Enantioselective formal total synthesis of the Dendrobatidae frog toxin, (+)-pumiliotoxin B, via O-directed alkyne free radical hydrostannation

Article abstract of DOI:10.1016/j.tetlet.2010.10.141

Herein we describe our application of the O-directed free radical hydrostannation of disubstituted alkylacetylenes (with Ph₃SnH and Et₃B) to the (+)-pumiliotoxin B total synthesis problem. Specifically, we report on the use of this method in the synthesis of the Overman alkyne 8, and thereby demonstrate the great utility of this process in a complex natural product total synthesis setting for the very first time. We also report here on a new, stereocontrolled, and highly practical enantioselective pathway to Overman's pyrrolidine epoxide partner 9 for 8, which overcomes the previous requirement for use of preparative HPLC to separate the 1:1 mixture of diastereomeric epoxides that was obtained in the original synthesis of 9.

Full text of DOI:10.1016/j.tetlet.2010.10.141

Tetrahedron Letters 52 (2011) 2080–2084
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective formal total synthesis of the Dendrobatidae frog toxin,
(+)-pumiliotoxin B, via O-directed alkyne free radical hydrostannation
Soraya Manaviazar a, Karl J. Hale a, , Amandine LeFranc b
⇑
a The School of Chemistry & Chemical Engineering and the CCRCB, Queen’s University Belfast, Stranmillis Road, Belfast, BT9 5AG Northern Ireland, UK
b The Christopher Ingold Laboratories, University College London, 20 Gordon Street, London WC1H 0AJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 31 October 2010
Herein we describe our application of the O-directed free radical hydrostannation of disubstituted alkyl-
acetylenes (with Ph3SnH and Et3B) to the (+)-pumiliotoxin B total synthesis problem. Specifically, we
report on the use of this method in the synthesis of the Overman alkyne 8, and thereby demonstrate
the great utility of this process in a complex natural product total synthesis setting for the very first time.
We also report here on a new, stereocontrolled, and highly practical enantioselective pathway to Over-
man’s pyrrolidine epoxide partner 9 for 8, which overcomes the previous requirement for use of prepara-
tive HPLC to separate the 1:1 mixture of diastereomeric epoxides that was obtained in the original
synthesis of 9.
Dedicated with fondness, respect and
admiration to a master chemist, Professor
Harry H. Wasserman, on the occasion of his
90th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
In 2005,1–3 we reported that the combination of Ph3SnH and
Et3B (0.1 equiv) in toluene at room temperature was remarkably
effective for performing the highly stereo- and regio-controlled
O-directed free radical hydrostannation of disubstituted alkyl acet-
ylenes to give trisubstituted vinyl triphenylstannanes of general
structure 2 (Scheme 1).1 We also noted, in these publications, that
Ph3SnH/Et3B typically out-performs Bu3SnH and various other free
radical initiators, including Et3B, when used in this capacity. We
further demonstrated that vinyl triphenylstannanes of general
structure 2 can efficiently be converted into stereodefined vinyl io-
dides 3 of identical geometry,2 by iodine–tin exchange,4 and that
these intermediates can often be elaborated into different target
trisubstituted alkenes 4, 5, and 6, in good yield, by application of
various Pd(0)-catalysed cross-coupling methods (Suzuki, Stille,
Negishi, Sonogashira etc.).2,5 Although a significant number of
challenging target alkene structures were prepared via this new
protocol,2 none of these targets were natural products.4
In an effort to remedy this situation, and demonstrate the
power of our new method for complex natural product total
synthesis,4 we decided to address the (+)-pumiliotoxin B6 synthetic
problem,7,8 where stereocontrolled installation of the acyclic
trisubstituted alkene side chain is well known to present special
challenges and difficulties. In this Letter, we now document suc-
cess in these efforts with our completion of a new asymmetric
formal total synthesis of (+)-pumiliotoxin B by a route which inter-
sects with Overman’s elegant second-generation synthetic path-
way7b to this compound. We note in advance that our new route
not only improves on the previous technology that was available
for preparing pyrrolidine epoxide 9 (which required a preparative
HPLC separation to resolve a 50:50 mixture of two epoxide diaste-
reoisomers), it also now provides Overman’s advanced alkyne
coupling partner 8 by a strategy that is 5 steps shorter overall than
his 1996 route. Our new pathway to 8 is also well suited to gener-
ating novel analogues that are modified at the C(13)–C(14)-trisub-
stituted olefin, and at the C(11)-, C(15)- and C(16)-stereocentres.
