Total synthesis of (-)-dictyostatin, a microtubule-stabilising anticancer macrolide of marine sponge origin

Article abstract of DOI:10.1016/j.tet.2010.01.083

An efficient convergent synthesis of the anticancer marine macrolide (-)-dictyostatin is described that proceeds in 4.6% yield over 27 steps. Most of the stereocentres were configured using substrate control, making use of a common building block to insta

Full text of DOI:10.1016/j.tet.2010.01.083

Tetrahedron 66 (2010) 6534–6545
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of (ꢀ)-dictyostatin, a microtubule-stabilising anticancer
macrolide of marine sponge origin
*
Ian Paterson , Robert Britton, Oscar Delgado, Nicola M. Gardner, Arndt Meyer,
Guy J. Naylor, Karine G. Poullennec
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient convergent synthesis of the anticancer marine macrolide (ꢀ)-dictyostatin is described that
proceeds in 4.6% yield over 27 steps. Most of the stereocentres were configured using substrate control,
making use of a common building block to install the C12–C14 and C20–C22 stereotriads, with a lactate
Received 9 September 2009
Received in revised form 12 November 2009
Accepted 21 January 2010
boron aldol reaction employed to construct a C4–C10 b-ketophosphonate as utilised in the pivotal Still–
Available online 1 February 2010
Gennari HWE coupling step with a fully elaborated C11–C26 aldehyde. Following introduction of the
(2Z,4E)-dienoate, a modified Yamaguchi macrolactonisation and deprotection delivered the requisite
22-membered macrocyclic lactone.
Dedicated to Professor Steven Ley on
the occasion of his receipt of the
Tetrahedron Prize
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Macrolide
Cytotoxic
Tubulin
Aldol reaction
Olefination
1. Introduction
multidrug-resistant cell lines and a characteristic Taxol-like
mode of action was revealed, causing an accumulation of cells in
the G2/M phase of the cell cycle, extensive microtubule bundling
and cellular death via apoptosis. Complementing the benchmark
of Taxol (2), this clinically proven microtubule-stabilising mech-
anism is shared with discodermolide (3)5 and epothilone B (4),6 as
well as a number of other structurally distinct natural products
that have emerged as important leads for anticancer drug dis-
covery programmes.7
The planar structure of dictyostatin featuring a 26-carbon
backbone with 11 stereogenic centres, a 22-membered macro-
lactone, an endocyclic (2Z,4E)-dienoate and a pendant (Z)-diene
moiety was deduced by the Pettit group, primarily on the basis of 2D
NMR spectroscopic data.3 The elucidation of the complete stereo-
structure as in 1 was achieved in our laboratory in 2004,8 based on
the use of NOESY experiments and Murata’s method of J-based
configurational analysis. Recently, extensive NMR analysis, molec-
ular modelling and docking studies were employed to propose
a bound conformation for dictyostatin in the taxoid binding site on
Marine organisms have proven to be a rich source of bi-
ologically active natural products.1,2 Many of these novel chemo-
types exhibit exceptional levels of biological activity, combined
with unique modes of action, which may have value as lead
structures for the development of new therapeutic agents. Dic-
tyostatin (1, Fig. 1) is a potent cytotoxic marine macrolide, first
isolated in 1994 by Pettit et al.3 from the same Indian Ocean
sponge as the spongistatins. Due to the low isolation yield
(1.35 mg from 400 kg of wet sponge), relatively few biological
assays were performed. However, these revealed dictyostatin to
have promising antitumour properties, strongly inhibiting the
growth of a selection of cancer cell lines. Almost a decade passed
until Wright et al. reisolated dictyostatin in 2003 from a Caribbean
sponge of the family Corallistidae, collected with a manned sub-
mersible at great depth off the coast of Jamaica.4 Providing
a somewhat more abundant source, this allowed more extensive
biological evaluations, which demonstrated significant inhibition
of cancer cell proliferation at low nanomolar concentrations.
Significantly, this potent antimitotic activity was retained against
b
-tubulin.9 The results support a high degree of overlap between the
bioactive conformations of dictyostatin and discodermolide,10
stimulating the design and synthesis of hybrid molecules as novel
microtubule-stabilising agents that retain potent antiproliferative
activity.11
* Corresponding author. E-mail address: ip100@cam.ac.uk (I. Paterson).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.083

I. Paterson et al. / Tetrahedron 66 (2010) 6534–6545
6535
Bz
OH
NH
AcO
O
OH
Ph
O
O
HO
O
O
HO
O
H
HO
BzO
AcO
OH
OH
1: dictyostatin
2: Taxol (paclitaxel)
OH
O
HO
S
NH2
O
HO
N
OH
O
O
OH
O
O
OH
O
O
3: discodermolide
4: epothilone B
Figure 1. Natural products with a shared microtubule-stabilising mode of action.
The impressive biological profile of dictyostatin, coupled with
its elaborate stereostructure and low natural abundance, have led
to its widespread identification as an important synthetic tar-
get.12–17 As well as providing a sustainable supply for preclinical
evaluation, an efficient and flexible synthetic strategy should en-
able extensive SAR studies to help define the pharmacophore with
a view to simplifying the structure whilst retaining functionality. As
a conformationally constrained macrolide, dictyostatin represents
an attractive template for the optimisation of a new structural class
of microtubule-stabilising anticancer agent. Soon after the full
stereostructure was disclosed by our laboratory, the first two total
syntheses of (ꢀ)-dictyostatin were reported concurrently by our-
selves13 and the Curran group.14 Subsequently, there have been two
further completed total syntheses by the groups of Phillips15 and
Ramachandran,16 as well as a growing number of fragment syn-
theses.17 Additionally, the synthesis and biological activities of
a range of structural analogues of dictyostatin have been reported
independently by ourselves18 and Curran and Day.19 Notably,
Eiseman and Curran have recently demonstrated the promising
in vivo antitumour properties associated with 6-epi-dictyostatin
in xenograft mouse studies.20
olefination22,23 between
b-ketophosphonate 5 and aldehyde 7. In
turn, the C11–C26 subunit 7 was planned to arise through a Horner–
Wadsworth–Emmons (HWE) coupling of aldehyde 8 and phospho-
nate 9. The shared stereochemical triad of these two intermediates
indicated that they could both be accessed via
a common
intermediate 10, which is readily available by boron-mediated aldol
methodology developed in the context of our discodermolide
work.24 The isolated methyl-bearing stereocentre at C16 in aldehyde
8 would be configured by a Myers alkylation. While these discon-
nections are shared with our original route, we chose to revise the
synthesis of the pivotal C4–C10 subunit 5 having the C7 hydroxyl
now protected as a PMB ether,11,18a utilising our lactate aldol meth-
odology25 in preference to the Brown crotylation used previously. In
addition, we elected to configure the C9 hydroxyl-bearing stereo-
centre after the Still–Gennari-type fragment coupling and before the
macrolactonisation step. A judicious selection of protecting groups
was expected to help further refine the synthesis.
3. Results and discussion
The synthesis of the C11–C26 fragment 7, containing eight of the
eleven stereocentres and the terminal diene of dictyostatin, re-
quired the efficient construction of the requisite HWE coupling
partners 8 and 9 from the common precursor 10. Using our boron
aldol methodology, this valuable stereotriad building block can be
prepared on a multi-gram scale from the ethyl ketone 11 derived
from (S)-Roche ester (67%, five steps), as described previously.24
Preparation of the C11–C17 aldehyde 7 began with selective
iodination26 of the primary hydroxyl in 1,3-diol 10, followed by
secondary hydroxyl protection of 12 with TBSOTf and 2,6-lutidine,
to yield iodide 13 in 92% yield (Scheme 2). Myers’ propionamide
1427 was then treated with LDA to generate the lithium enolate 15,
before addition of iodide 13 effected formation of the desired al-
kylation product 16. This homologation sequence proceeded in
high yield to configure the C16 methyl-bearing stereocentre with
excellent diastereoselectivity (99%, >20:1 dr). Pleasingly, upon re-
ductive cleavage of the amide in 16 with BH3$NH3, the pseudoe-
phedrine auxiliary could be recovered by recrystallisation prior to
chromatographic purification of the resulting primary alcohol
Despite these remarkable efforts, there remains a pressing need
to develop a more practical and efficient route to dictyostatin itself.
Herein, we report full details of an improved total synthesis of
dictyostatin that evolved from our previously reported strategy13
and parallel work on SAR studies.18 Notably, this route has been
used to prepare sufficient quantities of synthetic dictyostatin to
facilitate further biological evaluation of this promising anticancer
agent.
2. Retrosynthetic analysis and general synthetic strategy
As devised originally, our modular synthetic strategy13 for
dictyostatin was designed to be highly convergent and readily ame-
nable to analogue synthesis by late-stage diversification. As outlined
in Scheme 1, we envisaged
a late-stage Yamaguchi macro-
lactonisation preceded by
a Stille–Liebeskind cross-coupling
reaction21 with vinyl stannane 6 to generate the (2Z,4E)-dienoate.
The (10Z)-alkene would be installed via a complex Still–Gennari

6536
I. Paterson et al. / Tetrahedron 66 (2010) 6534–6545
I
OH
I
26
15
OH
TBSO
HO
HO
a
b
HO
(92%,
Yamaguchi
macrolactonisation
11
O
O
2 steps)
1
OPMB
13
OPMB
OPMB
10
10
12
Still-Gennari
olefination
OH
OH
Stille-Liebeskind
cross-coupling
1: dictyostatin
Me
OH
Me
N
OLi
c
N
Ph
Ph
(99%)
O
OLi
15
CO2TIPS
aldol
14
4
CF3CH2O
CF3CH2O
Bu3Sn
10
3
P
I
6
Me
OH
O
O
OPMB
O
d,e
16
N
5
Ph
(72%)
TBSO
H
PMBO
OTBS
O
HWE olefination
TBS
O
16
11
8
26
OPMB
Scheme 2. (a) PPh3, I2, pyr, PhMe, 0 ꢁC/rt, 16 h; (b) TBSOTf, 2,6-lutidine, CH2Cl2,
ꢀ78 ꢁC, 2 h; (c) i-Pr2NH, LiCl, n-BuLi, THF, ꢀ78 ꢁC/0 ꢁC/rt, 90 min; 13, THF, 0 ꢁC/rt,
16 h; (d) LDA, BH3$NH3, THF, rt, 2 h; (e) DMP, NaHCO3, CH2Cl2, 0 ꢁC, 2 h.
TBSO
H
11
OH
7
O
initiated by addition of (MeO)2P(O)CH2Li, before the resulting epi-
meric mixture of alcohols was then reoxidised with Dess–Martin
periodinone (91%). Reaction between the aldehyde 8 and phos-
phonate 9 using HWE conditions developed in our group (Ba(OH)2
in wet THF),29 resulted in isolation of the enone 18 as exclusively
the (E)-isomer in excellent yield (89%) when performed on a 5 g
scale. The enone 18 then underwent a conjugate reduction with
Myers alkylation
O
O
(MeO)2P
16
26
O
18
TBSO
11
H
Stryker’s reagent,30 to yield the corresponding
a,b-saturated ketone
9
OPMB
8
19 in 98% yield. Interestingly, it was found that addition of traces of
water significantly increased the rate of hydride transfer. However,
attempts to utilise a catalytic amount of Stryker’s reagent proved
unrewarding,31 leading to lower yields.
OPMB
With the entire C11–C26 carbon backbone now in place, we next
focused on achieving an efficient, stereoselective reduction of the
C19 carbonyl group. Rather than proceed by cleavage of both PMB
ethers and chelation-controlled reduction of the resulting
PMBO
OH
OH
10
aldol
b-hydroxyketone using Zn(BH4)2, followed by a two-step sequence
to selectively introduce a TBS ether at C19 over C21 as implemented
previously,13 we elected to initially retain the PMB ethers to help
streamline the synthesis. Gratifyingly, after screening a number of
ref 24
32
metal hydrides, it was found that LiAlH(OtBu)3 at low tempera-
ture (ꢀ30 ꢁC, THF) reduced the ketone 19 smoothly to the requisite
(19R)-alcohol in excellent diastereoselectivity (>20:1 dr) on
a multi-gram scale. Subsequently, treatment with TBSOTf and 2,6-
lutidine protected the C19 hydroxyl, before a bis-PMB deprotection
via oxidative cleavage with DDQ, in a biphasic solution of DCM and
pH 7 buffer, afforded the corresponding diol in 65% yield from
ketone 19. Selective oxidation33a of the primary over the secondary
alcohol using the Piancatelli protocol (catalytic TEMPO and
PMBO
O
11
Scheme 1. Retrosynthetic analysis for dictyostatin leading to key building blocks.
product. Oxidation of this alcohol with Dess–Martin periodinone
provided the corresponding aldehyde 8 (72%, two steps),28 set for
the key HWE fragment union. In comparison, efforts to convert the
alkylation product 16 directly to aldehyde 8, by treatment with
LiAlH(OEt)3, led to poor yields, epimerisation and extensive by-
product formation.
PhI(OAc)2)33b resulted in formation of the
a-chiral aldehyde 7 in
89% yield, without any epimerisation. This efficient and scaleable
synthesis of the fully elaborated C11–C26 subunit 7 was completed
in 20 steps and 16% overall yield along the longest linear sequence
starting from (S)-Roche ester, in readiness for its Still–Gennari
coupling with the complex phosphonate 5.
The b-ketophosphonate coupling partner 9 was also prepared
from common intermediate 10 (Scheme 3), whereby a previously
described24 sequence afforded the (Z)-diene substituted aldehyde
17 (53%, seven steps), as used to great effect in our discodermolide
work. Conversion of 17 into the desired phosphonate 9 was
Synthesis of the C4–C10 fragment 5 relied on a boron-mediated
aldol reaction to configure the anti-related C6 and C7 stereocentres
(Scheme 4). The ethyl ketone 20 was prepared in three steps and 65%
yield from (R)-isobutyl lactate, as described previously.25a Selective

