Total synthesis and biological evaluation of monorhizopodin and 16-epi-monorhizopodin

Article abstract of DOI:10.1002/anie.201006780

Convergence and a biological dichotomy! Monorhizopodin (see structure) and its C16 epimer have been synthesized through a highly convergent strategy. Unlike the antitumor agent rhizopodin which is their naturally occurring dimer, monorhizopodin and its epimer exhibit potent inhibition of actin polymerization but no significant cytotoxicity.

Full text of DOI:10.1002/anie.201006780

DOI: 10.1002/anie.201006780
Natural Product Synthesis
Total Synthesis and Biological Evaluation of Monorhizopodin and
16-epi-Monorhizopodin**
K. C. Nicolaou,* Xuefeng Jiang, Peter J. Lindsay-Scott, Andrei Corbu, Sawako Yamashiro,
Andrea Bacconi, and Velia M. Fowler
For many years, polyketide natural products have provided
the scientific community with a rich source of novel molecular
architectures, many of which have become important ther-
apeutics for clinical use.[1] In 1993, the polyketide rhizopodin
was isolated from the myxobacterium Myxococcus stipita-
tus.[2] It was shown to display an interesting array of biological
properties, including potent antitumor activity against a range
of cancer cell lines in the low nanomolar range and the ability
to inhibit the polymerization of actin.[2,3] Despite its original
structural assignment as the 19-membered monomeric lac-
tone 1a (monorhizopodin), recent studies revealed dimeric
structure 2 to be the correct architecture of rhizopodin
(Scheme 1).[4] These molecules have started to attract atten-
tion from the synthetic community, although no total
syntheses have been reported to date.[5]
We were intrigued as to whether the originally proposed
structure for monorhizopodin (1a) might exhibit comparable
biological properties to its parent dimer (2), as these
molecules contain several common structural elements,
including an enamide side chain that is crucial for biological
activity. X-ray crystallographic analysis of a rhizopodin–actin
complex indicated that the binding of 2 to actin was largely a
result of favorable van der Waals interactions between the
enamide side chain and certain hydrophobic residues in the
binding cleft.[6] Thus, the construction of 1a might shed light
on the effect of the macrocycle itself upon the binding affinity
Scheme 1. Structures of monorhizopodin (1a), 16-epi-monorhizopodin
(1b), and rhizopodin (2).
of these compounds. Herein, we describe a highly convergent
and enantioselective total synthesis of monorhizopodin (1a)
[*] Prof. Dr. K. C. Nicolaou, Dr. X. Jiang, Dr. P. J. Lindsay-Scott,
and its C16 epimer (1b), as well as preliminary biological
evaluation of these compounds.
Scheme 2 depicts, in retrosynthetic format, the outline of
the synthetic strategy employed for the construction of
monorhizopodin (1a) and 16-epi-monorhizopodin (1b).
Dr. A. Corbu
Department of Chemistry and The Skaggs Institute for Chemical
Biology, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
Fax: (+1)858-784-2469
À
Thus, rupture of the macrolactone and the C22 C23 and
À
C29 N bonds led, after functional group adjustments, to
hydroxy carboxylic acid 3 and ketophosphonate 4 as potential
precursors to the target molecules. Disassembly of 3 at the
Dr. S. Yamashiro, Dr. A. Bacconi, Prof. Dr. V. M. Fowler
Department of Cell Biology, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: kcn@scripps.edu
À
indicated bond (C15 C16) through a SmI2-mediated Barbier
reaction revealed iodoester 5 and aldehyde 6 as the required
building blocks for its construction. Finally, disconnection of
the diene system of 5 through a Stille coupling traced the
origins of this compound to vinyl iodide 7 and oxazole-
containing vinyl stannane 8. The choice for the SmI2-
mediated Barbier coupling over the more conventional
Grignard reaction was based on the remarkably mild nature
of the former reagent.[7] This characteristic was thought to be
essential for the survival of the resulting secondary alcohol,
[**] Financial support for this work was provided by grants from the
National Institute of Health (USA) to K.C.N (CA100101) and to
V.M.F (HL083464), a fellowship from Institut de Chimie des
Substances Naturelles (ICSN) to A.C., and by funds from The
Skaggs Institute for Research. We are indebted to Prof. Scott
Denmark for a generous gift of his catalyst (24).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006780.
