Synthesis of Cyclopropane Fatty Acids by C(sp3)?C(sp3) Cross-Coupling Reaction and Formal Synthesis of α-Mycolic Acid

Article abstract of DOI:10.1002/adsc.201800901

An iterative Ni-catalyzed C(sp³)?C(sp³) cross-coupling reaction of a novel cis-cyclopropane containing bifunctional building blocks with alkyl halides and alkyl Grignard reagents enabled the introduction of a cyclopropane ring into the desired position(s) of saturated carbon frameworks, providing a straightforward synthetic route to cyclopropane fatty acids. The present method creates a direct route for the construction of saturated carbon frameworks, and can avoid the tedious multistep operations based on unsaturated functional group manipulations that are often employed in conventional synthetic routes. This method could be applicable to the synthesis of trans-cyclopropane fatty acids and enantioenriched cyclopropane fatty acids. Formal synthesis of α-mycolic acid was achieved by the C(sp³)?C(sp³) cross-coupling reaction of cyclopropane-containing bifunctional building blocks. (Figure presented.).

Full text of DOI:10.1002/adsc.201800901

Title: Synthesis of Cyclopropane Fatty Acids by C(sp³)–
C(sp³) Cross-coupling Reaction and Formal
Synthesis of α-Mycolic Acid
Authors: Takanori Iwasaki, Shohei Terahigashi, Yufei Wang, Arisa
Tanaka, Hanqing Zhao, Yukari Fujimoto, Koichi Fukase, and
Nobuaki Kambe
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800901
Link to VoR: http://dx.doi.org/10.1002/adsc.201800901

10.1002/adsc.201800901
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Cyclopropane Fatty Acids by C(sp3)–C(sp3) Cross-
coupling Reaction and Formal Synthesis of -Mycolic Acid
Takanori Iwasaki,a,b,* Shohei Terahigashi,a Yufei Wang,a Arisa Tanaka,a Hanqing
Zhao,a Yukari Fujimoto,c Koichi Fukase,d and Nobuaki Kambea,*
a
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Fax: (+81)-6-6879-7390; phone: (+81)-6-6879-7389; E-mail: kambe@chem.eng.osaka-u.ac.jp
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo,
b
Bunkyo-ku, Tokyo 113-8656, Japan
Fax: (+81)-3-5841-7263; phone: (+81)-3-5841-7262; E-mail: iwasaki@chembio.t.u-tokyo.ac.jp,
Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
c
Yokohama, Kanagawa 223-8522, Japan
Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
d
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An iterative Ni-catalyzed C(sp3)–C(sp3) cross- employed in conventional synthetic routes. This method
coupling reaction of a novel cis-cyclopropane containing could be applicable to the synthesis of trans-cyclopropane
bifunctional building blocks with alkyl halides and alkyl fatty acids and enantioenriched cyclopropane fatty acids.
Grignard reagents enabled the introduction of a cyclopropane Formal synthesis of -mycolic acid was achieved by the
ring into the desired position(s) of saturated carbon C(sp3)–C(sp3) cross-coupling reaction of cyclopropane-
frameworks, providing a straightforward synthetic route to containing bifunctional building blocks.
cyclopropane fatty acids. The present method creates a direct
route for the construction of saturated carbon frameworks, and
can avoid the tedious multistep operations based on
unsaturated functional group manipulations that are often
Keywords: alkylation; cyclopropane; C–C coupling; fatty
acids; mycolic acids
Introduction
cis-Cyclopropane rings are biologically synthesized
by CFA synthase[1] and found in microorganisms,[2]
protozoa,[3] and plants[4] as cyclopropane fatty acids
(CFAs) and their phospholipids and glycolipids. In
addition, owing to its unique structural motif, the
cyclopropane moiety is often used in drug
development as a bioisostere of olefins, amides, and
other compounds.[5] A simple route to access CFAs is
the cyclopropanation of the corresponding unsaturated
fatty acid. However, there are some drawbacks: the
stereoselective construction of cyclopropane rings is
difficult, and only CFAs with available parent
unsaturated fatty acids are accessible. To synthesize
CFAs and their bioactive derivatives such as lipids, the
construction of not only the cyclopropane rings,[6] but
also of saturated hydrocarbon frameworks are
important. For instance, a class of long CFAs, mycolic
acids, has one or two cyclopropane ring(s) in a
saturated 60- to 90-carbon chain, as represented by -
mycolic acid shown in Scheme 1.[7] Therefore,
Scheme 1. Structure of -Mycolic Acid (1)
combining building blocks that contain a cyclopropane
ring and saturated carbon chain(s) is a more rational
route to access CFAs.[8] In this context,
1
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10.1002/adsc.201800901
Advanced Synthesis & Catalysis
Scheme 2. Synthetic routes of alkyl chains including a
cyclopropane ring.
some cyclopropane building blocks have been
developed for the total synthesis of CFAs and
employed in the synthesis of enantioenriched CFAs.[9]
These building blocks, however, require multistep
manipulations, including Wittig and Julia-type
olefination or the introduction of alkyne units and the
subsequent reduction of the unsaturated bonds to alkyl
chains (Scheme 2a-c).
