Direct aldol strategy in enantioselective total synthesis of thuggacin b

Article abstract of DOI:10.1002/chem.201304297

An enantioselective total synthesis of thuggacin B, a natural product exhibiting antibiotic activity against Mycobacterium tuberculosis, is described. Asymmetric direct aldol reactions promoted by Cu and Zn catalysts play a pivotal role in constructing four stereogenic centers. The use of direct aldol reactions as the initial steps for the synthesis of two key fragments allowed the construction of the other stereogenic centers through chirality transfer. Antibiotic activity against Mycobacterium tuberculosis is exhibited by the natural product thuggacin B, the enantioselective total synthesis of which is described. Catalytic asymmetric direct aldol reactions promoted by Cu and Zn catalysts played a pivotal role in constructing four stereogenic centers. The execution of direct aldol reactions as the initial steps for the synthesis of two key fragments allowed the construction of the other stereogenic centers through chirality transfer. PG=protecting group. Copyright

Full text of DOI:10.1002/chem.201304297

DOI: 10.1002/chem.201304297
Communication
&
Natural Product Synthesis
Direct Aldol Strategy in Enantioselective Total Synthesis of
Thuggacin B
Akinobu Matsuzawa,[a, b] Christopher R. Opie,[a] Naoya Kumagai,*[a] and
Masakatsu Shibasaki*[a, c]
analysis.[2] Particular interest in these novel antibiotics arises
Abstract: An enantioselective total synthesis of thugga-
cin B, a natural product exhibiting antibiotic activity
from their promising potency against Mycobacterium tuberculo-
sis (TB). TB is a life-threatening airborne infectious disease and
against Mycobacterium tuberculosis, is described. Asym-
the second highest cause of death among infectious diseas-
metric direct aldol reactions promoted by Cu and Zn cata-
es.[2] The recent emergence of multidrug-resistant (MDR) and
lysts play a pivotal role in constructing four stereogenic
extensively drug-resistant (XDR) TB strains has stimulated ex-
centers. The use of direct aldol reactions as the initial
tensive research in seeking novel medications to combat the
steps for the synthesis of two key fragments allowed the
disease.[3–5] Thuggacins proved effective against TB via a differ-
construction of the other stereogenic centers through
ent mode of action from that of antibiotics in current first- and
second-line treatments.[1,2] Together with the intriguing poten-
chirality transfer.
tial for TB treatment, the structural features of the polyol
system have attracted our particular attention for enantioselec-
Thuggacins A–C are polyketide antibiotics identified in extracts
from the myxobacterium Sorangium cellulosum So ce895 in
bioactivity-guided isolation by
tive synthesis utilizing our asymmetric catalysts. Just one ex-
ample of the total synthesis of thuggacin B as well as its ste-
Jansen et al. in 2007 (Figure 1).[1]
Key structural characteristics are
five consecutive stereogenic cen-
ters at C16–C20, a macrolide em-
bedded by a thiazole ring, an
E,Z-conjugated diene, and an E-
unsaturated ester, which are all
shared in thuggacins A–C. They
differ in macrolactone ring size
and interconvert by transacyla-
tion in methanol.[1a] A pendant
hexyl group at C2 is unusual
among the secondary metabo-
lites and its biosynthetic origin
was addressed by gene cluster Figure 1. Structure of thuggacins A–C.
reochemical determination by extensive NMR studies has been
completed by Kirschning et al.[6] Synthetic studies were report-
ed based on a chiral auxiliary approach.[7,8] Herein, we report
a convergent synthesis of thuggacin B utilizing two distinct
direct aldol reactions promoted by Zn and Cu catalysts devel-
oped in our group. These catalysts were deployed in the initial
stage of the synthesis of two key fragments, allowing the con-
struction of the other stereogenic centers through chirality
transfer.
[a] A. Matsuzawa, Dr. C. R. Opie, Dr. N. Kumagai, Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry (BIKAKEN), Tokyo
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
Fax: (+81)3-3441-7589
E-mail: nkumagai@bikaken.or.jp
mshibasa@bikaken.or.jp
Homepage: http://www.bikaken.or.jp/research/group/shibasaki/shibasaki-
lab/index_e.html
[b] A. Matsuzawa
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Our retrosynthesis of thuggacin B is delineated in Scheme 1.
Two CÀC bonds at C7–C8 and C16–C17 are to be constructed
with concomitant generation of four stereogenic centers by
direct catalytic asymmetric aldol reactions that were developed
by our group. The macrocycle was disconnected by Sonoga-
shira coupling and macrolactonization to give known key frag-
[c] Prof. Dr. M. Shibasaki
JST, ACT-C
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304297.
