Synthesis of di- and trihydroxy proline derivatives from D-glycals: Application in the synthesis of polysubstituted pyrrolizidines and bioactive 1C-aryl/alkyl pyrrolidines

Article abstract of DOI:10.1016/j.carres.2019.02.004

Six different types of O-benzyl protected proline derivatives have been synthesized from D-glycals and 2C-formyl-glycals. One of the di-O-benzyl protected proline derivatives has been utilized for the synthesis of polysubstituted pyrrolizidines via [3 + 2

Full text of DOI:10.1016/j.carres.2019.02.004

Accepted Manuscript
Synthesis of di- and trihydroxy proline derivatives from D-glycals: Application in the
synthesis of polysubstituted pyrrolizidines and bioactive 1C-aryl/alkyl pyrrolidines
Ashish Kumar Verma, Sateesh Dubbu, Ande Chennaiah, Yashwant D. Vankar
PII:
S0008-6215(19)30003-5
https://doi.org/10.1016/j.carres.2019.02.004
CAR 7677
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 3 January 2019
Revised Date: 1 February 2019
Accepted Date: 14 February 2019
Please cite this article as: A.K. Verma, S. Dubbu, A. Chennaiah, Y.D. Vankar, Synthesis of di- and
trihydroxy proline derivatives from D-glycals: Application in the synthesis of polysubstituted pyrrolizidines
and bioactive 1C-aryl/alkyl pyrrolidines, Carbohydrate Research (2019), doi: https://doi.org/10.1016/
j.carres.2019.02.004.
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Graphical abstract:

ACCEPTED MANUSCRIPT
Synthesis of Di- and Trihydroxy Proline Derivatives from D-
Glycals: Application in the Synthesis of Polysubstituted
Pyrrolizidines and Bioactive 1C-Aryl/Alkyl Pyrrolidines
Ashish Kumar Verma, Sateesh Dubbu, Ande Chennaiah and Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
E-mail: vankar@iitk.ac.in
Abstract
Six different types of O-benzyl protected proline derivatives have been synthesized from
D-glycals and 2C-formyl-glycals. One of the di-O-benzyl protected proline derivatives has been
utilized for the synthesis of polysubstituted pyrrolizidines via [3+2] cycloaddition in a
stereoselective manner. Further, we also report on the stereoselective synthesis of biologically
active 1C-aryl/alkyl pyrrolidines i.e. 4-epi-radicamine B, 4-epi-radicamine A, 1C-butyl and 1C-
methyl pyrrolidines through double reductive amination of a variety of
D-glucal derived
diketones with p-methoxybenzylamine.
Keywords: Carbohydrates · Polyhydroxy Prolines · Pyrrolizidines · 1C-Aryl/Alkyl
Pyrrolidines · Double Reductive Amination
Introduction
Carbohydrates are indispensable components of biological systems wherein they play an
integral role in vital life processes.1 They exist either in free forms, or as glycoconjugates, i.e. a
carbohydrate bound to another carbohydrate, a lipid or a protein molecule by a glycosidic
linkage.1e-g Glycosidases and glycosyltransferases are the two major classes of carbohydrate
processing enzymes in all living organisms. Inhibitors of glycosidases and glycosyltransferases
act as therapeutic agents against diseases such as diabetes, Gaucher’s disease, Fabry disease,
AIDS, etc.1h-j Among several classes of glycosidase inhibitors, polyhydroxylated pyrrolidines
(five membered nitrogen containing iminosugars) (Figure 1) are a functionally rich class of
biologically active molecules that have broad therapeutic potential.1h-j,2
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Proline is a unique five-membered cyclic amino acid where the –COOH group is
connected to the carbon bearing the nitrogen atom.3 It plays an important role in molecular
recognition, particularly in intracellular signaling. Modular protein domains such as WW (rsp5-
domain) and SH3 (Src homology 3) are proline-rich motifs which are responsible for several
signaling cascades.3e-d Likewise, polyhydroxylated pyrrolidines along with a proline based
skeleton show various biological properties.4,5 For example, 3-hydroxy bulgecinine 1 shows
