Synthesis of (+)-discodermolide by catalytic stereoselective borylation reactions

Article abstract of DOI:10.1002/anie.201405455

The marine natural product (+)-discodermolide was first isolated in 1990 and, to this day, remains a compelling synthesis target. Not only does the compound possess fascinating biological activity, but it also presents an opportunity to test current methods for chemical synthesis and provides an inspiration for new reaction development. A new synthesis of discodermolide employs a previously undisclosed stereoselective catalytic diene hydroboration and also establishes a strategy for the alkylation of chiral enolates. Furthermore, this synthesis of discodermolide provides the first examples of the asymmetric 1,4-diboration of dienes and borylative diene-aldehyde couplings in complex-molecule synthesis. Borylation-based synthesis: The development of a strategy for stereocontrol in catalytic diene hydroboration enables the synthesis of a critical building block for the assembly of (+)-discodermolide. Combined with asymmetric catalytic diboration, hydroformylation, and borylative aldehyde-diene coupling reactions, (+)-discodermolide could then be prepared from simple hydrocarbon-based building blocks.

Full text of DOI:10.1002/anie.201405455

Angewandte
Chemie
DOI: 10.1002/anie.201405455
Asymmetric Synthesis Hot Paper
Synthesis of (+)-Discodermolide by Catalytic Stereoselective
Borylation Reactions**
Zhiyong Yu, Robert J. Ely, and James P. Morken*
Abstract: The marine natural product (+)-discodermolide was
first isolated in 1990 and, to this day, remains a compelling
synthesis target. Not only does the compound possess fascinat-
ing biological activity, but it also presents an opportunity to test
current methods for chemical synthesis and provides an
inspiration for new reaction development. A new synthesis of
discodermolide employs a previously undisclosed stereoselec-
tive catalytic diene hydroboration and also establishes a strat-
egy for the alkylation of chiral enolates. Furthermore, this
synthesis of discodermolide provides the first examples of the
asymmetric 1,4-diboration of dienes and borylative diene–
aldehyde couplings in complex-molecule synthesis.
D
iscodermolide is a marine natural product that is a highly
[
1]
potent microtubule-stabilizing agent. Notably, it exhibits
activity against paclitaxel-resistant cell lines and has been
found to possess synergism with paclitaxel in human carci-
Figure 1. Diastereoselective diene hydroboration (a) and stereoselec-
tive alkylation of enolates (b) are advanced to facilitate the synthesis
of (+)-discodermolide. R =larger substituent, R =smaller substitu-
[
2,3]
L
S
noma cells.
Because of these promising features and
ent.
[
4]
because isolation from its natural source, Discodermia
dissoluta, provides only 7.0 mg of discodermolide from
4
34 grams of sponge, this natural product has been the
employed a reaction sequence that occurred in 30% yield for
[
5]
[6]
subject of many total synthesis efforts. Most notably, a group
at Novartis prepared 64 g of synthetic material to support
clinical trials. Whereas pulmonary toxicity was observed
with two patients and prompted the abandonment of dis-
codermolide as a clinical candidate, subsequent studies on
the metabolism of the drug found near-complete oxidation
after one hour in the presence of human liver microsomes.
Currently, it is unknown whether the pulmonary toxicity
alluded to above arises from discodermolide itself or from
metabolic side products.
the construction of the C13ꢀC14 region. To enable a rapid
synthesis of discodermolide and new analogues, it is most
critical to construct this fragment concisely and in an efficient
fashion. To accomplish this objective, we considered two key
innovations: First, we intended to use a nickel-catalyzed 1,4-
[6]
[
1]
[
9]
diene hydroboration to establish a Z-configured trisubsti-
tuted alkene bearing an allylic functional group (Figure 1a).
Use of this reaction in the construction of discodermolide
requires developing a process that results in stereoselective
H-atom addition to the prochiral carbon atom at the C12
position. Second, to connect the C16 carbon atom to an
electrophile derived from the trisubstituted alkene, we
considered an enolate alkylation (Figure 1b). A central
requirement for this step was the design of a transformation
that allows the stereoselective a-alkylation of an enolate with
control by an a’ stereocenter. It is most important in the
development of this process that it provides the product with
high stereoselectivity and yield without requiring an excess of
precious building blocks.
