A shortcut to the smaller fragment of pamamycin-607

Article abstract of DOI:10.1016/S0040-4039(01)01044-9

Starting from a key intermediate for the synthesis of the larger hydroxy acid constituent of pamamycin-607 (1), an efficient three-step route to the methyl ester of the smaller fragment of 1 involving a Yamaguchi lactonization with concomitant C(2) epimerization was developed. Alternatively, the methyl ester of the smaller hydroxy acid portion of 1 was prepared by direct C(2) epimerization.

Full text of DOI:10.1016/S0040-4039(01)01044-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5377–5380
A shortcut to the smaller fragment of pamamycin-607†
Heiko Bernsmann,a Margit Gruner,a Roland Fro¨hlichb and Peter Metza,*
aInstitut fu¨r Organische Chemie, Technische Universita¨t Dresden, Mommsenstraße 13, D-01062 Dresden, Germany
bOrganisch-Chemisches Institut, Universita¨t Mu¨nster, Corrensstraße 40, D-48149 Mu¨nster, Germany
Received 17 May 2001; accepted 15 June 2001
Abstract—Starting from a key intermediate for the synthesis of the larger hydroxy acid constituent of pamamycin-607 (1), an
efficient three-step route to the methyl ester of the smaller fragment of 1 involving a Yamaguchi lactonization with concomitant
C(2) epimerization was developed. Alternatively, the methyl ester of the smaller hydroxy acid portion of 1 was prepared by direct
C(2) epimerization. © 2001 Elsevier Science Ltd. All rights reserved.
In the course of our studies1 toward the enantioselective
total synthesis of the macrodiolide antibiotic
pamamycin-607 (1)2–4 (Scheme 1), we have recently
communicated a straightforward access to the methyl
ester 31a of the larger hydroxy acid constituent 2 from
furan via sultone methodology.5 Using a similar strat-
egy, we also developed a six-step route to the methyl
ester 5 of the smaller fragment 4 from 2-bromo-4-
methylfuran.1c,d Here we report two alternative synthe-
ses of methyl ester 5 from an intermediate of our
sequence to 3, both of which provide a considerable
shortcut to the smaller fragment of pamamycin-607 (1).
tones 8a and 9a. While the formation of medium-sized
lactones10,11 is often hampered by competing diolide or
oligomer production, the conformational constraint
imposed by the 2,5-cis disubstituted tetrahydrofuran
moiety is probably responsible for the high combined
yield of lactones obtained in this case. To our surprise,
the major lactone 8a had undergone epimerization at
C(2), which was clearly revealed by a 2D NOESY
investigation of both lactone diastereomers 8a and 9a.12
A similar observation was made for the Yamaguchi
lactonization of racemic nonactic acid (rac-7b) pre-
pared from racemic methyl nonactate (rac-6b).6b,c
Again, the major resulting lactone (rac-8b) turned out
to be epimerized at C(2),12 which was unambiguously
proven by X-ray diffraction (Fig. 1).13,14
Due to our general interest in the chemistry of actic
acids,6 we investigated the Yamaguchi lactonization7 of
the enantiopure hydroxy acid 7a, itself readily available
by saponification8 of the corresponding methyl ester 6a
that we used as a key precursor of 31a (Scheme 2).
Cyclization under high dilution conditions7,9 proceeded
smoothly to give a mixture of two diastereomeric lac-
While partial epimerization during Yamaguchi lac-
tonizations had been reported earlier,11b,15 the high
degree of inversion observed here is unprecedented to
the best of our knowledge. Nevertheless, this unex-
O
OH
NMe2
NMe2
RO
O
O
H
H
H
H
3
6
2
O
O
7
9
1
8
10
13
15
O
O
18
2: R = H, 3: R = Me
OH
O
1'
O
8'
O
11'
2'
O
6'
3'
+
RO
O
H
H
pamamycin-607 (1)
4: R = H, 5: R = Me
Scheme 1.
Keywords: antibiotics; medium-ring heterocycles; epimerisation; Yamaguchi lactonisation.
* Corresponding author. Tel.: +49-351-463-7006; fax: +49-351-463-3162; e-mail: metz@coch01.chm.tu-dresden.de
† Dedicated to Professor Barry M. Trost on the occasion of his 60th birthday.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01044-9

