Probing o-diphenylphosphanyl benzoate (o-DPPB)-directed C - C bond formation: Total synthesis of dictyostatin

Article abstract of DOI:10.1002/chem.201406252

Herein, we report a robust total synthesis of dictyostatin. This polyketide natural product has attracted much attention because of its impressive antiproliferative activity against several human cancer-cell lines. We accomplished its synthesis in a highly convergent manner from three fragments of equal complexity, which were prepared on multigram scale. The southern and northwestern subunits were constructed through application of our o-DPPB-directed hydroformylation and allylic substitution methodology, respectively. These methods generated the C6 and C14 stereocenters of dictyostatin with good diastereoselectivities and simultaneously allowed further elaboration of the fragments by Wittig olefination and Sharpless asymmetric epoxidation, respectively. The compelling performance of the hydroformylation and allylic substitution with regard to practicability, selectivity, and scale underline their value for the construction of propionate motifs.

Full text of DOI:10.1002/chem.201406252

DOI: 10.1002/chem.201406252
Communication
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Synthetic Methods
Probing o-Diphenylphosphanyl Benzoate (o-DPPB)-Directed CÀC
Bond Formation: Total Synthesis of Dictyostatin
Sebastian Wꢀnsch and Bernhard Breit*[a]
et al. were the first to isolate dictyostatin from marine sponges
Abstract: Herein, we report a robust total synthesis of dic-
in the genus Spongia sp. and found the compound to inhibit
tyostatin. This polyketide natural product has attracted
the growth of murine lymphocytic leukemia cells.[5] Fifteen
much attention because of its impressive antiproliferative
years later, Wright et al. isolated dictyostatin from a marine
activity against several human cancer-cell lines. We ac-
sponge of the Corallistidae family and discovered that it was
complished its synthesis in a highly convergent manner
cytotoxic in human lung adenocarcinoma, breast adenocarci-
from three fragments of equal complexity, which were
noma, and uterine sarcoma cell lines in low nanomolar concen-
prepared on multigram scale. The southern and north-
trations.[6] Additionally, it inhibited the growth of two paclitax-
western subunits were constructed through application of
el-resistant human cancer-cell lines. In 2013, Smith et al. pub-
our o-DPPB-directed hydroformylation and allylic substitu-
lished their pharmacological studies with mice, in which they
tion methodology, respectively. These methods generated
found dictyostatin to cross the blood–brain barrier, to exhibit
the C6 and C14 stereocenters of dictyostatin with good
extended brain retention, and to cause prolonged stabilization
diastereoselectivities and simultaneously allowed further
of microtubules in the brain—effects that might be beneficial
elaboration of the fragments by Wittig olefination and
for the reversal of neurodegenerative disorders.[7]
Sharpless asymmetric epoxidation, respectively. The com-
The first synthetic preparations of the macrolide date back
pelling performance of the hydroformylation and allylic
to 2004 when Paterson et al.[8] and Curran et al.[9] released their
substitution with regard to practicability, selectivity, and
total syntheses of dictyostatin in consecutive articles in the
scale underline their value for the construction of propio-
same journal. Six years later, both research groups published
nate motifs.
revised total syntheses, the one from the Paterson group af-
fording dictyostatin in a batch of 40 mg.[10,11] To date, three
other total syntheses were presented by Phillips,[12] Ramachan-
dran,[13] and Leighton.[14] In addition, the promising biological
Reactions that enable reliable and predictable carbon–carbon
bond formation, which are either stereoselective or stereospe-
cific, are of particular value for organic synthesis. In this con-
text, we designed the o-diphenylphosphanyl benzoate
(o-DPPB) group as a catalyst-directing group[1] that allows for
regio- and stereochemical control of the rhodium-catalyzed hy-
droformylation,[2] as well as regioselective and stereospecific
SN2’ substitution of allylic o-DPPB esters with carbon nucleo-
philes delivering perfect syn-1,3-chirality transfer.[3] These meth-
ods can be used effectively for the stereoselective construction
of propionates—typical elements in polyketide natural prod-
ucts.[4] We intended to demonstrate their usefulness and found
dictyostatin (1) to be an ideal target molecule. Its structure
suggests application of the directed hydroformylation and al-
lylic substitution for the formation of dictyostatin’s C5ÀC7 and
C12ÀC14 moiety, respectively.
