Synthesis of (1R,2R,3R,7R,7aR)-hexahydro. 3-(hydroxymethyl)- 1H- pyrrolizine-1,2,7-triol: 7-Epiaustraline [6]

Full text of DOI:10.1021/ja980705p

J. Am. Chem. Soc. 1998, 120, 7357-7358
Scheme 1
7357
Synthesis of (1R,2R,3R,7R,7aR)-Hexahydro-
3-(Hydroxymethyl)-1H-pyrrolizine-1,2,7-triol:
7-Epiaustraline
Scott E. Denmark* and B. Herbert
Department of Chemistry, Roger Adams Laboratory
UniVersity of Illinois, Urbana, Illinois 61801
ReceiVed March 3, 1998
The alexines and australines are a unique subset of pyrrolizidine
alkaloids.1a,b The presence of a hydroxymethyl group adjacent to
the ring nitrogen [C(3)] distinguishes this group from the larger
class of necine bases which bear carbon substituents at C(1). In
addition, each member possesses (at least) five contiguous
stereogenic centers, three of which bear hydroxyl groups. Several
members of this alkaloid family display glucosidase inhibitory
properties1b-e,2a as well as viral and retroviral1f suppression
characteristics. The combination of functional group density and
impressive biological activity makes the alkaloids attractive
synthesis targets. We selected, as point of entry, 7-epiaustraline
(1)2 for an illustration of a general strategy based on the tandem
[4 + 2]/[3 + 2] cycloaddition chemistry of nitroalkenes.3 (+)-
7-Epiaustraline was isolated along with another stereoisomer from
extracts of Castanospermum australe, and its structure was
assigned by spectroscopic methods as well as by analogy to
crystallographically defined natural epimers.2a In addition, a
synthesis of (+)-7-epiaustraline has been reported.2b
Scheme 2
contained all of the requisite functionality and that also promised
to give a rapid and regioselective [3 + 2] cycloaddition. The
absolute configuration of 1 is properly established by the use of
nitronate (+)-4 (previously employed in our synthesis of (-)-
hastanecine) derived from (1S,2R)-2-phenylcyclohexanol.4
The synthesis of 8 was straightforward and high yielding as
depicted in Scheme 2. Addition of the magnesio silyl acetylide
prepared from 55 to (dimethylthexylsilyloxy)acetaldehyde6 pro-
vided the propargylic alcohol 6 in 86% yield.7 While Lindlar
semi-hydrogenation proved capricious, the hydroboration-pro-
tonolysis of 6 with dicyclohexylborane8 resulted in the clean
conversion to cis-alkene 7 (71%, >99% cis by 1H NMR analysis).
The preparation was completed by Swern oxidation9 of 7 to
provide 8 in 97% yield without detectable isomerization of the
alkene.
The tandem sequence began with the preparation of nitronate
4 by [4 + 2] cycloaddition (67% yield, >99/1 dr) as previously
described.4 The intermolecular thermal cycloaddition between
nitronate 4 and dipolarophile 8 proceeded smoothly at room
temperature to provide nitroso acetal 9 in 97% yield as a 26/1
ratio of diastereoisomers, Scheme 3.10 Comparison of the 1H and
13C NMR chemical shifts of C(2), C(3), and C(3a), (as assigned
by 2D NMR spectroscopy), allowed the conclusion that the major
nitroso acetal was formed as a head-to-head regioisomer. On
the basis of our prior [3 + 2] cycloaddition studies11 with nitronate
4, both major and minor isomers were assigned structures
The synthesis of 1 posed several new challenges to the tandem
cycloaddition technology that concern the construction and
transformation of key nitroso acetal 2, Scheme 1. First, the
installation of the hydroxymethyl group at C(3) required an
alkylation to close the second pyrrolidine ring and thus the
installation of a suitably configured nucleofugal group LG.
Second, the cis/trans/trans relationship between HC(2)/HC(3)/HC-
(3a)/HC(4) in 2 mandated an exo selective intermolecular [3 +
2] cycloaddition of nitronate 4 with a Z-configured dipolarophile
(3) from the face of the nitronate opposite the C(4) substituent.
Moreover, the dipolarophile must contain the latent hydroxyl
functionality for C(1) in 1. To accommodate these requirements,
we formulated the activated dipolarophile 8 (Scheme 2) that
(1) Alexine isolation: (a) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet,
G. W. J.; Derome, A. E.; Hamor, T. A.; Scofield, A. M.; Watkin, D. J.
Tetrahedron Lett. 1988, 29, 2487. Australine isolation: (b) Molyneux, R. J.;
Benson, M.; Wong, R. Y.; Tropea, J. E.; Elbein, A. D. J. Nat. Prod. 1988,
51, 1198. Biological studies: (c) Harris, C. M.; Harris, T. M.; Molyneux, R.
