A stereocontrolled synthetic route to the C1-C18 subunit of pamamycin-607

Article abstract of DOI:10.1016/S0040-4039(02)00655-X

The C1-C18 subunit 2 of the 16-membered macrodiolide pamamycin-607 has been synthesized stereoselectively using the Ag₂CO₃-mediated intramolecular iodoetherification for the two cis-2,5-disubstituted tetrahydrofurans, crotylation and cuprate epoxide opening for the hydroxyl and methyl substituents.

Full text of DOI:10.1016/S0040-4039(02)00655-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3613–3616
A stereocontrolled synthetic route to the C1ꢀC18 subunit of
pamamycin-607
Sung Ho Kang* and Joon Won Jeong
Center for Molecular Design and Synthesis, Department of Chemistry, School of Molecular Science (BK21), Korea Advanced
Institute of Science and Technology, Daejeon 305-701, South Korea
Received 16 March 2002; revised 28 March 2002; accepted 3 April 2002
Abstract—The C1ꢀC18 subunit 2 of the 16-membered macrodiolide pamamycin-607 has been synthesized stereoselectively using
the Ag2CO3-mediated intramolecular iodoetherification for the two cis-2,5-disubstituted tetrahydrofurans, crotylation and cuprate
epoxide opening for the hydroxyl and methyl substituents. © 2002 Elsevier Science Ltd. All rights reserved.
Pamamycin-607 is the lowest homolog of pamamycin
family, isolated from Streptomyces alboniger and Strep-
tomyces aurantiacus JA4570.1 Its unique structural fea-
ture is the composition of 16-membered macrodiolide,
and three cis-2,5-disubstituted tetrahydrofurans retain-
ing anti- and syn-methyl substituents a to the rings.2 It
exhibits various biological activities such as antimicro-
bial, autoregulatory and anionophoric properties.1,3
Noticeably, it possesses the promising potency against
multiple antibiotic-resistant strains of Mycobacterium
tuberculosis.3f Due to its intriguing structural and bio-
logical aspects as well as its purification difficulty, our
efforts have been directed to a total synthesis of
pamamycin-607. Herein we describe a stereoselective
synthesis of the C1ꢀC18 subunit 2 of pamamycin-607
1.4
the double bonds of which were expected to be gener-
ated by Wittig olefination. The two requisite compo-
nents for 4, corresponding to aldehyde and
phosphonium salt, could be derived from the common
alkene 5. In addition, the adjacent hydroxyl and methyl
functional groups of 5 would be elaborated by Roush’s
crotylboronate methodology.6
The synthesis of 2 began with crotylation of the alde-
hyde, generated from the known alcohol 6,7 with (E)-
crotylboronate 7 to afford alcohol 5 in 80% ee and 87%
overall yield (Scheme 2). To attain not only the
intended derivatization but also enantiomeric separa-
tion, 5 was subjected to esterification with N-Cbz-L-
proline, dihydroxylation, oxidative cleavage and
NaBH4 reduction in sequence to furnish a 9:1 separable
mixture of the desired alcohol 8 and its diastereomeric
alcohol in 87% combined yield. Conversion of 8 into
iodide 9 ([h]2D6=+36.3, c=1.00, CHCl3) was carried out
in 86% overall yield via a sequence of basic hydrolysis,
protection as acetonide, debenzylation by dissolving
metal reduction and iodination using iodine in the
presence of Ph3P and imidazole.8 Acidic hydrolysis of 9
yielded labile diol, which was disilylated consecutively
with TBDPSCl and TESOTf, and then reacted with
Ph3P to render phosphonium salt 10 in 83% overall
yield. To prepare the coupling partner of 10 as alde-
hyde, 8 was oxidized under Swern conditions,9 reacted
with vinyl Grignard reagent and then hydrolyzed to
give the craved allylic alcohol 12 ([h]2D7=+19.8, c=1.16,
CHCl3) in 53% overall yield along with 17% of the
diastereomeric alcohol 11. Subjection of alcohol 11 to
Mitsunobu inversion10 and basic hydrolysis produced a
3.3:1 mixture of 12 and the rearranged primary allylic
3
6
1
O
O
O
10
O
11'
O
O
13
O
1'
6'
3'
Me2N
18
1
Based on the retrosynthetic analysis toward 2, its two
indispensable cis-2,5-disubstituted tetrahydrofurans
were envisaged to be installed by iodocyclization of
g-triethylsilyloxyalkenes (Scheme 1).5 Accordingly,
alkenes 3 and 4 were chosen as the key intermediates,
* Corresponding author. Tel.: +82-42-869-2825; fax: +82-42-869-2810;
e-mail: shkang@kaist.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00655-X

3614
S. H. Kang, J. W. Jeong / Tetrahedron Letters 43 (2002) 3613–3616
OBn
TBDPSO
1
HO2C
O
O
O
H
OPMB
TESO
3
OTES
N3
2
O
O
TBDPSO
OBn
OBn
OH
OTES
5
4
Scheme 1. Retrosynthetic analysis.