Scheme 3. Synthesis of CFAs using a cyclopropane-
containing building block.
Results and Discussion
cis-Cyclopropane-containing building block 7 was
A good alternative method to attach a carbon chain
to a cyclopropane building block is a transition-metal-
catalyzed cross-coupling reaction.[10-12] Recently, the
authors (Y.F. and K.F.) reported the total synthesis of
cardiolipins using cross-coupling reactions, where a
synthesized
from
commercially
available
homopropargyl alcohol 2 (Scheme 4). Homologation
of the protected homopropargyl alcohol 3 via lithiation
and subsequent trapping by formaldehyde afforded 4.
Stereoselective hydrogenation of the internal alkyne 4
by Lindlar catalyst gave cis-allylic alcohol 5.[18] The
cyclopropanation of 5 by Zn(CH2I)2 proceeded
smoothly to give cis-cyclopropane-containing
monosilylated diol 6 as the sole stereoisomer in 77%
yield. Subsequent bromination of the hydroxy group
by CBr4-PPh3 afforded the cis-cyclopropane building
block 7 in 79% yield.
Pd-catalyzed
Sonogashira-type
cross-coupling
reaction followed by reduction of the C–C triple bond
(Scheme 2c) was used to connect an alkyl group and a
cyclopropane, along with Cu-catalyzed alkyl-alkyl
cross-coupling for the further extension of the
saturated carbon chain.[13]
We have reported Ni, Cu, Co, and Fe-catalyzed
cross-coupling reactions of alkyl halides with alkyl
Grignard reagents in the presence of unsaturated
hydrocarbon additives as promising routes for the
construction of saturated hydrocarbon frameworks.[14]
These alkyl-alkyl cross-coupling reactions are useful
for the preparation of fatty acids and their derivatives,
including glycerolipids and sphingolipids.[15,16] In
addition, trans-fatty acids were synthesized using
trans-6-bromo-1-(tert-butyldimethylsiloxy)-3-hexene
as a trans-olefin building block.[15]
These successful results prompted us to investigate
a practical synthetic route to access CFAs using
building blocks containing a cyclopropane (Scheme
2d). Scheme 3 depicts our strategy, in which we
devised an unsymmetric cyclopropane building block
having bromomethyl and 2-siloxyethyl groups on the
cyclopropane ring. The cross-coupling reaction at the
C–Br bond of the building block with an alkyl
Grignard reagent enables the single-step introduction
of a saturated hydrocarbon chain. The siloxy group in
the coupling product can be transformed into a halogen
group (X) in one step and subsequently used in the
cross-coupling reactions to access CFAs. When a
building block carrying a trans-cyclopropane ring or
an enantioenriched building block is used, trans-CFAs
or enantioenriched CFAs, respectively, are expected to
be synthetized in a similar way. Herein, we report the
synthesis of novel building blocks carrying a cis- or
trans-cyclopropane ring, and the results of assembling
CFAs by C(sp3)–C(sp3) cross-coupling reactions
employing the building blocks. This could be used in
the formal synthesis of a cyclopropane-containing
long fatty acid, -mycolic acid, following a reported
procedure.[17]
Scheme 4. Synthesis of cis-cyclopropane-containing
building block 7.
As
shown in Scheme
5, asymmetric
cyclopropanation of cis-allylic alcohol 5 by the
combined use of the chiral borane reagent 8 and
Zn(CH2I)2 as reported by Charette[19] afforded the
optically active 6 in 82% enantiomeric excess (ee),
suggesting that the present synthetic route could be
applicable to the asymmetric synthesis of CFAs (vide
infra).
2
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10.1002/adsc.201800901
Advanced Synthesis & Catalysis
Scheme 7. C(sp3)–C(sp3) coupling reaction of building
block 7 with an alkyl Grignard reagent.
