A concise synthesis of (-)-deoxoprosopinine

Article abstract of DOI:10.1055/s-2007-991056

A simple and highly efficient approach to (-)-deoxoprosopinine from racemic epoxide as a starting material is described employing a Jacobsen's hydrolytic kinetic resolution (HKR) and Sharpless asymmetric dihydroxylation (AD) as key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991056

2894
LETTER
A Concise Synthesis of (–)-Deoxoprosopinine
Synthesis of (–
a
)-Deoxopr
t
osopini
y
ne endra Kumar Pandey, Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Fax +91(20)25902629; E-mail: pk.tripathi@ncl.res.in
Received 13 July 2007
Abstract: A simple and highly efficient approach to (–)-deoxo-
prosopinine from racemic epoxide as a starting material is described
employing a Jacobsen’s hydrolytic kinetic resolution (HKR) and
Sharpless asymmetric dihydroxylation (AD) as key steps.
H
H
N
O
N
O
Co
t-Bu
t-Bu
Key words: Jacobsen’s HKR, Sharpless AD, hydroboration–oxi-
dation, piperidine alkaloids, total synthesis
OAc
t-Bu
t-Bu
(R,R)-Co(III)(salen)·OAc
Naturally occurring alkaloids containing multifunctional-
ized piperidine rings are found abundantly in nature and
many of them exhibit biological activity of medicinal
interest.1 Prosopis alkaloids, one of the subgroup of these
piperidine alkaloids, were isolated from the leaves of
Prosopis afrikana Tab, contains 2,6-disubstituted piperi-
din-3-ol piperidine framework such as prosopinine (1),
prosophylline (2), and their deoxo analogues deoxo-
prosopinine (3), deoxoprosophylline (4), respectively
(Figure 1).2 These alkaloids exhibit antibiotic, anaesthet-
ic, analgesic, and CNS stimulating properties and there-
fore have attracted considerable interest as synthetic
targets.
Figure 2
O
( )
10
5a
O
a
+
( )
OH
10
5
OH
( )
10
5b
Scheme 1 Reagents and conditions: (a) (R,R)-Co(III)(salen)·OAc
(0.5 mol%), distilled H2O (0.55 equiv), 0 °C, 24 h, (41% for 5a, 43%
for 5b).
epoxytetradecane (5a) as a single enantiomer (>99% ee),5
which was easily isolated from the more polar diol 5b by
distillation (Scheme 1).
OH
OH
OH
OH
N
With enantiomerically pure (R)-1,2-epoxytetradecane
(5a) in hand, we then subjected it to copper-catalyzed
(CuI) regioselective opening with vinylmagnesium bro-
mide to give the homoallylic alcohol 6 in excellent yield.
The free hydroxyl group of 6 was converted into O-mesy-
late, which on nucleophilic displacement with sodium
azide in anhydrous DMF afforded compound 7 in 93%
yield. The azide 7 was subjected to Staudinger reaction6
and converted into amine, which on Cbz protection with
benzyl chloroformate led to 8 in 90% yield (two steps, one
pot). The compound 8 was then subjected to hydrobora-
tion–oxidation reaction to afford the alcohol 9 in 87%
yield. With substantial amount of 9 in hand, our next aim
was to carry out the two-carbon homologation by means
of Wittig reaction in order to generate the trans-olefin
required for AD reaction. To this end, compound 9 was
oxidized to the aldehyde under Swern conditions,7 fol-
lowed by treatment with (ethoxycarbonylmethyl-
ene)triphenylphosphorane in anhydrous THF at room
temperature to furnish the trans-Wittig product 10 in
excellent yield (Scheme 2).
N
8
8
H
H
X
X
(+)-prosophylline (2, X = O)
(+)-deoxoprosophylline (4, X = H2)
(–)-prosopinine (1, X = O)
(–)-deoxoprosopinine (3, X = H2)
Figure 1
Various syntheses of this class of compounds have been
reported. Majority of the syntheses of deoxoprosopinine
employ chiral pool starting materials such as sugars and
amino acids and involve many steps.3 As part of our on-
going program towards asymmetric synthesis of biologi-
cally active natural products,4 we became interested in
developing a simple and flexible route to (–)-deoxoproso-
pinine. Herein, we report a new and short synthesis of
(–)-deoxoprosopinine employing a Jacobsen’s HKR and a
Sharpless AD as the source of chirality.
