Synthesis of (+)-uniflorine A: A structural reassignment and a configurational assignment

Article abstract of DOI:10.1021/ol8009144

(Chemical Equation Presented) The total synthesis of (+)-uniflorine A has allowed for the structural reassignment and the configurational assignment of the alkaloid (-)-uniflorine A from a 1,2,6,7,8-pentahydroxyindolizidine structure to (-)-(1R,2R,3R,6R,7S,7aR)-1,2,6,7-tetrahydroxy-3- hydroxymethylpyrrolizidine (6-epi-casuarine).

Full text of DOI:10.1021/ol8009144

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2769-2771
Synthesis of (+)-Uniflorine A: A
Structural Reassignment and a
Configurational Assignment†
Thunwadee Ritthiwigrom and Stephen G. Pyne*
School of Chemistry, UniVersity of Wollongong, Wollongong,
New South Wales 2522, Australia
spyne@uow.edu.au
Received April 21, 2008
ABSTRACT
The total synthesis of (+)-uniflorine A has allowed for the structural reassignment and the configurational assignment of the alkaloid (-)-
uniflorine A from a 1,2,6,7,8-pentahydroxyindolizidine structure to (-)-(1R,2R,3R,6R,7S,7aR)-1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine
(6-epi-casuarine).
The alkaloids (-)-uniflorine A and (+)-uniflorine B, along
with the known alkaloid (+)-(3R,4R,5ꢀ)-1-methylpiperidine-
3,4,5-triol, were isolated in 2000 from the leaves of the tree
Eugenia uniflora L.1–3 The water-soluble extract of these
leaves has been used as an antidiabetic agent in Paraguayan
traditional medicine. Uniflorines A and B were found to be
inhibitors of the R-glucosidases, rat intestinal maltase (IC50
values of 12 and 4.0 µM, respectively), and sucrase (IC50
values 3.1 and 1.8 µM, respectively).1 The structures of
uniflorines A and B were deduced from NMR analysis to
be that of the pentahydroxyindolizidine structures 1 and 3,
respectively.1 The proposed structure of uniflorine A is
similar to that of castanospermine, except for the stereo-
chemistry at C-1 and the extra hydroxyl substitution at C-2.
As part of our program concerned the synthesis of polyhy-
droxylated indolizidine and pyrrolizidine alkaloids,4–12 we
reported an efficient 9-step synthesis of the purported
structure of uniflorine A from L-xylose.10 The structure of
our synthetic 1 was unequivocally established by a single-
crystal X-ray crystallographic study of its pentaacetate
derivative.10 The 1H and 13C NMR spectral data for synthetic
1, however, did not match with those reported for uniflorine
1
A; the latter showed many more downfield peaks in the H
NMR spectrum, perhaps consistent with the amine salt. The
1H NMR spectrum of the hydrochloride salt of synthetic 1,
however, did not match the literature spectral data either.
We therefore concluded that the structure originally assigned
to uniflorine A was not correct.10
(4) Lindsay, K. B.; Tang, M.; Pyne, S. G. Synlett 2002, 731–734
(5) Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774–7780
(6) Tang, M.; Pyne, S. G. J. Org. Chem. 2003, 68, 7818–7824
(7) Lindsay, K. B.; Pyne, S. G. Aust. J. Chem. 2004, 57, 669–672
(8) Tang, M.; Pyne, S. G. Tetrahedron 2004, 60, 5759–5767
(9) Pyne, S. G.; Davis, A. S.; Gates, N. J.; Hartley, J. P.; Lindsay, K. B.;
Machan, T.; and Tang, M. Synlett 2004, 2670–2680
(10) Davis, A. S.; Pyne, S. G.; Skelton, B. W.; White, A. H. J. Org.
Chem. 2004, 69, 3139–3143
(11) Au, C. W. G.; Pyne, S. G. J. Org. Chem. 2006, 71, 7097–7099
(12) Machan, T.; Davis, A. S.; Liawruangrath, B.; Pyne, S. G. Tetra-
hedron 2008, 64, 2725–2732
.
.
.
.
† This paper is dedicated to E. J. Corey on the occasion of his 80th
birthday.
(1) Matsumura, T.; Kasai, M.; Hayashi, T.; Arisawa, M.; Momose, Y.;
.
.
Arai, I.; Amagaya, S.; Komatsu, Y. Pharm. Biol. 2000, 38, 302–307
.
(2) Arisawa, M.; Hayashi, T.; Momose, Y. Food Style 21 2001, 5, 69–
.
73.
.
(3) Momose, Y. Jpn. Kokai Tokkyo Koho 2000, 7. (JP 2000072770, CAN
132:203147).
.
10.1021/ol8009144 CCC: $40.75
Published on Web 06/03/2008
2008 American Chemical Society

