A Highly Convergent Total Synthesis of Leustroducsin B

Article abstract of DOI:10.1021/jacs.5b07438

Leustroducsin B exhibits a large variety of biological activities and unique structural features. An efficient and highly convergent total synthesis of Leustroducsin B was achieved in 17 longest linear and 39 total steps by disconnecting the molecule into three fragments having similar levels of complexity. These pieces were connected via a highly efficient chelate-controlled addition of a vinyl zincate to an α-hydroxy ketone and a silicon-mediated cross-coupling. The stereochemistry of the central and western fragments was set catalytically in high yields and excellent de by a zinc-ProPhenol-catalyzed aldol reaction and a palladium-catalyzed asymmetric allylic alkylation.

Full text of DOI:10.1021/jacs.5b07438

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Communication
A Highly Convergent Total Synthesis of Leustroducsin B.
Barry M. Trost, Berenger Biannic, Cheyenne S. Brindle,
B. Michael O'Keefe, Thomas J Hunter, and Ming-Yu Ngai
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07438 • Publication Date (Web): 27 Aug 2015
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A Highly Convergent Total Synthesis of Leustroducsin B.
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Barry M. Trost,* Berenger Biannic, Cheyenne S. Brindle, B. Michael O’Keefe, Thomas J. Hunter
and Ming-Yu Ngai.
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Department of Chemistry, Stanford University, Stanford, California 94305-5580, United States.
Supporting Information Placeholder
complexity (Scheme 1). We envisioned that western fragment
2 and central fragment 3 could be coupled via α-alkoxy-
directed diastereoselective vinyl zinc addition to generate the
C7-C8 bond.10 Fragment 4 could be united to the rest of the
molecule by the modified Hiyama11 silicon-based palladium-
catalyzed cross coupling reaction (C13-C14 bond) developed
in our group.12 To enhance the efficiency of the synthesis, the
absolute and relative stereochemistry of fragments 3 and 4 is
derived respectively from a zinc-ProPhenol catalyzed aldol
ABSTRACT: Leustroducsin B exhibits a large variety of bio-
logical activities and unique structural features. An efficient
and highly convergent total synthesis of Leustroducsin B was
achieved in 17 longest linear and 39 total steps by disconnect-
ing the molecule into three fragments having similar levels of
complexity. These pieces were connected via a highly effi-
cient chelate-controlled addition of a vinyl zincate to an α-
hydroxy ketone and a silicon-mediated cross-coupling. The
stereochemistry of the central and western fragments was set
catalytically in high yields and excellent ee by a zinc-
,
reaction13 14 and a palladium-catalyzed asymmetric allylic
alkylation.15
ProPhenol-catalyzed aldol reaction and
catalyzed asymmetric allylic alkylation.
a
palladium-
Scheme 1. Retrosynthetic Analysis of Leustroducsin
B.
Leustroducsins A-C were first identified and isolated from
a culture broth of the soil bacterium Streptomyces platensis
SANK 60191 in 1993 by Kohama and co-workers at Sankyo.1
These compounds belong to the phoslactomycin family2 and
exhibit a range of potentially useful bioactivities, such as
antibacterial, antifungal, and antitumor activity.3 They
showed high potency and selectivity towards inhibition of
protein serine/threonine phosphatase 2A (PP2A), an enzyme
that plays a central role in the regulation of cell growth and
inhibition of metastasis.4 Leustroducsin B has specifically
shown potent in vitro induction of cytokine production by
KM-102 cells3d as well as an increase of host in vivo resistance
to E. Coli infections4a and thrombocytosis induction3b when
administered to mice. These remarkable biological activities,
and its unique highly congested linear structure makes
Leustroducsin B a synthetic target of strong interest for the
scientific community.1,5
Currently, two total syntheses,6 two formal syntheses,7 and
a semi-synthesis8 starting from leustroducsin H have been
reported. These excellent efforts reveal the difficulty of the
challenge as the shortest prior synthesis required 37 linear
and 64 total steps, therefore, a more efficient total synthesis
of leustroducsin B remains of high interest. As part of our
ongoing program aimed at synthesizing highly potent mole-
cules bearing structural complexity in a step and atom eco-
nomical fashion,9 we report herein a concise and highly con-
vergent synthesis of leustroducsin B.
