New route to N-alkylated trans-pyrrolidine diols from 2,2,3,3- tetramethoxybutane-protected dimethyl tartrate

Article abstract of DOI:10.1080/00397910801916520

A short synthesis of some trans-pyrrolidine diols is described starting from (2R,3R,5R,6R)-5,6-dimethoxy-5,6-dimethyl[1,4]dioxane-2,3-dicarboxylic acid dimethyl ester 3. The key step was the occurrence of a tandem azide reduction/cyclization sequence on mono-azide intermediate 6 upon catalytic hydrogenation. This method afforded both (3R,4R)-(+)-1-benzyl-3,4- pyrrolidinediol 9a and (3R,4R)-(+)-1-allyl-3,4-pyrrolidinediol 9b starting from 3. Cytotoxicity tests were performed on compounds 9a and 9b using the brine shrimp bioassay, but each showed no activity, as were anti-oxidant tests using the stable free radical diphenylpicrylhydrazyl (DPPH). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801916520

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New Route to N‐Alkylated
trans‐Pyrrolidine Diols from
2,2,3,3‐Tetramethoxybutane‐Protected
Dimethyl Tartrate
J. Graça Martins a , P. Cambeiro Barrulas a , Carolina S. Marques a & Anthony
J. Burke a
a Chemistry Department and Évora Chemistry Centre , University of Évora ,
Évora, Portugal
Published online: 25 Apr 2008.
To cite this article: J. Graça Martins , P. Cambeiro Barrulas , Carolina S. Marques & Anthony J. Burke (2008)
New Route to N‐Alkylated trans‐Pyrrolidine Diols from 2,2,3,3‐Tetramethoxybutane‐Protected Dimethyl
Tartrate, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 38:9, 1365-1374, DOI: 10.1080/00397910801916520
To link to this article: http://dx.doi.org/10.1080/00397910801916520
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Synthetic Communicationsw, 38: 1365–1374, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801916520
New Route to N-Alkylated trans-Pyrrolidine
Diols from 2,2,3,3-Tetramethoxybutane-
Protected Dimethyl Tartrate
J. Grac¸a Martins, P. Cambeiro Barrulas, Carolina
S. Marques, and Anthony J. Burke
´
Chemistry Department and Evora Chemistry Centre, University of Evora,
´
´
Evora, Portugal
Abstract: A short synthesis of some trans-pyrrolidine diols is described starting
from (2R,3R,5R,6R)-5,6-dimethoxy-5,6-dimethyl[1,4]dioxane-2,3-dicarboxylic acid
dimethyl ester 3. The key step was the occurrence of a tandem azide reduction/cycliza-
tion sequence on mono-azide intermediate 6 upon catalytic hydrogenation. This
method afforded both (3R,4R)-(þ)-1-benzyl-3,4-pyrrolidinediol 9a and (3R,4R)-(þ)-
1-allyl-3,4-pyrrolidinediol 9b starting from 3. Cytotoxicity tests were performed
on compounds 9a and 9b using the brine shrimp bioassay, but each showed no
activity, as were anti-oxidant tests using the stable free radical diphenylpicrylhydrazyl
(DPPH).
Keywords: Alkylation, azidation, cyclization, dihydroxylated indolizidines
INTRODUCTION
trans-Dihydroxylated indolizidine alkaloids are a very important group of
compounds from the pharmacological and medical point of view, given that
in general they exhibit strong biological activities. Compounds such as (þ)-
lentiginosine, with potent amyloglucosidase inhibitory activity,[1] (2)-aniso-
mycin[2,3] and (2)-deacetylanisomycin,[4] which show strong and selective
Received in Poland September 3, 2007
Address correspondence to Anthony J. Burke, Chemistry Department and Evora
´
´
´
Chemistry Centre, University of Evora, Rua Roma˜o Romalho 59, Evora 7000,
Portugal. E-mail: ajb@dquim.uevora.pt
1365