potent β-lactam inhibitor activity.4a Similarly, N-methyl proline amide 2 with
L-ido configuration
is a potential glycosidase inhibitor with IC50 4.5 µM range.4b Dihydroxyprolines 3 and 4 were
identified as the sixth residue in the repeating decapeptide unit of Mefp1, where Mefp1 is an
adhesive protein produced by the marine mussel Mytilus edulis.5
One of the major drawbacks associated with imino-analogues of glycosidase inhibitors is
their instability caused by the lability of the N,O-acetal function thus hindering their use as drug
candidates.6 By analogy with C-glycosides, the replacement of the oxygen atom of the N,O-
acetal function by an aryl or an alkyl group provides a stable C–C bond at C-1 thereby producing
stable analogues of glycoconjugates. Thus, as expected polyhydroxylated pyrrolidines with
aryl/alkyl substitution at C-1 anomeric position, are stable and known to display a wide range of
biological activities (Figure 1).7 In this context, a new class of pyrrolidine alkaloids with an aryl
moiety at the C-1 position such as radicamine A 5 and radicamine B 6 have been isolated from
Lobelia chinensis LOUR which show potent α-glucosidase inhibitory activity (Figure 1).8a
Further, α-1-C-butyl-
L
-arabinitol 7,8b-c a polyhydroxylated pyrrolidine analogue inhibits α-
glucosidase and thus shows antidiabetic activity. Similarly trideoxy-2,5-iminohexitol derivative
8, a polyhydroxylated pyrrolidine, is an excellent α-L
-fucosidase inhibitor.8d-e
2

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Figure 1. Biologically important sugar amino acids and 1C-aryl/alkyl pyrrolidines.
There is an ever-growing interest in the synthesis of such molecules owing to their
immense significance from therapeutic as well as synthetic point of view. A number of synthesis
of pyrrolidine iminosugars (polyhydroxy proline amino acids and 1C-aryl/alkyl pyrrolidines) are
reported from different starting materials.9
Scheme 1. Synthesis of polyhydroxy proline amino acids and 1C-aryl/alkyl pyrrolidines.
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Glycals are versatile synthons10 in carbohydrate chemistry. During the past years, we
have developed a variety of methodologies for the functionalization of glycals towards the
synthesis of N-glycopeptides,10e-f nitrosugars,10g-i halosugars,10j 2-deoxy-O-glycosides10k-l and
biologically active glycosidase inhibitors.10m In this context, glycals were also utilized in the
synthesis of 2-deoxysugars10n and 2-deoxy-C-glycosides.10o-p In continuation of our interest in
the synthesis of aza/imino sugars over the past few years11 we have recently reported12 the
synthesis and enzyme inhibition studies of radicamine B, codonopsine and codonopsinine
analogues from
amino acids13 and pyrrolidines,12,14 herein we report on the synthesis of various
polyhydroxyproline derivatives from -glycals and 2C-formyl-glycals. We also describe a
divergent approach for the synthesis of 1C-aryl/alkyl pyrrolidines via double reductive amination
of a variety of -glucal derived diketones (Scheme 1).
D-mannitol. In continuation of our interest in the synthesis of sugar derived
D
D
Results and discussion
Very recently, we synthesized N-Boc protected amino alcohols 11 and 12 from
D-glucal 9
and
D
-galactal 10 via double nucleophilic displacement reactions.14a We envisaged that the O-
benzyl protected free proline derivatives 15 and 16 could be prepared from compounds 11 and
12. Accordingly, we prepared starting materials 11 and 12 using our strategy.14a Toward the
present endeavor, oxidation of the free hydroxy groups in 11 and 12 with Jones reagent in
acetone at room temperature conveniently provided the desired acids 13 and 14 in 89% and 82%
yields, respectively. Further, deprotection of the N-Boc group in 13 and 14 was carried out using
CF3COOH in dichloromethane to give di-O-benzyl protected free proline derivatives 15 and 16
in 5 h at 0 °C in 78% and 82% yields, respectively.
