The stereoselective total synthesis of (+)-8-ethylnorlobelol from anti-1,3-aminoalcohols

Article abstract of DOI:10.1016/j.tetlet.2013.07.026

A novel and efficient approach has been developed for the total synthesis of (+)-8-ethylnorlobelol (1) in a highly stereoselective manner. The key anti-1,3-aminoalcohol core is constructed through the reductive opening of 2-iodomethyl-4-amidotetrahydropyranyl ether which is prepared by a Prins/Ritter amidation sequence.

Full text of DOI:10.1016/j.tetlet.2013.07.026

Tetrahedron Letters 54 (2013) 4960–4962
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The stereoselective total synthesis of (+)-8-ethylnorlobelol from
anti-1,3-aminoalcohols
⇑
B. V. Subba Reddy , B. Phaneendra Reddy, P. Sivaramakrishna Reddy, Y. Jayasudhan Reddy, J. S. Yadav
Natural Products Chemistry, 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:
A novel and efficient approach has been developed for the total synthesis of (+)-8-ethylnorlobelol (1) in a
highly stereoselective manner. The key anti-1,3-aminoalcohol core is constructed through the reductive
opening of 2-iodomethyl-4-amidotetrahydropyranyl ether which is prepared by a Prins/Ritter amidation
sequence.
Received 18 May 2013
Revised 2 July 2013
Accepted 4 July 2013
Available online 10 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Piperdine alkaloids
Prins–Ritter reaction
anti-1,3-Aminoalcohols
Ring closing metathesis
Piperidine alkaloids (Fig. 1)1 are abundant in nature and many
of them exhibit a broad range of biological activities, which are
being used for the treatment of nicotine drug abuse and neurolog-
ical disorders such as asthma, anxiety, Alzheimer’s and Parkinson’s
diseases.2 Consequently, several synthetic approaches have been
developed for the synthesis of these alkaloids because of their scar-
city from natural sources. Among them, Sedum and Lobelia inflata
family of piperidine alkaloids have attracted great interest due to
their potent biological profiles. (+)-8-Ethylnorlobelol (1) was first
isolated by Wieland from Lobeliu inflata,3 consisting of a 2-(2-
hydroxyalkyl)piperidine core. The absolute configuration of (+)-8-
ethylnorlobelol (1) was initially assigned as 2S,8R and subse-
quently it was corrected as 2S,8S by Claude Hootele and co-work-
ers via its total synthesis.4
N
OH
Ph
OH
OH
N
H
N
H
(+)-
Allosedamine
HN
1
(+)-
(+)-8-Ethylnorlobelol ( )
Sedridine
OH
OH
OH
N
H
n-C9H19
N
H
(+)-Pseudoconhydrine
Halosaline
214-D
OH
OH
NH
N
OH
In continuation of our work on Prins type cyclizations,5 we
herein report the total synthesis of (+)-8-ethylnorlobelol via a
Prins–Ritter amidation sequence. The retro synthetic analysis of
(+)-8-ethylnorlobelol (1) (R=Et) is shown in Scheme 1. We envis-
aged that the target molecule could be achieved from intermediate
7, which could easily be prepared by means of a highly stereoselec-
tive Prins/Ritter amidation followed by a reductive opening of 2-
iodomethyl-4-amidotetrahydropyranyl ether (6).
Accordingly, we commenced the synthesis of (+)-8-ethylnor-
lobelol (1) from a chiral homoallylic alcohol 2. As shown in Scheme
2, the chemoselective protection of homoallylic diol with TsCl in
the presence of dibutyltin oxide and triethyl amine gave the de-
sired homoallylic alcohol 3.6 Treatment of 3 with propanaldehyde
N
OH
(+)-β-Conhydrine
OH
N-Methyl-2-(2-hydroxybutyl)-
6-(2-hydroxypentyl)-piperidine
(+)-Lentiginosine
Figure 1. Piperidine alkaloids.
