Concise total synthesis of (-)-myxalamide A

Article abstract of DOI:10.1002/anie.201203093

The MIDA touch: A concise and highly convergent protecting-group-free total synthesis of (-)-myxalamide A involves a stereoselective vinylogous Mukaiyama aldol reaction of a vinylketene silyl N,O-acetal, together with a one-pot Stille/Suzuki-Miyaura cross-coupling reaction using Burke's N- methyliminodiacetic acid (MIDA) boronate to connect left- and right-hand fragments of the molecule (see scheme). Copyright

Full text of DOI:10.1002/anie.201203093

Angewandte
Chemie
DOI: 10.1002/anie.201203093
Natural Product Synthesis
Concise Total Synthesis of (À)-Myxalamide A**
Kazuhiro Fujita, Ryosuke Matsui, Takahiro Suzuki, and Susumu Kobayashi*
Myxalamide A–D (1–4) were first isolated from the gliding
bacterium Myxococcus xanthus by Jansen and co-workers in
1983 and were identified as polyene antibiotics[1] (Scheme 1).
Initially, our strategy was to construct the conjugated
pentaene structure during the final step of the synthesis
through a one-pot Stille/Suzuki–Miyaura cross-coupling reac-
tion involving the three fragments, 6, 7, and (Z)-boronate 8,
the latter of which is derived from N-methyliminodiacetic
acid (MIDA) (Scheme 2).[10] This one-pot Stille/Suzuki–
Scheme 1. Structure of (À)-myxalamide A and its analogues.
The characteristic structural feature of the myxalamides and
an analogue, stipiamide[2] (5), is the labile (E,E,Z,E,E)-
pentaene motif, the synthesis of which has attracted consid-
erable attention. Indeed, Mapp and Heathcock achieved an
elegant total synthesis of 1 in 22 steps.[3] Syntheses of other
myxalamides and structurally related compounds have also
been reported;[4–6] for example, the 16-step synthesis of 5 by
Andrus and Lepore[4a] and the synthesis of 2’-O-methylmyx-
alamide D in 11 steps by Coleman et al.[5]
Scheme 2. Convergent retrosynthetic strategy for 1. TBS=tert-butyldi-
methylsilyl.
We have previously reported a highly stereoselective
vinylogous Mukaiyama aldol reaction (VMAR) involving
vinylketene silyl N,O-acetals.[7] This methodology can provide
the anti-d-hydroxy-a,g-dimethyl-a,b-unsaturated carbonyl
moiety, which is found in a number of naturally occurring
polyketides. In fact, many groups have successfully utilized
the VMAR in natural product syntheses.[8,9] We envisaged
that the C9-C13 segment of 1 could be constructed by using
our methodology. Herein, we disclose a highly convergent,
concise, and protecting-group-free synthesis of 1.
Miyaura cross-coupling reaction has the advantage of mini-
mizing the handling of the labile Z olefin. The left-hand
fragment 6 could be constructed by the VMAR involving
aldehyde 9, a reaction, which would lead to the formation of
À
the C12 C13 bond with the required anti stereochemistry.
The right-hand fragment 7 could be derived from a Horner–
Wadsworth–Emmons reaction and an amidation reaction
with the amine, (S)-alaninol (11).
Firstly, we synthesized the left-hand fragment
6
(Scheme 3). The enal 9 was prepared in four steps from
commercially available (S)-2-methylbutanol.[11] When 9 was
subjected to the VMAR according to the protocol established
in our laboratory, that is, the use of the TiCl4 in CH2Cl2 and
the employment of two equivalents of the aldehyde, the anti
aldol adduct 13 was obtained in 86% yield with high
diastereoselectivity (d.r. > 20:1). Furthermore, the addition
of a catalytic amount of water (10 mol%) led to an
accelerated VMAR that gave product with similar yield and
diastereoselectivity.[7d] Reductive removal of the chiral aux-
iliary with LiBH4, and oxidation of the resulting primary
alcohol with MnO2 provided aldehyde 14 in 91% yield (two
steps).[12]
[*] K. Fujita, Dr. R. Matsui, Dr. T. Suzuki, Prof. Dr. S. Kobayashi
Faculty of Pharmaceutical Sciences, Tokyo University of Science
2641 Yamazaki, Noda-shi, Chiba 278-8510 (Japan)
E-mail: kobayash@rs.noda.tus.ac.jp
Homepage: http://www.rs.noda.tus.ac.jp/kobalab/index.html
[**] This research was supported in part by a Grant-in-Aid for a Scientific
Research (B, KAKENHI No. 22390004) from the Japan Society for
the Promotion Science. We sincerely thank Dr. Kentaro Okano
(Tohoku University) for helpful discussion.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203093.
