Palladium-mediated reductive coupling, a stereoselective approach to the 8-dehydropumiliotoxin skeleton

Article abstract of DOI:10.1016/j.tetlet.2009.03.122

Reductive cyclisation of an E-vinyl bromide with an allylic acetate proceeds under palladium catalysis to give the 8-dehydropumiliotoxin skeleton, a potential advanced precursor to 8-deoxypumiliotoxin alkaloids. Control of the stereochemistry of the E-vin

Full text of DOI:10.1016/j.tetlet.2009.03.122

Tetrahedron Letters 50 (2009) 3669–3671
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-mediated reductive coupling, a stereoselective approach
to the 8-dehydropumiliotoxin skeleton
*
Stephanie A. Feutran, Helena McAlonan, Paul J. Stevenson , Andrew D. Walker
School of Chemistry and Chemical Engineering, Queen’s University, Belfast, BT9 5AG, Northern Ireland, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Reductive cyclisation of an E-vinyl bromide with an allylic acetate proceeds under palladium catalysis to
give the 8-dehydropumiliotoxin skeleton, a potential advanced precursor to 8-deoxypumiliotoxin alka-
loids. Control of the stereochemistry of the E-vinyl bromide precursor is achieved readily using the Kogen
or Bruckner bromophosphonate reagents and the reductive cyclisation proceeds with retention of the
vinyl bromide stereochemistry. The mechanism for the cyclisation involves an in situ conversion of the
allylic acetate to an allyl stannane followed by an intramolecular Stille-type coupling.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 15 January 2009
Revised 12 March 2009
Accepted 16 March 2009
Available online 21 March 2009
The pumiliotoxin alkaloids, isolated from the defensive skin
secretions of Dendrobates frogs have an indolizidine ring with a
Z-exocyclic alkene at C6.1–3 Most of these alkaloids have a methyl
group at C8 and the different classes are distinguished by the oxy-
genation pattern on the six-membered ring. The vast majority of
pumiliotoxins have a tertiary alcohol at C8 and the allopumiliotox-
ins have an additional hydroxy group at C7. Recently, a new class of
pumiliotoxin, Figure 1, devoid of the tertiary alcohol at C8, was iso-
lated and the structure of deoxypumiliotoxin 251H was assigned
by NMR spectroscopy.4 Since, an additional eleven members of this
class have been isolated and their structures tentatively assigned
as deoxypumiliotoxins.5 To date, no syntheses of the deoxypumi-
liotoxin class of alkaloid have been reported.
The main difficulty in pumiliotoxin alkaloid synthesis is con-
trol of the stereochemistry of the exocyclic trisubstituted double
bond. Many ingenious solutions have emerged to solve this
problem including iminium ion chemistry,6–10 aldol methodolo-
gies,11–15 Wittig Horner reaction,16 allylic rearrangement,17
organonickel18–20 or titanium21 chemistry of alkynes and organo-
chromium chemistry of vinyl iodides.22–24 Recently, we demon-
strated that vinyl bromides are versatile substrates for
controlling the stereochemistry of the exocyclic trisubstituted al-
kene in diene-based pumiliotoxins via intramolecular Heck reac-
tion.25–27 However, this chemistry was complicated by the fact
that the vinyl bromide underwent a stereochemical inversion
on endo-cyclisation and for the desired pumiliotoxin stereochem-
istry, the less reactive, more problematic Z-vinyl bromides were
required. Furthermore, the conjugated dienes produced could not
be chemoselectively functionalised at the endocyclic alkene.
8-Dehydropumiliotoxins with the double bond exocyclic,
although not naturally occurring, are likely candidates for the syn-
thesis of 8-deoxypumiliotoxins. Since the two alkenes have differ-
ent substitution patterns, the 8-methylene group should reduce
faster under catalytic hydrogenation conditions than the 6-trisub-
stituted double bond. Given that we have already shown, in similar
systems, that catalytic hydrogenation and oxidation preferentially
occur from the concave face,28,29 these substrates are thus ideal
intermediates for 8-deoxypumiliotoxin synthesis with the desired
R-configuration at C8.
We now report a robust approach to the 8-dehydropumiliotoxin
skeleton 8, based on an intramolecular reductive coupling reaction
of an E-vinyl bromide, 5, with an allylic acetate, which proceeded
with retention of vinyl bromide stereochemistry, Scheme 1.
The starting diene 3 was prepared as previously described25
with the variation that Wittig Horner-type reactions of
mophosphonates 1a–c were used to prepare the E- -bromoacry-
lates, 2, Scheme 2. The McKenna bromophosphonate, 1a,30
a-bro-
a
favoured formation of the Z-
a-bromoacrylate with low de. In order
1
H
H
Me
Me
N
8
N
6
OH
Me
Me
deoxypumiliotoxin 251H
deoxypumiliotoxin 235V
* Corresponding author. Tel.: +44 2890974426.
E-mail address: p.stevenson@qub.ac.uk (P.J. Stevenson).
Figure 1. Structure of deoxypumiliotoxins 251H and 235V.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.122