1366
J. G. Martins et al.
Figure 1. Biologically active trans-dihydroxylated indolizidine alkaloids.
activity against pathogenic protozoa and fungi, and 2,5-dideoxy-2,5-imino-D-
mannitol (DMDP), which is an important glycosidase inhibitor[5] (Fig. 1),
contain this structure as their core unit.
Although some strategies exist[6] for the construction of the trans-pyrroli-
dine 3,4-diol unit, perhaps the most efficient way of accessing this important
structural unit is via tartaric acid, as it possesses the requisite relative stereo-
chemistry. There is the classical method of Nagel,[7] which uses (þ)-tartaric
acid and involves a very cumbersome imide reduction to give the pyrrolidine
in modest yields, or a similar method devised by Marson and Melling,[8]
which involves condensing (3R,4R)-diacetoxysuccinic anhydride with amines
followed by NaBH4/I2 reduction of the imide to the corresponding
di-acetoxy pyrrolidine intermediate, followed by a two-stage hydrolytic
workup to give trans-pyrrolidine 3,4-diols in only modest yields. Then there
are less direct methods with increased functional group manipulation, for
example, the method of McCaig et al.[9] starting from diethyl tartrate and
involving expensive methoxymethyl (MOM) protection of the hydroxyl
groups or the multistep method of Iida et al.[10] starting from 4-O-benzyl-2,3-
O-bis(methoxymethyl)-L-threose.
Over the past 10 years, (2R,3R,5R,6R)-5,6-dimethoxy-5,6-dimethyl[1,4]-
dioxane-2,3-dicarboxylic acid dimethyl ester 3, which was originally
unexpectedly prepared and used to form a 2,3-O-isopropylidene-2,3-
dihydroxy-1,4-bis(diphenylphosphino) butane (DIOP) analog[11] and there-
after used successfully as a chiral template for the synthesis of a variety of
biologically active targets,[12] something that had been predicted pre-
viously.[13] In our quest to obtain biologically active trans-dihydroxylated
indolizidine alkaloids, particularly with functionality in the 2 and 5
Scheme 1. Our approach to substituted trans-dihydroxylated indolizidine alkaloids.

N-Alkylated trans-Pyrrolidine Diols
1367
positions, we have considered the use of this building block as a starting point,
particularly for the translation of the natural chirality of (þ)-tartaric acid via
so-called chirality memory effects[14] (Scheme 1).
In this article we describe our preliminary results in the development of
this strategy.
RESULTS AND DISCUSSION
The strategy we selected involved converting the bis-acetal diester 3 to the
corresponding dimesylate 5 because of the efficiency of these two steps
(Scheme 2).[15] The azidation step predominantly gave the monoazide 6
with some of a known diazide derivative.[16] After some more experimen-
tation, we optimized the yield of 6 to 51%.
To increase the yield, we also looked at using the bulky azide transfer
reagent, diphenyl phosphoryl azide,[17] but this predominantly gave the
starting material. The method of Thompson et al.,[18] which can directly substi-
tute hydroxyl groups with azide groups, was evaluated. To probe this method,
we carried out a model reaction with (þ)-2,3-di-O-isopropylidene-L-threitol
10,[19] but the reaction failed to give the desired diazide 11 (Scheme 3).
We then used catalytic hydrogenation to reduce the azide to the corre-
sponding amine, but instead of getting the amine-mesylate 12, gratifyingly
we obtained the bicyclic chiral ammonium salt 7, with the pyrollidine ring
Scheme 2. (a) Ref. [15]; (b) Ref. [15]; (c) NaN3, CH3CN, reflux, 41% (with 24% dia-
zide product[16]; (d) 5% Pd/C, H2(g) (balloon), EtOAc (79%); (e) PPh3, H2O, THF
(90%); (f) NEt3 (4 eq), PhCH2Br (1.5 eq.; yield ¼ 38%) or allylbromide (1.5 eq.;
yield ¼ 30%), DMF, 60 8C; (g) 6 M HCl, MeOH, 80 8C.