J.; Tropea, J. E.; Elbein, A. D. Tetrahedron Lett. 1989, 30, 5685. (d) Scofield,
A. M.; Rossiter, J. T.; Witham, P.; Kite, G. C.; Nash, R. J.; Fellows, L. E.
Phytochemistry 1990, 29, 107. (e) Tropea, J. E.; Molyneux, R. J.; Kaushal,
G. P.; Pan, Y. T.; Mitchell, M.; Elbein, A. D. Biochemistry 1989, 28, 2027.
(f) Fellows, L. E.; Nash, R. PCT Int. Appl. WO GB Appl. 89/7, 951; Chem.
Abstr. 1990, 114, 143777f.
(2) Isolation: (a) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.;
Girdhar, A.; Ramsden, N. G.; Peach, J. M.; Hegarty, M. P.; Scofield, A. M.
Phytochemistry 1990, 29, 111. Reported synthesis: (b) Pearson, W. H.; Hines,
J. V. Tetrahedron Lett. 1991, 32, 5513.
(3) (a) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137. (b)
Denmark, S. E.; Thorarensen, A. J. Am. Chem. Soc. 1997, 119, 125. (c)
Denmark, S. E.; Hurd, A. R.; Sacha, H. J. J. Org. Chem. 1997, 62, 1668. (d)
Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1997, 62, 1675.
(4) Denmark, S. E.; Thorarensen, A. J. Org. Chem. 1994, 59, 5672.
(5) Fleming, I.; Takaki, K.; Thomas, A. P. J. Chem. Soc., Perkin Trans. 1
1987, 2269.
(6) The aldehyde was prepared in 2 steps (86% yield) from 1,4-butenediol
by diol protection and ozonolysis of the alkene.
(7) All yields reported are for analytically pure materials, and all new
compounds were fully characterized (see the Supporting Information for
details).
(8) Brown, H. C. Organic Synthesis Via Boranes; Wiley: New York, 1975;
pp 28, 100.
(9) Mancuso, A. J.; Brownfain, D. S.; Swern, D. J. Org. Chem. 1979, 44,
4148. (b) Tidwell, T. T. Org. React. 1990, 39, 297.
(10) The ratio was determined by 1H NMR analysis. The minor diastereomer
has been tentatively assigned as an exo head-to-tail regioisomer.
(11) Denmark, S. E.; Seierstad, M. J.; Herbert, B. Manuscript in preparation.
See also ref 4.
S0002-7863(98)00705-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/29/1998

7358 J. Am. Chem. Soc., Vol. 120, No. 29, 1998
Communications to the Editor
Table 1. Comparative H NMR Data for 7-epiaustraline (1)
1
Scheme 3
proton isolateda Pearson’s syntheticb
(-)-1c
HC(1) 4.02 (dd) 4.06 (t, J ) 7.7)
HC(2) 3.70 (dd) 3.73 (t, J ) 8.8)
HC(3) 2.50 (m) 2.58 (m)
HC(5) 2.97 (m) 3.00 (m)
2.50 (m) 2.58 (m)
HC(6) 1.85 (m) 1.85 (m)
1.73 (m) 1.79 (m)
3.55 (t, J ) 7.9)
3.61 (t, J ) 8.4)
2.51 (ddd, J ) 9.3, 6.4, 3.8)
2.92 (m)
2.72 (m)
1.92 (m)
1.62 (m)
HC(7) 4.19 (m) 4.21 (m)
4.19 (m)
HC(7a) 2.98 (dd) 3.05 (dd, J ) 7.6, 4.4) 2.85 (dd, J ) 7.9, 2.0)
HC(8) 3.59 (dd) 3.63 (dd, J ) 11.8, 3.4) 3.62 (dd, J ) 11.7, 3.8)
3.42 (dd) 3.45 (dd, J ) 11.9, 6.6) 3.48 (dd, J ) 11.7, 6.4)
a Spectra taken in D2O and assigned by COSY. b Spectra taken in
D2O and assigned by comparison with data for isolated material (J
values are given in hertz). c Spectra taken in D2O and assigned by
COSY (J values are given in hertz).
on Dowex-50 and recrystallization from MeOH/CHCl3 provided
7-epiaustraline (1) in 61% yield.
Upon completion of the synthesis it was immediately apparent
that the physical and spectroscopic data for our final product did
not match either those reported for the natural product or those
reported for the synthetic material prepared by Pearson.2b For
example, the synthetic product is a highly crystalline (mp 193-
194 °C) levorotatory material ([R]2D3 -13.0° (c ) 0.55, H2O))
while “natural” 7-epiaustraline is described as a dextrorotatory
oil ([R]2D3 +11.6° (c ) 0.37, H2O)).2a The most striking
consistent with the approach of the dipolarophile from the face
opposite the C(4) benzoate. The high stereoselectivity was
attributed to a combination of the kinetic anomeric effect12 and
the conformation of the nitronate.4 The reduction of ketone 9
with L-Selectride at -74 °C provided the epimeric alcohols in
excellent yield and diastereoselectivity (87%, 14/1). A single-
crystal, X-ray structure of the major carbinol 10 confirmed that
all 5 contiguous stereogenic centers required for the synthesis of
7-epiaustraline were correctly installed in both relative and
absolute senses with respect to the 1S,2R auxiliary. The high
selectivity was most likely due to preferential shielding of one
face of the carbonyl group by the phenyldimethylsilyl moiety.
