A general sultone route to the pamamycin macrodiolides - Total synthesis of pamamycin-621A and pamamycin-635B

Article abstract of DOI:10.1002/anie.200501511

(Chemical Equation Presented) Sultones swing again: The first total syntheses of the title antibiotics (see scheme) were achieved by application of sultone methodology. Since the final lactonizations with formation of the ester linkage between C1′ and the

Full text of DOI:10.1002/anie.200501511

Angewandte
Chemie
Table 1: Selected pamamycin homologues.
R1
R2
R3
R4
R5
Pamamycin
1a
1b
1c
1d
1e
1 f
1g
M
Me
Et
Me
Me
Et
e
Me
H
Me
Me
Me
Me
M
e
M
e
M
e
H
Me
Me
Et
Me
Me
Et
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
621A
621B
635A
635B
635C
649B
Natural Product Synthesis
DOI: 10.1002/anie.200501511
Et
A General Sultone Route to the Pamamycin
Macrodiolides—Total Synthesis of Pamamycin-
621A and Pamamycin-635B**
readily assembled by regioselective opening of an enantio-
merically pure terminal epoxide with lithiated furan,[4,8,9] an
alternative protocol was required for efficiently securing the
key hydroxyalkylfuran needed for targets with R5 ¼ H. Here
we report a solution to this problem that eventually led to a
straightforward route to pamamycin-621A (1b)[10–13] and
pamamycin-635B( 1e)[13a,14] using a sultone approach.
Petra Fischer, Ana BelØn García Segovia,
Margit Gruner, and Peter Metz*
In memory of Udo Gräfe
Following the strategy that was successful for 1a,[4] the
pamamycins 1b and 1e were at first retrosynthetically
disconnected to give the silylated larger hydroxy acid 2 and
benzyl esters 3a and 3b, respectively (Scheme 1). Acid 2 had
The pamamycins (1) are a class of 16-membered macrodiolide
homologues that have been isolated from various Streptomy-
ces species (Table 1).[1,2] Besides displaying pronounced
autoregulatory, anionophoric, and antifungal activities, sev-
eral members of this family have been shown to be highly
active against Gram-positive bacteria including multiple
antibiotic-resistant strains of Mycobacterium tuberculosis.[1a,3]
We have recently accomplished a total synthesis of
pamamycin-607 (1a)[4,5] by extensive application of sultone
methodology.[6] To facilitate more detailed studies of struc-
ture–activity relationships with respect to the antimycobacte-
rial action of the pamamycins, we decided to utilize our
sultone route to (n)actic acids and analogues[7] for the
preparation of selected higher homologues of 1a as well. A
major problem that had to be addressed in this context was
the enantioselective synthesis of the smaller hydroxy acids
incorporated in 1 featuring R5 ¼ H. Whereas the smaller
fragment of pamamycin-607 (1a) with R5 = H could be
Scheme 1. Retrosynthetic analysis of 1b and 1e. TBS=tert-butyldi-
methylsilyl
already been used as the larger fragment in our synthesis of
1a, and the smaller hydroxy acid corresponding to 3a also
occurs in the pamamycins 1c, 1d, 1 f, and 1g. Very recently,
we found that our published route to 1a[4] can be further
streamlined by employing the more easily accessible benzyl
ester of the smaller fragment epimeric at C2’, since the final
macrolactonization is accompanied by complete epimeriza-
tion at C2’.[2] As a consequence, we felt that use of 4a,b
instead of 3a,b might be a viable alternative for a related
route to pamamycin-621A (1b) and pamamycin-635B( 1e) as
well.
[*] Dipl.-Chem. P. Fischer, MSc A. B. García Segovia, Dr. M. Gruner,
Prof. Dr. P. Metz
Institut für Organische Chemie
Technische Universität Dresden
Bergstrasse 66, 01069 Dresden (Germany)
Fax: (+49)351-4633-3162
E-mail: peter.metz@chemie.tu-dresden.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(Graduierten-Kolleg “Struktur-Eigenschafts-Beziehungen bei Hete-
rocyclen”) and the Fonds der Chemischen Industrie. A.B.G.S.
acknowledges a fellowship from the Spanish Ministry of Science
and Technology. We thank Prof. Dr. U. Gräfe,† Hans-Knöll-Institut
für Naturstoff-Forschung, Jena, for a sample of natural pamamycin-
621A and Prof. Dr. M. Natsume, Tokyo University of Agriculture and
Technology, for 1H NMR spectra of natural pamamycin-635B.
