An asymmetric synthesis of (+)-desoxoprosophylline

Article abstract of DOI:10.1016/j.tetlet.2008.06.074

An efficient synthesis of (+)-desoxoprosophylline is described. The key steps in the reaction sequence include the preparation of an N-Cbz-sulfilimine from the corresponding sulfoxide using the Burgess reagent, regio- and stereoselective hetero-functionalization of an alkene using the pendant sulfilimine as the nucleophile and a stereoselective amidomercuration to form the cis-2,6-disubstituted piperidine ring.

Full text of DOI:10.1016/j.tetlet.2008.06.074

Tetrahedron Letters 49 (2008) 5169–5171
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An asymmetric synthesis of (+)-desoxoprosophylline
*
Sadagopan Raghavan , Shaik Mustafa
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of (+)-desoxoprosophylline is described. The key steps in the reaction sequence
include the preparation of an N-Cbz-sulfilimine from the corresponding sulfoxide using the Burgess
reagent, regio- and stereoselective hetero-functionalization of an alkene using the pendant sulfilimine
as the nucleophile and a stereoselective amidomercuration to form the cis-2,6-disubstituted piperidine
ring.
Received 22 April 2008
Revised 9 June 2008
Accepted 17 June 2008
Available online 19 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Amino alcohol
Asymmetric synthesis
Sulfoxide
N-Cbz-sulfilimine
Desoxoprosophylline
2,6-Disubstituted piperidin-3-ols such as (+)-desoxoprosophyl-
line 1, (+)-prosophylline 2 and related compounds (Fig. 1) occur
widely among the alkaloids isolated from the plant genera Cassia
and Prosopis.1,2 Numerous compounds possessing 2,6-cis, 2,6-trans
OH
OH
OH
OH
X
N
H
X
N
H
8
8
and 3a or 3b configurations have been discovered. These alkaloids
(+)-desoxoprosophylline 1, X = CH2
(+)-prosophylline 2, X = CO
(+)-desoxoprosopinine 3, X = CH2
(+)-prosopinine 4, X = CO
display a range of bioactivities including acetylcholinesterase
inhibitory activity,3a cytotoxic,3b antibacterial,3c–f antimycotic,3c,e
DNA binding,3g anaesthetic and analgesic.3h,i Desoxoprosophylline
1 and prosophylline 2 have been isolated from the African mimosa
Prosopis africana Taub.4
OH
OH
O
O
Desoxoprosophylline is characterized by the presence of a polar
head group that is known to be essential for glycosidase inhibitory
activity5 and is thereby expected to be useful for the treatment of
diseases such as diabetes, arthritis and cancer. The hydrophobic
side chain facilitates its transport across lipid membranes.6 The
interesting structural features and the varied biological activity
of 1 have attracted the attention of synthetic chemists and several
reports detail its synthesis. Many among them rely on chiral pool
starting materials7 and there are only a few reports on asymmetric
syntheses.8
We describe herein an efficient synthesis of desoxoprosophyl-
line utilizing a methodology that we reported on the oxidative
functionalization of alkenes into bromo-sulfonamides mediated
by a pendant N-Ts sulfilimine.9 A drawback with the reported
methodology was the difficulty in removing the N-Ts group in
the product to access free NH– derivatives. We report herein the
preparation of N-Cbz sulfilimines from the corresponding sulfox-
N
N
10
7
H
H
OH
(+)-spectaline 5
(+)-prosafrinine 6
Figure 1.
ides and utility for the synthesis of bromo-carbamates, the advan-
tage being that the carbamate moiety can be removed under very
mild conditions. The retrosynthetic analysis of 1 is depicted in
Scheme 1. (+)-Desoxoprosophylline would be obtained from 7 by
a Mitsunobu inversion followed by deprotection. Piperidine deriv-
ative 7 was visualized to derive from electrophile promoted cycli-
zation of unsaturated amido compound 8, which in turn can be
derived from amino alcohol derivative 9. Compound 9 can be
obtained from b-siloxy sulfoxide 10.
The synthesis began from the known b-siloxy sulfoxide10 10,
which on treatment with the Burgess reagent11 11 according to
the protocol recently described by us12 yielded sulfilimines 12anti
and 12syn in equimolar amounts (78%).13 These same compounds
were also obtained by treatment of 10 with CbzNSO.10 Reaction of
* Corresponding author. Tel.: +91 040 27191643; fax: +91 040 27160512.
