An efficient synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenyl piperidine and N-Boc-safingol

Article abstract of DOI:10.1016/j.tetlet.2012.08.075

An efficient strategy has been developed for the stereo selective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenyl piperidine and N-Boc-safingol from benzaldehyde and N-Boc-imine.

Full text of DOI:10.1016/j.tetlet.2012.08.075

Tetrahedron Letters 53 (2012) 5993–5995
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Tetrahedron Letters
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An efficient synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenyl piperidine
and N-Boc-safingol
⇑
Maddimsetti Venkateswara Rao, Kotha kapu Sridhar Reddy, Batchu Venkateswara Rao
Organic and Biomolecular Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2012
Revised 17 August 2012
Accepted 19 August 2012
Available online 1 September 2012
An efficient strategy has been developed for the stereo selective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-
phenyl piperidine and N-Boc-safingol from benzaldehyde and N-Boc-imine.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N-Boc-imine
Manich reaction
Wittig reaction
DIBALH-reduction
Cyclisation
Ru-oxidation
BH3-reduction
A number of naturally occurring alkaloids and their derivatives
exhibit important biological properties. In particular, hydroxylated
pyrrolidine, piperidine, pyrrolizidine and indolizidine alkaloids and
their derivatives have received extensive attention due to their
well-established action as glycosidase inhibitors.1 Among hydrox-
ylated piperidine alkaloids N-Boc-(2S,3S)-3-hydroxy-2-phenylpi-
peridine 1 is an important intermediate from which non-peptidic
neurokinin NK1 receptor antagonists (+)-(2S,3S)-L-733,060 22 and
(+)-(2S,3S)-CP-99,994 33 have been prepared (Fig. 1), which are
known to exhibit a variety of interesting biological activities.4–9
1,2-Amino alcohol units with unique stereochemistry are consid-
ered as essential components of many biologically active natural
products and important pharmaceuticals. Some of the examples of
this class are sphingosine 4, safingol 5 and sphiganine 7 (Fig. 1).
Safingol 5 is a synthetic sphingosine which exhibits antineoplastic
and antipsoriatic activities.10 It is currently in clinical trials as a
sphingosine kinase inhibitior. It also inhibits protein kinase C11
and has been implicated in ceramide generation and apoptosis
induction. Recent studies showed that safingol induces autophagy
through inhibition of PKCs and PI3K.12 It also enhances the cytotoxic
effect of the chemotherapeutic agent mitomycin C in gastric cancer
cells by promoting drug induced apoptosis.13–15 Because of their
pharmacological importance,16 various methods have been devel-
oped to access compound 117 and safingol 5.18 However, most of
the reports deal with chiral pool strategies, classical resolution of
recemates and use of expensive transition-metal complexes often
involving many steps. In continuation of our efforts in the synthesis
of alkaloids,19 herein we wish to report an efficient stereoselective
synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenyl piperidine 1 and
N-Boc-safingol 6 from syn b-amino aldehyde 10 which was obtained
by asymmetric Mannich reaction of N-Boc-imine 8 with aldehyde 9
in presence (R)-proline as a catalyst, as per the report of Cordova
et al.20
The reaction of N-Boc-imine 8 with aldehyde 9 in the presence
of proline gave the required syn b-amino aldehyde 1020 with high
enantioselectivity as shown in Scheme 1. Wittig reaction of com-
pound 10 with PPh3CHCOOEt at 0 °C afforded trans and cis isomers
11 and 11a in 9:1 ratio. Ester functionality in 11 was reduced to
alcohol 12 and subsequently treated with MsCl/Et3N to afford 13.
Treatment of crude 13 with Pd/C and NaOAc in MeOH under H2
atmosphere21 yielded directly N-Boc-(2S,3S)-3-hydroxy-2-phen-
ylpiperidine 122. The spectral and analytical data of compound 1
are in good agreement with the literature values.17f
For the synthesis of N-Boc-safingol 6, compound 10 was treated
with C14 Wittig ylide at 0 °C to give the alkene derivative 14
(Scheme 2). Deprotection of the benzyl group and reduction of
double bond in compound 14 were carried out with Pd/C under
H2 atmosphere to afford 15. Protection of the alcohol with TBSCl
in 15 gave compound 16. The Ru-mediated oxidative cleavage of
a phenyl group in 16 gave acid which on reduction with BH3ꢀDMS
afforded alcohol 17. Deprotection of TBS group in compound 17
yielded N-Boc-safingol 623. The physical and spectroscopic data
of compound 6 are in good agreement with the literature values.18g
In summary, an efficient stereoselective synthesis of N-Boc-
(2S,3S)-3-hydroxy-2-phenyl piperidine 1 and N-Boc-safingol 6
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.075

5994
M. V. Rao et al. / Tetrahedron Letters 53 (2012) 5993–5995
CF3
H
N
O
OH
OMe
CF3
N
N
Boc
N
H
H
2
3
1
NH2
NHR
NH2
HO
(CH2)14CH3
HO
(CH2)14CH3
HO
(CH2)12CH3
OH
OH
OH
5
6
R = H
R = Boc
7
4
Figure 1. Important 2-phenyl piperidines and sphingosines.