1368
J. G. Martins et al.
Scheme 3. (a) (PhO)2PON3, DBU, THF, rt.
in place. However, we have previously observed that other protected systems
do not undergo this facile spontaneous cyclization in which the monoazide
acetonide 13 was transformed exclusively to the corresponding cyclic
monoamine acetonide 14.[20] The spontaneous cyclization observed in the
former case is most probably an indication of negligible or acceptable strain
in the bicyclic pyrrolidine 7.
As an alternative approach, we investigated the Staudinger azide
reduction;[21] however, this also gave the cyclic product 7 in excellent yield.
The ammonium salt 7 was then alkylated with benzylamine and allyl
bromide (these reactions were not optimized) to give the corresponding
tertiary amines 8a and 8b, which were then hydrolyzed to give the corres-
ponding trans-pyrrolidinediols, 9a ([a]2D2 ¼ þ22.5 [c ¼ 0.63, MeOH],
lit.[22] [a]D20 ¼ þ33.6 + 3 [c ¼ 1.05, MeOH]) and 9b ([a]2D3 ¼ þ11.9
[c ¼ 0.31, MeOH]), respectively.
The cytotoxicity (DL50) of compounds 9a and 9b were evaluated using
the brine shrimp bioassay (with Artemia salina).[23,24] However, no biological
activity was recorded using this model system. Tests to evaluate the anti-
oxidant activity of these compounds with the stable free radical diphenylpi-
crylhydrazyl (DPPH)[25] also were negative.[24]
We have demonstrated a simple and facile synthetic approach to alkylated
trans-pyrrolidinediols using the diacetal-protected tartaric acid precursor 3. In
terms of chemical diversity, besides furnishing a plethora of useful tertiary
trans-pyrrolidinediols, this approach should also give trans-pyrrolidinediol
amides, carbamates, sulphonamides, and other derivatives upon reacting 7
(Scheme 2) with suitable electrophiles. We are currently testing these
dihydroxylated indolizidines for antifungal activity and evaluating synthetic
methodologies for the incorporation of functional groups in the 2 and 5
positions.

N-Alkylated trans-Pyrrolidine Diols
EXPERIMENTAL
1369
General Methods
All reagents were obtained from Aldrich, Fluka, Alfa Aesar, or Acros.
Solvents were dried using common laboratory methods. The dimesylate
compound 5 was prepared according to the literature procedure.[15]
Column chromatography was carried out on silica gel (sds, 70–200 mm),
and flash chromatography with silica gel (Merck, 40–63 mm and sds, 40–
63 mm). Thin-layer chromatography (TLC) was carried out on aluminium-
backed Kiselgel 60 F254 plates (Merck). Plates were visualised either by UV
light or with phosphomolybdic acid in ethanol.
Melting points were recorded on a Leica Galen III apparatus and on a
1
Barnstead Electrothermal 9100 apparatus and are uncorrected. The H NMR
and 13C NMR spectra were recorded on either a Bruker AMX300 (1H:
300 MHz and 13C: 75 MHz) or a Bruker Avance instrument (1H: 400 MHz
and 13C: 100 MHz) using CDCl3 as solvent and TMS as internal standard
(for measurements made with the Bruker AMX300 instrument) and the
signal from residual CHCl3 as an internal standard (for the measurements
made with the Bruker Avance instrument). Mass spectra were recorded on a
VG Autospec M spectrometer using the FAB technique. Infrared spectra
were recorded using a Perkin-Elmer Paragon 1000 instrument. Optical
rotations were measured with a Perkin-Elmer 241 polarimeter using a
10-cm cell, and the concentrations are quoted in g/100 mL.
[(2R,3R,5S,6S)-5-Azidomethyl-2,3-dimethoxy-2,3-dimethyl-1,4-
dioxan-6-yl]methyl Methanesulphonate (6)
A suspension of sodium azide (0.17 g, 2.62 mmol) in acetonitrile (30 mL) was
added to a solution of the dimesylate 5 (0.97 g, 2.46 mmol) in acetonitrile
(30 mL) at rt. The mixture was then heated to 40 8C over a 21-h period and
then refluxed for another 3 h. The temperature was lowered to rt and stirred
at this temperature for another 16 h. Sodium azide (0.161 g, 2.48 mmol)
was added, and the suspension was refluxed for a further 4 h. The temperature
was lowered to rt, water (20 mL) was added, and the mixture was extracted
with CH2Cl2 (4 ꢀ 20 mL). The organic phase was dried (MgSO4) and the
solvent evaporated in vacuo to give the crude product mixture that existed
as a colorless oil and was purified by silica column chromatography
(EtOAc/hexane, 1/2), giving two bands.
Band 1
[(2R,3R,5S,6S)-5,6-bis(Azidomethyl)-2,3-dimethyl-2,3-dimethoxy-1,4-dioxane[16]
as a white solid (0.096 g, 24%); mp 77.8–79.4 8C; ymax(KBr) 2953, 2915,