Scheme 1
In 2006, Dhavale et al.13 also reported the synthesis of
compound 1; their sample had NMR spectral data identical
to ours. This paper also reported the synthesis of 8a-epi-1
and 1,2,8a-triepi-1. In 2005, Mariano14 reported the synthesis
of 1-epi-1, while that of 1,2-di-epi-1 was reported by Fleet15
in 1996, before uniflorine A was even isolated, and later by
Mariano14 and by us in 2008.16 In 2008, we also reported
the synthesis of 2-epi-1.16 These 1,2,6,7,8-pentahydroxyin-
dolizidine molecules also had NMR spectral data significantly
different from that of uniflorine A.
Our analysis of the NMR spectral data for uniflorine B
and its optical rotation clearly indicated that uniflorine B was
the known alkaloid casuarine 4, an identified inhibitor of
R-glycosidases.16 The published NMR spectral data for
uniflorine A revealed to us that this alkaloid was also a
1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine with the
same relative C-7-C-7a-C-1-C-2-C-3 configuration as
casuarine 4. From the published NMR data we suggested
that uniflorine A was 6-epi-casuarine (2).16 We now report
here the unequivocal proof that (-)-uniflorine A is 6-epi-
casuarine from the synthesis of its enantiomer, (+)-uniflorine
A, from D-xylose. This synthesis also established the absolute
configuration of the natural product to that shown in structure
2.
The synthesis of (+)-uniflorine A is shown in Scheme 1.
The enantiomer of the known tetrol 510 was prepared in one
step from the boronic acid-Mannich reaction (Petasis
reaction)10 of D-xylose, allylamine, and (E)-styrene boronic
acid and then converted to its N-Boc derivative 6.10 The
terminal diol functionality of 6 was selectively protected as
the acetonide derivative 7 under standard conditions. A ring-
closing metathesis (RCM) reaction of the diene 7 using
Grubbs’ first-generation ruthenium catalyst provided the 2,5-
dihydropyrrole 8 in 94% yield that underwent an osmium-
(VIII)-catalyzed syn-dihydroxylation (DH) reaction to furnish
the tetrol 9 as a single diastereomer in 68% yield. The
stereochemical outcome of this DH reaction was expected
due to the stereodirecting effect of the C-2 pyrrolidine
substituent in 8.4,5,10,16 The configuration of this diol was
established from ROESY NMR studies on the final product
15. The tetrol 9 was readily converted to its per-O-benzyl-
protected derivative 10 in 86% yield using standard reaction
conditions.10 Treatment of 10 under acidic conditions (HCl/
MeOH) resulted in N-Boc and acetonide hydrolysis and gave
the aminodiol 11 in 78% yield. Regioselective silylation of
11 with TBSCl/Et3N/DMAP gave the primary silyl ether 12
which underwent cyclization under Mitsunobu reaction
conditions using pyridine6,17 as the solvent to give a mixture
(ca. 4: 1) of the desired pyrrolizidine 13 and an indolizidine
product (structure not shown) in a combined yield of 30%
after purification of the crude reaction mixture by column
(13) Karanjule, N. S.; Markad, S. D.; Dhavale, D. D. J. Org. Chem.
2006, 71, 6273–6276.
(14) Zhao, Z.; Song, L.; Mariano, P. S. Tetrahedron 2005, 61, 8888–
8894.
(15) Bell, A. W.; Pickering, L.; Watson, A. A.; Nash, R. J.; Griffiths,
R. C.; Jones, M. G.; Fleet, G. W. J. Tetrahedron Lett. 1996, 37, 8561–
8564.
(16) Davis, A. S.; Ritthiwigrom, T.; Pyne, S. G. Tetrahedron 2008, 64,
4868–4879.
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Org. Lett., Vol. 10, No. 13, 2008

