Total synthesis of pamamycin-607

Article abstract of DOI:10.1016/S0040-4039(01)01665-3

The macrodiolide antibiotic pamamycin-607 has been synthesized by coupling of the two hydroxy acid constituents using the Yamaguchi method. While the final lactonization with formation of the ester linkage between C(1) and the C(8′) oxygen proceeded with complete C(2) epimerization, the alternative ring closure involving the carboxylic acid of the smaller fragment and the hydroxyl group of the larger fragment yielded the target molecule.

Full text of DOI:10.1016/S0040-4039(01)01665-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7801–7804
Total synthesis of pamamycin-607†
Yuzhou Wang, Heiko Bernsmann, Margit Gruner and Peter Metz*
Institut fu¨r Organische Chemie, Technische Universita¨t Dresden, Bergstraße 66, D-01069 Dresden, Germany
Received 23 July 2001; revised 3 September 2001; accepted 4 September 2001
Abstract—The macrodiolide antibiotic pamamycin-607 has been synthesized by coupling of the two hydroxy acid constituents
using the Yamaguchi method. While the final lactonization with formation of the ester linkage between C(1) and the C(8%) oxygen
proceeded with complete C(2) epimerization, the alternative ring closure involving the carboxylic acid of the smaller fragment and
the hydroxyl group of the larger fragment yielded the target molecule. © 2001 Elsevier Science Ltd. All rights reserved.
The macrodiolide pamamycin-607 (1) isolated from
various Streptomyces species displays pronounced
antibiotic, autoregulatory, anionophoric and antifungal
activities (Scheme 1).1,2 Through the extensive applica-
tion of sultone methodology,3 we have been able to
develop straightforward routes to the methyl ester 3 of
the larger C(1)-C(18) fragment 2, as well as to the
methyl ester 5 of the smaller C(1%)-C(11%) fragment 4.4
Here we report the completion of the total synthesis5,6
of 1 by coupling of the two hydroxy acid building
blocks.
use methyl ester 34b for the intermolecular coupling
process, while the smaller fragment methyl ester 54a,d
had to be modified accordingly.
To this end, hydroxy ester 5 was first silylated, and the
resulting silyl ether 6 was saponified to give the car-
boxylic acid 7 without any detectable epimerization
(Scheme 2). A subsequent intermolecular Yamaguchi
esterification8 of 7 (1.65 equiv.) with 3 afforded the
desired coupling product 8 in nearly quantitative yield
when the acylation step was performed at 0.05 M
concentration of 3 in toluene. The high efficacy of this
fragment coupling shows that the Yamaguchi protocol
works well even with a rather hindered secondary alco-
hol. Desilylation of 8 proceeded smoothly to yield the
known hydroxy ester 9.1c However, whereas hydrolysis
of the methyl ester function in 9 succeeded with com-
plete chemoselectivity leaving the internal ester unaf-
fected, epimerization to give a 2:1 mixture of two
Concerned by reports on the sluggish acylation of the
secondary alcohol present in the larger hydroxy acid
2,1c,7 we decided to execute the final macrolactonization
with formation of the ester linkage between C(1) and
the C(8%) oxygen. Next to avoiding potential reactivity
problems during this critical intramolecular step, this
end game strategy also offered the option to directly
O
OH
NMe2
19
20
NMe2
RO
O
O
H
H
H
H
3
6
2
O
O
7
9
1
8
10
21
13
15
O
O
18
2: R = H, 3: R = Me
OH
O
1'
O
8'
O
11'
2'
O
6'
3'
+
12'
RO
O
H
H
pamamycin-607 (1)
4: R = H, 5: R = Me
Scheme 1.
Keywords: antibiotics; epimerisation; macrodiolide; Yamaguchi lactonisation.
* Corresponding author. Tel.: +49-351-463-7006; fax: +49-351-463-3162; e-mail: peter.metz@chemie.tu-dresden.de
†
Dedicated to Professor Ju¨rgen Fabian on the occasion of his 65th birthday.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01665-3

7802
Y. Wang et al. / Tetrahedron Letters 42 (2001) 7801–7804
hydroxy acids 10 and 10% could not be avoided despite
extensive variation of the reaction conditions. Reduc-
tive cleavage of this mixture with lithium aluminum
hydride indicated that partial epimerization occurred at
C(2%), while the configuration at C(2) was maintained.9
All the more surprising was the result of the
Yamaguchi macrolactonization8,10 of the 2:1 seco acid
mixture. To our disappointment, only 2-epi-
pamamycin-607 (11)11 and 2,2%-bisepi-pamamycin-607
(12)12 were isolated in 28 and 17% yields, respectively,
after mixed anhydride activation of the acid function
and reflux in toluene under high dilution in the pres-
ence of DMAP. Attempted cyclization using modified
Yamaguchi conditions at room temperature13 did not
afford 1 either.
