Total Synthesis of the Proposed Structure of Maltepolide C

Article abstract of DOI:10.1021/acs.orglett.6b01981

The first total synthesis of the proposed structure of cytotoxic macrolide maltepolide C has been achieved via an E-selective intramolecular Heck cyclization as a key step. Other key features of the synthesis are Z-selective Wittig olefination, Sharpless asymmetric dihydroxylation followed by Williamson-type cyclo-etherification, Brown asymmetric allylation, and Noyori reduction of an alkynone. Detailed NMR study confirms the structure and stereochemistry of the synthetic maltepolide C unambiguously. However, the deviation of the spectra of the synthetic maltepolide C from those of the natural maltepolide C indicates a possible error in the original structural assignment.

Full text of DOI:10.1021/acs.orglett.6b01981

Letter
pubs.acs.org/OrgLett
Total Synthesis of the Proposed Structure of Maltepolide C
K. Nageswara Rao,† M. Kanakaraju,‡ A. C. Kunwar,‡ and Subhash Ghosh*,†
‡
†Organic and Biomolecular Chemistry Division and Centre for NMR & Structural Chemistry, CSIR-Indian Institute of Chemical
Technology, Tarnaka, Hyderabad 500007, India
S
* Supporting Information
ABSTRACT: The first total synthesis of the proposed structure of cytotoxic macrolide
maltepolide C has been achieved via an E-selective intramolecular Heck cyclization as a
key step. Other key features of the synthesis are Z-selective Wittig olefination,
Sharpless asymmetric dihydroxylation followed by Williamson-type cyclo-etherification,
Brown asymmetric allylation, and Noyori reduction of an alkynone. Detailed NMR
study confirms the structure and stereochemistry of the synthetic maltepolide C
unambiguously. However, the deviation of the spectra of the synthetic maltepolide C
from those of the natural maltepolide C indicates a possible error in the original
structural assignment.
n 2013, Prusov and co-workers isolated a series of unusual
macrolides from the fermentation broth of the Myxobacte-
structures of maltepolides C and D were proposed via
correlations of the NMR chemical shifts with those of the
parent compounds. Structurally, maltepolides A−F are quite
unique in nature, containing either a tetrahydrofuran ring or
vinylic epoxide in the macrolactone ring. A panel of cell lines
was screened against all of the maltepolides, and it was found
that maltepolide C has potent cytostatic activity (2.5 μg mL−1).
In spite of its potent cytostatic activity and attractive
architecture, surprisingly except for one synthetic study,2 so
far no total synthesis has been reported in the literature. Our
continuous interest in the area of total synthesis of biologically
important natural products3 led us to initiate a program on the
total synthesis of maltepolide C, the most potent cytostatic
compound of the maltepolide family, and herein, we describe
the first total synthesis of the proposed structure of maltepolide
C.
I
rium Sorangium cellulosum So ce 1485 and named them
maltepolides A−F (Figure 1).1 The structure and absolute
Structurally, maltepolide C is a 20-membered macrolide
connected to a side chain through an E-double bond. The
macrolactone core of the molecule contains seven stereo-
centers, one E,E-diene unit, one highly substituted Z-olefin, one
substituted E-olefin in conjugation with the lactone carbonyl,
and a highly substituted THF moiety. From this structural
information, we realized that the formation of the E,E-diene
unit from 7 via an intramolecular Heck reaction could construct
the macrocycle in the molecule (Scheme 1). The acyclic
precursor 7 for intramolecular Heck cyclization could be
synthesized from acid 8 and alcohol 9 via an esterification
reaction. The alcohol 9 might be accessed through addition of
the alkyne 11 to the aldehyde 10 to give a propargylic alcohol,
which on Red-Al reduction could install the C20−C21 E-olefin.
The aldehyde 10 could be obtained from compound 12 by
means of asymmetric allylation followed by functional group
interconversion. Compound 12 could derive from compound
13 by partial reduction of the ester functionality followed by Z-
Figure 1. Structures of maltepolides A−F.
stereochemistry of maltepolides A, B, and E were confirmed via
extensive NMR analysis and the Mosher ester method, whereas
the absolute stereochemistry of maltepolide F (methanolyis
product of maltepolide B) was unambiguously established via
X-ray analysis of its di-TBS derivative. Although the structure
and absolute stereochemistry of maltepolides A, B, E, and F
were confirmed from detailed NMR and X-ray analysis, the
Received: July 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01981
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Letter
Scheme 1. Retrosynthetic Analysis of Maltepolide C
Scheme 2. Synthesis of Aldehyde 10
selective Wittig reaction and further functional group
manipulation. We realized that the tetrahydrofuran ring in 13
could be accessed from compound 14 through Sharpless
asymmetric dihydroxylation followed by in situ cyclo-ether-
ification. Finally, compound 14 might be obtained from known
compound 15 by means of a cross-metathesis reaction with
ethyl acrylate. The acid fragment 8 could be accessed from
known aldehyde 17 by way of a Mukaiyama aldol reaction.