OBn
OBn
a,b
c-e
f-i
j-l
+
-
I
5
PPh3I
O2C
HO
O
O
N
TBDPSO
OTES
10
OH
(TBDPS = SiPh2t-Bu)
Cbz
9
6
8
a,m,f
I
CO2-i-Pr
X
OH
O
TBDPSO
o-q
r
OBn
OBn
B
4
O
O
O
O
CO2-i-Pr
7
11 : X = α-OH
12 : X = β-OH
13
n, f
,
Scheme 2. (a) Swern oxidation; (b) 7, 4 A MS, PhMe, −78°C, then 2N NaOH, 0°C; (c) N-Cbz-L-proline, DCC, DMAP, CH2Cl2,
rt; (d) OsO4, NMO, aq. acetone, rt; (e) NaIO4, aq. THF, rt, then NaBH4, 0°C; (f) LiOH, aq. MeOH, rt; (g) PPTS, Me2C(OMe)2,
PhMe, reflux; (h) Li, NH3(l), THF, −78°C; (i) I2, Ph3P, imidazole, THF, 0°C; (j) conc. HCl, MeOH, 0°C; (k) TBDPSCl, DMAP,
Et3N, CH2Cl2, −15°C, then TESOTf, −15°C; (l) Ph3P, K2CO3, MeCN, reflux; (m) CH2ꢁCHMgBr, Et2O, −78°C; (n) PhCO2H,
Ph3P, DEAD, THF, −20°C; (o) PPTS, Me2C(OMe)2, acetone, rt; (p) O3, NaHCO3, CH2Cl2, MeOH, −78°C, then Me2S, rt; (q)
10, t-BuLi, THF, −78 to −5°C, then aldehyde, 10°C; (r) I2, Ag2CO3, Et2O, rt.
alcohol in 84% combined yield. The aldehyde derived
from 12 via acetonide protection and ozonolysis reacted
with the ylid generated from 10 with t-BuLi to provide
only cis-alkene 4 ([h]2D5=−7.9, c=1.03, CHCl3) in 85%
overall yield. With g-triethylsilyloxyalkene 4 precursory
to cis-2,5-disubstituted tetrahydrofuran in hand, exten-
sive iodocyclization conditions were examined. Conse-
quently, treatment of 4 with iodine in the presence of
Ag2CO3 resulted in a remarkable stereoselectivity to
give rise to cis-tetrahydrofuran 13 ([h]2D6=−17.9, c=
1.06, CHCl3) as a single stereoisomer in 94% yield,11 the
stereochemistry of which was corroborated by the NOE
experiments of 15 (vide infra).
group of 14 was unprotected, the epoxide opening
reaction yielded the wrong regioisomer as the major.
Hydrogenolysis of 15 was implemented in 96% yield to
unmask benzyl and triethylsilyl groups concurrently.
