Synthesis of Dehydro-Dephospho-Fostriecin and Formal Total Synthesis of Fostriecin

Article abstract of DOI:10.1021/acs.orglett.9b03120

A formal synthesis of fostriecin (1) and a total synthesis of its related congener dihydro-dephospho-fostriecin 2 have been achieved. The route relies upon the use of the Sharpless dihydroxylation to set the absolute stereochemistry at C-8/9 and Noyori tr

Full text of DOI:10.1021/acs.orglett.9b03120

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Dehydro-Dephospho-Fostriecin and Formal Total
Synthesis of Fostriecin
Dong Gao,† Bohui Li,‡ and George A. O’Doherty*
†Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506, United States
‡Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States
S
* Supporting Information
ABSTRACT: A formal synthesis of fostriecin (1) and a total
synthesis of its related congener dihydro-dephospho-fostriecin 2
have been achieved. The route relies upon the use of the
Sharpless dihydroxylation to set the absolute stereochemistry at
C-8/9 and Noyori transfer hydrogenation and Leighton
allylation to set the C-11 and C-5 relative stereochemistry,
respectively. Finally, the divergent functionalization of a C-12/13 alkyne was used to establish the Z,E-dienyne of dehydro-
dephospho-fostriecin 2 and the Z,Z,E-triene of fostriecin (1).
ostriecin (1, CI-920) is a phosphorylated polyene-,
by us in 2010 (Scheme 1).12l Key to our approach to fortriecin
Fpolyol-, and pyranone-containing natural product isolated (1) was the recognition that the C-8−11 triol stereochemistry
from Steptomyces pulveraceus in 1983.1 In addition to these
unique structural features, fostriecin has garnered a great deal
of attention due to its ability to inhibit several phosphatases.
For example, it has been shown to inhibit protein phosphatase
1, 2A, and 4 (aka, PP1, PP2A, and PP4). In addition to its
potency of inhibition, its selectivity in inhibiting PP2A and PP4
over PP1 is also intriguing (i.e., PP1, IC50 = 45 nM; PP2A,
IC50 = 1.5 nM; PP4 IC50 = 3.0 nM).2 This protein
phosphatase activity appears to result in significant cancer
cell cytotoxicity against a broad range of cell lines3 (e.g.,
leukemia, lung cancer, breast cancer, ovarian cancer, and
leukemia).4 Fostriecin’s unique structure and compelling
biological activity has inspired extensive synthetic5 and
biochemical3a,6 investigations. In addition to the numerous
mechanism-of-action (MOA) and structure activity relation-
ship (SAR) studies, the investigation of fostriecin (1) as a
potential therapy has advanced to the clinical trial stage at the
National Cancer Institute.7 While the results of these studies
remain promising, there is still a need for fortriecin analogues
with better selectivities and ADME properties. In this regard,
we became interested in a synthesis of fostriecin (1), as well as
its related congener dehydro-dephospho-fostriecin 2 as
potential launching points for an SAR study.
The first synthetic effort toward this class of natural products
was a synthesis of the C-9 epimer of dephospho-fostriecin, by
Just.8 Not long after the discovery of its potent protein
phosphatase activity, the synthetic activity around the
fostriecins significantly increased. This increased activity
began with its full stereochemical assignment (1997)9 and
the first synthesis of fostriecin (1) by Boger.10 Not long after
Boger’s first synthesis of fostriecin, a second total synthesis was
reported by Jacobsen.11 Subsequently, there have been 11
other total or formal syntheses12 of fostriecin (1), as well as
related approaches.13 The last of these was an effort reported
Scheme 1. Our First Generation Approach to Fostriecin (1)
could be installed by an iterative asymmetric hydration14 and
dihydroxylation of polyene 3, which in turn could be prepared
from allylic alcohol 5. Our renewed interest in the synthesis of
fostriecin (1) and dehydro-dephospho-fostriecin 212i along
with the fact that the allylic alcohol 5 is no longer commercially
available inspired us to develop a new synthetic route.
