Total synthesis without protecting groups: Pyrrolidines and cyclic carbamates

Article abstract of DOI:10.1021/ol802484y

(Chemical Equation Presented) A protecting group free synthesis of 2,3-cis substituted hydroxypyrrolidines is reported. Two novel reaction methodologies allow for the stereoselective formation of cyclic carbamates from olefinic amines, and the formation o

Full text of DOI:10.1021/ol802484y

ORGANIC
LETTERS
2009
Vol. 11, No. 3
535-538
Total Synthesis Without Protecting
Groups: Pyrrolidines and Cyclic
Carbamates†
Emma M. Dangerfield,‡,§ Mattie S. M. Timmer,*,‡,§ and Bridget L. Stocker*,‡
Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand, and
School of Chemical and Physical Sciences, Victoria UniVersity of Wellington,
PO Box 600, Wellington, New Zealand
bstocker@malaghan.org.nz
Received October 28, 2008
ABSTRACT
A protecting group free synthesis of 2,3-cis substituted hydroxypyrrolidines is reported. Two novel reaction methodologies allow for the
stereoselective formation of cyclic carbamates from olefinic amines, and the formation of primary amines via a Vasella/reductive amination
reaction, both performed in aqueous media.
As noted inhibitors of glycosidases, imino-sugars have
enormous therapeutic potential in diseases such as viral
infection, bacterial infection, lysosomal storage disorders,
cancer and diabetes.1 Although the nature of the glycosidases
that will be inhibited by certain imino-sugars can, to some
extent, be predicted from the number, position and config-
uration of the substituents, there can be marked differences
in the inhibition of isoenzymes of a given glycosidase in
different species and even within the same cell.1a Many
tumor cells display aberrant glycosylation due to an altered
expression of glycosyltransferases2 and levels of glycosidases
are elevated in the sera of many patients with tumors.3
However, largely due to the limited availability of the imino-
sugars, only few [principally 1-deoxynojirimycin (DNJ),
1-deoxymannojirimycin (DMJ), Castanospermine, and Swain-
sonine (Figure 1)] have been widely studied for their
therapeutic potential.1b
Figure 1. Imino-sugars widely studied for their therapeutic potential.
† Dedicated to Professor Brian Halton on the occasion of his 40th year
at Victoria University of Wellington.
‡ Malaghan Institute of Medical Research.
Five-membered imino-sugars are also known as hydroxy-
pyrrolidines and include the R-galactosidase inhibitor 1,4-
dideoxy-1,4-imino-D-lyxitol (1),4 the mannosidase inhibitors
1,4-dideoxy-1,4-imino-D-mannitol (2)5 and its 6-deoxy ana-
logue (3),6 1,4-dideoxy-1,4-imino-D-xylitol (4),7 and 1,4-
§ Victoria University of Wellington.
(1) For reviews see: (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet,
G. W. Tetrahedron Asymm. 2000, 11, 1645–1680. (b) Watson, A. A.; Fleet,
G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phytochemistry 2001,
56, 265–295. (c) Wrodnigg, T. M.; Steiner, A. J.; Ueberbacher, B. J.
Anticancer Agents Med. Chem. 2008, 8, 77–85. (d) Butters, T. D.; Dwek,
R. A.; Platt, F. M. Curr. Top. Med. Chem. 2003, 3, 561–574.
(2) Hakomori, S. Cancer Res. 1985, 45, 2405–2414.
(4) Fleet, G. W. J.; Nicholas, S. J.; Smith, P. W.; Evans, S. V.; Fellows,
L. E.; Nash, R. J. Tetrahedron Lett. 1985, 26, 3127–3130.
(3) Wollen, J. W.; Turner, P. Clin. Chim. Acta 1965, 12, 671–683.
