Stereoselective approach to 2,6-disubstituted piperidin-3-ol: Synthesis of (-)-deoxoprosopinine and (+)-deoxoprosophylline

Article abstract of DOI:10.1002/ejoc.201402363

A simple and highly efficient approach to an enantioenriched 2,6-disubstituted piperidin-3-ol skeleton is developed from an aldehyde as a starting material by using organocatalytic and asymmetric dihydroxylation as the key steps. Its application to the total synthesis of (-)-deoxoprosopinine and (+)-deoxoprosophylline is also reported.

Full text of DOI:10.1002/ejoc.201402363

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FULL PAPER
DOI: 10.1002/ejoc.201402363
Stereoselective Approach to 2,6-Disubstituted Piperidin-3-ol:
Synthesis of (–)-Deoxoprosopinine and (+)-Deoxoprosophylline
Vishwajeet Jha,[a] Shruti Vandana Kauloorkar,[a] and Pradeep Kumar*[a]
Keywords: Synthetic methods / Alkaloids / Amino alcohols / Amination / Wittig reactions
A simple and highly efficient approach to an enantioenriched
2,6-disubstituted piperidin-3-ol skeleton is developed from
an aldehyde as a starting material by using organocatalytic
and asymmetric dihydroxylation as the key steps. Its applica-
tion to the total synthesis of (–)-deoxoprosopinine and (+)-
deoxoprosophylline is also reported.
the hydrophobic tail facilitates transfer across the lipid
membrane, which enhances their therapeutic potential for
the treatment of diseases such as diabetes, viral infection
and cancer.
Introduction
Naturally occurring alkaloids that contain a multi-func-
tionalized piperidine ring system as a key constituent are
abundant in nature. Most of them exhibit potent biological
activity and are of medicinal and pharmacological inter-
est.[1] Among them, prosopis alkaloids that were isolated
from the leaves of Prosopis afrikana Taub,[2] exhibit anti-
biotic, anesthetic, analgesic and central nervous system
stimulating properties. Typical representatives include pro-
sopinine 1, prosophylline 2 and their deoxo analogues de-
oxoprosopinine 3, deoxoprosophylline 4, which all contain
a 2,6-disubstituted piperidin-3-ol framework (Figure 1).
The unique structural features of these alkaloids are known
to resemble the acyclic structure of sphingolipids such as,
safingol 5 and sphingosine 6, which contain a hydrophobic
aliphatic tail and a hydrophilic headgroup.[3] The polar
headgroup is required for glycosidase inhibition,[4] whereas
Owing to their promising biological activities and struc-
tural features, these alkaloids have received considerable
interest as synthetic targets. Various syntheses[5,6] of this
class of compounds have been reported, however the litera-
ture describing a general synthetic strategy to construct the
2,6-disubstituted piperidin-3-ols framework is sparse.[5g,5j]
Also the majority of the syntheses of deoxoprosopinine and
deoxoprosophylline employ chiral-pool starting materials
such as sugars and amino acids, which involve a large
number of steps, protection-deprotection strategies that re-
sult in lower overall yields. Therefore, it is highly desirable
to develop a concise, enantioselective and general synthetic
route that provides a common pivotal intermediate from
which piperidin-3-ol derivatives with desired stereochemical
variations can be synthesized.
In continuation of our interest in organocatalysis,[7] we
herein describe a general, stereoselective and protecting-
group-free synthetic strategy to the 2,6-disubstituted piper-
idin-3-ols framework, which has led to the total syntheses
of (–)-deoxoprosopinine 3 and (+)-deoxoprosophylline 4 by
using sequential α-amination and Horner–Wadsworth–Em-
mons (HWE) olefination reaction catalyzed by proline,[8] as
well as asymmetric dihydroxylation[9] as the key steps.
Results and Discussion
Figure 1. Examples of prosopis alkaloids (1-4) and sphingoid bases
(5 and 6).
Our synthetic approach was envisioned to be through the
retro-synthetic route shown in Scheme 1. Amino diol 7 was
thought to be a common intermediate for the synthesis of
compounds 3 and 4, which could be synthesized from
alcohol 8. Alcohol 8 could in turn be obtained from sequen-
tial α-amination and HWE olefination followed by re-
duction of aldehyde 9.
[a] Division of Organic Chemistry, CSIR – National Chemical
Laboratory,
Pune 411008, India
E-mail: pk.tripathi@ncl.res.in
http://newhome.ncl.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402363.
Eur. J. Org. Chem. 0000, 0–0
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V. Jha, S. V. Kauloorkar, P. Kumar
FULL PAPER
formation of cis-olefin 12, the reaction was carried out in
toluene under reflux conditions to provide trans-olefin 11
in 70% yield with a small amount of cis-olefin 12. All three
products were easily separated by using silica-gel column
chromatography (Scheme 2).
Table 1. Optimization of Wittig reaction conditions.
Entry
Wittig
reagent
Base
Solvent
11
[%]
12
[%]
13
[%]
1
2
3
4
HWE[a] NaH
THF
CH3CN
17
32
34
54
75
60
57
14
HWE
HWE
2-C
DBU
Cs2CO3 CH3CN
–
–
THF
26
7
Wittig[b]
2-C
5
Toluene
(reflux)
70
16
Wittig
Scheme 1. Retrosynthetic route to the synthesis of 2,6-disubstituted
piperidin-3-ols framework.