The resulting triol was protected as 1,3-dioxane and
subsequently transformed into phosphonium salt via
iodide to furnish 16 in 90% overall yield. The aldehyde
19 required for the Wittig olefination with 16 was
obtained from the known homoallylic alcohol 17.12
Hydrogenation of 17 followed by benzylation and
acidic hydrolysis generated diol 18 ([h]2D5=+14.6, c=
1.37, CHCl3) in 70% overall yield. After oxidative
cleavage of 18, the produced aldehyde 19 was olefinated
with the ylid derived from 16 to give a 10:1 mixture of
cis- and trans-alkenes 20 in 88% combined yield. Acidic
hydrolysis and the following silylation furnished g-tri-
ethylsilyloxyalkenes 3 in 89% overall yield. Formation
of the second cis-2,5-disubstituted tetrahydrofuran
from 3 proceeded uneventfully under the cyclization
conditions established in that of 4 and the ensuing
reductive deiodination13 of the iodo products rendered
cis-tetrahydrofuran 21 ([h]2D4=+10.7, c=1.50, CHCl3)
as the only stereoisomer in 77% overall yield. Coinci-
dent deprotection of benzyl and triethylsilyl groups of
21 by hydrogenolysis provided diol 22 ([h]2D5=−20.9,
c=1.98, CHCl3) in 95% yield. The sterically less hin-
dered hydroxyl group of 22 was chemoselectively con-
Since the left tetrahydrofuran of 2 was secured
efficiently, it was necessary to introduce the second
right ring. Conversion of 13 into epoxide 14 ([h]2D6=
−11.5, c=1.00, CHCl3) was accomplished in 87% over-
all yield by acidic deprotection, cyclization and silyla-
tion in sequence (Scheme 3). Cuprate reaction of 14
with lithium dimethylcuprate afforded the desired alco-
hol 15 ([h]2D6=−6.8, c=1.13, CHCl3) in 78% yield along
with 15% of its regioisomer. While the molecular
arrangement of 15 was ascertained by its COSY spec-
trum, the NOE experiments between H-3 and H-6 (3%
enhancement) evidenced the cis relationship of the tet-
rahydrofuranyl ring. When the secondary hydroxyl

S. H. Kang, J. W. Jeong / Tetrahedron Letters 43 (2002) 3613–3616
3615
a,b
c
TBDPSO
TBDPSO
13
OBn
OBn
3
6
O
O
O
OH OTES
OTES
15
14
d-g
-
+
TBDPSO
PPh3I
O
O
O
OBn
H
l
TBDPSO
16
OBn
O
P1O
OP2
OH
20 : P1-P2 = CMe2
3 : P1,P2 = TES
OBn
h-j
k
m,n
O
O
HO
O
OH
18
17
19
o,p
q,r
TBDPSO
R
3
10
OPMB
13
6
O
O
O
O
OP2
N3
OP1
21 : P1 = TES, P2 = Bn
22 : P1, P2 = H
23 : R = CH2OTBDPS
2 : R = CO2H
d
s,t
Scheme 3. (a) PPTS, MeOH, THF, rt, then K2CO3, rt; (b) TESOTf, 2,6-lutidine, CH2Cl2, −78°C; (c) Me2CuLi, Et2O, 10°C; (d)
H2, Pd(OH)2/C, EtOH, rt; (e) PPTS, acetone, rt; (f) I2, Ph3P, imidazole, THF, 0°C; (g) Ph3P, K2CO3, MeCN, reflux; (h) H2, 10%
Pd/C, MeOH, rt; (i) NaH, BnBr, n-Bu4NI, THF, 0°C; (j) 1N HCl, MeOH, rt; (k) NaIO4, acetone, H2O, 0°C; (l) n-BuLi, THF,
−78 to −5°C, then 19, 10°C; (m) PPTS, MeOH, THF, rt; (n) TESOTf, 2,6-lutidine, CH2Cl2, rt; (o) I2, Ag2CO3, Et2O, rt; (p)
Ph3SnH, Et3B, THF, 0°C; (q) HN3, Ph3P, DEAD, PhH, 0°C; (r) PMBCl, n-Bu4NI, DMF, 0°C, then KHMDS, 0°C; (s) n-Bu4NF,
THF; (t) Jones oxidation, 0°C.
verted into azido group under Mitsunobu conditions,14
and the remaining one was protected as p-methoxyben-
zyl ether to give rise to azide 23 ([h]2D6=−6.0, c=1.38,
CHCl3) in 86% overall yield, the stereochemistry of
which was determined by the NOE experiments
between H-3 and H-6 (3% enhancement), and between
H-10 and H-13 (3% enhancement). Successive desilyla-
tion and Jones oxidation of 23 afforded the C1ꢀC18
subunit 2 ([h]2D5=+11.1, c=1.40, CHCl3) in 85% overall
yield.11
Antibiot. 1995, 48, 1159–1164; (f) Hartl, A.; Stelzner, A.;
Schlegel, R.; Heinze, S.; Hu¨lsmann, H.; Fleck, W.; Gra¨fe,
U. J. Antibiot. 1998, 51, 1040–1046; (g) Kozone, I.;
Chikamoto, N.; Abe, H.; Natsume, M. J. Antibiot. 1999,
52, 329–333.
2. (a) Kondo, S.; Yasui, K.; Katayama, M.; Marumo, S.;
Kondo, T.; Hattori, H. Tetrahedron Lett. 1987, 28, 5861–
5864; (b) Natsume, M.; Kondo, S.; Marumo, S. Chem.