R2
R1
R2
R1
O
O
Ph3SnH, Et3B,
air, PhMe, rt
R3
SnPh3
R3
1
R2 = H, Alkyl, Bn, (R)2C(O)
2
I2 (1 eq),
(R4)4Sn or
R2
O
CH2Cl2,
-78 oC to
rt
(R4)B(OH)2,
or (R4)4ZnX,
cat. (L)4Pd,
THF
R3
R1
R4
4
R2
O
R2
O
cat. (L)4Pd, CO (1 atm),
THF, ROH, rt
R3
R1
R3
R1
I
3
CO2R
5
R4
CuI, Et3N,
R2
R1
O
cat. (L)4Pd,
THF
R3
6
R4
⇑
Corresponding author. Tel.: +44(0)2809097 5525; fax: +44(0)289097 4579.
E-mail address: k.j.hale@qub.ac.uk (K.J. Hale).
Scheme 1. Trisubstituted alkene synthesis via O-directed free radical
hydrostannation.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.141

S. Manaviazar et al. / Tetrahedron Letters 52 (2011) 2080–2084
2081
Triphenylstannane,
Triethylborane,
PhMe, air
Overma
Me
Me
Ph Sn
3
Iodide-Promoted,
Iminium Ion
Me
O
O
Me
Me
O
11
EtO
O
H
Cyclisation and
n
16
O
H
Me
De-iodination
EtO
O
Me OH
Me
14
H
H
14
16
Me
Me
Triphenylstannane,
Triethylborane,
PhMe, air
21
15
Me Me
11
13
5
8
HCHO
Me
OH
Rapidly Inverting,
High Energy Alkyl Vinyl Radical
N
H
O
EtO
+
H
H
O
Me
Me
OH
Me
O
NH
Me
11
Internal
1,5-Atom
16
7
O
(+)-Pumiliotoxin B
Abstraction
OH
Me
H
O
Ph Sn
3
Me
Me
23
Epoxide Opening,
Ph Sn
3
Tandem
Z-Group Removal
Rapidly Inverting,
Epoxidation-
Me
O
O
High Energy Alkyl Vinyl Radical
Me
Me
N-Carbamoylation
H
Internal
1,5-Atom
Quench
with
EtO
O
Me Me
O
CF
3
H
Me
Abstraction
NZ
H
Ph SnH
3
N
H
O
+
22
O
Me
EtO
H
Me
O
I
More stable 2º free radical
8
Me
H
Me
OH
9
O
Me
Overman's Advanced
Intermediates
10
O
Quench with
O
Me
Ph Sn
3
Me
Ph SnH
3
24
CF
3
FGI
o
N-Trifluoroacetamido
-Directed
More stable 2 free radical
Me Me
N
O
Quench with
Ph Sn
3
Me
Me
Iodohydroxylation
Ph SnH
3
Triphenylstannane,
Triethylborane,
PhMe, air
O
Me
H
EtO
O
O
O
Me
Me
Me
O
EtO
Me
Me
Me
11
Me
O
EtO
O
12
Iodine-Tin Exchange,
Stille Cross-Coupling
Isomerising
13
O-Directed Free Radical
Hydrostannation
O
Ph Sn Addition
3
O
Ph Sn
3
PREDICTED
FAVOURED
PRODUCT
Me
-Elimination
Me
and Vinyl Radical
Ph Sn
3
Me
Quenching with Ph SnH
25
3
Me
Me
Me
O
O
O
Scheme 3. Some of the mechanistic events3 that would be likely to be operating in
the O-directed hydrostannation of 14 with Ph3SnH and Et3B.
Me
O
EtO
O
EtO
O
Me
Me
13
Me
14
O-Desilylation,
Bromination
Sharpless AD,
Protection
radicals 22 and 24 would then almost certainly be rapidly
quenched by the excess stannane that would be present in the
reaction mixture. Thus, for 14, it was our belief that none of the
newly incorporated stereocentres in the chain would ever be put
at risk by applying the O-directed free radical hydrostannation pro-
cess. Moreover, because the propargylic O-atom of 14 should be
capable of satisfactorily coordinating to the mildly Lewis acidic
Ph3Sn radical, as well as the stannane itself, we considered that
these combined events would greatly favour triphenyltin radical
OTBDPS
Me
OTBDPS
Br
18
15
Me
O
Me
O
Me
17
Me
O
+
O
Me
Me
Me
Me
OTBDPS
SO
Me
2
Br
Me
+
N
16
20
O
19
addition to the a-carbon of 14 (based upon our many past experi-
ences) and this, along with the multiple Ph3SnÅ addition–elimina-
tion/isomerisation pathways that are known to operate3 in these
reactions, led us to predict that the formation of 13 would ulti-
mately be favoured.
