A concise and stereoselective synthesis of (+)- and (-)-deoxoprosophylline

Article abstract of DOI:10.1016/j.tetlet.2003.10.142

An efficient synthesis of (+)- and (-)-deoxoprosophylline was accomplished from the readily available cis-2-butene-1,4-diol in which the Sharpless asymmetric dihydroxylation was used as the key step.

Full text of DOI:10.1016/j.tetlet.2003.10.142

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 421–423
A concise and stereoselective synthesis of (+)- and
())-deoxoprosophylline
Subhash P. Chavan* and Cherukupally Praveen
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pashan, Pune 411 008, India
Received 18 September 2003; revised 13 October 2003; accepted 23 October 2003
Abstract—An efficient synthesis of (+)- and ())-deoxoprosophylline was accomplished from the readily available cis-2-butene-1,4-
diol in which the Sharpless asymmetric dihydroxylation was used as the key step.
Ó 2003 Elsevier Ltd. All rights reserved.
Multifunctionalized piperidine alkaloids possessing the
2,6-disubstituted piperidin-3-ol skeleton have been
found abundantly in nature.1 Prosopis alkaloids, one of
the subgroups of these piperidine alkaloids, were iso-
lated from Prosopis africana Taub.2 Structurally, these
compounds possessing a polar head group and a
hydrophobic aliphatic tail can be considered as cyclic
analogues of the membrane lipid sphingosine.3 Besides
their interesting structural features, these polysubsti-
tuted piperidine alkaloids exhibit a variety of pharma-
cological properties, such as anaesthetic, analgesic, and
antibiotic activities.4
HO
HO
HO
HO
N
H
N
H
8
8
X
X
(-)-Prosophylline (3, X = O)
(-)-Deoxoprosophylline (4, X = H2)
(+)-Prosophylline (1, X = O)
(+)-Deoxoprosophylline (2, X = H2)
O
O
HO
HO
O
8
BnO
8
NHCbz
BnO
Sharpless
ADH
13
O
OH
BnO
BnO
OEt
Claisen
Although many elegant synthesis of (+)- and ())-
deoxoprosophylline have been documented in the liter-
ature,5 most of the syntheses use chiral pool starting
materials such as sugars, aminoacids and involve many
steps. Due totheir interesting structural features and the
biological significance of this class of compounds, we
were encouraged to design a short and effective synthesis
of (+)- and ())-deoxoprosophylline, using Sharpless
asymmetric dihydroxylation as the source of chirality.
Scheme 1 shows our retrosynthetic analysis for deoxo-
prosophylline. As illustrated in Scheme 1, the retrosyn-
thetic strategy envisions the use of hydroxy lactone 8 as
the key intermediate for the proposed synthesis, which
would be formed from the allylic alcohol 6 by a Claisen
6
7
Scheme 1. Retrosynthetic analysis for 2.
orthoester rearrangement and Sharpless asymmetric di-
hydroxylation.
As outlined in Scheme 2, the desired monoprotected
allylic alcohol 6 was prepared in twosteps from the
inexpensive and readily available cis-2-butene-1,4-diol 5
according to the literature procedure.6 Claisen rear-
rangement of the allylic alcohol 6 with triethyl ortho-
acetate in the presence of catalytic propionic acid at
140 °C gave the, c,d-unsaturated ester 7.7 Sharpless
asymmetric dihydroxylation8 employing AD-mix-a and
in situ cyclization of the, c,d-unsaturated ester 7 fur-
nished the hydroxy lactone 8. Mesylation of the hydroxy
lactone 8 and displacement of the mesylate with NaN3 in
DMF at 90 °C gave the azidolactone 10. The azide was
Keywords: deoxoprosophylline; Claisen rearrangement; Sharpless
asymmetric dihydroxylation; piperidine alkaloids.
* Corresponding author. Tel.: +91-20-5893614; fax: +91-20-5893614;
e-mail: spchavan@dalton.ncl.res.in
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.142