properties of dictyostatin fueled efforts in the preparation of
analogues. The groups of Paterson[15] and Curran[11,16] were es-
pecially productive and made dozens of compounds. Although
most of them were less potent than the natural product, the
biological results taken together allowed the development of
qualitative structure–activity relationships.[16d,17]
The synthetic routes towards dictyostatin and its analogues
revealed two major drawbacks of the previous syntheses. The
first problem was isomerization of the C2=C3 double bond
with (Z)-geometry. The most severe case of isomerization was
reported when macrolactonization of a dictyostatin precursor
was performed under Yamaguchi conditions and gave the de-
sired as well as the undesired, (E)-configured macrolactone in
a ratio of 1:2.5.[18] A second problem arose during deprotection
of the macrolactone: Irrespective of the reaction conditions,
Paterson,[15e] Curran,[15d] and Cossy[18] observed translactoniza-
tion of the carbonyl group to the C19 hydroxyl group, generat-
ing a 20-membered macrolactone ring. In all cases, the two re-
gioisomers were formed in roughly equal amounts. We wanted
to circumvent these drawbacks in our own total synthesis of
dictyostatin and developed a strategy that replaced the dien-
oate with an enynoate moiety. An alkyne in the C2ÀC3 posi-
tion would prevent isomerization and should favor the 22-
membered lactone. Lindlar hydrogenation in the very last step
would then generate the (Z)-configured double bond of dic-
In fact, the polyketide natural product dictyostatin has been
arousing the interest of several research groups after its potent
antiproliferative activity had been disclosed in 1994. Pettit
[a] S. Wꢀnsch, Prof. Dr. B. Breit
Institut fꢀr Organische Chemie, Albert-Ludwigs-Universitꢁt Freiburg
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406252.
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tyostatin.[19] Interestingly, Paterson proposed an enynoate-con-
taining dictyostatin analogue in one of his patents.[20]
The synthesis of the northeastern fragment commenced
with p-methoxybenzyl (PMB) -protected diol 9, which had
been derived from the (S)-Roche ester (Scheme 2). Swern oxi-
dation[26] was followed by Evans aldol reaction[27] to install the
C20 and C21 stereocenters of dictyostatin. Several previous
Similar to other total syntheses, our retrosynthetic analysis
began with disconnection at the C10=C11 double bond and at
the lactone functionality (Scheme 1). This allowed assembly of
Scheme 2. Preparation of the northeastern fragment.
syntheses of oxazolidinone 10 provided the compound as
a colorless oil.[28–31] We obtained the same product as a crystal-
line, white solid and therefore accepted the moderate yield of
36%. The chiral auxiliary was removed with lithium borohy-
dride, and the primary alcohol was protected with tert-butyldi-
methylsilyl (TBS) chloride. Migration of the PMB group from
the primary to the secondary hydroxyl group was achieved by
formation of the p-methoxyphenyl (PMP) acetal with dichloro
dicyano quinone (DDQ) and acetal opening with diisobutylalu-
minium hydride (DIBALH) to give intermediate 11. After trans-
formation of the alcohol into the corresponding aldehyde with
Dess–Martin periodinane[32] (DMP), the diene unit was installed
through the established sequence of Nozaki–Hiyama reac-
tion[33] and Peterson olefination.[34] Deprotection of the hydrox-
yl group at C19, DMP oxidation, and Pinnick oxidation[35] even-
tually allowed introduction of the Weinreb amide in the pres-
ence of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU).[36] Following this route, several grams
of fragment 3 were prepared.
As was mentioned above, the northwestern fragment (4)
should be synthesized from o-DPPB ester 5 and bromide 6.
The preparation of the former compound began with an
enzyme-catalyzed, enantioselective addition of hydrogen cya-
nide to crotonaldehyde.[37] After four more steps, the desired
allylic ester was successfully synthesized on multigram scale
and with an enantiomeric purity of 95% (see the Supporting
Information). Bromide 6 had been reported earlier by Golec
et al.[38] who had used Oppolzer’s sultam[39] for the generation
of the stereocenter (C16 of dictyostatin). The required Oppolz-
er sultam could be easily prepared in three steps from
(À)-camphorsulfonic acid.[40] Five more steps then delivered
the bromide with an ee of 96% (see the Supporting Informa-
tion).
Scheme 1. Retrosynthetic analysis of dictyostatin.
a northern and southern (2) building block through Still–Gen-
nari olefination[21] and macrolactonization. The northern build-
ing block was a known intermediate from Ramachandran’s
total synthesis of dictyostatin.[13] We envisaged its preparation
through nucleophilic substitution of Weinreb[22] amide 3 with
lithiated iodide 4. Hence, our strategy relied on the synthesis
of three fragments of similar complexity. The northeastern
fragment (3) could be made following literature precedence,
for example, Paterson’s route towards discodermolide.[23] The
northwestern fragment (4) resembles propionate–deoxypropio-
nate motifs, which are accessible by allylic substitution of
o-DPPB esters with organocopper reagents. In fact, the stereo-
triade in 4 had been constructed earlier by our group by
o-DPPB-directed allylic substitution of ester 5 with the organo-
copper reagent derived from bromide 6.[24] The southern frag-
ment (2) was derived from enyne 7 and should obtain its
phosphonate unit by addition of a metalated methyl phospho-
nate to an acid chloride.[8] We envisaged introducing the
enyne moiety through a sequence of hydroformylation and
Wittig olefination[25] starting with olefin 8. Allylic o-DPPB ester
8 would allow application of our o-DPPB-directed hydroformy-
lation methodology for the diastereoselective formation of
anti-propionate-type aldols.[2]
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With both precursors in hand, bromide 6 was transformed
into the corresponding Grignard[41] reagent and employed for
the allylic substitution of o-DPPB ester 5 (Scheme 3). The dia-
stereomeric purity of the product (12) was best verified by its
13C NMR spectrum, which indicated a diastereomeric ratio (d.r.)