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Scheme 4. Synthesis of right-hand fragment 7. Reagents and condi-
tions: a) TMSOK, THF, RT; b) 11, PyBroP, iPr2NEt, CH2Cl2, 08C to RT,
94% (2 steps). THF=tetrahydrofuran, TMS=trimethylsilyl, PyBroP=
bromotripyrrolidinophosphonium hexafluorophosphate.
Scheme 3. Synthesis of left-hand fragment 6. Reagents and conditions:
a) TiCl4, 9, CH2Cl2, À78 to À508C, 86% (d.r.>20:1); b) LiBH4, MeOH
(cat), Et2O, 08C; c) MnO2, CH2Cl2, RT, 91% (2 steps);
P(2-furyl)3 the triene 18 was obtained, but the yield was
moderate and variable (approximately 30–60%; Table 1,
entry 5). Ethenyl boronate[18] was observed as a degradation
product, thus suggesting that the catalytic cycle was hampered
after the oxidative addition reaction of (Z)-boronate 8 and
the palladium catalyst, probably because of the instability of
the resulting palladium complex. Thus we examined the
reaction further by employing Buchwaldꢀs monodentate
biaryldialkylphosphine ligands.[19] To our delight, after exten-
sive experimentation, we found that the desired triene 18
could be obtained in high yield when using JohnPhos as
a monodentate ligand (Table 1, entries 7 and 8).
Next, we aimed to find suitable reaction conditions for
achieving the Suzuki–Miyaura coupling reaction of 18 and
vinyl iodide 6. In doing so, the instability of the conjugated
pentaene moiety had to be considered. The use of SPhos and
JohnPhos in basic solution afforded (À)-myxalamide A (1) in
62% and 56% yields, respectively.[20] Although the coupling
reaction proceeded smoothly the yield was moderate because
of isomerization of the Z double bond of 1. Several measures
were adopted to minimize this isomerization. Manipulations
were conducted in the dark and all solvents that were used for
the reaction and for chromatography were thoroughly
degassed prior to use. Unfortunately, isomerization of the
Z double bond into the stable E double bond could not be
completely suppressed (Figure 1).
d) (MeO)2P(O)CHN2, KOtBu, THF, À788C to RT, 75%; e) HZrCp2Cl,
THF, 08C, then I2, À788C, 58% (E/Z>20:1).
We next investigated the transformation of aldehyde 14
into vinyl iodide 6. The use of the Takai–Utimoto olefina-
tion[13] (CHI3 and CrCl2), as a means to achieve this trans-
formation directly, was unsuitable because of low yield and
low selectivity. Thus aldehyde 14 was first converted into the
enyne 15 by using the Seyferth–Gilbert reagent.[14] Hydro-
zirconation of enyne 15 by using the Schwartz reagent and
treatment of the resulting vinyl zirconium species with iodine
led to vinyl iodide 6 with high selectivity (E/Z > 20:1).
Next, we examined the synthesis of the right-hand frag-
ment 7 (Scheme 4). Allyl alcohol 12 was converted into ester
16 in two steps.[15] Hydrolysis of ester 16 with TMSOK gave
carboxylic acid 17. The crude carboxylic acid 17 was coupled
with (S)-alaninol (11) by using PyBrop as the coupling
reagent to give vinyl stannane 7 in 94% yield (two steps).
Having all fragments, that is, 6, 7, and 8,[16] in hand, we
next focused on the Stille coupling reaction of 7 and 8
(Table 1). Unfortunately, the use of standard Stille coupling
reaction conditions[17] resulted in the decomposition of
(Z)-boronate 8 (Table 1, entry 1–4). When the reaction was
conducted at low temperature and in the presence of
Table 1: Completion of the total synthesis of (À)-myxalamide A by a stepwise Stille/Suzuki–Miyaura coupling.
Entry
Equiv. of 8
Catalyst (mol%)
Additive (mol%)
Solvent
T
Yield [%]
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.6
1.3
1.6
1.2
1.2
[Pd(PPh3)4] (10)
[Pd(PPh3)4] (10)
CuI (150)
CuTC (150)
AsPh3 (20)
THF/DMF
DMF
THF/DMF
THF/DMF
THF
THF/DMF
THF/DMF
CH3CN/DMF
RT
RT
decomposed
trace
decomposed
trace
51
45
88
99
[PdCl2(CH3CN)2] (10)
[Pd2(dba)3·CHCl3] (10)
[Pd2(dba)3·CHCl3] (20)
[Pd2(dba)3·CHCl3] (10)
[Pd2(dba)3·CHCl3] (5.0)
[Pd2(dba)3·CHCl3] (5.0)
08C to RT
À208C
À208C
À208C
À308C
À108C
dppe (40)
P(2-furyl)3 (50)
SPhos (40)
JohnPhos (20)
JohnPhos (20)
dba=dibenzylideneacetone, DMF=N,N-dimethylformamide, dppe=1,2-bis(diphenylphosphino)ethane, JohnPhos=2-(di-tert-butylphosphino)
biphenyl, SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, TC=2-thiophenecarboxylate.
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Angew. Chem. Int. Ed. 2012, 51, 7271 –7274