The reduction then proceeded in accord with the Cornforth
model.13
With all of the stereogenic centers required for the synthesis
of 7-epiaustraline properly installed with high selectivity, we
turned our attention to the activation of the secondary alcohol,
the ring closing hydrogenolysis, and the completion of the
synthesis. Once again, after extensive experimentation, the ideal
solution proved deceptively simple. Treatment of alcohol 10 with
methanesulfonic anhydride in pyridine provided mesylate 11 in
96% yield. The use of that specific reagent combination in this
case was critical for clean and rapid activation. Catalytic
reduction (Raney Ni, H2/160 psi, MeOH) of the nitroso acetal-
mesylate 11 proceeded according to plan to provide the pyrrolizi-
dine 12 in 77% yield with 98% recovery of the auxiliary, (+)-
2-phenylcyclohexanol. We were pleased that our standard
reaction conditions provided for appropriate timing of the critical
unmasking events (N-O hydrogenolysis, reductive amination and
intramolecular alkylation).
1
difference in the H spectra was the chemical shift position of
HC(1), Table 1. In the synthetic material, that proton was found
at 3.55 ppm, 0.5 ppm upfield from the natural material. The
chemical shifts of the adjacent protons, HC(2) and HC(7a) in our
sample were also displaced (by 0.10-0.15 ppm upfield) relative
to the reported data. These disturbing discrepancies prompted
us to unambiguously confirm the structure of the our product.
Single-crystal, X-ray analysis (see the Supporting Information)
clearly established the identity of the synthetic material as
(1R,2R,3R,7R,7aR)-hexahydro-3-(hydroxymethyl)-1H-pyrrolizine-
1,2,7-triol.15,16
In conclusion, a highly efficient and selective synthesis of the
title compound has been completed in nine steps from silane 5.
A single-crystal, X-ray structure analysis of synthetic (-)-1
confirmed that the targeted structure was successfully synthesized.
However, the spectroscopic and physical characteristics of the
synthetic material did not match the published data for the natural
material. Subsequent reinvestigation has revealed that 7-epiaus-
traline is not a known natural product.
Acknowledgment. We are grateful to the National Institutes of Health
(GM-30938) for generous financial support. We also acknowledge Drs.
G. W. J. Fleet, M. A. Wormald (Oxford), R. J. Nash (Aberystwyth), and
Prof. W. H. Pearson (Michigan) for helpful exchange of information.
The final stages of the synthesis of 7-epiaustraline involved
three functional group manipulations, the removal of the silyl ether
and benzoate protecting groups and the conversion of the PhMe2-
Si group to a hydroxyl. All three steps were efficiently ac-
complished under the conditions of the Tamao-Fleming oxida-
tion.14 Educt 12 was allowed to react with Hg(O2CCF3)2 in
trifluoroacetic acid at ambient temperature for 1 h to effect
dearylation. The reaction mixture was then diluted with peroxy-
acetic acid and heated at 50 °C for 24 h to promote the oxidation
of the silyl group. Under those conditions, the pyrrolizidine was
converted to its N-oxide which was isolated by ion exchange
chromatography (Dowex-50) and was subsequently reduced (H2,
10% Pd-C, MeOH/HOAc) to the free base. Final purification
Supporting Information Available: Preparation and full spectro-
scopic and analytical data (1H NMR, 13C NMR, IR, MS, TLC, [R]D) for
all new compounds along with 1H and 13C NMR spectra, crystallographic
parameters, atomic coordinates, and bond lengths and angles for 1 (40
pages, print/PDF). See any current masthead page for ordering informa-
tion and Web access instructions.
JA980705P
(15) As a direct consequence of our work, the assignment of the substance
reported as 7-epiaustraline2a is incorrect and this has led to a complete
reevaluation of all the published data on naturally occurring australines
(Wormald, Nash, Hrnciar, White, Molyneux, and Fleet, submitted; M. R.
Wormald, personal communication). Thus, 7-epiaustraline had not yet been
reported as a natural product.
(12) (a) Vasella, A. HelV. Chim. Acta 1977, 60, 1273. (b) Petrzilka, M.;
Felix, D.; Eschenmoser, A. HelV. Chim. Acta 1973, 56, 2950.
(13) Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc. 1959,
112.
(16) Pearson has learned that his synthetic material2b originally assigned
as 7-epiaustraline on the basis of NMR comparisons is in fact australine and
that some of the literature NMR data are incorrect. A full account of Pearson’s
work will be forthcoming (W. Pearson, personal communication).
(14) Review: Fleming, I. Chemtracts: Organic Chem. 1996, 9, 1.