I. Paterson et al. / Tetrahedron 66 (2010) 6534–6545
6537
O
OH
ref 24
(MeO)2P
26
26
19
23
a,b
7 steps
H
O
O
18
OH
PMBO
19
(53%)
(91%)
10
OPMB
OPMB
9
17
c
8
(89%)
TBS
O
26
18
O
O
e−h
d
TBSO
TBSO
TBSO
(98%)
(58%)
H
11
OPMB
OPMB
OH
7
19
18
OPMB
OPMB
O
Scheme 3. (a) (MeO)2P(O)Me, n-BuLi, THF, ꢀ78 ꢁC, 20 min; (b) DMP, CH2Cl2, rt, 30 min; (c) 8, Ba(OH)2, THF/H2O, rt, 90 min; (d) [(Ph3P)CuH]6, PhMe/H2O, rt, 16 h; (e) LiAlH(Ot-Bu)3,
THF, ꢀ30 ꢁC, 72 h; (f) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ78/0 ꢁC, 30 min; (g) DDQ, CH2Cl2/pH 7 buffer, 0 ꢁC, 2 h; (h) PhI(OAc)2, cat. TEMPO, CH2Cl2, 0 ꢁC/rt, 16 h.
generation of the (E)-boron enolate 21 was achieved using our
standard conditions of treatment with (c-Hex)2BCl/Me2NEt in Et2O.
Addition of aldehyde 22 at ꢀ78 ꢁC, followed by oxidative work-up,
afforded the expected 1,4-syn-1,3-anti adduct 23 in excellent yield
and selectivity (89%, >97:3 dr). This aldol reaction is believed to
proceed preferentially through the bicyclic boat-like transition state
TS-1, stabilised by a formyl hydrogen bond between the benzoate
carbonyl oxygen and the aldehyde with minimisation of A(1,3) strain
a
between the
a-stereocentre of the enolate and the methyl sub-
stituent.25a,34 Consequently, the requisite stereocentres at C6 and C7
in dictyostatin could be installed in a facile and efficient manner on
a multi-gram scale, where this procedure was found to be opera-
tionally simpler than the Brown crotylation protocol employed ear-
lier,13 involving significantly less effort in chromatographic
purification and delivering improved levels of stereocontrol. We
have since used this more convenient aldol-based route to synthe-
sise a potent hybrid of dictyostatin and discodermolide.11a
OBz
OBz
OB(c-Hex)2
21
O
20
Ph
O
H
O
Me
H
TBSO
O
L
O
B
(89%,
22
H
L
Me
TS-1
O
>97:3 dr)
After screening for the most effective Lewis or Brønsted acid, the
aldol adduct 23 was transformed into its PMB ether by treatment
with p-methoxybenzyl-trichloroacetimidate and catalytic Sc(OTf)3
(0.03 mol %). In a one-pot sequence, reduction of the ketone
(NaBH4) and cleavage of the benzoate (K2CO3, MeOH) then pro-
R
H
b−d
(81%)
TBSO
O
TBSO
OBz
vided the 1,2-diol in 91% yield from
glycol cleavage afforded the base-sensitive,
b
-hydroxyketone 23. Periodate
-chiral aldehyde 24,
PMBO
H
OH
O
a
23
24
which was then converted into the corresponding vinyl iodide 25
via a Takai olefination,35,36 without epimerisation of the C6 ster-
eocentre and in good yield (74%) and selectivity (15:1 E/Z).
(74%)
e
At this stage, we needed to introduce the bis-(2,2,2-tri-
fluoroethyl)-methylphosphonate functionality in 5, in readiness
for the complex Still–Gennari olefination with the C11–C26 alde-
hyde 7. Thus cleavage of the TBS ether in 25 was implemented by
treatment with AcOH-buffered TBAF. The ensuing primary alcohol
was then subjected to a two-step oxidation sequence (Dess–Mar-
tin periodinane then Pinnick oxidation37) to afford acid 26 on
a multi-gram scale. This acid was then advanced directly onto the
next step without purification. Treatment with Ghosez’s reagent38
provided the intermediate acid chloride cleanly under mild con-
ditions, as found in our discodermolide work.23 This was then
added to a solution of lithiated bis-(2,2,2-trifluoroethyl)-methyl-
f−h
(86%)
TBSO
O
I
I
PMBO
OH
OPMB
26
25
(83%)
i
4
CF3CH2O
CF3CH2O
10
P
I
O
O
OPMB
5
phosphonate at ꢀ98 ꢁC to yield
b-ketophosphonate 5 in 71% yield
from 25. Overall, this readily scaleable synthesis of the C4–C10
subunit 5 was completed in 12 steps and 25% yield from (R)-iso-
butyl lactate.
With both of the key coupling partners 5 and 7 in hand, the stage
was set for the complex Still–Gennari-type HWE olefination which
was modelled on the pivotal fragment coupling step employed in our
third-generation discodermolide synthesis.23 After extensive
Scheme 4. (a) c-Hex2BCl, Me2NEt, Et2O, ꢀ78/0 ꢁC, 1 h; 22, ꢀ78/ꢀ20 ꢁC, 19 h; H2O2,
MeOH, pH 7 buffer, 0 ꢁC/rt, 1 h; (b) PMBTCA, cat. Sc(OTf)3, THF, 0 ꢁC, 50 min; (c)
NaBH4, MeOH, 0 ꢁC/rt, 45 min; K2CO3, 0 ꢁC/rt, 16 h; (d) NaIO4, MeOH/pH 7 buffer,
0
ꢁC/rt, 35 min; (e) CrCl2, CHI3, dioxane/THF, 0 ꢁC, 18 h; (f) TBAF, AcOH, THF, rt, 18 h;
(g) DMP, pyr, CH2Cl2, 0 ꢁC, 2 h; (h) NaClO2, Na2H2PO4, t-BuOH/2-methyl-2-butene, rt,
2 h; (i) 1-chloro-N,N-trimethylpropenyl-amine, CH2Cl2, rt, 1 h; LiHMDS, bis(2,2,2-
trifluoroethyl)-2-methylphosphonate, THF, ꢀ98 ꢁC, 90 min.

6538
I. Paterson et al. / Tetrahedron 66 (2010) 6534–6545
screening of conditions, including base, solvent, concentration and
temperature, we found that the optimal yield and selectivity were
achieved by using an excess of phosphonate 5 (1.5 equiv) and
treating this with K2CO3 and 18-crown-6 in the presence of aldehyde
7 in PhMe/HMPA (10:1) (Scheme 5). Good selectivity (6:1 Z:E) could
then be realised for the desired (Z)-enone 27, which was isolated in
65% yield.39 This pivotal Still–Gennari-type fragment coupling
strategy has figured prominently in our synthesis of a variety of
dictyostatin analogues for SAR studies.18
reagent42 and BH3$THF at ꢀ30 ꢁC, providing the 1,3-anti diol in 7:1
dr. Conversion to the corresponding acetonide 30, with 2,2-dime-
thoxypropane and catalytic PPTS, then allowed for straightforward
chromatographic purification, proceeding in 85% yield from 28. At
this stage, the 1,3-anti relationship between C7 and C9 was also
confirmed by 13C NMR acetonide analysis, utilising the Rychnovsky
method.43
The endgame strategy commenced with the completion of the
full dictyostatin backbone. Employing a copper-mediated Stille–
Liebeskind cross-coupling protocol,21 a mixture of vinyl iodide 30
and stannane 644 was treated with CuTC in deoxygenated NMP to
afford an acid-sensitive TIPS ester, which was immediately depro-
tected with KF in THF/MeOH to yield the seco-acid 31,45 in prepa-
ration for subjection to a modified Yamaguchi macrolactonisation
protocol.46 Thus, treatment of 31 with 2,4,6-trichlorobenzoyl-
chloride, Et3N and DMAP in PhMe at room temperature afforded
the 22-membered macrocyclic lactone 32 in 87% yield from vinyl
iodide 30. An initial problem encountered with this step was the
sensitive dienoate moiety partly isomerising to the more stable
(2E,4E)-isomer under the reaction conditions. This is likely due to
a reversible Michael addition of DMAP onto the C3 (or C5) position,
where free rotation of the C2–C3 bond then allows formation of the
thermodynamically favoured (2E,4E)-dienoate. Pleasingly, this
Oxidative cleavage of the PMB ether occurred on exposure of
adduct 27 to DDQ, affording the diol 28 cleanly (85%). This
b-hydroxyketone was intended for use in a directed reduction of
the enone moiety and our initial attempts focused on the Evans–
Saksena protocol40 using NaBH(OAc)3 in MeCN/AcOH. However,
this afforded a mixture of epimers at C9 (90% yield), formed in
a modest 2:1 dr in favour of the 1,3-anti diol 29. Similar results were
obtained in our analogue work,18b–d indicating that such complex
(Z)-enones are poor substrates for this particular hydroxyl-directed
reduction method. In an attempt to improve the diaster-
eoselectivity, the samarium (II) iodide mediated Evans–Tishchenko
protocol41 was next attempted, yielding the desired 1,3-anti diol
relationship in an improved 5:1 dr (70%). Finally, the most suc-
cessful and scaleable results were obtained using the (R)-CBS
TBS
TBS
O
O
5
TBSO
TBSO
a
b
OH
OH
(65%)
(85%)
I
I
7
O
OPMB
O
OH
28
27
c
CO2TIPS
Bu3Sn
6
TBS
O
TBS
O
TBS
O
TBSO
TBSO
TBSO
d
OH
OH
OH
e
(85%,
CO2H
2 steps)
I
I
O
O
O
O
OH OH
31
30
29
(87%,
2 steps)
f
TBS
O
OH
g
TBSO
HO
(70%)
O
O
O
O
O
O
OH
OH
32
1: (−)-dictyostatin
Scheme 5. (a) K2CO3, 18-crown-6, PhMe/HMPA, 0 ꢁC, 6 d; (b) DDQ, CH2Cl2/pH 7 buffer, 0 ꢁC, 1 h; (c) (R)-CBS$BH3, THF, ꢀ40 ꢁC, 16 h; (d) cat. PPTS, (MeO)2CMe2/CH2Cl2, 0 ꢁC/rt,
16 h; (e) 6, CuTC, NMP, rt, 16 h; KF, THF/MeOH, rt, 3 h; (f) 2,4,6-trichlorobenzoylchloride, Et3N, PhMe, rt, 2 h; DMAP, PhMe, rt, 18 h; (g) HF$pyr, THF, 0 ꢁC/rt, 96 h.

