Flexibility in the partial reduction of 2,5-disubstituted pyrroles: application to the synthesis of DMDP.

Article abstract of DOI:10.1021/ol027504h

[reaction: see text] The partial reduction of electron-deficient 2,5-disubstituted pyrroles has been developed into a flexible procedure that gives control of relative stereochemistry by variation of the reduction conditions. After the reaction, the pyrro

Full text of DOI:10.1021/ol027504h

ORGANIC
LETTERS
2003
Vol. 5, No. 7
999-1002
Flexibility in the Partial Reduction of
2,5-Disubstituted Pyrroles: Application
to the Synthesis of DMDP
,†
Timothy J. Donohoe,* Catherine E. Headley,†,‡ Rick P. C. Cousins,§ and
Andrew Cowley†,|
Dyson Perrins Laboratory, UniVersity of Oxford, South Parks Road,
Oxford, OX1 3QY, United Kingdom, Department of Chemistry,
UniVersity of Manchester, Oxford Road, Manchester, M13 9PL,
United Kingdom, GlaxoSmithKline, Medicines Research Centre,
Gunnels Wood Road, SteVenage, SG1 2NY, United Kingdom
timothy.donohoe@chem.ox.ac.uk
Received December 19, 2002
ABSTRACT
The partial reduction of electron-deficient 2,5-disubstituted pyrroles has been developed into a flexible procedure that gives control of relative
stereochemistry by variation of the reduction conditions. After the reaction, the pyrroline products were dihydroxylated at C-3,4 to give either
the cis or trans isomers; this flexibility means that a variety of polyhydroxylated pyrrolidines can be prepared in a short sequence. Finally,
this method was applied to a synthesis of the naturally occurring glycosidase inhibitor DMDP.
Polyhydroxylated pyrrolizidines and pyrrolidines are a series
of natural products with intriguing structures and potent
biological activity, which centers around their ability to
inhibit a variety of glycosidases, Figure 1.1
Our approach to this polyhydroxylated skeleton derives
from the partial reduction of substituted pyrroles2 and, in
In particular, there are two stereochemical motifs that are
common to several of these natural products: most have
either cis or trans hydroxymethyl substituents at C-2 and C-5,
combined with either a cis or trans array of hydroxyl groups
at C-3 and C-4.
† University of Oxford.
‡ University of Manchester.
§ GlaxoSmithKline.
| To whom correspondence regarding the crystal structures should be
addressed.
(1) See: (a) White, J. D.; Hrnciar, P. J. Org. Chem. 2000, 65, 9129. (b)
Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi,
I.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1.
Figure 1.
10.1021/ol027504h CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/08/2003