Sonogashira
Coupling
Oppolzer Enolate
Alkylation
Scheme 2. Our retrosynthetic analysis for (+)-pumiliotoxin B.
Thereafter, we believed that 13 (Scheme 2) would be capable of
being converted into the desired vinylic iodide by tin–iodine ex-
change2 which, if successful, would allow a subsequent Stille
cross-coupling reaction with tetramethylstannane to complete
the final elaboration of the trisubstituted olefin 12 (Scheme 2).
Conversion of the ester 12 into the terminal alkyne 8 would then
complete our intersection with Overman’s second-generation
route to (+)-pumiliotoxin B, which has a truly superb end-game.7b
With respect to introducing the C(11)-Me substituent of 8, we
favoured an Oppolzer-type alkylation9 between 16 and the acti-
vated propargylic bromide 15 to achieve this objective, due to
the improved nucleophilicity of such metal enolates compared
with their Evans N-acyl oxazolidinone counterparts. A logical
way of installing the two O-stereocentres in 15 would be to per-
form a Sharpless AD reaction10 on the eneyne 18, and then to effect
a series of standard functional group interconversions, but this par-
ticular option would obviously require a potentially very challeng-
ing Sonogashira coupling to be effected between 19 and 20.
As soon as one retrosynthetically dissects the structure of al-
kyne 8 (Scheme 2) and one moves forward towards the propargylic
acetal 14, one can very soon see that this alkyne is perfectly set up
for application of the O-directed free radical hydrostannation pro-
cess. In this regard, one must remember that this is a mechanisti-
cally complex reaction,3 in which the triphenylstannyl radical is
capable of reversibly adding to either alkyne carbon to generate
two individual, transient, highly reactive, vinylic radicals at either
C-atom of the original alkyne structure. Moreover, once generated,
these rapidly-inverting, high energy, vinyl radicals can frequently
engage in internal 1,5-H-atom abstraction events at appropriately
positioned carbons.4
In the case of alkyne 14 (Scheme 3), the two potential vinylic
radical 1,5-H-atom abstraction sites would be at the methyl groups
attached to C(11) and C(16), and the resulting secondary carbon

2082
S. Manaviazar et al. / Tetrahedron Letters 52 (2011) 2080–2084
(i) To 20 (5 g) in
mCPBA, CH Cl ,
23 ºC (81%)
(dr 9 : 27 = 1:1)
2
2
pyrrolidine (62 mL)
OTBDPS
add (Ph P) Pd
3
4
OTBDPS
Me
OH
(0.038 eq), stir at rt
10 min, then add
(ii) AD-Mix-β,
t-BuOH, H O
NZ
H
NZ
H
NZ
H
2
+
Br
Me
Me
OTBDPS
MeSO NH ,
2
2
O
O
OH
mCPBA, hexane,
Me
Me
Me
0 ºC, 48 h
19
(11.1 g)
o
28
18
23 C (60%)
(93%, > 99% ee)
20
26
9
27
(dr 9 : 27 = 2:1)
in pyrrolidine (62mL)
(iii) Me C(OMe) (10 eq),
2
2
stir at rt, 10 min then add
CuI (0.25 eq), stir, 3 h (75%)
PPTS ( 1 eq), CH Cl , rt,
2
2
Scheme 4. Overman’s preparation of chiral epoxide 9.
6 h (96%)
(vi)
Me
Me
(iv) n-Bu NF (1 eq),
SO
N
Me
4
2
OTBDPS
Br
THF, rt,
3 h 45 min
(93-99%)
16
Me
Me
In Overman’s originally published strategy to epoxide 9,7a alkene
26 was epoxidised with mCPBA in CH2Cl2 (Scheme 4), but, rather
unfortunately, this reaction lacked good stereocontrol (dr = 1:1)
and it required a preparative HPLC separation to obtain 9 in pure
condition. Even when this epoxidation was performed in the
slightly more stereoselective solvent, hexane, this process still only
delivered 9 with a 2:1 level of diastereoselectivity (61% yield) and,
because of substrate solubility issues, hexane could not ultimately
be used for the subsequent large scale synthesis of 9.