E-mail addresses: sraghavan@iict.res.in (S. Raghavan), purush101@yahoo.com
(S. Raghavan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.074

5170
S. Raghavan, S. Mustafa / Tetrahedron Letters 49 (2008) 5169–5171
STol-
p
OH
OH
OP
OH
N
H
HN
N
P
11
11
Cbz OP
OP
10
1
8
7
O
S
OTBS
O
S
OH
p
-Tol
p-Tol
Br
NHCbz
P = Protecting group
9
10
Scheme 1.
CbzN
CbzN
OP
OP
O
OTBS
Et3NSO2NCbz (11)
PhH, 0 oC to rt
S
S
+
S
p
-Tol
p-Tol
p
-Tol
10
12anti, P = TBS
13anti, P = H
12syn, P = TBS
13syn, P = H
78%
TBAF
THF, 93%
TBAF
THF, 93%
R2
S
R1
O
R1 R2
S
OMe
OMe
OH
NCbz
NBS, H2O
TFAA, DCM
p
-Tol
p
-Tol
Br
NHCbz
14syn, R1 = O, R2 =
14anti, R2 = O, R1 =
Toluene, 85%
Cat. CSA, DCM
85%
Br
15syn, R1 = O, R2 =
15anti, R2 = O, R1 =
O
O
NCbz
NCbz
Br
S
S
p
-Tol
p-Tol
11
SnCl4
65%
F3C(O)CO
Br
17
16
10
Scheme 2.
sulfilimines14 13anti and 13syn, obtained by deprotection of
12anti and 12syn, with NBS afforded cleanly bromo-carbamates10
14anti and 14syn, which were further transformed into acetonides
15anti and 15syn (Scheme 2).
material. We therefore resorted to an oxidation–reduction
sequence to prepare the inverted alcohol. In the event, treatment
of 22 with IBX in refluxing ethyl acetate furnished the correspond-
ing ketone, which was not stable to column chromatography on
22
Treatment of 15 with TFAA afforded the Pummerer intermedi-
ate 16, which without isolation was reacted with 1-tetradecene
silica gel. The crude product was reduced with NaBH4 to yield
alcohol 23 as the sole product. Deprotection of the oxazolidinone
was achieved by base promoted hydrolysis23 to afford (+)-desoxo-
prosophylline 1 with physical characteristics that were in excellent
agreement with those reported in the literature.7a
15
in the presence of stoichiometric amounts of SnCl4 to yield
homoallyl sulfide 17 in 65% yield.16 Displacement of bromine with
a hydroxy group by treatment of 17 with excess sodium nitrite in
DMF17 followed by deprotection of the acetonide furnished diol 19.
It was necessary to protect the hydroxy groups to involve the car-
bamate selectively in the electrophile promoted cyclization. Thus
treatment of 19 with TBS-OTf in the presence of 2,6-lutidine
yielded cleanly the disilyl ether 20. Amidomercuration of 20 using
mercuric trifluoroacetate proceeded stereoselectively18 in DCM to
furnish oxazolidinone 21 as the sole product19 after demercuration
and concomitant desilylation using LiBH4 (Scheme 3).20
In summary, we have described a novel asymmetric synthesis of
desoxoprosophylline in 8.6% overall yield from b-siloxy sulfoxide
10 using a sulfilimine as an intramolecular nucleophile. The sulfil-
imine was readily obtained from the corresponding sulfoxide using
the Burgess reagent as the source of the carbamate moiety. The
route disclosed is suitable for the synthesis of several related nat-
ural products by varying (a) the nucleophile used for bromide dis-
placement (C-heteroatom and C–C bonds can be made); (b) the
chain length of the alkene employed in the Pummerer ene reac-
tion; (c) the conditions of amidomercuration, using kinetic24 rather
than thermodynamic conditions to prepare 2,6-trans-di-substi-
tuted piperidine derivatives.
The p-tolyl thio group was removed by hydrogenolysis on treat-
ment with Ra-Ni to furnish alcohol 22, an enantiomeric homolog of
desoxosafrinine. Attempted Mitsunobu reaction on 22 using chlo-
roacetic acid21 as the acid partner only returned unreacted starting

S. Raghavan, S. Mustafa / Tetrahedron Letters 49 (2008) 5169–5171
5171
OP
O
NCbz
p
-TolS
S
NaNO2, DMF
90 oC, 90%
Cat. CSA, MeOH
OP
p-Tol
17
HN
88%
OH
Cbz
TBS-OTf,
2,6-Lutidine
DCM, 100%
19, P = H
20, P = TBS
18
10
10
X
OH
OH
Hg(OC(O)CF3)2, DCM
IBX, EtOAc
NaBH4, MeOH
70%
then LiBH4
72%
N
O
N
O
11
11
O
O
21, X = STol-p
22, X = H
23
Ra-Ni, EtOH,
100%
OH
OH
8N KOH, EtOH
90%
N
H
11
(+)-desoxoprosophylline 1
Scheme 3.