I. Paterson et al. / Tetrahedron 66 (2010) 6534–6545
6539
unwanted side reaction could be reduced to <5% by using the
minimum possible equivalents of Yamaguchi reagent (1.8 equiv)
and slow, portionwise addition of DMAP (0.5 equiv) to the solution
of the preformed mixed anhydride. This result represents a useful
improvement over our first-generation route,13 where a different
seco-acid was macrolactonised under conventional Yamaguchi
conditions.
(7.00 mL, 59.7 mmol, 4.0 equiv) then TBSOTf (6.85 mL, 29.8 mmol,
2.0 equiv). The reaction mixture was warmed to 0 ꢁC and stirred for
2 h before addition of satd aq NH4Cl (250 mL). The phases were
separated, the aqueous phase extracted with CH2Cl2 (3ꢂ200 mL),
and the combined organic extracts dried (MgSO4) and concentrated
in vacuo. Flash chromatography (light petroleum/10% EtOAc/light
petroleum) afforded TBS ether 13 (6.78 g, 92% over two steps) as
20
All that now remained to complete the total synthesis was the
global deprotection of macrocycle 32. On larger scale runs, re-
moving the protecting groups with 3 M HCl/MeOH (1:3) caused
a significant amount of translactonisation onto the C19 hydroxyl, to
afford the isomeric 20-membered macrocycle. However, switching
a colourless oil: Rf 0.72 (40% EtOAc/hexane); [
a
]
D
þ15.1 (c 1.04,
CH2Cl2); IR (CH2Cl2)/cmꢀ1 2989, 1394, 1066; 1H NMR (400 MHz,
CDCl3)
d
7.25 (2H, d, J¼8.7 Hz, ArH), 6.88 (2H, d, J¼8.7 Hz, ArH), 4.42
(1H, d, J¼11.3 Hz, OCHxHyAr), 4.38 (1H, d, J¼11.3 Hz, OCHxHyAr),
3.81 (3H, s, OMe), 3.68 (1H, dd, J¼5.9, 2.8 Hz, H13), 3.50 (1H, dd,
J¼9.2, 4.7 Hz, H11a), 3.19–3.26 (2H, m, H11bþH15a), 3.11 (1H, dd,
J¼9.4, 7.3 Hz, H15b), 1.86–1.99 (2H, m, H12þH14), 0.99 (3H, d,
J¼6.8 Hz, Me14), 0.94 (3H, d, J¼6.8 Hz, Me12), 0.88 (9H, s,
SiC(CH3)3), 0.07 (3H, s, SiCH3), 0.05 (3H, s, SiCH3); 13C NMR
to a more dependable protocol18c using HF$pyridine converted 32
20
into (ꢀ)-dictyostatin (1), [
a
]
ꢀ32.7 (c 0.22, MeOH),47 in 70% yield
D
with minimal ring contraction. This material was spectroscopically
identical to an authentic sample. To date, we have used this mod-
ified synthetic route to prepare 40 mg batches of dictyostatin for
further biological studies, as well as a series of structural analogues.
(125 MHz, CDCl3)
d 159.1, 130.7, 129.2, 113.8, 76.2, 72.7, 72.3, 55.3,
39.6, 38.1, 26.1, 18.8, 15.3, 14.9, 14.5, 3.7, ꢀ4.1; HRMS (þESI) calcd for
C21H41INO3Si [MþNH4]þ: 510.1895, found: 510.1902.
4. Conclusions
5.1.3. Amide 16. To a solution of i-Pr2NH (8.00 mL, 57.2 mmol,
8.4 equiv) and LiCl (5.72 g, 136 mmol, 20 equiv) in THF (30 mL) at
ꢀ78 ꢁC was added n-BuLi (34.9 mL of a 1.6 M solution in hexanes,
55.9 mmol, 8.2 equiv). After 30 min at 0 ꢁC, the solution was cooled
to ꢀ78 ꢁC and amide 14 (6.03 g, 27.3 mmol, 4.0 equiv) in THF
(12 mL) was added. The reaction mixture was stirred for 1 h at
ꢀ78 ꢁC, 20 min at 0 ꢁC and 5 min at rt before being re-cooled to
0 ꢁC. To the resulting enolate solution was added iodide 13 (3.35 g,
6.81 mmol, 1.0 equiv) in THF (12 mL) pre-cooled to 0 ꢁC. After stir-
ring at rt for 16 h, satd aq NH4Cl (60 mL) was added and the phases
separated. The aqueous phase was extracted with EtOAc (3ꢂ60 mL)
and the combined organic extracts dried (MgSO4) and concentrated
in vacuo. The excess amide 14 was recrystallised (PhMe) from the
crude product, filtered and the crystals washed with cold PhMe.
The filtrate was concentrated in vacuo and purified using flash
chromatography (40% EtOAc/light petroleum) to give amide 16
(3.93 g, 99%) as a colourless oil: Rf 0.25 (10% EtOAc/hexane); IR
(CH2Cl2)/cmꢀ1 2958, 2929, 2856, 1614, 1513, 1462, 1248; 1H NMR
In summary, an improved synthesis of the anticancer macrolide
(ꢀ)-dictyostatin (1) has been completed based on a highly con-
vergent strategy. This proceeds in 4.6% yield over 27 steps in the
longest linear sequence (from (S)-Roche ester), and has the po-
tential to produce the larger quantities of dictyostatin required for
further preclinical studies. Most of the stereocentres are configured
using substrate control, making use of the common building block
10 to install the C12–C14 and C20–C22 stereotriads, with a lactate
boron aldol reaction serving to construct the key b-ketophospho-
nate 5 required for the pivotal Still–Gennari fragment coupling step
with the fully elaborated C11–C26 aldehyde 7. The majority of the
steps have been performed on a multi-gram scale, facilitating ma-
terial throughput. This evolution of our original synthetic strategy
should enable the preparation of substantial quantities of dictyos-
tatin, as well as facilitate access to further structural analogues,18,19
as required for further biological evaluation, particularly with
regard to in vivo xenograft studies.20
(500 MHz, CDCl3)
d
7.30–7.40 (5H, m, ArH), 7.27 (2H, d, J¼8.8 Hz,
5. Experimental
ArH), 6.87 (2H, d, J¼8.8 Hz, ArH), 4.59 (1H, d, J¼7.6 Hz, OH), 4.38–
4.45 (3H, m, OCH2ArþPhCH), 3.81 (3H, s, OMe), 3.55 (1H, dd, J¼9.1,
4.7 Hz, H11a), 3.48 (1H, dd, J¼6.3, 2.2 Hz, H13), 3.26 (1H, t, J¼8.2 Hz,
H11b), 2.84 (3H, s, NMe), 2.66–2.75 (1H, m, NCH), 1.90–1.99 (1H, m,
H12), 1.73–1.81 (1H, m, H16), 1.54–1.62 (1H, m, H14), 1.19–1.27 (2H,
m, H15aþH15b), 1.13 (3H, d, J¼6.6 Hz, Me), 1.09 (3H, d, J¼6.9 Hz,
Me16), 0.96 (3H, d, J¼6.9 Hz, Me12), 0.90 (9H, s, SiC(CH3)3), 0.78
(3H, d, J¼Me14), 0.04 (3H, s, SiCH3), 0.03 (3H, s, SiCH3); 13C NMR
5.1. Data for compounds
5.1.1. Iodide 12. To a solution of diol 1024 (4.00 g, 14.9 mmol,
1.0 equiv) in PhMe (200 mL) at 0 ꢁC was added Ph3P (5.68 g,
22.4 mmol, 1.5 equiv) and pyridine (3.74 mL, 46.2 mmol, 3.1 equiv).
To this mixture was added a solution of I2 (5.48 g, 20.9 mmol,
1.4 equiv) in PhMe (100 mL) over 1.5 h, before warming to rt and
stirring for 16 h. Cold hexane (300 mL) was added, and after 30 min,
the reaction mixture was filtered through Celite and concentrated in
vacuo. Flash chromatography (10% EtOAc/hexane) afforded iodide 12
(125 MHz, CDCl3)
d 179.0, 159.0, 142.7, 130.9, 129.1, 128.7, 128.3,
127.5, 127.0, 126.3, 113.7, 77.8, 76.5, 72.9, 72.6, 55.3, 40.0, 38.4, 34.2,
33.4, 26.24, 26.18, 18.5, 18.3, 14.8, 14.4, 13.9, ꢀ3.6, ꢀ4.0; HRMS
(þESI) calcd for C34H56NO5Si [MþH]þ: 586.3922, found: 586.3916.
as a colourless oil, which was used directly in the next step: Rf 0.42
20
(20% EtOAc/hexane); [
a]
þ46.9 (c 1.81, CHCl3); IR (liquid film)/cmꢀ1
5.1.4. Aldehyde 8. To a solution of i-Pr2NH (2.80 mL, 20.1 mmol,
4.2 equiv) in THF (10 mL) at ꢀ78 ꢁC was added n-BuLi (11.7 mL of
a 1.6 M solution in hexanes, 18.2 mmol, 3.9 equiv). After 30 min at
0 ꢁC, the preformed solution of LDA was added to a suspension of
BH3$NH3 in THF (20 mL), stirred for 15 min at rt and re-cooled to
0 ꢁC. To this solution was then added via cannula the amide 16
(2.81 g, 4.79 mmol, 1.0 equiv) in THF (30 mL). After 2 h at rt, the re-
action mixture was cooled to 0 ꢁC and quenched by the addition of
3 M HCl (50 mL). The phases were separated, the aqueous phase
extracted with Et2O (3ꢂ60 mL) and the combined organic extracts
D
3482, 2963, 2932, 1613, 1586, 1513, 1462; 1H NMR (500 MHz, CDCl3)
d
7.23 (2H, d, J¼8.7 Hz, ArH), 6.87 (2H, d, J¼8.7 Hz, ArH), 4.47 (1H, d,
J¼11.4 Hz, OCHxHyAr), 4.42 (1H, d, J¼11.4 Hz, OCHxHyAr), 3.79 (3H, s,
OMe), 3.69 (1H, s, OH), 3.63 (1H, d, J¼8.8 Hz, H13), 3.57 (1H, dd, J¼9.1,
3.9 Hz, H11a), 3.46 (1H, t, J¼9.1 Hz, H11b), 3.35 (1H, dd, J¼9.6, 7.7 Hz,
H15a), 3.17 (1H, dd, J¼9.5, 6.6 Hz, H15b), 1.90–1.97 (1H, m, H12),
1.82–1.90 (1H, m, H14), 0.99 (3H, d, J¼6.9 Hz, Me14), 0.77 (3H, d,
J¼6.6 Hz, Me12); 13C NMR (125 MHz, CDCl3)
d 159.4, 129.5, 129.4,
113.9, 78.1, 76.1, 73.2, 55.3, 38.8, 36.1, 13.3, 13.2, 12.9; HRMS (ESIþ)
calcd for C15H27INO3 [MþNH4]þ: 396.1030, found: 396.1032.
concentrated in vacuo. The resulting crude alcohol was used directly
20
in the next step: Rf 0.50 (40% EtOAc/hexane); [
a
]
ꢀ14.3 (c 0.45,
D
5.1.2. TBS ether 13. To a solution of iodide 12 (5.64 g, 14.9 mmol,
1.0 equiv) in CH2Cl2 (300 mL) at ꢀ78 ꢁC was added 2,6-lutidine
CH2Cl2); IR (CH2Cl2)/cmꢀ1 3397, 2929, 1513, 1247, 1037; 1H NMR
(500 MHz, CDCl3)
7.27 (2H, d, J¼8.5 Hz, ArH), 6.89 (2H, d, J¼8.5 Hz,
d