particular, our ability to partially reduce compound 1 (Figure
1).3 We sought a method of varying the stereochemistry
obtained after reduction and, in addition, the means to
produce either cis- or trans-diols at the C-3,4 positions. We
view this flexible approach to the simple pyrrolidine skeleton
(see DMDP4) as an introduction to the synthesis of the more
complex pyrrolizidine analogues such as australine, alexine
and hyacinthacine C1.1
This program of research relies on an efficient synthesis
of the diester starting material 1. After some experimentation,
we found that commercially available N-Boc pyrrole could
be doubly lithiated with lithium 2,2,6,6-tetramethylpiperidide
(LiTMP), followed by a quench with methyl chloroformate,
Scheme 1.5 With a multigram, one-step synthesis of 1 in
Figure 2.
Scheme 1a
The mechanism of reduction can be explained by forma-
tion of a relatively stable dianion A after addition of two
electrons to the starting material 1 (Figure 2). We suggest
that reaction with a bulky acid such as 2,6-di-tert-butylphenol
means that, after a single protonation, the resulting mo-
noenolate B reacts from the least hindered face to produce
cis-2. The reason for the trans selectivity during (kinetic)
protonation in ammonia is more obscure. At this juncture,
we wish only to point out the differences between reduction/
protonation in ammonia versus that in THF: (1) the
aggregation state of the enolate intermediate B is likely to
be very different in ammonia versus THF;8 (2) the geometry
of enolate B is not known and may differ depending on the
amount of chelation between the enolate OLi and the Boc
group; and (3) ammonia solvent has the ability to act as an
acid whereby the proton that becomes attached to the enolate
carbon may not be the same one as that added to the reaction
mixture as ammonium chloride.9
With the synthesis of cis- and trans-2 in hand, we
attempted to prepare the substitution pattern of the pyrrolidine
natural products. Ideally, we want to be able to set the
stereochemistry of the C-3,4 hydroxyl groups as either cis
or trans, starting from both cis- and trans-2.
Initially, the protected diols 3 and 6 were prepared via a
two-step sequence from the corresponding esters, Scheme
2. X-ray structural analysis confirmed the stereochemistry
of trans-2.
a Reagents and conditions: (a) LiTMP, MeOCOCI; (b) Li, NH3,
THF, then NH4Cl; (c) Li, cat. DBB, THF, then 2,6-di-tert-
butylphenol.
hand, we then examined the partial reduction of this com-
pound, searching for conditions that would influence the
stereochemistry of this process.
By variation of the reaction conditions, we discovered that
pyrrole 1 could be reduced to give the trans isomer of 2
with good diastereoselectivity, using lithium in ammonia and
quenching with ammonium chloride, Scheme 1.3 Remark-
ably, reduction under “ammonia-free” conditions (Li, cata-
lytic DBB, THF)6 followed by protonation with 2,6-di-tert-
butylphenol gave cis-2 exclusively.7 Control experiments
showed that each isomer was formed under kinetic control
and that cis-2 did not equilibrate under ammonia conditions.
This chemistry effectively achieves our first goal and allows
us to set the stereochemistry at C-5,6 at will.
The corresponding C-3,4 cis-diol motif was easily prepared
by dihydroxylation with catalytic osmium tetroxide. The
facial selectivity of oxidation is not an issue during formation
of 4 because compound 3 can only form a single cis
diastereoisomer. However, the oxidation of 6 was diaste-
reoselective upon dihydroxylation; the product 7 was shown
to be the C-2,3 anti compound by X-ray crystallography on
the N-Boc tetrol 9 derived from deprotection of 7. In both
(2) (a) Donohoe, T. J.; Guyo, P. M. J. Org. Chem. 1996, 61, 7664. (b)
Donohoe, T. J.; Guyo, P. M.; Beddoes, R. L.; Helliwell, M. J. Chem. Soc.,
Perkin Trans. 1 1998, 667.
(3) Donohoe, T. J.; Harji, R. R.; Cousins, R. P. C. Tetrahedron Lett.
2000, 41, 1327.
(4) Evans, S. V.; Fellows, L. E.; Shing, T. K. M.; Fleet, G. W. J.
Phytochemistry 1985, 24, 1953.
(5) Hasan, I.; Marinelli, E. R.; Lin, L.-C. C.; Fowler, F. W.; Levy, A. B.
J. Org. Chem. 1981, 46, 157.
(6) (a) Donohoe, T. J.; Harji, R. R.; Cousins, R. P. C. Tetrahedron Lett.
2000, 41, 1331. (b) Donohoe, T. J.; House, D. J. Org. Chem. 2002, 67, 5015.
(7) The diethyl ester analogue of 1 has previously been reduced and
reductively alkylated in ammonia.3 While reductive alkylation proceeds to
give the trans isomers exclusively, protonation in ammonia had been reported
to give a (7:3) mixture of cis and trans isomers. This ratio is our error, and
further study confirms that reduction (followed by protonation) in ammonia
definitely proceeds to give the trans isomer as the major compound (6:1).
(8) Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A. G.;
Welch, M. J. Am. Chem. Soc. 1988, 110, 7828.
(9) See: Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624. This
is reminiscent of the Grotthus mechanism for proton transfer in water; see:
Pilling, M. J.; Seakins, P. W. Reaction Kinetics; Oxford University Press:
New York, 1995.
1000
Org. Lett., Vol. 5, No. 7, 2003

