Stereoselective synthesis of 2-(2-hydroxyalkyl)piperidine alkaloids through prins-ritter reaction

Article abstract of DOI:10.1080/00397911.2013.869603

A stereoselective total synthesis of the 2-(2-hydroxyalkyl)piperidine alkaloids has been accomplished by a Prins-Ritter amidation sequence. Other steps involved in this synthesis are Jacobsen's hydrolytic kinetic resolution (HRK) and ring-closing metathes

Full text of DOI:10.1080/00397911.2013.869603

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Stereoselective Synthesis of 2-(2-
Hydroxyalkyl)piperidine Alkaloids
Through Prins–Ritter Reaction
B. V. Subba Reddy a , Supriya Ghanty a b , N. Siva Senkar Reddy a , Y.
Jayasudhan Reddy a & J. S. Yadav a
a Natural Product Chemistry, CSIR–Indian Institute of Chemical
Technology , Hyderabad , India
b Associate Institution of University of Hyderabad , Hyderabad ,
India
Accepted author version posted online: 10 Feb 2014.Published
online: 14 May 2014.
To cite this article: B. V. Subba Reddy , Supriya Ghanty , N. Siva Senkar Reddy , Y. Jayasudhan Reddy
& J. S. Yadav (2014) Stereoselective Synthesis of 2-(2-Hydroxyalkyl)piperidine Alkaloids Through
Prins–Ritter Reaction, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 44:11, 1658-1663, DOI: 10.1080/00397911.2013.869603
To link to this article: http://dx.doi.org/10.1080/00397911.2013.869603
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Synthetic Communications1, 44: 1658–1663, 2014
Copyright # Indian Institute of Chemical Technology
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.869603
STEREOSELECTIVE SYNTHESIS OF
2-(2-HYDROXYALKYL)PIPERIDINE ALKALOIDS
THROUGH PRINS–RITTER REACTION
B. V. Subba Reddy,1 Supriya Ghanty,1,2
N. Siva Senkar Reddy,1 Y. Jayasudhan Reddy,1 and
J. S. Yadav1
1Natural Product Chemistry, CSIR–Indian Institute of Chemical Technology,
Hyderabad, India
2Associate Institution of University of Hyderabad, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A stereoselective total synthesis of the 2-(2-hydroxyalkyl)piperidine alkaloids has
been accomplished by a Prins–Ritter amidation sequence. Other steps involved in this
synthesis are Jacobsen’s hydrolytic kinetic resolution (HRK) and ring-closing metathesis
(RCM).
Keywords anti-1,3-aminoalcohol; 2-(2-hydroxyalkyl)piperidine alkaloids; Prins–Ritter
amidation; ring-closing metathesis (RCM)
INTRODUCTION
Piperidine alkaloids are widely distributed in nature and found to display a
broad spectrum of biological activities.[1] In particular 2-substituted piperidine alka-
loids (Fig. 1) have attracted considerable attention because of their potent biological
activities such as memory-enhancing properties. They can also be used in the treat-
ment of cognitive disorder.[2] Beyerman’s and Schopf’s groups have independently
isolated (ꢀ)-sedridine (1a), an alkaloid consisting of a piperidine core from Sedum
acre, which is a perennial plant native to Europe, and they have also determined
its absolute configuration.[3] Consequently, several synthetic approaches have been
developed for the synthesis of these alkaloids because of their scarcity from natural
sources.[4]
Received September 30, 2013.
Address correspondence to B. V. Subba Reddy, Natural Product Chemistry, CSIR–Indian Institute
of Chemical Technology, Hyderabad 500 607, India. E-mail: basireddy@iict.res.in
1658

SYNTHESIS OF 2-(2-HYDROXYALKYL)PIPERIDINES
1659
Figure 1. Representative examples of biologically active 2-substituted piperidine alkaloids.
DISCUSSION
In continuation of our work on Prins cyclization and its utilization in the total
synthesis of natural products,[5] we herein report an elegant approach for the syn-
thesis of (ꢀ)-sedridine via a Prins–Ritter amidation sequence. As per our retrosyn-
thetic analysis for the synthesis of 2-(2-hydroxy)piperidine alkaloids, (ꢀ)-sedridine
1a (R ¼ Me) could be synthesized from the intermediate 7, which in turn could easily
be prepared through Prins–Ritter amidation followed by reductive opening of the
2-iodomethyl-4-amidotetrahydropyran 6 (Scheme 1).
Accordingly, we commenced the synthesis of (ꢀ)-serdidine (1a) from the chiral
homoallylic alcohol 3. As shown in Scheme 2, the chiral (R)-homoallylicdiol 3 was
prepared from the corresponding epoxide following Jacobsen’s hydrokinetic resol-
ution (HKR).[6] Chemoselective tosylation of the primary alcohol of 3 with TsCl
Scheme 1. Retrosynthetic analysis of total synthesis of 2-(2-hydroxyalkyl)piperidine alkaloids.