Commun. 1989, 1911–1913.
3. (a) Stengel, C.; Reinhardt, G.; Gra¨fe, U. J. Basic Micro-
biol. 1992, 32, 339–345; (b) Gra¨fe, U.; Schlegel, R.;
Dornberger, K.; Ihn, W.; Ritzau, M.; Stengel, C.; Beran,
M.; Gu¨nther, W. Nat. Prod. Lett. 1993, 265–271; (c)
Gra¨fe, U.; Schlegel, C.; Mo¨llmann, U.; Heinisch, L.
Pharmazie 1994, 49, 343–346; (d) Fujii, K.; Hara, O.;
Marumo, S.; Sakagami, Y. Bioorg. Med. Chem. Lett.
1995, 5, 843–846; (e) Grigoriev, P. A.; Berg, A.; Schlegel,
R.; Gra¨fe, U. Bioelectrochem. Bioenerget. 1996, 39, 295–
298; (f) Pogell, B. M. Cell. Mol. Biol. 1998, 44, 461–463;
(g) Natsume, M. Recent Res. Devel. Agric. Biol. Chem.
1999, 3, 11–22.
In summary, we have established a stereocontrolled
synthesis of the upper subunit 2 for a total synthesis of
pamamycin-607 using the developed stereoselective
intramolecular iodoetherification in the presence of
Ag2CO3, which is expected to be of general utility.
Acknowledgements
This work was supported by CMDS and the Brain
Korea 21 Project.
4. For a total synthesis of 1, see: (a) Germany, O.; Kumar,
N.; Thomas, E. J. Tetrahedron Lett. 2001, 42, 4969–4974;
(b) Lee, E.; Jeong, E. J.; Kang, E. J.; Sung, L. T.; Hong,
S. K. J. Am. Chem. Soc. 2001, 123, 10131–10132; (c)
Wang, Y.; Bernsmann, H.; Gruner, M.; Metz, P. Tetra-
hedron Lett. 2001, 42, 7801–7804. For the synthetic
approaches to 1, see: (a) Walkup, R. D.; Kim, S. W.;
Wagy, S. D. J. Org. Chem. 1993, 58, 6486–6490; (b)
Walkup, R. D.; Kim, S. W. J. Org. Chem. 1994, 59,
3433–3441; (c) Walkup, R. D.; Kim, Y. S. Tetrahedron
Lett. 1995, 36, 3091–3094; (d) Mavropoulos, I.; Perlmut-
ter, P. Tetrahedron Lett. 1996, 37, 3751–3754; (e)
Mandville, G.; Girard, C.; Bloch, R. Tetrahedron: Asym-
References
1. (a) McCann, P. A.; Pogell, B. M. J. Antibiot. 1979, 32,
673–678; (b) Kondo, S.; Yasui, K.; Natsume, M.;
Katayama, M.; Marumo, S. J. Antibiot. 1988, 41, 1196–
1204; (c) Natsume, M.; Yasui, K.; Kondo, S.; Marumo,
S. Tetrahedron Lett. 1991, 32, 3087–3090; (d) Natsume,
M. J. Antibiot. 1992, 45, 1026–1028; (e) Natsume, M.;
Tazawa, J.; Yagi, K.; Abe, H.; Kondo, S.; Marumo, S. J.

3616
S. H. Kang, J. W. Jeong / Tetrahedron Letters 43 (2002) 3613–3616
metry 1997, 8, 3665–3673; (f) Mandville, G.; Bloch, R.