6540
I. Paterson et al. / Tetrahedron 66 (2010) 6534–6545
ArH), 4.41 (1H, d, J¼11.9 Hz, OCHxHyAr), 4.37 (1H, d, J¼11.9 Hz,
OCHxHyAr), 3.82 (3H, s, OMe), 3.55 (1H, dd, J¼9.1, 5.3 Hz, H11a), 3.49–
3.53 (1H, m, H17a), 3.46 (1H, dd, J¼5.6, 2.8 Hz, H13), 3.36–3.41 (1H,
m, H17b), 3.24 (1H, dd, J¼9.1, 6.9 Hz, H11b), 2.00 (1H, sep, J¼5.9 Hz,
H12), 1.71–1.79 (1H, m, H14), 1.65–1.71 (1H, m, H16), 1.39 (1H, dt,
J¼13.5, 5.8 Hz, H15a), 0.96 (3H, d, J¼6.9 Hz, Me12), 0.93–0.95 (1H, m,
H15b), 0.94 (3H, d, J¼6.6 Hz, Me16), 0.90 (9H, s, SiC(CH3)3), 0.88 (3H,
d, J¼6.4 Hz, Me14), 0.05 (3H, s, SiCH3), 0.04 (3H, s, SiCH3); 13C NMR
5.1.6. Enone 18. To solid Ba(OH)2$8H2O (2.62 g, 8.29 mmol,
1.0 equiv; dried by heating under high vacuum) was added a solution
of phosphonate 9 (3.40 g, 8.29 mmol, 1.0 equiv) in THF (130 mL) via
cannula. After stirring for 1 h at rt, a solution of aldehyde 8 (3.50 g,
8.29 mmol, 1.0 equiv) in THF/water (40:1, 66.3 mL) was added via
cannula. After 1.5 h, the reaction mixture was quenched by the ad-
dition of brine (200 mL) and the phases separated. The aqueous layer
was extracted with CH2Cl2 (3ꢂ200 mL) and the combined organic
extracts dried (MgSO4) and concentrated in vacuo. Flash chroma-
(125 MHz, CDCl3)
d 159.1, 130.8, 129.2, 113.7, 77.4, 72.7, 67.3, 55.3,
38.2, 37.9, 33.5, 33.1, 26.2, 18.5, 17.8, 15.4, ꢀ3.6, ꢀ4.0; HRMS (þESI)
calcd for C24H44NaO4Si [MþNa]þ: 447.2907, found: 447.2935.
A suspension of the above alcohol (4.88 g, 11.5 mmol, 1.0 equiv)
and NaHCO3 (9.70 g, 115 mmol, 10 equiv) in CH2Cl2 (200 mL) at 0 ꢁC
was treated with Dess–Martin periodinane (5.80 g, 13.8 mmol,
1.2 equiv). After 2 h, the reaction mixture was concentrated in
vacuo and purified by flash chromatography (20% EtOAc/light pe-
tography (15% EtOAc/hexane/EtOAc) afforded (E)-enone 18 (5.20 g,
20
89%) as a colourless oil: Rf 0.30 (10% EtOAc/hexane); [
a
]
þ16.1 (c
D
0.21, CH2Cl2); IR (CH2Cl2)/cmꢀ1 2958, 1690, 1664, 1613, 1513, 1247,
1038; 1H NMR (400 MHz, CDCl3)
d
7.27 (2H, d, J¼8.7 Hz, ArH), 7.24
(2H, d, J¼8.7 Hz, ArH), 6.87 (4H, d, J¼8.7 Hz, ArH), 6.68 (1H, dd,
J¼15.3, 8.3 Hz, H17), 6.39 (1H, dt, J¼16.7, 10.6 Hz, H25), 6.03 (1H, d,
J¼15.8 Hz, H18), 6.00 (1H, t, J¼11.0 Hz, H24), 5.52 (1H, t, J¼10.6 Hz,
H23), 5.14 (1H, d, J¼16.7 Hz, H26a), 5.00 (1H, d, J¼10.3 Hz, H26b),
troleum) to afford aldehyde 8 (3.50 g, 72% over two steps) as
20
a colourless oil: Rf 0.30 (10% EtOAc/hexane); [
a
]
ꢀ18.2 (c 0.44,
4.55 (1H, d, J¼10.6 Hz, OCHxHyAr), 4.53 (1H, d, J¼10.6 Hz, OCHx
D
-
CH2Cl2); IR (CH2Cl2)/cmꢀ1 2930, 1726, 1513, 1247, 1037; 1H NMR
(400 MHz, CDCl3)
9.53 (1H, d, J¼2.4 Hz, H17), 7.24 (2H, d, J¼8.7 Hz,
HyAr), 4.40 (1H, d, J¼11.7 Hz, OCHxHyAr), 4.38 (1H, d, J¼11.7 Hz,
OCHxHyAr), 3.78 (6H, s, 2ꢂOMe), 3.68 (1H, dd, J¼8.2, 3.1 Hz, H21),
3.48 (1H, dd, J¼9.0, 4.7 Hz, H11a), 3.43 (1H, dd, J¼6.3, 2.3 Hz, H13),
3.23 (1H, t, J¼8.5 Hz, H11b), 2.92 (1H, qn, J¼7.8 Hz, H20), 2.72–2.81
(1H, m, H22), 2.33 (1H, sep, J¼7.0 Hz, H16), 1.85–1.96 (1H, m, H12),
1.54–1.63 (1H, m, H14),1.40 (1H, ddd, J¼13.4, 8.9, 4.7 Hz, H15a),1.20–
1.28 (1H, m, H15b),1.18 (3H, d, J¼6.8 Hz, Me20),1.08 (3H, d, J¼6.8 Hz,
Me22), 1.00 (3H, d, J¼6.8 Hz, Me16), 0.92 (3H, d, J¼6.8 Hz, Me12),
0.88 (9H, s, SiC(CH3)3), 0.82 (3H, d, J¼6.8 Hz, Me14), 0.03 (3H, s,
d
ArH), 6.87 (2H, d, J¼8.7 Hz, ArH), 4.41 (1H, d, J¼11.5 Hz, OCHxHyAr),
4.37 (1H, d, J¼11.5 Hz, OCHxHyAr), 3.80 (3H, s, OMe), 3.50 (1H, d,
J¼5.6 Hz, H11a), 3.49 (1H, dd, J¼12.7, 5.6 Hz, H13), 3.25 (1H, dd,
J¼9.0, 7.5 Hz, H11b), 2.40 (1H, sex, J¼6.6 Hz, H16), 1.94 (1H, sep,
J¼6.1 Hz, H12), 1.79 (1H, ddd, J¼13.4, 8.0, 5.4 Hz, H15a), 1.62–1.73
(1H, m, H14), 1.19 (1H, ddd, J¼14.4, 8.9, 5.7 Hz, H15b), 1.07 (3H, d,
J¼7.0 Hz, Me16), 0.94 (3H, d, J¼7.0 Hz, Me12), 0.89 (9H, s,
SiC(CH3)3), 0.87 (3H, d, J¼7.0 Hz, Me14), 0.03 (6H, s, Si(CH3)2); 13C
SiCH3), 0.02 (3H, s, SiCH3); 13C NMR (100 MHz, CDCl3)
d 203.1, 159.1,
NMR (100 MHz, CDCl3)
d
205.2, 159.1, 130.8, 129.1, 113.7, 77.0, 72.7,
159.0, 152.8, 134.0, 132.4, 130.85, 130.83, 129.6, 129.3, 129.1, 127.9,
117.4,113.7, 84.2, 77.4, 75.3, 72.7, 72.6, 55.2, 48.5, 41.1, 37.9, 36.4, 34.3,
33.8, 26.1, 20.2, 18.9, 18.4, 15.3, 14.4, 14.1, ꢀ3.6, ꢀ4.1; HRMS (þESI)
calcd for C43H67O6Si [MþH]þ: 707.4701, found: 707.4696.
55.2, 44.2, 38.0, 35.9, 33.7, 26.1, 18.4, 15.1, 14.5, 14.3, ꢀ3.7, ꢀ4.1;
HRMS (þESI) calcd for C24H42NaO4Si [MþNa]þ: 445.2750, found:
445.2750.
5.1.5. Phosphonate 9. To a solution of dimethyl methylphosphonate
(6.43 mL, 59.3 mmol, 3.1 equiv) in THF (250 mL) at ꢀ78 ꢁC was
added dropwise n-BuLi (44.2 mL of 1.6 M solution in hexanes,
70.7 mmol, 3.7 equiv). The reaction mixture was stirred at ꢀ78 ꢁC
for 30 min before the addition via cannula of a solution of freshly
prepared aldehyde 1724 (5.51 g, 19.1 mmol, 1.0 equiv) in THF
(125 mL) pre-cooled to ꢀ78 ꢁC. After stirring for 20 min at ꢀ78 ꢁC,
the reaction was quenched by the addition of brine (200 mL) and
warmed to rt. The phases were separated and the aqueous layer
extracted with EtOAc (3ꢂ150 mL). The combined organic extracts
were dried (MgSO4) and concentrated in vacuo and purified by flash
5.1.7. Ketone 19. To a solution of enone 18 (1.00 g, 1.42 mmol,
1.0 equiv) in freeze-thaw deoxygenated PhMe/water (400:1, 20 mL)
was added [(Ph3P)CuH]6 (1.11 g, 0.566 mmol, 0.4 equiv). After stir-
ring for 16 h at rt, the reaction mixture was filtered through Celite,
washed with EtOAc (60 mL) and concentrated in vacuo. Flash
chromatography (light petroleum/20% EtOAc/light petroleum)
afforded the ketone 19 (985 mg, 98%) as a colourless oil: Rf 0.38
20
(10% EtOAc/hexane); [
a
]
þ1.2 (c 0.60, CH2Cl2); IR (CH2Cl2)/cmꢀ1
D
2929, 1709, 1613, 1513, 1247, 1037; 1H NMR (500 MHz, CDCl3)
d 7.28
(2H, d, J¼8.5 Hz, ArH), 7.27 (2H, d, J¼8.5 Hz, ArH), 6.89 (4H, d,
J¼8.5 Hz, ArH), 6.46 (1H, dt, J¼17.0, 10.7 Hz, H25), 6.05 (1H, t,
J¼11.0 Hz, H24), 5.55 (1H, t, J¼10.7 Hz, H23), 5.20 (1H, d, J¼16.1 Hz,
H26a), 5.09 (1H, d, J¼10.4 Hz, H26b), 4.55 (1H, d, J¼10.4 Hz,
OCHxHyAr), 4.49 (1H, d, J¼10.4 Hz, OCHxHyAr), 4.40 (1H, d,
J¼11.4 Hz, OCHxHyAr), 4.39 (1H, d, J¼11.4 Hz, OCHxHyAr), 3.82 (6H,
s, 2ꢂOMe), 3.66 (1H, dd, J¼8.2, 3.4 Hz, H21), 3.54 (1H, dd, J¼9.1,
4.4 Hz, H11a), 3.46 (1H, dd, J¼6.3, 2.5 Hz, H13), 3.26 (1H, t, J¼8.5 Hz,
H11b), 2.79 (1H, ddd, J¼10.1, 6.9, 3.1 Hz, H20), 2.75 (1H, qn,
J¼7.6 Hz, H22), 2.37–2.44 (2H, m, H18aþH18b), 1.92–1.99 (1H, m,
H12), 1.70–1.76 (1H, m, H14), 1.62–1.69 (1H, m, H17a), 1.37–1.46
(1H, m, H16), 1.23–1.30 (1H, m, H15a), 1.19 (3H, d, J¼7.2 Hz, Me20),
1.18–1.20 (1H, m, H17b), 1.11 (3H, d, J¼6.9 Hz, Me22), 1.00–1.08 (1H,
m, H15b), 0.97 (3H, d, J¼6.9 Hz, Me12), 0.90 (9H, s, SiC(CH3)3), 0.85
(3H, d, J¼6.9 Hz, Me14), 0.82 (3H, d, J¼6.6 Hz, Me16), 0.05 (3H, s,
chromatography (EtOAc) to give an epimeric mixture of
phosphonates (7.87 g, 98%) as a pale yellow oil: Rf 0.28 (EtOAc).
To a stirred solution of the above -hydroxyphosphonates
b-hydroxy-
b
(6.73 g, 19.6 mmol, 1.0 equiv) in CH2Cl2 (250 mL) at rt was added
Dess–Martin periodinane (8.31 g, 23.5 mmol, 1.2 equiv). The re-
action mixture was stirred for 30 min and the resulting slurry
concentrated in vacuo to a volume of ca. 5 mL and purified by flash
chromatography (EtOAc) to give b-ketophosphonate 9 (6.22 g, 93%)
20
as a pale yellow oil: Rf 0.42 (EtOAc); [
a
]
ꢀ2.8 (c 1.7, CHCl3); IR
(liquid film)/cmꢀ1 2959,1711,1574,1248; 1DH NMR (500 MHz, CDCl3)
d
7.25 (2H, d, J¼8.5 Hz, ArH), 6.86 (2H, d, J¼8.5 Hz, ArH), 6.49 (1H,
dt, J¼16.8, 10.7 Hz, H25), 6.02 (1H, t, J¼11.0 Hz, H24), 5.50 (1H, t,
J¼10.3 Hz, H23), 5.20 (1H, d, J¼16.8 Hz, H26a), 5.12 (1H, d,
J¼10.1 Hz, H26b), 4.55 (1H, d, J¼10.8 Hz, OCHxHyAr), 4.51 (1H, d,
J¼10.8 Hz, OCHxHyAr), 3.79 (3H, s, OMe), 3.76 (3H, d, J¼11.0 Hz,
POMe), 3.74 (3H, d, J¼11.3 Hz, POMe), 3.58 (1H, dd, J¼6.3, 3.8 Hz,
H21), 3.30 (1H, dd, J¼22.0, 14.4 Hz, H18a), 2.91–3.02 (2H, m,
H18bþH22), 2.76–2.84 (1H, m, H20), 1.19 (3H, d, J¼7.0 Hz, Me20),
SiCH3), 0.04 (3H, s, SiCH3); 13C NMR (125 MHz, CDCl3)
d 214.3, 159.1,
159.0, 134.0, 132.1, 130.9, 130.8, 129.6, 129.3, 129.1, 117.8, 113.7, 83.8,
75.3, 73.0, 72.7, 55.3, 50.4, 42.6, 40.3, 38.2, 36.2, 33.2, 29.77, 29.73,
26.2, 25.8, 20.0, 18.8, 18.5, 15.2, 14.7, 14.0, ꢀ3.6, ꢀ4.0; HRMS (þESI)
calcd for C43H68NaO6Si [MþNa]þ: 731.4677, found: 731.4665.
1.06 (3H, d, J¼6.8 Hz, Me22); 13C NMR (125 MHz, CDCl3)
d 204.6 (d,
J¼3.8 Hz), 159.2, 133.5, 132.1, 130.4, 129.9, 129.4, 118.1, 113.7, 83.5,
74.2, 55.2, 52.9, 50.6, 41.3, 40.3, 35.8, 18.9, 12.7; HRMS (þESI) calcd
for C21H32O6P [MþH]þ: 411.1931, found: 411.1932.
5.1.8. Alcohol 19a. To a solution of ketone 19 (1.90 g, 2.69 mmol,
1.0 equiv) in THF (20 mL) at ꢀ30 ꢁC was added LiAlH(OtBu)3
(13.4 mL of a 1 M solution in THF,13.4 mmol, 5.0 equiv) over 10 min.