Our plan for overcoming this 1:1 mixture issue would take
advantage of a novel trifluoroacetamido-assisted iodo-hydroxyl-
ation reaction11 on the alkene 11 to set the tertiary OH-stereo-
chemistry of 10 and, most importantly, this would position a
fairly easily removed N-protecting group within the product that
could potentially be detached under the very mild, aqueous, basic
conditions that we planned to use to form the epoxide itself. If al-
lied with in situ N-acylation with ZCl, such a ploy would possibly
allow the requisite Z-group to be successfully installed within 9
in a multi-component, one-pot, operation that, hopefully, would
efficiently deliver this compound with near complete stereocon-
trol, and totally overcome the previous need to do preparative
HPLC purification. With this as background, we will now discuss
the final formal synthesis that we have devised.
An early objective in our route to alkyne 8 was the preparation
of eneyne 18 and, for this, we decided to investigate the Sonogash-
ira coupling between 20 (Aldrich) and 19 (Scheme 5). Initially, we
followed a closely related literature report12 in which propargyl
alcohol was coupled to 20 and we noted, almost immediately, that
this low yielding Sonogashira procedure (28%) failed to use copper
iodide as an additive. When we applied similar Cu-free conditions
for the Pd-catalysed cross-coupling of 19 with 20, we too only saw
a low yield of product. Fortunately, however, and after some quite
painstaking experimentation on our part, which included the addi-
tion of catalytic CuI to the reaction mixture, we were eventually
able to reproducibly obtain a 75% yield of 18, using the reaction
conditions specified in Scheme 5, which employed neat pyrrolidine
as the reaction solvent, and (Ph3P)4Pd as the co-catalyst, and which
conducted the reaction for only 3 h at room temperature.
With this key obstacle overridden, the stage was set for per-
forming the Sharpless AD reaction that was required to install
the C(15)- and C(16)-hydroxyls of the natural product. The latter
reaction performed admirably in this capacity, delivering 28 as
essentially a single enantiomer, in very high yield (93%) (see the
Mosher ester analysis we did in the Supplementary data). The
1,2-diol unit of 28 was next protected as an O-isopropylidene ace-
tal. The O-silyl group was then detached from 17 and bromination
was performed with triphenylphosphine and carbon tetrabromide
in THF. Although bromide 15 was somewhat unstable, it could be
successfully purified in 73–88% yield by SiO2 flash chromatography
and it was subsequently characterised by high field NMR spectros-
copy (see Supplementary data).
(1 eq)
O
O
O
n-BuLi in hex (2.5 M)
(1 eq), stir 80 min,
(v) Ph P (2 eq),
CBr (2 eq),
THF, rt, 50 min
(73-88%)
3
O
Me
O
Me
Me
17
4
15
Me
then add 21 (1 eq) in
HMPA (3 eq),
stir at -78 ºC, 4 h
(72%)
Me
Me
Me
Me
Me
Me
(vii) Ti(OEt) (10 eq),
4
SO
2
O
O
O
EtO
N
O
O
Me
EtOH, Δ,
72 h (83%)
Me
O
Me
14
Me
29
(viii) Ph SnH (2 eq),
3
Et B (0.4 eq), PhMe,
3
rt, 19 h (97%)
Ph Sn
3
Me
I
Me
Me
Me
(ix) I (1.2 eq), CH Cl ,
2
2
2
O
O
0 ºC, then warm to rt,
2 h (82%)
O
O
Me
Me
O
EtO
O
EtO
Me
Me
13
30
(x) Me Sn (3.3 eq), DMF, Et N (72 eq),
(dr = ca. 18:1)
4
3
CuI (0.1 eq), Ph As (0.1 eq),
3
PdCl (MeCN) (0.1 eq), 110 ºC, 3 h (91%)
2
2
Me Me
Me Me
(xi) i-Bu AlH (2.5 eq), THF,
2
Me
Me
-78 ºC, 4 h, warm to rt (95%)
O
O
O
Me
O
Me
(xii) PhI(OAc) (4.1 eq),
2
O
Me
O
EtO
Me
TEMPO (0.16 eq), CH Cl ,
31
2
2
12
rt, 4 h (86%)
(xiii) Ph P (4 eq),
3
CBr (2 eq), CH Cl ,
4
2
2
rt, 40 min (68%)
Me Me
Me Me
(xiv) n-BuLi (2.5 M
in hex, 2 eq),
Me
Me
O
O
Br
O
Me
THF, -78 ºC, 1 h
(73%)
O
Me
Me
Br
Me
32
8
Scheme 5. Our new route to Overman’s advanced alkyne intermediate 8 for the
total synthesis of (+)-pumiliotoxin B.
