Total synthesis and stereochemical reassignment of (+)-dolastatin 19, a cytotoxic marine macrolide isolated from Dolabella auricularia

Article abstract of DOI:10.1016/j.tet.2007.01.048

Using conformational analysis and biogenetic considerations, a revised configurational assignment for the cytotoxic marine macrolide dolastatin 19 is proposed, together with its validation by completion of the first total synthesis. Key features of the hi

Full text of DOI:10.1016/j.tet.2007.01.048

Tetrahedron 63 (2007) 5806–5819
Total synthesis and stereochemical reassignment of
(D)-dolastatin 19, a cytotoxic marine macrolide
isolated from Dolabella auricularia
*
Ian Paterson, Alison D. Findlay and Gordon J. Florence
University Chemical Laboratory, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Received 27 November 2006; revised 10 January 2007; accepted 22 January 2007
Available online 25 January 2007
Abstract—Using conformational analysis and biogenetic considerations, a revised configurational assignment for the cytotoxic marine
macrolide dolastatin 19 is proposed, together with its validation by completion of the first total synthesis. Key features of the highly stereo-
controlled route include an asymmetric vinylogous Mukaiyama aldol reaction to simultaneously install both the remote C13 stereocenter and
the C10–C11 (E)-trisubstituted olefin, two sequential 1,4-syn boron-mediated aldol reactions, and a late-stage, a-selective Mukaiyama
glycosylation to append the L-rhamnose-derived pyranoside.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Marine organisms provide an enormous reservoir of struc-
H
N
H
N
turally diverse secondary metabolites with unique molecular
architectures.1 Dolabella auricularia, a sea hare from the
aplysiidae family of marine opisthobranchs, has proven to
be a prolific source of bioactive marine natural products.2
A collection of this shell-less mollusc from the Indian Ocean
by the Pettit group led to the isolation of a novel series of
potent cytotoxic depsipeptides, designated as the dolasta-
tins.3 These include dolastatins 10 (1, Fig. 1) and 15 (2),
both of which possess potent anticancer activity4 and have
progressed into clinical trials.5 It is generally believed that
the majority of these bioactive secondary metabolites are
not produced by the sea hare itself, but are instead of cyano-
bacterial origin, consumed by the sea hare whilst grazing on
algae and seaweeds, and then concentrated in the digestive
glands. Conceivably, these sequestered compounds may
function as a chemical defence for the sea hare against
predators.6
N
H
N
N
S
MeO
O
Me
Me2N
OMe O
O
O
1: Dolastatin 10
OMe
H
H
N
N
N
O
H
N
N
O
Me
O
Me2N
O
O
O
O
O
2: Dolastatin 15
Figure 1. Structures of dolastatin 10 (1) and dolastatin 15 (2).
sample collection from the Gulf of California. In 2004,
this work led to the isolation of a novel marine polyketide,
designated as dolastatin 19.8 Initial biological screening
indicated significant cancer cell growth inhibitory activity
(GI50 values of 0.72 mg/mL and 0.76 mg/mL for breast
MCF-7 and colon KM20L2 cell lines, respectively). How-
ever, further biological evaluation of dolastatin 19, including
elucidation of the mechanism of action, was precluded by its
scarce availability from the natural source (0.5 mg was
obtained from 600 kg of D. auricularia), inspiring our
efforts towards the realization of a total synthesis.9 Herein,
we now report the full details of the evolution of our
proposed stereochemical reassignment of dolastatin 19 and
its subsequent validation, achieved through completion of
the first total synthesis.
Examination of the cytotoxic extracts of Japanese specimens
of D. auricularia by Yamada and co-workers led to the
isolation and characterization of the 14-membered macro-
lides, aurisides A (3, Fig. 2) and B (4).7 The marked struc-
tural variations in the peptidic and polyketide constituents
of D. auricularia prompted the Pettit group to extract a
Keywords: Macrolide; Cytotoxic; Conformational analysis; Stereochemical
reassignment; Aldol reaction; Glycosylation.
* Corresponding author. Tel.: +44 1223 336407; fax: +44 1223 336362;
e-mail: ip100@cus.cam.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.048

I. Paterson et al. / Tetrahedron 63 (2007) 5806–5819
5807
O
O
OH
O
MeO
O
OMe
MeO
O
NH
O
5
5
7
3
3
7
O
O
H
OH 1
O
H
OH 1
O
MeO
O
MeO
O
13
13
Br
Cl
5: Dolastatin 19
original structure
6: Callipeltoside A
OH
Figure 4. (a) Overlay of global minimum energy conformations of the auri-
side and callipeltoside aglycons and (b) calculated minimum energy confor-
mation of dolastatin 19 aglycon (Pettit assignment).
OR
MeO
OMe
5
O
R =
7
3
O
O
OMe
O
O
NH2
OMe
O
MeO
MeO
H
OH 1
O
O
O
assignment proposed by Pettit and co-workers may have
been incorrect. To gain further insight into the preferred
conformations adopted by these related marine macrolides,
detailed molecular modelling studies were performed on
the parent aglycons. Using Macromodel (Version 8.0),
a 10,000 step Monte Carlo conformational search was per-
formed with the MM2* force field and chloroform solvent
model. Reassuringly, both the auriside and callipeltoside
aglycons share a similar diamond lattice arrangement of
the macrolide rings. The six-membered hemiacetal ring
adopts a chair conformation, in which all the substituents
are equatorially disposed and anomeric stabilization is
achieved at C3 (Fig. 4). This preferred conformation also
facilitates a stabilizing hydrogen bond between the anomeric
C3–OH and the oxygen of the lactone carbonyl, and mini-
mizes steric interactions throughout the carbon framework.
By contrast, examination of the structure proposed by Pettit
for dolastatin 19 predicts a boat conformation for the pyran
ring.14 Consequently the structure gains no anomeric stabili-
zation, as the C3–OH is now essentially equatorially dis-
posed, and the remaining region of the macrolide is highly
distorted relative to the common, and presumably favour-
able, diamond lattice conformation adopted by the auriside
and callipeltoside aglycons.
O
Br
13
3: Auriside A
4: Auriside B
Figure 2. Dolastatin 19 (5) and structurally related 14-membered marine
macrolides.
2. Proposed stereochemical reassignment of dolastatin 19
Following extensive spectroscopic analysis by Pettit and co-
workers, the original structure of dolastatin 19 was proposed
as 5 (Fig. 2).8 As a 14-membered macrolide containing a
six-membered cyclic hemiacetal and appended with an
(E,E)-diene and a 2,4-di-O-methyl-L-rhamnopyranoside,
dolastatin 19 is related to aurisides A (3) and B (4), and
also to callipeltoside A (6), isolated from the lithistid sponge
Callipelta sp.10 Examination of the linear seco-acids 7 and
8 of these macrocycles (Fig. 3) serves to highlight the
structural similarities. Notably, the stereochemistry of the
aurisides and callipeltoside has been rigorously established
by total synthesis, as reported by ourselves11 and other
groups.12 On careful inspection, the pseudo-enantiomeric
assignment of the configuration of dolastatin 19 across
C5–C7 and at C13 in the corresponding seco-acid 9 appears
inconsistent with the anticipated common bacterial biogen-
esis of these polyketides.13
This evidence, together with the assumption of a common
biogenesis, prompted us to propose configurational inver-
sions of both the C5–C7 stereotriad and the isolated C13
carbinol stereocentre, leading to the putative structure 10
(Scheme 1).
Prior to the onset of a synthetic venture towards dolastatin
19, these noted structural ambiguities prompted us to
consider the possibility that the initial stereochemical
O
O
O
OH OH
6
O
OH
13
7 (aurisides)
1
7
17
17
5
HO
HO
Br
O
1
OH OH OMe
6
OH
13
8 (callipeltosides)
7
5
Cl
O
1
O
OH OH OMe
6
OH
13
9 (dolastatin 19;
7
5
17
original structure)
HO
Br
Figure 3. Open chain seco-acids of dolastatin 19 and related macrolides.

5808
I. Paterson et al. / Tetrahedron 63 (2007) 5806–5819
OH
O
OH
O
MeO
O
OMe
MeO
O
OMe
glycosylation
*
*
*
*
*
O
H
*
O
OH
H
OH
MeO
O
O
MeO
O
O
macrolactonization
Br
Br
*
*
10: Reassigned Dolastatin 19
5: Dolastatin 19
(original structure)
OTBS
OMe
MeO
F
Proposed
reassignment
B-aldol # 1
TES
OH
O
O
7
OMe
9
OTBS
13
O
11
1
5
17
OH
DMBO
Br
MeO
O
OMe
12
1,4-syn
O
B-aldol # 2
*
*
H
TES
O
* denotes inversion
of configuration
O
O
7
OMe
9
OTBS
13
*
O
OH
O
5
17
DMBO
H
Br
Br
MeO
O
15
13
Br
*
1,4-syn
10: Dolastatin 19
(stereochemically
reassigned)
AVM
OTBS
O
O
H
Scheme 1. Proposed stereochemical reassignment of dolastatin 19.
DMBO
13
17
13
14
Scheme 2. Retrosynthetic analysis for dolastatin 19 leading to key building
blocks 13 and 14.
3. Retrosynthetic analysis and general synthetic strategy
Our retrosynthetic analysis of dolastatin 19, outlined in
Scheme 2, envisaged a late-stage glycosylation of the puta-
tive dolastatin 19 aglycon with L-rhamnose-derived fluoro-
sugar 11, following macrolactonization and hemiacetal
formation at C3 of the acyclic C1–C17 precursor 12. Careful
inspection of the complete aglycon framework reveals two
1,4-syn relationships that can be selectively installed using
iterative boron-mediated aldol reactions, both involving
a-chiral ketone 13.15 The first 1,4-syn aldol coupling,
between aldehyde 14 and ketone 13, would introduce the
requisite C9 stereocenter, while the second coupling would
involve the more complex aldehyde 15. Aldehyde 14 can
in turn be accessed utilizing an asymmetric vinylogous
Mukaiyama (AVM) aldol reaction, as developed in our
previous syntheses of callipeltoside A and the aurisides,11
to install both the C13 stereocenter and (10E)-trisubstituted
double bond.
and enantioselectivity (94% ee). In this single step, the regio-
selectivity (g-addition vs a-addition), E/Z geometry of the
C10–C11 trisubstituted double bond, and the absolute con-
figuration of the C13 stereocenter (as determined by Mosher
ester analysis11) were all effectively controlled. With adduct
18 in hand, a series of functional and protecting group
OMe
O
TMSO
H
Br
17
16
a
(93%)
OH
O
MeO
Br
Br
Br
18
b,c (88%)
OTBS
4. Results and discussion
HO
In initiating our synthetic efforts, we focused on construction
of the C9–C17 subunit 14 via an asymmetric vinylogous
Mukaiyama aldol coupling16 between (E,E)-bromodienal
1617 and silyl dienolate 17 (Scheme 3).18 The conditions
had been optimized during our earlier synthesis of callipelto-
side A (6),11 where (R)-BINOL-Ti(Oi-Pr)2, formed in situ
from (R)-BINOL and Ti(Oi-Pr)4, had been identified as an
optimal chiral Lewis acid promoter. Under these conditions,
the desired aldol adduct 18 was obtained in high yield (93%)
19
d
(86%)
OTBS
O
H
14
Scheme 3. (a) (R)-BINOL, Ti(Oi-Pr)4, THF, ꢀ78 ꢁC; (b) TBSCl, imidazole,
CH2Cl2, rt; (c) DIBAL-H, CH2Cl2, ꢀ78 ꢁC; (d) MnO2, Et2O, rt.