[a] HWE: triethyl phosphonoacetate. [b] 2-C Wittig: (ethoxy-
carbonylmethylene)triphenylphophorane.
As illustrated in Scheme 2, the synthesis starts with myri-
styl aldehyde 9, which on sequential α-amination with
DBAD (dibenzyl azodicarboxylate) as a nitrogen source, d-
proline as the catalyst, CH2Cl2 as the solvent and subse-
quent HWE olefination with the ylide generated from tri-
ethyl phosphonoacetate[10a,10b] furnished γ-amino α,β-un-
saturated ester 10 in 82% yield and 94% ee.[11] With γ-
amino α,β-unsaturated ester 10 in hand, we next reduced
the ester group. For this purpose ester 10 was treated with
LiBH4, with concomitant reduction of the double bond[7c]
Surprisingly, compound 13 was reduced with LiBH4 to
reform starting alcohol 8 (Scheme 3).
Scheme 3. Reduction of cyclized product 13.
With desired trans-olefin 11 in hand, the stage was set to
to give alcohol 8 in 95% yield. To prepare trans-olefin 11, functionalize the double bond. For this purpose, olefin 11
alcohol 8 was oxidized with Dess–Martin periodinane was subjected to Sharpless asymmetric dihydroxylation[9]
(DMP)[12] to furnish the aldehyde, which was then subjected reaction conditions with (DHQD)2PHAL as a ligand to
to HWE olefination (ylide generated from triethyl phos- give diol 7a in 95% yield and 92:8 dr ratio. Regioselective
phonoacetate with NaH as a base), but to our disappoint- monotosylation[13] of diol 7a with tosyl chloride (TsCl) re-
ment we obtained hemiaminal 13 as the major product with sulted in the α-tosylate that upon concomitant cleavage of
desired trans-olefin 11 in only 18% yield. The formation of the N–N bond with Raney-Ni gave the free amine, which
13 was confirmed by using NMR spectroscopy and HRMS. on nucleophilic displacement of the α-tosylate led to the
We then tried various other conditions to increase the yield formation of cyclized product 14 in 73% yield. Finally, re-
of the trans-olefin and the results are summarized in duction of 14 with LiBH4 produced (–)-deoxoprosopinine 3
Table 1. There was no substantial increase in yield when in 96% yield (Scheme 4).
different bases [such as 1,8-diazabicycloundec-7-ene (DBU),
In a similar way, as illustrated in Scheme 5, (+)-deoxo-
Cs2CO3 and so on] were used to generate the ylide from prosophylline (4) was synthesized by using (DHQ)2PHAL
triethyl phosphonoacetate. When (ethoxycarbonylmethyl- as a ligand in the Sharpless asymmetric dihydroxylation re-
ene)triphenyl phosphorane[10c] was used as the Wittig rea- action step by following a series of reactions analogous to
gent in THF solvent, we obtained trans-olefin 11 in 54% those shown in Scheme 4.
yield along with cis-olefin 12 in 26% yield, and cyclized
We have successfully completed the total synthesis of
product 13 in 14% yield (Table 1, Entry 4). To reduce the (–)-deoxoprosopinine 3 in approximately 33% overall yield
Scheme 2. Synthesis of trans-olefin 11.
2
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Stereoselective Approach to 2,6-Disubstituted Piperidin-3-ol
Fine Chemical Co. India or Spectrochem India. Standard syringe
and cannula techniques were used to transfer air- and moisture-
sensitive reagents.
IR spectra were recorded with a Perkin–Elmer infrared spectrome-
ter model 599-B and model 1620 FT-IR. 1H NMR spectra were
recorded with Bruker AC-200, Bruker AV-400, Jeol-400 and Bruker
DRX – 500 instruments and deuterated solvent. Proton coupling
constants are reported with multiplicity (br., broadened; s, singlet;
d, doublet; t, triplet; m, multiplet). 13C NMR spectra were recorded
with Bruker AC-200, Bruker AV-400, Jeol-400 and Bruker DRX-
500 instruments operating at 50 MHz, 100 MHz, and 125 MHz,
respectively. 13C NMR chemical shifts are reported relative to the
central line of CDCl3 (δ = 77.0 ppm). All HPLC analyses used to
determine enantiomeric purity were calibrated with a sample of the
racemate.
Scheme 4. Synthesis of (–)-deoxoprosopinine.
Dibenzyl (R,E)-1-(1-Ethoxy-1-oxohexadec-2-en-4-yl)hydrazine-1,2-
dicarboxylate (10): To a cooled solution of DBAD (0.588 g,
1.97 mmol) and d-proline (0.028 g, 10 mol-%) in CH2Cl2 (30 mL)
at 0 °C was added aldehyde 9 (0.5 g, 2.4 mmol) and the mixture
was stirred for 24 h at 0 °C and further for 6 h at 10 °C. This was
followed by addition of lithium chloride (0.125 g, 2.95 mmol), tri-
ethyl phosphonoacetate (0.7 mL, 2.95 mmol) and DBU (0.3 mL,
1.97 mmol) in that sequence and the mixture was stirred at 5 °C
for 45 min. The reaction was then quenched with aq. ammonium
chloride solution (15 mL) and extracted with ethyl acetate (3ϫ
15 mL). The combined organic layers were washed with brine, dried
Scheme 5. Synthesis of (+)-deoxoprosophylline.
and (+)-deoxoprosophylline (4) in approximately 35% over-
all yield from commercially available myristyl aldehyde in
eight steps. The physical and spectroscopic data of com-
pounds 3 and 4 are in good agreement with the reported with anhyd. Na2SO4 and concentrated under reduced pressure. Sil-
data. [For (–)-deoxoprosopinine 3, m.p. 90 °C, {ref.[5e] 89.5–
ica gel column chromatography (petroleum ether/ethyl acetate, 9:1)
90 °C}, [α]D25 = –15.8 (c = 0.30, CHCl3), {ref.[5e] [α]D25 = –14.7
of the crude product gave compound 10 (enantiomeric excess 94%)
as a colorless solid (1.121 g, 82%); m.p. 46–48 °C. [α]2D5 = –6.26 (c
(c = 0.30, CHCl3)}, and for (+)-deoxoprosophylline 4, m.p.