Vinyl iodide fragment 2 was most efficiently synthesized
from commercially available oxazolidinone 5 and propiolal-
dehyde 6 in five steps (Scheme 2). This synthesis is an alter-
native strategy to the ring-closing metathesis approach re-
currently used in the preparation of the 6-membered α,β-
unsaturated lactone moiety found in the leustroducsin,7
phoslactomycin,16 fostriecyn17 and cytostatin18 families. Alco-
hol 7 was obtained in high yield and excellent diastereomeric
ratio following Evan’s aldol protocol19 and the chiral auxiliary
was removed using diisobutylaluminum hydride to afford
aldehyde 8 as a solution in toluene upon work-up.20 This
aldehyde was treated under mild phase-transfer Wittig reac-
tion
conditions
in
the
presence
of
tris[2-(2-
methoxyethoxy)ethyl]amine (TDA) and phosphonium bro-
mide 9 to obtain a mixture of alcohols 10 and 11 in 56% yield
over two steps.21 Ketalization using a catalytic amount of p-
toluenesulfonic acid in methanol was followed by addition of
potassium carbonate to deprotect the terminal alkyne in a
one-pot procedure. Lastly, hydrozirconation of the terminal
alkyne and addition of molecular iodine gave access to key
Our retrosynthetic approach takes advantage of a highly
convergent strategy involving two key disconnections to pro-
vide three intermediates with similar size and structural
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intermediate 2 in 62% yield over two steps on a multigram
ard (S,S)-Trost ligand and the sodium salt of carboxylic acid
scale.22
22 (prepared in five synthetic steps from commercially avail-
able materials)26 to deliver ester 23 in 93% yield and 99% de.15
In this particular asymmetric alkylation, the intermediate π-
allyl palladium complex is pseudo-meso, thus both enantio-
mers of the starting material can be used in the alkylation.
Previous studies showed a so-called memory effect indicating
the non-symmetrical nature of the π-allylpalladium interme-
diate. 27 To insure its full equilibration prior to nucleophilic
attack, tetrahexylammonium bromide (THAB) is added to
slow the rate of carboxylate attack to maximize the effective
symmetry and therefore ee. Alcohol 24 was then obtained by
hydrogenolysis of ester 23 followed by selective reduction of
the carboxylic acid using BH3·Me2S. Oxidation of alcohol 24
to the corresponding aldehyde was accomplished with Dess-
Martin periodinane (DMP) and the resulting aldehyde was
subject to a Stork-Zhao olefination to afford vinyl iodide 4
with high Z-selectivity.28
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Scheme 2. Synthesis of Eastern Fragment 2.
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With fragment 2 in hand, an efficient route to synthesize
central key intermediate 3 was developed (Scheme 3). First,
carbonyl addition of the enolate of ester 12 to methyl formate
followed by acidic hydrolysis (pH 4) of the hemiacetal inter-
mediate delivered aldehyde 13. The latter was immediately
subjected to Wittig olefination conditions followed by reduc-
tion of the ester functionality to give aldehyde 14 in good
yield. The zinc-ProPhenol catalyzed aldol reaction between
aldehyde 14 and ketone 1517b delivered adduct 16 in 78% yield
and 99% ee.14 The 1,3-anti relationship of diol 17 was then set
by a asymmetric transfer hydrogenation using Noyori’s cata-
lyst (R,R)-TsDPEN-Ru(p-cymene)23 in 90% yield and > 20:1
dr.17b Use of achiral reagent Me4NB(OAc)3H at -35 °C (Evans’
conditions)24 gave moderate 3:1 dr. Although the selectivity
was lower, the two diastereomers were separable and 1,3-anti
diol 17 could be isolated in 61% yield. The undesired dia-
stereomer could also be recycled back to the ynone 16 using
manganese dioxide. Protection of the less sterically encum-
bered hydroxyl group with tert-butyldimethylsilylchloride
was followed by addition of alkyl chloride 18 to afford 19 in
almost quantitative yield. Finally, one-pot deprotection of the
diethoxyacetal and conversion of the resulting enone into
azide 3 was accomplished in 91% yield.
Scheme 4. Synthesis of Western Fragment 4.
The coupling of the western fragment 2 and central frag-
ment 3 has been the most challenging part of this program
(scheme 5). In order to increase the convergent character of
our approach for the preparation of leustroducsin B, we in-
vestigated the direct addition of vinyl iodide 2 to ketone 3 to
generate tertiary allylic alcohol 26 with sensitive functional
groups present in the molecule. The desired transformation
required formation of metal vinyl species 25 generated from
vinyl iodide 2 to add to β-azido ketone 3 in a diastereoselec-
tive fashion by chelation to the α-alkoxy group (27 to 28) to
finally access alcohol 26.10 Extensive screening and reaction
optimization29 revealed that the addition proceeded in high
yield and remarkable diastereoselectivity when dimethyl-
zinc30 was used to generate vinyl zincate complex 25 as the
precursor for the chelation-controlled addition. The success
of the zincate addition highly depends on the quality of the
organometallic reagent employed and the reaction tempera-
ture must be kept rigorously under -50 °C in order to avoid
decomposition of ketone 3.
Scheme 3. Synthesis of Central Fragment 3.
Scheme 5. Chelation Controlled Addition of 2 to 3.