for 4 h, a highly stereocontrolled asymmetric alkylation took place,
with the C(11)-Me group being introduced with total stereocontrol
in a really quite respectable 72% yield. With this key C–C bond-
forming step negotiated, we could now think about implementing
our O-directed hydrostannation step. Although our original plan
had been to detach the auxiliary from 29 and then apply the
Ph3SnH/Et3B hydrostannation on 14 we did, nevertheless, feel that
it would be worthwhile examining the viability of this process on
29, to see how well this substrate behaved but, to our great disap-
pointment, no reaction took place at all. We can only surmise that
the sulfonamido unit of the Oppolzer camphorsultam auxiliary
inhibits the free radical hydrostannation process in some way.
We, therefore, proceeded with our original plan of cleaving the
chiral auxiliary from 29 with Ti(OEt)4 and EtOH at reflux;13 the
reaction took 3 days to reach completion but, when the end-point
was finally reached, 14 was isolable in 83% yield. When we now
applied the O-directed free radical hydrostannation process to
14, over 19 h, we observed that a chromatographically inseparable
18:1 mixture of regioisomeric vinyl triphenylstannanes was
When n-BuLi was used as the base for enolisation of Oppolzer’s
camphorsultam-tethered9 propionamide 16 (Scheme 5), and a
solution of the bromide 15 in HMPA was added to this lithium eno-
late at low temperature, and the À78 °C conditions were preserved

S. Manaviazar et al. / Tetrahedron Letters 52 (2011) 2080–2084
2083
formed in which 13 predominated. Importantly, the purified 18:1
mixture enriched in 13 could be isolated in pure condition in
97% yield following SiO2 flash chromatography. As expected, io-
dine-tin exchange and Stille cross-coupling of 30 with Me4Sn and
Pd(0), both proceeded smoothly to deliver the desired trisubsti-
tuted olefin 12 in essentially pure condition in 75% yield over
two steps.
Ester 12 was now reduced to the primary alcohol with DIBAL-
H, and this product oxidized to aldehyde 31 with catalytic TEMPO
and excess iodobenzene diacetate, using the excellent procedure
of Piancatelli.14 Significantly, all of the other oxidants that were
examined in this reaction also caused an extensive, and highly
problematical, epimerization of the C(11)-methyl stereocentre
Concurrent with our development of this new pathway to al-
kyne 8, we also addressed the synthesis of epoxide 9 (Scheme 6).
Our new route repeated some of the excellent chemistry of Steven-
son18 for the acquisition of alkene 36. The latter had its Boc-group
replaced by an N-trifluoroacetamido-group in order to permit the
anchimerically-assisted stereoselective iodo-hydroxylation reac-
tion on 11; a reaction which proceeded in 87–89% yield and deliv-
ered 10 as the major component of a 11.7:1 mixture.11 Treatment
of the latter with excess 3 M aqueous NaOH in dioxane thereafter
simultaneously formed the terminal epoxide and cleaved the
N-trifluoroacetamido substituent to allow an in situ N-acylation
with benzyl chloroformate to obtain 9. Although this new route
to 9 is 3 steps longer than the previous Overman route it does,
nonetheless, proceed with high stereocontrol and, it does now fi-
nally overcome the previous requirement to use preparative HPLC
to continue the synthesis.