The synthesis of (–)-deoxoprosopinine started from com-
mercially available racemic 1,2-epoxytetradecane (5)
which was subjected to Jacobsen’s HKR using (R,R)-
Co(III)(salen)·OAc catalyst (Figure 2) to give (R)-1,2-
The dihydroxylation of olefin 10 with osmium tetroxide
and potassium ferricyanide as co-oxidant in the presence
of (DHQD)2PHAL under the Sharpless asymmetric
conditions8 gave the diol 11 in 97% yield as a single
SYNLETT 2007, No. 18, pp 2894–2896
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-991056; Art ID: G24507ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
7

LETTER
Synthesis of (–)-Deoxoprosopinine
2895
N3
OH
and analogues such as epi-deoxoprosopinine and deoxo-
prosophylline. Currently, studies are in progress in this
direction.
b
a
5a
( )
( )
10
10
6
7
NHCbz
NHCbz
Acknowledgment
c
d
OH
( )
( )
S.K.P. thanks CSIR, New Delhi, for a research fellowship. Financi-
al support from DST, New Delhi (Project Grant No. SR/S1/OC-40/
2003) is gratefully acknowledged. This is NCL communication No.
6705.
10
10
9
8
NHCbz
e
OEt
10
References and Notes
10
O
(1) For reviews that include piperidine alkaloids, see:
(a) Strunz, G. M.; Findlay, J. A. In The Alkaloids, Vol. 26;
Brossi, A., Ed.; Academic Press: New York, 1985, 89.
(b) Foder, G. B.; Colasanti, B. The Pyridine and Piperidine
Alkaloids: Chemistry and Pharmacology, In Alkaloids:
Chemical and Biological Perspectives, Vol. 3; Pelletier, S.
W., Ed.; Wiley: New York, 1985, 1. (c) Numata, A.; Ibuka,
T. In The Alkaloids, Vol. 31; Brossi, A., Ed.; Academic
Press: New York, 1987, 193; and references therein.
(d) Schneider, M. J. Pyridine and Piperidine Alkaloids: An
Update, In Alkaloids: Chemical and Biological
Scheme 2 Reagents and conditions: (a) vinylmagnesium bromide,
CuI, THF, –78 °C, 12 h, 94%; (b) i) MsCl, Et3N, anhyd CH2Cl2, 2 h;
ii) NaN3, anhyd DMF, 45 °C, 93%; (c) i) PPh3, THF–H2O (6:1), r.t.,
12 h; ii) benzyl chloroformate, Na2CO3, 1,4-dioxane–H2O (1:1), 0 °C
to r.t., 90% (two-step, one-pot); (d) i) BH3·SMe2, THF, 0 °C to r.t.,
3 h; ii) 2 equiv NaOH, H2O2, 0 °C to r.t., 6 h, 87%; (e) i) (COCl)2,
DMSO, CH2Cl2, –78 °C, 30 min, Et3N, –60 °C, 30 min; (ii)
Ph3P=CHCO2Et, THF, r.t., 24 h, 96%.
diastereoisomer (>98% de).9 Regioselective mono-
tosylation10 of this diol with tosyl chloride (TsCl) resulted
in the a-tosylate 12 in excellent yield. Concomitant depro-
tection of Cbz and nucleophilic displacement of a-tosy-
late on hydrogenation with Pd(OH)2 led to the cyclized
product 1311 in 97% yield. Finally, reduction of 13 with
LiAlH4 produced (–)-deoxoprosopinine (3) in 86% yield;
Perspectives, Vol. 10; Pelletier, S. W., Ed.; Pergamon:
Oxford, 1996, 155. (e) Wang, C. J.; Wuonola, M. A. Org.
Prep. Proced. Int. 1992, 24, 585. (f)Laschat, S.;Dickner, T.
Synthesis 2000, 1781. (g) Weintraub, P. M.; Sabd, J. S.;
Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59,
2953.