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Scheme 3. Construction of ketophosphonate 4. Reagents and condi-
tions: a) (À)-(Ipc)2-trans-crotyl borane (1.2 equiv), BF3·OEt2 (1.2 equiv),
THF, À788C, 1 h; 3 n NaOH (aq), H2O2, Et2O, 258C, 10 h, 91%,
d.r.>10:1; b) NaH (1.5 equiv), MeI (1.5 equiv), THF, 0 to 258C, 1 h,
76%; c) O3, CH2Cl2, À788C; then PPh3 (1.5 equiv), 258C, 1 h, 84%;
d) MeP(O)(OMe)2 (5.5 equiv), nBuLi (5.5 equiv), THF, À788C, 1 h; 12
(1.0 equiv), À788C, 2.5 h; DMP (1.4 equiv), CH2Cl2, 258C, 10 min,
98% for two steps. DMP=Dess–Martin periodinane, Ipc=isopino-
campheyl, THF=tetrahydrofuran.
Aldehyde 6 was synthesized from known diol 13[9] as
summarized in Scheme 4. Thus, acetonide formation from 13
(Me2C(OMe)2, (Æ )-CSA (cat.), 96% yield) and subsequent
ozonolysis of the resulting olefin (14, O3; Ph3P, 83% yield) led
to aldehyde 15, which was subjected to reagent-controlled
crotylation under Brown’s conditions ((+)-(Ipc)2-cis-crotyl
borane) to afford secondary alcohol 16 in 75% yield as a
single diastereomer. Methylation of 16 (NaH, MeI) and
subsequent ozonolysis (O3; Ph3P) and reduction with NaBH4
gave primary alcohol 18, whose silylation (TBDPSCl, imida-
zole, DMAP (cat.)) led to acetonide TBDPS ether 19, via
intermediates 17 and 18, in 75% overall yield for the four
steps. Liberation of the 1,3-diol system of 19 required mild
acid conditions (PPTS) and recycling (3 ꢁ ) to avoid signifi-
cant degradation of the TBDPS ether and resulted in 56%
yield of diol 20 (plus 33% recovered starting material).
Selective oxidation of the primary hydroxy group of 20
(PhI(OAc)2, TEMPO (cat.)), and subsequent TES protection
(TESOTf, 2,6-lutidine), furnished, via intermediate 21, the
required aldehyde 6 (75% overall yield for the 2 steps).
Scheme 5 summarizes the construction of vinyl iodide 7.
By following a procedure developed by Denmark et al., a,b-
unsaturated aldehyde 22[10] was treated with silyl ketene
acetal 23[11] in the presence of catalyst 24 and SiCl4[12] to afford
secondary alcohol 25 in 69% yield and > 90% ee. Exposure of
25 to KHMDS and benzaldehyde afforded benzylidene acetal
26 (71% yield), whose configuration was confirmed by nOe
interactions. Subsequent treatment of 26 with (Æ )-CSA in
MeOH revealed dihydroxy methyl ester 27 through cleavage
of the acetal group and transesterification (54% yield plus
44% recovered starting material). Selective protection of the
hydroxy group proximal to the ester moiety was achieved
through d-lactone formation within 27 (K2CO3; pTsOH, 96%
overall yield) and silylation (TBSCl, DMAP, 84% yield), thus
leading to TBS ether 29 via hydroxy compound 28. Subse-
quent opening of the d-lactone moiety of 29 (NaOMe, 86%
yield), and subsequent methylation (Me3OBF4, 2,6-di-tert-
Scheme 2. Retrosynthetic analysis of monorhizopodin (1). HWE=
Horner–Wadsworth–Emmons, TBDPS=tert-butyldiphenylsilyl,
TBS=tert-butyldimethylsilyl, TES=triethylsilyl.
whose facile elimination toward the oxazole moiety was
considered to be potentially problematic.