Angewandte
Chemie
Received: April 23, 2012
Published online: June 13, 2012
Keywords: aldol reaction · cross-coupling · polyene antibiotics ·
.
protecting-group-free synthesis · total synthesis
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Figure 1. A downfield section of the 1H NMR spectrum of our synthetic
(À)-myxalamide A (5.0–7.2 ppm).
Having established the total synthesis of 1 by stepwise
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(Scheme 5). Compound 8 (1.3 equivalents) and vinyl stan-
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Scheme 5. Completion of the total synthesis of (À)-myxalamide A by
a one-pot Stille/Suzuki–Miyaura coupling reaction. Reagents and
conditions: 8, [Pd2(dba)3·CHCl3], JohnPhos, CH3CN, DMF, À108C,
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nane 7 (1.0 equivalent) in CH3CN and DMF was treated with
JohnPhos (20 mol%) and [Pd2(dba)3·CHCl3] (5.0 mol%) and
the resulting reaction mixture was allowed to stir at À108C for
24 hours; subsequently, 1m aqueous NaOH, vinyl iodide 6
(1.3 equivalents), and [Pd2(dba)3·CHCl3] (5.0 mol%, to accel-
erate Suzuki–Miyaura coupling) were added and the reaction
mixture was stirred at room temperature for 22 hours, thus
affording (À)-myxalamide
A
in 59% yield. The 1H-,
13C NMR, IR, and HRMS spectra, as well the optical rotation
of our synthetic (À)-1 were identical to those of natural (À)-1.
In summary, we have accomplished a protecting-group-
free total synthesis of (À)-myxalamide A in six steps from
N,O-acetal 10 (ten steps from commercially available (S)-2-
methylbutanol). The characteristic features of the synthesis
À
are: (i) a concise construction of the C9 C13 moiety using
a vinylogous Mukaiyama aldol reaction; (ii) a one-pot Stille
and Suzuki–Miyaura coupling reaction for connecting frag-
ments 6 and 7 with (Z)-boronate 8; and (iii) the first example
of a natural product synthesis achieved by a research group
other than that of Burke, wherein Burkeꢀs N-methyliminodi-
acetic acid (MIDA) boronates are employed. Our highly
convergent synthetic strategy represents an efficient means
for preparing a conjugated pentaene motif.
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[20] Notably, whereas the reaction proceeded smoothly in CH3CN or
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adduct 13 into aldehyde 14. After extensive efforts, we found
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