4 in acrylonitrile in the presence of 10 mol % BF3ꢀOEt2 afforded
4-amidotetrahydropyran 5 in good yield with a high diastereose-
lectivity. The reaction proceeds through a cascade of Prins/Ritter
reaction affording the cis-diastereomer predominantly which is
consistent with earlier reports.7 Compound 5 was converted into
the corresponding iodide 6 in 89% yield using NaI in refluxing ace-
tone. Reductive ring opening of compound 6 using Zn dust in eth-
anol afforded the desired anti-1,3-aminoalcohol 7 in 92% yield,8
which is a key intermediate for the synthesis of (+)-8-ethylnor-
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.026

B. V. Subba Reddy et al. / Tetrahedron Letters 54 (2013) 4960–4962
4961
O
highly stereoselective manner. Our approach involves mainly a
Prins/Ritter amidation followed by a reductive ring opening se-
quence. It is a modular approach, which can also be employed
for the synthesis of several piperidine alkaloid analogs.
HN
O
R
R
OH HN
HN
OH
I
R
1
6
7
O
Acknowledgements
O
B.P.R. and P.S.R.K.R. thank CSIR and Y.J.S.R. thank UGC, New Del-
hi, for the award of fellowships.
HN
CN
R
H
O
+
OTs
OTs
HO
R
O
References and notes
5
1. (a) Strunzard, G. M.; Finlay, J. A. The Alkaloids In In Brossi, A., Ed.; Academic
Press: New York, 1986; vol 26, pp 89–174; (b) Jones, T. H.; Blum, M. S.;
Robertson, H. G. J. Nat. Prod. 1990, 53, 429; (c) Marion, L. Can. J. Res. 1945, 23B,
165; (d) Marion, L.; Lavigne, R.; Lemay, L. Can. J. Chem. 1951, 29, 347; (e) Franck,
B. Chem. Ber. 1958, 91, 2803; (f) Franck, B. Chem. Ber. 1960, 93, 2360; (g) Fodor,
G.; Butruille, D.; Huber, S. C.; Letourneau, F. Tetrahedron 1971, 27, 2055; (h)
Kim, J. H.; Hart, H. T.; Stevens, J. F. Phytochemistry 1996, 41, 1319; (i)
Weiland, H.; Koschara, K.; Dane, E.; Renz, J.; Schwarze, W.; Linde, W. Liebigs
Ann. Chem. 1939, 540, 103; (j) Schopf, C.; Kauffmann, T.; Berth, P.; Bundschuh,
W.; Dummer, G.; Fett, H.; Habermehl, G.; Wieters, E.; Wust, W. Liebigs Ann.
Chem. 1957, 608, 88; (k) Davies, F. A.; Santhanaram, M. J. Org. Chem. 2006, 71,
4222; (l) Voituriez, A.; Ferreira, F.; Perez-Luna, A.; Chemla, F. Org. Lett. 2007, 9,
4705.
2. (a) Nechev, L. V.; Kozedov, I.; Harris, C. M.; Harris, T. M. Chem. Res. Toxicol. 2001,
14, 1506; (b) Felpin, F. X.; Lebreton, J. J. Org. Chem. 2002, 67, 9192; (c) Flammia,
D.; Dukat, M.; Damaj, I.; Martin, B.; Glennon, R. J. Med. Chem. 1999, 42, 3726; (d)
Jensen, A. A.; Frølund, B.; Liljefors, T.; Krogsgaard-Larsen, P. J. Med. Chem. 2005,
48, 4705; (e) Felpin, F. X.; Lebreton, J. Tetrahedron 2004, 60, 10127.
3. Wieland, H.; Koschara, W.; Dane, E.; Renz, J.; Schwarze, W.; Linde, W. Liebigs
Ann. Chem. 1939, 540, 103.
Scheme 1. Retrosynthetic analysis of (+)-8-ethylnorlobelol (1).
OH
OH
i
OTs
HN
OH
3
2
O
O
HN
ii
iii
I
OTs
O
6
O
5
4. Mill, S.; Durant, A.; Hootele, C. Liebigs Ann. 1996, 2083.
5. (a) Yadav, J. S.; Rao, P. P.; Reddy, M. S.; Rao, N. V.; Prasad, A. R. Tetrahedron Lett.
2007, 48, 1469; (b) Yadav, J. S.; Thrimurtulu, N.; Gayathri, K. U.; Reddy, B. V. S.;
Prasad, A. R. Tetrahedron Lett. 2008, 49, 6617; (c) Yadav, J. S.; Lakshmi, K. A.;
Reddy, N. M.; Prasad, A. R.; Reddy, B. V. S. Tetrahedron 2010, 66, 334; (d) Reddy,
B. P.; Pandurangam, T.; Yadav, J. S.; Reddy, B. V. S. Tetrahedron Lett. 2012, 53,
5749.
iv
v
TBSO HN
8
OH HN
7
O
O
6. (a) Shanzer, A. Tetrahedron Lett. 1980, 21, 221; (b) Martinelli, M. J.; Nayyar, N.