3670
S. A. Feutran et al. / Tetrahedron Letters 50 (2009) 3669–3671
reportedly converts aldehydes to E-bromoacrylates in high yield.
H
H
However, our preference was to use a single component reagent
and on further experimentation, conditions were found to reduce
selectively the dibromide component to the monobromide which
gave a homogeneous reagent, 1c. This was achieved by titrating a
solution of tin(II) chloride into the crude mixture of mono and dib-
romophosphonates and by monitoring the instantaneous reduc-
tion by 31P NMR spectroscopy. An end-point was readily found
where the dibromophosphonate contaminant was selectively
reduced to the desired monobromophosphonate, with no over
reduction. Using Bruckner’s conditions, with pure mono-
bromophosphonate 1c, gave the required bromoacrylate, 2c, in
96% crude yield with 94:6 selectivity in favour of the E-isomer.
O
O
N
(a)
N
Cl
Br
Br
C6H13
C6H13
3
4
(b)
H
H
The E-a-bromoacrylate 2c was converted into the enantioen-
O
(d)
riched diene 3 as previously reported.25 Functionalisation of the
allylic methyl group was achieved in moderate yield using Wolin-
sky’s conditions to give the allylic chloride 4.39,40 Nucleophilic sub-
stitution with acetate gave the prerequisite allylic acetate 5.
Although this reaction sequence was convenient, in that it gave
the desired material from a known diene, purification following
the chlorination step was difficult and a new procedure for gener-
ating the allylic alcohol was desirable. The key reductive cyclisa-
tion employed chemistry pioneered by Trost,41 which
surprisingly to date, has seen very little use in synthesis. This in-
volved an in situ conversion of an allylic acetate to an allylstann-
ane, using (tri-n-butylstanny1)diethylalane, under palladium
catalysis, followed by an intramolecular Stille-type cyclisation
using the same catalyst. This sequence was convenient in that
there was no need to isolate the intermediate allylstannane
reagent. Using Trost’s conditions, compound 5 cyclised to give a
2:1 mixture of dienes 6 and 7, in 60% yield, plus other unidentified
products. It was reasoned that the cyclisation had proceeded as
planned, but that the exocyclic alkene 8 had isomerised to the
thermodynamically more stable endocyclic alkenes 6 and 7 under
the reaction conditions. In the original paper the initial heating
period, at 60 °C, was required to convert the acetate to the stann-
ane and the higher temperature, 105 °C, was required for the cyc-
lisation. By varying the temperature it was found that the
cyclisation also proceeded at 60 °C and gave the desired bis-exocy-
clic diene 8 in 65% isolated yield. Interestingly no products of intra-
molecular Heck reaction were detected, even though we have
demonstrated that diene 3 undergoes intramolecular Heck reac-
tion at room temperature.25
O
N
N
OAc
Br
C6H13
8
5
C6H13
(c)
H
O
O
N
N
ratio 2:1
C6H13
C6H13
7
6
Scheme 1. Reagents and conditions: (a) Ca(oCl)2, CO2(s), CH2Cl2/H2O 5:1, 30 min
(62%); (b) KOAc, DMF, 120 °C, 1 h (66%); (c) (Bu3Sn)2, BuLi, Et2AlCl, Pd2(dba)3CHCl3,
Ph3P, THF, 4 h, 60 °C, then 10 h, 105 °C (60%); (d) (Bu3Sn)2, BuLi, Et2AlCl,
Pd2(dba)3CHCl3, Ph3P, THF, 6 h, 60 °C (65%).
Br
R1O2C
C6H13
Br
O
(a, b or c)
RO
P
CO2R1
RO
C6H13
H
O
heptanal
1a-c
2a-c
With the crucial cyclisation accomplished, in a simple model
system, efforts were directed towards preparing more alkaloid-like
side chains and to make the route more convergent. This necessi-
tated early introduction of the allylic alcohol functionality into
the pyrrolidinone before attachment of the vinyl bromide.
Scheme 2. Reagents and conditions: (a) 1a R = R1 = Et, McKenna’s reagent, THF,
NaH, 0 °C, 1 h (85%), de 20% Z-alkene; (b) 1b R = CF3CH2, R1 = Me, Kogen’s reagent,
tBuOK, 18-crown-6, À78 °C, 2 h (95%), only E-isomer detected by NMR (c) 1c, R = Ph,
R
1 = Et, Bruckner’s reagent, NaHMDS, THF, 0 °C, 30 min (96%), de 88% E-alkene.
Scheme 3 outlines how the side chain 11, for deoxypumiliotoxin
251H was assembled. Sharpless asymmetric dihydroxylation,42 of
to achieve high E-selectivity it was necessary to place electron-
withdrawing groups on the phosphonate ester. Two reagents, the
trifluoroethyl and diphenyl esters, 1b and 1c, respectively, have re-
cently been developed by Kogen31–33 and Bruckner34 to accomplish
this transformation with high E-selectivity. These reagents are
merely bromo analogues of the Still–Gennari35 and Ando36 re-
agents, respectively, routinely used for preparing Z-acrylates.
Reaction of heptanal with the Kogen reagent, 1b, gave exclu-
sively the desired E-bromoacrylate, 2b, in 95% yield as a single dia-
stereoisomer. Unfortunately, in our hands, there was difficulty in
reproducibly preparing this reagent and at best, the yield was
always low, and the purification tedious. In situ methods for gen-
erating this reagent are known,37,38 but our preference was to
use an isolated reagent, which was pure by 31P NMR spectroscopy.
Attention was next turned to the Bruckner reagent 1c. This was ini-
tially prepared as a 2:1 mixture of mono and dibromophospho-
nates (by 31P NMR spectroscopy) as reported. This mixture
OTBS
10
H
(a-g)
OPMB
O
9
(h)
OTBS
H
Br
CO2Et
11
Scheme 3. Reagents and conditions: (a) AD-mix-b, tBuOH/H2O, 0 °C, 12 h (97%); (b)
TsCl, Et3N, Bu2SnO, DCM, rt, 16 h (98%); (c) Amberlite IRA-400(OH), EtOH, 48 h, rt
(100%); (d) Red-Al, THF, 0 °C–rt, 16 h (85%); (e) TBSCl, imidazole, DMF, À10 °C, 6 h
(91%); (f) DDQ, CH2Cl2/H2O, rt, 2 h (82%); (g) Dess Martin periodinane, rt, 2 h (88%);
(h) KHMDS, THF, bromophosphonate 1c, 0 °C, 3h (47%).