I. Paterson et al. / Tetrahedron 63 (2007) 5806–5819
5809
O
OBL2
O
OTBS
a
DMBO
DMBO
DMBO
H
Br
(88%, >95:5 dr)
13
20
14
78
27 °C
DMB
O
OH
OTBS
O
Me
H
L
Br
H
O
B
21
L
O
R'
TS 1
Scheme 4. (a) (+)-Ipc2BCl, Et3N, Et2O, 0 ꢁC; 14, ꢀ78/ꢀ27 ꢁC.
manipulations were required to access the aldehyde 14. Pro-
tection of the newly introduced C13 hydroxyl in 18 (TBSCl/
imidazole) was followed by DIBAL-H reduction of the ester
to provide allylic alcohol 19. Subsequent MnO2-mediated
oxidation of alcohol 19 gave aldehyde 14 (75% over three
steps) in preparation for the first boron-mediated aldol
reaction.
bond in the aldol transition state with the oxygen of the DMB
ether, acting in unison with the minimization of steric inter-
actions between the a-stereocenter of the enolate and the
aldehyde, leading to TS 1 for the preferred reaction pathway.
To enhance the inherent levels of diastereoselectivity
observed in the aldol coupling of ketone 13 and aldehyde
14, the matched chiral boron reagent (+)-Ipc2BCl was
used, leading to essentially complete stereocontrol in favour
of 1,4-syn adduct 21.
The stage was now set for the first 1,4-syn aldol reaction with
methyl ketone 13.19 Experience gained in our synthesis of
callipeltoside A11 proved useful in selecting a suitable pro-
tecting group. The 3,4-dimethoxybenzyl (DMB)20 ether in
13 was chosen in place of the more standard 4-methoxy-
benzyl (PMB) variant, to alleviate potential chemoselectivity
complications relating to competitive DDQ-mediated oxida-
tion of the allylic TBS ether at C13 in the later stages of the
synthesis. Treatment of methyl ketone 13 with (+)-Ipc2BCl
and Et3N provided the intermediate boron enolate 20 which,
upon addition of aldehyde 14, generated the expected15
1,4-syn aldol adduct 21 in 88% yield and >95:5 dr (Scheme
4). Recent in silico studies by Goodman and Paton regarding
the origin of remote stereoinduction in the boron-mediated
aldol reactions of b-alkoxy methyl ketones have shown
such processes to proceed via a boat-like transition state.21
The high levels of enolate p-facial selectivity observed are
governed by the formation of a stabilizing formyl hydrogen
Elaboration of aldol adduct 21 to the C5–C17 aldehyde 15
began with an Evans–Tischenko 1,3-anti reduction (Scheme
5).22 Treatment of 21 with a premixed solution of SmI2 and
propionaldehyde provided the alcohol 22 (80%, >95:5 dr).23
Protection of the free hydroxyl at C7 in 22 with TESOTf/2,6-
lutidine (90%) was followed by reductive removal of the C9
propionate ester with DIBAL-H to provide alcohol 24
(87%). The requisite C9 methyl ether of dolastatin 19 was
then introduced via treatment of 24 with Meerwein’s salt
(Me3O$BF4) and Proton SpongeÔ to provide 25 in 96%
yield.24 At this point, cleavage of the primary DMB ether
at C5 in the presence of the potentially labile allylic TBS
ether at C13 was required. Pleasingly, use of conditions em-
ployed in our synthesis of callipeltoside A11 (treatment with
DDQ in CH2Cl2/pH 7 buffer (10:1), 60 ꢁC, 10 min) provided
alcohol 26 in 77% yield (99% based on recovered starting
ODMB
ODMB
ODMB
a
c
O
OR
OTES
(87%)
(80%, >95 : 5 dr)
HO
OTBS
21
EtCO2
OTBS
HO
OTBS
Br
Br
Br
24
22: R = H
b
(90%)
23: R = TES
d
(96%)
O
OH
ODMB
H
f
e
(77%)
(85%)
OTES
OTBS
OTES
OTBS
OTES
OTBS
MeO
MeO
MeO
Br
Br
Br
15
26
25
Scheme 5. (a) SmI2, EtCHO, THF, ꢀ10 ꢁC; (b) TESOTf, 2,6-lutidine, CH2Cl2, ꢀ78 ꢁC; (c) DIBAL-H, CH2Cl2, ꢀ78 ꢁC; (d) Me3O$BF4, Proton SpongeÔ,
CH2Cl2, rt; (e) DDQ, CH2Cl2, pH 7 buffer, 60 ꢁC; (f) Dess–Martin periodinane, pyridine, CH2Cl2, rt.

5810
I. Paterson et al. / Tetrahedron 63 (2007) 5806–5819
material 25). Finally, Dess–Martin periodinane oxidation25
of 26 completed the preparation of C5–C17 aldehyde 15
(85%), in readiness for the second 1,4-syn aldol coupling
with ketone 13.
Pinnick oxidation27 of the intermediate aldehyde to provide
the corresponding carboxylic acid 32 in 96% yield. Selective
cleavage of the allylic TBS ether at C13 was achieved by
treatment of 32 with TBAF to give the requisite seco-acid
31 (98%). The 14-membered macrolide was readily formed
under standard Yamaguchi macrolactonization conditions.28
Thus, treatment of 31 with 2,4,6-trichlorobenzoylchloride
and Et3N, followed by slow addition of the intermediate
anhydride to DMAP in toluene at 60 ꢁC, provided the pro-
tected aglycon 33 in 64% yield.
This complex aldol coupling was achieved by enolization of
methyl ketone 13 with c-Hex2BCl/Et3N, followed by addi-
tion of aldehyde 15, to provide the expected Felkin–Anh
adduct 12 in excellent yield and diastereoselectivity (89%,
>95:5 dr) (Scheme 6). The high levels of substrate control
for the 1,4-syn product can be attributed to the matched dia-
stereofacial selectivity of the coupling partners. With the
complete C1–C17 carbon backbone in place, attention was
now focused on the assembly of the putative aglycon 27 of
stereochemically reassigned dolastatin 19. Treatment of 12
with PPTS and trimethyl orthoformate in MeOH triggered
cleavage of the C7-TES ether, with concomitant cyclization
and methyl acetal formation, to provide 28 (78%). Confirma-
tion of the stereochemical relationship across the hemiacetal
moiety was provided by NOE analysis, with irradiation of
H5 providing diagnostic enhancements of C3–OMe and
C6–Me, which is consistent with their 1,3-diaxial and 1,2-
syn orientations, respectively. Following TBS protection of
the C5 hydroxyl (90%), the stage was set to prepare the
C1 terminus for macrolactonization. In initial experiments,
treatment of 29 with DDQ under the conditions used previ-
ously for the DMB deprotection of 25 led to hydrolysis of the
methyl acetal at C3, along with undesired oxidation25 of the
C13-TBS ether. Following extensive optimization, oxidative
cleavage of the primary DMB ether was achieved by treat-
ment of 29 with DDQ in CH2Cl2 and pH 9 buffer (4:1) at
0 ꢁC for 10 min, to provide primary alcohol 30 in 53% yield.
As shown in Scheme 7, completion of the dolastatin 19
aglycon 27 was achieved by cleavage of the remaining silyl
group at C5 with TBAF (83%), followed by mild acidic
hydrolysis (PPTS) of the methyl acetal 34 (81%). At this
stage, an early indication of the likely validity of our stereo-
chemical reassignment was provided by the remarkably
1
close correlation of both the H and 13C NMR spectra of
the synthetic aglycon 27 with the reported data for the
macrolide region of dolastatin 19.8
Completion of the synthesis of dolastatin 19 required the
stereocontrolled glycosylation of aglycon 27. L-Rhamnose
derived fluorosugar 11, previously utilized in our synthesis
of aurisides A and B,11 was prepared in seven steps from
alcohol 35.29 The coupling of 27 and 11 was performed
using Mukaiyama’s conditions (SnCl2/AgClO4)30 to yield
36 with complete a-selectivity (49%). Finally, removal of
the remaining TBS ether with HF$pyridine provided stereo-
chemically reassigned dolastatin 19 (10) in 79% yield.
Gratifyingly, the spectroscopic data obtained for synthetic
10 (1H and 13C NMR, IR and MS), together with the mea-
sured specific rotation ([a]2D0 +2.2 (c 0.18, MeOH) cf. +7.5
(c 0.04, MeOH)), correlated fully with that of natural
dolastatin 19.8 Molecular modelling (Fig. 5) of the structure
indicated in 10 (i.e., 2S, 3S, 5S, 6R, 7S, 9S, 13R) reveals that
Gratifyingly, the subsequent three-step elaboration of alco-
hol 30 to the seco-acid 31 proved straightforward. Oxidation
of 30 with Dess–Martin periodinane26 was followed by
O
O
OH O
OR
ODMB
2.5%
ODMB
H
13
H7
H5
OMe
H
2.4%
Me
a
OTES
OTBS
OTES
OTBS
O
b
O
MeO
MeO
MeO
(78%)
(89%; >95 : 5 dr)
Br
MeO
TBSO
ODMB
OP
H6
H
Br
Br
= nOe
15
12
28: R = H
c
(90%)
29: R = TBS
d
(53%)
OTBS
OTBS
OTBS
e,f
h
O
O
O
(64%)
(96%)
MeO
MeO
MeO
CO2H
MeO
O
O
MeO
RO
MeO
TBSO
OH
Br
Br
Br
32: R = TBS
31: R = H
33
30
g
(98%)
Scheme 6. (a) c-Hex2BCl, Et3N, Et2O, 0 ꢁC; 13, ꢀ78/ꢀ27 ꢁC; (b) PPTS, (MeO)3CH, MeOH; (c) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ78 ꢁC; (d) DDQ, pH 9
buffer, CH2Cl2, 0 ꢁC; (e) Dess–Martin periodinane, NaHCO3, CH2Cl2, rt; (f) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, rt; (g) TBAF, THF, 0 ꢁC/rt;
(h) 2,4,6-Cl3C6H2COCl, Et3N, 31, toluene, rt; then DMAP, 60 ꢁC.

I. Paterson et al. / Tetrahedron 63 (2007) 5806–5819
5811
O
O
OH
35
MeO
O
ref. 30
OR
O
OTBS
MeO
O
OMe
MeO
F
OMe
11
OR2
O
c
O
R1O
O
H
(49%)
MeO
O
O
OH
MeO
O
O
Br
33: R1 = Me; R2 = TBS
Br
a
b
36: R = TBS
10: R = H
34: R1 = Me; R2 = H (83%)
27: R1 = R2 = H (81%)
d
(79%)
Reassigned Dolastatin 19
ꢁ
ꢁ
ꢁ
˚
Scheme 7. (a) TBAF, THF, 0 C/rt; (b) PPTS, wet MeCN, rt; (c) SnCl2, AgClO4, Et2O, 4 A molecular sieves, 0 C/rt; (d) HF$pyridine, THF, 0 C/rt.
6. Experimental
6.1. General
Molecular modelling was performed using Macromodel
(Version 8.0).33 To thoroughly probe the conformational
potential surface, a 10,000 step Monte Carlo Multiple
Minimum34 search was performed using the MM2 force
Figure 5. Global minimum energy conformation of dolastatin 19 aglycon
(stereochemically reassigned).
field,35 in conjunction with the generalized Born/surface
area (GB/SA) chloroform solvent model.36
this structure is indeed also predicted to adopt a similar con-
6.1.1. Aldol adduct 18. To a stirred solution of (R)-BINOL
formation as both the auriside and callipeltoside aglycons.
(5.33 g, 18.6 mmol) and powdered CaH2 (250 mg) in THF
(60 mL) at rt was added Ti(Oi-Pr)4 (5.50 mL, 18.6 mmol)
Further convincing evidence in support of our stereochem-
dropwise. The resultant orange solution was stirred at rt for
ical reassignment of the natural product is provided by the
1 h before being cooled to ꢀ78 ꢁC. Silyl dienolate 1718
comparable levels of biological activity displayed by
(6.00 g, 37.3 mmol) in THF (50 mL) was added via cannula
synthetic dolastatin 19 to that isolated in nature. In screening
and the solution was stirred for 10 min before a solution
assays against three representative cancer cell lines HT-29
of (E,E)-bromodienal 1617 (14.8 g, 74.5 mmol) in THF
(colon), NSCLC (lung) and MDA-MB-231 (breast), syn-
(50 mL) was added via cannula. The reaction mixture was
thetic dolastatin 19 displayed GI50 values of 0.89, 1.04 and
stirred at ꢀ78 ꢁC for 72 h and quenched by addition of satu-
1.20 mg/mL, respectively, consistent with the biological
rated aqueous NaHCO3 (200 mL). The resultant suspension
activity reported for natural dolastatin 19.31
was filtered through Celite with CH2Cl2 (400 mL). The
layers were separated and the aqueous phase was extracted
5. Conclusions
with CH2Cl2 (2ꢂ100 mL). The combined organic phases
were dried (MgSO4), concentrated in vacuo and purified by
flash column chromatography (10% EtOAc/hexane) to yield
aldol adduct 18 as a colourless oil (9.58 g, 93%; 94% ee); Rf
0.28 (30% EtOAc/hexane); [a]2D0 +19.7 (c 2.2, CHCl3); IR
In summary, a stereochemical reassignment of the cytotoxic
marine macrolide (+)-dolastatin 19, isolated from the sea
hare D. auricularia, has been made, based upon information
gained from conformational analysis and comparison with
related natural products.32 This reassignment has been vali-
dated by completion of the first total synthesis of dolastatin
19 (23 steps, 1.7% overall yield). The highly stereocon-
trolled route utilizes contemporary aldol methodology and
has generated sufficient quantities of material to facilitate
biological studies which, in turn, provided further compel-
ling evidence for the validity of our stereochemical reassign-
ment and should give valuable information about the
potential of dolastatin 19 as an anticancer agent.
(neat) 3452, 1646, 1228, 1153, 666 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d 6.70 (1H, dd, 13.6, 10.9 Hz, H16),
6.35 (1H, d, J¼13.6 Hz, H17), 6.20 (1H, dd, J¼15.0,
10.9 Hz, H15), 5.77–5.69 (2H, m, H10 and H14), 4.36 (1H,
m, H13), 3.69 (3H, s, OCH3), 2.35 (2H, d, J¼6.8 Hz, H12a
and H12b), 2.19 (3H, s, Me11), 1.80 (1H, br s, OH); 13C
NMR (100 MHz, CDCl3) d 166.7, 155.3, 136.4, 135.7,
127.9, 118.3, 109.6, 69.7, 50.9, 48.5, 19.0; HRMS (ES+)
Calculated for C11H15BrO3Na [M+Na+] 297.0102, found
297.0104.