Scheme 3. Preparation of the northwestern fragment.
Scheme 4. Generation of the anti-propionate moiety of the southern frag-
ment.
of >90:10. Notably, the allylic substitution reaction succeeded
in a scale of 20 mmol with respect to ester 5. After removal of
the TBS group, the allylic alcohol was subjected to Sharpless
asymmetric epoxidation[42] (SAE, with d-(À)-DET). Opening of
the epoxide with lithium cyanodimethylcuprate completed the
stereocenters at dictyostatin’s carbons C12 and C13.[43] Final
elaboration of compound 13 comprised TBS protection, hydro-
boration,[44] and Appel reaction[45] with molecular iodine to
afford subunit 4. Counting from camphorsulfonic acid, the
preparation of the northwestern fragment proceeded in 4.4%
yield over 15 steps.
Next, the right-hand part of the southern fragment should
be completed by introducing carbon C1 of dictyostatin
(Scheme 5). This succeeded best by the following route: After
protection of the secondary alcohol in 17, the terminal TBS
group was removed with silver(I) fluoride (7).[50] Because the al-
dehyde was required at a later stage, the Weinreb amide was
reduced with DIBALH to aldehyde 18. After protection of the
aldehyde function as the dimethyl acetal, the terminal alkyne
was deprotonated and reacted with paraformaldehyde. The re-
sulting propargylic alcohol was then protected with TBS chlo-
ride, and the aldehyde was regenerated in the presence of TES
triflate and 2,6-lutidine[51] to give intermediate 19. In analogy
to Paterson’s introduction of the bis(trifluoroethyl) phospho-
nate moiety,[8] aldehyde 19 underwent Pinnick oxidation, fol-
lowed by transformation of the carboxylic acid into the corre-
sponding acid chloride with Ghosez’s reagent.[52] The acid chlo-
ride was directly subjected to deprotonated bis(trifluoroethyl)
For the synthesis of the southern fragment (2), we needed
enantiopure Weinreb amide 8. Access to an enantiopure pre-
cursor of 8 had been developed by Ghosh and Yuan,[46] who
had employed Amano Lipase PS[47] for the enzymatic resolution
of the corresponding racemate (Scheme 4). In our case, the de-
sired enantiomer was the acetate. Therefore, we also per-
formed the saponification in the presence of Amano Lipase PS
and obtained b-hydroxy Weinreb amide 14 with an ee of 97%.
The catalyst-directing group was then introduced by Steglich
esterification to give o-DPPB ester 8.[48] Hydroformylation was
accomplished in the presence of 1.8 mol% of rhodium catalyst
and 40 bar syngas pressure and delivered the branched alde-
hyde in a ratio of 94:6 (branched/linear) and a d.r. of 88:12.
The scale of the reaction (7 mmol) was only limited to the
volume of the autoclave (100 mL). Aldehyde 15 immediately
underwent Wittig olefination with the phosphorus ylide de-
rived from phosphonium bromide 16 to generate the C4=C5
double bond of dictyostatin. Subsequent removal of the
o-DPPB group by Staudinger ligation provided alcohol 17.[49]
Because compound 17 was a crystalline solid, it could be sepa-
rated from the undesired diastereomeric (syn/anti), regioiso-
meric (l/b), and geometrical (Z/E) isomers by recrystallization,
and its absolute configuration could be corroborated by X-ray
structure analysis.
Scheme 5. Completion of the southern fragment.
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methylphosphonate to provide the desired Still–Gennari re-
agent (2).
The assembly of the complete northern building block took
place through iodin–lithium exchange of iodide 4 and addition
of Weinreb amide 3 to give ketone 20 (Scheme 6). Reduction
with lithium tri-tert-butoxyaluminum hydride[10] installed the
stereocenter at C19. After TBS protection, the primary hydroxyl
group was deprotected with HF·pyridine and oxidized to alde-
hyde 21.
Scheme 6. Preparation of the northern building block.