Scheme 2a
Scheme 3a
a Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2,
-78 °C (b) Tf2O, pyr, CH2Cl2, then KOAc, DMF; (c) NaOMe,
MeOH; (d) HCI, MeOH; (e) TFA, CH2CI2.
protection is free from complications arising from regio-
chemistry. However, the monosilylation (4f13) is rational-
ized by reaction of the least hindered hydroxyl group at -78
°C. Mitsunobu inversion of the free hydroxyl group within
either 10 or 13 was unsuccessful, so we formed the reactive
triflates from these two monoalcohols. Neither of these
triflates were isolated but instead reacted immediately with
potassium acetate in DMF to furnish the inverted derivatives
11 and 14 in good yield (Scheme 3). In each case, the Boc
protecting group was removed so that the symmetry of
compounds 12 and 15 was apparent from the NMR spectra.11
a Reagents and conditions: (a) LiEt3BH, THF; (b) Ag2O, BnBr;
(c) OsO4 (cat.), NMO, acetone, H2O; (d) HCI, MeOH; (e) LiBH4,
THF; (f) NaH, BnBr, TBAI; (g) TFA, CH2Cl2; (h) H2, Pd/C, MeOH.
Finally, compound 14 could be converted into the (race-
mic) natural product DMDP by simple deprotection; the
spectroscopic data for this compound was an exact match
with that in the literature12 (Scheme 4).
series, the Boc group was deprotected to reveal the free
pyrrolidines 5 and 8 in good yield.10
Formation of the trans-diol isomers at C-3,4 proved to be
much more troublesome than their cis counterparts. While
we were able to form the epoxides derived from 3 and 6,
opening to the trans-diol under either acidic or basic
conditions was not successful and, if forced, gave re-
aromatized products. Other methods of directly forming the
trans-diol array such as the Woodward-Prevost conditions
(I2, AgOAc, H2O) were also not viable.
Scheme 4a
Therefore, we set about inverting one of the hydroxyl
groups from the cis compounds 4 and 7, Scheme 3. In each
case, monoprotection was accomplished with TBSOTf at low
temperatures. The symmetrical nature of 7 means that mono-
a Reagents and conditions: (a) NaOMe, MeOH; (b) HCI, MeOH;
(c) H2, Pd/C, MeOH; (d) HCI, MeOH, ion-exchange chromatog-
raphy.
Org. Lett., Vol. 5, No. 7, 2003
1001

To conclude, we report here that disubstituted pyrroles
can serve as versatile precursors for the synthesis of
polyhydroxylated pyrrolidine natural products. Variation of
the reduction procedure is sufficient to influence the stereo-
chemistry at C-5,6, while that at C-3,4 can be set by cis-
dihydroxylation (followed by inversion). The flexibility that
this sequence holds for the synthesis of diastereoisomeric
pyrrolidines has been exemplified, and the stage is now set
for application of this method to more complex systems.
(10) Compound 5: 13C NMR (100 MHz, CDCl3, APT) δ 60.0 (-), 62.1
(-), 68.4 (+), 68.9 (+), 71.9 (-), 73.4 (-), 73.5 (+), 73.6 (+), 127.9 (-),
128.0 (-), 128.5 (-), 137.3 (+), 137.4 (+). Compound 8: 13C NMR (100
MHz, CDCl3, APT) δ 63.0 (+), 69.3 (-), 72.7 (+), 73.3 (-), 127.7 (+),
127.8 (+), 128.5 (+), 137.6 (-).
Acknowledgment. We would like to thank the EPSRC
and GlaxoSmithKline for funding this project. Pfizer and
Novartis are also thanked for generous unrestricted support.
(11) Compound 12: 13C NMR (100 MHz, CDCl3, APT) δ 58.9 (-),
63.9 (-), 69.3 (+), 70.7 (+), 73.5 (+), 73.6 (+), 78.8 (-), 80.6 (-),
127.8 (-), 127.9 (-), 128.5 (-), 137.4 (+) 137.7 (+). Compound 15: 13C
NMR (100 MHz, CDCl3) δ 64.3, 72.1, 74.0, 81.0, 128.3, 128.4, 129.0,
137.9.
Supporting Information Available: Copies of 1H NMR
spectra and detailed spectroscopic data for all new com-
pounds and representative experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) For a copy of the 1H NMR spectrum of (+)-DMDP, see: Fechter,
M. H.; Gradnig, G.; Berger, A.; Mirtl, C.; Schmid, W.; Stu¨tz, A. E.
Carbohydr. Res. 1998, 309, 367. For general references to the isolation
and previous syntheses of DMDP, see: Izquierdo, I.; Plaza, M. T.; Franco,
F. Tetrahedron: Asymmetry 2002, 13, 1503.
OL027504H
1002
Org. Lett., Vol. 5, No. 7, 2003