5378
H. Bernsmann et al. / Tetrahedron Letters 42 (2001) 5377–5380
O
OH
O
OH
MeO
R
MeO
O
O
H
H
H
H
6; a: R = Pr, rac-b: R = Me
5
for 8a:
Cl
Cl
2N NaOH
25 °C
cat. BF3·Et2O
MeOH, 25 °C
72 %
a)
b)
Cl
COCl
Et3N, THF, 25 °C
DMAP, toluene, reflux
O
OH
3
3
O
O
O
O
2
2
+
HO
R
8
8
O
H
H
O
R
O
R
7a : 100 %
rac-7b: 99 %
8a : 71 %
rac-8b: 59 %
9a : 10 %
rac-9b: 13 %
Scheme 2.
mol) and 9a (−149.39 kcal/mol) pointed to a contra-
thermodynamic formation of these compounds.
Indeed, these calculations were experimentally verified
by exposing the major epimer 8a to a thermodynami-
cally controlled base catalyzed equilibration in DBU at
100°C (Scheme 3, Table 1). After 24 h, a 19:81 mixture
of lactones favoring the thermodynamically more stable
epimer 9a was isolated in 74% combined yield.
Thus, the Yamaguchi cyclization of 7a to give a 71:10
mixture of 8a and 9a proceeds under kinetic control.
The configurational inversion at C(2) is either due to an
equilibration at the stage of the mixed anhydride cou-
pled with a faster cyclization of the (2S) compound or
to the intermediate formation of a ketene, as has been
observed for Mukaiyama lactonizations,19 coupled with
a stereoselective protonation of the enol resulting from
a hydroxy ketene cyclization.20 Interestingly, no epimer-
ization at all was observed for the Yamaguchi lac-
tonization of the smaller fragment 421 under the
conditions listed in Scheme 2, and 8a was obtained as
the only cyclized product in 82% yield.
Figure 1. Crystal structure of lactone rac-8b; arbitrarily cho-
sen enantiomer.13,14
pected result could be nicely exploited for our synthetic
purposes. Subjecting the major lactone 8a, easily sepa-
rated from 9a by flash chromatography,16 to a Lewis
acid catalyzed ring opening methanolysis17 directly pro-
vided the isomerically pure methyl ester 5 of the smaller
fragment. Since we prepare 6a as a precursor for the
larger fragment of 1 anyway,1a only three extra steps
are necessary this way to additionally secure 5.
We first suspected this stereochemical result was due to
a basic equilibration of the lactones subsequent to the
cyclization. However, semi-empirical calculations using
PM318 (Scheme 3) of both epimers 8a (−146.31 kcal/
Encouraged by the efficient epimerization of 8a to 9a,
we investigated if a direct epimerization of methyl ester
6a to 5 was possible as well. To our delight, using
conditions similar to those reported to be successful for
Scheme 3. Equilibration of lactone 8a.18

H. Bernsmann et al. / Tetrahedron Letters 42 (2001) 5377–5380
OH OH
5379
O
O
DBU, 100 °C (4 h)
+
6a
MeO
MeO
O
O
H
H
H
H
6a
5
38 %
32 %
Scheme 4.
Table 1. Equilibration of lactone 8aa
2. (a) Ha¨rtl, A.; Stelzner, A.; Schlegel, R.; Heinze, S.; Hu¨ls-
mann, H.; Fleck, W.; Gra¨fe, U. J. Antibiot. 1998, 51,
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Gra¨fe, U. Bioelectrochem. Bioenerg. 1996, 39, 295–298;
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Basic Microbiol. 1992, 32, 339–345; (g) Natsume, M.;
Kondo, S.; Marumo, S. J. Chem. Soc., Chem. Commun.
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Time (h)
Ratio 8a:9ab
0
3
5
11
14
24c
100:0
91:9
84:16
62:38
47:53
19:81
a 8a (1.34 mmol), DBU (3.75 mmol), 100°C.
b Isomeric ratio determined by GC.
c Work-up after 24 h yielded 60% 9a and 14% 8a.
methyl nonactate,8c,22 a 1.2:1 mixture of the two C(2)
epimers was obtained rather cleanly after a short reac-
tion time, from which the desired isomer 5 could be
isolated in 38% yield via careful flash chromatography23
(Scheme 4).
3. For reviews on pamamycins, see: (a) Natsume, M. Recent
Res. Devel. Agric. Biol. Chem. 1999, 3, 11–22; (b) Pogell,
B. M. Cell. Mol. Biol. 1998, 44, 461–463.
Obviously, there is hardly any ring opening of the
tetrahydrofuran by b-elimination and subsequent stereo-
random recyclization.24 Though the three-step sequence
depicted in Scheme 2 affords a higher total yield of 5
from 6a, only one extra step is required for the synthesis
of the smaller fragment’s methyl ester 5 via the DBU
mediated isomerization depicted in Scheme 4.
4. For further synthetic approaches to 1, see: (a) Furuya,
Y.; Kiyota, H.; Oritani, T. Heterocyclic Commun. 2000,
6, 427–430; (b) Solladie´, G.; Salom-Roig, X. J.; Hanquet,
G. Tetrahedron Lett. 2000, 41, 2737–2740; (c) Solladie´,
G.; Salom-Roig, X. J.; Hanquet, G. Tetrahedron Lett.
2000, 41, 551–554; (d) Mandville, G.; Bloch, R. Eur. J.
Org. Chem. 1999, 2303–2307; (e) Mandville, G.; Girard,
C.; Bloch, R. Tetrahedron: Asymmetry 1997, 8, 3665–
3673; (f) Arista, L.; Gruttadauria, M.; Thomas, E. J.
Synlett 1997, 627–628; (g) Mavropoulos, I.; Perlmutter,
P. Tetrahedron Lett. 1996, 37, 3751–3754; (h) Walkup, R.
D.; Kim, Y. S. Tetrahedron Lett. 1995, 36, 3091–3094; (i)
Walkup, R. D.; Kim, S. W. J. Org. Chem. 1994, 59,
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J. Org. Chem. 1993, 58, 6486–6490; (k) Walkup, R. D.;
Park, G. Tetrahedron Lett. 1988, 29, 5505–5508.
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Prakt. Chem. 1998, 340, 1–10.
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Acknowledgements
Financial support of this work by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemis-
chen Industrie is gratefully acknowledged. We thank
the BASF AG and the ASTA Medica AG for generous
gifts of chemicals.
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