Using building block 7, we attempted the synthesis
of an analogue of (Z)-octadec-9-enoic acid, oleic acid
(C18:1), having a cis-cyclopropane ring instead of the
cis-olefin and its analogues. We conducted the Ni-
catalyzed cross-coupling reaction of bromide 7 with
various alkyl Grignard reagents under the optimized
conditions, and subjected the crude coupling products
to bromination by in situ generated Br2PPh3 to afford
the corresponding bromide 13. Table 1 summarizes the
yields of the two-step manipulations, where the
somewhat lower yields for Et and nPr Grignard
Scheme 5. Asymmetric synthesis of building block 7.
A building block containing a trans-cyclopropane
was also synthesized in a similar manner. Sodium
bis(2-methoxyethoxy) aluminum hydride (Red-Al)-
mediated trans-selective reduction of the common
intermediate 4 afforded trans-allylic alcohol 9. The
cyclopropanation of 9 by Zn(CH2I)2 and the
subsequent bromination of the hydroxy group in
compound 10 gave the corresponding trans-
cyclopropane-containing building block 11 (Scheme
6).
Table 1. C(sp3)–C(sp3) coupling reaction of building block
7 with alkyl Grignard reagents.
Entry
AlkylMgCl 13
Yield [%]
1
2
3
4
5
6
7
8
EtMgCl
nPrMgCl
59
57
70
69
93
75
61
72
13a, -4
13b, -5
13c, -6
13d, -7
13e, -8
13f, -9
13g, -10
13h, -11
nBuMgCl
nPenMgCl
nHexMgCl
nHepMgCl
nOctMgCl
nNonMgCl
Scheme 6. Synthesis of trans-cyclopropane-containing
building block 11.
With building blocks bearing a cyclopropane ring in
hand, we next examined the cross-coupling reaction of
building block 7 with an alkyl Grignard reagent
(Scheme 7). The cross-coupling reaction of building
block 7 with nOctMgCl in the presence of 1 mol% of
NiCl2 and 20 mol% of 1,3-butadiene[14a] in THF at 25
ºC afforded the corresponding coupling product 12 in
72% yield. Lowering the reaction temperature to 0 ºC
improved the yield of 12 to 92%. It should be noted
that the bromide 7 could undergo a ring-opening
reaction of the cyclopropane when the corresponding
alkyl radical is generated via electron transfer;
however, no evidence of the radical ring-opening was
observed under the reaction conditions. This result is
consistent with our mechanistic studies on the Ni/1,3-
butadiene catalytic system.[14a,20] In contrast, the
attempt to generate the corresponding Grignard
reagent from bromide 7 under standard conditions
failed due to the radical opening of the cyclopropane
ring.
reagents are probably due to the volatility of the
resulting bromides 13a and 13b.
Next, we examined the cross-coupling reaction of
bromide 13 with bromoalkanoic acid 14 to produce
CFAs. We have previously reported the cross-
coupling reaction of in situ protected bromoalkanoates
14, formed by the treatment of bromoalkanoic acids
with tBuMgCl, with alkyl Grignard reagents to
synthesize various fatty acids.[15] Using the same in
situ protection, an analogue of oleic acid (C18:1)
having a cyclopropane ring (15f) was obtained in 55%
yield by the Ni/1,3-butadiene-catalyzed cross-
coupling reaction of in situ generated Grignard reagent
with magnesium 5-bromohexanoate 14 (n = 5) (Table
2, entry 6). By changing the carbon length of the
coupling partners, its regioisomers carrying the cis-
cyclopropane ring at the -4 to -11 positions were
obtained in moderate yields (entries 1-5 and 7-8). In
addition, CFAs consisting of different carbon lengths,
i.e., (Z)-hexadec-9-enoic acid and (Z)-icos-9-enoic
Table 2. Synthesis of cis-CFAs.
3
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10.1002/adsc.201800901
Advanced Synthesis & Catalysis
obtained the corresponding coupling product 18a in
49% yield after deprotection of the silyl group by
tetrabutylammonium fluoride (TBAF). An analogue of
elaidic acid, a trans-fatty acid (C18:1), having a trans-
cyclopropane ring instead of the trans-olefin, was
successfully synthesized by Jones oxidation of the
hydroxy group in 93% yield (Scheme 8).
Table 3 summarizes the results of the coupling
reactions of 11 with various alkyl Grignard reagents
followed by the second coupling reaction of the thus
formed bromides 16 with -siloxyalkyl Grignard
reagents 17 to afford 18, which has a trans-
cyclopropane ring at a different position from that of
18a. Both the first and second cross-coupling reactions,
along with the functional group transformations,
proceeded smoothly, giving rise to the correspond
alcohols 18b-g, bearing a cyclopropane ring at the -
4 to -10 positions, in moderate yields.