The synthesis of monorhizopodin (1a) and its 16-epi-
diastereoisomer (1b) commenced with the construction of the
requisite building blocks in their enantiomerically pure forms,
starting with ketophosphonate 4. Thus, as shown in Scheme 3,
enantioselective crotylation of aldehyde 9[8] with (À)-(Ipc)2-
trans-crotyl borane by employing Brownꢀs protocol afforded
alcohol 10 in 91% yield as a > 10:1 mixture of diastereomers
and > 95% ee. Methylation (NaH, MeI, 76% yield) and
cleavage of the terminal olefin by ozonolysis (O3; Ph3P, 84%
yield) of the latter compound led to aldehyde 12 through
intermediate 11. Reaction of aldehyde 12 with the lithium
species derived from dimethyl methylphosphonate and
nBuLi, and subsequent DMP oxidation of the resulting
mixture of diastereomeric alcohols, furnished ketophospho-
nate 4 in 98% overall yield.
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Scheme 5. Construction of vinyl iodide 7. Reagents and conditions:
a) 23 (1.2 equiv), cat. (R,R)-24 (0.015 equiv), SiCl4 (1.1 equiv), iPr2NEt
(0.20 equiv), CH2Cl2, À788C, 2 h, 69%; b) PhCHO (3.3 equiv), KHMDS
(0.30 equiv), THF, 08C, 1 h, 71%; c) (Æ)-CSA (0.30 equiv), MeOH,
258C, 20 h, 54% (44% recovered 26); d) K2CO3 (2.0 equiv), MeOH,
H2O, 258C, 15 min; pTsOH (1.0 equiv), THF, 258C, 1 h, 96% for two
steps; e) TBSCl (2.4 equiv), DMAP (3.9 equiv), CH2Cl2, 258C, 2 h,
84%; f) NaOMe (2.0 equiv), MeOH, 08C, 1 h, 86%; g) Me3OBF4
(4.0 equiv), 2,6-di-tert-butyl-4-methyl pyridine (5.0 equiv), CH2Cl2, 258C,
12 h, 80%; h) NIS (3.0 equiv), MeCN, 608C, 10 h, 96%. CSA=cam-
phorsulfonic acid, KHMDS=potassium hexamethyldisilazide, NIS=N-
iodosuccinimide, pTsOH=para-toluenesulfonic acid.
Scheme 4. Construction of aldehyde 6. Reagents and conditions:
a) (Æ)-CSA (0.010 equiv), Me2C(OMe)2, DMF, 258C, 2 h, 96%; b) O3,
CH2Cl2, À788C; then PPh3 (2.0 equiv), 258C, 1 h, 83%; c) (+)-(Ipc)2-
cis-crotyl borane (1.2 equiv), BF3·OEt2 (1.2 equiv), THF, À788C, 1 h;
3n NaOH (aq), H2O2, Et2O, 258C, 10 h, 75%; d) NaH (1.3 equiv), MeI
(2.0 equiv), THF, 0 to 258C, 1 h, 89%; e) O3, CH2Cl2, À788C; then
PPh3 (2.0 equiv), 258C, 1 h; NaBH4 (1.1 equiv), MeOH, 08C, 30 min,
86% for two steps; f) TBDPSCl (1.1 equiv), imidazole (1.3 equiv),
DMAP (0.10 equiv), CH2Cl2, 0 to 258C, 1 h, 98%; g) PPTS (1.0 equiv),
CH2Cl2, MeOH, 258C, 16 h, 56% (33% recovered 19); h) TEMPO
(0.30 equiv), PhI(OAc)2 (3.0 equiv), CH2Cl2, 258C, 12 h, 85%;
i) TESOTf (1.2 equiv), 2,6-lutidine (2.4 equiv), CH2Cl2, À788C, 30 min,
88%. DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylforma-
mide, PPTS=pyridinium para-toluenesulfonate, TEMPO=2,2,6,6-tetra-
methyl-1-piperidinyloxy.