The synthesis of aldehyde 10 (Scheme 2) commenced from
known compound 15, which was prepared from commercially
available (S)-Roche ester 19 according to the reported
procedure.4 Cross-metathesis reaction5 between 15 and ethyl
acrylate in the presence of Grubbs second-generation catalyst in
CH2Cl2 at room temperature produced required compound 20
in 82% yield with complete E-selectivity. To construct the
tetrahydrofuran ring, the hydroxyl group was converted to its
mesylate with MsCl and Et3N, and then the corresponding
mesyl compound 14 was subjected to dihydroxylation. From
our previous experience3a and also from a literature report,2 we
realized that under dihydroxylation conditions hydroxylation
followed by in situ cycloetherification could lead to the
formation of the tetrahydrofuran ring. However, to our surprise,
under dihydroxylation conditions cycloetherification reaction
did not take place. Gratifyingly, the crude diol compound on
stirring at 120 °C in pyridine underwent cycloetherification
reaction smoothly and provided the desired product 21 (dr =
18:1) in 72% yield over three steps.6 Methylation of the
hydroxyl group in 21 with Ag2O7a and methyl iodide afforded
the required product in poor yield (<30%). However, with
trimethyloxonium tetrafluoroborate and Proton Sponge,7b the
methylation reaction proceeded smoothly and provided
compound 13 in 65% yield. To construct the C12−C13 Z-
olefinic moiety, the ester group of compound 13 was subjected
to partial reduction with DIBAL-H to furnish an aldehyde,
which on reaction with Still−Gennari phosphonate (27)8 in the
presence of KHMDS in THF provided chromatographically
pure compound 22 in 75% yield over two steps. The ester
functionality in 22 was reduced with DIBAL-H to give alcohol
23 (90%) which, on oxidation with MnO2,9 followed by Brown
asymmetric allylation of the resulting aldehyde, afforded
secondary alcohol 24 (dr > 20:1) in 70% over two steps.
Alcohol 24 on protection with TBS-OTf furnished compound
25 (80%), which on PMB deprotection under buffered DDQ
conditions yielded the primary alcohol 26 in 90% yield.10
Finally, oxidation of the primary alcohol with DMP in CH2Cl2
furnished the aldehyde 10 in quantitative yield.11
The alkyne fragment 11 was synthesized from the known
compound 1612 in two steps as shown in Scheme 3.
Methylation of alcohol 16 with MeI13 followed by TMS
deprotection under K2CO3/MeOH conditions completed the
synthesis of the alkyne fragment 11.
After synthesizing the aldehyde 10 and alkyne 11, our next
objective was to couple them to obtain the alcohol 9 (Scheme
4). Accordingly, anion generated from 11 with n-BuLi was
added to the aldehyde 10 to give an inseparable diastereomeric
mixture (2.5:1) of propargylic alcohols which on oxidation with
DMP afforded alkynone 29 in 80% over two steps.
Asymmetric reduction of the keto functionality in 29 was
carried out under Noyori conditions14 to provide diastereo-
B
DOI: 10.1021/acs.orglett.6b01981
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Scheme 3. Synthesis of Alkyne 11
Scheme 6. Completion of the Synthesis
Scheme 4. Synthesis of Alcohol 9
acid 8 with alcohol 9 under Yamaguchi conditions18 furnished
compound 33 in 68% yield. PMB deprotection from compound
33 with DDQ afforded alcohol 7 in 74% yield. Now the stage
was set for the crucial intramolecular Heck reaction.3a,17,19
Accordingly, compound 7 on treatment with Pd(OAc)2 in the
presence of Cs2CO3 and Et3N in DMF furnished a highly
unstable cyclized compound which, on oxidation with MnO2,
gave stable compound 34 in 55% yield over two steps. Finally,
both TBS groups were deprotected with HF/Py in acetonitrile
to give maltepolide C (3) in 71% yield.
A quick comparison of the 13C spectra (see Table 1 in the SI)
of the synthetic maltepolide C with the one reported for the
natural one in the literature1 showed that they are very similar.
However, a careful analysis around 57−58 ppm region
(resonances arising from methoxy carbons) showed that
while the reported spectra displays two 13C resonances
overlapped at 57.9 ppm; for synthetic malepolide C (3) there
are two resonances at 57.06 and 57.78 ppm. Such a difference
merically pure propargylic alcohol in 70% yield, which on
treatment with Red-Al15 in THF at 0 °C underwent reduction
of the alkyne functionality and furnished alcohol fragment 9 in
72% yield.