Encouraged by the efficient intermolecular Yamaguchi
esterification of 3 to give 8, we next focussed on the
alternative sequence of events for fragment coupling
involving lactonization with formation of the ester link-
age between C(1%) and the C(8) oxygen. In order to
prevent potential problems with methyl ester cleavage,
we chose benzyl ester 14 instead of 5 as the smaller
fragment surrogate. Upon treatment of lactone 13,
which is available in only two steps from an intermedi-
ate for the synthesis of 3,4a with the lithium alkoxide of
benzyl alcohol,13a coupling component 14 was readily
obtained (Scheme 3).
Silylation of methyl ester 3 followed by mild saponifica-
tion of the silyloxy ester 15 yielded the larger fragment
coupling component 16 as
a single stereoisomer
Thus, quite similarly to the recently communicated
extensive epimerization during the Yamaguchi cycliza-
tion of a hydroxy acid precursor of 3 to give medium-
ring lactone 13,4a an inversion of configuration at C(2)
is observed, and it is even complete in the case of the
substrates 10 and 10%. Again, either equilibration at the
stage of the mixed anhydride coupled with a faster
cyclization of the (2S) compound or formation of a
ketene intermediate coupled with a stereoselective pro-
tonation of the enol or enolate resulting from a
hydroxy ketene cyclization14 could account for this
unexpected result.
(Scheme 4). Subsequent intermolecular Yamaguchi
esterification of 16 with 14 (1.1 equiv.) then provided
the coupling product 17 in high yield. Desilylation of 17
using aqueous HF and reductive debenzylation of the
resultant benzyl ester 18 proceeded uneventfully to give
the desired seco acid 19. To our delight, the final
Yamaguchi macrolactonization of 19 performed at
reflux in toluene under high dilution in the presence of
DMAP afforded pamamycin-607 (1)1h,i,15 as the major
product in 42% yield. Most gratifyingly, modified
Yamaguchi cyclization at 6.4×10−3 M concentration of
NMe2
O
R2O2C
O
OR1
O
c
OR1
O
R2O
O
O
H
H
2'
O
5 : R1 = H, R2 = Me
6 : R1 = TBDMS, R2 = Me
7 : R1 = TBDMS, R2 = H
a
8 : R1 = TBDMS, R2 = Me
9 : R1 = H, R2 = Me
b
d
e
10 : R1 = H, R2 = H
+
C(2') epimer 10'
NMe2
NMe2
O
O
2
2
O
O
O
O
f
O
O
O
O
+
O
O
2'
O
O
11
12
Scheme 2. (a) TBDMSCl, imidazole, DMAP, DMF, 25°C, 100%; (b) 1N KOH, MeOH, THF, 25°C, 99%; (c) (i) 2,4,6-
trichlorobenzoyl chloride, Et3N, THF, 25°C, (ii) 3, DMAP, toluene, 25°C, 98%; (d) aq. HF, MeCN, 25°C, 92%; (e) 0.2N LiOH,
THF, MeOH, 25°C, 100%; (f) (i) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 25°C, (ii) DMAP, toluene, reflux, 28% 11, 17% 12
BnOLi, BnOH
O
OH
THF, 25 °C
83 %
O
BnO
O
H
H
O
O
14
13
Scheme 3.

Y. Wang et al. / Tetrahedron Letters 42 (2001) 7801–7804
7803
NMe2
O
O
OR1
NMe2
O
O
c
R1O
O
R2O
CO2R2
O
O
H
H
H
H
O
3 : R1 = H, R2 = Me
15 : R1 = TBDMS, R2 = Me
16 : R1 = TBDMS, R2 = H
a
17 : R1 = TBDMS, R2 = Bn
18 : R1 = H, R2 = Bn
19 : R1 = H, R2 = H
b
d
e
f
1
Scheme 4. (a) TBDMSOTf, 2,6-lutidine, CH2Cl2, 25°C, 90%; (b) 0.2N LiOH, THF, MeOH, 25°C, 81%; (c) (i) 2,4,6-trichloroben-
zoyl chloride, Et3N, THF, 25°C, (ii) 14, DMAP, toluene, 25°C, 88%; (d) aq. HF, MeCN, 25°C, 95%; (e) H2, 10% Pd/C, THF,
,
MeOH, 25°C, 98%; (f) 2,4,6-trichlorobenzoyl chloride, DMAP, 4 A sieves, CH2Cl2, 25°C, 69%
19 at room temperature in dichloromethane13a even
improved the yield of 1 to 69%.
Katayama, M.; Marumo, S. J. Antibiot. 1988, 41, 1196–
1204; (i) Kondo, S.; Yasui, K.; Katayama, M.; Marumo,
S.; Kondo, T.; Hattori, H. Tetrahedron Lett. 1987, 28,
5861–5864.