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Scheme 1. Retrosynthetic analysis of thuggacin B.
Scheme 2. Synthesis of fragment 1. Reagents and conditions: a) MeOTf,
NaHCO3, CH2Cl2, RT; then HÀlÀCysÀOMe, EtOH, RT, 80%; b) BrCCl3, DBU,
CH2Cl2, 08C, 90%; c) TBSOTf, 2,6-lutidine, CH2Cl2, RT; d) NH4F, MeOH, 508C,
87% (2 steps); e) Dess–Martin periodinane, CH2Cl2, RT, 96%; f) LiÀCꢀC(TMS),
ether, À788C, anti/syn=6/1, 74%; g) TBAF, THF, RT, 84%; h) 2,2-dimethoxy-
propane, PPTS, THF, RT, 63% (after separation of the undesired diastereo-
mer); i) [Cp2Zr(H)Cl], THF, RT; then I2, RT, 56%; j) Dess–Martin periodinane,
CH2Cl2, RT, 95%; k) phosphonate 20, LHMDS, THF, À788C, E/Z=6/1, 93%.
PPTS=pyridinium p-toluenesulfonate; LHMDS=lithium bis(trimethylsilyl)-
amide.
ments 1 and 2. The thiazole ring of fragment 1 would be fur-
nished from thioamide 3, which we expected would be pro-
duced by the direct catalytic asymmetric aldol reaction of thio-
amide 7 in enantio- and diastereoselective fashion by a Cu-
based soft Lewis acid/hard Brønsted base cooperative catalyst.
Fragment 2 was further disconnected to form aldehyde 4 and
ketone 5 by a diastereoselective aldol reaction. The direct cata-
lytic asymmetric aldol reaction of hydroxyketone 9 promoted
by a trinuclear Zn catalyst was planned to be applied for enan-
tio- and diastereoselective access of the chiral aldehyde 4.
Synthesis of fragment 1 commenced with the syn-selective
direct aldol reaction of O-functionalized aldehyde 10 and thio-
propanamide 7, promoted by 2 mol% of the cooperative
separable, and the mixture was treated with TBAF to remove
two silyl groups. After protecting the 1,3-diol unit as an aceto-
nide, 18 was isolated chromatographically as a single dia-
stereomer.[18] The requisite E-alkenyl iodide of 19 for Sonoga-
shira coupling with fragment 2 was furnished by hydrozircona-
tion/iodination. The ester at the thiazole ring was simultane-
ously reduced to a primary alcohol by Schwartz’s reagent,[19]
and the alcohol was elongated by oxidation followed by
a Horner–Wadsworth–Emmons reaction with phosphonate 20
to afford fragment 1.[20]
The direct aldol reaction of hydroxyketone 9 and O-function-
alized aldehyde 21 under proton transfer conditions initiated
the synthesis of fragment 2 (Scheme 3).[21] The catalytically
active trinuclear Zn complex prepared from 2 and 1 mol% of
Et2Zn and linked-BINOL, respectively, promoted the reaction
leading to the preferential formation of the syn-diol unit in
93% ee. Facile chromatographic separation of the undesired
anti-diastereomer followed by a single recrystallization provid-
ed enantiopure syn-22 in 84% yield. After protection of 1,2-
catalyst
composed
of
mesitylcopper/(R,R)-Ph-BPE/11
(Scheme 2).[9–11] The thioamide functionality was particularly ad-
vantageous for the rapid construction of the requisite thiazole
ring. Desired diastereomer 12 was obtained almost exclusively
in 84% yield with 93% ee. S-selective methylation by MeOTf
followed by the addition of l-cysteine methyl ester furnished
the thiazoline ring of 14 through the intermediacy of 13.[12,13]
Oxidative aromatization by bromotrichloromethane and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) gave thiazole 15 in 90%
yield.[14] Treatment with NH4F after the protection of the secon-
dary alcohol of 15 by a tert-butyldimethylsilyl ether (TBS)
group liberated the primary alcohol,[15] which was oxidized by
Dess–Martin periodinane to afford aldehyde 16.[16] Alkynylation
by Li-acetylide in diethyl ether proceeded in a diastereoselec-
tive fashion to give the desired propargylic alcohol 17 prefer-
entially.[17] Compound 17 and its minor diastereomer were in-
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Communication
which was oxidized to the aldehyde with tetrapropylam-
monium perruthenate (TPAP). Subsequent treatment with
Ohira–Bestmann’s reagent furnished fragment 2.[26]
Completion of the total synthesis of thuggacin B was con-
ducted by using a modification of the reported procedure
(Scheme 4).[6b] The two fragments 1 and 2 were assembled by
Sonogashira coupling in 72% yield and two TBS groups were
removed with TBAF to give free diol 30. C20 epimer was sepa-
rated by HPLC at this stage. The ester was hydrolyzed and sub-
sequent partial reduction of alkyne by Lindlar catalyst with
quinoline produced cyclization precursor 31 with the E,Z-1,3-
diene at C10–C13. Macrolactonization under Shiina’s conditions
using 2-methyl-6-nitrobenzoic anhydride (MNBA) gave rise to
the requisite carbon framework with its 18-membered ring
core;[27] the two acetonide moieties were hydrolyzed with CSA
to afford thuggacin B. All the spectroscopic data of the syn-
thetic thuggacin B matched the reported data.