(2) Prosopis alkaloids from the leaves, stems, and roots of
Prosopis africana: (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, 425.
(c) Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R.
Bull. Soc. Chim. Belg. 1972, 81, 443.
25
mp 90 °C (ref. 3a: 89.5–90 °C); [a]D –15. 81 (c 0.30,
25
CHCl3) {ref. 3a: [a]D
–14.7 (c 0.30, CHCl3)}
(Scheme 3). The physical and spectroscopic data were in
full agreement with the literature.3a
(3) Previous asymmetric synthesis of deoxoprosopinine:
(a) Saitoh, Y.; Moriyama, Y.; Takahashi, T. Tetrahedron
Lett. 1980, 21, 75. (b) Saitoh, Y.; Moriyama, Y.; Hirota, H.;
Takahashi, T.; Khuong-Huu, Q. Bull. Chem. Soc. Jpn. 1981,
54, 488. (c) Ciufolini, M. A.; Hermann, C. W.; Whitmire, K.
H.; Byrne, N. E. J. Am. Chem. Soc. 1989, 111, 3473.
(d) Tadano, K.; Takao, K.; Nigawara, Y.; Nishino, E.;
Takagi, I.; Maeda, K.; Ogawa, S. Synlett 1993, 565.
(e) Takao, K.; Nigawara, Y.; Nishino, E.; Takagi, I.; Maeda,
K.; Tadano, K.; Ogawa, S. Tetrahedron 1994, 50, 5681.
(f) Yuasa, Y.; Ando, J.; Shibuya, S. Tetrahedron:
NHCbz
OR
c
a
OEt
10
( )
10
OH
11
O
R = H
b
R = Ts
12
OH
OH
OH
d
OEt
( )
( )
10
N
H
N
10
H
Asymmetry 1995, 6, 1525. (g) Yuasa, Y.; Ando, J.; Shibuya,
S. J. Chem. Soc., Perkin Trans. 1 1996, 793. (h) Kadota, I.;
Kawada, M.; Muramatsu, Y.; Yamamoto, Y. Tetrahedron
Lett. 1997, 38, 7469. (i) Kadota, I.; Kawada, M.;
Muramatsu, Y.; Yamamoto, Y. Tetrahedron: Asymmetry
1997, 8, 3887. (j) Agami, C.; Couty, F.; Mathieu, H.
Tetrahedron Lett. 1998, 39, 3505. (k) Agami, C.; Couty, F.;
Lam, H.; Mathieu, H. Tetrahedron 1998, 54, 8783.
(l) Comins, D. L.; Sandelier, M. J.; Grillo, T. A. J. Org.
Chem. 2001, 66, 6829. (m) Wang, Q.; Sasaki, N. A. J. Org.
Chem. 2004, 69, 4767.
O
3
13
Scheme 3 Reagents and conditions: (a) (DHQD)2PHAL, OsO4 (0.4
mol%), K2CO3, K3Fe(CN)6, MeSO2NH2, t-BuOH–H2O (1:1), 0 °C,
24 h, 97%; (b) TsCl, Et3N, CH2Cl2, 5 °C, 72 h, 88%; (c) 20%
Pd(OH)2/C, H2, EtOAc, r.t., 12 h, 97%; (d) LiAlH4, THF, 0 °C to r.t.,
2 h, 86%.
In conclusion, a simple, flexible and highly efficient route
to (–)-deoxoprosopinine has been developed employing
Jacobsen’s HKR and Sharpless asymmetric dihydroxyla-
tion as the key steps. The merits of this synthesis are high
enantio- and diastereoselectivity with high yielding reac-
tion steps. The synthetic strategy described has significant
potential for stereochemical variations at C-2, C-3, and C-
6 positions and further extension to other stereoisomers,
(4) (a) Pandey, S. K.; Kandula, S. V.; Kumar, P. Tetrahedron
Lett. 2004, 45, 5877. (b) Pandey, S. K.; Kumar, P.