1370
J. G. Martins et al.
1
2102, 1449, 1286, 1132 cm21; H NMR (CDCl3, 400 MHz) d (ppm): 1.32
(s, 6H, CH3), 3.19–3.23 (dd, J ¼ 13.5, 2.8, 2H, CHHN3), 3.31 (s, 6H,
OCH3), 3.33–3.39 (m, 2H, CHHN3), 3.86–3.88 (t, J ¼ 2.8, CHO) (agrees
with that given in Ref. [16b]).
Band 2
Title compound 6 as a colorless oil that solidified later (0.343 g, 41%), mp
80.4–80.6 8C; ([a]D22 ¼ 2114.5 (c ¼ 1.53, CHCl3);
ymax(KBr) 2948,
2832, 2104, 1455, 1354, 1128 cm21; H NMR (CDCl3, 400 MHz) d (ppm),
1.27 (s, 3H, CH3), 1.29 (s, 3H, CH3), 3.08 (s, 6H, SO3CH3), 3.25 (s, 3H,
OCH3), 3.26 (s, 3H, OCH3), 3.29–3.40 (m, 2H, CH2N3), 3.92 (m, 2H,
CHO), 4.20–4.35 (m, 2H, CH2SO3); 13C NMR (CDCl3, 100 MHz) d (ppm):
17.2, 37.8, 48.1, 50.6, 67.7, 68.9, 99.1; FAB-MS m/z: 340.09 [M þ H]þ,
308.07 [M þ H-OMe]þ, 280.08 [M þ H-2 ꢀ OMe]þ.
1
(2R,3R,5S,6S)-2,3-Dimethoxy-2,3-dimethyl-hexahydro-1,4-
dioxino[2,3-c]pyrrol-6-ium Mesylate (7)
Method A
Monoazide 6 (0.851 g, 2.51 mmol) was dissolved in EtOAc (25 mL) under a
nitrogen atmosphere. Palladium (5%) on carbon (0.086 g) was added, and
after 30 min, hydrogen was supplied using a balloon. After stirring for 22 h
at rt, the reaction mixture was filtered and the solvent evaporated in vacuo
to give the title compound 7 as a white solid (0.52 g, 79%), mp 154.3–
154.4 8C; [a]2D3 ¼ 243.4. (c ¼ 0.59, CHCl3); H NMR (CDCl3, 400 MHz)
1
d (ppm): 1.32 (s, 6H, CH3), 2.78 (s, 3H, SO3CH3) 3.15 (m, 2H, CHHN),
3.27 (m, 6H, OCH3), 3.52–3.57 (m, 2H, CHHN), 4.10 (m, 2H, CHO); 13C
NMR (CDCl3, 100 MHz) d (ppm): 17.8, 39.1, 43.0, 48.2, 68.6, 77.1, 100.9;
FAB-MS m/z: 218.12 [C10H20NOþ4 ]. Anal. calcd. for C11H23NO7S: C,
42.16; H, 7.41; N, 4.47; S, 10.3. Found: C, 42.28; H, 7.53; N, 4.38; S, 9.78.
Method B
Triphenylphosphine (1.15 g, 4.38 mmol) was added to the monoazide 6
(0.973 g, 2.87 mmol) dissolved in dry THF (7 mL) under a nitrogen atmos-
phere. After 15 min, water (1.8 mL) was added, and a small piece of boiling
stone was added to check the liberation of nitrogen gas. The reaction
mixture was kept at rt for 13 h, and thereafter the solvent was evaporated to
give a white solid (0.35 g, 90%), mp 152.9–153.1 8C; ymax(KBr) 3345,
2945, 1642, 1402, 1378, 1134 cm21
.