In summary, enantioselective total synthesis of thuggacin B
was achieved by harnessing enantio- and diastereoselective
direct aldol methodologies. Two distinct catalysts were used in
the initial steps for each key fragment and the other stereo-
genic centers were constructed through efficient chirality
transfer, highlighting the particular utility in stereoselective
synthesis of the polyketide framework.
Scheme 3. Synthesis of fragment 2. Reagents and conditions: a) triphosgene,
pyridine, CH2Cl2, 08C, quant.; b) mCPBA, NaH2PO4, CH2Cl2, 408C, 94%; c) Red-
Al, THF, 08C, 91%; d) TBSOTf, 2,6-lutidine, CH2Cl2, 08C, quant.; e) RuCl3
(10 mol%), NaIO4, CH3CN/CCl4/H2O, RT, 82%; f) CSA, EtOH, 08C, 76%;
g) TEMPO, PhI(OAc)2, CH2Cl2, RT, 88%; h) enol silyl ether 27, BF3·OEt2, CH2Cl2,
À408C, 49% (desired stereoisomer); i) Et2BOMe, NaBH4, THF/MeOH, À408C,
84%; j) 2,2-dimethoxypropane, CSA, DMF, RT; k) K2CO3, MeOH, RT, 85%
(2 steps); l) TPAP (10 mol%), NMO, MS 3 ꢁ, CH2Cl2, RT, 77%; m) Ohira–Best-
mann’s reagent, K2CO3, MeOH, RT, 73%. NMO=4-methylmorpholine N-oxide.
Acknowledgements
This work was financially supported by JST, ACT-C, and JSPS
KAKENHI Grant Number 25713002. A.M. thanks JSPS for a pre-
doctoral fellowship.
diol 22 as a cyclic carbonate, Baeyer–Villiger oxidation was ef-
fected by meta-chloroperoxybenzoic acid (mCPBA) to give
guaiacol ester 24 exclusively, due to the predominant rear-
rangement of the electron-rich o-anisolyl group.[22] Carbonyl
functionalities were reduced by Red-Al and the triol thus ob-
tained was protected by TBS groups. Benzylic oxidation of 25
followed by treatment with camphorsulfonic acid (CSA) result-
ed in selective removal of the terminal TBS group to generate
the primary alcohol, which was oxidized by (2,2,6,6-tetrame-
thylpiperidin-1-yl)oxidanyl (TEMPO)/PhI(OAc)2 to afford alde-
hyde 26. Subsequent diastereoselective Mukaiyama aldol reac-
tion with enol silyl ether 27 generated from dienone 5 pro-
duced the aldol product 28 with the desired stereochemistry
in 49% yield.[23] syn-Selective reduction of the b-hydroxyketone
moiety was attempted with Et2BOMe/NaBH4 to construct the
requisite 5-contiguous stereogenic centers of 29,[24] the known
intermediate for fragment 2 reported by Kirschning et al.[6b]
Whereas the desired diastereomer with all-syn orientation was
obtained as the major product,[25] the inseparable diastereo-
mixture containing the C20 epimer was forwarded to frag-
ment 2 bearing a terminal alkyne by using the reported proce-
dure.[6b] After protecting the free 1,3-diol as an acetonide,
methanolysis of the benzoate generated a primary alcohol,
Scheme 4. Completion of total synthesis of thuggacin B. Reagents and con-
ditions: a) 2, [PdCl2(PPh3)2] (10 mol%), CuI, Et3N, CH3CN, À208C to RT, 72%;
b) TBAF, THF, RT, 97%; after HPLC separation, 50%; c) KOH, EtOH, H2O, RT,
quant.; d) Lindlar catalyst, H2, quinoline, AcOEt, RT; e) MNBA, DMAP, MS 3 ꢁ,
toluene, 708C, 38% (2 steps); f) CSA, MeOH, RT, 39%. MNBA=2-methyl-6-ni-
trobenzoic anhydride.
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Keywords: direct aldol reactions · thioamides · thuggacins ·
total synthesis · tuberculosis
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Published online on December 2, 2013
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