Matteson Homologation-Based Total Synthesis of Lagunamide A

Article abstract of DOI:10.1021/acs.orglett.8b00576

Matteson homologation was found to be an excellent tool for the synthesis of the polyketide fragment of lagunamide A. Starting from a chiral boronic ester, a central building block containing all stereogenic centers of the polyketide chain was synthesized via six iterative Matteson homologation steps.

Full text of DOI:10.1021/acs.orglett.8b00576

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Matteson Homologation-Based Total Synthesis of Lagunamide A
Jan Gorges and Uli Kazmaier*
Saarland University, Organic Chemistry I, Campus, Bldg. C4.2, D-66123 Saarbrucken, Germany
̈
S
* Supporting Information
ABSTRACT: Matteson homologation was found to be an excellent tool for the synthesis of the polyketide fragment of
lagunamide A. Starting from a chiral boronic ester, a central building block containing all stereogenic centers of the polyketide
chain was synthesized via six iterative Matteson homologation steps.
he lagunamides A and B (Figure 1) belong to a class of
structurally related marine natural products, such as
growing carbon chain (Scheme 1).7 The stereoselectivities
obtained with chiral boronic esters are generally outstanding
T
Scheme 1. Matteson Homologation
and can provide diastereomeric ratios of up to 1000:1. The
reaction also allows the introduction of a wide range of
nucleophilic substituents, such as alkyl groups,8 O-function-
alities,9 azides,10 or esters.10a,11 The stereochemical outcome of
the reaction is independent of the alkyl chain and completely
relies on the chiral diol used in the boronic ester.
Figure 1. Lagunamides.
odoamide,1 kulokekahilide-2,2 and aurilide.3 They have been
isolated from lyngbya majuscule, a sponge found in the southern
lagoon of Pulau Hantu Besar in Singapore.4 Both lagunamides
show high cytotoxicity toward a panel of tumor cell lines in a
nanomolar range and, also, interesting antimalaria activity. Not
surprisingly, the promising biological activities raised the
interest of synthetic chemists. The first total synthesis of
various stereoisomers of lagunamide A was accomplished by Ye
et al. in 2012 and led to a revision of the postulated
configuration of the natural product.5 Another total synthesis
was published by Lin et al. using a different approach for the
ring closure of the macrocycle.6 Both syntheses used mainly
aldol reactions for the generation of the stereogenic centers of
the polyketide part of the molecule. This led to moderate
stereoselectivities in some cases and also, in the latter case, to
the formation of the wrong isomer, which had to be converted
into the desired one.
Because of our interest in the synthesis of cytotoxic and
antibiotic peptide natural products,12 we became interested in
the synthesis of lagunamide A. We tried to develop a synthesis
that allows a wide range of modifications at almost all positions
of lagunamide A, to get access to libraries of lagunamide
derivatives for SAR studies. While variations in the peptide part
are not an issue, our goal was to use a nonaldol approach for
the synthesis of the polyketide fragment, which should later on
allow the introduction of various substituents at several
positions. Therefore, we chose the classic Matteson homo-
logation (Scheme 1) for the generation of the four stereogenic
centers.
We started our synthesis with methylboronic ester 1,13 which
was subjected to a Matteson homologation with an ethyl
Grignard reagent to give prolonged boronic ester 2 in almost
quantitative yield and as a single diastereomer (Scheme 2). The
The Matteson homologation is a very potent tool for the
synthesis of complex structures using a chiral boronic ester to
generate subsequently (several) stereogenic centers in a
Received: February 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00576
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
separation of the product, the crude mixture was treated with
methylboronic acid resulting in the formation of 8 and an
almost quantitative recovery of 1.
Scheme 2. Matteson Homologation toward Aldehyde 8
A Horner−Wadsworth−Emmons reaction of aldehyde 8
should generate the desired polyketide fragment. We decided to
use a phosphonate already connected to the α-hydroxy acid,
which can be obtained from rather expensive D-allo-
isoleucine.5,15 Because we were interested also in the synthesis
of derivatives of the lagunamides, we established an alternative
route using an Ireland−Claisen rearrangement (Scheme 3),
which should allow variations at the β-position and also in the
side chain.
Scheme 3. Synthesis of Phosphonate 12
Starting from the chiral ester 9,16 we were able to obtain the
protected rearrangement product 10 as a 9:1 diastereomeric
mixture after protection of the carboxylic acid formed with
Boc2O.17 To remove the methyl group via metathesis, we used
Grubbs catalysts under an ethylene atmosphere.18 Interestingly,
no reaction was observed with the Grubbs I catalyst, and the
best results with the Grubbs II complex were obtained at a
pressure of 2 bar, while a higher pressure led to lower
conversion rates. Hydrogenolysis of benzyl ether 11 and
simultaneous reduction of the double bond provided the
corresponding saturated alcohol, which was coupled with
phosphonopropionic acid to the desired phosphonate 12 in
excellent yield. Unfortunately, separation of the diastereomers
was not possible at this stage.
As the third building block, we had to synthesize the peptide
fragment. To overcome problems with epimerization of the
isoleucine during activation, which occurred during the total
synthesis of structurally related odoamide,19 we decided to
introduce the peptide stepwise. For this approach, we
synthesized tripeptide 15 (Scheme 4), which cannot epimerize,