To summarise, we have completed a new and greatly improved
formal asymmetric total synthesis of (+)-pumiliotoxin B that inter-
sects with Overman’s elegant 1996 synthesis7b of this natural
product. Significantly our new route to his advanced intermediates
8 and 9 is 2 steps shorter than his second-generation path to this
target, and its major advantage resides in the fact that it is highly
stereocontrolled and it now removes the need to do preparative
HPLC to advance forward. By completing this new formal route,
we have demonstrated here, for the first time ever that our new
O-directed free radical hydrostannation process can be beneficially
and powerfully used to position an ornate trisubstituted olefin
within a complex natural product. Further applications of the O-di-
rected free radical hydrostannation process in the total synthesis of
other complex natural products will be reported in due course.
a- to the aldehydo group, and quite considerable oxidant screen-
ing was required before we eventually identified these optimal
oxidation conditions. Following SiO2 flash chromatography, alde-
hyde 31 was isolated in pure condition in 86% yield and it was
used directly for the subsequent Corey–Fuchs dibromolefination15
step without delay. The latter reaction was first applied on 31 by
Kibayashi8d in his total synthesis of allo-pumiliotoxin 339A. Dib-
romoalkene 32 also featured in Overman’s pathway to (+)-pumi-
liotoxin B and, in this context, 32 had previously been converted
into alkyne 8 by low temperature treatment with two equivalents
of n-BuLi in THF;7b both sets of chemistry were successfully re-
peated by us.
Although we did indeed attempt the direct alkynylation of alde-
hyde 31 with the Ohira–Bestmann reagent,16 the fairly basic
conditions under which this method operates proved totally
incompatible with preservation of the C(11)-Me stereochemistry
in 31. Whilst the reaction was itself chemically successful at deliv-
ering the alkynylated product 8 in high yield, it also led to a signif-
icant amount of terminal alkyne diastereomer at C(11), which
proved inseparable by SiO2 flash chromatography. Thus, this par-
ticular direct method for converting 31 into 8 was simply not via-
ble, making the lengthier two-step Corey–Fuchs alkynylation
pathway to 8 almost mandatory.17
Acknowledgements
We thank Novartis Pharma AG, the ACS and Queen’s University
Belfast for financial support. We thank Dr. Paul Stevenson (QUB)
for helpful advice on the preparation of 36.
Supplementary data
(i) Et N (2 eq), DMF,
3
0 ºC, 45 min, filter
off salt, cool filtrate
(ii) MeMgI (3M in Et O)
2
Supplementary data (copies of the 400 and 500 MHz 1H and
125 MHz 13C NMR spectra are supplied for all the new and previ-
ously unreported intermediates described in this route) associated
with this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.10.141.
NH Cl
2
NBoc
NBoc
H
(3 eq), Et O, 0 ºC, then
2
OH
Me
warm to rt, 6 h
(87%, 2 steps)
CO Me
CO Me
2
to 0ºC, add Boc
O
2
2
H
H
(1.1 eq) in DMF over
20 min, warm to rt,
stir, 19 h
Me
35
33
34
(iii) To 35 in THF,
CF
at -78 ºC, add
3
(iv) CF CO H (10 eq),
3
2
SOCl (2.1 eq),
2
References and notes
NBoc
N
H
O
CH Cl , rt, 2 h
2
2
stir 2.5 h, then add
Et N (17 eq) dropwise,
stir at -78 ºC, 2 h, and
warm to rt (62%)
(v) (CF CO) O (4 eq),
3
1. Dimopoulos, P.; Athlan, A.; Manaviazar, S.; George, J.; Walters, M.; Lazarides, L.;
Aliev, A. E.; Hale, K. J. Org. Lett. 2005, 7, 5369–5372.
2. Dimopoulos, P.; Athlan, A.; Manaviazar, S.; Hale, K. J. Org. Lett. 2005, 7, 5373–
5376.
3
2
H
Me
Me
Et N (8 eq), CH Cl ,
3
2
2
11
36
rt, 16 h (87%)
3. For our detailed investigations into the mechanism of the O-directed
alkylacetylene hydrostannation, see: Dimopoulos, P.; George, J.; Manaviazar,
S.; Tocher, D. A.; Hale, K. J. Org. Lett. 2005, 7, 5377–5380.
4. For an account of our attempts to use this stannation method in the synthesis
of the A83586C/kettapeptin pyran side-chain, see: Hale, K. J.; Manaviazar, S.;
George, J. Chem. Commun. 2010, 46, 4021–4042.
CF
3
(vii) 3M aq. NaOH
(20 eq), 1,4-
NZ
(vi) NIS (2 eq), THF:H O
2
N
H
O
dioxane, rt, 0.5 h,
(50:1), -20 ºC , 1.5 h,
then rt, 16 h (87-89%)
I
then add
H
O
OH
Me
10
Me
9
ZCl (1 eq), 4.5 h
(64%)
5. See: Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.,
Ed.; Wiley-Interscience: New York, 2002; Vols. 1–2,.
