A Short Synthesis of (+)-Brefeldin C through Enantioselective Radical Hydroalkynylation

Article abstract of DOI:10.1002/chem.201903392

A very concise total synthesis of (+)-brefeldin C starting from 2-furanylcyclopentene is described. This approach is based on an unprecedented enantioselective radical hydroalkynylation process to introduce the two cyclopentane stereocenters in a single step. The use of a furan substituent allows a high trans diastereoselectivity to be achieved during the radical process and it contains the four carbon atoms C1–C4 of the natural product in an oxidation state closely related to the one of the target molecule. The eight-step synthesis requires six product purifications and it provides (+)-brefeldin C in 18 % overall yield.

Full text of DOI:10.1002/chem.201903392

A Journal of
Accepted Article
Title: A Short Synthesis of (+)-Brefeldin C via Enantioselective Radical
Hydroalkynylation
Authors: Philippe Renaud, Lars Gnägi, Severin Vital Martz, Daniel
Meyer, and Robin Marc Schärer
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A Short Synthesis of (+)-Brefeldin C via Enantioselective Radical
Hydroalkynylation
Lars Gnägi, Severin Vital Martz, Daniel Meyer, Robin Marc Schärer, and Philippe Renaud*[a]
Abstract: A very concise total synthesis of (+)-brefeldin C starting
from 2-furanylcyclopentene is described. This approach is based on
an unprecedented enantioselective radical hydroalkynylation process
to introduce the two cyclopentane stereocenters in a single step. The
biological properties of BFA)[48,53] and Tsunoda.[54] Following the
pioneer work of Corey and Wollenberg,[11] the majority of the
syntheses of brefeldin A and C accessed the 13-membered ring
lactone in high yields by macrolactonization.[55] On the other hand,
the preparation of the polysubstituted 5-membered ring has been
achieved using very diverse strategies. Among them, the one
reported by Kobayashi which used a furan moiety to introduce the
C(1)–C(4) carbon atoms retained all our attention due to its
conciseness.[35]
use of
a furan substituent allows to achieve a high trans
diastereoselectivity during the radical process and it contains the four
carbon atoms C1–C4 of the natural product in an oxidation state
closely related to the one of the target molecule. The eight-step
synthesis require six product purifications and it provides (+)-brefeldin
C in 18% overall yield.
Recently, our group reported a method for enantioselective
hydroazidation of trisubstituted nonactivated alkenes.[56] This
reaction
was
extended
to
other
enantioselective
In 1958, the group of Singleton isolated a new compound called
decumbin from Penicillium decumbens, which showed toxicity
properties against rats and goldfish.[1] Four years later, Betina et
al. isolated a compound called cyanein from Penicillium cyaneum,
which displayed antibiotic properties against pathogenic and non-
pathogenic fungi and demonstrated significant inhibition of HeLa
cell multiplication.[2,3] Later, Härri isolated and characterized two
new compounds from Penicillium brefeldianum, named brefeldin
A and brefeldin C.[4] Sigg later confirmed the equivalence of
decumbin, cyanein and brefeldin A (Figure 1).[5] Few compounds
have triggered so much the interest of the scientific community.
Indeed, brefeldin A has been investigated as a lead molecule for
drug development due to its promising biological activities in the
antitumor,[6] antifungal,[4] and antiviral[7] fields. Its ability to disrupt
the Golgi apparatus acted as a magnet for biochemists and
chemical biologists interested in intracellular protein trafficking.[8,9]
hydrofunctionalization processes such as hydrobromination,[56]
hydrofluroination,[57] hydrosulfurization[56], and hydroallylation.[56]
Brown et al. have pioneered the enantioselective hydralkynylation
of alkenes.[58] However, their multistep approach was lengthy and
required severe reaction conditions to convert alkylboronates to
thexyl(alkyl)boranes before treatment with lithium acetylide and
iodine under Zweifel type conditions.[59–62] Due to its obvious
synthetic interest, the enantioselective hydroalkynylation of
unactivated alkenes has been recently reinvestigated[63] but its
scope remains so far limited to electron rich[64,65] and electron poor
alkenes.[66,66] The only unactivated alkenes that were
enantioselectively hydroalkynylated were strained system such
as cyclopropene[67] and norbornene derivatives[68–70] and aryl
substituted conjugated dienes.[71] The simple enantio-random
hydroalkynylation of non-activated alkenes with Markovnikov
regioselectivity has been described in 2017 by Cui and co-
workers using iron catalysis.[72] Before that, we had developed the
enantio-random hydroalkynylation of unactivated alkenes using a
hydroboration radical alkynylation process.[73]
However, these promises have not yet led to clinical applications.
O
1
3
2
HO
4
15
14
O
(+)-brefeldin A (R = OH)
(+)-brefeldin C (R = H)
H
5
9
8
10
12
Herein, we report a concise synthesis of (+)-brefeldin C based on
an unprecedented enantioselective version of our radical
mediated hydroalkynylation. The conciseness of the reaction
could be achieved by using a furan ring to introduce the first four
carbon of the macrolactone with the desired oxidation state in a
particularly straightforward manner.