= 1.5, CHCl ). IR (CHCl ): ν = 3294, 2981, 1717, 1498,
˜
max
84 °C, {ref.[6h] 85–86 °C}, [α]D25 = +13.9 (c = 0.22, CHCl3),
{ref.[6h] +12.50 (c 0.22, CHCl3)}.
3
3
1
1219 cm–1. H NMR (200 MHz, CDCl3): δ = 0.88 (t, J = 6.7 Hz,
3 H), 1.25 (m, 23 H), 1.64–1.69 (m, 2 H), 4.18 (q, J = 7.1 Hz, 2
H), 4.68–4.75 (m, 1 H), 5.05–5.22 (m, 4 H), 5.90 (d, J = 15.6 Hz,
1 H), 6.39 (s, 1 H), 6.85 (dd, J = 6.9, 15.8 Hz, 1 H), 7.26–7.38 (m,
10 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 14.0, 14.1, 22.6, 25.9,
29.3, 29.4, 29.6, 30.9, 31.9, 58.9, 60.5, 67.8, 68.3, 122.9, 127.9,
128.1, 128.2, 128.3, 128.5, 135.6, 144.9, 155.6, 156.7, 166.2 ppm.
MS (ESI): m/z = 603.42 [M + Na]+. HRMS: calcd. for C34H48N2O6
[M + H]+ 581.3585; found 581.3586. calcd. for C34H48N2O6 [M +
Na]+ 603.3405; found 603.3405.
Conclusions
In conclusion, a simple and highly efficient strategy to
2,6-disubstituted piperidin-3-ol has been developed by em-
ploying an α-amination and Sharpless asymmetric di-
hydroxylation reaction as the key steps. Its usage is illus-
trated in the total synthesis of (–)-deoxoprosopinine and
(+)-deoxoprosophylline. The merits of this synthesis are
high enantio and diastereoselectivity with high yielding re-
action steps. The synthetic strategy described has significant
potential for stereochemical variations at the C-2, C-3 and
C-6 positions and further extension to other stereoisomers
and analogues.
Dibenzyl (S)-1-(1-Hydroxyhexadecan-4-yl)hydrazine-1,2-dicarboxyl-
ate (8): To a solution of ethyl ester 10 (0.600 g, 1.04 mmol) in THF
(8 mL), was added LiBH4 (0.045 g, 2.08 mmol) at 0 °C. The reac-
tion mixture was stirred at room temp. for 1 h. It was then
quenched with aq. ammonium chloride solution (1 mL) and ex-
tracted with ethyl acetate (3ϫ 5 mL). The combined organic layers
were washed with brine, dried with anhyd. Na2SO4 and concen-
trated under reduced pressure. Silica gel column chromatography
(petroleum ether/ethyl acetate, 7:3) of the crude product gave 8 as
a colorless solid (0.530 g, 95%); m.p. 85–87 °C. [α]2D5 = –5.75 (c =
Experimental Section
1.0, CHCl ). IR (CHCl ): ν = 3446, 3285, 2927, 1709, 1454,
˜
max
3
3
General Methods: All reactions requiring anhydrous conditions
were performed under a positive pressure of argon with oven-dried
glassware (110 °C), which was cooled under argon. Solvents used
for chromatography were distilled at respective boiling points by
using known procedures.
1221, 1057 cm–1. 1H NMR (200 MHz, CDCl3): δ = 0.88 (t, J =
6.9 Hz, 3 H), 1.25 (m, 22 H), 1.30–1.53 (m, 4 H), 3.31–3.74 (m, 2
H), 3.96–4.24 (m, 1 H), 5.13–5.18 (m, 4 H), 6.41 (s, 1 H), 7.26–7.36
(m, 10 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 14.1, 22.7, 26.5,
28.6, 29.3, 29.4, 29.6, 31.9, 32.7, 62.4, 64.7, 67.9, 127.7, 128.2,
128.5, 128.6, 135.5, 156.2, 157.3 ppm. MS (ESI): m/z = 563.18 [M
+ Na]+. HRMS: calcd. for C32H48N2O5 [M + H]+ 541.3636; found
541.3638. calcd. for C32H48N2O5 [M + Na]+ 563.3455; found
563.3452. HPLC: Chiralcel OD-H (250ϫ 4.6 mm) (2-propanol: Pet
ether = 4:96, flow rate 0.7 mL/min, λ = 254 nm). Retention time
All commercial reagents were obtained from Sigma–Aldrich Chem-
ical Co. and Lancaster Chemical Co. (UK). Progress of the reac-
tions was monitored by TLC with precoated aluminum plates
(Merck kieselgel 60 F254). Column chromatography was performed
on silica gel 60–120/100–200/230–400 mesh obtained from S. D.