Scheme 2. Synthesis of di-O-benzyl protected free proline amino acids from D-glucal and D-
galactal.
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After successful synthesis of di-O-benzyl protected free proline derivatives 15 and 16, we
decided to synthesize di-O-benzyl protected free proline derivatives having a –CH2OBn at C-4
position which are analogues of 3-hydroxy bulgecinine 1. Accordingly, we synthesized
N-Boc protected amino alcohols 19a-b and 20a-b from 2C-formyl-D-glucal 17 and 2C-formyl-D-
galactal 18, respectively by utilizing our reported strategy.14b-c These N-Boc protected amino
alcohols 19a-b and 20a-b were converted to tri-O-benzyl protected free amino acids 23a-b and
24a-b (Scheme 3) via N-Boc protected proline amino acids 21a-b and 22a-b using the same
sequence of reactions as used in the synthesis of 15 and 16. Typically, the presence of the
carboxylic acid group was ascertained by the characteristic appearance of the carbonyl carbon in
the 13C NMR spectra at ~170.0 ppm, in addition to other spectral data (see supporting
information).
OBn
OBn
OBn
OBn
H
Boc
Boc
R3
R4
R3
R4
O
N
N
R3 TFA, CH2Cl2,
N
ref. 14b,c
CHO
0 oC, 5 h
Jones reagent
acetone, rt, 5 h
R4
R1
R2
R1
R1
R1
OBn
OBn
OBn
R2
R2
R2
OBn
R1 = H, R2 = OBn, 17
R1 = OBn, R2 = H, 18
R1 = H, R2 = OBn,
R3 = CH2OH, R4 = H,
R1 = H, R2 = OBn,
R3 = COOH, R4 = H,
R1 = H, R2 = OBn,
R3 = COOH, R4 = H, 23a, 92%
19a
21a
, 90%
R1 = H, R2 = OBn,
R1 = H, R2 = OBn,
R1 = H, R2 = OBn,
21b
R3 = H, R4 = COOH,
, 88%
R3 = H, R4 = CH2OH, 19b
R3 = H, R4 = COOH, 23b, 89%
R1 = OBn, R2 = H,
R1 = OBn, R2 = H,
R1 = OBn, R2 = H,
20a
22a
R3 = CH2OH, R4 = H,
R3 = COOH, R4 = H,
, 82%
R3 = COOH, R4 = H, 24a, 80%
R1 = OBn, R2 = H,
R1 = OBn, R2 = H,
R1 = OBn, R2 = H,
22b
, 88%
R3 = H, R4 = COOH,
R3 = H, R4 = CH2OH, 20b
R3 = H, R4 = COOH, 24b, 78%
Scheme 3. Synthesis of tri-O-benzyl protected free proline amino acids 23a-b and 24a-b from
2C-formyl- -glucal 17 and 2C-formyl- -galactal 18.
D
D
Di- and tri-O-benzyl protected free proline derivatives 15, 16, 23a-b, and 24a-b
(Schemes 2 and 3) are useful synthons for the construction of different nitrogen heterocycles and
organocatalysts.15 Proline has been cleverly utilized as an azomethine ylide for annulations via
[3+2] cycloaddition by Seidel et al.16 Therefore, we considered to demonstrate the utility of the
di-O-benzyl protected proline derivative 16 for the synthesis of polysubstituted pyrrolizidines via
[3+2] cycloaddition. Thus, we attempted the reaction of 16 with β-nitrostyrene 25 and p-
anisaldehyde 26a in different solvents like chloroform, THF, ethanol and acetonitrile (Table 1,
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entries-1, 2, 3 and 4) at various temperatures. Among them, the best result was observed with
toluene at room temperature to 80 oC which led to 27a in 78% yield (Table 1, entry 5).