Entry Alkyl n of 14 15
Yield
[%]
1
2
3
4
5
6
7
8
Et
nPr
nBu
nPen
nHex
nHep
nOct
nNon
nHep
nHep
10
9
8
7
6
5
4
3
3
51
52a)
63
55
56
55
59
58
64
54
15a (C18:1, -4)
15b (C18:1, -5)
15c (C18:1, -6)
15d (C18:1, -7)
15e (C18:1, -8)
15f (C18:1, -9)
15g (C18:1, -10)
15h (C18:1, -11)
15i (C16:1, -9)
15j (C20:1, -9)
Because a cyclopropane ring consists of sp3-carbons,
it could contain a chiral center. Therefore, the
stereocontrolled synthesis of CFAs and related
compounds is important for the study of their
biological activities. We thus investigated the stability
9
10
7
a) Isolated as the corresponding Me ester.
acid, were synthesized in the same manner in good
yields (entries 9 and 10). These results demonstrate the
versatility of the present synthetic method for the
synthesis of various CFAs.
Table 3. Synthesis of 18 bearing a trans-cyclopropane ring
at different positions.
Next, the introduction of a trans-cyclopropane ring
into the fatty acids was examined using the trans-
cyclopropane building block 11. Under the same
conditions as shown in Table 1, the coupling reaction
of building block 11 with nHepMgCl proceeded
smoothly to give the corresponding coupling product
16a in 75% yield after bromination of the siloxy group
(Scheme 8).
Entry Alkyl
n of 17 18
Yield [%]
16
18
1
2
3
4
5
6
EtMgCl
nPrMgCl
nBuMgCl
nPenMgCl
nHexMgCl
nOctMgCl
11
10
9
8
7
38
40
46
69
96
66
52
54
62
53
56
52
18b, -4
18c, -5
18d, -6
18e, -7
18f, -8
18g, -10
5
Scheme 8. Synthesis of an analogue of elaidic acid having
a trans-cyclopropane.
As seen in Scheme 3, the obtained bromides can be
used as both bromides (Scheme 3, top) and Grignard
reagents (Scheme 3, bottom) in the successive
coupling reaction. We thus conducted the subsequent
coupling reaction of bromide 16a with siloxyhexyl
Grignard reagent 17a in the presence of 1 mol% of
NiCl2 and 1 equiv of 1,3-butadiene in THF, and
Scheme 9. Synthesis of an enantioenriched CFA.
4
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10.1002/adsc.201800901
Advanced Synthesis & Catalysis
of the chiral center of the enantioenriched building
block 7 (Scheme 5) throughout the present synthetic
route. The reaction of (S,S)-7 with nHepMgCl afforded
the corresponding coupling product 13f in 66% yield,
where no epimerization of the -chiral center of 7,
namely isomerization into a trans-cyclopropane, was
observed. This result indicates that the -carbon of the
reacting carbon center is stereochemically stable under
the present C(sp3)–C(sp3) coupling reaction. The
subsequent coupling reaction of the corresponding
Grignard reagent with 14f afforded enantioenriched
15f in 52% yield, as shown in Scheme 9.
rings in its saturated carbon chain, and which was
initially isolated from Mycobacterium Tuberculosis in
1938.[7] It is known that mycolic acids produced by
Mycobacterium Tuberculosis are a mixture of -
hydroxy acids. These acids contain at least one
cyclopropane ring on a long, saturated carbon chain
containing more than 40 carbons and possessing a
branched alkyl chain at the -position. The first total
synthesis of -mycolic acid was reported by Baird et
al. in 2003,[17,21] where a Wittig reaction or Julia
olefination and the subsequent diimide reduction of the
We next tried to synthesize -mycolic acid (1),
which is a long fatty acid containing two cyclopropane
Scheme 10. Synthesis of meromycolate moiety 26 of -mycolic acid.
resulting olefin moiety were employed to extend the
saturated carbon chain of -mycolic acid. In addition,
for the extension of the carbon chain, multistep
transformations of the reacting sites were required.
In contrast, the present method using the building
blocks mentioned above requires only one step, the
direct bromination of the siloxy group by Br2-PPh3, for
the subsequent coupling reaction with Grignard
reagents. In addition, by an additional transformation
of the bromide to the corresponding Grignard reagent,
the coupling reaction with alkyl halides could be
conducted. Accordingly, we assembled the
meromycolate moiety 26 of -mycolic acid 1 by
means of the present sequential coupling reaction of
the building blocks (Scheme 10).