After synthesizing compound 9, we turned our attention for
the synthesis of the acid fragment 8, and as per our
retrosythetic analysis, this was planned with vinylogous
Mukaiyama aldol reaction developed by Kobayashi and co-
workers.16 Accordingly, the known iodo acrylate 1717 was
subjected to Mukaiyama aldol reaction with the enolate 18 in
the presence of TiCl4 to furnish alcohol 3116b as a single isomer
in 75% yield. PMB-protection of hydroxyl group in 31 with 4-
methoxybenzyl-2,2,2-trichloroacetimidate, followed by removal
of the chiral auxiliary with LiOOH, afforded the acid fragment 8
in 56% yield over two steps (Scheme 5).
1
also persisted with the H spectra (see Table 2 in the SI). The
reported values show that the OMe protons appear at δ 3.34
and 3.35 ppm, whereas in 3 the two methoxy resonances
appear at δ 3.29 and 3.33 ppm, thus suggesting a probable
conflict in the assigned configuration at the carbons attached to
the methoxy groups. It was deemed felt necessary to find out
possible structural differences in the synthesized molecule (3)
and those reported for natural maltepolide C. Accordingly,
detailed NMR studies in CD3OD followed by molecular
dynamics (MD) calculations were performed.
The final strategy for completion of the synthesis of
maltepolide C is depicted in Scheme 6. Esterification of the
1
Complete assignments of the H and 13C resonances were
achieved with HSQC/HMBC experiments along with the
reported data (Supporting Information). Thus, methoxy
proton/carbon of −OCH3(30) and −OCH3(31) were assigned
at 3.29/57.78 ppm and 3.33/57.06 ppm, respectively. The
Scheme 5. Synthesis of Acid 8
3
3
coupling constants JH8/H9 = 14.8 Hz and JH20/H21 = 15.6 Hz
3
confirm the E-double bonds at C8−C9 and C20−C21. JH8/H9
3
= 14.8 Hz. Value of JH3/H4 = 11.5 Hz and the NOE
correlations H3/CH3(26) and CH3(25)/H4 are consistent
with a E-double bond geometry between C2 and C3 carbons.
The C12−C13 Z-double bond was very well supported by
strong NOE correlation CH3(28)/H13. The 20-membered
3
macrocycle appears quite rigid with most of the JH−H <4.2 Hz
or >9.5 Hz in the ring. In fact, even in the side chain C19−C24,
3
small value of JH22/H23 = 4.2 Hz along with several
C
DOI: 10.1021/acs.orglett.6b01981
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Letter
characteristic NOE correlations suggests a fair amount of
AUTHOR INFORMATION
Corresponding Author
■
rigidity. In view of this, if 3JH19/H20 = 6.5 Hz and 3JH21/H22 = 8.1
3
Hz and JH22/H23 = 4.2 Hz are assumed to arise from a single
*E-mail: subhash@iict.res.in.
Notes
predominant conformation about the C−C bonds, correspond-
ing to dihedral angles H19−C19−C20−H20 (θ3) ∼ 60°, H21−
C21−C22−H22 (θ2) ∼ 180°, and H22−C22−C23−H23 (θ1)
∼ 60°, respectively.20 The observed NOE correlations H20/
H22, H22/CH3(24), H21/CH3(24), H17/H20, and H20/
CH3(29) emphatically support the R-configuration at C22.
Similarly, an S-configuration at C15 was justified by the
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
K.N.R. and M.K. thank the CSIR and UGC, New Delhi, for
research fellowships. S.G. is thankful to CSIR for funding
through ORIGIN and a CSIR-Young Scientist Research Grant.
observed couplings (3JH13/H14 = 8.2, 3JH14/H15 = 4.0, 3JH15/H16a
=
3
3
3
1.5, JH15/H16b = 4.0, JH16a/H17 = 5.0, and JH16b/H17 = 10.5 Hz)
and NOE correlations [H16a/-OCH3(30), H14/H16b, H13/
H17, H16b/H18, H17/CH3(29), H13/CH3(28)] involving a
tetrahydrofuran ring. One of the minimum energy structures
obtained from the restrained molecular dynamics calculations,
carried out using the distance constraints, derived from the
NOE correlations is shown in Figure 2 (see Table 10 in the SI).
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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.6b01981.
Experimental procedures and full spectroscopic data for
compounds 3, 7−9, 11, 13, 20−26, and 29−34 (PDF)
D
DOI: 10.1021/acs.orglett.6b01981
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