A novel, concise and efficient protocol for non-natural piperidine compounds

Article abstract of DOI:10.1039/c4ra04558k

Formal synthesis of l-altro-1-deoxynojirimycin, cis-3-hydroxypipecolic acid along with synthesis of (R)-piperidinol and a conceptually different advanced intermediate for non-natural piperidine alkaloids is reported from cis-butene-1,4-diol. The key react

Full text of DOI:10.1039/c4ra04558k

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A novel, concise and efficient protocol for non-
natural piperidine compounds†
Cite this: RSC Adv., 2014, 4, 32594
*
Subhash P. Chavan, Nilesh B. Dumare and Kailash P. Pawar
Received 15th May 2014
Accepted 17th July 2014
DOI: 10.1039/c4ra04558k
www.rsc.org/advances
Formal synthesis of L-altro-1-deoxynojirimycin, cis-3-hydroxy- activity towards mammalian a-glucosidase and b-galactosidase
pipecolic acid along with synthesis of (R)-piperidinol and a concep- enzymes.2 Most of the synthetic efforts have been devoted
tually different advanced intermediate for non-natural piperidine towards the synthesis of D-fagomine 1 (Fig. 1) and its isomers
alkaloids is reported from cis-butene-1,4-diol. The key reactions which possess D conguration. Relatively there has been less
involved are Johnson–Claisen rearrangement, Sharpless asymmetric attention paid towards the synthesis L- congured fagomine 2
dihydroxylation, reductive lactamization and novel regioselective (Fig. 1) and its isomers. Recently, there is report on synthesis of
elimination.
L-fagomine (ref. 3 and 4) and its isomers. In literature,5 there are
various protocols used for synthesis of fagomine 1 (Fig. 1) and
its isomers. (S)-Pipecolic acid 3 (ref. 6) (Fig. 1) is a natural
product and forms an important structural core for many
alkaloids7 and bicyclic alkaloids.8
Literature survey revealed that L-isomer of deoxynojirimycin
(DNJ) also possesses inhibitory activity against various glyco-
sidases.9a L-1-Deoxyallonojirimycin (L-allo-1-DNJ) 4 has been
reported to have more inhibitor activity against a-mannosidase
than the D-manno-DNJ 5 (Fig. 1). Based on the protocol reported
by our group towards the asymmetric synthesis of piperidine
alkaloids15a we wish to report the utility of key synthon 16 for the
synthesis of polyhydroxypiperidine alkaloids viz. L-fagomine
2, its isomers, L-allo-1-DNJ 4,9 L-galacto-1-deoxynojirimycin
(L-galacto-1-DNJ) 6 (ref. 10) and L-altro-1-deoxynojirimycin
(L-altro-1-DNJ) 7.11,19
Naturally and non-naturally occurring polyhydroxy compounds
containing a piperidine core have shown promising biological
activity, specically as glycosidase inhibitors, anticancer
agents and antiviral agents.1 D-Fagomine (Fig. 1) has inhibitory
A retrosynthetic analysis of 8 is outlined in Scheme 1.
Unsaturated piperidine framework 8 can be obtained from
hydroxy compound 9 which in turn could be prepared from the
Fig. 1 Piperidine alkaloids.
CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune-411008,
Maharashtra, India. E-mail: sp.chavan@ncl.res.in
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra04558k
Scheme
1 Retrosynthetic analysis of (R)-tert-butyl-2-hydroxy-
methyl)-5,6-dihydropyridine-1(2H)-carboxylate.
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lactam 10. Lactam 10 could be easily generated from azido- isomer16 19 by oxidation of 9 to afford 18 (Scheme 3), followed
lactone 11 via reductive lactamisation. Azidolactone 11 could be by reduction with sodium borohydride. Alcohol 19 was sub-
obtained from hydroxy lactone 12. Hydroxy lactone 12 in turn jected to the treatment with triphenyl phosphine, imidazole
can be accessed from cis-butene-1,4-diol 13.