starting from protected sarcosine 13. The synthesis of the
tripeptide was accomplished by using EDC and HOBt or
HOAt, and a final saponification of the methyl ester gave access
to acid 15.
For the completion of the total synthesis, we next focused on
the Horner−Wadsworth−Emmons reaction and the selective
deprotection of the benzyl ether of building block 8; what we
found was not a trivial issue. The only approach that finally
worked was the protection of the aldehyde as an acetal,
followed by hydrogenolysis with Raney-nickel to compound 17
(Scheme 5). Using palladium as a catalyst resulted in the
hydrogenolysis of both of the benzylic ethers. Cleavage of the
acetal of 17 using aqueous HCl in acetone,20 aqueous
trifluoroacetic acid in THF,21 or iodine in acetone22 led to
next homologation step with benzyl alcoholate as the
nucleophile provided ester 3. While the first homologation
reaction was a very clean one, at this stage we had to use
column chromatography to purify the product. This explains
the lower yield due to partial decomposition of the boronic
ester on silica gel. The next homologation step to 4, this time
with methyl Grignard reagent, again proceeded smoothly but
required a long reaction time of 14 days. The formation of the
last stereogenic center was accomplished by another homo-
logation reaction using p-methoxybenzylate. While the
introduction of alkyl substituents is obviously a clean process,
this is not the case for the introduction of CH2-groups. All
attempts to prolong 5 to 6 by using the described procedures,7
such as reduction of the corresponding α-chloro boronic esters
etc., failed. Finally, we succeeded in introducing the CH2-group
by reaction with bromomethyl lithium, which was generated in
situ from dibromomethane and n-BuLi at −60 °C.14 To achieve
a complete conversion, the reaction had to be carefully carried
out at −60 °C using a defined temperature program. Applying
these conditions to other boronic esters led to incomplete
conversions, emphasizing the difficulty of introducing CH2-
groups. The final homologation of 6 to 7 was again
straightforward and aldehyde 8 was finally obtained by
oxidation of the α-chloroboronic ester 7 and subsequent
addition of sodium iodide and sodium thiosulfate. To
regenerate the methylboronic ester 1 and to simplify the
B
DOI: 10.1021/acs.orglett.8b00576
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthesis of the Protected Tripeptide 15
Scheme 6. Synthesis of Lagunamide A
Scheme 5. Synthesis of Polyketide Fragment 20
amino acid was again activated using Ghosez’s reagent, usage of
other coupling reagents resulted in low conversion, and, also,
epimerization of the isoleucine due to long reaction times. After
Fmoc-deprotection, the resulting amine was coupled with the
tripeptide 15 using COMU. Cleavage of the Boc-group, the
tert-butyl ester, and the PMB-ether was accomplished using
trifluoroacetic acid. Finally, the natural product was obtained by
ring closing using HATU and HOAt under high dilution in
DMF. At this last stage, separation of the diastereomers was
possible, giving access to lagunamide A as a single stereoisomer.
In conclusion we could show that the Matteson homo-
logation is an excellent tool for the synthesis of the polyketide
fragment of lagunamide A. By starting from a chiral boronic
ester, a central building block (8) was synthesized with an
overall yield of 30% via six iterative Matteson homologation
steps and subsequent oxidation. The main advantages of the
Matteson approach are the high stereoselectivities obtained and
the accessibility of derivatives by using different nucleophiles.
Further applications for the synthesis of lagunamide derivatives
for SAR studies are currently in progress.
the undesired elimination of the PMB-ether. Therefore, we
decided to first introduce the protected alanine derivative,
which was activated using Ghosez’s reagent.23 The resulting
ester 18 was then carefully treated with catalytic amounts of
Amberlyst 15 to yield aldehyde 19 in quantitative yield. An
extended reaction time again led to undesired elimination
products. Adapting the Horner−Wadsworth−Emmons proto-
col from the former synthesis of Ye et al. resulted in a low
conversion of the aldehyde 19. Better results were obtained via
a mild method using the lithium salt of hexafluoroisopropanol
(HFIP) as a base, providing 20 in acceptable yield.24 Despite
using this mild base, we still observed partial epimerization of
the N-methylalanine, which resulted in a second set of 13C
NMR signals for the carbon atoms close to the stereogenic
center of alanine.
An initial attempt to couple the polyketide fragment 20
directly with the corresponding tetrapeptide resulted in
complete epimerization of the C-terminal isoleucine. Therefore,
we decided to introduce the tetrapeptide stepwise. First, 20 was
deprotected with diethyl amine, followed by coupling with
Fmoc-isoleucine to 21 (Scheme 6). In this case, the Fmoc-
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.8b00576.
Detailed experimental procedures and copies of NMR
spectra (PDF)
C
DOI: 10.1021/acs.orglett.8b00576
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(21) Hanna, I.; Wlodyka, P. J. Org. Chem. 1997, 62, 6985−6990.
(22) Sun, J.; Dong, Y.; Cao, L.; Wang, X.; Wang, S.; Hu, Y. J. Org.
Chem. 2004, 69, 8932−8934.
(23) Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.;
Ghosez, L. J. Chem. Soc., Chem. Commun. 1979, 1180−1181.
(24) Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281−4283.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: u.kazmaier@mx.uni-saarland.de.
ORCID
Uli Kazmaier: 0000-0001-9756-0589
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Deutsche Forschungsgemein-
schaft.
■
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DOI: 10.1021/acs.orglett.8b00576
Org. Lett. XXXX, XXX, XXX−XXX