[7]
A short route to discodermolide (see Figure 1 for its
[8]
structure) that might enable the synthesis of new analogues
should be founded upon the enantioselective construction of
key chiral building blocks from readily available feedstocks.
Considering the specific structural demands presented by the
assembly of discodermolide, the construction of the Z-
configured trisubstituted alkene at the C13ꢀC14 position
has proven to be a most challenging task. Indeed, the
manufacturing process for clinical trials of discodermolide
Previous studies in our laboratory have established that
the nickel-catalyzed 1,4-hydroboration of 1,3-dienes provides
[
*] Z. Yu, R. J. Ely, Prof. J. P. Morken
Department of Chemistry, Boston College, Merkert Research Labs
Z alkenes with excellent control over the olefin geometry
[9,10]
(> 20:1 Z/E).
The application of this process to the
2609 Beacon Street, Chestnut Hill, MA 02467 (USA)
construction of discodermolide required the reaction of
prochiral diene substrates, such as in A (Figure 2). A critical
question thus arises as to the influence of neighboring
stereocenters on the diastereoselectivity of the reduction
process (A!B), and to probe these features, we examined
several chiral dienol derivatives. The reaction of an unpro-
E-mail: morken@bc.edu
[
**] This work was supported by grants from the National Institutes of
Health (GM 059417 and GM 064451). Z.Y. and R.J.E. were
supported by LaMattina Fellowships.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405455.
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b-oxygen atom at the C13 position; these reactions proceeded
in modest selectivity (6:1 d.r.) and required an excess of
[
5e]
electrophile (2 equiv).
Despite important precedents
[
12]
involving anti aldol reactions of a-chiral E enolates, the
use of 1,3-allylic strain to control the a’-alkylation of non-
chelated a-chiral ketone enolates remains undeveloped. In
[
13]
line with established strategies for the conformational control
[14]
of acyclic structures, it was considered that the E enolate
derived from D (Figure 3), in the absence of intervening
Figure 2. The nickel-catalyzed hydroboration of chiral dienols results in
chiral trisubstituted alkenes. Reactions were conducted at a substrate
concentration of 0.25m, and the reaction intermediates were oxidized
with H O (30%) and NaOH (3m). The reactions for the synthesis of
2
2
5
and 6 were run for 12 hours at RT. Yields refer to isolated purified
Figure 3. Stereoselective alkylation of a’-chiral E enolates. Minimiza-
tion of 1,3-allylic strain in the E enolate derived from D establishes
material, and values denote the average of two experiments. Bn=ben-
zyl, cod=1,5-cyclooctadiene, Cy=cyclohexyl, TBS=tert-butyldimethyl-
silyl, TES=triethylsilyl.
a conformation wherein the R at the stereocenter impedes approach
L
of a reacting electrophile, which results in stereoselective alkylation.
LiTMP=lithium tetramethylpiperidide.
tected alcohol at 08C for three hours with pinacolborane and
2
.5% each of [Ni(cod) ] and PCy followed by oxidative
2 3
workup furnished the hydroboration product 1 in moderate
yield, moderate diastereoselectivity, and excellent olefin
Z stereoselectivity. Although the alcohol-derived substrate
reacted well, a significant improvement in both yield and
stereoselectivity was observed upon incorporation of silicon
protecting groups. As shown in Figure 2, the use of a TES
protecting group furnished the reaction product 2 not only in
excellent yield, but also with enhanced selectivity relative to
the unprotected substrate (12:1 vs. 6:1 d.r.). The use of larger
protecting groups served to enhance selectivity such that with
the tert-butyldiphenylsilyl (TBDPS)-protected substrate, the
product was obtained as a single stereoisomer according to
chelation effects, would favor conformer F. Subsequent
alkylation might occur preferentially from the Re face. In
a preliminary experiment aimed at addressing this issue,
alkylation to give 7 was accomplished by subjecting the
corresponding ethyl ketone starting material to deprotona-
tion with lithium tetramethylpiperidide in the presence of
lithium bromide, which are conditions known to generate
the E enolate even from hindered ketones. Treatment with
allyl iodide (1.5 equiv) at ꢀ788C delivered 7 in excellent yield
and in good selectivity. It is of vital importance for an eventual
scale-up of complex-fragment couplings that the reaction
yield was excellent even when enolate and electrophile were
employed in a 1:1 stoichiometry. The selective construction of
8 demonstrates that this alkylation strategy also applies to syn
aldol products, and the selective formation of product 9
indicates that simple hydrocarbon-derived nucleophiles can
react with useful levels of selectivity.