NHBoc
NHBoc
O
NHBoc
O
NBoc
a
ref 20
OBn
OEt
Ph
O
Ph
Ph
OEt
Ph
Ph
OBn
OBn
11
OBn
11a
O
8
9
10
NHBoc
OH
Ph
NHBoc
d
b
c
11
OMs
Ph
OH
N
OBn
13
Boc
OBn
12
1
Scheme 1. Synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine 1. Reagents and conditions: (a) PPh3 = CH–COOEt, DCM, 0 °C to rt, 1 h, trans and cis isomers (9:1) 90%;
(b) DIBAL, DCM, 1 h, ꢁ78 °C, 95%; (c) MsCl, Et3N, DCM, rt, 1 h; (d) Pd/C, H2, NaOAc, EtOAc, rt, 12 h; 60% (over two steps).
NHBoc
NHBoc
NHBoc
a
b
c
Ph
Ph
Ph
Ph
O
12
12
OH
OBn
14
OBn
10
15
NHBoc
NHBoc
NHBoc
HO
d, e
f
HO
12
12
12
OH
OTBS
OTBS
17
6
16
Scheme 2. Synthesis of N-Boc-safingol 6. Reagents and conditions: (a) PPh3 = CH–(CH2)12–CH3, THF, 0 °C, 2 h, 69%; (b) Pd/C, H2, MeOH:THF (1:1), rt, 6 h, 82%; (c) TBSCl,
imidazole, DCM, rt, overnight, 70%; (d) NaIO4, RuCl3ꢀH2O (cat. amount), Na2HPO4ꢀ2H2O, CCl4, MeCN, H2O rt, 18 h; (e) BH3ꢀDMS, THF, 0 °C, 2 h, 65% (over two steps); (f) TBAF,
THF, rt, 2 h, 88%.
Choi, S. S.; Fairbanks, A. J.; Fleet, G. W. J. J. Biochem. 1993, 290, 743. and references
cited therein; (c) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999, 38,
750–770.
has been accomplished in good overall yields. This strategy will be
useful to make some more biologically active compounds having
chiral 1,2 amino alcohol moieties.
2. (a) Baker, R.; Harrison, T.; Hollingworth, G. J.; Swain, J.; Williams, B. J. 1993, EP
528, 495A1; (b) Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg. Med.
Chem. Lett. 1994, 4, 2545–2550.
3. Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.; Snider, R. M. J. Med.
Chem. 1992, 35, 4911–4913.
Acknowledgments
4. Lotz, M.; Vaughan, J. H.; Carson, D. A. Science 1988, 241, 1218–1221.
5. Perianan, A.; Snyderman, R.; Malfroy, B. Biochem. Biophys. Res. Commun. 1989,
161, 520–524.
6. Moskowitz, M. A. Trends Pharmacol. Sci. 1992, 13, 307–311.
7. Lotz, M.; Vaughan, J. H.; Carson, D. A. Science 1987, 235, 893–895.
8. Otsuka, M.; Yanagisawa, M. J. Physiol. (London) 1988, 395, 255–270.
9. (a) Rupniak, N. M.; Carlson, E. C.; Harrison, T., et al Neuropharmacology 2000, 39,
1413–1421; (b) Bang, R.; Saas, G.; Kiemer, A. K.; Vollmar, A. M.; Neuhuber, W.
L.; Tiegs, G. J. Pharmacol. Exp. Ther. 2003, 305, 31–39; (c) Muñoz, M.; Rosso, M.;
Pérez, A.; Coveñas, R.; Rosso, R.; Zamarriego, C.; Soult, J. A.; Montero, I. Invest.
M.V.R. and K.S.R. thank CSIR, New Delhi, for research fellowship.