dd, J=11.2, 4.2 Hz), 4.00 (1H, dd, J=9.7, 4.0 Hz), 3.82
(1H, dd, J=11.2, 1.5 Hz), 3.74 (1H, dd, J=9.7, 7.0 Hz),
3.63–3.54 (2H, m), 3.40–3.30 (2H, m), 3.23 (1H, dt,
J=7.4, 4.2 Hz), 2.13–2.00 (2H, m), 1.93–1.84 (1H, m),
1.73–1.45 (7H, m), 1.29 (3H, s), 1.26 (3H, s), 1.19 (9H, s),
1.02 (3H, d, J=6.8 Hz), 0.85 (3H, d, J=6.7 Hz); 13C
NMR (100 MHz, C6D6) l 139.5, 136.1, 134.5, 134.4,
129.9 (two peaks), 128.5, 128.1, 127.6, 101.6, 81.2, 75.5
(two peaks), 73.0, 70.4, 70.3, 67.1, 43.0, 41.2, 40.7, 32.3,
31.7, 29.2, 27.2, 26.9, 25.0, 23.8, 19.6, 14.1, 10.8; IR
(neat) 1225, 1173, 1112, 1065, 1027 cm−1; HRMS (EI)
Eur. J. Org. Chem. 1999, 2303–2307; (g) Solladie´, G.;
Salom-Roig, X. J.; Hanquet, G. Tetrahedron Lett. 2000,
41, 551–554; (h) Calter, M. A.; Bi, F. C. Org. Lett. 2000,
2, 1529–1531; (i) Solladie´, G.; Salom-Roig, X. J.; Han-
quet, G. Tetrahedron Lett. 2000, 41, 2737–2740; (j) Berns-
mann, H.; Fro¨hlich, R.; Metz, P. Tetrahedron Lett. 2000,
41, 4347–4351; (k) Bernsmann, H.; Gruner, M.; Metz, P.
Tetrahedron Lett. 2000, 41, 7629–7633; (l) Bernsmann,
H.; Gruner, M.; Fro¨hlich, R.; Metz, P. Tetrahedron Lett.
2001, 42, 5377–5380.
5. (a) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc.
1981, 103, 3963–3964; (b) Boivin, T. L. B. Tetrahedron
1987, 43, 3309–3362; (c) Cardillo, G.; Orena, M. Tetra-
hedron 1990, 46, 3321–3408; (d) Harmange, J.-C.;
Figadere, B. Tetrahedron: Asymmetry 1993, 4, 1711–1754;
(e) Kang, S. H.; Lee, S. B. Tetrahedron Lett. 1993, 34,
7579–7582.
6. Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A.
D.; Halterman, R. L. J. Am. Chem. Soc. 1990, 112,
6339–6348.
1
calcd for C41H57IO5Si: 784.3020, found: 784.3062. 2: H
NMR (400 MHz, CDCl3) l 7.23 (2H, d, J=8.6 Hz), 6.84
(2H, d, J=8.6 Hz), 4.55 (2H, dd, J=36.4, 11.1 Hz), 4.19
(1H, td, J=7.5, 2.9 Hz), 3.92–3.82 (2H, m), 3.77 (3H, s),
3.77–3.68 (2H, m), 3.43–3.36 (1H, m), 2.54 (1H, p, J=7.3
Hz), 2.03–1.80 (5H, m), 1.75–1.30 (11H, m), 1.16 (3H, d,
J=7.1 Hz), 0.91 (3H, t, J=7.2 Hz), 0.81 (3H, d, J=6.9
Hz), 0.80 (3H, d, J=6.9 Hz); 13C NMR (100 MHz,
CDCl3) l 176.8, 158.9, 131.7, 129.1, 113.6, 81.0, 80.3,
79.7, 79.5, 75.7, 74.0, 60.4, 55.2, 44.1, 41.3, 40.4, 39.2,
36.2, 31.3, 29.9, 29.7, 28.4, 19.2, 13.8, 13.0, 10.3, 9.5; IR
(neat) 2101, 1712, 1248, 1062, 1039, 962 cm−1; HRMS
(EI) calcd for C29H45N3O6: 531.3308, found: 531.3312.
12. Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.; Park, J.
C. J. Org. Chem. 1990, 55, 4109–4117.
13. Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.;
Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1989, 62,
143–147.
14. (a) Hughes, D. L. Org. React. 1992, 42, 335–656; (b)
Fabiano, E.; Golding, B. T.; Sadeghi, M. M. Synthesis
1987, 190–192.
7. Morimoto, Y.; Yokoe, C. Tetrahedron Lett. 1997, 38,
8981–8984.
8. (a) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem.
Commun. 1979, 978–980; (b) Garegg, P. J.; Samuelsson,
B. J. Chem. Soc., Perkin Trans. 1 1980, 2866–2869; (c)
Garegg, P. J.; Johansson, R.; Ortega, C.; Samuelsson, B.
J. Chem. Soc., Perkin Trans. 1 1982, 681–683.
9. Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
10. Mitsunobu, O. Synthesis 1981, 1–28.
11. The selected spectroscopic data are reported below. 13:
1H NMR (400 MHz, C6D6) l 7.82–7.79 (4H, m), 7.33–
7.07 (11H, m), 4.35 (2H, dd, J=15.9, 13.0 Hz), 4.33 (1H,