10.1021/ol802484y CCC: $40.75
Published on Web 12/23/2008
2009 American Chemical Society

dideoxy-1,4-imino-L-lyxitol (5)8 (Figure 2). More elaborate
members include Swainsonine9 (Figure 1) (whose properties
include the inhibition of both lysosomal R-mannosidase10
and mannosidase II11), the antibiotic Anisomycin (6),12
Broussonetinine A (7),13 and the potent inhibitor of ꢀ-ga-
lactosidase and R-mannosidase, Gualamycin (8)14 (Figure
2).
and all employ standard protecting group manipulations. The
use of protecting groups has the disadvantage of requiring
organic solvents for reaction, workup, and purification, which
is environmentally deleterious. In addition, extensive protect-
ing group manipulations lead to lengthy syntheses requiring
both a protection and deprotection step per protecting group,
resulting in reduced atom economy, and hence reaction
efficiency. In view of this, we investigated a protecting-group
free synthesis of polyhydroxylated pyrrolidine alkaloids.
It has previously been reported that cyclic carbamates can
be prepared, in modest yield, from the reaction of acylic
amines equipped with a halogen-leaving group and either
tetraethylammonium bicarbonate17 or sodium carbonate.18
In view of this, we postulated that the imino-sugars 9 could
be prepared via an iodine-promoted halocyclization/in situ
carbonylation reaction to give carbamates 10, which could
be subsequently hydrolyzed (Scheme 1). The linear amino-
Figure 2. Compounds containing the 2,3-cis-disubstituted hydroxy-
pyrrolidine core.
Scheme 1. Retrosynthesis for the Formation of
Polyhydroxylated Pyrrolidines via Cyclic Carbamates
Many strategies for the synthesis of cis-2-substituted-3-
hydroxypyrrolidines (such as 1, 4, and 5) have been
reported.15,16 Though elegant and creative, many of these
strategies are lengthy, some show poor diastereoselectivity,
(5) Fleet, G. W. J.; Smith, P. W.; Evans, S. V.; Fellows, L. E. J. Chem.
Soc., Chem. Commun. 1984, 1240–1241.
alcohols 11 are in turn accessible via reductive amination
of hydroxyaldehydes, themselves obtained following Vasella
reaction of methyl iodofuranosides 12,19 prepared in two
steps from pentose monosaccharides. Thus, the chiral
information embedded within the pentose carbohydrate
precursors would be translated into the final products and,
without the use of protecting groups, the complete synthesis
will be amenable to chemistry in aqueous media.
(6) Eis, M. J.; Rule, C. J.; Wu¨rzburg, B. A.; Ganem, B. Tetrahedron
Lett. 1985, 26, 5397–5398.
(7) Saludes, J. P.; Lievens, S. C.; Molinski, T. F. J. Nat. Prod. 2007,
70, 436–438.
(8) Nash, R. J.; Bell, E. A.; Williams, J. M. Phytochemistry 1985, 24,
1620–1622.
(9) Guengerich, F. P.; DimMari, S. J.; Bromquist, H. P. J. Am. Chem.
Soc. 1973, 95, 2055.
(10) Liao, Y. F.; Lal, A.; Moreman, K. W. J. Biol. Chem. 1996, 271,
28348–28358.
The synthesis of the hydroxypyrrolidines starts with the
conversion of D-xylose (13, Scheme 2) into its methyl
(11) Kaushal, G. P.; Szumilo, T.; Pastuszak, I.; Elbein, A. D. Biochem-
istry 1990, 29, 2168–2176.
(12) Sobin, B. A.; Tanner, F. W., Jr. J. Am. Chem. Soc. 1954, 76, 4053.
(13) Shibano, M.; Kitagawa, S.; Nakamura, S.; Akazawa, N.; Kusano,
G. Chem. Pharm. Bull. 1997, 45, 700–705.
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T.; Shimada, N.; Kobayashi, K. J. Antibiot. 1995, 48, 626–629.