We also thank Dr. J.S. Yadav and Dr. G.V.M. Sharma for their
constant support and encouragement.
References and notes
1. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645; (b) Winchester, B.; Daher, S. A.; Carpenter, N. C.; Cenci di Bello, I.;

M. V. Rao et al. / Tetrahedron Letters 53 (2012) 5993–5995
5995
Ophthalmol. Vis. Sci. 2005, 46, 2567; (d) Miguel, M.; Marisa, R.; Rafael, C. Lett.
Drug Discov. 2006, 3, 323.
10. USP Dictionary of USAN and International Drug Names; US Pharmacopeia:
Rockville, MD, 2000; p 636.
11. Schwartz, G. K.; Jiang, J.; Kelsen, D.; Albino, A. P. J. Natl. Cancer Inst. 1993, 85,
402.
12. Coward, J.; Ambrosini, G.; Musi, E.; Truman, J. P.; Friedman, A. H.; Allegood, J.
C.; Wang, E.; Merril, A. H., Jr.; Schwartz, G. K. Autophagy 2009, 5, 184–193.
13. Sachs, C. W.; Safa, A. R.; Harrison, S. D.; Fine, R. L. J. Biol. Chem. 1995, 270, 26639.
14. Schwartz, G. K.; Haimovitz-Friedman, A.; Dhupar, K.; Ehleiter, D.; Maslak, P.;
Lawrence, L.; Loganzo, F.; Kelsen, D.; Fuks, Z.; Albino, A. P. J. Natl. Cancer Inst.
1995, 87, 1394.
15. Kedderis, L. B.; Bozigian, H. P.; Kleeman, J. M.; Hall, R. L.; Palmer, T. E.; Harrison,
S. D. Fundam. Appl. Toxicol. 1995, 25, 201.
16. (a) Giardina, G. A. M.; Raveglia, L. F.; Grugni, M. Drugs Future 1997, 22, 1235–
1257; (b) Chandrasekhar, S.; Mohanty, P. K. Tetrahedron Lett. 1999, 40, 5071–
5072.
Tetrahedron Lett. 2002, 43, 9027–9030; (i) Nakai, K.; Ibuka, T.; Otaka, A.;
Tamamura, H.; Fujii, N.; Yamamoto, Y. Tetrahedron Lett. 1995, 36, 6247–6250;
(j) Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K. J. Org. Chem. 2003, 65, 7675–
7680; (k) Ibuka, T.; Nakai, K.; Akaji, M.; Tamamura, H.; Fujii, N.; Yamamoto, Y.
Tetrahedron 1996, 52, 11739–11752; (l) Prevost, S.; Ayad, T.; Phansavath, P.;
Ratovelomanana-Vidal, V. Adv. Synth. Catal. 2011, 353, 3213–3226. references
cited there in; (m) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.;
Shibasaki, M. J. Org. Chem. 1995, 60, 7388–7389.
19. (a) Kumar, A. R.; Reddy, J. S.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5687–5689;
(b) Bhaskar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44, 915–917; (c) Madhan, A.;
Rao, B. V. Tetrahedron Lett. 2003, 44, 5641–5643; (d) Madan, A.; Rao, B. V.
Tetrahedron Lett. 2005, 46, 323–324; (e) Chandrasekhar, B.; Madhan, A.; Rao, B.
V. Tetrahedron 2007, 63, 8746–8751; (f) Reddy, J. S.; Rao, B. V. J. Org. Chem.
2008, 72, 2224–2227; (g) Chandrasekhar, B.; Rao, B. V.; Rao, K. V. M.; Jagadeesh,
B. Tetrahedron: Asymmetry 2009, 20, 1217–1223; (h) Reddy, K. S.; Rao, B. V.
Tetrahedron: Asymmetry 2011, 22, 190–194; (i) Reddy, K. S.; Rao, B. V.; Raju, S. S.
Tetrahedron: Asymmetry 2011, 22, 662–668.
17. (a) Cherian, S. K.; Kumar, P. Tetrahedron: Asymmetry 2007, 18, 982–987; (b)
Stadler, H.; Bos, M. Heterocycles 1999, 51, 1067–1071; (c) Kandula, S. R. V.;
Kumar, P. Tetrahedron: Asymmetry 2005, 16, 3579–3583; (d) Lee, J.; Hoang, T.;
Lewis, S.; Weissman, S. A.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett.