I. Paterson et al. / Tetrahedron 66 (2010) 6534–6545
6541
After stirring for 72 h, the reaction mixture was quenched by the
addition of satd aq NH4Cl (20 mL) and warmed to rt. The phases
were separated, the aqueous phase extracted with EtOAc (3ꢂ20 mL)
and the combined organic extracts dried (MgSO4) and concentrated
in vacuo. The resulting alcohol (>95:5 dr at C19) could be used di-
rectly in the next step. Flash chromatography (20% EtOAc/hexane)
(3ꢂ12 mL) and the combined organic extracts dried (MgSO4) and
concentrated in vacuo. Flash chromatography (light petroleum/
10% Et2O/1% CH2Cl2/light petroleum) afforded the corresponding
diol (1.08 g, 65% over three steps) as a colourless oil: Rf 0.25 (10%
20
EtOAc/light petroleum); [
a
]
ꢀ11.5 (c 1.23, CHCl3); IR (CH2Cl2)/cmꢀ1
D
3377, 2956, 2929, 2857, 1462; 1H NMR (500 MHz, CDCl3)
d 6.62 (1H,
provided a pure sample for characterisation: Rf 0.33 (20% EtOAc/
dt, J¼16.9, 10.5 Hz, H25), 6.09 (1H, t, J¼11.1 Hz, H24), 5.40 (1H, t,
J¼10.6 Hz, H23), 5.20 (1H, d, J¼17.0 Hz, H26a), 5.11 (1H, d, J¼10.3 Hz,
H26b), 3.72–3.76 (1H, m, H19), 3.55–3.61 (2H, m, H11aþH11b), 3.44–
3.48 (2H, m, H13þH21), 2.75–2.83 (1H, m, H22), 2.43 (1H, s, OH), 2.27
(1H, s, OH), 1.84 (1H, sep, J¼6.9 Hz, H12), 1.66–1.74 (2H, m,
H14þH20), 1.56–1.65 (2H, m, H17aþH18a), 1.36–1.46 (2H, m,
H16þH18b),1.24–1.35 (2H, m, H15aþH17b),1.02–1.07 (1H, m, H15b),
0.95 (3H, d, J¼6.6 Hz, Me22), 0.94 (3H, d, J¼6.9 Hz, Me12), 0.90–0.91
(12H, m, SiC(CH3)3þMe20), 0.88 (9H, s, SiC(CH3)3), 0.87 (3H, d,
J¼6.8 Hz, Me16), 0.86 (3H, d, J¼7.0 Hz, Me14), 0.10 (3H, s, SiCH3),
0.07–0.08 (9H, m, SiCH3þSi(CH3)2); 13C NMR (CDCl3, 125 MHz)
20
hexane); [
a
]
þ15.2 (c 0.46, CHCl3); IR (liquid film)/cmꢀ1 2957, 1513,
D
1249, 1037; 1H NMR (500 MHz, CDCl3)
d
7.28 (2H, d, J¼8.5 Hz, ArH),
7.26 (2H, d, J¼8.7 Hz, ArH), 6.89 (2H, d, J¼8.7 Hz, ArH), 6.86 (2H, d,
J¼8.5 Hz, ArH), 6.69 (1H, dt, J¼16.9, 10.4 Hz, H25), 6.09 (1H, t,
J¼11.0 Hz, H24), 5.52 (1H, t, J¼10.4 Hz, H23), 5.25 (1H, d, J¼15.9 Hz,
H26a), 5.16 (1H, d, J¼10.1 Hz, H26b), 4.71 (1H, d, J¼10.3 Hz, OCHx
-
HyAr), 4.40–4.47 (3H, d, J¼10.3 Hz, OCHxHyArþOCH2Ar), 3.82 (3H, s,
OMe), 3.80 (3H, s, OMe), 3.71 (1H, br t, J¼6.2 Hz, H19), 3.54 (1H, dd,
J¼9.0, 4.5 Hz, H11a), 3.46 (1H, dd, J¼6.1, 2.6 Hz, H13), 3.42 (1H, dd,
J¼6.7, 4.1 Hz, H21), 3.26 (1H, t, J¼8.9 Hz, H11b), 3.08 (1H, dqn, J¼9.9,
6.6 Hz, H22), 1.91–1.99 (1H, m, H12), 1.67–1.76 (2H, m, H14þH20),
1.41–1.51 (4H, m, H16þH17aþH18aþH18b), 1.25–1.32 (2H, m,
H15aþH17b), 1.03–1.05 (1H, m, H15b), 1.04 (3H, d, J¼6.8 Hz, Me22),
0.95–0.99 (6H, m, Me12þMe20), 0.90 (9H, s, SiC(CH3)3), 0.88 (3H, d,
J¼6.3 Hz, Me16), 0.84 (3H, d, J¼6.7 Hz, Me14), 0.05 (3H, s, SiCH3),
d
135.2, 132.3, 130.0, 117.7, 80.6, 77.3, 76.4, 66.1, 41.6, 38.3, 37.8, 36.1,
35.1, 31.9, 31.4, 30.5, 26.1, 25.9, 20.4, 18.3, 18.0, 17.7, 16.1, 15.2, 7.0,
ꢀ3.79, ꢀ3.81, ꢀ4.0, ꢀ4.4; HRMS (þESI) calcd for C33H68NaO4Si2
[MþNa]þ: 607.4554, found: 607.4561.
0.04 (3H, s, SiCH3); 13C NMR (125 MHz, CDCl3)
d
159.2, 159.0, 135.3,
5.1.11. Aldehyde 7. To a solution of the foregoing diol (851 mg,
1.46 mmol, 1.0 equiv) in CH2Cl2 (25 mL) at 0 ꢁC was added
PhI(OAc)2 (938 mg, 2.91 mmol, 2.0 equiv) then TEMPO (91.0 mg,
0.582 mmol, 0.4 equiv). After warming slowly to rt, the reaction
mixture was stirred for 16 h, then treated with satd aq Na2S2O3
(25 mL) and stirred for an additional 30 min. The phases were
separated, the aqueous phase extracted with CH2Cl2 (3ꢂ30 mL) and
the combined organic extracts dried (MgSO4) and concentrated in
vacuo. Flash chromatography (5% EtOAc/light petroleum) afforded
132.4, 131.0, 130.3, 129.7, 129.5, 129.1, 117.8, 113.8, 113.7, 87.7, 77.4,
75.3, 74.1, 73.0, 72.6, 55.3, 42.6, 38.9, 38.2, 35.6, 33.3, 32.7, 32.5, 30.3,
26.2, 20.3,18.5,18.1,15.2,14.7, 6.6, ꢀ3.6, ꢀ4.0; HRMS (þESI) calcd for
C43H71O6Si [MþH]þ: 711.5014, found: 711.5017.
5.1.9. TBS ether 19b. To a solution of the foregoing alcohol (1.91 g,
2.69 mmol, 1.0 equiv) in CH2Cl2 (50 mL) at ꢀ78 ꢁC was added 2,6-
lutidine (562 mL, 4.82 mmol, 1.8 equiv) then TBSOTf (738 mL,
3.21 mmol,1.2 equiv). The reaction mixture was warmed to 0 ꢁC and
stirred for 30 min before being quenched by the addition of satd aq
NH4Cl (50 mL). The phases were separated, the aqueous phase
extracted with CH2Cl2 (3ꢂ50 mL) and the combined organic extracts
dried (MgSO4) and concentrated in vacuo. The resulting TBS ether
could be used directly in the next step. Flash chromatography (20%
aldehyde 7 (755 mg, 89%) as a colourless oil: Rf 0.66 (20% EtOAc/
20
hexane); [
a
]
D
ꢀ28.3 (c 1.43, CHCl3); IR (CH2Cl2)/cmꢀ1 2952, 2929,
2857, 1725; 1H NMR (500 MHz, CDCl3)
d
9.76 (1H, d, J¼2.8 Hz, H11),
6.63 (1H, ddd, J¼11.2, 10.1, 1.2 Hz, H25), 6.10 (1H, td, J¼11.2, 0.7 Hz,
H24), 5.41 (1H, t, J¼10.6 Hz, H23), 5.21 (1H, dd, J¼16.9, 2.1 Hz,
H26a), 5.12 (1H, d, J¼10.1 Hz, H26b), 3.76–3.77 (2H, m, H13þH19),
3.47 (1H, dt, J¼7.6, 2.4 Hz, H21), 2.78–2.83 (1H, m, H22), 2.52–2.57
(1H, m, H12), 2.24 (1H, d, J¼2.3 Hz, OH), 1.67–1.76 (2H, m,
H14þH20), 1.59–1.65 (2H, m, H18aþH17a), 1.37–1.47 (2H, m,
H16þH18b), 1.25–1.34 (1H, m, H15aþH17b), 1.07 (3H, d, J¼7.1 Hz,
Me12), 0.99–1.04 (1H, m, H15b), 0.96 (3H, d, J¼6.8 Hz, Me22), 0.91
(3H, d, J¼6.9 Hz, Me20), 0.89 (9H, s, SiC(CH3)3), 0.87–0.89 (6H, m,
Me14þMe16), 0.88 (9H, s, SiC(CH3)3), 0.085 (3H, s, SiCH3), 0.08 (3H,
s, SiCH3), 0.06 (3H, s, SiCH3), 0.04 (3H, s, SiCH3); 13C NMR (CDCl3,
EtOAc/hexane) provided a pure sample for characterisation: Rf 0.49
20
(20% EtOAc/hexane); [
a
]
þ5.4 (c 0.17, CHCl3); IR (liquid film)/cmꢀ1
D
1
2956, 292, 2855, 1613, 1586, 1513, 1462; H NMR (500 MHz, CDCl3)
d
7.32 (2H, d, J¼8.4 Hz, ArH), 7.28 (2H, d, J¼8.4 Hz, ArH), 6.90 (4H, d,
J¼7.7 Hz, ArH), 6.62 (1H, dt, J¼16.8, 10.7 Hz, H25), 6.04 (1H, t,
J¼11.0 Hz, H24), 5.61 (1H, t, J¼10.6 Hz, H23), 5.21 (1H, d, J¼16.7 Hz,
H26a), 5.12 (1H, d, J¼1.0 Hz, H26b), 4.59 (1H, d, J¼10.6 Hz, OCHx
-
HyAr), 4.53 (1H, d, J¼10.6 Hz, OCHxHyAr), 4.45 (1H, d, J¼12.1 Hz,
OCHxHyAr), 4.43 (1H, d, J¼12.1 Hz, OCHxHyAr), 3.83 (6H, s, 2ꢂOMe),
3.63–3.68 (1H, m, H19), 3.55 (1H, dd, J¼8.8, 4.5 Hz, H11a), 3.46 (1H, d,
J¼5.4 Hz, H13), 3.34–3.39 (1H, m, H21), 3.27 (1H, t, J¼8.7 Hz, H11b),
2.98–3.06 (1H, m, H22), 1.99–2.01 (1H, m, H12), 1.64–1.73 (2H, m,
H14þH20), 1.54–1.64 (1H, m, H18a), 1.29–1.45 (3H, m,
H16þH17aþH18b), 1.20–1.27 (2H, m, H15aþH17b), 1.14 (3H, d,
J¼6.7 Hz, Me22), 1.01–1.08 (1H, m, H15b), 0.97–1.00 (6H, m,
Me12þMe20), 0.89–0.94 (21H, m, 2ꢂSiC(CH3)3þMe16), 0.84 (3H, d,
J¼6.5 Hz, Me14), 0.12 (3H, s, SiCH3), 0.11 (3H, s, SiCH3), 0.06 (6H, s,
125 MHz)
d 205.1, 135.3, 132.3, 130.0, 117.8, 78.0, 77.4, 76.4, 50.1,
41.2, 37.8, 36.1, 35.0, 31.9, 30.5, 26.0, 25.9, 20.4, 18.3, 18.1, 17.7, 15.1,
12.3, 7.0, ꢀ3.83, ꢀ3.78, ꢀ4.2, ꢀ4.4; HRMS (þESI) calcd for
C33H66NaO4Si2 [MþNa]þ: 605.4397, found: 605.4395.
5.1.12. Aldol adduct 23. To a stirred solution of c-Hex2BCl (6.11 mL,
27.9 mmol, 1.2 equiv) and Me2NEt (2.77 mL, 25.6 mmol, 1.1 equiv) in
Et2O (60 mL) at ꢀ78 ꢁC was added freshly azeotroped ketone 2025a
(5.75 g, 27.9 mmol, 1.2 equiv) in Et2O (60 mL) via cannula. The re-
action mixture was then warmed to 0 ꢁC and stirred for 1 h. A white
precipitate formed before the solution was re-cooled to ꢀ78 ꢁC and
aldehyde 22 (4.38 g, 23.3 mmol,1.0 equiv) in Et2O (85 mL) was added
via cannula. The reaction mixture was stirred for 3 h, then main-
tained at ꢀ20 ꢁC for 16 h, before the addition of MeOH (80 mL), pH 7
buffer (80 mL) and H2O2 (80 mL of 30 mol % solution) at rt. The
mixture was stirred for 1 h, then water (250 mL) was added and the
phases separated. The aqueous phase was extracted with CH2Cl2
(4ꢂ200 mL), before the combined organic phases were dried
(MgSO4) and concentrated in vacuo. Flash chromatography (50%
Si(CH3)2); 13C NMR (125 MHz, CDCl3)
d 159.1, 159.0, 134.6, 132.4,
132.3, 131.4, 131.0, 129.1, 128.9, 117.2, 113.69, 113.68, 84.4, 77.3, 75.1,
73.0, 72.8, 72.7, 55.2, 42.9, 40.5, 38.2, 35.2, 33.0, 32.4, 31.7, 30.3, 26.2,
26.0, 25.9, 20.1, 18.8, 18.5, 18.2, 18.1, 15.1, 14.4, 9.2, ꢀ3.57, ꢀ3.61, ꢀ4.0,
ꢀ4.5; HRMS (þESI) calcd for C49H88NO6Si2 [MþNH4]þ: 842.6145,
found: 842.6150.
5.1.10. Diol 19c. To a solution of the foregoing TBS ether (2.22 g,
2.69 mmol, 1.0 equiv) in CH2Cl2/pH 7 buffer (10:1, 12.6 mL) at 0 ꢁC
was added DDQ (3.10 g,13.5 mmol, 5 equiv). After stirring for 2 h, the
reaction mixture was diluted with pH 7 buffer (12 mL) and the
phases separated. The aqueous phase was extracted with CH2Cl2
Et2O/light petroleum) afforded aldol adduct 23 (8.19 g, 89%, >97:3
20
dr) as a pale yellow oil: Rf 0.59 (50% Et2O/light petroleum); [
a
]
ꢀ9.8
D