5812
I. Paterson et al. / Tetrahedron 63 (2007) 5806–5819
6.1.2. TBS ether 18a. To a stirred solution of aldol adduct 18
(1.61 g, 5.85 mmol) in CH2Cl2 (25 mL) at 0 ꢁC was added
TBSCl (2.21 g, 14.6 mmol) followed by imidazole (1.08 g,
15.8 mmol). The reaction mixture was stirred at rt for 2 h be-
fore partitioning between NaHCO3 and CH2Cl2 (3ꢂ30 mL).
The combined organic layers were dried (MgSO4) and con-
centrated in vacuo. The crude product was purified by flash
column chromatography (5–10% EtOAc/hexane) to yield
TBS ether 18a as a colourless oil (2.28 g, 99%); Rf 0.43
(20% EtOAc/hexane); [a]2D0 +5.1 (c 3.1, CHCl3); IR (neat)
6.3 Hz, H14), 4.31 (1H, m, H13), 2.40 (1H, dd, J¼13.1,
7.2 Hz, H12a), 2.34 (1H, dd, J¼13.1, 5.2 Hz, H12b), 2.18
(3H, s, Me11), 0.87 (9H, s, SiC(CH3)3), 0.02 (3H, s,
SiCH3), 0.01 (3H, s, SiCH3); 13C NMR (100 MHz, CDCl3)
d 191.3, 159.6, 136.6, 136.5, 130.0, 127.3, 109.2, 71.5,
49.1, 25.7, 18.6, 18.1, ꢀ4.4, ꢀ4.9; HRMS (ES+) Calculated
for C16H27BrSiO2Na [M+Na+] 381.0861, found 381.0864.
6.1.5. Methyl ketone 13. To a stirred solution of methyl-
(R)-3-hydroxy-2-methylpropionate (6.04 mL, 54.5 mmol)
was added 3,4-dimethoxybenzyl-2,2,2-trichloroacetimidate
(20.4 g, 65.4 mmol) in CH2Cl2 (150 mL) at rt followed by
PPTS (1.64 g, 6.54 mmol). After stirring for 1 h the reaction
was quenched by the addition of saturated aqueous NaHCO3
(100 mL) and the phases were separated. The aqueous phase
was extracted with CH2Cl2 (3ꢂ50 mL) and the combined or-
ganic phases were dried (MgSO4) and concentrated in vacuo.
The resulting yellow solid was triturated with ice-cold hex-
ane (3ꢂ100 mL). The hexane fractions were concentrated in
vacuo and purified by flash silica column (20–30% EtOAc/
hexane) to yield the corresponding dimethoxybenzyl ether
(9.94 g, 68%) as a colourless oil; Rf 0.49 (50% EtOAc/
hexane); [a]2D0 ꢀ8.5 (c 1.14, CHCl3); IR (neat) 2950, 2861,
1
3064, 1719, 1648, 1584, 666 cmꢀ1; H NMR (400 MHz,
CDCl3) d 6.69 (1H, dd, 13.5, 10.8 Hz, H16), 6.30 (1H, d,
J¼13.5 Hz, H17), 6.10 (1H, dd, J¼15.3, 10.9 Hz, H15),
5.69 (1H, obsd, H14), 5.68 (1H, s, H10), 4.30 (1H, m, H13),
3.69 (3H, s, OCH3), 2.34 (2H, dd, J¼13.0, 7.3 Hz, H12a),
2.26 (1H, dd, J¼13.0, 5.4 Hz, H12b), 2.17 (3H, s, Me11),
0.87 (9H, s, SiC(CH3)3, 0.02 (3H, s, SiCH3), 0.01 (3H, s,
SiCH3); 13C NMR (100 MHz, CDCl3) d 166.9, 155.7,
137.0, 136.6, 126.9, 118.3, 108.8, 71.2, 50.8, 49.6, 25.7,
25.3, 19.6, ꢀ4.5, ꢀ5.0; HRMS (ES+) Calculated for
C17H29BrSiO3Na [M+Na+] 411.0967, found 411.0958.
6.1.3. Allylic alcohol 19. To a stirred solution of ester 18a
(2.69 g, 9.82 mmol) in CH2Cl2 (25 mL) at ꢀ78 ꢁC was
added DIBAL-H (1 M in CH2Cl2, 18.7 mL, 18.7 mmol).
The resulting solution was stirred at ꢀ78 ꢁC for 30 min
and then added via cannula to a mixture of CH2Cl2
(50 mL) and saturated aqueous sodium potassium tartrate
(50 mL). The mixture was stirred at rt for 1 h and the phases
were then separated. The aqueous phase was extracted with
CH2Cl2 (3ꢂ50 mL) and the organic layers were combined,
washed with brine (100 mL), dried (MgSO4) and concen-
trated in vacuo. Purification by flash column chromato-
graphy (20% EtOAc/hexane) yielded alcohol 19 (1.97 g,
88%); Rf 0.21 (20% EtOAc/hexane); [a]2D0 +0.3 (c 3.0,
;
1737, 1593, 1516, 1463 cmꢀ1 1H NMR (400 MHz,
CDCl3) d 6.85–6.79 (3H, m, ArH), 4.43 (2H, s, OCH2Ar),
3.86 (3H, s, ArOCH3), 3.84 (3H, s, ArOCH3), 3.66 (3H, s,
OCH3), 3.62 (1H, dd, J¼9.3, 7.3 Hz, H1a), 3.44 (1H, dd,
J¼9.2, 5.9 Hz, H1b), 2.80–2.71 (1H, m, H2), 1.15 (3H, d,
J¼7.0 Hz, Me2), 1.07 (3H, s, H4); 13C NMR (100 MHz,
CDCl3) d 175.2, 148.9, 148.5, 130.6, 120.0, 110.9, 110.8,
72.9, 71.6, 55.8, 55.7, 51.6, 40.1, 13.9; HRMS (ES+) Calcu-
lated for C14H24NO5 [M+NH+4] 286.1654, found 286.1649.
N,O-Dimethylhydroxylamine
hydrochloride
(5.42 g,
55.6 mmol) was placed in a flask and dried by stirring under
vacuum (1 mmHg) for 1 h. The flask was flushed with argon
and a solution of dimethoxybenzyl ether (9.94 g, 37.0 mmol)
in THF (150 mL) was added via cannula. The resulting slurry
was cooled to ꢀ20 ꢁC and isopropylmagnesium chloride
(2.0 M in THF, 55.6 mL, 111 mmol) was added dropwise,
maintaining the temperature at ꢀ20 ꢁC. After stirring for
1.5 h the reaction was quenched by the addition of saturated
aqueous NH4Cl (100 mL) and the phaseswere separated. The
aqueous phase was extracted with CH2Cl2 (2ꢂ50 mL) and
the combined organic phases were dried (MgSO4) and evap-
orated in vacuo. Purification by flash column chromato-
graphy (50% EtOAc/hexane) yielded the corresponding
Weinreb amide (9.17 g, 83%) as a colourless oil; Rf 0.21
(50% EtOAc/hexane); [a]2D0 ꢀ7.9 (c 1.04, CHCl3); IR
(neat) 3820, 1650, 1593, 1514, 1462, 1419 cmꢀ1; 1H NMR
(400 MHz, CDCl3) d 6.87–6.80 (3H, m, ArH), 4.45
(2H, AB spin system, J¼12.0 Hz, OCH2Ar), 3.87 (3H, s,
ArOCH3), 3.86 (3H, s, ArOCH3), 3.71–3.67 (1H, m, H1a),
3.69 (3H, s, NOCH3), 3.40 (1H, dd, J¼8.8, 5.8 Hz, H1b),
3.30–3.23 (1H, m, H2), 3.20 (3H, s, NCH3), 1.11 (3H, d,
J¼7.0 Hz, Me2); 13C NMR (100 MHz, CDCl3) d 175.9,
148.9, 148.4, 130.9, 120.0, 110.9, 110.8, 73.0, 72.3, 65.1,
61.4, 55.8, 55.7, 35.8, 14.1; HRMS (ES+) Calculated for
C15H24O5Na [M+H+] 298.1654, found 298.1651.
1
CHCl3); IR (neat) 3331, 3063, 1667, 1584, 666 cmꢀ1; H
NMR (400 MHz, CDCl3) d 6.68 (1H, dd, 13.4, 10.9 Hz,
H16), 6.27 (1H, d, J¼13.5 Hz, H17), 6.07 (1H, dd, J¼15.2,
10.9 Hz, H15), 5.70 (1H, dd, J¼15.2, 6.0 Hz, H14), 5.42
(1H, dd, J¼6.8, 6.0 Hz, H10), 4.24 (1H, m, H13), 4.12 (2H,
m, CH2OH), 2.24 (1H, dd, J¼13.3, 7.1 Hz, H12a), 2.15
(1H, dd, J¼13.3, 5.8 Hz, H12b), 1.68 (3H, s, Me11), 1.24
(1H, m, OH), 0.88 (9H, s, SiC(CH3)3, 0.02 (3H, s, SiCH3),
0.00 (3H, s, SiCH3); 13C NMR (100 MHz, CDCl3) d
137.8, 136.9, 135.6, 127.0, 126.4, 108.2, 71.5, 59.3, 48.4,
29.7, 25.8, 25.3, 17.1, ꢀ4.5, ꢀ4.9; HRMS (ES+) Calculated
for C16H29BrSiO2Na [M+Na+] 383.1018, found 383.1013.
6.1.4. Aldehyde 14. To a stirred solution of alcohol 18
(1.64 g, 4.54 mmol) in Et2O (5 mL) at rt was added MnO2
(3.95 g, 45.4 mmol). After 30 min, TLC analysis showed
some reaction proceeding and further MnO2 (3.95 g,
45.4 mmol) was added. The suspension was stirred for 1 h
before addition of more MnO2 (3.95 g, 45.4 mmol). After
a further 1 h, the mixture was then filtered through a short
plug of Celite and washed thoroughly with Et2O. Flash
column chromatography (20% EtOAc/hexane) afforded the
desired aldehyde 14 (1.40 g, 86%); Rf 0.51 (20% EtOAc/
hexane); [a]2D0 +3.81 (c 1.1, CHCl3); IR (neat) 1674,
666 cmꢀ1 1H NMR (500 MHz, CDCl3) d 9.97 (1H, d,
;
J¼7.9 Hz, H9), 6.68 (1H, dd, J¼13.4, 10.9 Hz, H16), 6.31
(1H, d, J¼13.4 Hz, H17), 6.10 (1H, dd, J¼15.2, 10.9 Hz,
H15), 5.87 (1H, d, J¼7.9 Hz, H10), 5.68 (1H, dd, J¼15.2,
To a stirred solution of Weinreb amide19 (5.94 g, 20.0 mmol)
in THF (80 mL) at 0 ꢁC was added methylmagnesium iodide
(3.0 M in Et2O, 16.6 mL, 49.9 mmol). The resulting solution