2001, 42, 6223–6225; (e) Yoon, Y.-J.; Joo, J. E.; Lee, K.-Y.; Kim, Y.-H.; Oh, C.-Y.;
Ham, W.-H. Tetrahedron Lett. 2005, 46, 739–741; (f) Bhaskar, G.; Rao, B. V.
Tetrahedron Lett. 2003, 44, 915–917; (g) Bodas Mandar, S.; Upadhyay Puspesh,
K.; Kumar, P. Tetrahedron Lett. 2004, 45, 987–988; (h) Huang, P.-Q.; Liu, L.-X.;
Wei, B.-G.; Ruan, Y.-P. Org. Lett. 2003, 5, 1927–1929; (i) Calvez, O.; Langlois, N.
Tetrahedron Lett. 1999, 40, 7099–7100; (j) Venkataiah, M.; Rao, B. V.; Fadnavis,
N. W. Tetrahedron: Asymmetry 2009, 20, 198–201.
18. (a) Shibasaki, M.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Shibasaki, M. J. Org.
Chem. 1995, 60, 7388–7389; (b) Masui, M.; Shioiri, T. Tetrahedron Lett. 1998, 39,
5199–5200; (c) Shibuya, H.; Kawashima, K.; Narita, N.; Ikeda, M.; Kitagawa, I.
Chem. Pharm. Bull. 1992, 40, 1154–1165; (d) Azumn, H.; Tamagaki, S.; Ogino, K.
J. Org. Chem. 2000, 65, 3538–3541; (e) Sharma, A.; Sunita, G.; Chattopadhyay, S.
Tetrahedron Lett. 2007, 48, 633–634; (f) Prasad, K. H.; Sagar, R.; Vankar, Y. D.
Tetrahedron Lett. 2008, 49, 4728–4730; (g) Kumar, P.; Dubey, A.; Puranik, V. G.
Org. Biomol. Chem 2010, 8, 5074–5086; (h) Cook, G. R.; Pararajasingham, K.
20. Dziedzic, P.; Vesely, V.; Cordova, A. Tetrahedron Lett. 2008, 49, 6631–6634.
21. (a) Afarinkia, K.; Bahar, A. Tetrahedron: Asymmetry 2005, 16, 1239–1287; (b)
Lee, B. W.; Jeong, I.-Y.; Yang, M. S.; Choi, S. U.; Park, K. H. Synthesis 2000, 1305.
22. Compound (1): ½a D25
ꢂ
+37.0 (c 1.0, CHCl3) [lit16f
½
a 2D5
ꢂ
+38.30 (c 1.92, CHCl3)]. IR
(film) m .
max 3441, 2924, 2854, 1666, 1415, 1172, 1147, 1080, 771 cmꢁ1 1H NMR
(300 MHz, CDCl3): d 7.17–7.57 (m, 5H), 5.27 (d, J = 5.6 Hz, 1H), 3.91–4.10 (m,
2H), 3.0 (m, 1H), 1.56–1.85 (m, 4H), 1.36 (s, 9H). 13C NMR (75 MHz, CDCl3): d
155.39, 138.4, 128.35, 127.17, 79.88, 70.02, 59.21, 39.43, 29.65, 28.28, 27.64,
23.03. ESIMS m/z: 278 (M++1), 300 (M++Na). HRMS (C16H23NO3Na): Calcd:
300.1575. Found 300.1589.
23. Compound (6): ½a D25
ꢂ
+16.6 (c 1.0, CHCl3) [lit17g
½
a 2D5
ꢂ
+18.8(c 1.0, CHCl3)] IR (film)
mmax 3344, 2920, 2852, 1686, 1530, 1463, 1246, 1171, 1051 cmꢁ1 1H NMR
.
(500 MHz, CDCl3): d 5.40 (br s, 1H), 3.97 (dd, J = 2.9 Hz, 11.8 Hz, 1H) 3.70–3.80
(m, 2H), 3.52(br s, 1H), 2.67–2.91 (2 br s, 2H), 1.42–1.58 (m, 11H), 1.22–1.36
(m, 26H), 0.88 (t, 3H) 13C NMR (75 MHz, CDCl3): 156.07, 79.71, 74.27, 62.58,
54.85, 34.42, 31.89, 29.66, 29.63, 29.58, 29.54, 29.33, 28.37, 25.93, 22.65, 14.06.
ESIMS m/z: 402 (M++1), 424 (M++Na). HRMS (C23H47NO4Na): Calcd: 424.3402.
Found 424.3416.