Table 1. Optimization of conditions for the synthesis of polysubstituted pyrrolizidines.
With β-nitrostyrene 25 as a reacting partner, the substrate scope for the [3+2]
cycloaddtion was examined. For example, the reaction of p-tolualdehyde afforded pyrrolizidine
27b in 69% yield (Scheme 4). Similarly, benzaldehyde smoothly underwent cycloaddition and
led to product 27c in moderate yield (Scheme 4). Pyrrolizidines and their analogues are
important structural motifs in many alkaloids (vide supra) with biological activities such as
antibacterial, antimalarial, and antitumor properties.17 Hence, the present strategy could be one of
the routes for the synthesis of polysubstituted pyrrolizidines.
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Scheme 4. Synthesis of polysubstituted pyrrolizidines.
The structures of compounds 27a-27c were confirmed by spectral means and
stereochemistry of the newly generated stereocenters were established based on COSY followed
by NOE studies.18 Thus, in NOE studies of compound 27a (Figure 2), irradiation of the H-4
proton at δ 3.75–3.71 resulted in an enhancement of the H-6 proton at δ 3.97 and H-2 proton at δ
4.97–4.92. It indicates that H-4 proton is in cis orientation to H-2 and H-6 protons. Further,
irradiation of the H-5 proton at δ 4.09 resulted in an enhancement of the H-3 proton at δ 4.97–
4.92 and H-7 proton at δ 4.26 indicating that H-5 proton is in cis orientation to H-3 and H-7
protons. It is clear that a stereochemically single cycloaddition product was obtained. In order to
gain insight of the reaction mechanism, we reacted the amino acid 16 with p-anisaldehyde 26a in
Figure 2. NOE of compound 27a.
presence of phenylacetylene, instead of β-nitrostyrene, in presence of CuI in toluene solvent at
o
80 C temperature and observed the formation of compound 28 in 92% yield exclusively
(Scheme 5). It confirms that the reaction proceeds via the formation of a dipolar interemediate B
(Scheme 6) exclusively.
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Scheme 5. Reaction of di-O-benzyl protected free proline amino acid 16 with phenylacetylene
and CuI.
A plausible mechanism for the formation of polysubstituted pyrrolizidines 27a-27c and
pyrrolidine 28 is shown in Scheme 6. Initially, proline derivative 16 condenses with p-
anisaldehyde 26a and forms intermediate A which subsequently undergoes decarboxylation to
give the dipolar intermediate B. This dipolar intermediate B could react with β-nitrostyrene 25 in
a stepwise manner to form intermediate C which leads to polysubstituted pyrrolizidines (27a-
27c) via intramolecular nucleophilic addition.
Scheme 6. A plausible mechanism for the formation of polysubstituted pyrrolizidines and
pyrrolidine 28.
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On the other hand, reaction of phenylacetylene with copper iodide leads to the formation of
copper acetylide and HI. The dipolar intermediate B then undergoes protonation with HI
resulting in the formation of ion pair D which undergoes intermolecular nucleophilic addition
with copper acetylide to give product 28.
Double reductive amination is one of the most feasible approaches for the synthesis of
piperidines and pyrrolidines with a dicarbonyl compound and a primary amine.19 Hence, after
exploring the synthesis and utility of di- and tri-O-benzyl protected proline derivatives, we
wished to exploit the usefulness of
active 1C-aryl/alkyl pyrrolidines via double reductive amination. Thus, conversion of tri-O-
benzyl- -glucal 30 (Scheme 7) into its aldehydoformate 31 was undertaken by using our
D-glucal derived diketones for the synthesis of biologically
D
strategy.14a Treatment of the aldehydoformate 31 with Grignard reagents 29a–29d (Figure 3)
gave the corresponding diols 32a–32d in good to excellent yields (Scheme 7).
Figure 3. Grignard reagents.