I. Paterson et al. / Tetrahedron 63 (2007) 5806–5819
5813
was stirred for 1.5 h and quenched by the addition of
saturated aqueous NH4Cl (100 mL). The phases were sepa-
rated and the aqueous phase was extracted with EtOAc
(2ꢂ80 mL). The combined organic phases were dried
(MgSO4), concentrated in vacuo and purified by flash
column chromatography (25–30% EtOAc/hexane) to yield
ketone 13 as a colourless oil (3.85 g, 77%); Rf 0.30 (50%
EtOAc/hexane); [a]D20 ꢀ7.7 (c 1.04, CHCl3); IR (neat)
aqueous NaHCO3 (100 mL) and stirred for 10 min. The
phases were separated and the aqueous phase was extracted
with Et2O (3ꢂ60 mL). The combined organic layers were
dried (MgSO4), washed with brine (100 mL), concentrated
in vacuo and purified by flash column chromatography
(20–25% EtOAc/hexane) to yield hydroxy ester 22 as a
colourless oil (4.81 g, 80%); Rf 0.29 (30% EtOAc/hexane);
[a]2D0 ꢀ16.9 (c 1.0, CHCl3); IR (neat) 3498, 2934, 2856,
1
1712, 1515, 1464, 1262 cmꢀ1
;
1H NMR (400 MHz,
1732 cmꢀ1; H NMR (400 MHz, CDCl3) d 6.88–6.81 (3H,
CDCl3) d 6.84–6.80 (3H, m, ArH), 4.46 (2H, s, OCH2Ar),
3.89 (3H, s, ArOCH3), 3.87 (3H, s, ArOCH3), 3.66 (1H,
dd, J¼9.0, 8.0 Hz, H1a), 3.49 (1H, dd, J¼9.0, 5.3 Hz, H1b),
2.92–2.83 (1H, m, H2), 1.09 (3H, s, Me2), 1.07 (3H, s,
H4); 13C NMR (100 MHz, CDCl3) d 211.0, 149.0, 148.6,
130.6, 120.1, 111.0, 110.9, 73.1, 71.8, 55.9, 55.8, 47.2,
29.0, 13.4; HRMS (ES+) Calculated for C14H20O4Na
[M+Na+] 275.1259, found 275.1259.
m, ArH), 6.66 (1H, dd, J¼13.6, 10.8 Hz, H16), 6.26 (1H,
d, J¼13.6 Hz, H17), 6.03 (1H, dd, J¼15.5, 11.0 Hz, H15),
5.78–5.71 (1H, m, H9), 5.66 (1H, dd, J¼15.3, 5.9 Hz,
H14), 5.15 (1H, d, J¼9.2 Hz, H10), 4.44 (2H, s, OCH2Ar),
4.25 (1H, dd, J¼12.7, 6.3 Hz H13), 3.88 (3H, s, ArOCH3),
3.88 (3H, s, ArOCH3), 3.54–3.44 (3H, m, H5a, H5b and
H7), 3.35 (1H, d, J¼4.2 Hz, OH), 2.29 (2H, dq, J¼8.0,
3.1 Hz, OC(O)CH2CH3), 2.23 (1H, dd, J¼13.2, 6.8 Hz,
H12a), 2.12 (1H, dd, J¼12.9, 6.3 Hz, H12b), 1.87–1.78 (2H,
m, H6 and H8a), 1.75 (3H, s, Me11), 1.53–1.46 (1H, m,
H8b), 1.20 (3H, t, J¼7.5 Hz, OC(O)CH2CH3), 0.92 (3H, d,
J¼7.0 Hz, Me6), 0.88 (9H, s, SiC(CH3)3), 0.02 (3H, s,
SiCH3), 0.01 (3H, s, SiCH3); 13C NMR (100 MHz, CDCl3)
d 174.4, 149.0, 148.6, 137.8, 136.9, 136.0, 130.7, 127.1,
126.4, 120.2, 111.0, 111.0, 108.1, 73.8, 73.2, 71.3, 70.7,
68.4, 55.9, 55.8, 48.4, 40.4, 38.8, 27.8, 25.8, 18.2, 17.5,
13.9, 9.2, ꢀ4.4, ꢀ4.9; HRMS (ES+) Calculated for
C33H57O7Si79BrN [M+NH4+] 686.3082, found 686.3105.
6.1.6. Aldol adduct 21. To a stirred solution of (+)-Ipc2BCl
(12.9 g, 40.2 mmol) [dried by stirring under vacuum
(1 mmHg) at rt for 1.5 h] in Et2O (25 mL) at 0 ꢁC was added
triethylamine (7.32 mL, 52.5 mmol), followed by ketone 13
(7.76 g, 30.9 mmol) in Et2O (30 mL) via cannula. The reac-
tion mixture was stirred for 1 h, cooled to ꢀ78 ꢁC and a
solution of aldehyde 14 (3.70 g, 10.3 mmol) in Et2O
(30 mL) then added via cannula. The reaction mixture was
stirred at ꢀ78 ꢁC for 1 h and at ꢀ27 ꢁC for 16 h. The reac-
tion then was quenched by the addition of pH 7 buffer
(100 mL) and stirred at 0 ꢁC for 1 h. The phases were sepa-
rated and the aqueous phase was extracted with Et2O
(3ꢂ60 mL). The combined organic layers were washed
with brine (100 mL) and stirred over silica gel for 30 min.
The resulting slurry was filtered, concentrated in vacuo,
and purified by flash column chromatography (20–50%
EtOAc/hexane) to yield aldol adduct 21 as a pale yellow
oil (5.54 g, 88%); Rf 0.26 (30% EtOAc/hexane); [a]D20
ꢀ5.84 (c 1.25, CHCl3); IR (neat) 3464, 2929, 2856,
The 1,3-anti stereochemistry was proved using Rychnov-
sky’s method for the assignment of diol stereochemistry.23
6.1.8. TES ether 23. To a stirred solution of alcohol 22
(950 mg, 1.42 mmol) in CH2Cl2 (20 mL) at ꢀ78 ꢁC was
added 2,6-lutidine (0.66 mL, 5.67 mmol). The reaction mix-
ture was stirred at ꢀ78 ꢁC for 10 min before triethylsilyl
trifluoromethanesulfonate (0.96 mL, 4.26 mmol) was added.
The reaction mixture was stirred at ꢀ78 ꢁC for 30 min and
then quenched by the addition of saturated aqueous NH4Cl
(20 mL). The phases were separated and the aqueous phase
was extracted with CH2Cl2 (3ꢂ50 mL). The combined
organic phases were dried (MgSO4), concentrated in vacuo
and purified by flash column chromatography (15–20%
EtOAc/hexane) to yield TES ether 23 (1.00 g, 90%); Rf
0.55 (30% EtOAc/hexane); [a]2D0 ꢀ3.7 (c 1.0, CHCl3); IR
1
1708 cmꢀ1; H NMR (400 MHz, CDCl3) d 6.85–6.81 (3H,
m, ArH), 6.68 (1H, dd, J¼13.6, 11.0 Hz, H16), 6.27 (1H,
d, J¼13.6 Hz, H17), 6.06 (1H, dd, J¼15.2, 11.0 Hz, H15),
5.69 (1H, dd, J¼15.2, 5.8 Hz, H14), 5.20 (1H, d, J¼8.4 Hz,
H10), 4.85–4.77 (1H, m, H9), 4.42 (2H, s, OCH2Ar), 4.25
(1H, dd, J¼12.4, 5.9 Hz, H13), 3.88 (3H, s, ArOCH3), 3.87
(3H, s, ArOCH3), 3.60 (1H, dd, J¼8.7, 8.4 Hz, H5a), 3.46
(1H, dd, J¼8.9, 5.1 Hz, H5b), 2.97 (1H, d, J¼3.3 Hz, OH),
2.91–2.84 (1H, m, H6), 2.72–2.66 (1H, m, H8a), 2.66–2.62
(1H, m, H8b), 2.22 (1H, dd, J¼13.6, 7.1 Hz, H12a), 2.12
(1H, dd, J¼13.4, 5.8 Hz, H12b), 1.68 (3H, s, Me11), 1.07
(3H, d, J¼7.0 Hz, Me6), 0.88 (9H, s, SiC(CH3)3), 0.02
(3H, s, SiCH3), 0.00 (3H, s, SiCH3); 13C NMR (100 MHz,
CDCl3) d 214.0, 149.1, 148.7, 137.8, 136.9, 134.9,
130.4, 129.1, 127.9, 126.4, 111.0, 110.9, 108.2, 73.2,
71.7, 71.4, 64.6, 55.9, 55.8, 48.7, 48.2, 46.9, 25.8, 18.2,
17.4, 13.2, ꢀ4.4, ꢀ4.9; HRMS (ES+) Calculated for
C30H47O6Si79BrNa [M+Na+] 633.2223, found 633.2217.
(neat) 2955, 2877, 1734 cmꢀ1
;
1H NMR (400 MHz,
CDCl3) d 6.89–6.81 (3H, m, ArH), 6.64 (1H, dd, J¼13.6,
11.2 Hz, H16), 6.24 (1H, d, J¼13.8 Hz, H17), 6.02 (1H, dd,
J¼15.3, 10.8 Hz, H15), 5.64 (1H, dd, J¼15.5, 5.9 Hz, H14),
5.52–5.45 (1H, m, H9), 5.02 (1H, d, J¼9.1 Hz, H10), 4.43
(2H, AB spin system, J¼12.4 Hz, OCH2Ar), 4.23 (1H, dd,
J¼12.5, 6.1 Hz, H13), 3.93–3.85 (1H, obsd, H7), 3.88 (3H,
s, ArOCH3), 3.88 (3H, s, ArOCH3), 3.35 (1H, dd, J¼9.2,
7.3 Hz, H5a), 3.26 (1H, dd, J¼9.2, 6.6 Hz, H5b), 2.26–2.18
(1H, obsd, H12a), 2.22 (2H, q, J¼7.1 Hz, OC(O)CH2CH3),
2.08 (1H, dd, J¼12.9, 6.6 Hz, H12b), 2.03–1.98 (1H, m,
H6), 1.76 (3H, s, Me11), 1.69–1.61 (1H, m, H8a), 1.47–1.38
(1H, m, H8b), 1.08 (3H, t, J¼7.7 Hz, OC(O)CH2CH3),
0.95 (9H, t, J¼8.2 Hz, Si(CH2CH3)3), 0.89 (3H, d,
J¼7.1 Hz, Me6), 0.87 (9H, s, SiC(CH3)3), 0.58 (6H, q,
J¼7.8 Hz, Si(CH2CH3)3), 0.02 (3H, s, SiCH3), 0.01 (3H, s,
SiCH3); 13C NMR (100 MHz, CDCl3) d 173.6, 149.0,
148.5, 137.9, 137.0, 135.2, 131.3, 127.6, 126.3, 120.0,
110.9, 110.8, 108.0, 72.9, 72.5, 71.1, 69.4, 68.9, 55.9,
6.1.7. Hydroxy ester 22. To a stirred solution of propion-
aldehyde (3.90 mL, 54.1 mmol) in THF (45 mL) at ꢀ10 ꢁC
was added freshly prepared samarium diiodide (45.1 mL,
0.1 M in THF, 4.51 mmol). A solution of aldol adduct 21
(5.54 g, 9.01 mmol) in THF (45 mL) was added via cannula
and the resulting yellow solution was stirred at ꢀ10 ꢁC for
1 h. The reaction was quenched by the addition of saturated