monorhizopodin (1a) and its 16-epi-diastereoisomer (1b). As
shown in Scheme 7, a mixture of 5 (1.0 equiv) and 6
(1.5 equiv) was exposed to the action of SmI2 in THF and
afforded a 1:1 diastereomeric mixture of alcohols 37 at C16
(56% yield). Given the complexity of these substrates, the
performance of SmI2 in this coupling reaction is remarkable
and provides further testament for the power of this reagent
in organic synthesis.[7] Having achieved coupling of the key
fragments, the resulting mixture of alcohols 37 was oxidized
through the action of DMP and afforded ketone 38 in 95%
yield. Saponification of the methyl ester of 38 (LiOH, 608C)
and subsequent removal of the TES group (PPTS) then led to
hydroxy acid 3 (62% overall yield), which was now primed for
macrolactonization. After screening several reaction condi-
tions we found that optimal results could be obtained by
employing the protocol developed by Shiina et al.[16] Thus,
slow addition of hydroxy acid 3 to solution of MNBA in
toluene and DMAP at 608C afforded keto macrolactone 39 in
good yield. Owing to its tailing TLC properties, this ketone
was difficult to purify and, therefore, was reduced with
NaBH4 in the presence of CeCl3 in MeOH at À208C to give
hydroxy compounds 40a and 40b as a chromatographically
separable mixture of diastereomers (ca. 2:1 in favor of 40a;
under the high dilution conditions employed in the macro-
lactonization process, no dimeric material was observed).
butyl-4-methyl pyridine, 80% yield) and iodination (NIS,
96% yield), furnished vinyl iodide 7 via intermediates 30 and
31.
Vinyl stannane 8 was constructed from known oxazole
aldehyde 32[13] and converted into advanced iodide 5 as
summarized in Scheme 6. Thus, treatment of 32 with allenyl-
tri-n-butylstannane in the presence of Ti(OiPr)4 and (S)-
BINOL afforded alcohol 33 in 60% yield (plus 24%
recovered starting material) and > 95% ee.[14] Methylation
of 33 (NaH, MeI, 93% yield) and subsequent desilylation
(aqueous HF, 86% yield) led to primary alcohol 35 via
intermediate 34. Regio- and stereoselective addition of tri-n-
butyltin hydride to the terminal acetylene unit of 35 was
achieved through palladium catalysis ([Pd2(dba)3],
Cy3P·HBF4, iPr2NEt, (nBu)3SnH, 67% yield) and afforded
vinyl stannane 8. Coupling of this stannane with vinyl iodide 7
in the presence of CuTC[15] led to alcohol 36 (75% yield),
which was converted into the desired advanced iodide 5 by
sodium iodide through its mesylate derivative (MsCl, Et3N;
NaI, 96% overall yield).
With fragments 4–6 now available, the stage was set for
their coupling and elaboration to the targeted molecules
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Scheme 6. Synthesis of vinyl stannane 8 and advanced iodide 5.