Benzyl esters 3a,b and 4a,b were synthesized enantiose-
lectively as illustrated in Scheme 2 and Scheme 3. Addition of
butyl Grignard to 2-acetylfuran (5) followed by acid-cata-
lyzed dehydration of the resulting tertiary alcohol under
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Benzyl esters 3a,b featur-
ing the relative configuration
at C2’ present in 1b and 1e
were prepared in a three-step
sequence[9] from methyl esters
12a,b (Scheme 3). After sapo-
nification of 12a,b and Yama-
guchi lactonization[20,21] of hy-
droxy acids 13a,b, the C2’-
epimerized lactones 14a,b
were isolated as the major
products, which was revealed
by 2D NOESY investigation of
both lactone diastereomers.
Lactone 14a was recently iso-
lated from Streptomyces glo-
bisporus and exhibited signifi-
cant antibacterial activity.[22]
Subsequent cleavage of the
medium-sized lactones 14a,b
with the lithium alkoxide pre-
pared from benzyl alcohol[4,23]
gave isomerically pure 3a,b.
The absolute configuration
Scheme 2. Sultone route to hydroxy esters 12a,b. a) BuMgBr, Et2O, reflux; b) cat. HCl, CH2Cl2, reflux, 58%
from 5, E/Z=93:7; c) 1. IpcBH2, THF, À258C, 2. H2O2, NaOH, 708C, 76% 7 (81% ee) + syn isomer;
=
d) 1. CH2 CHSO2Cl, NEt3, THF, 08C!RT, 2. recrystallization, 74% (ꢀ99% ee); e) 1. 2MeLi (for 9a) or
2EtLi (for 9b), THF, À788C!RT, 2. NH4Cl, H2O, À788C!RT, 53% 9a, 68% 9b; f) 1. O3, NaHCO3,
CH2Cl2, MeOH, À788C, 2. Ac2O, pyridine, CH2Cl2, RT!reflux, 87% 10a, 86% 10b; g) PhSH, BF3·Et2O,
CH2Cl2, RT, 79% 11a, 80% 11b; h) Raney Ni (W2), 50 bar H2, EtOH, RT, 59% 12a, 58% 12b. IpcBH2 =
monoisopinocampheylborane.
of 3a and hence 3b was
proven by comparison of
the optical rotation data of
the known diol 16,[13a]
which was derived from
3a,
with
literature
values.[24] On the other
hand, dibutyltin oxide cat-
alyzed
transesterifica-
tion[25] of 12a,b with
benzyl alcohol directly
provided 4a,b in excellent
yields.
Scheme 3. Synthesis of the smaller fragment surrogates 3a,b and 4a,b. a) 2n NaOH, RT (for 13a) or 908C (for
13b), 100% 13a, 79% 13b; b) 1. 2,4,6-trichlorobenzoyl chloride, Et3N, THF, RT, 2. DMAP, toluene, reflux, 65%
14a, 11% 15a, 68% 14b, 14% 15b; c) BnOLi, BnOH, THF, RT, 59% 3a, 40% 3b (yield based on recovered
starting material); d) LiAlH4, Et2O, RT!reflux, 70% from 3a; e) BnOH, 10 mol% Bu2SnO, 1608C, 93% 4a,
100% 4b. DMAP=4-(N,N-dimethylamino)pyridine.
Yamaguchi coupling[20]
of the silylated larger hy-
droxy acid 2 with the nat-
urally configured smaller
building
block
3a
(1.2 equiv) for 1b effi-
ciently furnished the doubly protected seco acid 17
(Scheme 4). After desilylation and reductive debenzylation,
modified Yamaguchi macrolactonization[23] of 19 (1.3 ”
10À3 m) at room temperature in dichloromethane gave a
high yield of pamamycin-621A (1b).[11,26,27] Since utilization
of 4a instead of 3a for fragment coupling promised a shortcut
to 1b, we decided to explore such a simplified approach as
well. Intermolecular Yamaguchi esterification of 2 with 4a
(1.2 equiv) provided the coupling product 20 in high yield.
Desilylation followed by debenzylation proceeded unevent-
fully to give seco acid 22. Most gratifyingly, Yamaguchi
macrolactonization of 22 (1.2 ” 10À3 m) under Fleming con-
ditions[23] again afforded pamamycin-621A (1b)[11,26,27] as the
single macrodiolide product in 64% yield. Thus, as was noted
for the corresponding ring closure to give 1a,[2] the cyclization
of 22 is accompanied by complete epimerization at C2’ under
equilibrating conditions delivered olefin 6 as a mixture of
isomers (E/Z = 93:7, Scheme 2). Asymmetric hydrobora-
tion[15] of this mixture with monoisopinocampheylborane
derived from (+)-a-pinene (91% ee) followed by oxidative
workup led to the desired anti alcohol 7 (81% ee according to
chiral GC) and some of the syn isomer in 76% combined
yield. Treatment of this mixture with vinylsulfonyl chloride
induced
a smooth domino esterification/intramolecular
Diels–Alder reaction[6,8,16,17] to give the pure exo sultone 8
(ꢀ 99% ee according to chiral HPLC) after chromatographic
purification and recrystallization. Application of the reaction
sequence[7,8,18] domino elimination/alkoxide-directed 1,6-
addition,[19] sequential ozonolysis/cyclization, Lewis acid
catalyzed hydroxy/phenylthio exchange, and domino reduc-
tive elimination/hydrogenation converted sultone 8 to methyl
esters 12a,b.