5814
I. Paterson et al. / Tetrahedron 63 (2007) 5806–5819
55.8, 48.7, 39.7, 37.7, 27.8, 25.8, 18.2, 17.2, 11.6, 9.1, 6.9,
5.1, ꢀ4.5, ꢀ4.9; HRMS (ES+) Calculated for C39H67O7
Si279BrNa [M+Na+] 805.3506, found 805.3510.
m, H8a), 1.39–1.30 (1H, m, H8b), 0.97 (9H, t, J¼7.8 Hz,
Si(CH2CH3)3), 0.91 (3H, d, J¼7.1 Hz, Me6), 0.88 (9H, s,
Si(CH3)3), 0.62 (6H, q, J¼7.7 Hz, Si(CH2CH3)3), 0.03 (3H,
s, SiCH3), 0.02 (3H, s, SiCH3); 13C NMR (125 MHz,
CDCl3) d 149.0, 148.4, 137.9, 136.9, 134.7, 131.4, 129.9,
126.5, 119.9, 110.8, 110.8, 108.2, 73.4, 72.8, 72.7, 71.5,
69.6, 55.9, 55.8, 55.4, 48.7, 40.0, 39.0, 25.8, 18.2, 17.2,
12.0, 7.0, 5.2, ꢀ4.4, ꢀ4.9; HRMS (ES+) Calculated for
C37H65O6Si279BrNa [M+Na+] 763.3401, found 763.3401.
6.1.9. Alcohol 24. To a stirred solution of ester 23 (1.00 g,
1.28 mmol) in CH2Cl2 (15 mL) at ꢀ78 ꢁC was added
DIBAL-H (1 M in CH2Cl2, 6.38 mL, 6.38 mmol). The
resulting solution was stirred at ꢀ78 ꢁC for 30 min and
then added via cannula to a mixture of CH2Cl2 (20 mL)
and saturated aqueous sodium potassium tartrate (20 mL).
The mixture was stirred at rt for 1 h and the phases were
then separated. The aqueous phase was extracted with
CH2Cl2 (3ꢂ15 mL) and the organic phases were combined,
washed with brine (50 mL), dried (MgSO4) and concen-
trated in vacuo. Purification by flash column chromato-
graphy (20% EtOAc/hexane) yielded alcohol 24 as
a colourless oil (0.80 g, 87%); Rf 0.41 (30% EtOAc/hexane);
[a]2D0 ꢀ0.96 (c 1.05, CHCl3); IR (neat) 3443, 2953,
6.1.11. Alcohol 26. To a refluxing (60 ꢁC), stirred solution of
DMB ether 25 (200 mg, 0.27 mmol) in CH2Cl2/pH 7 buffer
(25 mL/2.5 mL) was added DDQ (73 mg, 0.32 mmol). After
10 min, the reaction was quenched by the addition of satu-
rated aqueous NaHCO3 (15 mL) and the phases were sepa-
rated. The aqueous phase was extracted with CH2Cl2
(3ꢂ10 mL) and the organic phases were combined, dried
(MgSO4) and purified by flash column chromatography
(15–20% EtOAc/hexane) to yield alcohol 26 as a colourless
oil (123 mg, 77%) and unreacted starting material 25
(45 mg, 22%); Rf 0.46 (30% EtOAc/hexane); [a]2D0 ꢀ14.5
1
1594 cmꢀ1; H NMR (400 MHz, CDCl3) d 6.91–6.80 (3H,
m, ArH), 6.68 (1H, dd, J¼13.6, 11.2 Hz, H16), 6.26 (1H,
d, J¼13.4 Hz, H17), 6.06 (1H, dd, J¼15.0, 11.0 Hz, H15),
5.70 (1H, dd, J¼15.3, 5.9 Hz, H14), 5.21 (1H, d, J¼8.2 Hz,
H10), 4.64–4.57 (1H, m, H9), 4.43 (2H, AB spin system,
J¼11.8 Hz, OCH2Ar), 4.25 (1H, dd, J¼12.2, 6.1 Hz, H13),
4.01 (1H, dd, J¼10.1, 5.9 Hz, H7), 3.88 (3H, s, ArOCH3),
3.87 (3H, s, ArOCH3), 3.44 (1H, dd, J¼8.9, 5.6 Hz, H5a),
3.30 (1H, dd, J¼8.7, 6.6 Hz, H5b), 2.56 (1H, d, J¼3.0 Hz,
OH), 2.21 (1H, dd, J¼13.1, 7.1 Hz, H12a), 2.14–2.07 (1H,
obsd, H6), 2.11 (1H, dd, J¼12.4, 5.6 Hz, H12b), 1.68
(3H, s, Me11), 1.57–1.51 (2H, m, H8a and H8b), 0.97 (9H,
t, J¼8.0 Hz, Si(CH2CH3)3), 0.93 (3H, d, J¼7.0 Hz, Me6),
0.87 (9H, s, SiC(CH3)3), 0.63 (6H, q, J¼7.8 Hz,
Si(CH2CH3)3), 0.02 (3H, s, SiCH3), 0.00 (3H, s, SiCH3);
13C NMR (100 MHz, CDCl3) d 149.1, 148.5, 138.0, 136.9,
133.4, 131.7, 131.2, 126.3, 120.1, 111.0, 110.9, 108.1,
72.9, 72.4, 71.5, 71.4, 65.4, 55.9, 55.8, 48.4, 39.5, 38.9,
25.8, 18.2, 17.2, 12.8, 6.9, 5.0, ꢀ4.4, ꢀ4.9; HRMS (ES+)
Calculated for C36H63O6Si79BrNa [M+Na+] 749.3244,
found 749.3244.
(c 2.14, CHCl3); IR (neat) 3425, 2954 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 6.67 (1H, dd, J¼13.5, 10.9 Hz, H16),
6.26 (1H, d, J¼13.6 Hz, H17), 6.05 (1H, dd, J¼15.3,
11.0 Hz, H15), 5.69 (1H, dd, J¼15.3, 6.2 Hz, H14), 5.03
(1H, d, J¼9.0 Hz, H10), 4.26 (1H, dd, J¼12.6, 6.4 Hz,
H13), 4.03–3.98 (2H, m, H9 and H7), 3.73–3.67 (1H, m,
H5a), 3.53–3.47 (1H, m, H5b), 3.19 (3H, s, OCH3), 2.48–
2.44 (1H, m, H6), 2.30 (1H, dd, J¼13.6, 6.3 Hz, H12a),
2.18 (1H, dd, J¼13.3, 6.6 Hz, H12b), 1.78–1.73 (1H, m,
OH), 1.69 (3H, s, Me11), 1.65–1.61 (1H, m, H8a), 1.53–
1.47 (1H, m, H8b), 0.99 (9H, t, J¼8.0 Hz, Si(CH2CH3)3),
0.96 (3H, d, J¼6.7 Hz, Me6), 0.89 (9H, s, SiC(CH3)3),
0.65 (6H, q, J¼7.9 Hz, Si(CH2CH3)3), 0.04 (3H, s,
SiCH3), 0.02 (3H, s, SiCH3); 13C NMR (125 MHz, CDCl3)
d 137.7, 136.9, 135.4, 129.4, 126.6, 108.3, 73.9, 72.4,
71.7, 65.2, 55.4, 48.7, 40.6, 40.5, 25.8, 18.2, 17.4, 13.1,
6.9, 5.2, ꢀ4.4, ꢀ4.9; HRMS (ES+) Calculated for
C28H5579BrO4Si2Na [M+Na+] 613.2720, found 613.2720.
6.1.10. Methyl ether 25. To a stirred solution of alcohol 24
(2.93 g, 4.02 mmol) in CH2Cl2 (50 mL) at 0 ꢁC was added
Proton SpongeÔ (9.49 g, 44.3 mmol), followed by trimethyl-
oxonium tetrafluoroborate (5.39 g, 36.4 mmol). The result-
ing solution was stirred at rt for 1 h and quenched by the
addition of saturated aqueous NaHCO3 (50 mL). The phases
were separated and the aqueous phase was extracted with
CH2Cl2 (3ꢂ15 mL). The combined organic phases were
washed with citric acid (40 mL, 10% weight solution), dried
(MgSO4), concentrated invacuo and purified by flash column
chromatography (10–15% EtOAc/hexane) to yield 25 as
a colourless oil (2.86 g, 96%); Rf 0.55 (30% EtOAc/hexane);
[a]2D0 ꢀ10.9 (c 1.0, CHCl3); IR (neat) 2953, 1593,
6.1.12. Aldol adduct 12. To a solution of alcohol 26
(416 mg, 0.70 mmol) and pyridine (0.57 mL, 7.03 mmol)
in CH2Cl2 (6 mL) at rt was added Dess–Martin periodinane
(1.19 mg, 2.81 mmol). After stirring at rt for 1 h, hexane
(6 mL) was added and the resultant suspension filtered
through a silica plug (10% EtOAc/hexane) to provide alde-
hyde 15 as a colourless oil (350 mg, 85%), which was
used directly without further purification.
To a solution of ketone 13 (196 mg, 0.78 mmol) in Et2O
(2 mL) at 0 ꢁC was added triethylamine (39.1 mL,
0.28 mmol) and dicyclohexylboron chloride (51.2 mL,
0.23 mmol). The reaction mixture was stirred at 0 ꢁC for
1 h, cooled to ꢀ78 ꢁC and aldehyde 15 (92 mg, 0.16 mmol)
in Et2O (1 mL) was added via cannula. After 1 h at ꢀ78 ꢁC
and 16 h at ꢀ27 ꢁC, the reaction mixture was quenched by
the addition of pH 7 buffer (3 mL) and stirred at 0 ꢁC for
1 h. The phases were separated and the aqueous phase was
extracted with EtOAc (3ꢂ2 mL). The combined organic
layers were washed with brine (4 mL), dried (MgSO4), con-
centrated in vacuo and purified by flash column chromato-
graphy (1% Et3N in 20% EtOAc/hexane) to yield aldol
adduct 12 as a pale yellow oil (120 mg, 89%); Rf 0.25 (30%
1
1516 cmꢀ1; H NMR (500 MHz, CDCl3) d 6.91–6.80 (3H,
m, ArH), 6.66 (1H, dd, J¼13.4, 10.8 Hz, H16), 6.25 (1H, d,
J¼13.4 Hz, H17), 6.05 (1H, dd, J¼15.2, 10.8 Hz, H15), 5.69
(1H, dd, J¼15.3, 6.3 Hz, H14), 5.03 (1H, d, J¼9.2 Hz,
H10), 4.42 (2H, s, OCH2Ar), 4.26 (1H, dd, J¼12.7, 6.3 Hz,
H13), 4.08–4.00 (2H, m, H9 and H7), 3.88 (3H, s, ArOCH3),
3.87 (3H, s, ArOCH3), 3.39 (1H, dd, J¼9.4, 6.1 Hz, H5a),
3.23–3.17 (1H, m, H5b), 3.17 (3H, s, OCH3), 2.28 (1H, dd,
J¼13.2, 6.4 Hz, H12a), 2.15 (1H, dd, J¼13.2, 6.6 Hz, H12b),
2.03–1.95 (1H, m, H6), 1.67 (3H, s, Me11), 1.48–1.39 (1H,