Eur. J. Org. Chem. 0000, 0–0
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V. Jha, S. V. Kauloorkar, P. Kumar
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[min]: 38.850 (major) and 41.108 (minor). The racemic standard
was prepared in the same way by using dl-proline as a catalyst, ee
94%.
osmium tetroxide (0.05 mL, 0.1 m solution in toluene, 0.4 mol-%),
followed by methanesulfonamide (0.104 g, 1.09 mmol). After stir-
ring for 5 min at 0 °C, olefin 11 (0.660 g, 1.09 mmol) was added in
one portion. The reaction mixture was stirred at 0 °C for 24 h and
then quenched with solid sodium sulfite (2.0 g). The stirring was
continued for additional 15 min and then the solution was ex-
tracted with EtOAc (3ϫ 20 mL). The combined extracts were
washed with brine, dried with Na2SO4 and concentrated. Silica gel
column chromatography purification (petroleum ether/EtOAc, 4:6)
of the crude product gave 7a as a white solid (0.63 g, 95%); m.p.
Dibenzyl (S,E)-1-(1-Ethoxy-1-oxooctadec-2-en-6-yl)hydrazine-1,2-
dicarboxylate (11): To a solution of alcohol 8 (0.5 g, 0.93 mmol) in
CH2Cl2 (8 mL) was added DMP (0.780 g, 1.9 mmol) at 0 °C. The
reaction mixture was stirred at room temp. for 2 h. It was then
quenched with a 1:1 mixture of (10%) aqueous Na2S2O3 solution
and saturated NaHCO3 solution and extracted with diethyl ether
(3ϫ 5 mL). The combined organic layers were washed with brine,
dried with anhyd. Na2SO4 and concentrated under reduced pres-
sure to give the aldehyde as a colorless liquid, which was directly
used in the next step without further purification.
80–82 °C. [α]2D5 = –2.78 (c = 1.0, CHCl ). IR (CHCl ): νmax = 3434,
˜
3
3
3018, 1717, 1452, 1218 cm–1. 1H NMR (500 MHz, CDCl3): δ =
0.91 (t, J = 6.7 Hz, 3 H), 1.28–1.31 (m, 27 H), 1.43–1.72 (m, 4 H),
3.81–3.93 (m, 1 H), 3.95–4.82 (m, 4 H), 5.01–5.24 (m, 4 H), 6.65
(m, 1 H), 7.29–7.37 (m, 10 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 14.1, 22.6, 24.7, 26.4, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 30.1,
31.9, 32.7, 33.8, 57.9, 58.9, 61.9, 67.9, 72.3, 73.8, 127.6, 128.0,
128.2, 128.4, 128.5, 135.4, 135.8, 156.2, 156.9, 173.5 ppm. MS
(ESI): m/z = 665.07 [M + Na]+. HRMS: calcd. for C36H54N2O8 [M
+ Na]+ 665.3772; found 665.3762.
To a solution of (ethoxycarbonylmethylene)triphenyl phosphorane
(0.860 g, 2.47 mmol) in dry toluene (10 mL) was added a solution
of the above aldehyde in dry toluene (5 mL). The reaction mixture
was stirred at 110 °C (reflux conditions) for 12 h. It was then con-
centrated and purified by flash silica gel column chromatography
EtOAc/petroleum ether (1:9) to give olefin 12 as a waxy white solid
(0.040 g, 7%). Continued chromatography with EtOAc/petroleum
ether (1:9) gave olefin 11 as a waxy white solid (0.425 g, 70%).
Further chromatography with EtOAc/petroleum ether (1:8) gave
cyclized product 13 as a waxy solid (0.080 g, 16%). [α]2D5 = +2.96
Diastereomeric ratio was determined by HPLC analysis; dr 92:8
Column: Kromasil RP-18, Flow rate: 1.0 mL/min, MeOH:H2O/
85:15; tR for (anti)-isomer = 26.57 min and tR for (syn)-isomer =
29.25 min.
(c = 1.0, CHCl ). IR (CHCl ): ν = 3311, 2923, 1717, 1464,
˜
max
3
3
1
1263 cm–1. H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.1 Hz,
3 H), 1.26 (m, 23 H), 1.42–1.67 (m, 4 H), 2.02–2.45 (m, 2 H), 4.04–
4.22 (m, 3 H), 5.02–5.22 (m, 4 H), 5.82–5.85 (m, 1 H), 6.33–6.47
(m, 1 H), 6.94 (m, 1 H), 7.26–7.32 (m, 10 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 14.1, 14.2, 22.6, 26.4, 29.1, 29.2, 29.3, 29.5,
29.6, 30.9, 31.9, 32.3, 32.5, 33.7, 58.5, 60.1, 67.8, 68.3, 121.4, 127.9,
128.1, 128.2, 128.5, 128.6, 135.5, 135.7, 135.9, 148.5, 156.5, 156.8,
166.6 ppm. MS (ESI): m/z = 631.15 [M + Na]+. HRMS: calcd.
for C36H52N2O6 [M + H]+ 609.3898; found 609.3896. calcd. for
C36H52N2O6 [M + Na]+ 631.3718; found 631.3712.