In summary, starting from furan, racemic 1,2-
epoxypentane and vinylsulfonyl chloride,4 an enantio-
selective synthesis of pamamycin-607 (1) has been
accomplished in only 28 steps and thus, our route to 1
compares favorably to the recently disclosed5 alterna-
tive access to 1.
2. For reviews on pamamycins, see: (a) Natsume, M. Recent
Res. Devel. Agric. Biological Chem. 1999, 3, 11–22; (b)
Pogell, B. M. Cell. Mol. Biol. 1998, 44, 461–463.
3. (a) Plietker, B.; Seng, D.; Fro¨hlich, R.; Metz, P. Eur. J.
Org. Chem. 2001, in press; (b) Plietker, B.; Seng, D.;
Fro¨hlich, R.; Metz, P. Tetrahedron 2000, 56, 873–879; (c)
Plietker, B.; Metz, P. Tetrahedron Lett. 1998, 39, 7827–
7830; (d) Metz, P. J. Prakt. Chem. 1998, 340, 1–10.
4. (a) Bernsmann, H.; Gruner, M.; Fro¨hlich, R.; Metz, P.
Tetrahedron Lett. 2001, 42, 5377–5380; (b) Bernsmann,
H.; Gruner, M.; Metz, P. Tetrahedron Lett. 2000, 41,
7629–7633; (c) Bernsmann, H.; Fro¨hlich, R.; Metz, P.
Tetrahedron Lett. 2000, 41, 4347–4351; (d) Bernsmann,
H.; Hungerhoff, B.; Fechner, R.; Fro¨hlich, R.; Metz, P.
Tetrahedron Lett. 2000, 41, 1721–1724; (e) Metz, P.;
Bernsmann, H. Phosphorus Sulfur Silicon 1999, 153–154,
383–384.
Acknowledgements
Financial support of this work by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemi-
schen Industrie is gratefully acknowledged. We thank
the BASF AG and the ASTA Medica AG for generous
gifts of chemicals, Professor U. Gra¨fe, Hans-Kno¨ll-
Institut fu¨r Naturstoff-Forschung, Jena, for a sample of
a ca. 2:1 mixture of natural pamamycin-621A and
pamamycin-607 and Professor M. Natsume, Tokyo
University of Agriculture and Technology, for 1H
NMR and mass spectra of compounds 1, 3 and 9.
5. During the preparation of this manuscript, an alternative
synthesis of 1 has been published; see: Germay, O.;
Kumar, N.; Thomas, E. J. Tetrahedron Lett. 2001, 42,
4969–4974.
6. For further synthetic approaches to 1, see: (a) Furuya,
Y.; Kiyota, H.; Oritani, T. Heterocycl. 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,
3433–3441; (j) Walkup, R. D.; Kim, S. W.; Wagy, S. D.
J. Org. Chem. 1993, 58, 6486–6490; (k) Walkup, R. D.;
Park, G. Tetrahedron Lett. 1988, 29, 5505–5508.
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7804
Y. Wang et al. / Tetrahedron Letters 42 (2001) 7801–7804
7. Uhlmann, E.; Hornung, L.; Will, D. W.; Gra¨fe, U.
C-8%), 74.79 (d, C-8), 75.16 (d, C-6%), 76.56 (d, C-6), 80.06
(d, C-13), 80.22 (d, C-3), 81.06 (d, C-10), 82.34 (d, C-3%),
173.54 (s, C-1%), 174.88 (s, C-1); NOESY (500 MHz,
acetone-d6, excess CF3CO2D) diagnostic NOE’s observed
between 2-H and 3-H, 12%-H and 3%-H, 19-H and 20-H,
Nucleosides Nucleotides 1998, 17, 309–316.
8. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–
1993.
1
9. After reduction of an analytical sample of the mixture of
hydroxy acids 10 and 10% with lithium aluminum hydride
to give the corresponding diols and subsequent silylation
using excess MSTFA, capillary GC analysis showed a
single peak for the larger diol derivative, whereas two
peaks (ca. 2:1) were found for the smaller diol derivative.
10. Mulzer, J.; Kirstein, H. M.; Buschmann, J.; Lehmann,
C.; Luger, P. J. Am. Chem. Soc. 1991, 113, 910–923.