6542
I. Paterson et al. / Tetrahedron 66 (2010) 6534–6545
20
(c 0.49, CHCl3); IR (liquid film)/cmꢀ1 3503, 2930, 2857, 1719, 1602,
1452; 1H NMR (500 MHz, CDCl3)
a colourless oil: Rf 0.48 (20% EtOAc/hexane); [
CHCl3); IR (liquid film)/cmꢀ1 2953, 2929, 2857, 1708, 1613, 1514,
1463; 1H NMR (500 MHz, CDCl3)
a
]
þ3.8 (c 0.75,
D
d
8.08 (2H, dd, J¼8.4, 1.1 Hz, ArH),
7.58 (1H, t, J¼7.8 Hz, ArH), 7.45 (2H, t, J¼7.8 Hz, ArH), 5.44 (1H, q,
J¼7.1 Hz, H4), 4.02 (1H, t, J¼8.5 Hz, H7), 3.89 (1H, ddd, J¼10.3, 5.8,
4.6 Hz, H9a), 3.81 (1H, ddd, J¼10.1, 8.0, 3.9 Hz, H9b), 3.46 (1H, s, OH),
2.96 (1H, qn, J¼7.3 Hz, H6), 1.74–1.81 (1H, m, H8a), 1.60–1.64 (1H, m,
H8b), 1.57 (3H, d, J¼6.9 Hz, Me4), 1.19 (3H, d, J¼7.0 Hz, Me6), 0.88
(9H, s, SiC(CH3)3), 0.06 (6H, s, Si(CH3)2); 13C NMR (125 MHz, CDCl3)
d
9.73 (1H, d, J¼2.5 Hz, H5), 7.26
(2H, d, J¼8.5 Hz, ArH), 6.89 (2H, d, J¼8.5 Hz, ArH), 4.53 (1H, d,
J¼11.5 Hz, OCHxHyAr), 4.47 (1H, d, J¼11.5 Hz, OCHxHyAr), 3.94 (1H,
ddd, J¼7.0, 5.5, 4.0 Hz, H7), 3.82 (3H, s, OMe), 3.70–3.78 (2H, m,
H9aþH9b), 2.69–2.75 (1H, m, H6), 1.77–1.85 (1H, m, H8a), 1.69–1.76
(1H, m, H8b), 1.12 (3H, d, J¼7.0 Hz, Me6), 0.91 (9H, s, SiC(CH3)3),
0.075 (3H, s, SiCH3), 0.07 (3H, s, SiCH3); 13C NMR (125 MHz, CDCl3)
d
211.0, 166.0, 161.2, 133.4, 130.0, 128.6, 75.2, 73.4, 62.2, 48.5, 35.7,
26.0, 18.3, 15.8, 13.8, ꢀ5.4; HRMS (þESI) calcd for C21H35O5Si
d 204.2, 159.3, 130.3, 129.3, 113.8, 76.2, 71.7, 59.1, 55.3, 49.8, 34.7,
[MþH]þ: 395.2248, found: 395.2254.
25.9, 18.2, 9.9, ꢀ5.34, ꢀ5.37; HRMS (þESI) calcd for C20H34O4NaSi
[MþNa]þ: 389.2124, found: 389.2146.
5.1.13. PMB ether 23a. To a stirred solution of azeotroped alcohol
23 (5.90 g, 14.95 mmol, 1.0 equiv) and PMBTCA (6.34 g, 22.4 mmol,
1.5 equiv) in THF (250 mL) at 0 ꢁC was added Sc(OTf)3 (220 mg,
0.45 mmol, 0.03 equiv). After 50 min, satd aq NaHCO3 (300 mL) was
added and the phases separated. The aqueous phase was extracted
with EtOAc (3ꢂ300 mL) and the combined organic phases were
dried (MgSO4) and concentrated in vacuo. Flash chromatography
5.1.16. Vinyl iodide 25. To a vigorously stirred suspension of CrCl2
(13.6 g, 111 mmol, 8.0 equiv) in dioxane/THF (1:1, 75 mL) at 0 ꢁC was
added a solution of aldehyde 24 (5.08 g, 13.9 mmol, 1.0 equiv) in
dioxane/THF (1:1, 30 mL). After 5 min, CHI3 (19.1 g, 48.5 mmol,
3.5 equiv) was added to the reaction mixture. After 18 h at 0 ꢁC,
water (75 mL) and EtOAc (75 mL) were added and the phases sep-
arated. The aqueous layer was extracted with EtOAc (4ꢂ75 mL), and
the combined organic extracts dried (MgSO4) and concentrated in
vacuo. Flash chromatography (hexane/3% EtOAc/hexane) afforded
(9% EtOAc/light petroleum) afforded the PMB ether as a pale yellow
20
oil: Rf 0.50 (20% EtOAc/light petroleum); [
a]
þ7.8 (c 1.54, CHCl3);
D
IR (liquid film)/cmꢀ1 2928, 2856, 1718, 1613, 1586, 1514, 1452; 1H
NMR (500 MHz, CDCl3)
8.08 (2H, d, J¼7.3 Hz, ArH), 7.57 (1H, t,
d
the (E)-vinyl iodide 25 (4.97 g, 74%) as a colourless oil: Rf 0.59 (20%
20
J¼7.4 Hz, ArH), 7.45 (2H, t, J¼7.5 Hz, ArH), 7.16 (2H, d, J¼8.8 Hz,
ArH), 6.84 (2H, d, J¼8.8 Hz, ArH), 5.38 (1H, q, J¼7.0 Hz, H4), 4.40
(1H, d, J¼10.7 Hz, OCHxHyAr), 4.33 (1H, d, J¼10.7 Hz, OCHxHyAr),
3.91 (1H, ddd, J¼8.7, 7.0, 3.2 Hz, H7), 3.79 (3H, s, ArOMe), 3.74 (2H,
q, J¼5.5 Hz, H9aþH9b), 3.16 (1H, dq, J¼7.0, 5.8 Hz, H6), 1.82 (1H, dd,
J¼7.0, 3.5 Hz, H8a), 1.63–1.70 (1H, m, H8b), 1.47 (3H, d, J¼7.0 Hz,
Me4), 1.16 (3H, d, J¼7.0 Hz, Me6), 0.89 (9H, s, SiC(CH3)3), 0.05 (6H, s,
EtOAc/hexane); [
a
]
ꢀ8.7 (c 0.92, CHCl3); IR (liquid film)/cmꢀ1 2954,
D
2928, 2856,1612,1513,1462; 1H NMR (400 MHz, CDCl3)
d 7.24 (2H, d,
J¼8.5 Hz, ArH), 6.86 (2H, d, J¼8.5 Hz, ArH), 6.50 (1H, dd, J¼14.5,
8.0 Hz, H5), 6.02 (1H, d, J¼14.3 Hz, H4), 4.44 (2H, s, OCH2Ar), 3.80
(3H, s, OMe), 3.67 (2H, t, J¼6.5 Hz, H9aþH9b), 3.46 (1H, dt, J¼7.0,
4.8 Hz, H7), 2.42–2.52 (1H, m, H6),1.60–1.67 (2H, m, H8aþH8b),1.02
(3H, d, J¼6.8 Hz, Me6), 0.89 (9H, s, SiC(CH3)3), 0.03 (6H, s, Si(CH3)2);
Si(CH3)2); 13C NMR (125 MHz, CDCl3)
d
209.8, 165.9, 159.2, 133.3,
13C NMR (125 MHz, CDCl3)
d 159.1, 148.6, 130.7, 129.6, 113.7, 78.3,
130.7, 129.9, 129.8, 129.3, 128.6, 113.9, 75.1, 72.6, 59.0, 55.3, 47.1,
34.2, 29.8, 26.0, 18.3, 15.4, 13.4, ꢀ5.2, ꢀ5.3; HRMS (þESI) calcd for
C29H46NO6Si [MþNH4]þ: 532.3089, found: 532.3092.
75.4, 72.1, 59.6, 55.3, 44.0, 34.6, 26.0, 18.5, 15.0, ꢀ5.2; HRMS (þESI)
calcd for C21H36IO3Si [MþH]þ: 491.1473, found: 491.1476.
5.1.17. Alcohol 25a. To a stirred solution of TBS ether 25 (4.50 g,
9.17 mmol, 1.0 equiv) in THF (100 mL) at rt was added a pre-mixed
solution of TBAF (18.4 mL of 1 M solution in THF, 18.4 mmol,
2.0 equiv) and AcOH (1.8 mL, 32.1 mmol, 3.5 equiv). After 18 h, satd
aq NaHCO3 (100 mL) was added and the phases separated. The
aqueous layer was extracted with EtOAc (3ꢂ100 mL), and the
combined organic extracts dried (MgSO4) and concentrated in
vacuo. Flash chromatography (10% EtOAc/hexane) afforded the
5.1.14. Diol 23b. To a stirred solution of the foregoing PMB ether
(7.57 g, 14.95 mmol, 1.0 equiv) in MeOH (350 mL) at 0 ꢁC was added
NaBH4 (1.131 g, 29.9 mmol, 2.0 equiv). The reaction mixture was
warmed to rt and stirred for 45 min, before being re-cooled to 0 ꢁC
and K2CO3 (8.26 g, 59.8 mmol, 4.0 equiv) added. After warming to rt
and stirring overnight, water (200 mL) and pH 7 buffer (200 mL)
were added. The aqueous phase was extracted with CH2Cl2
(4ꢂ400 mL), and the combined organic phases were dried (MgSO4)
and concentrated in vacuo. Flash chromatography (20% EtOAc/light
corresponding alcohol (3.33 g, 95%) as a colourless oil: Rf 0.28 (40%
20
EtOAc/hexane); [
a
]
ꢀ3.4 (c 0.41, CHCl3); IR (liquid film)/cmꢀ1
D
petroleum/EtOAc) afforded the diol (5.60 g, 91% over two steps)
3404, 2963, 1612, 1514, 1461; 1H NMR (500 MHz, CDCl3)
d 7.27 (2H,
20
as a colourless oil: Rf 0.10 (20% EtOAc/light petroleum); [
a]
ꢀ4.9 (c
d, J¼8.7 Hz, ArH), 6.89 (2H, d, J¼8.7 Hz, ArH), 6.50 (1H, dd, J¼14.6,
7.9 Hz, H5), 6.09 (1H, dd, J¼14.4, 0.9 Hz, H4), 4.54 (1H, d, J¼11.0 Hz,
OCHxHyAr), 4.44 (1H, d, J¼11.0 Hz, OCHxHyAr), 3.91 (3H, s, OMe),
3.71–3.75 (2H, m, H9aþH9b), 3.54 (1H, qn, J¼4.0 Hz, H7), 2.58 (1H,
sex, J¼5.3 Hz, H6), 1.64–1.74 (2H, m, H8aþH8b), 1.05 (3H, d,
D
1.45, CHCl3); IR (liquid film)/cmꢀ1 3400, 2930, 2856, 1613, 1586,
1514, 1463; 1H NMR (500 MHz, CDCl3)
d
7.26 (2H, d, J¼8.6 Hz, ArH),
6.87 (2H, d, J¼8.6 Hz, ArH), 4.51 (1H, d, J¼10.7 Hz, OCHxHyAr), 4.46
(1H, d, J¼10.7 Hz, OCHxHyAr), 3.81–3.85 (1H, m, H9a), 3.80 (3H, s,
ArOMe), 3.68–3.76 (3H, m, H4, H7, H9b), 3.56 (1H, dd, J¼8.8, 3.6 Hz,
H5), 3.32 (1H, s, OH), 2.46 (1H, s, OH), 1.84–1.92 (2H, m, H8aþH8b),
1.69–1.77 (1H, m, H6), 1.16 (3H, d, J¼6.3 Hz, Me6), 0.90 (9H, s,
SiC(CH3)3), 0.85 (3H, d, J¼6.9 Hz, Me4), 0.06 (6H, s, Si(CH3)2); 13C
J¼6.9 Hz, Me6); 13C NMR (125 MHz, CDCl3)
d 159.4, 148.2, 130.1,
129.6, 113.9, 80.2, 75.6, 71.8, 60.4, 55.3, 43.3, 33.1, 21.0; HRMS (þESI)
calcd for C15H25INO3Si [MþNH4]þ: 394.0874, found: 394.0878.
NMR (125 MHz, CDCl3)
d
159.5, 130.5, 129.7, 114.1, 79.4, 71.6, 68.4,
5.1.18. Aldehyde 25b. To a stirred solution of the foregoing alcohol
(1.90 g, 5.05 mmol, 1.0 equiv) and pyridine (1.23 mL, 15.2 mmol,
3.0 equiv) in CH2Cl2 (40 mL) at 0 ꢁC was added Dess–Martin peri-
odinane (3.21 g, 7.58 mmol, 1.5 equiv). After 2 h, satd aq NaHCO3
(25 mL) and Na2S2O3 (25 mL) were added and the phases sepa-
rated. The aqueous layer was extracted with CH2Cl2 (3ꢂ50 mL), and
the combined organic extracts dried (MgSO4) and concentrated in
vacuo. Flash chromatography (5% EtOAc/hexane) afforded the cor-
60.2, 55.5, 38.5, 34.0, 26.1, 18.5, 16.3, 11.9, ꢀ5.1, ꢀ5.2; HRMS (þESI)
calcd for C22H44NO5Si [MþNH4]þ: 430.2983, found: 430.2983.
5.1.15. Aldehyde 24. To a stirred solution of the foregoing diol
(2.00 g, 4.85 mmol, 1.0 equiv) in MeOH/pH 7 buffer (56 mL: 14 mL)
at 0 ꢁC was added NaIO4 (4.15 g, 19.4 mmol, 4.0 equiv). After 5 min,
the reaction mixture was warmed to rt and stirred for 30 min, be-
fore water (60 mL) was added. The aqueous phase was extracted
with EtOAc (3ꢂ50 mL), and the combined organic phases were
dried (MgSO4) and concentrated in vacuo. Flash chromatography
(10% EtOAc/light petroleum) afforded aldehyde 24 (1.58 g, 89%) as
responding aldehyde (1.70 g, 90%) as a colourless oil: Rf 0.54 (40%
20
EtOAc/hexane); [
a]
ꢀ7.1 (c 4.22, CHCl3); IR (liquid film)/cmꢀ1
D
2929, 1723, 1612, 1586, 1514, 1463; 1H NMR (500 MHz, CDCl3)
d 9.78
(1H, d, J¼1.5 Hz, H9), 7.25 (2H, d, J¼8.5 Hz, ArH), 6.90 (2H, d,