The cross-coupling reaction of building block 7
with octadecyl Grignard reagent in the presence of 3
mol% of NiCl2 and 1 equiv of 1,3-butadiene in THF
gave the corresponding coupling product 20 in 85%
yield. The subsequent treatment of 20 with in situ
generated Br2PPh3 in dichloromethane at room
temperature afforded the corresponding bromide 21 in
88% yield. Next, we submitted bromide 21 to the
coupling reaction with Grignard reagent 22 under the
same catalytic conditions. The subsequent
deprotection of the silyl group by TBAF in the same
flask gave the desired product 23 in 56% yield. This
somewhat low yield is probably due to the lower
solubility of the long alkyl bromide 21 under the
coupling reaction conditions. Indeed, the reaction
mixture was a pale yellow suspension, and the yield of
the coupling reaction gradually decreased as the alkyl
chain of the bromides became longer.[22] In order to
improve the yield, the reaction conditions were
examined using bromide 21 and Grignard reagent 22.
When the reaction was conducted at an elevated
reaction temperature (50 ºC) in the presence of NiCl2
and 1,3-butadiene, the reaction mixture became a clear
solution, and the yield increased to 74%. At 50 ºC, a
copper/1-phenyl-1-propyne catalytic system[14b,c]
yielded the coupling product 23 in 64% yield, although
a cobalt/1,3-pentadiene catalytic system resulted in a
lower yield (21%).[14d-f] In addition, when the
corresponding fluoride was used instead of bromide 21,
the coupling product 23 was obtained in 65% yield by
the copper/1-phenyl-1-propyne catalyst at 50 ºC.
Treatment of 23 with PPh3, CBr4, and imidazole in
dichloromethane afforded the corresponding bromide
24 in 78% yield, which was then subjected to the Cu-
catalyzed cross-coupling reaction with Grignard
reagent 25. The subsequent deprotection furnished
meromycolate moiety 26 in 74% yield over two steps.
From the cyclopropane-containing building block 7,
we constructed a C38 saturated hydrocarbon chain
involving two cyclopropane rings in 32% total yield.
Meromycolate moiety 26 is a key intermediate in
Baird’s total synthesis of -mycolic acid 1.[17]
Conclusion
5
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10.1002/adsc.201800901
Advanced Synthesis & Catalysis
Various CFAs were prepared by the C(sp3)–C(sp3)
cross-coupling reaction of cyclopropane-containing
building blocks with alkyl Grignard reagents or alkyl
bromides using a Ni/1,3-butadiene or a Cu/alkyne
catalytic system, demonstrating the usefulness and
versatility of these cis- and trans-cyclopropane
building blocks for the assembly of CFAs. The present
synthetic method constructed the saturated carbon
frameworks directly, and constitutes a simpler route to
CFAs than hitherto-known synthetic methods. The
results reported herein, along with our previous
work,[15] demonstrate that the iterative C(sp3)–C(sp3)
cross-coupling reaction of bifunctional building
blocks is a powerful and straightforward synthetic tool
to access fatty acids bearing various motifs, such as
olefin and cyclopropane in their saturated carbon chain.
The usefulness of the iterative C(sp3)–C(sp3) cross-
coupling reaction was also demonstrated by the formal
total synthesis of a long fatty acid, -mycolic acid.
at 25 °C for 1 h. The reaction was carefully quenched by the
addition of 1N HCl aq. (10 mL) and extracted by Et2O (3 x
20 mL). The combined organic layer was dried over Na2SO4
and concentrated to obtain a crude product. The crude
product was used for next step without further purification.
A solution of PPh3 (2.36 g, 9.0 mmol) in CH2Cl2 (30 mL)
was added bromine until the color of bromine did not
disappear. To this mixture, the crude product was added and
stirred at rt. After 12 h, the mixture was added water (50
mL) and extracted by CH2Cl2 (3 x 30 mL). The organic layer
was dried over Na2SO4 and concentrated. Purification by
silica gel column chromatography afforded the
corresponding product.