chromatography. The undesired indolizidine product arose
from first base catalyzed O-TBS migration to the secondary
hydroxyl group in 12 followed by Mitsunobu cyclization onto
the primary carbon of the butyl side chain. These cyclized
products could be separated by a second, more careful,
column chromatographic separation. Acid hydrolysis of 13
gave the primary alcohol 14, which upon hydrogenolysis
using PdCl2/H26,16,18 gave (+)-uniflorine A 15 ([R]22D +6.6
(c 0.35, H2O) (lit.1 for (-)-uniflorine A, [R]D -4.4 (c 1.2,
H2O)), in 74% yield after ion-exchange chromatography and
in a total of 11 synthetic steps from D-xylose. The 1H NMR
spectral data (D2O) of 15 and that of the natural product
were essentially identical (∆δH ) 0.00-0.02 ppm, see Table
1 of the Supporting Information). The 13C NMR signals of
15 (in D2O with MeCN as an internal reference at δ 1.47),
however, were all consistently 2.1-2.2 ppm upfield of those
reported for the natural product (Supporting Information).
The observed cross-peaks in the ROESY spectrum of 15
were fully consistent with the configurational assignment of
15 as shown in Figure 1. Thus our synthesis of 15, the
Figure 1. ROESY NMR correlations for 15.
enantiomer of (-)-uniflorine A, provides unequivocal proof
that (-)-uniflorine A is 6-epi-casuarine. This synthesis also
establishes the absolute configuration of (-)-uniflorine A as
that shown in structure 2. (-)-Uniflorine A therefore
represents one of now two known natural product stereoi-
somers of casuarine.20
We16 noted earlier that while the H NMR spectral data
1
reported for uniflorine B and casuarine were also essentially
identical, the 13C NMR shifts reported for casuarine were
all consistently 3.0-3.2 ppm upfield of the corresponding
13C NMR resonances reported for uniflorine B.1 We sug-
gested that alternative referencing between the two samples
accounts for this consistent discrepancy.16 The 13C NMR
spectrum of casuarine was referenced to acetone at δ 29.80
while that of uniflorines A and B were apparently referenced
to TMS as an internal standard (a standard not known for
its water (D2O) solubility).1 Thus, the consistent differences
in the 13C NMR chemical shifts between synthetic 15 and
that of (-)-uniflorine A can also be ascribed to the differ-
ences in referencing between the different samples.19
Acknowledgment. We thank the Australian Research
Council and the University of Wollongong for financial
support and Chiang Mai University and the Thai Government
for a PhD scholarship to T.R.
Supporting Information Available: Full experimental
and spectroscopic details of all compounds shown in Scheme
1. A table of the NMR spectal data of 15 and (-)-uniflorine
A and copies of the 1H, 13C, COSY, and HSQC NMR spectra
of 15. This information is available free of charge via the
Internet at http://pubs.acs.org.
OL8009144
(17) (a) Mulzer, J.; Dehmlow, H. J. Org. Chem. 1992, 57, 3194–3202.
Casiraghi, G.; Ulgheri, F.; Spanu, P.; Rassu, G.; Pinna, L.; Gasparri, F. G.;
Belicchi, F. M.; Pelosi, G. J. Chem. Soc., Perkin Trans. 1 1993, 2991–
2997. Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1994, 59, 1358–
1364.
(19) Unfortunately, we have not been able to obtain a copy of the NMR
spectra of uniflorine A for comparison purposes from the original authors.
(20) For the recent isolation of 3-epi-casuarine, see: Van Ameijde, J.;
Horne, G.; Wormald, M. R.; Dwek, R. A.; Nash, R. J.; Jones, P. W.;
Evinson, E. L.; Fleet, G. W. J. Tetrahedron: Asymmetry 2006, 17, 2702–
2712.
(18) Zhao, H.; Hans, S.; Chemg, X.; Mootoo, D. R. J. Org. Chem. 2001,
66, 1761–1767. Zhou, W.-S.; Xie, W.-G.; Lu, Z.-H.; Pan, X.-F. Tetrahedron
Lett. 1995, 36, 1291–1294
.
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