N-Alkylated trans-Pyrrolidine Diols
1371
6-Benzil-2,3-dimethoxy-2,3-dimethylhexahydro-[1,4]dioxino[2,3-c]
pyrrole (8a)
The ammonium salt 7 (0.276 g, 0.881 mmol) was dissolved in DMF (3 mL)
under an atmosphere of nitrogen. NEt3 (0.5 mL, 3.523 mmol) and benzylbro-
mide (0.16 mL, 1.32 mmol) were added slowly by syringe. The reaction
mixture was heated at 60 8C for 45 h, and the reaction monitored by TLC.
The reaction mixture was then cooled to rt, and then water (10 mL) and
CH2Cl2 (10 mL) were added. The organic phase was separated, and the
aqueous phase extracted with CH2Cl2 (3 ꢀ 10 mL). The combined organic
phase was washed with water (8 ꢀ 10 mL) to remove residual DMF. It was
then dried (MgSO4) and filtered, and the solvent evaporated in vacuo to
give a brown oil. This was purified by flash chromatography on silica gel,
using hexane/EtOAc (5:1) giving the title compound 8a as a pale yellow
1
oil (0.104 g, 38%); [a]2D3 ¼ 2169.3 (c ¼ 1.52, CHCl3); H RMN (CDCl3,
400 MHz) d (ppm): 1.34 [s, 6H (CH3)], 2.80–2.93 [m, 4H (RCH2N)], 3.28
[s, 6H (OCH3)], 3.70–3.90 [m, 2H (CHO)], 4.09–4.11 [m, 2H (PhCH2N)],
7.27–7.32 [s, 5H (Ar)]; 13C NMR (CDCl3, 100.61 MHz) d (ppm): 18.04,
47.85, 51.55, 61.53, 70.37, 100.71, 128.26, 138.94; ymax(KBr) 3020, 2839,
1519, 1215, 1037, 758 cm21; FAB-MS m/z: 308.15 (Mþ þ 1), 307.07
(C17H25NOþ4 ).
6-Allyl-2,3-dimethoxy-2,3-dimethylhexahydro-[1,4]-dioxino[2,3-c]
pirrole (8b)
The ammonium salt 7 (0.5 g, 1.6 mmol) was dissolved in DMF (6 mL) under
an atmosphere of nitrogen. NEt3 (0.9 mL, 6.38 mmol) and allylbromide
(0.21 mL, 2.4 mmol) were added slowly by syringe. The reaction mixture
was heated at 60 8C for 23 h, and the reaction was monitored by TLC. The
reaction mixture was then cooled to rt, and then water (20 mL) and CH2Cl2
(20 mL) were added. The organic phase was separated, and the aqueous
phase was extracted with CH2Cl2 (3 ꢀ 10 mL). The combined organic
phase was washed with water (8 ꢀ 10 mL) to remove residual DMF. It was
then dried (MgSO4) and filtered, and the solvent was evaporated in vacuo to
give a brown oil. This was purified by flash chromatography on silica gel,
using hexane/EtOAc (2:1) to give the title compound 8b as a pale yellow
1
oil (0.121 g, 30%); [a]2D2 ¼ 2132.11 (c ¼ 0.85, CHCl3); H NMR (CDCl3,
300 MHz) d (ppm): 1.32 [s, 6H (CH3)], 2.78–2.84 [m, 4H (RCH2N)],
2.96–3.01 [m, 2H (NCH2C55C)], 3.27 [s, 6H (OCH3)], 5.17–5.26 [m, 2H
(CH255C)], 5.80–5.93 [m, 1H (RCH55C)]; 13C NMR (CDCl3, 100.61
MHz) d (ppm): 17.99, 48.02, 50.80, 59.82, 69.59, 100.84; ymax(KBr) 3053,
2986, 1549, 1530, 1265, 1144, 748 cm21; FAB-MS m/z: 258.18 (Mþ þ 1),
257.17 (C13H23NOþ4 ), 242.15 (C12H20NOþ4 ), 230.18 (C11H20NOþ4 ).