(15) La Fera, B.; Nicotra, F. Synthetic Methods for the Preparation of
Iminosugars. In Iminosugars as Glycosidase Inhibitors: Norjirimycin and
Beyond; Stu¨tz, A. E., Ed.; Wiley-VCH: Weinheim, Germany, 1999; Chapter
4, pp 68-92.
Scheme 2. Synthesis of cis-2,3-Disubstituted
Hydroxypyrrolidines Using Novel Annulation Methodology
(16) For recent examples see: (a) Merino, P.; Delso, I.; Tejero, T.;
Cardona, F.; Marradi, M.; Faggi, E.; Parmeggiani, C.; Goti, A. Eur. J. Org.
Chem. 2008, 292, 9–2947. (b) Huang, Y.; Dalton, D. R.; Carroll, P. J. J.
Org. Chem. 1997, 62, 372–376. (c) D´ıez, D.; Templo Bebe´itez, M.; Gil,
M. J.; Moro, R. F.; Marcos, I. S.; Garrido, N. M.; Basabe, G. P. Synthesis
2005, 4, 565–568. (d) Marradi, M.; Cicchi, S.; Delso, J. I.; Rosi, L.; Tejero,
T.; Merino, P.; Goti, A. Tetrahedron Lett. 2005, 46, 1287–1290. (e) Davis,
A. S.; Gates, N. J.; Lindsay, K. B.; Tang, M.; Pyne, S. G. Synlett 2004, 1,
49–52. (f) Lindsey, K. B.; Pyne, S. G. Aust. J. Chem. 2004, 57, 669–672.
(g) Espelt, L.; Parella, T.; Bujons, J.; Solans, C.; Joglar, J.; Delgado, A.;
Clape´s, P. Chem.-Eur. J. 2003, 9, 4887–4899. (h) Sawada, D.; Takahashi,
H.; Ikegami, S. Tetrahedron Lett. 2003, 44, 3085–3088. (i) Ghavami, A.;
Johnston, B. D.; Maddess, M. D.; Chinapoo, S. M.; Jensen, M. T.; Svensson,
B.; Pinto, B. M. Can. J. Chem. 2002, 80, 937–942. (j) Sugiura, M.; Hagio,
H.; Kobayashi, S. HelVetica Chemica Acta. 2002, 85, 3678–3691. (k) Lei,
A. L.; Liu, G.; Lu, X. J. Org. Chem. 2002, 67, 974–980. (l) Wang, C.-C.;
Luo, S.-Y.; Shie, C.-R.; Hung, S.-C. Org. Lett. 2002, 4, 847–849. (m)
Garner, P.; Dogan, O.; Youngs, W. J.; Kennedy, V. O.; Protasiewicz, J.;
Zaniewski, R. Tetrahedron 2001, 57, 71–85. (n) Lee, B.; Jeong, I.-L.; Yang,
furanoside by a Fisher glycosidation and treatment of the
crude product with iodine and triphenylphosphine to give
(17) Inesi, A.; Mucciante, V.; Rossi, L. J. Org. Chem. 1998, 63, 1337–
1338.
M. S.; Choi, S. U.; Park, K. H. Synthesis 2000, 9, 1305–1309
.
(18) Hassner, A.; Burke, S. S. Tetrahedron 1974, 30, 2613–2621.
536
Org. Lett., Vol. 11, No. 3, 2009

the methyl 5-iodofuranoside 14.20 Vasella reaction of io-
doglycoside 14 with zinc in ethanol in the presence of
catalytic acetic acid showed complete conversion of the
starting material to a less mobile product, as gauged by TLC,
but isolation of pure aldehyde proved problematic. In
contrast, in situ imine formation using (diphenylmethyl)-
amine and subsequent reduction with sodium cyanoborohy-
dride led to the smooth formation of amine 15 in a three-
step, one-pot procedure. Deprotection of crude amine 15,
using TFA and Et3SiH, gave linear amine 16 as the TFA
salt in 93% over the two steps. With the olefinic amine in
hand, we set out to produce the pyrrolidine ring system via
halocyclization. As anticipated, subjecting amine 16 to iodine
and NaHCO3 in water led to the formation of a single product
with a mass of 160.0605 [M + H+] and a carbonyl group,
as evidenced by a carbonyl peak at 1680 cm-1 in the IR and
δ164.4 in the 13C NMR spectra. Extensive 2D NMR analysis
(COSY, HMBC, HSQC) confirmed the compound to be
cyclic carbamate 17 {[M + H+] required:160.0604}, isolated
as a single diastereoisomer in near quantitative yield.