Reagents and conditions: a) Ti(OiPr)4 (1.0 equiv), (S)-BINOL
(1.0 equiv), M.S. (4 ꢀ), CH2Cl2, 408C, 1 h; 32 (1.0 equiv), allenyl-tri-n-
butylstannane (1.2 equiv), À248C, 72 h, 60% (24% recovered 32);
b) NaH (2.0 equiv), MeI (2.0 equiv), THF, 0 to 258C, 1 h, 93%; c) 48%
aq HF (2.0 equiv), MeCN, 258C, 3 h, 86%; d) [Pd2(dba)3]
(0.0050 equiv), Cy3P·HBF4 (0.020 equiv), iPr2NEt (0.040 equiv),
(nBu)3SnH (1.2 equiv), CH2Cl2, 258C, 10 min, 67%; e) 7 (1.0 equiv), 8
(1.0 equiv), CuTC (10.0 equiv), NMP, 08C, 30 min, 75%; f) MsCl
(1.2 equiv), Et3N (1.5 equiv), CH2Cl2, À788C, 30 min; NaI (5.0 equiv),
acetone, 258C, 1 h, 96% for two steps. BINOL=1,1’-bi(2-naphthol),
CuTC=copper(I) thiophene-2-carboxylate, Cy=cyclohexyl, dba=tran-
s,trans-dibenzylideneacetone, Ms=methanesulfonyl, M.S.=molecular
seives, NMP=N-methyl-2-pyrrolidinone.
Interestingly, reduction of ketone 39 with NaBH4 alone
delivered alcohol 40b exclusively. Other reducing agents led
to unsatisfactory results. The configurations of diastereomers
40a and 40b were determined by the 13C NMR method
Scheme 7. Fragment coupling and completion of the total synthesis of
monorhizopodin (1a). Reagents and conditions: a) 5 (1.0 equiv), 6
(1.5 equiv), SmI2 (3.0 equiv), THF, 258C, 5 min, 56%; b) DMP
(3.0 equiv), CH2Cl2, 258C, 15 min, 95%; c) LiOH·H2O (6.0 equiv),
(CH3)2CHOH/THF/H2O (4:1:1), 608C, 1 h; PPTS (1.0 equiv), CH2Cl2,
MeOH, 258C, 12 h, 62% for two steps; d) 3 (1.0 equiv in THF/toluene
(1:1), slow addition by syringe pump), MNBA (2.0 equiv), DMAP
(6.0 equiv), M.S. (4 ꢀ), toluene, 608C, 20 h; NaBH4 (3.0 equiv),
CeCl3·7H2O (10.0 equiv), MeOH, À208C, 30 min, 70% for two steps,
d.r.=2:1; e) TBAF (10.0 equiv), AcOH (10.0 equiv), DMF, 258C, 12 h,
89%; f) TESOTf (10.0 equiv), 2,6-lutidine (20 equiv), CH2Cl2, À788C,
30 min, 66%; g) PPTS (0.10 equiv), CH2Cl2, MeOH, 258C, 30 min,
89%; h) SO3·py (2.0 equiv), iPr2NEt (6.0 equiv), CH2Cl2, DMSO, 258C,
30 min, 81%; i) 4 (2.0 equiv), Ba(OH)2 (0.5 equiv), THF, H2O, 258C,
2 h, 65%; j) [{CuH(PPh3)}6] (1.0 equiv), benzene, 258C, 8 h, 87%;
k) TASF (5.0 equiv), DMF, 258C, 8 h, 70%; l) TEMPO (0.10 equiv),
PhI(OAc)2 (2.0 equiv), CH2Cl2, 258C, 4 h, 74%; m) HN(Me)CHO
(20 equiv), PPTS (0.14 equiv), M.S. (4 ꢀ), C6H6, 808C, 8 h, 78%.
DMSO=dimethylsulfoxide, MNBA=2-methyl-6-nitrobenzoic anhy-
dride, py=pyridine, TASF=tris(dimethylamino)sulfonium difluorotri-
methylsilicate, TBAF=tetra-n-butylammonium fluoride.