S. A. Feutran et al. / Tetrahedron Letters 50 (2009) 3669–3671
3671
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N
N
H
PMB
PMB
12
13
(d)
H
H
(e)
O
O
N
N
O
OH
MeO
MeO
15
14
Scheme 4. Reagents and conditions: (a) NaBH4, EtOH, 4 h, 45 °C (98%); (b) Dess
Martin periodinane, CH2Cl2, 18 h, rt (79 %); (c) Eschenmoser’s salt, Et3N, CH2Cl2, rt,
18 h (86%); (d) NaBH4, CeCl3, EtOH, 0 °C, 1 h (67%); (e) CAN, MeCN/H2O 1:1, rt, 1 h
(56%).
the known alkene 943 gave a diol with 87% de. Selective tosylation
of the primary alcohol, followed by treatment with a basic ion
exchange resin gave an epoxide. Reduction of the epoxide with
Red-Al gave a secondary alcohol, which was protected as the TBS
ether. Oxidative removal of the PMB group gave a primary alcohol,
which was oxidised to the aldehyde 10. Gratifyingly, reaction of
aldehyde 10 with the Bruckner bromophosphonate 1c gave exclu-
sively the E-bromoacrylate 11. Branching at the
a-carbon clearly
improves the E-stereoselectivity, albeit with a substantial reduc-
tion in yield.
Scheme 4 outlines an approach to the key enantiomerically en-
riched pyroglutamate allylic alcohol starting from the known ester
12.44 Sodium borohydride reduction of the ester, followed by Dess
Martin oxidation45,46 gave an aldehyde, which on aldol condensa-
tion with Eschenmoser’s salt47 gave the
a,b-unsaturated aldehyde
13. Luche reduction48 of the aldehyde gave the desired allylic alco-
hol 14. Attempted oxidative cleavage of the N-PMB, group using
ceric ammonium nitrate, was complicated in that the major prod-
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diastereoisomer.
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Work is currently in progress on hydrolysing N,O-acetal 15 and
completing the synthesis of deoxypumiliotoxin 251H.
Acknowledgements
We would like to thank DENI (H.M.A.), DEL (A.W.) and ESF
(S.A.F.) for studentships.
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