The formation of the cyclic carbamate can be rationalized
by the in situ reaction of the initial haloamine 18 in a tandem
carbonylation reaction, similar to that described for addition
of CO2 to 1,2-hydroxyhalides.21 In our case, the generated
haloamine is believed to react with CO2 formed in situ.
Interestingly, sodium bicarbonate and iodine have been used
in the halocyclization of preformed olefinic carbamates
(methoxycarbonyl amides), but cyclization of these substrates
led to mixtures of five- and six-membered cyclic amides.22
The reactions were slow (two weeks) and poor yielding.22
The halocyclization/ carbonylation reaction however, pro-
ceeds with complete diastereo- and regioselectively to give
the five-membered cis-2,3-product exclusively. The cis-2,3-
configuaration is in agreement with observations that iodine-
promoted intramolecular cyclizations are often directed by
the allylic hydroxyl to give preferentially the cis-product.23
The stereochemistry of carbamate 17 was unequivocally
proved by hydrolysis of the carbamate to form known D-xylo
pyrrolidine 416b in excellent yield (99%). Interestingly,
subjection of unprotected amine 16 to iodine in the presence
of DBU did not lead to product, while prolonged reaction
times or the use of a stronger base (NaOH) gave a complex
mixture resembling both isomers of iodomethylpyrrolidine
18 and iodopiperidine 19 products, as previously observed.24
Altering the source of iodine to N-iodosuccinimide (NIS),
without NaHCO3 as a base, gave a similar result. These
observations demonstrate the critical importance of both
NaHCO3 and I2 in this annulation.
Given the potential of this annulation methodology, we
set out to develop a method to synthesize precursor olefinic
amine 16 without any need for protecting groups. It is a well-
known fact that the use of ammonia or ammonium salts in
reductive amination reactions typically results in the forma-
tion of amine dimers (cf. 20, Table 1) due to the lower
nucleophilicity of ammonia compared to the primary amine
product of the reductive amination. However, given that our
initial experiments using ammonium chloride in the
reductive amination lead to mixtures of monomer and
dimer, we optimized the reaction conditions to achieve
preferential formation of monomer 16 and present the
results in Table 1.
Table 1. Vasella Reductive Aminations of Furan 14
yield
(16)d
,
entry
conditionsa b
ratio 16:20c
1
(NH4)2CO3 (10 equiv)
NH4Cl (10 equiv)
NH4HCO3 (10 equiv)
NH4OAc (10 equiv)
NH4OAc (100 equiv)
NH4OAc (sat.)
3:7
2:3
2:3
2:3
1:1
3:2
30%
2
40%
3
40%
4
40%
5
50%
6
60%
7
NH4OAc (sat.), AcOH (10 equiv) 4.5:5.5
45%
8
NH3 (30% solution in H2O)
NH3 (60 equiv), TFA (2 equiv)
NH3 (60 equiv), AcOH (7 equiv) 3:2
NH4OAc (sat.), NH3 (10 equiv)
NH4OAc (sat.), NH3 (60 equiv)
s
5.5:4.5
degradation
55%
9
10
11
12
60%
4:1
20:1
80%
96% (95%)e
a All reactions were performed by the addition of activated Zn (5 equiv),
amine (as indicated) and NaCNBH4 (2 equiv) to a solution of the
iodofuranoside in ethanol (20 mL/mmol). b NH3 was added as a 30%
solution in H2O. c Ratios calculated from the integral values of the
corresponding H NMR signals (16:20). d Molar yields. e Isolated yield.
