Stereoselective Synthesis of ( + )-α-Conhydrine from R-( + )-Glyceraldehyde

Exploiting natural products to ascertain a lead has always been important technique in drug discovery. Nature provides a rich source of bioactive compounds with significant biological activity and has therefore received considerable attention from the synthetic organic communities.Themajor class of biologically active molecules containing substituted piperidines has been widely present in the nature. The efforts to find a short and high yielding synthetic route for this class of natural productswere always a contemporary interest. Some of the hydroxylated piperidine alkaloids are reported to be highly toxic and have drawn significant attention through their biological activity [1–3]. Conhydrine is one of the classes of alkaloids which were isolated by Wertheim from the poisonous plant, Conium maculatum L [4], in 1856. A highly fatal toxin causing paralysis of the skeletal musculature, 2-(1-hydroxyalkyl)piperidine is a recurrent unit in many alkaloids such as Homopumiliotoxin 223 G 2, Slaframine 3, and Castanospermine 4 (Figure 1). Since the pioneering studies on the synthesis of (+)-α-Conhydrine 1 by Galinovasky and Mulley [5], various methods have been reported normally based on auxiliary supported or chiral pool approach [6–18]. In view of the interesting biological and structural properties, especially the nitrogen containing alkaloidsmakes (+)α-Conhydrine 1 as an attractive and challenging synthetic target. Asmentioned above (+)-α-Conhydrine 1was synthesized from various synthetic routes which involve a large number of steps to obtain the target molecule. Thus development of new methods for the synthesis of (+)-α-Conhydrine 1 constitutes an area of current interest. Herein, an efficient synthesis of (+)-α-Conhydrine 1 has been designed starting from 2,3-isopropylidene-R-(+)-Glyceraldehyde, by means of Zn-mediated stereoselective Barbier allylation as a key step, which was developed previously for the synthesis of different natural products in our laboratory [19–22]. To the best of our knowledge synthesis of (+)-α-Conhydrine via aza-Barbier zinc allylation was not reported so far.


Introduction
Exploiting natural products to ascertain a lead has always been important technique in drug discovery.Nature provides a rich source of bioactive compounds with significant biological activity and has therefore received considerable attention from the synthetic organic communities.The major class of biologically active molecules containing substituted piperidines has been widely present in the nature.The efforts to find a short and high yielding synthetic route for this class of natural products were always a contemporary interest.Some of the hydroxylated piperidine alkaloids are reported to be highly toxic and have drawn significant attention through their biological activity [1][2][3].
In view of the interesting biological and structural properties, especially the nitrogen containing alkaloids makes (+)--Conhydrine 1 as an attractive and challenging synthetic target.As mentioned above (+)--Conhydrine 1 was synthesized from various synthetic routes which involve a large number of steps to obtain the target molecule.Thus development of new methods for the synthesis of (+)--Conhydrine 1 constitutes an area of current interest.Herein, an efficient synthesis of (+)--Conhydrine 1 has been designed starting from 2,3-isopropylidene-R-(+)-Glyceraldehyde, by means of Zn-mediated stereoselective Barbier allylation as a key step, which was developed previously for the synthesis of different natural products in our laboratory [19][20][21][22].To the best of our knowledge synthesis of (+)--Conhydrine via aza-Barbier zinc allylation was not reported so far.

Materials and Methods
All reagents were purchased from Aldrich (Sigma-Aldrich, Bangalore, India).All reactions were monitored by TLC, performed on silica gel glass plates containing 60 F-254.Column chromatography was performed with Merck 60-120 mesh silica gel.IR spectra were recorded on a Perkin-Elmer RX-1 FT-IR system. 1 H NMR spectra were recorded on Bruker-300 MHz spectrometer;
The solution was concentrated under reduced pressure to afford desired epoxide (3.415 g, 90%).The formed epoxide was used without purification.

Results and Discussion
A retrosynthetic analysis for (+)--Conhydrine 1 based on chiron approach with diastereoselective Barbier allylic addition as the prominent strategy is pictorially presented in Scheme 1.We envisioned that the synthesis of (+)--Conhydrine could be achieved by employing stereoselective allylation and ring closing metathesis as key strategy to create this root as more feasible and simple.As illustrated in Scheme 1, we decided to prepare (+)--Conhydrine by intercepting olefinic intermediate 12 that we envisaged would be made available from ring closing metathesis of diene 11, which was successively obtained from the imine 6 by diastereoselective aza-Barbier zinc allylation.Subsequently this imine 6 could be easily attained from condensation of R-(+)-Glyceraldehyde 5 and allyl amine (Scheme 1).
The ratio of diastereomers was determined by gas chromatography.The diastereoselectivity [32][33][34] of this reaction can be explained by Felkin-Anh model (Figure 2), the carbon nucleophile preferentially approach from the less hindered side (i.e., from the side of H), thus resulting in the formation antidiastereomer predominantly.However, the syn-and antirelative configuration of stereogenic centre was unambiguously established based on 1 H NMR, in which proton at newly formed stereocentre of anti-isomer 7a appeared at  2.70 (q, J = 5.9 Hz, 1H) whereas syn-isomer 7b is at  2.62 (q, J = 6.5 Hz, 1H).These values were in good agreement with earlier reports [34].
The major diastereomer 7a upon treatment with Bocanhydride and TEA in DCM using catalytic amount of DMAP at 0 ∘ C to rt produced carbamate 8 with 79% yield.The acetonide deprotection of carbamate 8 wasachieved successfully by using catalytic amount of PTSA in methanol at room temperature for 12 h which gave desired diol 9 in 88% yield.The primary hydroxyl group of glycol 9 was regioselectively monotosylated [35][36][37] by using TsCl and Et 3 N in the presence of dibutyltinoxide at 0 ∘ C to rt in DCM to afford sulfonate 10 in 64% yield.Sulfonate 10 was treated with K 2 CO 3 followed by methyl magnesium iodide in dry THF at 0 ∘ C which affords dienol 11 via the formation of epoxide and regioselective ring opening; formation of epoxide was confirmed by its FT-IR spectrum which showed disappearance of absorption band at 3375 cm −1 (-OH stretching).Upon ring-closing metathesis [38][39][40] of dienol 11 in the presence of Grubb's 1st generation catalyst (5 mol %) in CH 2 Cl 2 at room temperature delivered tetrahydropyridine 12 in 89% yield.Catalytic hydrogenation of tetrahydropyridine 12 in presence of 10% Pd/C in MeOH at room temperature afforded piperidine 13 with 90% yield.Boc-deprotection of piperidine 13 with TFA in DCM accomplished desired compound 1 (Scheme 3).The physical and spectroscopic data of title compound 1 were in excellent agreement with the earlier report.

Conclusions
In conclusion, we achieved a stereoselective total synthesis of (+)--Conhydrine from a common carbohydrate precursor, (R)-2,3-isopropylidene glyceraldehyde.The prominent steps involved are zinc mediated Aza-Barbier allylation and construction of piperidine ring by RCM.Further investigations towards other 2-(-hydroxyl alkyl) piperidine analogues and indolizidines by introduction of various alkenyl substituents in the Barbier allylation are in progress.