[
15]
1
H NMR analysis (data not shown). Substrates with other
substituents and protecting groups also participated, and the
stereoselectivity trends appear to follow the model depicted
by C (Figure 2, inset). We reason that the Ni complex
associates with the diene in a manner that positions the
metal complex antiperiplanar with respect to the adjacent
oxygen atom. This orientation allows the p system of the
diene to mix with the CꢀO s* orbital, which enhances
With the central methods in place, construction of
discodermolide commenced. To prepare fragment 14, a reac-
tion sequence involving catalytic enantioselective 1,4-dibora-
[
11]
[16]
backbonding between metal and alkene. A conformation
such as C, wherein the carbinol hydrogen atom is directed
towards the metal complex and the carbinol substituent
directed away, serves to minimize steric interactions with the
catalyst and leads to a stereocontrolled reaction.
tion
of trans-pentadiene followed by in situ homologa-
[17]
tion and oxidation furnished 1,6-diol 11 in excellent yield
and selectivity (Scheme 1). Whereas monoactivation of diol
11 was non-selective, conversion of 11 into diene 12 was
readily accomplished by bis(tosylation), selective elimination
with a hindered basic alkoxide (potassium tert-butoxide), and
detosylation. Importantly, this simple three-step sequence
could be accomplished in excellent yield. Oxidation of 12 by
the Dess–Martin periodinane was followed by the recently
To establish the C15ꢀC16 linkage in discodermolide, we
considered alkylation of a ketone enolate with an electrophile
that is derived from the above-described diene hydrobora-
tion. Enolate alkylations that have established this connection
in previous syntheses of discodermolide have employed
Z-configured enolates that engage in chelation with the
[
18]
developed
Roush reductive aldol reaction; subsequent
alkylation and TMS protection furnished 14.
2
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operations. To complete the construction of 22, aldehyde 16
was subjected to the Walsh conditions for chelation-con-
[24]
trolled addition of vinyl zinc species 18, which is readily
available from hydroboration of 19 followed by boron–zinc
exchange. Nickel-catalyzed hydroboration and oxidation of
2
1 followed by iodinolysis furnished 22 in excellent yield and
diastereoselectivity.
Lastly, construction of fragment 29 employed a sequence
involving a catalytic diastereoselective borylative diene–
[
25]
aldehyde coupling (Scheme 3).
To begin this sequence,
Scheme 1. The synthesis of 14 from pentadiene in eight steps is
enabled by catalytic enantioselective tandem diene diboration/homo-
logation/oxidation and reductive aldol reactions. B (pin) =
2
2
bis(pinacolato)diboron, dba=(E,E)-dibenzylideneacetone,
DMP=1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one,
l
IPC=isopinocampheyl derived from (ꢀ)-a-pinene, OTf=trifluorome-
thanesulfonate, TMS=trimethylsilyl, Ts=para-toluenesulfonyl.
Scheme 3. Synthesis of 29 from the cyclic ortho-xylyl acetal of acrolein
23). dppm=bis(diphenylphosphino)methane, pTsOH=para-toluene-
(
sulfonic acid.
Scheme 2. Synthesis of 22 in five steps from TBS-protected allyl
alcohol 15. acac=acetylacetonate, HBpin=pinacolborane, ONf=no-
nafluorobutanesulfonate.
aldehyde 24 was prepared by Rh/PhBPE-catalyzed hydro-
[
26]
formylation of the cyclic ortho-xylyl acetal of acrolein (23).