Oxidation of the free hydroxy groups in 32a–32d with 2-iodoxybenzoic acid (IBX) in
DMSO solvent provided the desired diketones 33a–33d in good yields. With the diketones in
hand, we set out to produce the pyrrolidine ring system via double reductive amination with
p-methoxybenzylamine 34. Thus, diketone 33a was selected as the model compound for our
o
studies. Treatment of 33a with p-methoxybenzylamine 34 and in methanol at 0 C to room
o
temperature and even after a prolonged time up to 65 C (Table 2, entries 1 and 2) failed to
initiate the reaction, and beyond which substantial decomposition was noticed. However, using
ZnCl2 (1.0 equiv) as a catalyst formation of the desired product 35a was observed.
Unfortunately, the product 35a was found to be very unstable and could not be purified by
column chromatography. The formation of compound 35a, however, was confirmed by the ESI
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mass with [M + H]+ being 706.3532, and by disappearance of the carbonyl stretching frequencies
in the IR spectrum. Changing the catalyst to SnCl2 and TiCl4 gave lower yields and required
longer reaction time (Table 1, entries 4 and 5).
In order to prove the structure and stereochemistry of the product 35a, it was converted to
the corresponding N-CH3 amine derivative (Scheme 8). Thus, crude 35a was subjected to
selective hydrogenolysis using Pd(OH)2/C and 1 atm H2 for 15 min without affecting any of the
benzyl ethers present in the compound to give free amine 37 which was protected as N-CH3
derivative 38 by reacting it with MeI/K2CO3 exclusively obtained as a single diastereoisomer in
73% yield. The structure of 38 was confirmed by spectral studies and stereochemistry of the
newly generated stereocenters was established based on COSY followed by NOE studies (Figure
4).18 Thus, in NOE studies (Figure 4), irradiation of the H-1 proton at δ 3.18 resulted in an
enhancement of the H-4 proton at δ 2.94 and H-3 proton at δ 4.01 indicating that H-1 proton is in
cis orientation to H-4 and H-3 protons. On the other hand, irradiation of the H-2 proton at δ 3.82
did not result in the enhancement of the signals of H-4 proton. It indicates that H-2 proton is in
trans orientation to H-4 proton and thus confirms to the structure assigned. In addition, in the
present study the formation of the C-N bonds was clearly confirmed by the characteristic
chemical shift of carbons linked to nitrogen ranging from 40 to 60 ppm in their 13C NMR
spectrum.
Figure 4. NOE of compound 38.
Similarly diketones 33b–33d were also converted into the corresponding pyrrolidines
derivatives 35b-35d by using the same strategy as was used for the synthesis of 35a under
stabilized condition (Table 2, entry 3). Finally, removal of the benzyl groups in 35a-35d by
hydrogenolysis20 with Pd(OH)2/C in EtOH/EtOAc/HCl under H2 pressure (1 atm) at room
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temperature followed by passing through a Dowex (50X) basic resin column afforded 4-epi-
radicamine B 36a12, 4-epi-radicamine A 36b12, 1C-butyl pyrrolidine 36c8d and 1C-methyl
pyrrolidine 36d8d respectively, in moderate to good yields. The spectroscopic data for 36a-36d
were found to be in agreement with the reported data.
Scheme 7. Synthesis of 1C-aryl/alkyl pyrrolidines via double reductive amination of diketone
33a-33d with p-methoxybenzylamine 34.
11

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Table 2. Optimization of conditions for the synthesis of 1C-aryl/alkyl pyrrolidines.
Scheme 8. Selective N-debenzylation of compound 33a.
A plausible mechanism for the observed double reductive amination is depicted in
Scheme 9. Initially, diketone (33a-33d) condenses with p-methoxybenzylamine 34 to form the
iminium ion I which undergoes reduction with NaBH3CN to provide amine III via Zn-mediated
complex II. The formation of pyrrolidine skeleton (35a-35d) eventually may take place via the
formation of another iminium ion IV from III followed by reduction with NaBH3CN.