4. (a) Khuong-huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R. Bull. Soc. Chim. Belg.
1972, 81, 425; (b) Khuong-huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R. Bull. Soc.
Chim. Belg. 1972, 81, 443.
5. (a) Asano, N. Glycobiology 2003, 13, 93; (b) Junge, B.; Matzke, M.; Stoltefuss, J. In
Handbook of Experimental Pharmacology; Kuhlmann, J., Puls, W., Eds.; Springer:
Berlin, Heidelberg, New York, 1996; Vol. 119, pp 411–482; (c) Winchester, B.;
Fleet, G. W. J. Glycobiology 1992, 2, 199.
6. Kolter, T.; Sandhoff, K. Angew. Chem., Int. Ed. 1999, 38, 1532.
7. (a) Fuhshuku, K.; Mori, K. Tetrahedron: Asymmetry 2007, 18, 2104; (b) Tzanetou,
E. N.; Kasiotis, K. M.; Magiatis, P.; Haroutounian, S. A. Molecules 2007, 12, 735;
(c) Wang, Q.; Sasaki, N. A. J. Org. Chem. 2004, 69, 4767; (d) Jourdant, A.; Zhu, J.
Heterocycles 2004, 64, 249; (e) Dransfield, P. J.; Gore, P. M.; Prokes, I.; Shipman,
M.; Slawin, A. M. Z. Org. Biomol. Chem. 2003, 1, 2723; (f) Datta, A.; Kumar, J. S.
R.; Roy, S. Tetrahedron 2001, 57, 1169; (g) Herdeis, C.; Tesler, J. Eur. J. Org. Chem.
1999, 1407; (h) Ojima, I.; Vidal, E. S. J. Org. Chem. 1998, 63, 7999; (i) Kadota, I.;
Kawada, M.; Muramatsu, Y.; Yamamoto, Y. Tetrahedron: Asymmetry 1997, 8,
3887; (j) Takao, K.; Nigawara, Y.; Nishino, E.; Takagi, I.; Maeda, K.; Tadano, K.;
Ogawa, S. Tetrahedron 1994, 50, 5681; (k) Saitoh, Y.; Moriyama, Y.; Hirota, H.;
Takahashi, T.; Khuong-Huu, Q. Bull. Chem. Soc. Jpn. 1981, 54, 488.
8. (a) Chavan, S. P.; Praveen, C. Tetrahedron Lett. 2004, 45, 421; (b) Ma, N.; Ma, D.
Tetrahedron: Asymmetry 2003, 14, 1403; (c) Yang, C.; Liao, L.; Xu, Y.; Zhang, H.;
Xia, P.; Zhou, W.-S. Tetrahedron: Asymmetry 1999, 10, 2311.
9. Raghavan, S.; Naveen Kumar, Ch.; Tony, K. A.; Ramakrishna Reddy, S.;
Ravikumar, K. Tetrahedron Lett. 2004, 45, 7231.
10. Raghavan, S.; Mustafa, S. Tetrahedron Lett. 2008, 49, 3216.
11. Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Bella, M.; Reddy, M. V.
Angew. Chem., Int. Ed. 2002, 41, 834.
12. Raghavan, S.; Mustafa, S.; Kailash, R. Tetrahedron Lett. 2008, 49, 4256.
13. Following the reaction by TLC clearly indicated the formation of another
sulfoxide (epimeric at sulfur, a known compound). This points to the fact that
the Burgess reagent epimerizes the sulfoxide at a rate faster than its reaction to
afford the sulfilimine.
14. The silyl ether was deprotected because the bromo-carbamate from 12 did not
undergo Pummerer reaction due to the presence of an NH– group, see Ref. 10.
15. Ishibashi, H.; Komatsu, H.; Ikeda, M. J. Chem. Res. (S) 1987, 296.
16. Compound 18 was isolated as a single isomer; however, its structure could not
be assigned until further transformation into 21.
Acknowledgements
S.R. is thankful to Dr. J. M. Rao, Head, Org. Div. I, and Dr. J. S.
