 (t), 29.1 (t), 26.0 (t),
23.7 (t), 7.7 (q); IR (neat): 3300-3200, 1710 cm-1; MS (CI,
CH4) m/z 314 (MH+, 76), 300(100), 286(60), 272(14),
208(19), 194(12), 122(24), 104(14); HRMS (CI+, CH4) calcd
for C18H36NO3 (MH+) m/z 314.2695, found 314.2693.
(7) Determined by 1H NMR.
(8) [a]D20 +41.2 (c 2.0, CHCl3), lit.: [a]D20 - 42.5 (c 1.1, CHCl3)
for (–)-4: Miyazaki, H.; Nakamura, N.; Ito, T.; Sada, T.;
Oshima, T.; Koike, H. Chem. Pharm. Bull. 1989, 37, 2391.
(9) Irako, N.; Hamada, Y.; Shioiri, T. Tetrahedron 1992, 48,
7251.
(10) For cross-metathesis reactions see: Chatterjee, A. K.;
Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc.
2000, 122, 3783; and references therein.
Synlett 2001, No. 10, 1578–1580 ISSN 0936-5214 © Thieme Stuttgart · New York