1660
B. V. SUBBA REDDY ET AL.
Scheme 2. Total synthesis of (ꢀ)-sedridine 1a and (ꢀ)-halosaline 1b. Reagents and conditions: (i) Et3N,
dibutyltin oxide, TsCl, CH2Cl2, rt, 1 h; (ii) acetaldehyde (for 1a) or butyraldehyde (for 1b), acrylonitrile,
BF3 ꢁ OEt2 (10 mol%), rt, 2 h; (iii) NaI, acetone, reflux, 24 h; (iv) Zn dust, EtOH, reflux, 8 h; (v) TBSCl,
imidazole, DMAP (catalytic), CH2Cl2, 1 h; (vi) Grubb’s I (10 mol%), CH2Cl2, rt, 12 h; (vii) Pd=C, MeOH,
Et3N, H2 (1 atm); (viii) TBAF, THF, rt, 5 h; (ix) LiAlH4, Et2O, reflux, 2 h.
in the presence of dibutyltin oxide and Et3N gave the homoallylic alcohol 4 in 98%
yield.[7] Three-component, one-pot coupling of homoallyl alcohol 4 with acetal-
dehyde and acrylonitrile in the presence of 10 mol% BF3. Et2O under Prins–Ritter
reaction conditions gave the 4-amidotetrahydropyran 5 in 54% yield with high
diastereoselectivity. The relative configuration of 5 was confirmed by nuclear
Overhauser effect (NOE) experiments in which all the substituents exist in equatorial
position.[8] After establishing the structure, the tosylate 5 was converted into the cor-
responding iodomethyl tetrahydropyran 6 in 90% yield using NaI in acetone under
reflux conditions. Reductive ring opening of 6 with Zn dust in refluxing EtOH gave
the corresponding anti-1,3-amino alcohol 7 in 90% yield, which is a key intermediate
for the synthesis of (ꢀ)-sedridine. This strategy has been successfully applied for the
synthesis of (ꢀ)-halosaline using n-butaraldehyde instead of acetaldehyde.[9] After
establishing the structure of compound 7, the free hydroxyl group was protected
as its tert-butyldimethylsilyl (TBS) ether 8 using TBSCl in the presence of imidazole
in 95% yield. Ring-closing metathesis of 8 using Grubb’s I catalyst in dichloro-
methane gave the a,b-unsaturated-d-lactam 9 in 90% yield.[10] Reduction of 9 using
Pd=C in methanol gave the d-lactam 10 in 90% yield. Removal of the silyl ether of 10
using tetra butylammonium flouride (TBAF) in tetrahydrafuran (THF) gave the
desilylated d-lactam 11 in 95% yield. Finally, the reduction of 11 with LiAlH4 in
Et2O gave the target molecule (ꢀ)-sedridine (1) in 76% yield. The physical character-
istics of the synthetic molecule were in good agreement with the data reported for the
natural product in literature.[11]
Similarly, other 2-(2-hydroxy)piperidine alkaloids such as (þ)-8-ethylnorlobe-
lol 1c and (þ)-norallosedamine 1d have also been synthesized starting from antipode
precursor of 3 as chiral (S)-homoallyl alcohol (Scheme 3).[6,9]

SYNTHESIS OF 2-(2-HYDROXYALKYL)PIPERIDINES
1661
Scheme 3. Total synthesis of (þ)-8-ethylnorlobelol 1c and (þ)-norallosedamine 1d. Reagents and
conditions: (i) Et3N, dibutyltin oxide, TsCl, CH2Cl2, rt, 1 h; (ii) propionaldehyde (for 1c) or benzaldehyde
(for 1d), acrylonitrile, BF3 ꢁ OEt2 (10 mol%), rt, 2 h; (iii) NaI, acetone, reflux, 24 h; (iv) Zn dust, EtOH,
reflux, 8 h; (v) TBSCl, imidazole, DMAP (catalytic), CH2Cl2, 1 h; (vi) Grubb’s I (10 mol%), CH2Cl2, rt,
12 h; (vii) Pd=C, MeOH, Et3N, H2 (1 atm); (viii) TBAF, THF, rt, 5 h; (ix) LiAlH4, Et2O, reflux, 2 h.
CONCLUSION
In summary, a simple and efficient approach has been developed for the total
synthesis of the 2-(2-hydroxyalkyl)piperidine alkaloids, (ꢀ)-sedridine (1a), (ꢀ)-
halosaline (1b), (þ)-8-ethylnorlobelol (1c), and (þ)-norallosedamine (1d) in a highly
stereoselective manner. Our approach involves mainly the use of Prins–Ritter amida-
tion reaction followed by reductive ring-opening sequence.
FUNDING
S. G. thanks CSIR, New Delhi; N. S. S. R. thanks IICT–Hyderabad, and Y. J.
S. R. thanks UGC, New Delhi, for the award of fellowships.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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