I. Paterson et al. / Tetrahedron 66 (2010) 6534–6545
6543
J¼8.5 Hz, ArH), 6.51 (1H, dd, J¼14.5, 8.0 Hz, H5), 6.13 (1H, dd,
J¼14.5, 1.0 Hz, H4), 4.49 (2H, s, OCH2Ar), 3.90 (1H, dt, J¼8.0, 4.5 Hz,
H7), 3.83 (3H, s, OMe), 2.67 (1H, ddd, J¼17.0, 8.0, 2.5 Hz, H8a), 2.53–
2.58 (1H, m, H6), 2.50 (1H, ddd, J¼17.0, 4.0, 1.5 Hz, H8b), 1.08 (3H, d,
film)/cmꢀ1 3472, 2956, 2929, 2856, 1684, 1607, 1472, 1461, 1416; 1H
NMR (500 MHz, C6D6)
6.85 (1H, dt, J¼16.9, 11.0 Hz, H25), 6.66 (1H,
d
dd, J¼14.5, 8.6 Hz, H5), 6.43 (1H, dd, J¼11.6,10.0 Hz, H11), 6.23 (1H, t,
J¼11.1 Hz, H24), 5.88 (1H, d, J¼11.3 Hz, H10), 5.87 (1H, d, J¼14.6 Hz,
H4), 5.59 (1H, t, J¼10.5 Hz, H23), 5.28 (1H, d, J¼16.0 Hz, H26a), 5.19
(1H, d, J¼10.0 Hz, H26b), 4.08–4.16 (1H, m, H12), 4.00 (1H, q,
J¼6.3 Hz, H19), 3.85–3.91 (1H, m, H7), 3.64–3.68 (1H, m, H21), 3.58–
3.62 (1H, m, H13), 3.22 (1H, d, J¼3.0 Hz, OH), 2.97–3.06 (1H, m, H22),
2.40 (1H, dd, J¼17.6, 9.7 Hz, H8a), 2.15 (1H, dd, J¼17.5, 2.6 Hz, H8b),
1.99–2.02 (1H, m, H6), 1.87–1.98 (2H, m, H18aþH20), 1.80–1.86
(1H, m, H14), 1.69–1.75 (1H, m, H18b), 1.55–1.66 (3H, m,
H15aþH16þH17a),1.24 (3H, d, J¼6.7 Hz, Me12),1.23 (3H, d, J¼6.7 Hz,
Me20), 1.16 (9H, s, SiC(CH3)3), 1.14 (9H, s, SiC(CH3)3), 1.07–1.13 (11H,
m, H15bþH17bþMe14þMe16þMe22), 0.94 (3H, d, J¼7.0 Hz, Me6),
0.27 (3H, s, SiCH3), 0.26 (6H, s, Si(CH3)2), 0.23 (3H, s, SiCH3); 13C NMR
J¼7.0 Hz, Me6); 13C NMR (125 MHz, CDCl3)
d 201.0, 159.4, 147.3,
129.9, 129.5, 113.9, 76.4, 76.3, 72.0, 55.3, 45.8, 44.0, 14.7; HRMS (CI)
calcd for C15H23INO3 [MþNH4]þ: 392.0717, found: 392.0722.
5.1.19. Acid 26. To a stirred solution of the foregoing aldehyde
(2.00 g, 5.34 mmol, 1.0 equiv) in t-BuOH/2-methyl-2-butene (8:1,
17 mL) at rt was added a mixture of NaClO2 (1.92 g, 21.4 mmol,
4.0 equiv) and Na2H2PO4 (2.95 g, 21.4 mmol, 4.0 equiv) in water
(15 mL). After 2 h, brine (25 mL) and EtOAc (25 mL) were added and
the phases separated. The aqueous layer was extracted with CH2Cl2
(3ꢂ40 mL), and the combined organic extracts were dried (MgSO4)
and evaporated in vacuo. Flash chromatography (40% EtOAc/hex-
(125 MHz, C6D6)
d 201.4, 151.7, 147.7, 135.0, 132.6, 130.4, 125.7, 117.7,
ane) afforded acid 26 (2.14 g, 99%) as a colourless oil: Rf 0.48 (40%
80.1, 75.9, 75.7, 75.3, 70.0, 48.0, 45.8, 41.8, 39.2, 36.8, 36.4, 36.1, 32.2,
31.6, 31.0, 26.2, 26.0, 20.7, 18.9, 18.5, 18.2, 17.7, 16.3, 15.6, 8.4, ꢀ3.6,
ꢀ3.8, ꢀ4.5; HRMS (þESI) calcd for C41H78IO5Si2 [MþH]þ: 833.4427,
found: 833.4439.
20
EtOAc/hexane); [
a]
þ5.7 (c 1.06, CHCl3); IR (liquid film)/cmꢀ1
D
2965, 2932, 1706, 1612,1513, 1456; 1H NMR (500 MHz, CDCl3)
d 7.26
(2H, d, J¼8.9 Hz, ArH), 6.89 (2H, d, J¼8.9 Hz, ArH), 6.51 (1H, dd,
J¼14.5, 8.2 Hz, H5), 6.13 (1H, d, J¼14.5 Hz, H4), 4.56 (1H, d,
J¼10.8 Hz, OCHxHyAr), 4.49 (1H, d, J¼10.8 Hz, OCHxHyAr), 3.82 (4H,
s, OMeþH7), 2.47–2.62 (3H, m, H6þH8aþH8b), 1.08 (3H, d,
5.1.22. Diol 29. To a stirred solution of (R)-methyl-oxazaborolidine
(50
(50
m
m
L of a 1 M solution in PhMe) at 0 ꢁC was added BH3$DMS
L of a 1 M solution in THF). After 1 h, the pre-formed reductant
J¼6.8 Hz, Me6); 13C NMR (125 MHz, CDCl3)
d
176.6, 159.4, 147.2,
129.9, 129.5, 113.9, 77.9, 76.5, 72.3, 55.3, 44.1, 36.8, 14.9; HRMS
(50.4
m
L of 0.5 M solution in THF/PhMe, 25.2
mmol, 1.5 equiv) was
(þESI) calcd for C15H23INO4 [MþNH4]þ: 408.0666, found: 408.0667.
added dropwise to a solution of ketone 28 (14.0 mg, 16.8
mmol,
1.0 equiv) in THF (2.2 mL) at ꢀ40 ꢁC. After 16 h, the reaction mix-
ture was quenched by the slow addition of MeOH (2 mL) and
warmed to rt. The crude product was azeotroped from MeOH five
times and purified by flash chromatography (15% EtOAc/hexane) to
afford the 1,3-anti diol 29 (12.1 mg, 86%) and the epimeric 1,3-syn
5.1.20. Phosphonate 5. To a stirred solution of acid 26 (811 mg,
2.08 mmol, 1.0 equiv) in CH2Cl2 at rt was added 1-chloro-N,N-tri-
methylpropenyl-amine (550 mL, 4.16 mmol, 2.0 equiv). After 1 h,
the volatiles were removed in vacuo and the crude acid chloride
was dried for 2 h under high vacuum. A solution of (Me3Si)2NH
(1.43 mL, 6.85 mmol, 3.3 equiv) in THF (10 mL) at ꢀ78 ꢁC was
treated with n-BuLi (3.9 mL of 1.6 M solution in hexanes,
6.23 mmol, 3.0 equiv) and allowed to warm to 0 ꢁC for 5 min. A
solution of bis(2,2,2-trifluoroethyl)-2-methylphosphonate (1.62 g,
6.23 mmol, 3.0 equiv) in THF (10 mL), cooled to ꢀ98 ꢁC (MeOH/
liquid N2) for 20 min, was treated (via syringe addition) first with
the solution of LiHMDS (pre-cooled to ꢀ78 ꢁC), then with the pre-
formed acid chloride in THF (10 mL). After 1.5 h at ꢀ98 ꢁC, satd aq
NH4Cl (20 mL) was added and the phases separated. The aqueous
layer was extracted with Et2O (2ꢂ50 mL), the combined organic
extracts dried (MgSO4) and concentrated in vacuo. Flash chroma-
diol (1.8 mg, 13%) as colourless oils: Rf 0.26 (20% EtOAc/hexane);
20
[a
]
ꢀ44.8 (c 1.53, CHCl3); IR (liquid film)/cmꢀ1 3422, 2957, 2929,
D
2857, 1462, 1378, 1253; 1H NMR (500 MHz, C6D6)
d 6.72 (1H, dt,
J¼17.1, 10.8 Hz, H25), 6.51 (1H, dd, J¼14.4, 8.5 Hz H5), 6.10 (1H, t,
J¼11.4 Hz, H24), 5.80 (1H, dd, J¼14.1, 0.6 Hz, H4), 5.53 (1H, t,
J¼10.6 Hz, H11), 5.44 (1H, t, J¼10.2 Hz, H23), 5.40 (1H, dd, J¼11.0,
7.6 Hz, H10), 5.15 (1H, dd, J¼16.9, 1.9 Hz, H26a), 5.06 (1H, br d,
J¼10.2 Hz, H26b), 4.66 (1H, dt, J¼8.3, 3.4 Hz, H9), 3.87–3.90 (1H, m,
H19), 3.61–3.65 (1H, m, H7), 3.53 (1H, br t, J¼4.2 Hz, H21), 3.41 (1H,
dd, J¼5.3, 2.8 Hz, H13), 2.83–2.92 (2H, m, H12þH22), 2.04 (1H, br s,
OH), 1.89–1.95 (1H, m, H6), 1.77–1.85 (3H, m, H14þH18aþH20),
1.72–1.77 (1H, m, H18b), 1.61–1.70 (2H, m, H8aþH8b), 1.40–1.61
(3H, m, H15aþH16þH17a), 1.10–1.18 (2H, m, H15bþH17b), 1.10 (3H,
d, J¼6.8 Hz, Me20), 1.04 (9H, s, SiC(CH3)3), 1.01–1.04 (3H, m, Me12),
1.01 (9H, s, SiC(CH3)3), 0.98–1.00 (6H, m, Me14þMe22), 0.98 (3H, d,
J¼6.8 Hz, Me16), 0.82 (3H, d, J¼7.0 Hz, Me6), 0.16 (3H, s, SiCH3), 0.15
(3H, s, SiCH3), 0.14 (3H, s, SiCH3), 0.12 (3H, s, SiCH3); 13C NMR
tography (20% EtOAc/hexane) afforded the phosphonate 5 (1.09 g,
20
83%) as an oil: Rf 0.42 (40% EtOAc/hexane); [
a
]
þ21.5 (c 1.52,
D
CHCl3); IR (liquid film)/cmꢀ1 2973, 1719, 1613, 1515, 1455; 1H NMR
(500 MHz, CDCl3)
d
7.23 (2H, d, J¼8.8 Hz, ArH), 6.89 (2H, d,
J¼8.8 Hz, ArH), 6.49 (1H, dd, J¼13.8, 8.3 Hz, H5), 6.13 (1H, dd,
J¼14.7, 1.0 Hz, H4), 4.37–4.51 (6H, m, ArCH2Oþ2ꢂCF3CH2O), 3.88
(1H, qn, J¼4.1 Hz, H7), 3.82 (3H, s, OMe), 3.27 (2H, d, 2JH,P¼21.5 Hz,
H10aþH10b), 2.81 (1H, dd, J¼16.4, 8.2 Hz, H8a), 2.57 (1H, dd,
(125 MHz, CDCl3)
d 148.0, 135.9, 135.4, 132.3, 130.5, 130.0, 118.0,
79.4, 77.7, 76.7, 76.1, 71.4, 66.7, 47.0, 41.9, 39.9, 37.4, 36.3, 36.0, 34.2,
31.9, 31.4, 30.3, 26.3, 26.0, 20.4, 19.7, 18.5, 18.1, 17.7, 16.0, 15.0, 6.8,
ꢀ3.1, ꢀ3.67, ꢀ3.75, ꢀ4.3; HRMS (þESI) calcd for C41H79NaIO4Si2
[MþNa]þ: 857.4403, found: 857.4390.
J¼16.6, 3.9 Hz, H8b), 2.48–2.55 (1H, m, H6), 1.07 (3H, d, J¼6.9 Hz,
2
Me6); 13C NMR (125 MHz, CDCl3)
d
199.8 (d, JC,P¼6.6 Hz), 159.4,
147.1, 129.9, 129.6, 113.9, 77.3, 76.5, 72.4, 62.3 (2C, m), 55.2, 46.3 (d,
3JC,P¼4.8 Hz), 43.8, 42.5 (d, 1JC,P¼137.4 Hz), 14.5; HRMS (CI) calcd for
C20H28F6INO6P [MþNH4]þ: 650.0598, found: 650.0605.
5.1.23. Iodide 30. To a solution of diol 29 (73 mg, 87.5
1.0 equiv) in (MeO)2CMe2/CH2Cl2 (2:1, 9 mL) at 0 ꢁC was added PPTS
(1.0 mg, 1.75 mol, 0.02 equiv). After stirring at rt for 16 h, satd aq
mmol,
m
5.1.21. Alcohol 28. To a solution of PMB ether 2718b,39 (160 mg,
0.168 mmol, 1.0 equiv) in CH2Cl2/pH 7 buffer (10:1, 400 mL) at 0 ꢁC
was added DDQ (191 mg, 0.840 mmol, 5.0 equiv). After stirring for
1 h, pH 7 buffer (500 mL) was added and the phases separated. The
aqueous phase was extracted with CH2Cl2 (3ꢂ400 mL) and the
combined organic extracts dried (MgSO4) and concentrated in vacuo.
Flash chromatography (light petroleum/10% EtOAc/light petro-
NaHCO3 (10 mL) was added and the phases separated. The aqueous
phase was extracted with CH2Cl2 (3ꢂ10 mL) and the combined or-
ganic extracts dried (MgSO4) and concentrated in vacuo. Flash
chromatography (10% EtOAc/hexane) afforded iodide 30 (76 mg, 99%)
20
as a colourless oil: Rf 0.71 (20% EtOAc/light petroleum); [
a
]
ꢀ12.5 (c
D
1.28, CHCl3); IR (liquid film)/cmꢀ1 2958, 2929, 2857,1461,1378,1254,
1223, 1073; 1H NMR (500 MHz, C6D6)
d
6.71 (1H, dt, J¼16.6, 10.4 Hz,
leum) afforded alcohol 28 (119 mg, 85%) as a colourless oil: Rf 0.40
H25), 6.62 (1H, dd, J¼14.3, 8.1 Hz, H5), 6.08 (1H, t, J¼10.8 Hz, H24),
5.85 (1H, d, J¼14.7 Hz, H4), 5.66 (1H, t, J¼11.2 Hz, H11), 5.52 (1H, dd,
20
(40% EtOAc/light petroleum); [
a
]
þ0.3 (c 1.76, CHCl3); IR (liquid
D