General Procedure for the Cross-Coupling Reaction of
16 with Grignard Reagent 17 and Following
Deprotection (Scheme 8 and Table 3)
A Schlenk tube containing Mg (49 mg, 2 mmol) was added
THF (1 mL) and 1,2-dibromoethane (16 μL) to activate Mg
followed by the slow addition of
a
-(tert-
butyldimethylsiloxy)alkylbromide (1.0 mmol: For the
synthesis of this compound, see SI). The mixture was heated
at 60 °C for 30 min and then cooled to –78 °C and added 16
(0.5 mmol), 1,3-butadiene (11.2 mL, 0.5 mmol), and NiCl2
(0.7 mg, 1 mol%). After stirring at 0 °C for 1 h, the reaction
was quenched by adding 1N HCl aq. (5 mL). The product
was extracted by Et2O (3 x 20 mL), dried over Na2SO4, and
concentrated in vacuo. To the crude product, TBAF (1 M in
THF, 1.5 mL, 1.5 mmol) was added and stirred at rt for 3 h.
The reaction mixture was diluted with water (10 mL) and
extracted by Et2O (3 x 20 mL). The organic layer was dried
over Na2SO4, concentrated, and purified by silica gel
column chromatography.
Experimental Section
General Procedure for the Cross-Coupling Reaction of 7
with Alkyl Grignard Reagents and Following
Bromination (Table 1)
A Schlenk tube containing 7 (876 mg, 3.0 mmol) and THF
(1.0 mL) was added alkyl Grignard reagent (in THF, 6.0
mmol), 1,3-butadiene (13.5 mL as gas, 0.6 mmol), and
NiCl2 (3.9 mg, 1 mol%), successively, at –78 °C and stirred
at 0 °C for 1 h. The reaction was carefully quenched by the
addition of 1N HCl aq. (10 mL) and extracted by Et2O (3 x
20 mL). The combined organic layer was dried over Na2SO4
and concentrated to obtain a crude product. The crude
product was used for next step without further purification.
A solution of PPh3 (2.36 g, 9 mmol) in CH2Cl2 (30 mL) was
added bromine until the color of bromine did not disappear.
To this mixture, the crude product was added and stirred at
rt. After 12 h, the mixture was added water (50 mL) and
extracted by CH2Cl2 (3 x 30 mL). The organic layer was
dried over Na2SO4 and concentrated. Purification by silica
gel column chromatography afforded the corresponding
product.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific
Research (A) (JP25248025), a Grant-in-Aid for Young Scientists
(A) (JP16H06039), and JSPS Japanese-German Graduate
Externship from JSPS, Grant-in-Aid for Scientific Research on
Innovative Areas “Middle Molecular Strategy” (JP16H01150 and
JP18H04410) from MEXT, Japan.
References
[1] For reviews, see: a) M. Fontecave, M. Atta, E. Mulliez,
Trends Biochem. Sci. 2004, 29, 243; b) X. Bao, S. Katz,
M. Pollard, J. Ohlrogge, Proc. Natl. Acad. Sci. U. S. A.
2002, 99, 7172; c) J. E. Cronan Jr., Curr. Opin.
Microbiol. 2002, 5, 202.
General Procedure for the Cross-Coupling Reaction of
13 with Bromoalkanoic Acid (Table 2)
A Schlenk tube containing Mg (49 mg, 2 mmol) was added
THF (1 mL) and 1,2-dibromoethane (16 μL) to activate Mg
followed by the slow addition of bromide 13 (1.0 mmol).
The mixture was heated at 60 °C for 30 min. Another
Schlenk tube containing bromoalkanoic acid (0.5 mmol),
THF (0.5 mL), and NMP (50 μL) was cooled to –78 °C,
added tBuMgCl (in THF, 0.5 mmol), and stirred at the same
temperature for 10 min. The Schlenk tube containing
Grignard reagent was cooled with a dry ice-EtOH bath and
added 1,3-butadiene (11.2 mL, 0.5 mmol), the solution of
magnesium bromoalkanoate via a cannula, and NiCl2 (0.7
mg, 1 mol%), successively. The reaction mixture was stirred
at 0 °C for 1 h and then quenched by 1N HCl aq. (5 mL).
The product was extracted by Et2O (3 x 10 mL), dried over
Na2SO4, and purified by silica gel column chromatography.
[2] D. W. Grogan, J. E. Cronan Jr., Microbiol. Mol. Biol.
Rev. 1997, 61, 429.
[3] H. Meyer, G. G. Holz Jr., J. Bio. Chem. 1966, 241, 5000.
[4] R. C. Badami, K. B. Patil, Prog. Lipid Res. 1981, 19, 119.
[5] a) A. Reichelt, S. F. Martin, Acc. Chem. Res. 2006, 39,
433; b) T. T. Talele, J. Med. Chem. 2016, 59, 8712; c)
A. Mizuno, K. Matsui, S. Shuto, Chem. Eur. J. 2017, 23,
14394.
