Stereoselective Total Synthesis of Carolacton

Article abstract of DOI:10.1021/acs.orglett.7b00903

A short and convergent strategy for the stereoselective total synthesis of biologically active natural product carolacton has been accomplished. Our synthesis highlights the Urpi acetal aldol, Crimmins aldol, Ireland-Claisen rearrangement, TiCl₄

Full text of DOI:10.1021/acs.orglett.7b00903

Letter
pubs.acs.org/OrgLett
Stereoselective Total Synthesis of Carolacton
Tapan Kumar Kuilya and Rajib Kumar Goswami*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
S
* Supporting Information
ABSTRACT: A short and convergent strategy for the stereoselective total
synthesis of biologically active natural product carolacton has been
accomplished. Our synthesis highlights the Urpi acetal aldol, Crimmins
aldol, Ireland−Claisen rearrangement, TiCl4-assisted aldol followed by β-
hydroxy elimination to construct C7−C8 olefin, and ring-closing metathesis as
the key steps for achieving the target molecule with an overall yield of 18.8%.
arolacton (1, Figure 1) was discovered by the Kirschning
Kirschning and co-workers were the first to report an
attractive total synthesis of carolacton (22 linear steps, 4.3%
overall yield) using a series of metal-mediated reactions
followed by the Yamaguchi macrocyclization to construct the
macrocycle.5a Later, Phillips and co-workers developed a
shorter and elegant synthetic route (14 linear steps, 7.9%
overall yield) for carolacton, where the C11−C12 bond was
installed using Grubbs ring-closing metathesis (RCM) followed
by selective reduction of the resultant olefin in the presence of
other olefins using Pd/C-mediated hydrogenation.5b However,
the development of an alternative route toward the total
synthesis of carolacton would be highly valued if the RCM
could be performed to install the C15−C16 olefin rather than in
the construction of the C11−C12 bond. The advantage in the
former strategy is that the possibility of oversaturation of the
others olefinic groups, which often is the case in selective
hydrogenation of compounds having multiple olefinic groups,
can be rescinded completely. We initially envisaged its synthesis
as part of our continuing interest8 in the total synthesis of
bioactive natural products together with an urge to develop an
operationally simple and high-yielding synthetic route for
carolacton and its analogues. In this report, we disclose a highly
convergent and flexible synthetic route for the total synthesis of
carolacton.
C
and Muller groups from the extracts of Sorangium
̈
Figure 1. Structure of carolacton (1).
cellulosum strain So ce960.1 It is a potential secondary
metabolite that combats Streptococcus mutans and Streptococcus
pneumonia, the major bacterial pathogens responsible for
human dental caries and pneumococcal infections, respec-
tively.2 The formation of biofilms (dental plaque) through the
colonization of S. mutans is a serious issue in dental medicine
and eradication of such biofilms is quite strenuous.3 Carolacton,
in this regard, seemed to be an attractive agent as it reduced the
cell viability of bioflims in very low concentration (0.005 μg/
mL).4 It has been established that carolacton inhibits the
growth of Streptococcus mutans by interfering with serine/
threonine protein kinase PknB-mediated signaling in growing
cells.2d Recent results indicate that while it does not damage the
structure of the plasma membrane, it leads to gradual reduction
of the membrane potential in S. mutans and S. pneumonia.2d
Architecturally, carolacton is a 12-membered polyketide
macrocyclic lactone embedded with eight stereogenic centers,
two trans-olefin moieties, and an infrequently found side chain
with terminal acid functionality.1 The promising bioactivity of
carolacton (1) together with its natural scarcity as well as its
structural uniqueness has drawn considerable attention of the
scientific community. Synthetic efforts have resulted in two
complete5 and a few fragment6 and analogue7 syntheses of
carolacton.
Retrosynthetic analysis of carolacton (1) is illustrated in
Scheme 1. The targeted molecule 1 could be synthesized from
the advanced intermediate 2 by RCM followed by a number of
functional groups transformations. The RCM precursor 2 could
be conveniently assembled from alcohol 3 and acid 4 by
intermolecular esterification reaction. The alcohol subunit 3
could be constructed from compound 5 and aldehyde 6 by
TiCl4-assisted substrate-controlled syn-aldol reaction followed
by elimination of the resultant hydroxy group.