Likely because of the influence of a second electronegative
heteroatom at the allylic carbon atom, this hydroformylation
occurred with outstanding branched/linear selectivity (b/l =
13:1) and with excellent enantiocontrol, as for the example
shown in Scheme 2. Whereas the subsequent borylative
diene–aldehyde coupling reaction has precedent in our
laboratory using P(SiMe ) as a ligand, it was found that
The construction of fragment 22 was accomplished in four
synthesis steps from chiral aldehyde 16 (Scheme 2). In
designing this route, it was considered that access to 16 by
hydroformylation of protected allyl alcohol derivatives would
be an ideal strategy. Hydroformylation of this substrate class
has been addressed by Landis et al. using the bisdiazaphos
3
3
[19]
ligand, and similar reactions have been employed by the
PBn3 is equally effective and allows for high levels of
[20]
[21]
groups of Burke and Leighton for the construction of
polypropionate arrays. Unfortunately, the bisdiazaphos
ligands are not readily available. Expecting that related
electron-rich bidentate diphosphines might provide sufficient
selectivity, alternative ligands were examined in the hydro-
formylation of TBS-protected allyl alcohol 15. The electronic
stereoinduction for the conversion of aldehyde 24 into 25.
[
27]
Iridium-catalyzed hydroboration and oxidation followed by
neutral hydrogenolytic deprotection of the ortho-xylyl acetal,
oxidation, and esterification furnished 26. Primary alcohol 26
was converted into fragment 29 by oxidation, chlorination,
and carbonyl substitution employing a phosphoryl anion
derived from 28.
[22]
and steric properties of the commercially available DuPhos
ligand family appeared ideally suited to the task, and it was
found that phenyl-substituted bis(phospholano)ethane
In line with the enolate alkylation reactions described
above, the E-configured enolate derived from 14 (Scheme 4)
was treated with allylic iodide 22 (1.0 equiv), which furnished
30 in excellent yield and stereoselectivity. After replacement
of the TMS protecting group in 30 with a requisite primary
carbamate, the primary TBS protecting group was removed
and the product alcohol oxidized to give aldehyde 31. The
reaction sequence for completion of the target molecule was
(
1
PhBPE, 17) was most effective, delivering chiral aldehyde
6 in outstanding levels of enantioselectivity and yield and
[23]
with moderate, but useful levels of regiocontrol. Impor-
tantly, very low catalyst loadings were effective, and the
unpurified reaction product was sufficiently free from con-
taminants that it could be used directly in subsequent
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Scheme 4. Stereoselective enolate alkylation to give 30 and conversion
into discodermolide. LiTMP=lithium 2,2,6,6-tetramethylpiperidide,
PPTS=pyridinium para-toluenesulfonate.
influenced by expertise developed in the course of reported
[
5d,28]
prior syntheses.
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[
29]
olefination with 29 to give 32. Final conversion of 32 into
discodermolide was accomplished by the three-step reduction
and deprotective lactonization sequence depicted in
Scheme 4. H and C NMR spectra, optical rotation values,
and mass spectral data were identical to those reported for the
natural product.
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Received: May 20, 2014
Published online: && &&, &&&&
6
Keywords: asymmetric catalysis · diboration · discodermolide ·
3
.
hydroboration · total synthesis
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Communications
Asymmetric Synthesis
Z. Yu, R. J. Ely,
J. P. Morken*
&&&& — &&&&
Synthesis of (+)-Discodermolide by
Catalytic Stereoselective Borylation
Reactions
Borylation-based synthesis: The develop-
ment of a strategy for stereocontrol in
catalytic diene hydroboration enables the
synthesis of a critical building block for
the assembly of (+)-discodermolide.
Combined with asymmetric catalytic
diboration, hydroformylation, and bory-
lative aldehyde–diene coupling reactions,
(+)-discodermolide could then be pre-
pared from simple hydrocarbon-based
building blocks.
6
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