Asymmetric synthesis of polyhydroxylated pyrrolizidines via transannular iodoamination with concomitant N-debenzylation

Article abstract of DOI:10.1021/ol103090z

The doubly diastereoselective "matched" conjugate addition of lithium (R)-N-but-3-enyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl (4S,5R,E)-4,5-O-isopropylidene-2,7-dienoate (derived from d-ribose in 3 steps) and in situ enolate oxidation with (-)-camphorsulfonyloxaziridine was followed by ring-closing metathesis with Grubbs I to give a hexahydroazocine scaffold. Subsequent treatment with I₂ resulted in transannular iodoamination accompanied by loss of the α-methyl-p-methoxybenzyl group to give the corresponding pyrrolizidine scaffold as a single diastereoisomer upon direct crystallization from the crude reaction mixture. Further functional group manipulations enabled the preparation of (-)-7a-epi-hyacinthacine A1.

Full text of DOI:10.1021/ol103090z

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1594–1597
Asymmetric Synthesis of
Polyhydroxylated Pyrrolizidines via
Transannular Iodoamination with
Concomitant N-Debenzylation
E. Anne Brock, Stephen G. Davies,* James A. Lee, Paul M. Roberts, and
James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
steve.davies@chem.ox.ac.uk
Received December 21, 2010
ABSTRACT
The doubly diastereoselective “matched” conjugate addition of lithium (R)-N-but-3-enyl-N-(R-methyl-p-methoxybenzyl)amide to tert-butyl (4S,5R,E)-
4,5-O-isopropylidene-2,7-dienoate (derived from D-ribose in 3 steps) and in situ enolate oxidation with (-)-camphorsulfonyloxaziridine was followed by
ring-closing metathesis with Grubbs I to give a hexahydroazocine scaffold. Subsequent treatment with I2 resulted in transannular iodoamination
accompanied by loss of the R-methyl-p-methoxybenzyl group to give the corresponding pyrrolizidine scaffold as a single diastereoisomer upon direct
crystallization from the crude reaction mixture. Further functional group manipulations enabled the preparation of (-)-7a-epi-hyacinthacine A1.
Polyhydroxylated alkaloids are a subclass of alkaloids char-
acterized by an azacyclic core with dense oxygen func-
tionality.1 The five main classes of polyhydroxylated alkaloids
are pyrrolidines, piperidines, pyrrolizidines, indolizidines, and
nortropanes.1 Of the pyrrolizidine class, the structures of (þ)-
hyacinthacine A1 1, (þ)-australine 2, and (þ)-casuarine 3 are
representative of the common substitution patterns2 (Figure
1). The biological activity of polyhydroxylated alkaloids is
wide and varied, although most effects are attributed to their
ability to act as glycosidase inhibitors.3 In view of these
desirable properties, a considerable amount of effort has been
put into their isolation, structure elucidation, and synthesis.2,4
We have previously reported a novel iodine mediated ring-
closing iodoamination reaction with concomitant N-deben-
zylation of an ω-unsaturated amine to generate pyrrolidine5
and piperidine6 scaffolds. For instance, treatment of ε,ζ-
unsaturated amine 4 with I2 and NaHCO3 in MeCN gave an
81:19 mixture of diastereoisomeric iodomethyl pyrrolidines
(1) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash,
R. J. Phytochemistry 2001, 56, 265.
(2) Liddell, J. R. Nat. Prod. Rep. 2000, 17, 455.
(3) Winchester, B;Fleet, G.W. J.Glycobiology 1991, 2, 199. Winchester,
B. Biochem. Soc. Trans. 1992, 20, 699. Winchester, B. Tetrahedron:
Asymmetry 2009, 20, 645.
Figure 1. Structures of (þ)-hyacinthacine A1 1, (þ)-australine 2,
and (þ)-casuarine 3.
(4) Davis, B. G. Tetrahedron: Asymmetry 2009, 20, 652.
r
10.1021/ol103090z
Published on Web 03/03/2011
2011 American Chemical Society