Dibenzyl 1-[(2R,3S,6S)-1-Ethoxy-2,3-dihydroxy-1-oxooctadecan-6-
yl]hydrazine-1,2-dicarboxylate (7b): By using the same procedure as
described for the synthesis of 7a and with (DHQ)2PHAL as ligand
in the dihydroxylation step compound 7b was prepared; m.p. 77–
79 °C. [α]2D5 = +1.32 (c = 1.0, CHCl ). IR (CHCl ): ν
= 3434,
˜
max
3
3
3018, 1717, 1452, 1218 cm–1. 1H NMR (200 MHz, CDCl3): δ =
0.88 (t, J = 6.7 Hz, 3 H), 1.25–1.32 (m, 27 H), 1.53–1.76 (m, 4 H),
3.80–3.94 (m, 1 H), 3.98–4.15 (m, 2 H), 4.25 (q, J = 6.7 Hz, 2 H),
5.12–5.23 (m, 4 H), 6.74 (m, 1 H), 7.26–7.43 (m, 10 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 14.0, 22.6, 24.7, 26.4, 29.0, 29.2,
29.3, 29.4, 29.5, 29.6, 31.9, 32.8, 33.8, 43.1, 58.3, 59.4, 61.8, 67.8,
72.4, 72.8, 127.6, 128.0, 128.1, 128.5, 135.5, 135.8, 156.3, 156.9,
173.2 ppm. MS (ESI): m/z = 665.25 [M + Na]+. HRMS: calcd. for
C36H54N2O8 [M + Na]+ 665.3772; found 665.3764.
Dibenzyl (S,Z)-1-(1-Ethoxy-1-oxooctadec-2-en-6-yl)hydrazine-1,2-
dicarboxylate (12): [α]2D5 = +4.78 (c = 1.0, CHCl3). IR (CHCl3):
ν
= 3311, 2923, 1717, 1464, 1263 cm–1. 1H NMR (500 MHz,
˜
max
CDCl3): δ = 0.88 (t, J = 7.1 Hz, 3 H), 1.26 (m, 23 H), 1.42–1.67
(m, 4 H), 2.02–2.45 (m, 2 H), 4.04–4.22 (m, 3 H), 5.02–5.22 (m, 4
H), 5.82–5.85 (m, 1 H), 6.33–6.47 (m, 1 H), 6.94 (m, 1 H), 7.26–
7.32 (m, 10 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1, 14.2,
22.6, 26.4, 29.1, 29.2, 29.3, 29.5, 29.6, 30.9, 31.9, 32.3, 32.5, 33.7,
58.5, 60.1, 67.8, 68.3, 121.4, 127.9, 128.1, 128.2, 128.5, 128.6, 135.5,
135.7, 135.9, 148.5, 156.5, 156.8, 166.6 ppm. MS (ESI): m/z =
631.15 [M + Na]+. HRMS: calcd. for C36H52N2O6 [M + H]+
609.3898; found 609.3896. calcd. for C36H52N2O6 [M + Na]+
631.3718; found 631.3712.
Diastereomeric ratio was determined by HPLC analysis; dr 95:5
Column: Kromasil RP-18, Flow rate: 1.0 mL/min, MeOH/H2O/
85:15; tR for (anti)-isomer = 23.91 min and tR for (syn)-isomer =
26.34 min.
(2S,3S,6S)-Ethyl 6-Dodecyl-3-hydroxypiperidine-2-carboxylate (14):
To a one-neck round-bottomed flask were added diol ester 7a
(780 mg, 1.21 mmol), dry CH2Cl2 (10 mL) and Et3N (178 mg,
0.25 mL, 1.76 mmol). The flask was placed in an ice water bath
and allowed to equilibrate for 10–30 min, at which time the p-tolu-
enesulfonyl chloride (224 mg, 1.18 mmol) was added in one portion
by using a solid addition funnel. The flask was fitted with a serum
cap and placed in a refrigerator (5 °C) for 72 h. The mixture was
then concentrated to afford a paste, which was dissolved in Et2O.
The organic phase was washed three times with a aqueous HCl
(1 n), once with a saturated aqueous NaHCO3 solution, and once
with brine, dried with Na2SO4, and concentrated to afford the
crude tosyl compound, which was directly used in the next step
without further purification. The solution of crude tosyl compound
in MeOH (10 mL) and acetic acid (5 drops) was treated with Raney
nickel (0.8 g, excess) under H2 (60 psi) atmosphere for 24 h. The
reaction mixture was then filtered through Celite and concentrated.
Dibenzyl (3S)-3-Dodecyl-6-hydroxytetrahydropyridazine-1,2-dicarb-
oxylate (13): [α]2D5 = +5.21 (c = 1.0, CHCl ). IR (CHCl ): ν
=
˜
max
3
3
3448, 2932, 1719, 1450, 1232, 1054 cm–1. 1H NMR (200 MHz,
CDCl3): δ = 0.89 (t, J = 6.6 Hz, 3 H), 1.16–1.26 (m, 19 H), 1.49–
1.69 (m, 5 H), 1.90–2.11 (m, 2 H), 4.12–4.28 (m, 1 H), 4.98–5.28
(m, 4 H), 5.53–5.56 (m, 1 H), 7.27–7.37 (m, 10 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 14.1, 22.7, 23.3, 25.7, 26.2, 29.3, 29.5, 29.6,
31.9, 32.7, 54.6, 67.7, 67.8, 68.1, 127.6, 127.9, 128.0, 128.2, 128.5,
128.6, 135.6, 135.8, 136.1, 156.4, 156.6 ppm. MS (ESI): m/z =
561.01 [M + Na]+. HRMS: calcd. for C32H46N2O5 [M + Na]+
561.3299; found 561.3299.