I. Paterson et al. / Tetrahedron 63 (2007) 5806–5819
5815
EtOAc/hexane); [a]2D0 +17.7 (c 2.15, CHCl3); IR (neat) 3497,
2953, 2930, 2857, 1710 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 6.87–6.80 (3H, m, ArH), 6.67 (1H, dd, J¼13.4, 11.2 Hz,
H16), 6.26 (1H, d, J¼13.4 Hz, H17), 6.05 (1H, dd, J¼15.2,
11.0 Hz, H15), 5.69 (1H, dd, J¼15.3, 6.3 Hz, H14), 5.01
(1H, d, J¼9.1 Hz, H10), 4.44–4.40 (1H, obsd, H5) 4.42 (2H,
AB spin system, J¼12.0 Hz, OCH2Ar), 4.26 (1H, dd,
J¼12.7, 6.3 Hz, H13), 4.04–3.92 (2H, m, H7 and H9), 3.88
(3H, s, ArOCH3), 3.87 (3H, s, ArOCH3), 3.64–3.56 (1H, m,
H1a), 3.48–3.42 (1H, m, H1b), 3.18 (3H, s, OCH3), 2.94–
2.83 (1H, m, H2), 2.73 (1H, dd, J¼17.1, 8.0 Hz, H4a), 2.55
(1H, dd, J¼16.7, 4.7 Hz, H4b), 2.30 (1H, dd, J¼12.9,
5.6 Hz, H12a), 2.17 (1H, dd, J¼13.1, 7.1 Hz, H12b), 1.75–
1.60 (3H, obsd, H8a, H8b and H6), 1.67 (3H, s, Me11), 1.07
(3H, d, J¼7.3 Hz, Me2), 0.98 (9H, t, J¼8.0 Hz,
Si(CH2CH3)3), 0.96 (3H, d, J¼7.5 Hz, Me6), 0.89 (9H, s,
SiC(CH3)3), 0.64 (6H, q, J¼7.8 Hz, Si(CH2CH3)3), 0.05
(3H, s, SiCH3), 0.02 (3H, s, SiCH3); 13C NMR (100 MHz,
CDCl3) d 212.6, 149.0, 148.6, 137.6, 136.9, 135.6, 130.6,
129.2, 126.7, 120.1, 111.0, 110.9, 108.3, 73.8, 73.5, 73.1,
71.9, 71.8, 67.3, 55.9, 55.8, 55.3, 48.7, 47.0, 46.9, 41.7,
41.0, 25.8, 18.2, 17.5, 13.3, 10.6, 6.9, 5.2, ꢀ4.4, ꢀ4.9;
HRMS (ES+) Calculated for C42H7379BrO8Si2Na [M+Na+]
863.3925, found 863.3925.
added 2,6-lutidine (66 mL, 0.57 mmol). The reaction mix-
ture was stirred at ꢀ78 ꢁC for 10 min before t-butyldi-
methylsilyl trifluoromethanesulfonate (99 mL, 0.52 mmol)
was added. The reaction mixture was stirred at ꢀ78 ꢁC for
1 h and then quenched by the addition of saturated aqueous
NH4Cl (2 mL). The phases were separated and the aqueous
phase extracted with CH2Cl2 (3ꢂ2 mL). The combined
organic phases were dried (MgSO4), concentrated in vacuo
and purified by flash column chromatography (1% Et3N in
20% EtOAc/hexane) to yield TBS ether 29 (108 mg,
90%); Rf 0.70 (50% EtOAc/hexane); [a]2D0 ꢀ13.1 (c 1.3,
CHCl3); IR (neat) 2929, 2857, 1594 cmꢀ1 1H NMR
;
(500 MHz, C6D6) d 6.92–6.88 (2H, m, ArH), 6.65 (1H, d,
J¼8.2 Hz, ArH), 6.54 (1H, dd, J¼13.3, 10.8 Hz, H16),
5.93 (1H, d, J¼13.3 Hz, H17), 5.87 (1H, dd, J¼15.3,
11.0 Hz, H15), 5.48 (1H, dd, J¼15.5, 6.4 Hz, H14), 5.28
(1H, d, J¼8.6 Hz, H10), 4.46–4.38 (1H, m, H9), 4.41 (2H,
d, J¼2.2 Hz, OCH2Ar), 4.18 (1H, dd, J¼13.1, 6.1 Hz,
H13), 3.95 (1H, dt, J¼10.3, 4.8 Hz, H7), 3.83 (1H, dt,
J¼10.5, 1.6 Hz, H5), 3.74 (1H, dd, J¼8.7, 3.4 Hz, H1a),
3.49 (3H, s, ArOCH3), 3.43 (3H, s, ArOCH3), 3.43–3.40
(1H, m, H1b), 3.25 (3H, s, OCH3), 3.21 (3H, s, OCH3),
2.56–2.48 (1H, m, H2), 2.28 (1H, dd, J¼13.6, 6.9 Hz,
H12a), 2.14 (1H, dd, J¼13.3, 6.1 Hz, H12b), 2.12–2.04 (2H,
m, H8a and H4a), 1.78 (1H, dd, J¼12.7, 10.8 Hz, H8b), 1.70
(3H, s, Me11), 1.51 (1H, ddd, J¼13.7, 10.8, 2.0 Hz, H4b),
1.44–1.38 (1H, m, H6), 1.32 (3H, d, J¼7.0 Hz, Me2), 1.02
(3H, d, J¼6.7 Hz, Me6), 0.99 (9H, s, SiC(CH3)3), 0.98
(9H, s, Si(CH3)3), 0.12 (3H, s, SiCH3), 0.09 (3H, s,
SiCH3), 0.06 (3H, s, SiCH3), 0.03 (3H, s, SiCH3); 13C
NMR (125 MHz, C6D6) d 150.3, 149.7, 138.2, 137.2,
134.6, 131.9, 131.1, 128.6, 126.9, 120.1, 112.1, 112.0,
108.9, 102.1, 73.6, 73.4, 72.0, 71.5, 70.4, 55.7, 55.6, 55.6,
49.0, 46.7, 44.6, 40.5, 39.0, 38.3, 26.2, 26.1, 18.4, 18.3,
17.2, 13.6, 13.4, ꢀ3.8, ꢀ4.1, ꢀ4.5, ꢀ4.7; HRMS (ES+)
Calculated for C43H7579BrO8Si2Na [M+Na+] 877.4082,
found 877.4082.
6.1.13. Methyl acetal 28. To a stirred solution of ketone 12
(120 mg, 0.14 mmol) and trimethyl orthoformate (0.46 mL)
in MeOH (4.6 mL) at rt was added PPTS (3.6 mg,
0.014 mmol). The resulting solution was stirred at rt for
1 h and then quenched by the addition of saturated aqueous
NaHCO3 (5 mL). The phases were separated and the aque-
ous phase was extracted with EtOAc (3ꢂ3 mL). The com-
bined organic layers were washed with brine (8 mL), dried
(MgSO4), concentrated in vacuo and purified by flash
column chromatography (1% Et3N in 40% EtOAc/hexane)
to yield methyl acetal 28 as a pale yellow oil (81 mg,
78%); Rf 0.23 (50% EtOAc/hexane); [a]2D0 ꢀ19.2 (c 1.2,
1
CHCl3); IR (neat) 3450, 2932, 2857, 1594 cmꢀ1; H NMR
(400 MHz, CDCl3) d 6.93–6.81 (3H, m, ArH), 6.67 (1H,
dd, J¼13.4, 11.2 Hz, H16), 6.26 (1H, d, J¼13.2 Hz, H17),
6.06 (1H, dd, J¼15.3, 11.0 Hz, H15), 5.69 (1H, dd,
J¼15.3, 6.1 Hz, H14), 5.09 (1H, d, J¼8.7 Hz, H10), 4.45
(2H, AB spin system, J¼12.0 Hz, OCH2Ar), 4.26 (1H, dd,
J¼12.5, 6.3 Hz, H13), 4.23–4.17 (1H, m, H9), 3.89 (3H, s,
ArOCH3), 3.88 (3H, s, ArOCH3), 3.67–3.61 (1H, m, H5),
3.57 (1H, dd, J¼8.9, 3.3 Hz, H1a), 3.48–3.41 (1H, m, H7),
3.19 (1H, obsd, H1b), 3.15 (3H, s, OCH3), 3.15 (3H, s,
OCH3), 2.33–2.25 (2H, m, H12a and H2), 2.16 (1H, dd,
J¼13.2, 6.1 Hz, H12b), 1.87–1.81 (1H, m, H8a), 1.77 (1H,
dd, J¼12.5, 5.1 Hz, H4a), 1.66 (3H, s, Me11), 1.48–1.40
(1H, m, H4b), 1.34–1.24 (1H, m, H8b) 1.15–1.08 (1H, m,
H6), 1.06 (3H, d, J¼7.1 Hz, Me2), 0.95 (3H, d, J¼6.4 Hz,
Me6), 0.88 (9H, s, SiC(CH3)3), 0.03 (3H, s, SiCH3), 0.02
(3H, s, SiCH3); 13C NMR (100 MHz, CDCl3) d 149.0,
148.5, 137.9, 136.9, 134.7, 131.2, 130.0, 126.5, 120.0,
110.9, 110.9, 110.1, 101.4, 73.2, 73.1, 71.5, 71.1, 70.1,
69.7, 55.9, 55.8, 55.7, 48.6, 46.6, 43.7, 39.7, 37.7, 37.5,
25.8, 18.2, 17.0, 13.3, 12.6, ꢀ4.4, ꢀ4.9; HRMS (ES+) Cal-
culated for C37H6179BrO8SiNa [M+Na+] 763.3217, found
763.3243.
6.1.15. Alcohol 30. To a solution of DMB ether 30 (300 mg,
0.35 mmol) in CH2Cl2/pH 9 buffer (40 mL/10 mL) at 0 ꢁC
was added DDQ (399 mg, 1.76 mmol). After stirring at this
temperature for 10 min, the reaction was quenched by the
addition of saturated aqueous NaHCO3 (40 mL) and the
phases were separated. The aqueous phase was extracted
with CH2Cl2 (3ꢂ40 mL) and the organic phases were com-
bined, dried (Na2SO4) and purified by flash column chroma-
tography (1% Et3N in 15% EtOAc/hexane) to yield alcohol
30 as a colourless oil (130 mg, 53%); Rf 0.56 (30% EtOAc/
hexane); [a]2D0 ꢀ14.4 (c 0.50, MeOH); IR (neat) 3489,
1
2930, 1516, 1464, 1257 cmꢀ1; H NMR (500 MHz, C6D6)
d 6.53 (1H, dd, J¼13.3, 11.8 Hz, H16), 5.92 (1H, d,
J¼13.7 Hz, H17), 5.87 (1H, dd, J¼15.4, 11.1 Hz, H15), 5.47
(1H, dd, J¼13.5, 6.3 Hz, H14), 5.27 (1H, d, J¼9.3 Hz,
H10), 4.40 (1H, m, H9), 4.18 (1H, m, H13), 3.92–3.89 (1H,
obsd, H7), 3.81 (1H, t, J¼10.5 Hz, H5), 3.74–3.68 (1H, m,
H1a), 3.41–3.37 (1H, m, H1b), 3.22 (3H, s, OCH3), 3.19
(3H, s, OCH3), 2.31–2.22 (2H, m, H2 and H12a), 2.15 (1H,
dd, J¼13.4, 6.3 Hz, H4a), 2.10–2.00 (2H, m, H12b and H8a),
1.71 (3H, s, Me11), 1.68–1.62 (1H, obsd, H8b), 1.52–1.45
(1H, m, H4b), 1.42–1.35 (1H, m, H6), 1.02 (3H, obsd, Me2),
1.01 (9H, s, SiC(CH3)3), 1.00 (9H, s, Si(CH3)3), 0.94 (3H,
obsd, Me6), 0.13 (3H, s, SiCH3), 0.09 (3H, s, SiCH3), 0.07
(3H, s, SiCH3), 0.04 (3H, s, SiCH3); 13C NMR (125 MHz,
6.1.14. TBS ether 29. To a stirred solution of methyl acetal
28 (108 mg, 0.14 mmol) in CH2Cl2 (2 mL) at ꢀ78 ꢁC was