After the preparation of aldehyde 21 and phosphonate 2
had been worked out, the two compounds were coupled by
a Still–Gennari-type Horner–Wadsworth–Emmons olefination
with a moderate Z/E selectivity of 75:25 (Scheme 7). Neverthe-
less, the desired (Z)-configured olefin (22) was obtained in
good yield. To prevent isomerization of the C10=C11 double
bond, the carbonyl group in 22 was reduced by Corey–Bakshi–
Shibata (CBS) reaction with catecholborane.[53] The desired
epimer was formed with a d.r. of 83:17 and could be isolated
in 71% yield. After TBS protection of the alcohol, the hydroxyl
group at dictyostatin’s carbon C1 was deprotected and oxi-
dized to the corresponding aldehyde. Subsequent removal of
the PMB protecting group was carried out with DDQ to give
compound 23. Pinnick oxidation then transformed the alde-
hyde into the carboxylic acid. The crude seco acid was directly
used for the macrolactonization, which succeeded with Shiina’s
reagent[54] and afforded the desired lactone 24 in very good
yield.
Scheme 7. Completion of dictyostatin.
before considerable over-reduction of dictyostatin. The hydro-
genation was carried out several times with batches between
10 and 20 mg of the enynes (25/26). The product mixtures
were combined, purified by flash chromatography to remove
quinolone, and further purified by preparative HPLC to give
10 mg of pure dictyostatin. Its NMR spectroscopic data
matched those that had been previously reported by Paterson
et al.[8] and Curran et al.[9] The amount of isolated dictyostatin
(10 mg) would correspond to a yield of only 17% over two
steps from precursor 24. However, in the final step and after
preparative HPLC, we did not focus on the yield but on the
isolation of the desired product as a single compound. There-
fore, we settled on this route, which worked in a reliable and
practical manner. It allowed coupling of the northwestern,
northeastern, and southern fragments and their conversion
into dictyostatin in 2.1% yield over 15 steps (Schemes 6 and
7).
Overall deprotection of the macrolactone was accomplished
with HF·pyridine and gave the desired tetrol (25) together with
its ring-contracted isomer (26) in a ratio of 3:1. Hence, the
presence of an enyne moiety proved to be beneficial for the
preservation of the 22-membered lactone ring. Because the
two isomers could not be separated by flash chromatography,
their mixture was used for the next step. Lindlar hydrogena-
tion eventually gave the natural product, although dictyostatin
was formed together with several side products from over-hy-
drogenation. This could be suppressed to some extent by ad-
dition of a large excess (100 equiv) of quinoline. Also, careful
monitoring of the reaction by mass spectrometry helped to
stop the reaction after satisfying conversion of the alkyne and
Because we decided to employ Oppolzer’s sultam for the
generation of one of dictyostatin’s stereocenters, the longest
linear sequence resulted in 30 steps from camphorsulfonic acid
to the natural product and an average yield of 79% per step.
Gratifyingly, all of the reactions could be carried out on rela-
tively large scale and delivered the products in good yields. In
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with good to excellent selectivities. If this was not the case,
the undesired diastereomer could be removed by flash chro-
matography. Both the o-DPPB-directed hydroformylation and
allylic substitution proved to be valuable methods for the con-
struction of propionate motifs. Specifically, the rhodium-cata-
lyzed hydroformylation installed the C6 stereocenter of dic-
tyostatin and allowed concomitant introduction of the enyne
moiety by Wittig olefination. The allylic substitution reaction
introduced the C14 methyl group and allowed further manipu-
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Acknowledgements
We thank Novartis AG for generous donation of chemicals (al-
cohol 9 and Evans oxazolidinone). X-ray diffraction measure-
ments were carried out by Dr. Manfred Keller and Dr. Nils
Trapp from the Institute of Organic Chemistry and the Institute
of Inorganic and Analytical Chemistry, respectively. We thank
Dr. Tomislav Reiss and Dr. Stefan Gross for preliminary experi-
mental work, as well as Monika Lutterbeck for repeating the
synthesis of the southern fragment.
Keywords: allylic substitution · cancer · hydroformylation ·
structure–activity relationships · total synthesis
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Received: November 27, 2014
Published online on && &&, 0000
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Communication
COMMUNICATION
Directed catalysis: The antitumor agent
dictyostatin was synthesized by using
the catalyst-directing o-DPPB group for
the construction of various propionate
motifs. A propionate–deoxypropionate
entity was stereospecifically generated
through an o-DPPB-directed, copper-
catalyzed allylic substitution. An anti-
propionate–olefin moiety was construct-
ed in a regio- and stereoselective
manner by an o-DPPB-directed, rhodi-
um-catalyzed hydroformylation (see
scheme).
&
Synthetic Methods
S. Wꢀnsch, B. Breit*
&& – &&
Probing o-Diphenylphosphanyl
Benzoate (o-DPPB)-Directed CÀC Bond
Formation: Total Synthesis of
Dictyostatin
Chem. Eur. J. 2014, 20, 1 – 7
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These are not the final page numbers! ÞÞ