[6] O. G. Kulinkovich, Cyclopropanes in Organic
Synthesis, Wiley, New Jersey, 2015.
General Procedure for the Cross-Coupling Reaction of
11 with Alkyl Grignard Reagents and Following
Bromination (Scheme 8 and Table 3)
[7] a) F. H. Stodola, A. Lesuk, R. J. Anderson, J. Biol.
Chem. 1938, 126, 505; b) D. E. Minnikin, N. Polgar,
Tetrahedron Lett. 1966, 2643; c) D. E. Minnikin, N.
Polgar, Chem. Commun. 1966, 648; d) D. E. Minnikin,
A Schlenk tube containing 11 (876 mg, 3.0 mmol) and THF
(1.0 mL) was added alkyl Grignard reagent (in THF, 6.0
mmol), 1,3-butadiene (13.5 mL as gas, 0.6 mmol), and
NiCl2 (3.9 mg, 1 mol%), successively, at –78 °C and stirred
6
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10.1002/adsc.201800901
Advanced Synthesis & Catalysis
N. Polgar, Chem. Commun. 1967, 312; e) A. H. Etemadi,
J. Convit, Infec. Immun. 1974, 10, 236.
J. Org. Chem. 2014, 79, 8522; For Co: d) T. Iwasaki, H.
Takagawa, S. P. Singh, H. Kuniyasu, N. Kambe, J. Am.
Chem. Soc. 2013, 135, 9604; e) T. Iwasaki, H. Takagawa,
K. Okamoto, S. P. Singh, H. Kuniyasu, N. Kambe,
Synthesis 2014, 46, 1583; f) T. Iwasaki, K. Yamashita,
H. Kuniyasu, N. Kambe, Org. Lett. 2017, 19, 3691; For
Fe: g) T. Iwasaki, R. Shimizu, R. Imanishi, H. Kuniyasu,
N. Kambe, Chem. Lett. 2018, 47, 763.
[8] For reviews, see: a) R. Faust, Angew. Chem. 2001, 113,
2312; Angew. Chem. Int. Ed. 2001, 40, 2251; b) D. Y.-
K. Chen, R. H. Pouwer, J.-A. Richard, Chem. Soc. Rev.
2012, 41, 4631.
[9] a) S. Kobayashi, R. Tokunoh, M. Shibasaki, R.
Shinagawa, K. Murakami-Murofushi, Tetrahedron Lett.
1993, 34, 4047; b) G. D. Coxon, S. Knobl, E. Roberts,
M. S. Baird, J. R. Al Dulayymi, G. S. Besra, P. J.
Brennan, D. E. Minnikin, Tetrahedron Lett. 1999, 40,
6689; c) G. D. Coxon, J. R. Al-Dulayymi, M. S. Baird,
S. Knobl, E. Roberts, D. E. Minnikin, Tetrahedron
Asymmetry 2003, 14, 1211; d) S. Shah, J. M. White, S.
J. Williams, Org. Biomol. Chem. 2014, 12, 9427.
[15] T. Iwasaki, K. Higashikawa, V. P. Reddy, W. W. S.
Ho, Y. Fujimoto, K. Fukase, J. Terao, H. Kuniyasu, N.
Kambe, Chem. Eur. J. 2013, 19, 2956.
[16] T. Aiba, M. Sato, D. Umegaki, T. Iwasaki, N. Kambe,
K. Fukase, Y. Fujimoto, Org. Biomol. Chem. 2016, 14,
6672.
[17] a) J. R. Al Dulayymi, M. S. Baird, E. Roberts, Chem.
Commun. 2003, 228; b) J. R. Al Dulayymi, M. S. Baird,
E. Roberts, Tetrahedron 2005, 61, 11939; c) C. D.
Lawson, M. Maza-Iglesias, M. M. Sirhan, J. R. Al
Dulayymi, M. S. Baird, SynOpen 2017, 1, 103.
[10] A. de Meijere, F. Diederich, Eds. Metal-Catalyzed
Cross-Coupling Reactions, 2nd completely revised and
enlarged ed., Wiley-VCH, Weinheim, 2004, Vols. 1−2.
[11] K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem.
2005, 117, 4516; Angew. Chem. Int. Ed. 2005, 44, 4442.
[18] S. F. Kirsch, P. Klahn, H. Menz, Synthesis 2011, 3592.
[12] For recent reviews on C(sp3)–C(sp3) cross-coupling
reaction, see: a) T. Iwasaki, N. Kambe, Top. Curr. Chem.