12

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Scheme 9. A plausible mechanism for the formation of 1C-aryl/alkyl pyrrolidines.
Conclusion
In conclusion, we have synthesized six different types of O-benzyl protected proline
derivatives from -glycals and 2C-formyl-glycals. One of the di-O-benzyl protected proline
D
derivatives was utilized in the synthesis of polysubstituted pyrrolizidines via [3+2]
cycloaddition. Further, we also synthesized biologically active 1C-aryl/alkyl pyrrolidines i.e. 4-
epi-radicamine B, 4-epi-radicamine A, 1C-butyl and 1C-methyl pyrrolidines via double reductive
amination of D-glucal derived diketones with p-methoxybenzylamine. Further work to explore
the scope of di- and trihydroxy proline derivatives in organocatalysis is underway and will be
reported in due course of time.
Acknowledgements
We thank the Department of Science and Technology, New Delhi, India, for a J. C. Bose
National Fellowship (No. SR/S2/JCB-26/2010) to Y. D. V., S. D., A. C. thanks the Council of
Scientific and Industrial Research, New Delhi and A.K.V. thanks IIT Kanpur for Senior
Research Fellowships.
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Experimental Section
General procedure for Jones oxidation:
To a stirred solution of chromium trioxide (2.0 equiv) in 97% sulfuric acid (2.0 equiv) and water
(3.0 equiv) was added alcohol (11, 12, 19a-b and 20a-b) (200 mg, 1.0 equiv) in acetone (5 mL)
at room temperature. The reaction mixture was stirred at the same temperature for 5 h and
quenched with a saturated aqueous ammonium chloride solution (8 mL). The mixture was
extracted with EtOAc (3 x 15 mL) and the combined organics were washed with water (2 x 10
mL) and extracted with a 1 M sodium hydroxide aqueous solution (3 x 10 mL). The aqueous
extracts were combined, acidified to pH 4 with 1M hydrochloric acid aqueous solution and
extracted with EtOAc (3 x 10 mL). These organic extracts were combined, dried over anhydrous
Na2SO4, filtered, and concentrated. Column chromatography of the crude reaction mixture
afforded N-Boc protected proline amino acids 13, 14, 21a-21b and 22a-22b as white solids.
General procedure for deprotection of N-Boc group:
N-Boc protected proline amino acid (13, 14, 21a-21b and 22a-22b) (200 mg, 1.0 equiv) was
dissolved in dry CH2Cl2 (4 mL) and cooled to 0 °C. To this solution was added trifluoroacetic
acid (3.0 equiv) and stirred for 5 h at room temperature. The reaction mixture was quenched by
dropwise addition of saturated aqueous NaHCO3 solution (5 mL) and extracted with EtOAc (3 x
15 mL). These organic extracts were combined, dried over anhydrous Na2SO4, filtered, and
concentrated. Column chromatography of the crude reaction mixture afforded proline amino
acids 15, 16, 23a-23b and 24a-24b as white solids.
General procedure for double reductive amination:
To a solution of a diketone (33a–33d) (200 mg, 1.0 equiv) in EtOH (2.0 mL) were
successively added at room temperature p-methoxybenzylamine (4.0 equiv), NaBH3CN (3.0
o
equiv) and ZnCl2 (1.0 equiv) in EtOH (1.0 mL), and stirred the mixture for 8 h at 65 C. After
completion of the reaction (TLC monitoring), it was cooled to room temperature followed by
diluting the reaction mixture with aqueous KHSO4 solution and extracted with Et2O. The organic
layer was dried over anhydrous Na2SO4, filtered and evaporated to get crude product (35a-35d).
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Highlights
•
Six different types of O-Bn protected proline derivatives were synthesized from
glycals.
D-
•
•
Di-O-Bn protected proline derivative was converted to pyrrolizidine derivatives.
1C-aryl/alkyl pyrrolidines were synthesized via double reductive amination.