and iodine to provide two regioisomeric olens 16 and 20
Accordingly, asymmetric synthesis of piperidine core 8 (1.5 : 1) in 60% yield. This clearly demonstrated that the
started from achiral cheap starting material viz. cis-2-butene- stereochemistry of hydroxyl group has a profound effect on the
1,4-diol (Scheme 2). cis-Butene-1,4-diol was rearranged to outcome of product formation. The high distereoselectivity in
unsaturated ester 14 according to the procedure described in the reduction of carbonyl 18 to cis alcohol 19 can be predicted
the literature.12,13 Unsaturated ester 14 was subjected to Sharp- according to Felkin's torsional strain model which favours the
less asymmetric dihydroxylation reaction14 to furnish enantio- axial attack of hydride. This is in good agreement with the
merically enriched15b hydroxy lactone 12. Hydroxy lactone 12 observation made by Zhu and coworkers where they observed
was converted into corresponding mesylate 15 by using TEA and similar results.16 In alcohol 19 hydroxyl group is in axial posi-
methanesulphonyl chloride in 91% yield. The resultant mesy- tion and there are two protons present anti to hydroxyl group at
late 15 was subjected to SN2 displacement with sodium azide in C1 and C3 in piperidine ring (Scheme 4). This stereochemistry
DMF at 80 ꢀC to furnish azidolactone 11 in 87% yield. Reductive allows elimination from both the sides, where as In case of
lactamisation on 11 was carried out by using Pd(OH)2 under H2 compound 9 only C3 proton is anti to the hydroxyl group and
atmosphere at 30 psi to afford lactam 10. Lactam 10, without this allows elimination from this side only (Scheme 5). Hence,
purication, was reduced using LAH in THF to give amine single elimination product 16 is observed.
which without purication was treated with (Boc)2O to provide
carbamate 9 in 63% yield (over two steps).
O-Debenzylation of 16 was carried out by using sodium metal
in anhydrous THF in liquid ammonia to afford homoallylic
Earlier we have reported the synthesis of other enantiomer of alcohol 8 in 88% yield. It is pertinent to mention that homo-
compound 9.15a Conversion of alcohol 9 into the corresponding allylic alcohol3b 8 is an important precursor for the total
iodide was attempted using triphenyl phosphine and iodine in synthesis of L-fagomine 2 and its congeners. The olen 8 was
the presence of imidazole as the base but surprisingly, it fur-
nished olen 16 (ref. 21) as the only product in excellent yield
(Scheme 2). We did not observe its regioisomer.
In order to study the effect of stereochemistry of hydroxyl
group on the outcome of the reaction, we synthesized cis
Scheme 3 Reagents and conditions: (a) IBX, EtOAc, reflux, 3 h, 95%;
(b) NaBH4, MeOH, 0 ꢀC, 30 min, 88% and (c) PPh3, imidazole, I2,
toluene, reflux, 30 min, 60%.
Scheme 2 Reagents and conditions: (a) ref. 12 and 13; (b) K3Fe(CN)6,
K2CO3, (DHQD)2PHAL, OsO4, MeSO2NH2, t-BuOH : H2O (1 : 1), 0 ꢀC,
24 h, 94%; (c) MsCl, Et3N, DMAP (cat.), DCM, 5 h, 91%; (d) NaN3, DMF,
80 ꢀC, 18 h, 87%; (e) Pd(OH)2, H2, MeOH, 30 psi, rt, 3 h, 93%; (f) (i) LAH,
THF, 0 ꢀC to rt, 3 h; (ii) (Boc)2O, TEA, DMAP (cat.), THF rt, overnight,
63% (over two steps); (g) PPh3, imidazole, I2, toluene, 120 ꢀC, 30 min,
85%; (h) Na (metal), THF, ammonia, ꢁ78 ꢀC, 10 min, 88% and (i) Pd/C,
H2, MeOH, 50 psi, 92%.
Scheme 4 Formation of compounds 19–21.
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Scheme 5 Exclusively formation of compound 16.
reduced by using Pd/C as the catalyst in methanol under H2
atmosphere at 50 psi to afford hydroxymethyl piperidine core 17
which is an important precursor for the construction of bicyclic,
substituted piperidine alkaloids7,8 and (R)-pipecolic acid.
Following the same reaction sequence, racemic compound 17
was synthesized. There was no epimerization either during
elimination or reduction of the olen which was conrmed by
chiral HPLC (ee > 97%),17 and specic rotation (Scheme 6).
To extend application of advanced intermediate 16, olen
compound 16 was subjected to allylic oxidation18 by using
selenium dioxide in 1,4-dioxane under reux condition to
provide alcohol 21 in 35% yield (Scheme 4). Interestingly, this
oxidation took place in regiospecic and stereoselective
manner. We did not observe the formation of other diaste-
reomer 23. This may be attributed to the distorted chair
conformation of compound 16. The oxidation by SeO2 is fav-
oured from less hindered side as depicted, which leads to the
formation of alcohol 21 as the only observable product.