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Scheme 4. Final steps of the synthesis of pamamycin-621A (1b) and pamamycin-635B (1e). a) 1. 2,4,6-trichlorobenzoyl chloride, Et3N, THF,
08C!RT, 2. 3a, DMAP, toluene, RT, 94%; b) aq. HF, MeCN, RT, 97% 18, 95% 21, 95% 24; c) H2, 10% Pd/C, THF, RT, 100% 19, 84% 22, 100%
25; d) 2,4,6-trichlorobenzoyl chloride, DMAP, MS 4 ꢀ, CH2Cl2, RT, 78% 1b from 19, 64% 1b from 22; e) 1. 2,4,6-trichlorobenzoyl chloride, Et3N,
THF, 08C!RT, 2. 4a, DMAP, toluene, RT, 88%; f) 1. 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 08C!RT, 2. 4b, DMAP, toluene, RT, 78%;
g) 1. 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 08C!RT, 2. DMAP, toluene, reflux, 57%. MS=molecular sieves.
these conditions. Encouraged by the facile lactonization of 22
to 1b, we directly applied such a streamlined sequence to
access pamamycin-635B( 1e). However, seco acid 25 readily
obtained after coupling of 2 with the non-naturally configured
[1] Reviews: a) B. M. Pogell, Cell. Mol. Biol. 1998, 44, 461 – 463;
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[2] Review on synthetic studies toward the pamamycins: P. Metz,
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deblocking proved to be reluctant to cyclization under the
modified Yamaguchi conditions used for 1b. This is probably
a result of the increased steric shielding imparted by the C2’
ethyl group. To our delight, Yamaguchi macrolactoniza-
tion[20,21] of 25 performed by separate mixed-anhydride
activation of the acid function and subsequent reflux in
toluene under high dilution in the presence of 4-(N,N-
dimethylamino)pyridine eventually afforded pamamycin-
635B( 1e)[14,27,28] as the sole macrodiolide product in 57%
yield.
In summary, a short and highly stereoselective access to
the smaller fragment surrogates 3a,b and 4a,b of the
pamamycins 1b-g has been developed by means of asym-
metric hydroboration and application of sultone method-
ology. Using benzyl esters 3a and 4a, the first total synthesis
of the macrodiolide antibiotic pamamycin-621A (1b) has
been accomplished, while the first total synthesis of pama-
mycin-635B( 1e) was achieved using benzyl ester 4b. Further
synthetic work in this area and investigations on the biological
activity of the pamamycins will be reported in due course.
[3] P. Lef›vre, P. Peirs, M. Braibant, M. Fauville-Dufaux, R.
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[5] Total syntheses of 1a reported by other groups: a) O. Germay, N.
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molecular weight 621 as the major component: P. A. McCann,
B. M. Pogell, J. Antibiot. 1979, 32, 673 – 678.
Received: May 2, 2005
Published online: September 7, 2005
[11] Isolation and structural elucidation of pamamycin-621A: a) U.
Gräfe, R. Schlegel, K. Dornberger, W. Ihn, M. Ritzau, C.
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Keywords: antibiotics · domino reactions · natural products ·
sulfur heterocycles · total synthesis
.
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Communications
[12] Bioactivities of pamamycin-621A: a) W.-G. Chou, B. M. Pogell,
Antimicrob. Agents Chemother. 1981, 20, 443 – 454; b) W.-G.
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[24] Compound 16 prepared by reduction of 3a with LiAlH4: [a]D25
=
À19.1 (c = 1.03, benzene); ref. [13a]: [a]2D5 = À19.1 (c = 6, ben-
zene).
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[26] Analytical data of synthetic 1b match exactly those of the
natural product obtained by flash chromatography from a
mixture of natural pamamycin-621A (1b) and pamamycin-607
(1a) (ca. 2:1), which was kindly provided by Prof. Dr. U. Gräfe,†
Hans-Knöll-Institut für Naturforschung, Jena.
[27] Detailed 2D NMR analyses (COSY, HSQC, HMBC, NOESY)
confirmed the depicted relative configuration, in particular at C2
and C2’.
[28] 1H NMR data of synthetic 1e are identical to those of the natural
product kindly provided by Prof. Dr. M. Natsume, Tokyo
University of Agriculture and Technology.
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