Received: March 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00903
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Letter
isomer by transforming it into a known compound 911 in four
steps. First, compound 8 was treated with LAH to obtain the
corresponding alcohol, which was then protected as TBDPS
ether and subjected subsequently to oxidative cleavage followed
by Wittig olefination using Ph3PCH3Br/n-BuLi to obtain the
known compound 9 having a stereogenic center in the S-
configuration. Next, compound 8 was reacted with NH(Me)-
OMe/Et3N/DMAP to obtain the corresponding Weinreb
amide and subjected subsequently to EtMgBr addition followed
by hydrogenation to access alcohol 10 in good overall yield
(67%). Alcohol 10 was then oxidized to its corresponding
aldehyde using DMP and reacted further with PPh3CH3Br/n-
BuLi following Wittig olefination to achieve the required
compound 5 efficiently (73%).
Scheme 1. Retrosynthetic Analysis of Carolacton (1)
The synthesis of the requisite aldehyde 6 is described in
Scheme 3. The known acetal 11, prepared from 1,3-
Scheme 3. Synthesis of Aldehyde 6
The synthesis of compound 5 is described in Scheme 2. We
started our synthesis from the known alcohol 79 which was
Scheme 2. Synthesis of Intermediate 5
propanediol following a reported procedure,12 was subjected
to a reaction with the titanium enolate generated in situ from
(S)-phenylalanine-derived N-propionyl thiazolidinethione 1213
in the presence of TiCl4, Hunig’s base, and SnCl4 following the
Urpi diastereoselective anti acetal aldol reaction14 to provide
compound 13 as a major isomer (dr >15.1:1.0) in 87% yield.
Reduction of the thaizolidinethione moiety of compound 13
with DIBAL-H afforded the corresponding aldehyde, which was
further subjected to Crimmins aldol13 reaction in the presence
of the known chiral auxiliary 14,13 TiCl4, and Hunig’s base to
produce compound 15 as a major isomer with excellent overall
yield (76%) and diastereoselectivity (dr >12.5:1.0). Compound
15 was then silylated by TBSOTf/2,6-lutidine and subsequently
treated with DIBAL-H to obtain the required aldehydes 6 in
88% overall yield.
The synthesis of C1−C15 fragments (3 and 3a) of carolacton
(1) is described in Scheme 4. The two key fragments 5 and 6
(in our hand) were subjected to TiCl4-assisted syn-aldol
reaction15 to provide the corresponding aldol adducts with
very good yield (79%) and diastereoselectivity (dr >6:1). The
mixture of isomers was treated with MsCl/pyridine followed by
DBU16 to transmute them into α,β-unsaturated ketone 16
exclusively. The observed NOESY correlations of H3-19 methyl
protons with both of the H3-18 and H3-20 methyl protons
further confirmed the trans-geometry of C7−C8 olefin of
compound 16. The keto functionality of compound 16 was
transformed to the corresponding ester using propionic
anhydride/Et3N and was subsequently subjected to Ireland−
Claisen rearrangement8f,10 in the presence of LiHMDS/TBSCl
in THF/DMPU (4:1) to obtain the major isomer 8 in good
yield (73%) and diastereoselectvivity (dr >4.7:1). The major
isomer was separated from its minor counterpart using silica gel
column chromatography and was confirmed as the desired
B
DOI: 10.1021/acs.orglett.7b00903
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Letter
oxidation. Next, the major isomer 3 was subjected to
intermolecular esterification with acid 4 following the
Yamaguchi protocol18 to access ester 2. Note that the minor
isomer 3a was also transformed to the required ester 2 by
coupling with the same acid 4 following the Mitsunobu
esterification protocol.19 Thus, both of the isomers obtained
during DIBAL-H reduction could be converted to the desired
ester by choosing different esterification protocols. Next, the
precursor compound 2 was subjected to a ring-closing
metathesis reaction.8e,20 Both the Grubbs (G-II) and
Hoveyda−Grubbs (HG-II) catalysts have been tested under
different conditions. It was observed that G-II catalyst did not
function even after several attempts, but the HG-II catalyst