Yadav, Director, IICT, for constant support and encouragement.
S.M. is thankful to CSIR, New Delhi, for a fellowship. Financial assis-
tance from DST (New Delhi) is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.06.074.
References and notes
1. For selected reviews on piperidine alkaloids, see: (a) Strunz, G. M.; Findlay, J. A.
In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1985; Vol. 26, pp
89–183; (b) Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 3, pp 1–90; (c)
Angle, S. R.; Breitenbucher, J. G. Stud. Nat. Prod. Chem. 1995, 16, 453; (d)
Schneider, M. J. Alkaloids: Chem. Biol. Perspect. 1996, 10, 155; (e) Andersen, R. J.;
Van Soest, R. W. M.; Kong, F. Alkaloids: Chem. Biol. Perspect. 1996, 10, 301; (f)
Ojima, I.; Iula, D. M. Alkaloids: Chem. Biol. Perspect. 1999, 13, 371; (g) Plunkett,
O.; Sainsbury, M. In Rodd’s Chemistry of Carbon Compounds; Sainsbury, M., Ed.,
2nd ed.; Elsevier: Amsterdam, 1998; pp 365–421. Part F/Part G (partial); (h)
Rodriguez, J. Stud. Nat. Prod. Chem. (Part E) 2000, 24, 573.
2. For selected reviews on the synthesis of piperidines, see: (a) Buffat, M. G. P.
Tetrahedron 2004, 60, 1701; (b) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003,
3693; (c) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953; (d) Laschat, S.; Dickner, T. Synthesis 2000, 13, 1781;
(e) Baliah, V.; Jeyaraman, R.; Chandrasekaran, L. Chem. Rev. 1983, 83, 379.
3. (a) Choudhary, M. I.; Nawaz, S. A.; Zaheer-ul-Haq; Azim, M. K.; Ghayur, M. N.;
Lodhi, M. A.; Jalil, S.; Khalid, A.; Ahmed, A.; Rode, B. M.; Atta-ur-Rahman; Gilani,
A.-H.; Ahmad, V. U. Biochem. Biophys. Res. Commun. 2005, 332, 1171; (b)
Bolzani, V. S.; Gunatilaka, A. A. L.; Kingston, D. G. I. Tetrahedron 1995, 51, 5929;
(c) Sansores-Peraza, P.; Rosado-allado, M.; Brito-Loeza, W.; Mena-Rejon, G. J.;
Quijano, L. Fitoterapia 2000, 71, 690; (d) Aqeel, A.; Khursheed, A. K.; Viqaruddin,
A. Arzneim.-Forsch. 1991, 41, 151; (e) Aqeel, A.; Khursheed, A. K.; Viqaruddin,
A.; Sabiha, Q. Arzneim.-Forsch. 1989, 39, 652; (f) Ahmad, A.; Khan, K. A.; Ahmad,
V. U.; Qazi, S. Planta Med. 1986, 4, 285; (g) Luis, A. S.; Karin, J. S.; Schmeda-
Hirschmann, G.; Griffith, G. A.; Holt, D. J.; Jenkins, P. R. Planta Med. 1999, 65,
161; (h) Astudillo, S. L.; Jurgens, S. K.; Schmeda-Hirschmann, G.; Griffith, G. A.;
Holt, D. H.; Jenkins, P. R. Planta Med. 1999, 65, 161; (i) Aguinaldo, A. M.; Read, R.
W. Phytochemistry 1990, 29, 2309.
17. Raduchel, B. Synthesis 1980, 292.
18. Harding, K. E.; Marman, T. H. J. Org. Chem. 1984, 49, 2838.
19. The structure of 21 was proven by 1H NMR and NOE studies on the acetate
derivative, see Supplementary data. The structure of 18 can therefore be
assigned with the alkyl chain anti relative to the oxygen.
20. Takacs, J. M.; Helle, M. A.; Takusagawa, F. Tetrahedron Lett. 1989, 30, 7321.
21. Dodge, J. A.; Trujillo, J. I.; Preenel, M. J. Org. Chem. 1994, 59, 234.
22. Kano, S.; Yuasa, Y.; Mochizuki, N.; Shibuya, S. Heterocycles 1990, 30, 263.
23. Toyooka, N.; Yosida, Y.; Momose, T. Synlett 1993, 565.
24. (a) Singh, S.; Singh, O. V.; Han, H. Tetrahedron Lett. 2007, 48, 8270; (b) Singh, O.
V.; Han, H. Org. Lett. 2004, 6, 3067.