Our second-generation approach to fostriecin (1) is outlined
in Scheme 2. In this revised approach we targeted the triol/
pyranone 7 with a BDMS-protected terminal alkyne, which we
envisioned could be converted to fostriecin via the Trost
intermediate 6.12g In addition, we felt the BDMS-alkyne 7
could be divergently converted directly into dehydro-
dephospho-fostriecin 2. While we kept the use of a Sharpless
asymmetric dihydroxylation to install the C-8/9 diol15 and the
Leighton allylation,16 we decided to use a Noyori hydrogen
transfer asymmetric reduction to install the C-11 propargyl
alcohol.17 This we envision as commencing with the
Received: September 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03120
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Letter
exposure to TFA (80%). Exposure of pure 16a to the stabilized
Wittig reagent 17 selectively converted it into the E,E-dienoate
10a in 99% yield.20 At the outset of the synthesis, we worried
about the oxidative stability of the PMB group to the
dihydroxylation condition, particularly upon scale-up. So, we
decided to also prepare OTBS dienoate 10b. The PMB-
protecting group was removed (DDQ) and replaced with a
TBS-protecting group to give dienoate 10b in 73% yield for
the 2 steps. Subjecting dienoate 10a to our typical dienoate
Sharpless asymmetric dihydroxylation (1% OsO4, 2%
(DHQD)2PHAL) led exclusively to the formation of diol
18a as a single regioisomer (81%).21 The diol in 18a could be
protected as an acetonide 19a (92%), and the PMB group
could be removed (82%) to give alcohol 9. Previously, we had
shown that the Sharpless dihydroxylation (2% OsO4, 4%
(DHQD)2PHAL) of 10b occurs in good yield (82%) and with
excellent enantiocontrol (>98%)21 to give 18b which could be
similarly protected as an acetonide 19b (88%) and deprotected
with TBAF (95%) to give the same primary alcohol 9. The
alcohol 9 produced by either procedure gave material with the
same enantiopurity (98% ee)19 as judged by optical rotation
and chiral chromatography. Both diols 18a and 18b were
protected as an acetonide (2,2-dimethoxypropane, 10% CSA)
to give 19a (92%) and 19b (88%). A DDQ deprotection of the
PMB group in 18b (DDQ, 10:1 CH2Cl2/H2O) and a TBAF
deprotection of the PMB group in 19a and the TBS group in
19b provided the primary alcohol 9 in 82% and 95% yield,
respectively. Despite our earlier concerns, we found the route
with the PMB group was easier to purify after the
dihydroxylation, and gratifyingly, the route suffered no
problems upon scale-up.
Scheme 2. Fostriecin (1) Second Generation Retrosynthesis
asymmetric dihydroxylation of protected dienoate 10, which in
turn can be prepared from propanediol 11.
Our synthesis began with the preparation of PMB
monoprotected 1,3-propanediol 12 (Scheme 3). The primary
Scheme 3. Synthesis and Dihydroxylation of Dienoate 9
We next pursued the conversion of primary alcohol 9 into
the protected propargyl alcohol 8 with the BDMS-alkyne
(Scheme 4). This began with a Swern type DMSO oxidation of
Scheme 4. Noyori Reduction To Install C-11 Alcohol
alcohol 12 was oxidized into aldehyde 13 using the Swern
condition (83% yield).18 Horner-Emmons reaction on
aldehyde 13 with triethyl-2-phosphonopropionate 14 (NaH,
0 °C) gave α,β-unsaturated ester 15a/b as a 5.4:1 E/Z-mixture
(94% yield).19 Reduction of the mixture of esters 15a/b
followed by MnO2 oxidation yielded a similar E/Z-mixture of
enals 16a/b (83%, 2 steps). Fortunately, the undesired Z-
isomer could easily be isomerized into the E-isomer upon
alcohol 9 to aldehyde 20 (76%). Addition of the lithium
acetylide of BDMS-acetylene (21 plus n-BuLi) to aldehyde 20
afforded a 1:1 mixture of diastereomeric alcohols 22a and 22b
(82%). Without purification, the two propargylic alcohols were
oxidized with MnO2 to give ketone 23 (76%). The
diastereoselective reduction of ketone 23 was accomplished
using the Noyori catalyzed (1% 24, Et3N·HCO2H) to give the
B
DOI: 10.1021/acs.orglett.9b03120
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desired diastereomer 22a in 78% yield and excellent
diastereoselectivity (>20:1). The success of this 4-step
procedure in terms of high overall yield and stereoselectivity
dissuaded us from pursuing chiral acetylide anion additions to
aldehyde 20.22 The alcohol 22a was then converted to TBS-
ether 8 (TBSCl/imidazole in DMF) in 89% yield.
Turning to the other end of the carbon chain, we then
decided to investigate the diastereoselective installation of the
pyranone ring by a reagent controlled allylation/acylation/
RCM sequence (Scheme 5).23 This began with the conversion
The C-11 secondary hydroxyl group was selectively protected
as a TBS group with TBSOTf (1.2 equiv of 2,6-lutidine), and
the remaining C-8/9 diol was doubly protected as TES ethers
with excess TESOTf (10 equiv). This one-pot tris-protection
procedure was accomplished to afford the fully protected triol
31 in 70% yield. Selective removal of the C-9 TES group was
achieved upon treatment with aqueous acid (1 M HCl/THF/
CH3CN: 1/3/6) to give the C-9 free alcohol 6 in 86% yield.