(Scheme 7). Alcohol 21 was protected as its silyl ether by using
imidazole, TBDPSCl in DCM at room temperature to furnish
compound 22. Since the intermediate ent-22 (ref. 19) was earlier
Scheme 7 Stereospecific formation of allyl alcohol 21.
converted to D-allo-1-DNJ 4 and D-galacto-1-DNJ 6, hence the
present work constitutes formal syntheses of L-allo-1-DNJ 4 and
L-galacto-1-DNJ 6. Oxidation of allylic alcohol 21 was performed
by using IBX in ethyl acetate under reux conditions to give
enone 24 in 90% yield. Enone 24 was reduced under Luche's
reaction condition by using sodium borohydride in presence of
CeCl3 7H2O in methanol at 0 ꢀC to provide b-allylic alcohol 23 in
80% yield. Alcohol 23 was protected as its TBDPS ether and was
subjected to ash dihydroxylation20 to furnish 25 in 54% yield
(over two steps) as a single diastereomer. Since, compound 25
has been elaborated to L-altro-1-DNJ, this constitutes a formal
synthesis of L-altro-1-DNJ.19 It is pertinent to note that synthesis
of compound 19 also constitutes formal synthesis of cis-3-
hydroxypipecolic acid.21 Spectral data of the compounds 25 and
19 were in good agreement with those reported in literature.19,22
Conclusion
We have accomplished the syntheses of various compounds
containing piperidine core from a common precursor by
employing Sharpless asymmetric dihydroxylation, reductive
lactamization, novel regioselective elimination, regiospecic,
stereospecic allylic oxidation, stereoselective reduction and
stereoselective dihydroxylation as the key steps.
Since our method is exible, one can access the corre-
sponding enantiomers by switching the chiral ligands during
asymmetric dihydroxylation.
Acknowledgements
NBD and KPP thank CSIR, New Delhi, India, for fellowship. The
authors thank Dr H. B. Borate for his helpful discussion and
CSIR, New Delhi for nancial support as part of XIIth Five Year
plan programme under title ACT (CSC-0301) and Mrs S. S. Kunte
for HPLC facility.
Notes and references
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CH3CN : EtOAc : H2O, 0 ꢀC, 54% (over two steps).
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1.55 mmol), PPh3 (1.34 g, 5.11 mmol), imidazole (0.33 g,
4.96 mmol) and I2 (0.86 g, 3.41 mmol) was stirred under
nitrogen atmosphere in anhydrous toluene (10 ml) at
110 ꢀC for 30 minutes. Aer completion of the reaction
(TLC), the reaction mixture was cooled at room
temperature and was diluted with saturated solution of
Na2S2O3 and extracted with ethyl acetate (3 ꢂ 60 ml).The
organic layer was dried over anhydrous sodium sulphate,
ltered and concentrated under reduced pressure. The
residue was puried on silica gel by eluting with light pet.
ether : EtOAc (9 : 1) to afford 16 as a colorless syrup. The
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syrup was treated with pet. ether and ltered through a
cotton bed to remove the solid impurities and this was
repeated 3–4 times to afford 16 as a colorless syrup (0.40 g,
85% yield). Compound 16: ESIMS (m/z): 326.28(Na+);
HRMS calculated for [C18H25NO3 + Na] + 326.1727; found:
326.1734; 1H NMR (200 MHz, CDCl3 + CC4): 1.45 (s, 9H),
3.47–3.61 (m, 2H), 4.15 (bs, 1H), 4.49–4.66 (m, 3H), 5.70–
5.79 (m, 1H), 5.90–5.98 (m, 1H), 7.23–7.35 (m, 5H); 13C (50
MHz, CDCl3 + CCl4): 24.9, 28.5, 71.3, 73.0, 79.5, 126.7,
127.4, 128.3, 138.3, 154.5; please see spectroscopic
properties (1H NMR data and 13C NMR spectra) of other
relevent compounds in ESI.†
1.88–2.04 (m, 1H), 2.13–2.30 (m, 1H), 2.94 (bs, 1H), 22 B. Wang and R. Liu, Eur. J. Org. Chem., 2009, 2845–2851.
32598 | RSC Adv., 2014, 4, 32594–32598
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