Tetrahedron Lett. 2005, 46, 4091. (c) Pandey, S. K.; Kumar,
P. Tetrahedron Lett. 2005, 46, 6625. (d) Kumar, P.; Naidu,
S. V. J. Org. Chem. 2005, 70, 4207. (e) Kumar, P.; Naidu,
S. V.; Gupta, P. J. Org. Chem. 2005, 70, 2843. (f) Kumar,
P.; Bodas, M. S. J. Org. Chem. 2005, 70, 360. (g) Kumar,
Synlett 2007, No. 18, 2894–2896 © Thieme Stuttgart · New York

2896
S. Kumar Pandey, P. Kumar
LETTER
P.; Gupta, P.; Naidu, S. V. Chem. Eur. J. 2006, 12, 1397.
(h) Kumar, P.; Naidu, S. V. J. Org. Chem. 2006, 71, 3935.
(i) Pandey, S. K.; Kumar, P. Tetrahedron Lett. 2006, 47,
4167. (j) Pandey, S. K.; Kumar, P. Eur. J. Org. Chem. 2007,
369.
2.27 (br s, 2 H), 3.62–3.71 (m, 1 H), 3.91 (d, J = 6.45 Hz, 1
H), 4.06 (d, J = 1.61 Hz, 1 H), 4.29 (q, J = 6.72, 13.70 Hz, 2
H), 4.55 (d, J = 8.87 Hz, 1 H), 5.10 (s, 2 H), 7.32–7.38 (m, 5
H) ppm. 13C NMR (50 MHz, CDCl3): d = 14.0, 22.6, 25.8,
29.2, 29.6, 29.8, 31.4, 31.8, 35.5, 51.1, 61.8, 66.4, 72.3, 73.4,
127.9, 128.4, 136.5, 156.2, 173.4 ppm. ESI-MS: m/z = 516
[M + Na]+. Anal. Calcd (%) for C28H47NO6: C, 68.12; H,
9.60; N, 2.84. Found: C, 68.17; H, 9.58; N, 2.82.
(5) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N.
J. Am. Chem. Soc. 2002, 124, 1307.
(6) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635.
(7) For reviews on the Swern oxidation, see: (a) Tidwell, T. T.
Synthesis 1990, 857. (b) Tidwell, T. T. Org. React. 1990, 39,
297.
(10) Fleming, P. R.; Sharpless, K. B. J. Org. Chem. 1991, 56,
2869.
(11) Spectral data of compound 13: mp 96 °C; [a]D25 +5.65 (c
0.60, CHCl3). IR (CHCl3): n = 3583, 3436, 3019, 2928,
1725, 1519, 1455, 1215 cm–1. 1H NMR (200 MHz, CDCl3):
d = 0.88 (t, J = 6.07 Hz, 3 H), 1.26–1.79 (m, 30 H), 2.11 (br
s, 1 H), 2.65–2.74 (m, 1 H), 3.58 (d, J = 4.06 Hz, 1 H), 4.11–
(8) (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1996, 35, 448. (b) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483. (c) Torri, S.;
Liu, P.; Bhuvaneswari, N.; Amatore, C.; Jutand, A. J. Org.
Chem. 1996, 61, 3055.
4.17 (m, 1 H) 4.21 (q, J = 7.12, 13.86 Hz, 2 H) ppm. 13
C
NMR (50 MHz, CDCl3): d = 14.0, 14.2, 22.6, 26.1, 28.0,
29.3, 29.5, 29.6, 31.8, 35.8, 51.6, 60.8, 61.5, 65.5, 172.2
ppm. ESI-MS: m/z = 342 [M + H]+. Anal. Calcd (%) for
C20H39NO3: C, 70.33; H, 11.51; N, 4.10. Found: C, 70.35; H,
11.48; N, 4.12.
(9) The diastereoselectivity was determined from 1H NMR and
13C NMR spectral data. Spectral data of compound 11: mp
137 °C; [a]D25 +6.90 (c 1.00, CHCl3). IR (CHCl3): n = 3434,
3018, 2927, 1719, 1508, 1216 cm–1. 1H NMR (200 MHz,
CDCl3): d = 0.89 (t, J = 5.95 Hz, 3 H), 1.26–1.70 (m, 29 H),
Synlett 2007, No. 18, 2894–2896 © Thieme Stuttgart · New York

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