1372
J. G. Martins et al.
(3S,4S)-(1)-1-Benzyl-3,4-pyrrolidinediol (9a)
Compound 8a (0.143 g, 0.465 mmol) was dissolved in a solution of freshly
prepared MeOH/6 M HCl (1/1, 16 mL), and the resulting solution was sub-
sequently heated at 80 8C for 1 h. The temperature was lowered to 70 8C,
and the reaction mixture was heated at this temperature overnight.
Afterward the temperature was raised again to 80 8C for 4 h, after which it
was lowered to ice temperature using an ice bath. Solid sodium carbonate
was added until the pH reached 10. The solids were removed, and the
solvent was evaporated in vacuo. The residue was extracted with CH2Cl2
(8 ꢀ 10 mL), the combined organic extracts were dried (MgSO4), and the
solvent was evaporated in vacuo to give a brownish oil, which was purified
by silica-gel column chromatography with EtOAc to give the title
[22]
compound as a brownish gum (0.088 g, 98%); [a]D
¼ þ22.5 (c ¼ 0.63,
MeOH), lit.[22] [a]D20 ¼ þ33.6+3 (c ¼ 1.05, MeOH); 1H NMR (CDCl3,
400 MHz) d (ppm): 2.46–2.53 [m, 4H (RCH2N)], 2.93–3.00 [m, 2H
(CHOH)], 4.03–4.10 [m, 2H (PhCH2N)], 7.20–7.40 [s, 5H (Ar)]; 13C NMR
(CDCl3, 100.61 MHz) d (ppm): 60.05, 60.16, 77.29, 128.36, 137.24.
(3S,4S)-(1)-1-Allyl-3,4-pyrrolidinediol (9b)
Compound 8b(0.1 g, 0.389 mmol) wasdissolved in a solutionoffreshly prepared
MeOH/6 M HCl (1/1, 16 mL), and the resulting solution was subsequently
heated at 80 8C for 1 h. The temperature was lowered to 70 8C, and the
reactionmixturewasheatedatthistemperatureovernight. Afterwardthetempera-
ture was raised again to 80 8C for 4 h, after which it was lowered to ice tempera-
ture using an ice bath. Solid sodium carbonate was added until the pH reached 10.
The solids were removed, and the solvent was evaporated in vacuo. The residue
was extracted with CH2Cl2 (8 ꢀ 10 mL), the combined organic extracts were
dried (MgSO4), and the solvent was evaporated in vacuo to give a yellowish
sticky solid (0.045 g, 81%); [a]2D3 ¼ þ11.9 (c ¼ 0.31, MeOH); 1H NMR
(DMSO-d6, 300 MHz) d (ppm): 2.30–2.34 [m, 4H (RCH2N)], 2.73–2.78 [m,
2H (NCH2C55C)], 2.94–3.08 [m, 2H (CHOH)], 5.05–5.19 [m, 2H
(CH2C55C)], 5.74–5.87 [m, 1H (RCH55C)]; 13C NMR (DMSO-d6,
100.61 MHz) d (ppm): 58.68, 60.40, 77.20, 116.74, 135.75; ymax(KBr) 3405,
2925, 2852, 1645, 1572, 1231, 1095, 998 cm21; FAB-MS m/z: 143.94
(C7H13NOþ2 ), 125.09 (C7H11NOþ), 116.11 (C5H10NOþ2 ), 107.19 (C7H9Nþ).
ACKNOWLEDGMENTS
´
The personnel of the analytical service unit at Centro de Apoio Cientıfico-Tec-
´
´ ´
noloxico a Investigacion (CACTI) (University of Vigo, Spain) are gratefully
acknowledged for chemical analyses.

N-Alkylated trans-Pyrrolidine Diols
1373
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