5816
I. Paterson et al. / Tetrahedron 63 (2007) 5806–5819
C6H6) d 138.1, 137.1, 134.7, 131.0, 127.0, 108.9, 102.8, 73.6,
72.0, 71.3, 70.5, 64.6, 55.7, 49.0, 47.1, 44.4, 40.4, 39.1, 38.6,
26.1, 26.1, 18.4, 18.3, 17.2, 13.3, 12.5, ꢀ3.8, ꢀ4.1, ꢀ4.6,
ꢀ4.7; HRMS (ES+) Calculated for C34H6579BrO6Si2Na
[M+Na+] 727.3401, found 727.3395.
31 (25 mg, 0.041 mmol) in toluene (4 mL) at rt. After stir-
ring for 40 min, the solution was diluted with toluene
(15 mL) and added to a stirred solution of DMAP (25 mg,
0.21 mmol) in toluene (25 mL) at 80 ꢁC over 4 h via syringe
pump. The reaction mixture was allowed to cool to rt and
quenched by the addition of saturated aqueous NaHCO3
(30 mL). The phases were separated and the aqueous phase
extracted with CH2Cl2 (3ꢂ20 mL). The combined organic
layers were washed with brine (50 mL), dried (Na2SO4)
and concentrated in vacuo. The crude product was purified
by flash column chromatography (1% Et3N in 5% EtOAc/
hexane) to yield macrolactone 33 as a colourless oil
(16 mg, 64%); Rf 0.60 (20% EtOAc/hexane); [a]2D0 +12.4
6.1.16. seco-Acid 31. To a stirred solution of alcohol 30
(30 mg, 43 mmol) in CH2Cl2 (1.5 mL) at rt was added
NaHCO3 (29 mg, 0.34 mmol) followed by Dess–Martin
periodinane (72 mg, 0.17 mmol). The resulting solution
was stirred at rt for 1 h and then quenched by the addition
of hexane (2 mL). The resulting suspension was filtered
through a silica plug (1% Et3N in 10% EtOAc/hexane) to
provide the product aldehyde, which was used directly. To
a stirred solution of aldehyde (29 mg, 41 mmol) in t-BuOH
(4.0 mL) at rt was added 2-methyl-2-butene (0.5 mL). The
resulting solution was cooled to 0 ꢁC and a solution of
sodium chlorite (60 mg, 0.51 mmol) and sodium dihydrogen
phosphate (84 mg, 0.45 mmol) in H2O (1.3 mL) was added.
The resulting solution was stirred at this temperature for
10 min and then allowed to warm to rt. The solution was
stirred at rt for 1.5 h, recooled to 0 ꢁC and quenched by
the addition of pH 7 buffer (3 mL). The phases were sepa-
rated and the aqueous phase was extracted with CH2Cl2
(3ꢂ2 mL). The combined organic layers were washed with
brine (4 mL), dried (Na2SO4) and concentrated in vacuo to
yield crude acid 32, which was used without further purifica-
tion. To a stirred solution of acid 32 (30 mg, 41 mmol) in
THF (3 mL) at rt was added TBAF (1 M in THF, 46 mL,
46 mmol). The resulting solution was stirred at rt for 1 h,
recooled to 0 ꢁC and further TBAF was added (1 M in
THF, 46 mL, 46 mmol). After stirring at rt for 4 h, the reac-
tion was quenched by the addition of saturated aqueous
NH4Cl (4 mL). The phases were separated and the aqueous
phase was extracted with CH2Cl2 (3ꢂ2 mL). The combined
organic layers were washed with brine (4 mL), dried
(Na2SO4), concentrated in vacuo and purified by flash col-
umn chromatography (2.5% MeOH/CH2Cl2) to yield seco-
acid 31 as a pale yellow oil (25 mg, 94% based on 30); Rf
0.27 (50% EtOAc/hexane); [a]2D0 ꢀ15.6 (c 0.10, MeOH);
(c 1.1, MeOH); IR (neat) 2928, 1732, 1582, 1187 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d 6.68 (1H, dd, J¼13.5,
10.9 Hz, H16), 6.35 (1H, dd, J¼13.7 Hz, H17), 6.16 (1H,
dd, J¼15.2, 10.8 Hz, H15), 5.71 (1H, dd, J¼15.2, 10.8 Hz,
H14), 5.66 (1H, m, H13), 5.20 (1H, d, J¼9.4 Hz, H10), 3.90
(1H, m, H9), 3.52 (1H, dt, J¼10.4, 4.8 Hz, H7), 3.30 (1H,
m, H5), 3.24 (3H, s, OCH3), 3.17 (3H, s, OCH3), 2.57
(1H, q, J¼7.5 Hz, H2), 2.41 (1H, t, J¼13.1 Hz, H12a), 2.28
(1H, dd, J¼13.3, 2.9 Hz, H12b), 2.11 (2H, m, H8a and H4a),
1.76 (1H, m, H8b), 1.73 (3H, s, Me11), 1.28 (2H, m, H6
and H4b), 1.16 (3H, d, J¼7.2 Hz, Me2), 0.92 (3H, d, J¼
6.5 Hz, Me6), 0.87 (9H, s, Si(CH3)3), 0.05 (3H, s, SiCH3),
0.04 (3H, s, SiCH3); 13C NMR (125 MHz, C6H6) d 173.5,
136.1, 132.4, 132.2, 132.1, 129.1, 109.6, 100.8, 75.2, 74.2,
70.1, 69.7, 54.5, 49.3, 48.5, 45.1, 43.9, 43.4, 39.7, 25.5,
17.6, 15.7, 13.2, 12.7, ꢀ4.4, ꢀ5.1; HRMS (ES+) Calculated
for C28H4779BrO6SiK [M+K+] 625.1962, found 625.1957.
6.1.18. Alcohol 34. To a stirred solution of TBS ether 33
(10.5 mg, 17.9 mmol) in THF (1.8 mL) at 0 ꢁC was added
TBAF (1 M in THF, 179 mL, 179 mmol). The resulting solu-
tion was allowed to warm to rt, stirred for 2 h and then
quenched by the addition of saturated aqueous NH4Cl
(3 mL). The phases were separated and the aqueous phase
was extracted with CH2Cl2 (3ꢂ2 mL). The combined
organic layers were washed with brine (4 mL), dried
(Na2SO4), concentrated in vacuo and purified by flash col-
umn chromatography (1% Et3N in 0–100% EtOAc/hexane)
to yield alcohol 34 as a pale yellow oil (7 mg, 83%); Rf 0.35
(50% EtOAc/hexane); [a]D20 +13.1 (c 0.43, MeOH); IR (neat)
IR (neat) 2929, 2857, 1714, 1252 cmꢀ1
;
1H NMR
(500 MHz, C6D6) d 6.55 (1H, dd, J¼13.5, 11.0 Hz, H16),
5.95 (1H, d, J¼13.5 Hz, H17), 5.90 (1H, dd, J¼15.2,
11.0 Hz, H15), 5.39 (1H, dd, J¼15.3, 5.8 Hz, H14), 5.20
(1H, d, J¼8.9 Hz, H10), 4.32–4.27 (1H, m, H9), 3.99 (1H,
dd, J¼12.5, 6.2 Hz, H13), 3.88 (1H, dt, J¼10.3, 4.9 Hz,
H5), 3.79 (1H, dt, J¼10.4, 1.3 Hz, H7), 3.37 (3H, s,
OCH3), 3.13 (3H, s OCH3), 3.09–3.03 (1H, m, H2), 2.50
(1H, dd, J¼13.0, 5.0 Hz, H4a), 2.44 (1H, br s, OH), 2.13–
2.03 (2H, m, H12a and H12b), 2.03–1.95 (1H, m, H8a), 1.77
(1H, dd, J¼12.9, 11.1 Hz, H4b), 1.60 (3H, s, Me11), 1.44–
1.35 (1H, m, H4b), 1.35–1.28 (1H, m, H6), 1.25 (3H, d,
J¼7.2 Hz, Me2), 1.00 (9H, s, Si(CH3)3), 0.95 (3H, d,
J¼6.5 Hz, Me6), 0.14 (3H, s, SiCH3), 0.09 (3H, s, SiCH3);
13C NMR (125 MHz, C6H6) d 175.9, 137.4, 137.2, 135.3,
130.6, 127.2, 109.0, 101.5, 73.4, 71.4, 71.0, 69.8,
55.6, 47.8, 47.8, 45.4, 43.9, 40.0, 39.9, 26.1, 18.3, 16.8,
13.3, 12.9, ꢀ3.8, ꢀ4.6; HRMS (ES+) Calculated for
C28H4979BrO7SiNa [M+Na+] 627.2329, found 626.2347.
1
3430, 2920, 1730, 1180 cmꢀ1; H NMR (500 MHz, C6D6)
d 6.41 (1H, dd, J¼13.2, 10.8 Hz, H16), 5.85 (1H, dd,
J¼13.6 Hz, H17), 5.85 (1H, dd, J¼15.2, 10.5 Hz, H15),
5.72 (1H, m, H13), 5.39 (1H, d, J¼9.4 Hz, H10), 5.35 (1H,
dd, J¼15.4, 6.5 Hz, H14), 3.91 (1H, dt, J¼9.7, 2.0 Hz, H9),
3.44 (1H, br s, H5), 3.29 (3H, s, OCH3), 3.26 (1H, m, H7),
3.20 (3H, s, OCH3), 2.61 (1H, q, J¼7.3 Hz, H2), 2.28 (2H,
m, H12a and H8a), 2.10 (1H, dd, J¼12.5, 5.0 Hz, H4a), 2.00
(1H, dd, J¼13.1, 2.6 Hz, H12b), 1.88 (1H, dt, J¼13.9,
10.0 Hz, H8b), 1.66 (3H, s, Me11), 1.21 (1H, m, H6), 1.17
(3H, d, J¼7.3 Hz, Me2), 0.95 (1H, m, H4b), 0.88 (3H, d,
J¼6.6 Hz, Me6); 13C NMR (125 MHz, C6H6) d 173.3,
136.3, 133.3, 132.8, 131.4, 128.7, 109.7, 100.9, 75.3, 74.5,
70.0, 68.9, 54.2, 49.6, 49.1, 45.3, 44.1, 43.6, 40.3, 15.7,
12.9, 12.7; HRMS (ES+) Calculated for C22H3379BrO6Na
[M+Na+] 495.1358, found 495.1358.
6.1.17. Macrolactone 33. Triethylamine (35 mL,
0.25 mmol) and 2,4,6-trichlorobenzoylchloride (32 mL,
0.21 mmol) were added to a stirred solution of seco-acid
6.1.19. Dolastatin 19 aglycon, 27. To a stirred solution of
methyl acetal 34 (9 mg, 19.0 mmol) in MeCN/H2O (1 mL/
200 mL) at rt was added PPTS (approx. 1 mg, catalytic).