6
13
11
H
7
R
Figure 1. Structures of (+)-brefeldin A and C
The unique biological profile of brefeldin A, C, and analogues[10]
has attracted a lot of interest in the synthetic organic chemistry
community. The first synthesis of the racemic brefeldin A was
reported by Corey and Wollenberg[11] in 1976 followed by around
40 total and formal syntheses.[11–51] Brefeldin C was prepared for
the first time by total synthesis in 1988 by Schreiber and Meyers[52]
followed by Takano,[25] Guingant (along with aspects of the
[a]
L. Gnägi, S. Martz, Dr. D. Meyer, R. Schärer, and Prof. Dr. P.
Renaud
Department of Chemistry and Biochemistry
University of Bern
Freiestrasse 3, CH-3012 Bern, Switzerland
E-mail: philippe.renaud@dcb.unibe.ch
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201903392
Chemistry - A European Journal
COMMUNICATION
O
- reduction
- macro-
lactonization
O
1
afforded the TIPS-protected alkyne trans-2b in 43% yield when
run with di-tertbutyl hyponitrite[80] (DTBHN) as an initiator. By
initiating the reaction with to di-tert-butyl peroxyoxalate[81,82]
(DTBPO), the reaction time could be decreased from 1 day
(DTBHN) down to 40 min which resulted in an increased yield of
70% (up to 85% on small scale). An enantiomeric purity of 95:5
was determined after desilylation to 3 by HPLC. This enantiomeric
purity is identical within experimental error to the one measured
for 2-furanylcyclopentanol obtained upon oxidation of the
organoborane intermediate with NaOH/H2O2 (see supporting
information) demonstrating that the radical process is taking place
without epimerization. The absolute (1R,2R) configuration of 2b
3
3
1
2
HO
H
4
O
H
6
4
2
15
14
O
OH
5
5
15
13
9
9
8
10
12
10
12
14
6
13
11
11
H
H
OH
8
7
7
I
(+)-brefeldin C
1
2
1
2
Suzuki-Miyaura
cross-coupling
furan
oxidation
3
4
5
9
O
3
O
4
5
H
H
I
15
13
9
10
12
10
12
14
6
6
11
11
H
H
8
OH
8
7
7
III
II
1
2
1
2
3
enantioselective
hydroalkylation
3
and 3 was attributed by analogy to the work of Brown.[77]
O
O
hydrozirconation
4
4
5
1) (+)-IpcBH2 (1.2 equiv), Et2O
2) CH3CHO (6 equiv)
H
5
11
H
9
8
9
10
H
6
6
O
3) catechol (1.3 equiv)
(R)
O
8
7
7
4)
PhO2S
R (1.2 equiv)
V
IV
initiator
CH2Cl2, reflux
H
Scheme 1.Retrosynthesis of (+)-befeldin C
R
1
2a R = TMS
2b R = TIPS
one-pot process
The retrosynthetic analysis of the synthesis is depicted in Scheme
1. Brefeldin C will be prepared from the corresponding seco acid
I via Yamaguchi macrolactonization and stereoselective reduction
of the resulting α-β unsaturated ketone according to the seminal
work of Corey and Wollenberg.[11] In analogy to the work of
Kobayashi in his syntheses of brefeldin A[35] and of
macrosphelides A and B,[74,75] the 3-carboxyacryloyl chain (carbon
C1–C4) will be prepared via oxidative opening of the furan ring of
II. The pentan-4-ol-1-yl side chain (carbon C12–C16) will be
inserted via a Suzuki-Miyaura cross-coupling process starting
from iodide III in analogy to the work of Guingant.[48,53] The (E)-
TBAF
3
R = H, >95% yield
er 95:5
Producta initiator yield
H
H
2a
2b
2b
DTBHN 10–40%
DTBHN 43%
DTBPO 70%
O
2) and 3)
O
(R)
(R)
BCat
B(H)Ipc
H
H
a) trans/cis ≥ 98:2
Scheme 2. Enantioselective hydroalkynylation of 1
With the TIPS-protected alkyne 2b in hand, we next focussed on
the introduction of C12-C16 chain via Suzuki-Miyaura coupling in
analogy to work of Guingant (Scheme 3).[48] The p-methoxybenzyl
(PMB) (S)-configurated protected alkenol 4 was conveniently
accessible in two steps from (S)-propylene epoxide[48,83] and it
was converted to 5 by hydroboration with 9-BBN. Due to its
volatility and instability, the deprotected alkyne 3 obtained by
treatment of 2b with TBAF was immediately converted into the
vinyl iodide 6 via hydrozirconation using the Schwartz reagent
followed by treatment with iodine.[76,84] The Suzuki-Miyaura cross-
coupling process delivered 7 in good 53% yield over 3 steps. At
this stage, compound 7 contains all the C-atoms present in (+)-
brefeldin C and the remaining steps are dealing with functional
group interconversion. Oxidation of the furan to the access the
trans-4-oxo-2-alkenoic acid was attempted next. The oxidation
method reported by Salomon was tried first since it should deliver
directly the desired acid upon simple treatment with sodium
chlorite under acidic conditions.[85] The reaction conditions were
optimized on 2-cyclopentylfuran (see supporting material) to give
the desired acid in 74% yield. However, all attempts to oxidize 7
failed to give the desired product. Moreover, it was observed that
Salomon's conditions were partly deprotecting PMB ethers.