from which the major diastereoisomer 7 was isolated in 63%
yield.5 The mechanism of this transformation was proposed
to involve reversible iodonium ion formation from 4 fol-
lowed by preferential cyclization of iodonium 5 to give
ammonium 6. Preferential SN1-type loss of the R-methyl-
benzyl group7 from the sterically congested nitrogen atom
within ammonium 6 then gave pyrrolidine 7 (Scheme 1).5
went reaction with I2 and PPh3 to give iodide 10.11
Treatment of a 1:1 mixture of iodide 10 and tert-butyl
diethylphosphonoacetate in THF with n-BuLi12 pro-
moted
a
tandem transmetalation/ring-opening/
Wadsworth-Emmons olefination sequence of reactions
to give an 88:12 (E)/(Z) mixture of olefin isomers, with
chromatographic separation giving the desired (E)-isomer
11 as a single diastereoisomer in 55% yield from D-ribose 8
(Scheme 2).
Scheme 1
Scheme 2
The doubly diastereoselective “matched”13 conjugate addi-
tion of lithium (R)-N-but-3-enyl-N-(R-methylbenzyl)amide
1214 (99% ee)15 to R,β-unsaturated ester 1116 followed by in
situ enolate oxidation with (-)-camphorsulfonyloxaziridine
[(-)-CSO] 13 and chromatographic purification gave R-
hydroxy-β-amino ester 14 as a single diastereoisomer in
56% isolated yield.17 The absolute configuration within 14
was assigned by analogy to the well established stereochemical
outcome of our aminohydroxylation process.5b,18 Ring-
closing metathesis upon treatment of 14 with Grubbs I,14,19
and using P(CH2OH)3 to remove the spent catalyst,14,20 gave
hexahydroazocine 15 in 86% isolated yield. Transannular
iodoamination of 15 was attempted under a range of condi-
tions, with treatment with I2 (3 equiv) and NaHCO3 (3 equiv)
in CHCl3 giving ammonium 16 as a single diastereoisomer,
which was isolated in 70% yield after direct crystallization
from the crude reaction mixture. The relative configuration
Herein we report an application of this methodology to the
synthesis of polysubstituted pyrrolizidines using transan-
nular iodoamination of a hexahydroazocine scaffold8 with
concomitant N-debenzylation. This enables the rapid and
efficient assembly of this densely functionalized molecular
architecture, as demonstrated by a short asymmetric synth-
esis of (-)-7a-epi-hyacinthacine A1.9
An improved synthesis of tert-butyl (4S,5R,E)-4,5-
O-isopropylidene-2,7-dienoate 11 from D-ribose 8 was
developed.10 Treatment of D-ribose 8 with acetone and
methanol in the presence of HCl gave 9, which under-
(5) (a) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.;
Smith, A. D. Synlett 2004, 901. (b) Davies, S. G.; Nicholson, R. L.; Price,
P. D.; Roberts, P. M.; Russell, A. J.; Savory, E. D.; Smith, A. D.;
Thomson, J. E. Tetrahedron: Asymmetry 2009, 20, 758.
(6) Davies, S. G.; Hughes, D. G.; Price, P. D.; Roberts, P. M.;
Russell, A. J.; Smith, A. D.; Thomson, J. E.; Williams, O. M. H. Synlett
2010, 567.
(12) Modification of the procedure reported by Palmer, A. M.;
Volker, J. Eur. J. Org. Chem. 2001, 1293.
(13) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
(14) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D.
Tetrahedron 2009, 65, 10192.
(15) Enantiopure (R)-R-methylbenzylamine (99% ee) is commer-
cially available. Alkylation of (R)-R-methylbenzylamine upon treatment
with 4-bromobut-1-ene in the presence of K2CO3 gave (R)-N-but-3-enyl-
N-(R-methylbenzyl)amine; subsequent deprotonation with n-BuLi in
THF generated a yellow solution of lithium (R)-N-but-3-enyl-N-(R-
methylbenzyl)amide 12.
(16) For determination of the “matched” and “mismatched” reaction
pairings for the additions of the antipodes of lithium N-benzyl-N-(R-
methylbenzyl)amide to chiral R,β-unsaturated ester 11, see ref 10.
(17) Both the R-hydroxy-β-amino ester (14 or 18) and the corre-
sponding β-amino ester (14P or 18P) were present in the crude reaction
mixture.
(7) The R-methylbenzyl cation is then trapped by MeCN, with the
ensuing Ritter reaction giving racemic R-methylbenzyl acetamide.
(8) For an approach to polyhydroxylated pyrrolizidines employing
epoxidation of a hexahydroazocine scaffold and subsequent transan-
nular cyclization, see: White, J. D.; Hrnciar, P. J. Org. Chem. 2000, 65,
9129. Lauritsen, A.; Madsen, R. Org. Biomol. Chem. 2006, 4, 2898.
(9) For a previous synthesis of (()-7a-epi-hyacinthacine A1, see: (a)
Affolter, O.; Baro, A.; Frey, W.; Laschat, S. Tetrahedron 2009, 65, 6626.
For a previous synthesis of (þ)-7a-epi-hyacinthacine A1, see: (b)
ꢀ
Izquierdo, I.; Plaza, M. T.; Tamayo, J. A.; Franco, F.; Sanchez-Cantalejo,
F. Tetrahedron 2010, 66, 3788. For a previous synthesis of (-)-7a-epi-
hyacinthacine A1, see: (c) Garrabou, X.; Gomez, L.; Joglar, J.; Gil, S.;
Parella, T.; Bujons, J.; Clapes, P. Chem.;Eur. J. 2010, 16, 10691.
(10) Davies, S. G.; Durbin, M. J.; Goddard, E. C.; Kelly, P. M.;
Kurosawa, W.; Lee, J. A.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.;
Russell, A. J.; Scott, P. M.; Smith, A. D. Org. Biomol. Chem. 2009, 7, 761.
(11) Paquette, L. A.; Bailey, S. J. Org. Chem. 1995, 60, 7849.
Org. Lett., Vol. 13, No. 7, 2011
1595