Dibenzyl 1-[(2S,3R,6S)-1-Ethoxy-2,3-dihydroxy-1-oxooctadecan-6-
yl]hydrazine-1,2-dicarboxylate (7a): To a mixture of K3Fe(CN)6 The residue was purified by flash column chromatography
(1.10 g, 3.28 mmol), K2CO3 (0.455 g, 3.28 mmol), (DHQD)2PHAL with silica gel (MeOH/CH2Cl2, 1:9) to give compound 14
(10 mg, 1 mol-%) in tBuOH/H2O (1:1, 20 mL) at 0 °C was added
(301 mg, 73%); m.p. 94–96 °C. [α]2D5 = +5.65 (c = 0.60, CHCl3). IR
4
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Pages: 7
Stereoselective Approach to 2,6-Disubstituted Piperidin-3-ol
(CHCl ): ν = 3583, 3436, 3019, 2928, 1725, 1519, 1455,
analysis. The authors thank Council of Scientific and Industrial
Research (CSIR), New Delhi for financial support as part of XII
˜
3
max
1
1215 cm–1. H NMR (200 MHz, CDCl3): δ = 0.88 (t, J = 6.6 Hz,
3 H), 1.26–1.33 (m, 26 H), 1.43–1.56 (m, 2 H), 1.60–1.70 (m, 1 H), Five Year Plan under title ORIGIN (CSC0108).
1.72–1.81 (m, 1 H), 2.13 (br. s, 1 H), 2.68–2.76 (m, 1 H), 3.58 (d,
J = 4.0 Hz, 1 H), 4.15–4.16 (m, 1 H), 4.22 (q, J = 6.6 Hz, 2 H) ppm.
[1] For reviews that include piperidine alkaloids, see: a) G. M.
13C NMR (50 MHz, CDCl3): δ = 14.0, 14.2, 22.6, 25.7, 26.1, 28.0,
29.3, 29.5, 29.6, 31.8, 35.8, 51.6, 60.8, 61.5, 65.5, 172.2 ppm. MS
(ESI): m/z = 364.10 [M + Na]+. HRMS: calcd. for C20H39NO3 [M
+ Na]+ 364.2822; found 364.2821.
Strunz, J. A. Findlay, in: The Alkaloids (Ed.: A. Brossi), Aca-
demic Press, New York, 1985, 26, p. 89–183; b) G. B. Foder, B.
Colasanti, The Pyridine and Piperidine Alkaloids; Chemistry
and Pharmacology, in: Alkaloids: Chemical and Biological Per-
spectives (Ed.: S. W. Pelletier), Wiley, New York, 1985, 3, p. 1–
90; c) A. Numata, T. Ibuka, in: The Alkaloids (Ed.: A. Brossi),
Academic Press, New York, 1987, 31, p. 193–315, and refer-
ences cited therein; d) M. J. Schneider, Pyridine and Piperidine
Alkaloids: An Update, in: Alkaloids: Chemical and Biological
Perspectives (Ed.: S. W. Pelletier), Pergamon, Oxford, UK,
1996; 10, p. 155; e) C. J. Wang, M. A. Wuonola, Org. Prep.
Proced. Int. 1992, 24, 585; f) S. Laschat, T. Dickner, Synthesis
2000, 1781; g) P. M. Weintraub, J. S. Sabol, J. M. Kane, D. R.
Borcherding, Tetrahedron 2003, 59, 2953; for analgesic, anti-
biotic and anesthetic properties, see: h) P. Bourrinet, A. C. R.
Quevauviller, C. R. Soc. Biol. 1968, 162, 1138; i) P. Bourrinet,
A. Quevauviller, Ann. Pharm. Fr. 1968, 26, 787.
Ethyl (2S,3S,6S)-6-Dodecyl-3-hydroxypiperidine-2-carboxylate (15):
By using the same procedure as described for the synthesis of 14,
compound 15 was prepared; m.p. 92–94 °C. [α]2D5 = +2.47 (c = 0.60,
CHCl ). IR (CHCl ): ν = 3583, 3436, 3019, 2928, 1725, 1519,
˜
max
3
3
1455, 1215 cm–1. 1H NMR (200 MHz, CDCl3): δ = 0.88 (t, J =
6.6 Hz, 3 H), 1.26–1.36 (m, 27 H), 1.68–1.79 (td, J = 3.27,
12.79 Hz, 1 H), 1.99–2.24 (m, 2 H), 2.45–2.65 (m, 2 H), 3.17 (d, J
= 9.0 Hz, 1 H), 3.63–3.75 (m, 1 H), 4.26 (dq, J = 3.3, 7.2 Hz, 2
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 13.9, 22.5, 25.9, 29.2,
29.4, 29.5, 29.6, 30.6, 31.8, 32.3, 36.3, 55.9, 61.3, 64.6, 69.2,
172.6 ppm. MS (ESI): m/z = 364.10 [M + Na]+. HRMS: calcd. for
C20H39NO3 [M + Na]+ 364.2822; found 364.2820.
[2] Prosopis alkaloids from the leaves, stems, and roots of Prosopis
Africana, see: a) G. Ratle, X. Monseur, B. C. Das, J. Yassi, Q.