11. Compound 11: [h]2D5=+11.4 (c 0.95, CH2Cl2); 13C NMR
(125.8 MHz, acetone-d6, excess CF3CO2D): l 8.00 (q,
C-19), 8.82 (q, C-12%), 9.63 (q, C-21), 10.16 (q, C-20),
13.98 (q, C-18), 14.26 (q, C-11%), 18.98 (t, C-10%), 20.34 (t,
C-17), 27.78 (t, C-4%), 28.02 (t, C-5), 28.71 (t, C-4), 29.06
(t, C-16), 30.02 (t, C-11), 31.62 (t, C-12), 32.24 (t, C-5%),
34.38 (t, C-14), 36.58 (q, NCH3), 36.93 (d, C-7), 38.07 (t,
C-9%), 39.77 (t, C-7%), 41.36 (d, C-9), 42.02 (d, C-2), 42.20
(d, C-2%), 43.76 (q, NCH3), 68.63 (d, C-15), 71.99 (d,
C-8%), 75.26 (d, C-6%), 75.43 (d, C-8), 77.11 (d, C-6), 79.29
(d, C-3%), 79.98 (d, C-13), 80.23 (d, C-3), 81.04 (d, C-10),
174.67 (s, C-1), 174.90 (s, C-1%); NOESY (500 MHz,
acetone-d6, excess CF3CO2D) diagnostic NOE’s observed
12%-H and 21-H. H and 13C signals were assigned by 2D
NMR (COSY, HSQC, HMBC) spectra.
13. (a) Fleming, I.; Ghosh, S. K. J. Chem. Soc., Perkin Trans.
1 1998, 2733–2747; (b) Sakurai, Y.; Hikota, M.; Horita,
K.; Yonemitsu, O. Chem. Pharm. Bull. 1992, 40, 2540–
2542; (c) Hikota, M.; Tone, H.; Horita, K.; Yonemitsu,
O. Tetrahedron 1990, 31, 4613–4628.
14. Molecular modeling studies with MM2 (CS Chem3D
Pro, version 5.0; CambridgeSoft Corporation, Cam-
bridge, MA, USA) of the C(2) enol of 11 indeed suggest
preferential protonation to give epimer 11.
15. Pamamycin-607 (1): [h]2D5=+17.8 (c 0.60, CH2Cl2), [h]3D0=
+22.2 (c 0.25, MeOH) (Ref. 1i: [h]3D3=+22.8 (c 0.26,
MeOH)); 13C NMR (125.8 MHz, acetone-d6, excess
CF3CO2D): l 8.66 (q, C-12%), 9.76 (q, C-21), 10.36 (q,
C-20), 13.96 (q, C-18), 14.04 (q, C-19), 14.32 (q, C-11%),
18.76 (t, C-10%), 20.31 (t, C-17), 27.92 (t, C-4%), 28.06 (t,
C-5), 28.97 (t, C-16), 30.02 (t, C-11), 31.13 (t, C-4), 31.54
(t, C-12), 32.11 (t, C-5%), 34.23 (t, C-14), 36.47 (q, NCH3),
37.82 (t, C-9%), 37.85 (d, C-7), 39.41 (t, C-7%), 41.50 (d,
C-9), 42.08 (d, C-2%), 43.71 (q, NCH3), 47.87 (d, C-2),
68.68 (d, C-15), 71.48 (d, C-8%), 75.17 (d, C-6%), 75.22 (d,
C-8), 77.27 (d, C-6), 79.20 (d, C-3%), 79.96 (d, C-13), 81.05
(d, C-10), 83.16 (d, C-3), 173.70 (s, C-1), 174.95 (s, C-1%);
NOESY (500 MHz, acetone-d6, excess CF3CO2D) diag-
nostic NOE’s observed between 19-H and 3-H, 2%-H and
3%-H. 1H and 13C signals were assigned by 2D NMR
(COSY, HSQC, HMBC) spectra and match exactly those
of the natural product 1 separated on an analytical scale
by HPLC from a ca. 1:2 mixture of natural pamamycin-
607 (1) and pamamycin-621A1e,2 kindly provided by Pro-
fessor U. Gra¨fe, Hans-Kno¨ll-Institut fu¨r Naturstoff-
Forschung, Jena.
1
between 2-H and 3-H, 2%-H and 3%-H, 19-H and 20-H. H
and 13C signals were assigned by 2D NMR (COSY,
HSQC, HMBC) spectra.
12. Compound 12: [h]2D5=+8.3 (c 0.40, CH2Cl2); 13C NMR
(125.8 MHz, acetone-d6, excess CF3CO2D): l 7.91 (q,
C-19), 9.61 (q, C-21), 9.98 (q, C-20), 13.98 (q, C-12%),
13.98 (q, C-18), 14.32 (q, C-11%), 18.92 (t, C-10%), 20.34 (t,
C-17), 27.77 (t, C-5), 28.42 (t, C-4), 28.99 (t, C-16), 30.05
(t, C-11), 30.77 (t, C-4%), 31.57 (t, C-12), 31.62 (t, C-5%),
34.41 (t, C-14), 36.60 (q, NCH3), 36.79 (d, C-7), 37.82 (t,
C-9%), 40.88 (t, C-7%), 41.50 (d, C-9), 41.74 (d, C-2), 43.71
(q, NCH3), 49.05 (d, C-2%), 68.60 (d, C-15), 72.30 (d,