within 16 was unambiguously assigned by single crystal
X-ray analysis,21 with the absolute configuration follow-
ing from the known (R)-configuration of the N-R-
methylbenzyl stereocenter and the C(1)- and C(2)-
stereocenters derived from D-ribose. This analysis also
affirms the absolute configurations assigned to β-amino
ester 14 and hexahydroazocine 15.
Scheme 3
The observation that ammonium 16 is the major product
from transannular iodoamination of hexahydroazocine 15
is in contrast to our observations concerning the cyclization
of ε,ζ-unsaturated amine 4 in which N-debenzylation of
ammonium 6 occurs readily in situ by an SN1 pathway.5
Unfortunately, attempted removal of the R-methylbenzyl
group from 16 under a range of conditions failed, and
therefore the incorporation of an R-methyl-p-methoxyben-
zyl group (in place of an R-methylbenzyl group) into the
hexahydroazocine scaffold was investigated in an effort to
promote an SN1-type reaction pathway. Thus, amino-
hydroxylation of 11 using the doubly diastereoselective
“matched”13 conjugate addition of lithium (R)-N-but-3-
enyl-N-(R-methyl-p-methoxybenzyl)amide 1716 (>99%
ee)22 and in situ enolate oxidation with (-)-CSO 13 gave
R-hydroxy-β-amino ester 18 as a single diastereoisomer in
50% isolated yield.17 Ring-closing metathesis of 1814,19
gave hexahydroazocine 19 in 73% isolated yield. Under
optimized conditions, transannular iodoamination of
19 in CH2Cl2 (EtOH stabilized) was accompanied by
concomitant loss of the R-methyl-p-methoxybenzyl group
(presumably via an SN1-type process to generate the corre-
sponding cation) resulting in production of the correspond-
ing pyrrolizidine that was isolated as the hydroiodide salt 20
in 79% yield upon direct crystallization from the crude
reaction mixture. Concentration of the mother liquors and
chromatographic purification of the residue gave R-methyl-
p-methoxybenzyl ethyl ether 21 in 95% yield, consistent
with trapping of the R-methyl-p-methoxybenzyl cation by
the EtOH stabilizer present in the reaction solvent23
(Scheme 3). The relative configuration within 20 was un-
ambiguously established by single crystal X-ray analysis,24
with the absolute configuration being assigned from the
known configurations of the C(1)- and C(2)-stereocenters
derived from D-ribose 8. This analysis also secures the
assigned absolute configurations within β-amino ester 18
and hexahydroazocine 19.
The homochirality of 16 and 20 suggests an identical
mechanism of cyclization. The observed stereochemical
outcome of this process is presumably controlled by
reversible iodonium formation from hexahydroazocine
scaffolds 15 and 19 followed by preferential transannular
reaction of one of the corresponding diastereoisomeric
iodonium ions. Transannular reaction of iodoniums 22
(Ar = Ph) or 23 (Ar = PMP) is expected to be disfavored
due to the high degree of 1,2-strain between the N-protect-
ing group (R*) and the adjacent substituent (R); transan-
nular reaction of iodoniums 24 (Ar = Ph) or 25 (Ar =
PMP) does not suffer from such a severe steric interaction
and results in the production of the corresponding ammo-
niums 16 (Ar = Ph) and 26 (Ar = PMP). Subsequent SN1-
type loss of the N-protecting group under the reaction
conditions occurs only in the case of N-R-methyl-p-meth-
oxybenzyl protected 26, leading to the formation of pyr-
rolizidine 27 which undergoes salt formation with in situ
generated HI to give 20 (Figure 2).
(18) For selected examples, see: Bunnage, M. E.; Burke, A. J.; Davies,
S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D.
Org. Biomol. Chem. 2003, 1, 3708. Abraham, E.; Candela-Lena, J. I.;
Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Roberts, P. M.; Russell,
ꢀ
ꢀ
A. J.; Sanchez-Fernandez, E. M.; Smith, A. D.; Thomson, J. E. Tetra-
hedron: Asymmetry 2007, 18, 2510. Abraham, E.; Davies, S. G.;
Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org.
Biomol. Chem. 2008, 6, 1655. Abraham, E.; Brock, E. A.; Candela-Lena,
J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Perkins, J. H.;
ꢀ
ꢀ
Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez, E. M.; Scott, P. M.;
Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 1665.
(19) Davies, S. G.; Iwamoto, K.; Smethurst, C. A. P.; Smith, A. D.;
Rodriguez-Solla, H. Synlett 2002, 1146. Chippindale, A. M.; Davies,
S. G.; Iwamoto, K.; Parkin, R. M.; Smethurst, C. A. P.; Smith, A. D.;
Rodriguez-Solla, H. Tetrahedron 2003, 59, 3253.
(20) Maynard, H. D.; Grubbs, R. H. Tetrahedron Lett. 1999,
40, 4137.
(21) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 805283.
The utility of this approach to enable the synthesis of
polyhydroxylated pyrrolizidine natural products and their
diastereoisomers was next demonstrated by application to a
short asymmetric synthesis of (-)-7a-epi-hyacinthacine A1
30.9 Reduction of pyrrolizidine hydroiodide salt 20 with
LiAlH4 gave diol 28 in 87% isolated yield after chromato-
graphy. Oxidative cleavage of diol 28 was effected upon
treatment with NaIO4 in MeOH/H2O and was followed
immediately by treatment of the reaction mixture with
(22) Enantiopure (R)-R-methyl-p-methoxybenzylamine (>99% ee)
is commercially available. Alkylation of (R)-R-methyl-p-methoxyben-
zylamine upon treatment with 4-bromobut-1-ene in the presence of
K2CO3 gave (R)-N-but-3-enyl-N-(R-methyl-p-methoxybenzyl)amine;
subsequent deprotonation with n-BuLi in THF generated a yellow
solution of lithium (R)-N-but-3-enyl-N-(R-methyl-p-methoxybenzyl)-
amide 17.
(23) See also: Srihari, P.; Bhunia, D. C.; Sreedhar, P; Yadav, J. S.
Synlett 2008, 7, 1045.
(24) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 805284.
1596
Org. Lett., Vol. 13, No. 7, 2011