Khuong-Huu, R. Goutarel, Bull. Soc. Chim. Fr. 1966, 2945; b)
Q. Khuong-Huu, G. Ratle, X. Monseur, R. Goutarel, Bull. Soc.
Chim. Belg. 1972, 81, 425.
[3] T. Kolter, K. Sandhoff, Angew. Chem. Int. Ed. 1999, 38, 1532;
Angew. Chem. 1999, 111, 1632.
[4] a) N. Asano, Glycobiology 2003, 13, 93; b) B. Junge, M.
Matzke, J. Stoltefuss, in: Handbook of Experimental Pharma-
cology (Eds.: J. Kuhlmann, W. Puls), Springer, Berlin, 1996;
119, p. 411; c) B. Winchester, G. W. J. Fleet, Glycobiology 1992,
2, 199.
(–)-Deoxoprosopinine (3):
A suspension of LiBH4 (50 mg,
0.147 mmol) in anhydrous THF (10 mL) was stirred for 5 min at
0 °C, and a solution of 14 (65 mg, 0.73 mmol) in THF (5 mL) was
then added dropwise. The mixture was stirred for 1 h at room tem-
perature. Excess LiBH4 was destroyed by slow addition of aq.
NH4Cl solution and EtOAc (5 mL). The white precipitate was fil-
tered through a pad of neutral alumina and washed with MeOH
(3ϫ 15 mL). The filtrate was concentrated and the residue was
purified by silica gel column chromatography (MeOH/CH2Cl2, 2:8)
to give 3 as a colorless solid (42 mg, 96%); m.p. 90 °C, [ref.[5e] 89.5–
90 °C]. [α]2D5 = –15. 81 (c 0.30, CHCl3), [ref.[5e] [α]2D5 = –14.7 (c =
[5] For asymmetric synthesis of piperidin-3-ols, see: a) M. A.
Wijdeven, J. Willemsen, F. P. J. T. Rutjes, Eur. J. Org. Chem.
2010, 2831; b) P.-Q. Huang, Synlett 2006, 1133; c) N. Toyooka,
H. Nemoto, Synthetic studies on biologically active alkaloids
starting from lactam-type chiral building blocks, in: Studies in
Natural Products Chemistry (Ed.: Atta-ur-Rahman), Elsevier,
2003, vol. 29, p. 419; d) M. A. Ciufolini, C. Y. W. Hermann, Q.
Dong, T. Shimizu, S. Swaminathan, N. Xi, Synlett 1998, 105;
for synthesis of deoxoprosopinine, see: e) Y. Saitoh, Y. Mori-
yama, T. Takahashi, Q. Khuong-Huu, Tetrahedron Lett. 1980,
21, 75; f) D. L. Comins, M. J. Sandelier, T. A. Grillo, J. Org.
Chem. 2001, 66, 6829; g) Q. Wang, N. A. Sasaki, J. Org. Chem.
2004, 69, 4767; h) A. Kennedy, A. Nelson, A. Perry, Beilstein
J. Org. Chem. 2005, 1, No. 2, 1; i) S. K. Pandey, P. Kumar,
Synlett 2007, 2894; j) E. B. Arévalo-García, J. C. Colmenares,
Tetrahedron Lett. 2008, 49, 6972, and references cited therein.
[6] For the total syntheses of (+)-prosopinine, (+)-prosophylline,
(+)-prosopine, see: a) C. Gnamm, K. Brödner, C. M. Krauter,
G. Helmchen, Chem. Eur. J. 2009, 15, 10514; for a recent syn-
thesis of deoxoprosophylline, see: b) I. Ojima, E. S. Vidai, J.
Org. Chem. 1998, 63, 7999; c) P. J. Dransfield, P. M. Gore, M.
Shipman, A. M. Z. Slawin, Chem. Commun. 2002, 150; d) P. J.
Dransfield, P. M. Gore, I. Prokes, M. Shipman, A. M. Z. Sla-
win, Org. Biomol. Chem. 2003, 1, 2723; e) N. Ma, D. Ma, Tetra-
hedron: Asymmetry 2003, 14, 1403; f) S. P. Chavan, C. Praveen,
Tetrahedron Lett. 2004, 45, 421; g) A. Jourdant, J. Zhu, Hetero-
cycles 2004, 64, 249; h) I. S. Kim, C. B. Ryu, Q. R. Li, O. P.
Zee, Y. H. Jung, Tetrahedron Lett. 2007, 48, 6258; i) K.-i.
Fuhshuku, K. Mori, Tetrahedron: Asymmetry 2007, 18, 2104;
j) E. Abraham, E. A. Brock, J. I. Candela-Lena, S. G. Davies,
M. Georgiou, R. L. Nicholson, J. H. Perkins, P. M. Roberts,
A. J. Russell, E. M. Sánchez-Fernández, P. M. Scott, A. D.
Smith, J. E. Thomson, Org. Biomol. Chem. 2008, 6, 1665; k)
H. P. Kokatla, R. Lahiri, P. K. Kancharla, V. R. Doddi, Y. D.
Vankar, J. Org. Chem. 2010, 75, 4608; l) D. A. Devalankar, A.
Sudalai, Tetrahedron Lett. 2012, 53, 3213; m) R.-C. Liu, J.-H.