1
In optimizing the yield and selective formation of the
monomer, our efforts first focused on the effects of the anion
in the ammonium salt [NH4Cl, (NH4)2CO3, NH4HCO3 and
NH4OAc; Table 1, Entries 1-4]. With the exception of the
less soluble carbonate, the addition of 10 equivalents of salt
gave very similar results with monomer being formed in
reasonable yield (40%), but mediocre selectivity (2:3, mono-
mer:dimer, w/w). Next, taking advantage of the greater
solubility of NH4OAc in EtOH, we increased the concentra-
tion of NH4OAc in an attempt to drive monomer formation.
An increase from 10 to 100 equiv NH4OAc proved beneficial
with the monomer being formed in a 1:1 ratio (Entry 5).
Increasing the ammonia concentration through use of a
saturated solution of NH4OAc in EtOH again showed a
marked improvement in the formation of the monomer, both
in yield (60%) and selectivity (3:2) (Entry 6).
(19) (a) Bernet, B.; Vasella, A. HelV. Chim. Acta 1979, 62, 1990–2016.
(b) Bernet, B.; Vasella, A. HelV. Chim. Acta 1979, 62, 2400–2410.
(20) Skaanderup, P. R.; Poulsen, C. S.; Hyldtoft, L.; Jørgensen, M. R.;
Madsen, R. Synthesis 2002, 12, 1721–1727.
(21) Kihara, N.; Hara, N.; Endo, T. J. Org. Chem. 1993, 58, 6198–
6202.
(22) Tamaru, Y.; Kawamura, S.; Tanaka, K.; Yoshida, Z. Tetrahedron
Lett. 1984, 25, 1063–1066.
(23) (a) Chamberlin, A. R.; Mulholland, R. L.; Kahn, S. D.; Hehre, W. J.
J. Am. Chem. Soc. 1987, 109, 672–677. (b) Chamberlin, A. R.; Dezube,
M.; Dussault, P.; McMills, M. C. J. Am. Chem. Soc. 1983, 105, 5819–
5825. (c) Timmer, M. S. M.; Verhelst, S. H.; Grotenbreg, G. M.; Overhand,
M.; Overkleeft, H. S. Pure Appl. Chem. 2005, 77, 1173–1181.
(24) Verhelst, S. H. L.; Martinez, B. P.; Timmer, M. S. M.; Lodder, G.;
Van der Marel, G. A.; Overkleeft, H. S.; Van Boom, J. H. J. Org. Chem.
2003, 68, 9598–9603.
The nucleophilicity of amination product 16 is higher than
ammonia and causes the problems associated with the
formation of dimer 20. Likewise, amine 16 is more basic
Org. Lett., Vol. 11, No. 3, 2009
537

than ammonia. The correct balance between free and
protonated ammonia was thought, therefore, to be critical in
the optimization. To test this, a series of experiments were
performed in which the ammonium salt to ammonia ratio
was altered. First, the addition of AcOH to a saturated
solution of NH4OAc (Entry 7) led to a reduction in both
yield and selectivity compared to NH4OAc alone (cf. Entry
6); thus, a more basic reaction medium is needed. Use of
30% aqueous ammonia as the amine source with various
concentrations of added acids were assessed. Without acid
(Entry 8), degradation of starting material occurred and no
product could be detected. The use of trifluoroacetic acid
(TFA) or acetic acid (Entries 9 and 10) led to product
formation, albeit without significant improvements in mono-
mer yield. In contrast, adding ammonia (10 equiv) to a
saturated NH4OAc solution in EtOH provided a marked
improvement in both selectivity and monomer yield (80%),
(Entry 11). Further optimization via addition of 60 equiv of
ammonia (Entry 12), resulted in almost exclusive formation
of amine 16, in excellent yield (95%).