K.; Moher, E. D.; Dhokte, U. P.; Pawlak, J. M.; Vidyanathan, R. Org. Lett. 1999, 1,
447; (c) Liu, H. J.; Yip, J.; Shia, K. S. Tetrahedron Lett. 1997, 38, 2253.
7. Epstein, T.; Epstein, O. L.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 16480; (b) Al-
Mutairi, E. H.; Crosby, S. R.; Darzi, J.; Harding, J. R.; Hughes, R. A.; King, C. D.;
Simpson, T. J.; Smith, R. W.; Willis, C. L. Chem. Commun. 2001, 835; (c) Yadav, J.
S.; Reddy, B. V. S.; Kumar, G. G. K. S. N.; Reddy, G. M. Tetrahedron Lett. 2007, 48,
4903; (d) Reddy, U. C.; Raju, B. R.; Kumar, E. K. P.; Saikia, A. K. J. Org. Chem. 2008,
73, 1628; (e) Penning, T. P.; Djuric, S. W.; Hanek, R. A.; Kalish, V. J.; Miyashiro, J.
M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20, 307.
vii
ix
vi
TBSO HN
10
TBSO HN
9
O
O
viii
OH HN
11
8. Yadav, J. S.; Reddy, Y. J.; Reddy, P. A. N.; Reddy, B. V. S. Org. Lett. 2013, 15, 546.
9. Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123, 8420.
10. (a) Sosnicki, J. G. Tetrahedron Lett. 2009, 50, 178; (b) Nelson, D. J.; Carboni, D.;
Ashworth, I. W.; Percy, J. M. J. Org. Chem. 2011, 76, 8386.
OH HN
1
O
11. Analytical data for ((2R,4R,6S)-4-(acrylamido)-6-ethyl-tetrahydro-2H-pyran-2-
Scheme 2. Reagents and conditions: (i) Et3N, dibutyltin oxide, TsCl, DCM, rt, 1 h; (ii)
n-propanaldehyde, acrylonitrile, BF3.OEt2 (10 mol%), rt, 1 h; (iii) NaI, acetone, reflux,
6 h (iv) Zn dust, EtOH, reflux, 5 h; (v) TBSOTf, 2,6-lutidine, CH2Cl2, 10 min; (vi)
Grubb’s I catalyst (5 mol%), DCM, rt, 8 h; (vii) Pd/C, MeOH, Et3N, H2 (1 atm), 4 h;
(viii) TBAF, THF, rt, 3 h; (ix) LiAlH4, Et2O, reflux, 2 h.
yl)methyl-4-methylbenzenesulfonate: ½ ꢁ
a 2D5 +16.7 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.78 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 6.22–6.33
(m, 1H), 5.98–6.10 (m, 1H), 5.63–5.69 (m, 1H), 5.41 (br s, 1H), 3.92–4.12 (m,
3H), 3.53–3.66 (m, 1H), 3.20–3.31 (m, 1H), 2.44 (s, 3H), 1.85–2.06 (m, 2H),
1.34–1.57 (m, 2H), 0.93–1.56 (m, 3H), 0.88 (t, J = 6.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 164.7, 144.6, 132.2, 130.6, 129.5, 127.5, 126.0, 75.8, 72.8,
71.5, 45.4, 37.5, 37.1, 33.1, 20.1, 10.7; IR (KBr)m3281, 3065, 2928, 1660, 1625,
1542, 1359, 1177, 982, 814, 668 cmꢂ1; HRMS (m/z) calcd for C18H26NO5S
lobelol (1). The hydroxyl group of compound 7 was then protected
as its TBS ether 8 in 95% yield using TBSOTf in the presence of 2,6-
lutidine.9 Compound 8 was then subjected to ring closing metath-
368.1531, found: 368.1540.