The synthesis of vinyl iodide 4 started from racemic lac-
tone 20 (Scheme 4), which is easily accessible from commer-
cially available 3-cyclohexene-1-carboxylic acid via an iodo-
lactonization/elimination process.25 Lactone 20 was opened
with benzyl alcohol and the resulting hydroxyl group reacted
with methylchloroformate to form racemic 21 in 70% yield
over two steps. Carbonate 21 was treated with Pd(0), stand-
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Scheme 6. Completion of the Synthesis of Leustroducsin B.
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After we successfully coupled fragments 2 and 3, methyl
In conclusion, we have reported a highly convergent total
synthesis of (+)-leustroducsin B in only 39 total and 17 long-
est linear steps starting from commercially available material
12. In comparison to previously reported routes, our concise
approach reduced the total number of steps by 40% and ex-
hibits a strong convergent character. The number of longest
linear steps has been cut to less than half compared to the
previously reported total syntheses of leustroducsin B.6 Our
strategy takes advantage of the preparation of three key in-
termediates of similar complexity in terms of size and stereo-
chemistry. Particularly noteworthy is the high enantioselec-
tivity of both our zinc-ProPhenol aldol reaction and palladi-
um-catalyzed deracemization using a carboxylate nucleo-
phile. This synthesis also features the exceptionally diastere-
oselective addition of vinyl zincate 25 to ketone 3 in the pres-
ence of sensitive functional groups and a high yielding sili-
con-based palladium-catalyzed cross-coupling between two
highly functionalized molecules. Finally, the last step of the
synthesis removed three allyl and two silyl groups all at once,
revealing the mildness of these conditions. The brevity and
convergent nature of the synthesis reported herein offers an
opportunity to explore further the biological effects of chem-
ical modifications in the structure of leustroducsin B.
ketal 26 was oxidized to lactone 30 using pyridinium chloro-
chromate (PCC). The alkyne moiety was reduced chemose-
lectively to cis-alkene 31 by use of diimide under mild basic
,
conditions31 32 to avoid significant decomposition of starting
material. Cross-coupling between lactone 32 and vinyl iodide
4 was then examined in the presence of a catalytic amount of
Pd2dba3·CHCl3 and tetrabutylammonium fluoride (TBAF).12
To our delight, cis,cis-diene 33 was isolated in 70% yield.
Addition of acetic acid was essential to the success of this
transformation as it buffered the reaction mixture.33 32 and
33 could easily decompose in presence of residual hydroxide
species present in commercial TBAF. The stability of the az-
ide to this series of transformations is particularly notewor-
thy.
Secondary alcohol 33 was protected with triethylsilyltri-
flate followed by addition of trimethylsilyltriflate to selective-
ly silylate the hindered tertiary alcohol. The crude material
was directly subjected to 1,2-dichloro-4,5-dicyano-1,4-
benzoquinone (DDQ) in wet methylene chloride to promote
removal of the PMB-ketal functionality and afford secondary
alcohol 35 in 66% yield over two steps. Introduction of the
phosphate group was accomplished by treatment of alcohol
35 with phosphoramidite reagent 36 in the presence of te-
trazole, followed by oxidation of the phosphite intermediate
into phosphate 37 in 50% yield.6 We first attempted to re-
duce the azide during the final deallylation step using palla-
dium (0) under acidic conditions and an excess of PPh3. Alt-
hough NMR analysis revealed that the allyl groups had been
removed, it did not result in the formation of leustroducsin B
(1). To circumvent this difficulty, a stepwise protocol was
pursued. Reduction of azide 37 using standard Staudinger
reaction conditions was followed by in-situ addition of al-
lylchloroformate and pyridine to deliver carbamate 38 in 72%
yield. Similarly to previously reported synthesis of leustro-
ducsin B6 and to increase the conciseness of our synthesis,
we intended to remove both silyl and allyl protecting groups
at the last step using an excess of formic acid.34 Gratifyingly,
final deallylation of the phosphonate and the carbamate as
well as desilylation of the two hydroxyl groups was success-
fully achieved using a catalytic amount of Pd(PPh3)4, formic
acid, and triethylamine to reveal deprotected leustroducsin B
in 55% yield.6
ASSOCIATED CONTENT
Supporting Information
Experiment details, compound characterization data, and
spectra. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: bmtrost@stanford.edu.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the National Science Foundation (CHE-1145236),
the National Institute of Health (GM033049) for their gener-
ous support of our programs and the American Cancer Soci-
ety (PF-11-013-01-CDD) for a postdoctoral fellowship.
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ed.
(21) Daubresse, N.; Francesch, C.; Rolando, C. Tetrahedron 1998,
54, 10761-10770.
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(33) When the reaction was run without acetic acid, only traces of
product were observed.
(34) Chandra, T.; Broderick, W. E.; Broderick, J. B. Nucleosides,
Nucleotides and Nucleic Acids 2009, 28, 1016-1029.
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