Scheme 3. Synthesis of the cis-2,3-Disubstituted
Hydroxypyrrolidine 5 from D-Ribose
22 (67%), following literature proceedures.20 Again, Vasella
reductive amination proceeded smoothly to the olefinic amine
23 (91%). Halocyclization/carbonylation using our iodine-
promoted annulation methodology gave carabamate 24 in
93% yield, which was hydrolyzed (97%) to the cis-2,3-
disubstituted 1,4-dideoxy-1,4-imino-L-lyxitol 5, with data in
full agreement with those published.16b
Due to the absence of protecting groups and the associated
water solubility of monomer 16, removal of excess am-
monium acetate was achieved only after adding HCl in
isopropanol to the reaction mixture; the much less soluble
NH4Cl was removed by filtration through Celite. Following
normal phase SiO2 column chromatography, monomer 16
was isolated in 95% yield (as its HCl salt) and subsequently
cyclized to carbamate 17, again quantitatively. To the best
of our knowledge, this provides the first efficient synthesis
of a primary amine via reductive amination methodology
without any need for functional group protection. The
usefulness of this remarkably efficient transformation is ably
demonstrated by the five-step synthesis of imino-sugar 4, in
57% overall yield; this is the best reported to date. The
reductive amination with tandem halocyclization/carbony-
lation reaction shows promise, as cyclic carbamates them-
selves exhibit interesting biological activities,25 and are useful
synthetic intermediates for a wide range of imino-sugars,
including (-)-8-epi-swainsonine,26 pyrrolizidine alkaloids
such as (-)-7-epiaustraline, (-)-1,7-diepiaustraline,27 and
pyrrolam A.28
As illustrated, the entire synthetic route can be ac-
complished without need of group protection and with most
reactions being performed in nontoxic solvents (EtOH or
water). It is effected in a mere five steps, with an overall
yield of 55%, again the highest yet reported.
Herein we have reported a novel, stereoselective, five-
step strategy for the synthesis of cis-2,3-disubstituted hy-
droxypyrrolidines. This strategy is not merely competitive
in yield and the number of linear-steps, but employs many
of the principles of Green Chemistry. Few alternative total
syntheses proceed without the need for functional group
protection. Furthermore, we have identified two novel
reaction methodologies: the first for the stereoselective
formation of cyclic carbamates from olefinic amines, and
the second, for the formation of primary amines without the
need for protecting groups. Given the growing importance
of environmentally benign chemistry, our two new synthetic
methodologies are important additions to the Green Chem-
ist’s toolbox. We believe that both methodologies will find
wide application in the synthesis of a range of imino-sugars.
Further investigations into the scope and limitations of this
annulation reaction are underway in our laboratories.
To illustrate the versatility of the protecting group-free
synthesis of cis-2-substituted-3-hydroxypyrrolidines, we set
out to synthesize 1,4-dideoxy-1,4-imino-L-lyxitol (5) (Scheme
3). D-Ribose (21) was converted into methyl iodoglycoside
Acknowledgment. The Foundation for Science Research
and Technology (NZ) and the Tertiary Education Commis-
sion (NZ) for financial support. Dr J. Ryan (VUW) is
gratefully acknowledged for his assistance with NMR.
(25) Epple, R.; Urbina, H. D.; Russo, R.; Liu, H.; Mason, D.; Bursulaya,
B.; Tumanut, C.; Li, J.; Harris, J. L. Bioorg. Med. Chem. Lett. 2007, 17,
1254–1259.
Supporting Information Available: Full experimental
details and spectroscopic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(26) Murray, A. J.; Parsons, P. J.; Hitchcock, P. Tetrahedron 2007, 63,
6485–6492.
(27) Tang, M.; Pyne, S. G. J. Org. Chem. 2003, 68, 7818–7824.
(28) Aoyagi, Y.; Manabe, T.; Ohta, A.; Kurihara, T.; Pang, G.-L.;
Yuhara, T. Tetrahedron 1995, 52, 869–876.
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