6544
I. Paterson et al. / Tetrahedron 66 (2010) 6534–6545
J¼10.8, 8.1 Hz, H10), 5.43 (1H, t, J¼10.8 Hz, H23), 5.15 (1H, br d,
J¼16.6 Hz, H26a), 5.05 (1H, br d, J¼10.8 Hz, H26b), 4.71–4.78 (1H, m,
H9), 3.87–3.91 (1H, m, H19), 3.55 (1H, dt, J¼9.3, 5.8 Hz, H7), 3.52 (1H,
dd, J¼6.2, 3.5 Hz, H21), 3.42 (1H, dd, J¼5.0, 3.1 Hz, H13), 2.80–2.92
(2H, m, H12þH22), 1.97–2.05 (1H, m, H6), 1.78–1.86 (3H, m,
H14þH18aþH20), 1.75 (1H, ddd, J¼13.2, 9.5, 5.8 Hz, H8a), 1.60–1.69
(2H, m, H15aþH18b),1.45–1.58 (3H, m, H8bþH16þH17a),1.39 (3H, s,
CCH3), 1.31 (3H, s, CCH3), 1.12–1.18 (2H, m, H15bþH17b), 1.10 (3H, d,
J¼7.0 Hz, Me20), 1.08 (3H, d, J¼7.0 Hz, Me12), 1.04 (9H, s, SiC(CH3)3),
1.01 (9H, s, SiC(CH3)3), 1.005 (3H, d, J¼6.5 Hz, Me14), 0.99 (3H, d,
J¼6.5 Hz, Me16), 0.98 (3H, d, J¼7.0 Hz, Me22), 0.83 (3H, d, J¼7.0 Hz,
chromatography (20% hexane/toluene) afforded macrolactone 32
(25.9 mg, 88%) as a colourless oil: Rf 0.59 (10% EtOAc/light petro-
20
leum); [
a
]
D
þ2.6 (c 0.53, CHCl3); IR (liquid film)/cmꢀ1 2957, 2930,
2856, 1716, 1645, 1581, 1516, 1461; 1H NMR (500 MHz, C6D6)
d 7.65
(1H, dd, J¼14.9, 11.3 Hz, H4), 6.72 (1H, dt, J¼17.0, 10.6 Hz, H25), 6.25
(1H, t, J¼11.3 Hz, H3), 6.02 (1H, t, J¼11.3 Hz, H24), 5.76 (1H, t,
J¼11.3 Hz, H11), 5.68 (1H, dd, J¼15.6, 6.4 Hz, H5), 5.63 (1H, d,
J¼11.3 Hz, H2), 5.58 (1H, t, J¼9.9 Hz, H10), 5.51 (1H, d, J¼8.5 Hz,
H21), 5.44 (1H, t, J¼11.3 Hz, H23), 5.13 (1H, d, J¼16.3 Hz, H26a), 5.06
(1H, d, J¼10.6 Hz, H26b), 4.73 (1H, ddd, J¼14.9, 9.6, 6.0 Hz, H9),
3.89–3.94 (1H, m, H7), 3.44–3.50 (1H, m, H19), 3.38–3.41 (1H, m,
H13), 2.99–3.08 (1H, m, H22), 2.86–2.94 (1H, m, H12), 2.52–2.59
(1H, m, H6), 1.95–2.02 (1H, m, H20), 1.83–1.92 (1H, m, H18a), 1.69–
1.83 (3H, m, H8aþH14þH17a), 1.37–1.54 (2H, m, H8bþH16), 1.45
(3H, s, CCH3), 1.40 (3H, s, CCH3), 1.18–1.36 (2H, m, H15aþH18b), 1.25
(3H, d, J¼6.9 Hz, Me6), 1.14 (3H, d, J¼7.1 Hz, Me12), 1.10 (3H, d,
J¼7.1 Hz, Me20), 1.05 (9H, s, SiC(CH3)3), 1.03 (9H, s, SiC(CH3)3), 0.98
(6H, d, J¼6.5 Hz, Me14þMe22), 0.96 (3H, d, J¼6.7 Hz, Me16), 0.80–
0.89 (2H, m, H15bþH17b), 0.14 (3H, s, SiCH3), 0.12 (3H, s, SiCH3),
0.11 (3H, s, SiCH3), 0.10 (3H, s, SiCH3); 13C NMR (125 MHz, C6D6)
Me6), 0.15 (6H, s, Si(CH3)2), 0.13 (3H, s, SiCH3), 0.12 (3H, s, SiCH3); 13
C
NMR (125 MHz, CDCl3) d 148.2, 136.9, 135.3, 132.3, 130.0, 128.5, 117.8,
100.5, 79.4, 77.5, 76.5, 75.2, 69.2, 63.4, 45.0, 42.1, 37.8, 36.8, 36.4, 36.1,
34.4, 32.0, 31.5, 30.4, 26.2, 26.0, 25.0, 24.4, 20.4, 19.1, 18.4, 18.1, 17.7,
15.3, 15.1, 7.0, ꢀ3.4, ꢀ3.66, ꢀ3.73, ꢀ4.4; HRMS (þESI) calcd for
C44H83NaIO5Si2 [MþNa]þ: 897.4716, found: 897.4714.
5.1.24. Acid 31. To a solution of iodide 30 (42.2 mg, 48.2
1.0 equiv) and stannane 644 (50.0 mg, 96.2
mol, 2.0 equiv) in
freeze-thaw deoxygenated NMP (1800
L) at rt was added CuTC21
(46.0 mg, 241 mol, 5.0 equiv). After stirring for 14 h, satd aq
mmol,
m
m
d 165.6, 144.2, 144.0, 137.0, 134.8, 133.9, 132.6, 130.2, 130.0, 117.7,
m
115.6, 100.5 79.4, 75.8, 74.5, 67.9, 64.0, 41.3, 41.2, 40.5, 36.6, 36.1,
34.8, 33.8, 33.0, 31.4, 30.9, 26.3, 26.2, 25.4, 24.6, 20.4, 19.5, 18.7, 18.3,
17.9, 16.6, 11.8, 11.1, ꢀ3.5, ꢀ3.6, ꢀ3.8, ꢀ3.9; HRMS (þESI) calcd for
C47H85O6Si2 [MþH]þ: 801.5879, found: 801.5868.
NH4Cl (2 mL) was added and the phases separated. The aqueous
phase was extracted with CH2Cl2 (3ꢂ2 mL) and the combined or-
ganic extracts dried (MgSO4) and concentrated in vacuo
(0.1 mmHg/0 ꢁC to remove NMP). The crude silyl ester intermediate
was re-dissolved in THF/MeOH (3:1, 2 mL) and to this solution at rt
5.1.26. (ꢀ)-Dictyostatin (1). To a solution of macrolactone 32
was added KF (28.0 mg, 482
mmol,10 equiv). After 3 h, satd aq NH4Cl
(81.4 mg, 102
HF$pyr (400
four days, four aliquots of HF$pyr (300
m
mol, 1.0 equiv) in THF (11 mL) at 0 ꢁC was added
L) dropwise over 20 min. Over the course of the next
(2 mL) was added and the phases separated. The aqueous phase was
extracted with CH2Cl2 (3ꢂ2 mL) and the combined organic extracts
dried (MgSO4) and concentrated in vacuo. Flash chromatography
(5% EtOAc/light petroleum/20% EtOAc/light petroleum) afforded
acid 31 (40.6 mg, 99%) as a colourless oil contaminated with traces of
m
mL) were added at rt to this
stirred reaction mixture. The reaction mixture was then quenched
by its careful addition to satd aq NaHCO3 (50 mL) at 0 ꢁC, warmed to
rt and stirred for a further 30 min. The phases were separated, the
aqueous phase was extracted with EtOAc (3ꢂ50 mL) and the com-
bined organic extracts dried (Na2SO4) and concentrated in vacuo.
Flash chromatography (30% hexane/EtOAc) afforded (ꢀ)-dictyosta-
tin residues,45 which was used without further purification: Rf 0.22
20
(30% EtOAc/light petroleum); [
a
]
D
ꢀ23.2 (c 1.61, CHCl3); IR (liquid
film)/cmꢀ1 2957, 2928, 2856, 1692, 1637, 1601, 1515, 1462; 1H NMR
(500 MHz, C6D6)
7.69 (1H, br t, J¼13.0 Hz, H4), 6.71 (1H, dt, J¼17.4,
d
tin (1) (38.0 mg, 70%) as an amorphous white solid: Rf 0.47 (EtOAc);
20
10.6 Hz, H25), 6.31 (1H, br t, J¼10.8 Hz, H3), 6.10 (1H, t, J¼10.1 Hz,
H24), 6.03 (1H, dd, J¼16.2, 8.1 Hz, H5), 5.69 (1H, t, J¼10.8 Hz, H11),
5.46–5.62 (2H, m, H2þH10), 5.46 (1H, t, J¼10.1 Hz, H23), 5.15 (1H, d,
J¼17.5 Hz, H26a), 5.05 (1H, d, J¼10.8 Hz, H26b), 4.76–4.82 (1H, m,
H9), 3.85–3.91 (1H, m, H19), 3.71 (1H, ddd, J¼11.1, 10.1, 5.7 Hz, H7),
3.58–3.62 (1H, m, H21), 3.44 (1H, br t, J¼3.7 Hz, H13), 2.81–2.92
(2H, m, H12þH22), 2.21–2.28 (1H, m, H6), 1.79–1.89 (4H, m,
H8aþH14þH18aþH20), 1.46–1.70 (4H, m, H8bþH16þH17aþH18b),
1.46 (3H, s, CCH3), 1.22–1.39 (2H, m, H15aþH17b),1.37 (3H, s, CCH3),
1.10–1.15 (1H, m, H15b), 1.10 (3H, d, J¼6.0 Hz, Me12), 1.08 (3H, d,
J¼6.9 Hz, Me20),1.04 (9H, s, SiC(CH3)3), 1.03 (9H, s, SiC(CH3)3), 1.00–
1.02 (3H, m, Me6), 0.99 (6H, d, J¼6.5 Hz, Me14þMe16), 0.97 (3H, d,
J¼7.3 Hz, Me22), 0.17 (3H, s, SiCH3), 0.15 (3H, s, SiCH3), 0.14 (3H, s,
[a
]
ꢀ32.7 (c 0.22, MeOH);47 IR (liquid film)/cmꢀ1 2955, 2930,
D
2858, 1716, 1462, 1257; 1H NMR (700 MHz, CD3OD)
d 7.21 (1H, dd,
J¼15.5, 11.4 Hz, H4), 6.70 (1H, dt, J¼15.2, 10.4 Hz, H25), 6.65 (1H, t,
J¼11.4 Hz, H3), 6.18 (1H, dd, J¼15.5, 6.7 Hz, H5), 6.06 (1H, t,
J¼11.1 Hz, H24), 5.55 (1H, d, J¼11.4 Hz, H2), 5.55 (1H, t, J¼10.0 Hz,
H11), 5.41 (1H, dd, J¼10.8, 8.9 Hz, H10), 5.33 (1H, dd, J¼11.1, 10.6 Hz,
H23), 5.24 (1H, dd, J¼15.2,1.7 Hz, H26a), 5.14 (1H, dd, J¼10.4,1.7 Hz,
H26b), 5.13 (1H, dd, J¼6.9, 5.1 Hz, H21), 4.65 (1H, dddd, J¼10.1, 9.5,
2.9, 0.8 Hz, H9), 4.05 (1H, ddd, J¼10.6, 4.0, 2.7 Hz, H7), 3.34 (1H, m,
H19), 3.16 (1H, ddq, J¼10.6, 6.9, 6.8 Hz, H22), 3.10 (1H, dd, J¼8.1,
2.9 Hz, H13), 2.76 (1H, m, H12), 2.60 (1H, m, H6), 1.88 (1H, m, H20),
1.83 (1H, m, H18a),1.59 (1H, m, H14),1.57 (1H, m, H17a),1.53 (1H, m,
H16), 1.49 (1H, ddd, J¼14.0, 10.6, 2.9 Hz, H8a), 1.42 (1H, ddd, J¼14.0,
10.1, 2.7 Hz, H8b), 1.24 (1H, ddd, J¼13.8, 10.3, 3.8 Hz, H15a),1.15 (3H,
d, J¼6.9 Hz, Me27), 1.13 (3H, d, J¼7.0 Hz, Me28), 1.10 (1H, m, H18b),
1.07 (3H, d, J¼6.9 Hz, Me31), 1.01 (3H, d, J¼6.8 Hz, Me32), 0.95 (3H,
d, J¼6.5 Hz, Me29), 0.93 (3H, d, J¼6.6 Hz, Me30), 0.89 (1H, m, H15b),
SiCH3), 0.12 (3H, s, SiCH3); 13C NMR (125 MHz, C6D6)
d 170.9, 147.7,
147.4, 135.7, 135.0, 132.6, 130.7, 130.1, 117.9, 115.9, 114.1, 100.5, 79.8,
76.1, 75.5, 69.9, 64.0, 42.3, 42.1, 29.5, 37.3, 37.0, 36.6, 34.7, 32.3, 31.9,
30.8, 26.4, 25.9, 25.3, 24.6, 20.7, 19.3, 18.7, 18.4, 17.9, 16.1, 15.7, 8.7,
ꢀ3.1, ꢀ3.4, ꢀ3.6, ꢀ4.3; HRMS (þESI) calcd for C47H90NO7Si2
[MþNH4]þ: 836.6250, found: 836.6255.
0.69 (1H, m, H17b); 13C NMR (125 MHz, CD3OD)
d 168.0,146.3,144.8,
134.9, 134.5, 133.4, 131.3, 131.1, 128.5, 118.5, 118.0, 80.3, 78.6, 73.7,
70.3, 65.4, 44.0, 42.2, 40.8, 40.5, 35.8, 35.7, 35.3, 32.7, 32.5, 31.2, 21.8,
19.3, 18.0, 15.9, 13.6, 10.3; HRMS (þESI) calcd for C32H52NaO6
[MþNa]þ: 555.3662, found: 555.3663. This spectroscopic data was
identical to that recorded for an authentic sample of dictyostatin.
5.1.25. Macrolactone 32. To
a solution of acid 31 (30.1 mg,
36.8 mol, 1.0 equiv) in PhMe (2.5 mL) at rt was added Et3N
m
(13.8
(10.3
m
m
L, 99.3
L, 66.2
m
m
mol, 2.7 equiv) then 2,4,6-trichlorobenzoylchloride
mol, 1.8 equiv). After stirring for 2 h, the reaction
mixture was diluted with PhMe (50 mL) and DMAP (2.2 mg,
18.3 mol, 0.5 equiv) was added. After 18 h, satd aq NaHCO3
Acknowledgements
m
(50 mL) was added and the phases separated. The aqueous phase
was extracted with CH2Cl2 (3ꢂ40 mL) and the combined organic
extracts dried (MgSO4) and concentrated in vacuo. Flash
Financial support was provided by the EPSRC, the NSERC of
Canada (R.B.), the Gobernio de Canarias, the Cambridge European
Trust (O.D.), the EC (Network HPRN-CT-2000-18 and Marie Curie

I. Paterson et al. / Tetrahedron 66 (2010) 6534–6545
6545
Madiraju, C.; Balachandran, R.; Montgomery, K.; Shin, Y.; Fukui, Y.; Jung, W.-H.;
Curran, D. P.; Day, B. W. Mol. Pharmacol. 2008, 73, 718.
20. Eiseman, J. L.; Bai, L.; Jung, W.-H.; Moura-Letts, G.; Day, B. W.; Curran, D. P.
J. Med. Chem. 2008, 51, 6650.
21. Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748.
22. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
23. (a) Paterson, I.; Lyothier, I. Org. Lett. 2004, 6, 4933; (b) Paterson, I.; Lyothier,
I. J. Org. Chem. 2005, 70, 5494.
Fellowship to K.G.P.) and AstraZeneca (N.M.G.). We thank Dr. Amy
Wright (Harbour Branch Oceanographic Institution) for providing
an authentic sample of dictyostatin, Professor John Leonard
(AstraZeneca) for helpful discussions, Dr. Stuart Mickel (Novartis
Pharma AG) for the gift of chemicals and the EPSRC National Mass
Spectrometry Service (Swansea) for mass spectra.
24. (a) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; Scott, J. P.; Sereinig, N.
Org. Lett. 2003, 5, 35; (b) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.;
O’Brien, M.; Scott, J. P.; Sereinig, N. J. Org. Chem. 2005, 70, 150.
25. (a) Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639; (b) Paterson, I.;
Wallace, D. J.; Velazquez, S. M. Tetrahedron Lett. 1994, 35, 9083; (c) Paterson, I.;
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47. In comparison, the specific rotation measured for a natural sample of dictyostatin
20
was [
a
]
D
ꢀ27.4 (c 0.16, MeOH) and that reported by Pettit et al. (Ref. 3) was ꢀ20
(c 0.12, MeOH). For copies of NMR spectra of dictyostatin, see the Supplementary
data for Ref. 13.