422
S. P. Chavan, C. Praveen / Tetrahedron Letters 45 (2004) 421–423
HO
O
O
O
O
OH
HO
MsO
BnO
N3
a)
b)
c)
d)
ref 6
OH
O
O
O
BnO
h)
BnO
OEt
BnO
BnO
7
8
9
10
11
5
6
e)
O
O
HO
HO
O
g)
f)
HO
C
11H23
HO
BnO
C11H23
SO2Ph
CbzHN
BnO
O
N
H
8
BnO
NHCbz
NHCbz
Deoxoprosophylline (2)
13
12
Scheme 2. Reagents and conditions: (a) CH3C(OEt)3, cat. propionic acid, 140 °C, 2 h, 94%; (b) AD-mix-a, CH3SO2NH2, t-BuOH:H2O (1:1), 24 h,
0 °C, 95%, 93% ee; (c) CH3SO2Cl, Et3N, DCM, 92%; (d) NaN3, DMF, 90 °C, 89%; (e) i. TPP, H2O, C6H6, 8 h, ii. CbzCl, Et3N, cat. DMAP, DCM,
75% for two steps; (f) C12H25SO2Ph, n-BuLi, THF, )78 °C, 2 h, 94%; (g) 6% Na–Hg, Na2HPO4, CH3OH, )10 °C, 95%; (h) 20% Pd(OH)2/C, H2,
CH3OH, rt, 24 h, 76%.
2. (a) Ratle, G.; Monsieur, X.; Das, B.; Yassi, J.; Khuong-
Huu, Q.; Goutrarel, R. Bull. Soc. Chim. Fr. 1996, 2945–
2947; (b) Khuong-Huu, Q.; Rutle, G.; Monseux, X.;
Goutrarel, R. Bull. Soc. Chim. Belg. 1972, 81, 425–
458.
reduced tothe amine by using triphenylphosphine and
water and the resulting amine was protected as its Cbz
derivative by using CbzCl, TEA in the presence of a
catalytic amount of DMAP.
3. Kolter, T.; Sandhoff, K. Angew. Chem., Int. Ed. 1999, 38,
1532–1568.
4. Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and
Biological Perspective; Pelletier, S.W., Ed.; Wiley: New
York, 1985; Vol. 3, p 1.
Opening of the lactone of 11 was achieved using
C12H25SO2Ph and n-BuLi.9;10 Desulfonylation of 12
using 6% Na–Hg and Na2HPO4 at )10 °C gave the
ketone 13.11 Removal of the protecting groups and cy-
clization of the ketone 13 using catalytic Pd(OH)2 and
H2 in a one pot reaction, afforded (+)-deoxoproso-
phylline 2 in 76% yield. Having accomplished the synthesis
of natural 2, we turned our attention towards the syn-
thesis of its enantiomer. Accordingly, c,d-unsaturated
ester 7 was transformed in a similar fashion to afford
())-deoxoprosophylline 4 following a similar sequence
however, using AD-mix-b. The physical and spectro-
scopic data of our synthetic materials 212 and 4 were in
good agreement with those described in the literature.5d;e
5. (a) Saitoh, Y.; Moriyama, Y.; Hirota, H.; Takahashi, T.;
Khuong-Huu, Q. Bull. Chem. Soc. Jpn. 1981, 54, 488; (b)
Saitoh, Y.; Moriyama, Y.; Hirota, H.; Takahashi, T.;
Khuong-Huu, Q. Tetrahedron Lett. 1980, 21, 75; (c)
Kadota, I.; Kawada, M.; Muramatsu, Y.; Yamamoto, Y.
Tetrahedron: Asymmetry 1997, 8, 3887; (d) Takao, K.;
Nigawara, E.; Nishino, I.; Takagi, K.; Maeda, K.;
Tadano, K.; Ogawa Tetrahedron 1994, 50, 5681; (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. Commn. 2002, 150; (h) Datta, A.; Raviku-
mar, J. S.; Roy, S. Tetrahedron 2001, 57, 1169–1173; (i)
Ma, N.; Ma, D. Tetrahedron: Asymmetry 2003, 14, 1403–
1406.
6. Ramarao, A. V.; Bose, D. S.; Gurjar, M. K.; Ravindra-
nathan, T. Tetrahedron 1989, 45, 7031.
7. Trust, R.; Ireland, R. E. Org. Synth. (Coll. Vol.) 1998, 6,
606.
8. (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 448–481; (b) Torri, S.; Liu, P.; Bhuvanes-
wari, N.; Amatore, C.; Jutand, A. J. Org. Chem. 1996, 61,
3055–3060; (c) For a review on asymmetric dihydroxyla-
tion, see: Kolb, H. C.; Van Niewenhze, M. S.; Sharpless,
K. B. Chem. Rev. 1994, 94, 2483–2547; (d) The ee of the
compound 8 was determined tobe 93% by Chiral HPLC
analysis (Chiralcel OD, 80:20 hexane/i-PrOH, 1 mL/min,
254 nm).
In summary, (+)- and ())-deoxoprosophylline were
synthesized in efficient yields from readily available cis-
2-butene-1,4-diol. The present synthesis of (+)- and ())-
deoxoprosophylline having an overall yield of 37% in
eight steps starting from the known allyl alcohol 6 is
better than earlier reported syntheses. By using Sharp-
less asymmetric dihydroxylation as the key step, we have
demonstrated that both enantiomers of deoxoprosophyl-
line can be readily accessed.
Acknowledgements
C.P. thanks CSIR (New Delhi) for a research fellowship.
Funding from YSA (CSIR, New Delhi) to S.P.C. is
gratefully acknowledged.
9. (a) Meck, J. S.; Fowler, J. S. J. Org. Chem. 1968, 33, 3422;
(b) Basinski, K.; Zurawinski, R.; Drabowicz, J.; Kolajcz-
ylo, M. M. Tetrahedron 1988, 44, 6687.
10. (a) Brimble, M. A.; Rush, C. J.; Williams, G. M.; Baker,
E. N. J. Chem. Soc., Perkin. Trans. 1 1990, 414; (b)
Brimble, M. A.; Officer, D. L.; Williams, G. M. Tetrahe-
dron Lett. 1988, 29, 3609.
References and Notes
11. Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.
Tetrahedron Lett. 1976, 17, 3477.
1. 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.
12. Selected physical and spectroscopic data for 2: mp 85–86 °C,
24
½aŠ +13.5 (c 0.3, CHCl3). 1H NMR (200 MHz, CDCl3)
D
d, ppm: 0.88 (3H, t, J ¼ 6:5 Hz), 1.26 (24H, m), 1.72–1.79

S. P. Chavan, C. Praveen / Tetrahedron Letters 45 (2004) 421–423
423
(1H, m), 2.02–2.06 (1H, m), 2.54–2.58 (2H, m), 2.98 (3H,
br), 3.47 (1H, dt, J ¼ 10:1, 4.3 Hz), 3.71 (1H, dd, J ¼ 10:9,
13C NMR (50 MHz) d: 14.18, 22.75, 26.27, 29.37, 29.7,
29.8, 30.83, 31.97, 33.77, 36.35, 56.23, 63.4, 63.88,
69.8 ppm.
5.1 Hz),
3.83
(1H,
dd,
J ¼ 10:9,
4.3 Hz).