I. Paterson et al. / Tetrahedron 63 (2007) 5806–5819
5817
Table 1. Comparison of 1H NMR data for synthetic and natural dolastatin 19
Table 2. Comparison of 13C NMR data for synthetic and natural dola-
statin 19
Position Synthetic dolastatin 19 Natural dolastatin 19
(CD3CN, 500 MHz)
Ddsyn–nat
(+/ꢀ ppm)
—
—
—
(CD3CN, 500 MHz)
Position Synthetic dolastatin 19 Natural dolastatin 19 Ddsyn–nat
(CD3CN, 100 MHz)
(CD3CN, 100 MHz) (+/ꢀ ppm)
1
—
2.49 q (7.1)
—
—
2.49 q (7.5)
—
2
3
1
2
3
4
5
6
7
8
177.04
48.62
98.24
40.33
80.17
43.57
73.62
40.21
76.75
54.75
133.55
133.38
46.89
71.72
133.31
129.33
137.62
110.90
12.86
13.44
16.36
177.03a
48.62
98.24
40.33
80.17
+0.01
—
—
—
—
3-OH
4a
4b
5
4.47 d (2.6)
2.17 dd (12.2, 5.0)
1.24 m
3.51 m
1.18 m
4.47 d (2.0)
2.18 m
1.23 m
3.51 m
1.18 m
—
ꢀ0.01
+0.01
—
43.58
73.62
40.22
ꢀ0.01
6
—
—
ꢀ0.01
—
7
3.59 app. dt (11.3, 1.7) 3.57 m
2.03 app. dt (13.5, 2.1) 2.01 m
1.46 app. dt (13.5, 10.9) 1.46 m
3.78 app. dt (10.7, 1.9) 3.78 ddd (10.8, 9.0, 2.0) —
3.12 s
+0.02
+0.02
—
8a
8b
9
9
76.75b
54.74
9-OMe
10
11
12
13
14
15
16
17
+0.01
+0.02
+14.25
—
+0.01
ꢀ0.01
—
+0.01
+0.01
—
—
—
133.53
133.38c
46.89
9-OMe 3.11 s
10
12a
12b
13
14
15
16
17
ꢀ0.01
4.94 d (9.4)
2.31 d (13.3)
2.22 dd (12.8, 12.0)
5.75 m
5.83 dd (15.4, 6.0)
6.27 dd (15.2, 10.9)
6.77 dd (13.5, 10.7)
6.50 d (13.7)
1.08 d (7.2)
0.93 d (6.4)
4.94 d (10.8)
2.30 d (14)
2.23 d (14)
5.75 m (10.5, 6)
5.82 dd (15, 6)
6.27 dd (15, 11)
6.77 dd (14, 11)
6.50 d (14)
1.08 d (7.5)
0.93 d (6.5)a
1.71 s
—
+0.01
ꢀ0.01
—
+0.01
—
—
—
—
—
—
71.71
133.32
129.33
137.61d
110.89e
12.86
2-Me
6-Me
11-Me
13.44
16.36
2-Me
6-Me
11-Me 1.71 s
10
100.03
82.00
59.11
72.18
84.31
60.93
68.38
18.07
100.02
82.00
59.11
72.19
84.32
60.92
63.38
18.07
+0.01
—
—
ꢀ0.01
ꢀ0.01
+0.01
—
20
10
20
4.86 d (1.1)
3.35 dd (3.4, 1.5)
4.86 d (1)
3.35 dd (3.5, 1)
3.39 s
3.55 m (3.5, 9.5)
2.97 s
2.86 t (9.5)
3.46 s
3.53 m (9.5, 6.0)
1.15 d (6.0)
—
—
ꢀ0.01
+0.01
—
20-OMe
30
40
20-OMe 3.38 s
30
3.56 dt (9.0, 3.6)
40-OMe
30-OH 2.97 d (8.4)
50
60
40
2.86 t (9.6)
—
—
—
40-OMe 3.46 s
13C NMR data recorded: dC in parts per million. 13C NMR spectrum of
synthetic material 10 calibrated to C18 (12.86 ppm in Ref. 8). Footnotes
a–e denote carbon chemical shift altered relative to value quoted in Ref. 8
(based upon inspection of copies of original NMR spectra).
50
60
3.52 m
1.15 d (6.2)
ꢀ0.01
—
1H NMR data recorded in the order: chemical shift (dH in parts per million)
(multiplicity, coupling constant in hertz). 1H NMR spectrum of synthetic 10
calibrated to H10 (4.94 ppm in Ref. 8).
a
C1 is 177.03 ppm (177.43 ppm in Ref. 8).
C9 is 76.75 ppm (76.62 ppm in Ref. 8).
C11 is 133.38 ppm (119.13 ppm in Ref. 8).
C16 is 137.61 ppm (137.76 ppm in Ref. 8).
C17 is 110.89 ppm (110.77 ppm in Ref. 8).
b
a
c
Proton chemical shift altered relative to value quoted in isolation paper
(based upon inspection of copies of original NMR spectra)—Me6 is
0.93 ppm (0.98 ppm in Ref. 8).
d
e
The resulting solution was stirred at rt for 16 h and then
quenched by the addition of saturated aqueous NaHCO3
(2 mL). The phases were separated and the aqueous phase
was extracted with CH2Cl2 (3ꢂ1.5 mL). The combined
organic layers were dried (Na2SO4), concentrated in vacuo
and purified by flash chromatography (1% Et3N in 45%
EtOAc/hexane) to yield aglycon 27 as a colourless oil
(7.1 mg, 81%); Rf 0.35 (50% EtOAc/hexane); [a]2D0 +30.6
6.1.20. TBS ether 36. A solution of fluorosugar 1111,29
(2.8 mg, 8.97 mmol) and aglycon 27 (1.5 mg, 3.27 mmol)
˚
in Et2O (1.0 mL) was stirred over activated 4 A molecular
sieves (200 mg) for 10 min. The suspension was cooled to
0 ꢁC, whereupon tin(II) chloride (1.7 mg, 8.97 mmol) and
silver perchlorate (1.9 mg, 8.97 mmol) were added. After
8 h with warming to rt, the resulting suspension was filtered
through a Celite plug with Et2O (10 mL). The filtrate was
washed with saturated aqueous NaHCO3 (10 mL), then brine
(10 mL), dried (Na2SO4) and concentrated in vacuo. Flash
chromatography (1% Et3N in 10–30% EtOAc/hexane)
gave 36 as a pale yellow oil (1.2 mg, 49%); Rf 0.56 (30%
EtOAc/hexane); [a]2D0 +28.0 (c 0.20, MeOH); IR (neat)
(c 0.33, MeOH); IR (neat) 3441, 2927, 1705, 1185 cmꢀ1
;
1H NMR (500 MHz, CD3CN) d 6.79 (1H, dd, J¼13.5,
10.9 Hz, H16), 6.51 (1H, d, J¼13.5 Hz, H17), 6.28 (1H, dd,
J¼15.9, 11.0 Hz, H15), 5.84 (1H, dd, J¼15.2, 6.1 Hz, H14),
5.78–5.73 (1H, m, H13), 4.95 (1H, d, J¼9.5 Hz, H10), 4.43
(1H, d, J¼2.7 Hz, 3-OH), 3.83–3.75 (1H, m, H9), 3.58–
3.52 (1H, m, H7), 3.51–3.43 (1H, m, H5), 3.12 (3H, s,
OCH3), 2.78 (1H, d, J¼6.1 Hz, 5-OH), 2.51 (1H, q,
J¼7.2 Hz, H2), 2.32 (1H, d, J¼13.7 Hz, H12a), 2.24 (1H, d,
J¼11.6 Hz, H12b), 2.06–2.01 (2H, m, H4a and H8a), 1.72
(3H, s, Me11), 1.46 (1H, m, H8b), 1.11 (3H, d, J¼7.2 Hz,
Me2), 1.09–1.05 (2H, m, H4b and H6), 0.94 (3H, d,
J¼6.6 Hz, Me6); 13C NMR (125 MHz, CD3CN) d 177.4,
137.6, 133.6, 133.4, 133.3, 129.3, 110.9, 98.4, 76.9, 73.7,
71.7, 69.5, 54.8, 48.8, 46.9, 45.3, 41.7, 40.4, 16.4, 13.4,
12.9; HRMS (ES+) Calculated for C21H3279BrO6Na
[M+Na+] 481.1202, found 481.1196.
1
2930, 1710, 1460, 1380, 1190 cmꢀ1; H NMR (500 MHz,
CD3CN) d 6.78 (1H, dd, J¼13.6, 10.9 Hz, H16), 6.51 (1H,
d, J¼13.4 Hz, H17), 6.28 (1H, dd, J¼15.2, 10.6 Hz, H15),
5.84 (1H, dd, J¼15.3, 6.0 Hz, H14), 5.78–5.74 (1H, m,
H13), 4.95 (1H, d, J¼9.6 Hz, H10), 4.82 (1H, d, J¼1.8 Hz,
0
H1 ), 4.47 (1H, d, J¼2.7 Hz, 3-OH), 3.83–3.78 (2H, m, H9
0
and H3 ), 3.63–3.57 (1H, m, H7), 3.56–3.45 (2H, m, H5 and
0
H5 ), 3.43 (3H, s, OCH3), 3.41 (3H, s, OCH3), 3.32 (1H, dd,
0
J¼3.1, 2.0 Hz, H2 ), 3.12 (3H, s, OCH3), 2.94 (1H, t,
0
J¼9.6 Hz, H4 ), 2.50 (1H, q, J¼7.1 Hz, H2), 2.32 (1H, d,
J¼12.7 Hz, H12a), 2.24 (1H, J¼11.7 Hz, H12b), 2.21–2.18

5818
I. Paterson et al. / Tetrahedron 63 (2007) 5806–5819
8. Pettit, G. R.; Xu, J.-P.; Doubek, D. L.; Chapuis, J.-C.; Schmidt,
J. M. J. Nat. Prod. 2004, 67, 1252.
(1H, m, H4a), 2.06–2.01 (1H, m, H8a), 1.72 (3H, s, Me11),
1.52–1.43 (1H, m, H8b), 1.28–1.19 (2H, m H6 and H4b),
0
9. For a preliminary account of some of this work, see: Paterson,
I.; Findlay, A. D.; Florence, G. J. Org. Lett. 2006, 8, 2131.
10. Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.;
Roussakis, C. J. Am. Chem. Soc. 1996, 118, 11085.
11. Callipeltoside A: (a) Paterson, I.; Davies, R. D. M.; Heimann,
A.; Marquez, R.; Meyer, A. Org. Lett. 2003, 5, 4477; (b)
Paterson, I.; Davies, R. D. M.; Marquez, R. Angew. Chem.,
Int. Ed. 2001, 40, 603; Aurisides A and B: (c) Paterson, I.;
Florence, G. J.; Heimann, A. C.; Mackay, A. C. Angew.
Chem., Int. Ed. 2005, 44, 1130.
12. Callipeltoside A: (a) Trost, B. M.; Dirat, O.; Gunzner, J. L.
Angew. Chem., Int. Ed. 2002, 41, 841; (b) Evans, D. A.; Hu,
E.; Burch, J. D.; Jaeschke, G. J. Am. Chem. Soc. 2002, 124,
5654; (c) Huang, H.; Panek, J. S. Org. Lett. 2004, 6, 4383;
Aurisides A and B: (d) Suenaga, K.; Hoshino, H.; Yoshii, T.;
Mori, K.; Sone, H.; Bessho, Y.; Sakakura, A.; Hayakawa, I.;
Yamada, K.; Kigoshi, H. Tetrahedron 2006, 62, 7687.
13. Celmer’s configurational model, as developed for macrolide
antibiotics, may be usefully extended to predicting stereo-
chemical homology in marine-derived secondary metabolites
produced by polyketide synthases in genetically related
bacteria. Celmer, W. D. J. Am. Chem. Soc. 1965, 87, 1801.
14. The boat conformation of the pyran ring in dolastatin 19 was
proposed by the Pettit group from interpretation of NOE corre-
lations in 2D-ROESY experiments, leading to their stereo-
chemical assignment in structure 5 (Ref. 8).
1.16 (3H, d, J¼6.4 Hz, Me6 ), 1.09 (3H, d, J¼7.1 Hz, Me2),
0.94 (3H, obsd, Me6), 0.92 (9H, s, SiC(CH3)3), 0.10 (3H, s,
SiCH3), 0.09 (3H, s, SiCH3); 13C NMR (125 MHz,
CD3CN) d 177.0, 137.6, 133.5, 133.3, 133.3, 129.3, 110.9,
100.5, 98.2, 84.0, 82.5, 80.1, 76.7, 73.8, 73.6, 71.7, 69.1,
61.4, 59.5, 54.7, 48.6, 46.8, 43.5, 40.3, 40.1, 26.2, 18.7,
18.1, 16.3, 13.4, 12.8, ꢀ4.5, ꢀ4.6; HRMS (ES+) Calculated
for C35H5979BrO10SiNa [M+Na+] 769.2959, found769.2959.
6.1.21. Dolastatin 19. To a stirred solution of TBS ether 36
(3 mg, 4.02 mmol) in THF (1.5 mL) in a polypropylene ves-
sel at 0 ꢁC was added HF$pyridine (60 mL). After 16 h at rt
the reaction mixture was partitioned between saturated aque-
ous NaHCO3 (12 mL) and CH2Cl2 (12 mL). The combined
organic extracts were dried (Na2SO4) and concentrated in
vacuo. Flash chromatography (1% Et3N in 0–60% EtOAc/
hexane) gave the title compound 10 as an amorphous solid
(2.0 mg, 79%); Rf 0.50 (100% EtOAc); [a]2D0 +2.2 (c 0.18,
MeOH); IR (neat) 3440, 2930, 1710, 1380, 1190 cmꢀ1; H
1
NMR (500 MHz, CD3CN)—see Table 1; 13C NMR
(100 MHz, CD3CN)—see Table 2; HRMS (ES+) Calculated
for C29H4579BrO10Na [M+Na+] 655.2094, found 655.2094.
Acknowledgements
15. (a) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett.
1989, 30, 7121; (b) Paterson, I.; Oballa, R. M. Tetrahedron
Lett. 1997, 38, 8241.
16. Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles
1995, 41, 1435.
We thank the EPSRC (EP/C451677/1), Emmanuel College,
Cambridge (Research Fellowship to G.J.F.), and Merck
Research Laboratories for support; Professor G. R. Pettit
(Arizona State University) for copies of NMR spectra for
natural dolastatin 19; Dr. Carmen Cuevas (PharmaMar) for
providing cytotoxicity assays; and Dr. Jeremy Scott (Merck
Sharp & Dohme Research Laboratories, Hoddesdon) and
Robert Paton (Cambridge) for helpful discussions.
ꢀ
17. (a) Becher, J. Synthesis 1980, 589; (b) Soullez, D.; Ple, G.;
Duhamel, L. J. Chem. Soc., Perkin Trans. 1 1997, 1639.
18. Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455.
19. The corresponding ethyl ketone was used in our synthesis of
callipeltoside A (Ref. 11a).
References and notes
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based method for the assignment of diol stereochemistry:
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O
Et
OH
O
OTBS
DMBO
Br
Br
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22
a (52%)
c 25.0, 24.4
c 100.4
O
O
OTBS
DMBO
37
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29. The L-rhamnose-derived fluorosugar 11, also utilized in our
synthesis of aurisides A and B (Ref. 11c), was prepared in seven
steps and 35% overall yield from alcohol 35, according to:
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31. Biological screening of synthetic dolastatin 19 against cancer
cell lines HT-29, NSCLC and MDA-MB-231 was arranged
by Dr. Carmen Cuevas, PharmaMar, Spain.