+
6. Daly, J. W.; Myers, C. W. Science (Washington D.D.) 1967, 156, 970–973.
7. For previous (+)-pumiliotoxin B total syntheses, see: (a) Overman, L. E.; Bell, K.
L.; Ito, F. J. Am. Chem. Soc. 1984, 4192–4201; (b) Lin, N.-H.; Overman, L. E.;
Rabinowitz, M. H.; Robinson, L. A.; Sharp, M. J.; Zablocki, J. J. Am. Chem. Soc.
1996, 118, 9062–9072; (c) Kibayashi, C.; Aoyagi, S. J. Organomet. Chem. 2002,
653, 229–233; (d) Aoyagi, S.; Hirashima, S.; Saito, K.; Kibayashi, C. J. Org. Chem.
2002, 67, 5517–5526; For a review on pumiliotoxin alkaloid synthesis, see: (e)
Franklin, A.; Overman, L. E. Chem. Rev. 1996, 96, 505–522.
Me OH
Me
L.E. Overman
et al.
Me Me
Me
Me
O
OH
N
H
O
Me
Me
Reference 7 b
8
OH
Me
8. For recent syntheses of the structurally related allo-pumiliotoxins, see: (a)
Overman, L. E.; Goldstein, S. W. J. Am. Chem. Soc. 1984, 106, 5360–5361; (b)
Goldstein, S. W.; Overman, L. E.; Rabinowitz, M. H. J. Org. Chem. 1992, 57, 1179–
1190; (c) Trost, B. M.; Scanlan, T. S. J. Am. Chem. Soc. 1989, 111, 4988–4990; (d)
(+)-Pumiliotoxin B
Scheme 6. The final stages of our new formal total synthesis of (+)-pumiliotoxin B.

2084
S. Manaviazar et al. / Tetrahedron Letters 52 (2011) 2080–2084
Aoyagi, S.; Wang, T. C.; Kibayashi, C. J. Am. Chem. Soc. 1993, 115, 11393–11409;
(f) Tan, C. H.; Holmes, A. B. Chem. Eur. J. 2001, 7, 1845–1854; (e) Tang, X.-Q.;
Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6950–6954.
12. Pohnert, G.; Boland, W. Tetrahedron 1994, 50, 10235–10244.
13. Garner, P.; Ho, W. B.; Grandhee, S. K.; Youngs, W. J.; Kennedy, V. O. J. Org. Chem.
1991, 56, 5893–5903.
9. Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 41, 5603–5606.
10. Eneyne asymmetric dihydroxylation: (a) Jeong, K.-S.; Sjo, P.; Sharpless, K. B.
Tetrahedron Lett. 1992, 33, 3833–3836; For the AD procedure, see: (b)
Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.;
Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X. L. J. Org.
Chem. 1992, 57, 2768–2771.
14. De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974–6977.
15. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769–3772.
16. Toth, G.; Liepold, B.; Muller, S.; Bestmann, H. J. Synthesis 2004, 59–62.
17. Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107–108. We also examined the
reaction of crude aldehyde 31 with the Shioiri reagent derived from n-BuLi/
11. For a related stereocontrolled iodohydroxylation on the N-benzoyl-pyrrolidine
analogue of 11 see: Overman, L. E. McCready, R. J. Tetrahedron Lett. 1982, 23,
4887. This example proceeded with 10:1 stereoselectivity in favour of the
desired tertiary alcohol-iodide, but unfortunately, difficulties were
subsequently encountered in the removal of the N-benzoyl group. A priori,
we considered that use of an N-trifluoroacetamide might overcome these
difficulties and give rise to an identical stereochemical outcome, and lead to 10
with good stereocontrol.
TMSCHN2 in THF at À78 °C. Whilst the reaction worked in 70% yield,
a
mixture of alkyne C(11)-Me epimers was obtained. Since this aldehyde was
derived by TFAA/Me2SO/Et3N Swern-type oxidation, we now have good
reason to suspect that the latter process may have epimerized the C(11)-
centre before the alkynylation was effected. Our future full account will look
into this step again.
18. O’Mahony, G.; Nieuwenhuyzen, M.; Armstrong, P.; Stevenson, P. J. J. Org. Chem.
2004, 69, 3968–3971.