N-((4S,6S)-6-Hydroxyoct-1-en-4-yl)acrylamide: ½a D25
ꢁ
+9.3 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d 6.27–6.41 (m, 1H), 6.04–6.20 (m, 1H), 5.66–5.92 (m, 2H),
5.60 (d, J = 8.3 Hz, 1H), 5.09–5.20 (m, 2H), 4.29–4.44 (m, 1H), 3.49–3.61 (m,
1H), 2.22–2.41 (m, 2H), 1.23–1.64 (m, 5H), 0.89 (t, J = 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 166.5, 134.0, 130.2, 126.9, 117.9, 67.0, 46.0, 42.9, 39.1, 30.0,
esis using Grubb’s-I catalyst (5 mol%) in DCM to furnish a,b-unsat-
urated-d-lactam 9 in 98% yield.10 Reduction of olefin in compound
9 using palladium on carbon in methanol gave d-lactam 10 in 93%
yield. Deprotection of silyl ether 10 using TBAF in THF gave the
desilylated d-lactam 11 in 95% yield. Finally, the reduction of d-lac-
tam 11 with LiAlH4 in refluxing diethyl ether gave the target mol-
ecule, (+)-8-ethylnorlobelol (1) in 83% yield. The data of synthetic
(+)-8-ethylnorlobelol were in good agreement with the data re-
ported in the literature.11
20.9, 10.0; IR (KBr)
m3319, 3077, 2967, 1655, 1540, 1439, 1321, 1147, 987,
764 cmꢂ1; HRMS (m/z) calcd for C11H20NO2 198.1494, found: 198.1503.
N-((4S,6S)-6-((tert-Butyldimethylsilyl)oxy)oct-1-en-4-yl)acrylamide: ½ ꢁ +20.6
a 2D5
(c 0.4, CHCl3); 1H NMR (300 MHz, CDCl3): d 6.17–6.30 (m, 1H), 5.94–6.13 (m,
2H), 5.66–5.87 (m, 1H), 5.55–5.61 (m, 1H), 4.99–5.13 (m, 2H), 4.01–4.14 (m,
1H), 3.76–3.88 (m, 1H), 2.21–2.47 (m, 2H), 1.56–1.73 (m, 2H), 1.45–1.50 (m,
3H), 0.93 (s, 9H), 0.86 (t, J = 7.5 Hz, 3H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 164.9, 134.4, 131.1, 125.7, 117.5, 70.2, 46.7, 39.0, 20.8, 10.1,
ꢂ4.4, ꢂ4.5; IR (KBr)
m
;
3276, 3074, 2956, 1657, 1626, 1547, 1465, 1254, 1072,
HRMS (m/z) calcd for C17H34NO2Si 312.2358, found:
911, 773, 665 cmꢂ1
312.2363.
In conclusion, an efficient approach has been developed for the
total synthesis of piperidine alkaloid, (+)-8-ethylnorlobelol (1) in a
(R)-6-((S)-2-((tert-Butyldimethylsilyl)oxy)butyl)-5,6-dihydropyridin-2-(1H)-one:

4962
B. V. Subba Reddy et al. / Tetrahedron Letters 54 (2013) 4960–4962
½
a 2D5
ꢁ
+50.0 (c 0.25, CHCl3); 1H NMR (300 MHz, CDCl3): d 6.45–6.58 (m, 1H), 5.86
(+)-8-Ethylnorlobelol-I: ½a D25
ꢁ
+29.3 (c 0. 5, EtOH); 1H NMR (300 MHz, CDCl3): d
3.76–3.90 (m, 1H), 2.85–3.07 (m, 4H), 2.43–2.60 (m, 1H), 1.79–1.81 (m, 1H),
(d, J = 9.8 Hz, 1H), 3.75–3.90 (m, 2H), 2.05–2.34 (m, 2H), 1.68–1.85 (m, 1H),
1.46–1.66 (m, 2H), 1.22–1.39 (m, 2H), 0.92 (s, 9H), 0.87 (t, J = 7.5 Hz, 3H), 0.04–
0.11 (m, 6H); 13C NMR (75 MHz, CDCl3): d 165.8, 140.8, 124.7, 70.2, 47.7, 40.5,
1.32–1.65 (m, 9H), 0.91 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 70.5,
54.7, 41.7, 31.4, 30.7, 26.4, 25.2, 10.9; IR (KBr)
m
3270, 2928, 2864, 1560, 1408,
38.2, 31.0, 22.7, 10.0, ꢂ4.7, ꢂ4.6; IR (KBr)
m3450, 3227, 2931, 2857, 1679, 1464,
1263, 1013, 769 cmꢂ1
157.1568.
; HRMS (m/z) calcd for C9H19NO 157.1593, found:
1424, 1366, 1102, 829, 769 cmꢂ1; HRMS (m/z) calcd for C15H30NO2Si 284.2045,
found: 284.2046.