Scheme 4
intermediates 18-20, 28, and 29 can be confidently inferred
as >99% ee (Scheme 4).
In conclusion, the doubly diastereoselective “matched”
conjugate addition of lithium (R)-N-but-3-enyl-N-(R-
methyl-p-methoxybenzyl)amide to tert-butyl (4S,5R,E)-
4,5-O-isopropylidene-2,7-dienoate (derived from D-ribose
in 3 steps) and in situ enolate oxidation with (-)-camphor-
sulfonyloxaziridine was followed by ring-closing metath-
esis with Grubbs I to give a hexahydroazocine scaffold.
Subsequent treatment with I2 resulted in transannular iodoa-
mination accompanied by loss of the R-methyl-p-metho-
xybenzyl group to give the corresponding pyrrolizidine
scaffold as a single diastereoisomer upon direct crystalliza-
tion from the crude reaction mixture. Further functional
group manipulations enabled the preparation of (-)-7a-epi-
hyacinthacine A1. Further applications of this transannular
iodoamination protocol to facilitate the preparation of other
natural and unnatural polyhydroxylated bicyclic scaffolds
are currently under investigation in our laboratory.
Figure 2. Postulated mechanistic rationale for transannular
iodoamination of hexahydroazocines 15 and 19. R = (R)-CH-
(OH)CO2 Bu.
t
NaBH4 to give alcohol 29 in 88% yield over the 2 steps.
Finally, hydrolysis of 29 upon treatment with 3 M aq. HCl
in MeOH and purification on Dowex 1X8 200-400
(OH- form) ion-exchange resin gave (-)-7a-epi-hyacintha-
cine A1 309 {[R]D25 -45.9 (c 0.2 in H2O); lit.9c [R]D22 -45.3
(c 1.5 in H2O)} in 83% isolated yield as a single diastereoi-
somer. Given the known enantiomeric purity of the lithium
(R)-N-but-3-enyl-N-(R-methyl-p-methoxybenzyl)amide 12
(i.e., >99% ee) employed for the conjugate addition to
R,β-unsaturated ester 11 (itself derived from D-ribose), the
enantiomeric purity of (-)-7a-epi-hyacinthacine A1 30 and
Supporting Information Available. Experimental pro-
1
cedures, characterization data, copies of H and 13C
NMR spectra, and crystallographic information files
(for structures CCDC 805283 and 805284). This material is
available free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 7, 2011
1597