provided the required macrocycle 19 in good yield (74%). The
large coupling constant (J = 15.6 Hz) between the H-15 and H-
16 clearly indicated the trans-geometry of the newly formed
olefin. Next, compound 19 was treated with TBAF to obtain
the corresponding desilylated product5b and was subjected
subsequently to DMP followed by Pinnick oxidation to obtain
compound 20, which was finally treated with HF-Py to remove
Scheme 4. Synthesis of Compounds 3 and 3a
1
the acetonide protecting group to yield compound 1. The H
and 13C NMR data (see the comparison Table 1 in the
Supporting Information) and optical rotation {observed [α]23
then reduced by DIBAL-H following the Felkin−Ahn model to
obtain the alcohols 3 and 3a in excellent yield (93%) and
moderate diastereoselectivity (dr >2.5:1). Both of the isomers
were then separated by silica gel column chromatography, and
the stereochemistry of newly generated hydroxy center of the
major isomer 3 was determined by converting it to the
corresponding R- and S-Mosher’s esters 17 and 17a,
respectively.8a,g All of the protons of Mosher’s esters 17 and
D
= −197.0 (c 0.2, MeOH); reported [α]22 = −205 (c 1.07,
D
MeOH)} of the synthesized compound 1 were in good
agreement with the literature value of carolacton,1 which
unambiguously confirmed its total synthesis.
In summary, we have developed a highly convergent and
flexible route for the total synthesis of bioactive natural product
carolacton (1) from known compound 11 via a longest linear
sequence of 13 steps with 18.8% overall yield. The strategy
include implementation of diastereotopic Urpi acetal aldol for
installation of C-3 and C-4 centers and Crimmins aldol for C-6
center, TiCl4-mediated aldol, and subsequent β-hydroxy
elimination of both of the aldol products for construction of
the C7−C8 olefin, the Yamaguchi and Mitsunobu esterifications
for the utilization of both isomers 3 and 3a, and finally, the
construction of C15−C16 olefin using a Hoveyda−Grubbs ring-
closing metathesis protocol. It is noteworthy that a complex
diene substrate such as 2, which bears α and α,β-stereocenters
adjacent to the reaction site, participated in macrocyclization
following RCM to form the 12-membered lactone proficiently.
The above-mentioned attributes result in a highly efficient
synthetic route compared to the existing strategies in terms of
the number of steps involved, atom economy, and overall yield.
1
17a were assigned by H NMR (Scheme 4). The positive Δδ
values [Δδ = δS − δR] obtained for C-3, C-5, C-6, C-7, C-9,
and C-19 protons (easily detectable) from the set of esters 17
and 17a revealed that the C-9 center is in the S-configuration.
The final step in our synthetic endeavor of carolacton (1) is
shown in Scheme 5. The known alcohol 18, synthesized from L-
arabinose following a literature procedure,8c,17 was transformed
to acid 4 in 81% yield using TEMPO/BAIB-mediated
Scheme 5. Completion of Synthesis of Carolacton (1)
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00903.
Experimental procedures, spectroscopic data, comparison
Table 1, NMR (1H, 13C), and HRMS of representative
compounds; 2D NMR data for compound 16 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ocrkg@iacs.res.in.
ORCID
Rajib Kumar Goswami: 0000-0001-7486-0618
C
DOI: 10.1021/acs.orglett.7b00903
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(15) (a) Roush, W. R.; Newcom, J. S. Org. Lett. 2002, 4, 4739.
(b) Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc. 2005,
127, 6186.
Notes
The authors declare no competing financial interest.
(16) Dinh, M.-T.; Bouzbouz, S.; Peg
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ACKNOWLEDGMENTS
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T.K.K. thanks the Council of Scientific and Industrial Research,
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Department of Science and Technology (Project No. EMR/
2016/000988), India, to carry out this work is gratefully
acknowledged.
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