2016, 374, 66; b) T. Iwasaki, N. Kambe, Coupling
Reactions Between sp3 Carbon Centers in
Comprehensive Organic Synthesis, 2nd ed. (Eds.: A.
Molander, P. Knochel), Elsevier, Oxford, 2014; Vol. 3,
p 337; c) X. L. Hu, Chem. Sci. 2011, 2, 1867; d) N.
Kambe, T. Iwasaki, J. Terao, Chem. Soc. Rev. 2011, 40,
4937. For seminal reports on Ni-catalyzed alkyl-alkyl
cross-coupling reaction: e) A. Devasagayaraj, T.
Stüdemann, P. Knochel, Angew. Chem. 1995, 107, 2952;
Angew. Chem. Int. Ed. 1995, 34, 2723; f) J. S. Zhou, G.
C. Fu, J. Am. Chem. Soc. 2003, 125, 14726; g) T. J.
Anderson, G. D. Jones, D. A. Vicic, J. Am. Chem. Soc.
2004, 126, 8100; h) V. B. Phapale, E. Buñuel, M.
García-Iglesias, D. J. Cárdenas, Angew. Chem. 2007,
119, 8946; Angew. Chem. Int. Ed. 2007, 46, 8790; i) O.
Vechorkin, X. Hu, Angew. Chem. 2009, 121, 2981;
Angew. Chem. Int. Ed. 2009, 48, 2937.
[19] A. B. Charette, S. Prescott, C. Brochu, J. Org. Chem.
1995, 60, 1081.
[20] a) T. Iwasaki, A. Tsumura, T. Omori, H. Kuniyasu, J.
Terao, N. Kambe, Chem. Lett. 2011, 40, 1024; b) T.
Iwasaki, A. Fukuoka, W. Yokoyama, X. Min, I. Hisaki,
T. Yang, M. Ehara, H. Kuniyasu, N. Kambe, Chem. Sci.
2018, 9, 2195.
[21] Total synthesis of other mycolic acids was achieved in
a similar approach, see for recent reports: a) J. R. Al
Dulayymi, M. S. Baird, E. Roberts, M. Deysel, J.
Verschoor, Tetrahedron 2007, 63, 2571; b) G. Koza, C.
Theunissen, J. R. Al Dulayymi, M. S. Baird,
Tetrahedron 2009, 65, 10214; c) G. Koza, M. Muzael,
R. R. Schubert-Rowles, C. Theunissen, J. R. Al
Dulayymi, M. S. Baird, Tetrahedron 2013, 69, 6285; d)
D. Z. Al Kremawi, J. R. Al Dulayymi, M. S. Baird,
Tetrahedron 2014, 70, 7322; e) H. M. Ali, G. Koza, R.
T. Hameed, R. Rowles, C. Davies, J. R. Al Dulayymi, C.
D. Gwenin, M. S. Baird, Tetrahedron 2016, 72, 7143.
[13] S. Inuki, I. Ohta, S. Ishibashi, M. Takamatsu, K.
Fukase, Y. Fujimoto, J. Org. Chem. 2017, 82, 7832.
[22] For instance, nC10H21Br coupled with a siloxyalkyl
Grignard reagent in 84% yield by the Ni/1,3-butadiene
catalytic system at 0 ºC. However, the reaction of
nC23H47Br resulted in 50% yield under the same
conditions, and that of nC33H67Br resulted in 24% yield
even at rt.
[14] For Ni: a) J. Terao, H. Watanabe, A. Ikumi, H.
Kuniyasu, N. Kambe, J. Am. Chem. Soc. 2002, 124,
4222; For Cu: b) J. Terao, H. Todo, S. A. Begum, H.
Kuniyasu, N. Kambe, Angew. Chem. 2007, 119, 2132;
Angew. Chem. Int. Ed. 2007, 46, 2086; c) T. Iwasaki, R.
Imanishi, R. Shimizu, H. Kuniyasu, J. Terao, N. Kambe,
7
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10.1002/adsc.201800901
Advanced Synthesis & Catalysis
UPDATE
Synthesis of Cyclopropane Fatty Acids by C(sp3)–
C(sp3) Cross-coupling Reaction and Formal
Synthesis of -Mycolic Acid
Adv. Synth. Catal. Year, Volume, Page – Page
Takanori Iwasaki,* Shohei Terahigashi, Yufei
Wang, Arisa Tanaka, Hanqing Zhao, Yukari
Fujimoto,. Koichi Fukase, Nobuaki Kambe*
8
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