Therefore, it was decided to deprotect first the PMB ether. This
deprotection turned out to more difficult than expected since most
standard conditions (DDQ, trifluoroacetic acid, triflic acid, cerium
ammonium nitrate, etc.) were either degrading 7 or led to the
desired free alcohol 8 contaminated with impurities difficult to
remove by chromatographic purification. Gratifyingly, treatment of
7 in methanol with 4 M aqueous HCl afforded the clean
deprotected alcohol 8 in 89% yield. After another extensive
screening of furan oxidation conditions, we used a two-step one-
iodide III will be obtained from the alkyne IV via
a
hydrozirconation-iodination process.[76] The planed key reaction
of our approach is the enantioselective and diastereoselective
hydroalkynylation of 1-furanylcyclopentene V that has to be
designed based on our previous work.[73,56]
The enantioselective hydroalkynylation of 1-furanylcyclopentene
1 was investigated first since this substrate was already used in
our hydroazidation study[56] and we knew that it can be
hydroborated using (+)-monisopinocampheylbroane in high
enantiomeric excess to (1R,2R)-2-(furan-2-yl)cyclopentan-1-ol
following Brown's procedure.[77–79] Hydroboration of 1 with (+)-
monoisocampheylborane was directly followed by conversion of
the B-catecholborane upon successive treatment with
acetaldehyde and catechol according to the procedure developed
for the enantioselective hydroazidation reaction.[56] The in situ
generated
B-alkylcatecholborane
was
treated
with
trimethylsilylethynyl phenyl sulfone in the presence of di-tert-butyl
hyponitrite as a radical precursor (Scheme 2). Satisfyingly, the
desired hydroethynylated product 2a was obtained as a single
diastereomer (trans/cis ≥98:2) in 10–40% yield depending on the
run. The resulting TMS-protected alkyne 2a was immediately
desilylated to give the terminal alkyne 3 in nearly quantitative yield.
However, compounds 2a and 3 were found to be unstable when
heated. The irreproducibility of the yield of the hydroalkynylation
was attributed to partial decomposition of 2a during the radical
process in refluxing dichloromethane (about 60 °C). Therefore,
we decided to use the triisopropylsilyl (TIPS) protected ethynyl
sulfone as radical trap to introduce the ethynyl moiety. Gratifyingly
and in contrast to the TMS-protected sulfone, the preparation of
the triisopropylethynyl phenyl sulfone was achieved in 98% yield
from TIPS-acetylene and the corresponding product 2b is bench
stable. Running the hydroalkynylation reaction with this reagent
pot procedure inspired by the work of Jørgensen[86]
,
Kobayashi[35,75] and Blair.[87] Furan 8 was first treated with NBS in
H2O/acetone in the presence of NaHCO3 followed by treatment
with pyridine to obtain the ring opened 4-oxo-2-alken1-al
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10.1002/chem.201903392
Chemistry - A European Journal
COMMUNICATION
intermediate 9 that was rapidly filtered through a pad of silica gel.
Pinnick oxidation of the aldehyde 9 afforded the acid 10 in 85%
yield overall yield from furan 8. Yamaguchi type lactonization
provided 11 that was stereoselectively reduced to (+)-brefeldin C
upon treatment with NaBH4 in analogy to the work of Corey and
Wollenberg.[11] The structure of (+)-Brefeldin C was confirmed by
X-ray crystallography (Scheme 3).[88]
Keywords: hydroalkynylation • asymmetric synthesis •
enantioselective reaction • radical reaction • alkynylsulfone •
natural product.
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unprecedented enantioselective radical hydroalkynylation
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for the success of this synthesis. Indeed, it allows to achieve a
high trans diastereoselectivity during the radical process and it
contains the four carbon atoms C1–C4 of the natural product in
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10.1002/chem.201903392
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
A very concise total synthesis of (+)-
brefeldin C starting from 2-
furanylcyclopentene and based on an
unprecedented enantioselective
radical hydroalkynylation has been
achieved.
Lars Gnägi, Severin Vital Martz, Daniel
Meyer, Robin Marc Schärer, and
Philippe Renaud*
O
8 steps
18% yield
Page No. – Page No.
A Short Synthesis of (+)-Brefeldin C
via Enantioselective Radical
Hydroalkynylation
(+)-brefeldin C
This article is protected by copyright. All rights reserved.