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developed by Rychnovsky et al.[17] Thus, the acetonides
obtained from 40a and 40b upon reductive macrolactone
opening, selective protection of the primary alcohol with a
TBDPS group, and acetonide formation were employed (40a
gave anti-acetonide 40a’ (13C NMR (CDCl3): d =
101.61 ppm), while 40b gave syn-acetonide 40b’ (13C NMR
(CDCl3): d = 99.04 ppm); see the Supporting Information). In
preparation for the side chain attachment, the silyl protecting
groups of diastereomer 40a (corresponding to the C16
rhizopodin configuration) were removed (TBAF, AcOH)
and afforded triol 41a in 89% yield. The latter compound was
then converted into its tris-TES derivative 42a (TESOTf, 2,6-
lutidine, 66% yield), which underwent selective monodesily-
lation (PPTS, 89% yield) and oxidation (SO3·py, 81% yield)
and afforded aldehyde 44a through primary alcohol 43a. This
aldehyde was then treated with ketophosphonate 4 in the
presence of Ba(OH)2 and afforded the corresponding a,b-
unsaturated ketone (65% yield), which was reduced with
Strykerꢀs reagent and led to its saturated counterpart (45a) in
87% yield. At this juncture, all that remained to complete the
synthesis of monorhizopodin (1a) was global deprotection
and installation of the enamide moiety. To this end, tris-
silylated ketone 45a was first exposed to TASF (to produce
triol 46a, 70% yield) and then to PhI(OAc)2/TEMPO (cat.)
to furnish, through selective oxidation of the primary alcohol,
dihydroxy aldehyde 47a (74% yield). The latter was con-
densed with N-methyl formamide (PPTS, M.S. (4 ꢂ), 808C)
and afforded monorhizopodin (1a) in 78% yield as a mixture
of E/Z geometrical isomers (ca. 2:1 in favor of the E isomer).
By following the same sequence, 16-epi-monorhizopodin (1b)
was also synthesized from diastereoisomer 40b (see the
Supporting Information). The 1H and 13C NMR and IR
spectroscopic data of 1a and 1b were similar to those
reported for rhizopodin (2).[4] The monomeric structures of
these compounds were confirmed by mass spectrometry.
With synthetic samples of monorhizopodin (1a) and 16-
epi-monorhizopodin (1b) available to us, we were in a
position to evaluate their biological properties in actin
polymerization and cytotoxicity assays. As shown in
Figure 1, monorhizopodin (1a) exhibited potent inhibitory
activity of actin polymerization, as expected from its enamide
side chain structural motif. This activity, which is mimicked by
monorhizopodinꢀs 16-epi-isomer (1b), albeit with somewhat
lower potency, is comparable to that of latrunculin A (see
Figure 1), which was used as a standard in this assay.
However, neither monorhizopodin (1a) nor 16-epi-monorhi-
zopodin (1b) exhibited cytotoxicity against MDA-MB-231
breast cancer cells (up to 100 mm concentrations), thus
presenting an interesting dichotomy and a puzzle regarding
their divergence from rhizopodin (2). Although further
investigations are needed to explain this phenomenon, we
hypothesize that either these compounds are unable to
displace G-actin binding proteins, such as profilin,[18] within
cells, or that they fail to penetrate the cell membrane to reach
their target.
Figure 1. Inhibition of actin polymerization by monorhizopodin (1a).
The concentration of actin was 5 mm, that of monorhizopodin (1a) was
as indicated. For the corresponding graphs obtained with 16-epi-
monorhizopodin (1b) and further details of the assay, see the Support-
ing Information. LatA=latrunculin A.
biological investigations. Preliminary studies showed these
compounds to be endowed with actin-binding properties but
devoid of any associated cytotoxicity, thus posing interesting
questions regarding the role of the dimeric nature of
rhizopodin (2) in its mode of action. Further studies directed
toward the elucidation of the mechanism of action and the
differences of rhizopodin (2) and its monomeric homologues,
(1a) and (1b), as well as the total synthesis of the former are
in progress.
Received: October 28, 2010
Published online: January 7, 2011
Keywords: macrolactonization · natural products · polyketides ·
.
total synthesis
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