Trost has previously described the conversion of 6 to fostriecin
1 in 6 steps and 13% overall yield.12g
With a viable second generation approach to fostriecin (1),
we turned our attention to the synthesis of dehydro-
dephospho-fostriecin 2 (Scheme 6). This effort began with
Scheme 5. Formal Synthesis of Fostriecin (1)
Scheme 6. Synthesis of Dehydro-Dephospho-Fostriecin 2
the removal of the BDMS group from alkyne 7 with TBAF to
give triol 32 (78%). To our delight, we found that triol 32
could be directly converted into dehydro-dephospho-fostriecin
2 without the need for alcohol protection. Thus, exposure of a
mixture of triol 32 with dienyl iodide 33 to a typical Sonagashi
coupling procedure (10% PdCl2(PPh3)2, 20% CuI, Et3N)
cleanly gave dehydro-dephospho-fostriecin 2 in 61% overall
yield. To the best of our knowledge, this effort constitutes the
first synthesis of dehydro-dephospho-fostriecin 2. It should be
noted that Hayashi has prepared a C-18 TPDPS-protected
variant of 2, which could be reduced to form a C-18 TPDPS-
protected dephospho-fostriecin.12i,25 Imanishi had earlier
shown that the TPDPS-protected dephospho-fostriecin can
be converted into fostriecin (1) in five steps.12b,26
In summary, an enantioselective route to dehydro-
dephospho-fostriecin 2 and a formal synthesis of fostriecin
(1) have been described. The route featured the use of a
Sharpless dihydroxylation to set the absolute stereochemistry
at C-8/9 and a Noyori transfer hydrogenation and a Leighton
allylation to set the C-11 and C-5 relative stereochemistry,
respectively. A Sonogashira coupling was used to install the
desired Z,E-dienyne functionality of dehydro-dephospho-
fostriecin 2. This strategy, we believe, should facilitate the
syntheses of fostriecin analogues and similar structural natural
products. Efforts along these lines will be reported in due
course.
of 8 into aldehyde 25, by a two-step DIBAL-H reduction and
subsequent MnO2 oxidation of the crude allylic alcohol to
provide aldehyde 25 in excellent yield (86% for two steps). A
highly diastereoselective allylation of aldehyde 25 was easily
accomplished upon exposure to the Leighton reagent (R,R)-26
for 2 days at −10 °C and gave allylic alcohol 27 with near
perfect stereocontrol (88%). This result along with our past
success with the Leighton allylation, dissuaded us from
pursuing chiral allylation reactions.24 A DCC-promoted
esterification (4 equiv of acrylic acid, DCC) of the resulting
allylic alcohol 27 provided metathesis precursor triene 28
(78%). Exposure of a refluxing CH2Cl2 solution of the triene
28 to the Grubbs’ I catalyst 29 resulted in a clean cyclization to
the desired pyranone 30 in 87% yield.
With the pyranone installed in 30, it was only a matter of
manipulating the protecting groups to convert it into the Trost
intermediate used in his fostriecin (1) synthesis. Both the
acetonide and the TBS groups of 30 were cleanly removed
with 10% HCl/THF (1/1) at 65 °C to afford triol 7 (70%).
The three hydroxyl groups in 7 were then easily differentiated
by a selective protection/deprotection/protection sequence.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03120.
Complete experimental procedures and spectral data for
all new compounds (PDF)
C
DOI: 10.1021/acs.orglett.9b03120
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Letter
Relationship of Fostriecin, a Potent Inhibitor of Ser/Thr Protein
Phosphatases. FASEB J. 2006, 20, A924.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: G.ODoherty@neu.edu.
ORCID
(7) De Jong, R. S.; Mulder, N. H.; Uges, D. R. A.; Sleijfer, D. T.;
Hoppener, F. J. P.; Groen, H. J. M.; Willemse, P. H. B.; van der Graaf,
W. T.; de Vries, E. G. E. Phase I and pharmacokinetic study of the
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M.; Honkanen, R. E.; Boger, D. L. Fundamental role of the fostriecin
unsaturated lactone and implications for selective protein phosphatase
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George A. O’Doherty: 0000-0002-1699-2249
Author Contributions
D.G. and B.L. are co-first authors; the order is alphabetical.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the National Science
Foundation (CHE-1565788) and the National Institutes of
Health (AI146485, AI144196, and AI142040) for their support
of this work.
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