0.30, CHCl )]. IR (CHCl ): ν
= 3267, 2922, 2852, 1639, 1465,
˜
3
1
3
max
1376 cm–1. H NMR (200 MHz, CDCl3): δ = 0.88 (t, J = 6.7 Hz,
3 H), 1.26 (m, 20 H), 1.38–1.50 (m, 2 H), 1.53–1.60 (m, 2 H), 1.66–
1.77 (m, 2 H), 2.66 (br. s, 3 H), 2.79–2.92 (m, 1 H), 2.86 (q, J =
5.59, 12.73 Hz, 1 H), 3.51–3.59 (m, 1 H), 3.61–3.73 (m, 2 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 14.0, 22.6, 26.4, 27.0, 28.3, 29.3,
29.6, 29.7, 31.9, 33.3, 50.2, 57.9, 62.1, 67.8 ppm. MS (ESI): m/z =
300.16 [M + H]+. HRMS: calcd. for C18H37NO2 [M + H]+
300.2897; found 300.2895.
(+)-Deoxosoprosophylline (4): By using the same procedure as de-
scribed for the synthesis of 3, compound 4 was prepared; m.p.
84 °C, [ref.[6h] 85–86 °C]. [α]2D5 = +13.86 (c = 0.22, CHCl3), [ref.[6h]
[α]2D5 = +12.50 (c = 0.22, CHCl )]. IR (CHCl ): ν
= 3267, 2922,
˜
max
3
3
2852, 1639, 1465, 1376 cm–1. 1H NMR (200 MHz, CDCl3): δ =
0.88 (t, J = 6.7 Hz, 3 H), 1.23–1.30 (m, 22 H), 1.39–1.51 (m, 2 H),
1.77–1.85 (m, 1 H), 2.03–2.09 (m, 1 H), 2.58–2.66 (m, 2 H), 3.33
(br. s, 3 H), 3.54–3.63 (m, 1 H), 3.84–3.85 (m, 2 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 14.0, 22.6, 26.1, 29.3, 29.6, 29.7, 29.9, 31.9,
33.3, 35.5, 56.4, 62.2, 63.4, 68.2 ppm. MS (ESI): m/z = 300.18 [M
+ H]+. HRMS: calcd. for C18H37NO2 [M + H]+ 300.2897; found
300.2896.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra along with ee and dr
chromatograms.
Acknowledgments
V. J. and S. V. K. thank the University Grant Commission (UGC),
New Delhi for a fellowship. Ms. S. Kunte is thanked for HPLC
Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O42363
/KAP1
Date: 18-06-14 16:52:20
Pages: 7
V. Jha, S. V. Kauloorkar, P. Kumar
FULL PAPER
Wei, B.-G. Wei, G.-Q. Lin, Tetrahedron: Asymmetry 2008, 19,
2731; n) L.-D. Guo, P. Liang, J.-F. Zheng, P.-Q. Huang, Eur. J.
Org. Chem. 2013, 2230, and references cited therein.
M. S. Van Nieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94,
2483.
[10] a) W. Wadsworth, Org. React. 1977, 25, 73; b) M. A.
Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune,
W. R. Roush, T. Sakai, Tetrahedron Lett. 1984, 25, 2183; c) A.
Maercker, Org. React. 1965, 14, 270.
[7] a) P. Kumar, N. Dwivedi, Acc. Chem. Res. 2013, 46, 289; b)
S. V. Kauloorkar, V. Jha, P. Kumar, RSC Adv. 2013, 3, 18288;
c) P. Kumar, V. Jha, R. G. Gonnade, J. Org. Chem. 2013, 78,
11756; d) V. Jha, P. Kumar, RSC Adv. 2014, 4, 3238; e) V. Jha, [11] The enantiomeric excess of 10 was determined by converting it
N. B. Kondekar, P. Kumar, Org. Lett. 2010, 12, 2762.
[8] a) B. List, J. Am. Chem. Soc. 2002, 124, 5656; b) S. P. Kotkar,
V. B. Chavan, A. Sudalai, Org. Lett. 2007, 9, 1001; c) J. T. Suri,
D. D. Steiner, C. F. Barbas III, Org. Lett. 2005, 7, 3885.
[9] a) H. Becker, K. B. Sharpless, Angew. Chem. Int. Ed. Engl.
1996, 35, 448; Angew. Chem. 1996, 108, 447; b) H. C. Kolb,
into 8. Diastereomeric ratios of 7a and 7b were determined by
using HPLC analysis (see Supporting Information).
[12] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
[13] P. R. Fleming, K. B. Sharpless, J. Org. Chem. 1991, 56, 2869.
Received: April 7, 2014
Published Online: ᭿
6
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Job/Unit: O42363
/KAP1
Date: 18-06-14 16:52:20
Pages: 7
Stereoselective Approach to 2,6-Disubstituted Piperidin-3-ol
Organocatalysis
V. Jha, S. V. Kauloorkar,
P. Kumar* ......................................... 1–7
Stereoselective Approach to 2,6-Disubsti-
tuted Piperidin-3-ol: Synthesis of (–)-De-
oxoprosopinine and (+)-Deoxoprosophyl-
line
A simple and highly efficient approach to
an enantioenriched 2,6-disubstituted piper-
idin-3-ol skeleton is developed from an al-
dehyde as a starting material by using or-
ganocatalytic and asymmetric dihydroxyl-
ation as key steps. Its application to the to-
tal synthesis of (–)-deoxoprosopinine and
(+)-deoxoprosophylline is also reported.
Keywords: Synthetic methods / Alkaloids /
Amino alcohols / Amination / Wittig reac-
tions
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