Stereoselective synthesis of pamamycin-607

Article abstract of DOI:10.1021/ja0279646

A macrodiolide antibiotic pamamycin-607 was synthesized by joining two hydroxy acid components. Three cis-2, 5-disubstituted tetrahydrofuran rings in the molecule were stereoselectively prepared by radical cyclization reactions of β-alkoxyvinyl ketone intermediates and a β-alkoxymethacrylate substrate. The key step of the synthesis is characterized by the predominant threo product formation in the radical cyclization reaction of a β-alkoxymethacrylate intermediate.

Full text of DOI:10.1021/ja0279646

Published on Web 11/16/2002
Stereoselective Synthesis of Pamamycin-607
Eun Jeong Jeong, Eun Joo Kang, Lee Taek Sung, Sung Kil Hong, and Eun Lee*
Contribution from the School of Chemistry and Molecular Engineering,
Seoul National UniVersity, Seoul 151-747, Korea
Received August 1, 2002
Abstract: A macrodiolide antibiotic pamamycin-607 was synthesized by joining two hydroxy acid
components. Three cis-2, 5-disubstituted tetrahydrofuran rings in the molecule were stereoselectively
prepared by radical cyclization reactions of â-alkoxyvinyl ketone intermediates and a â-alkoxymethacrylate
substrate. The key step of the synthesis is characterized by the predominant threo product formation in
the radical cyclization reaction of a â-alkoxymethacrylate intermediate.
Pamamycins were first isolated by McCann and Pogell1 in
1979 from Streptomyces alboniger ATCC 12461 for their aerial
mycelium-inducing acitivity, and classified as new family type
antibiotics active against Gram-positive bacteria, Mycobacteria,
and Neurospora. Isolation of pamamycin-607 (1) was reported
by Marumo and co-workers2 in 1987 from S. alboniger IFO
12738, and they were also successful in structure determination
studies on the basis of spectroscopic analysis. Subsequent studies
by Marumo3 and other groups4 on pamamycins led to discovery
of their anionophoric activity and identification of further
members of the family (2, 3, 4, 5, and others) as well as
Figure 1. Representative pamamycins.
evaluation of structure-activity relationship (Figure 1). Pama-
mycin-607 (1) is especially interesting for its potent activity5
Scheme 1. Pamamycin-607
against gram-positive bacteria including multiple antibiotic-
resistant strains of Mycobacterium tuberculosis as well as against
phytopathogenic fungi.
Pamamycins are sixteen-membered macrodiolides incorporat-
ing two of the three cis-2, 5-disubstituted tetrahydrofuran rings
within the macrocycle framework. The prototype pamamycin-
607 (1) consists of the two hydroxy acids 6 and 7. The most
characteristic structural features in 6 and 7 are cis-2, 5-disub-
stituted tetrahydrofuran rings adjacent to methyl-substituted
stereogenic centers (Scheme 1). The hydroxy acid 6 is an erythro
(C2′-C3′) isomer, and the acid 7 features a threo (C2-C3)-
erythro (C6-C7)-threo (C9-C10) arrangement. Efficient and
stereoselective construction of these structural units is not trivial,
(1) McCann, P. A.; Pogell, B. M. J. Antibiot. 1979, 32, 673-678.
(2) Kondo, S.; Yasui, K.; Katayama, M.; Marumo, S.; Kondo, T.; Hattori, H.
and the difficulty therein is manifested by the absence of reports
Tetrahedron Lett. 1987, 28, 5861-5864.
on the total synthesis6 of pamamycins in the literature at the
(3) (a) Kondo, S.; Yasui, K.; Natsume, M.; Katayama, M.; Marumo, S. J.
Antibiot. 1988, 41, 1196-1204. (b) Natsume, M.; Kondo, S.; Marumo, S.
outset of this research, despite intense synthetic efforts by a
number of research groups.7-14
J. Chem. Soc. Chem. Comm. 1989, 1911-1913. (c) Natsume, M.; Yasui,
K.; Kondo, S.; Marumo, S. Tetrahedron Lett. 1991, 32, 3087-3090. (d)
Natsume, M.; Tazawa, J.; Yagi, K.; Abe, H.; Kondo, S.; Marumo, S. J.
Antibiot. 1995, 48, 1159-1164. (e) Natsume, M.; Honda, A.; Oshima, Y.;
Abe, H.; Kondo, S.; Tanaka, F.; Marumo, S. Biosci. Biotech. Biochem.
1995, 59, 1766-1768.
(6) A total synthesis of pamamycin-607 was communicated by Professor Sung
Ho Kang (Korea Advanced Institute of Science and Technology) at the
CMDS Symposium 2000, Nov. 9, 2000, Daejon, Korea. A preliminary
report on the total synthesis was communicated by us: (a) Lee, E.; Jeong,
E. J.; Kang, E. J.; Sung, L. T.; Hong, S. K. J. Am. Chem. Soc. 2001, 123,
10 131-10 132. One paper appeared in the literature before publication of
our communication and a second one appeared after publication of ours:
(b) Germay, O.; Kumar, N.; Thomas, E. J. Tetrahedron Lett. 2001, 42,
4969-4974 (c) Wang, Y.; Bernsmann, H.; Gruner, M.; Metz, P. Tetrahe-
dron Lett. 2001, 42, 7801-7804.
(4) (a) Stengel, C.; Reinhardt, G.; Gra¨fe, U. J. Basic Microbiol. 1992, 32, 339-
345. (b) Gra¨fe, U.; Stengel, C.; Mo¨llmann, U.; Heinisch, L. Pharmazie
1994, 49, 343-346. (c) Grigoriev, P.; Berg, A.; Schlegel, R.; Gra¨fe, U.
Bioelectrochem. Bioenerg. 1996, 39, 295-298. (d) Ha¨rtl, A.; Stelzner, A.;
Schlegel, R.; Heinze, S.; Hu¨lsmann, H.; Fleck, W.; Gra¨fe, U. J. Antibiot.
1998, 51, 1040-1046. (e) Kozone, I.; Chikamoto, N.; Abe, H.; Natsume,
M. J. Antibiot. 1999, 52, 329-331.
(5) Pogell, B. M. Cell. Mol. Biol. 1998, 44, 461-463.
9
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J. AM. CHEM. SOC. 2002, 124, 14655-14662
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A R T I C L E S
Jeong et al.
Scheme 2. Synthesis of (+)-Methyl Nonactate
Radical cyclization of â-alkoxyacrylates is a highly useful
method for stereoselective preparation of cis-2, 5-disubstituted
tetrahydrofurans and cis-2, 6-disubstituted tetrahydropyrans.15,16
Radical cyclization reactions of different â-alkoxyacrylates were
employed as key steps in the total syntheses of dactomelynes,17
kumausyne,18 and kumausallene,19 demonstrating the generality
of these reactions. Further development concerning these types
of reactions would be the control of the stereoselectivity outside
of the oxacycle when R-substituted â-alkoxyacrylates are
employed in the radical cyclization. In this context, reported
work by Guindon and co-workers on radical-mediated reduction
of R-halo carboxylates was highly pertinent; it was reported
that radical-mediated reduction of R-substituted â-alkoxy-R-
halo carboxylates resulted in high threo selectivity.20 Theoretical
studies indicated that the stereoselectivity originated primarily
from the preference for “outside alkoxy” conformation of the
intermediate radical species. In this model, both allylic 1, 3-strain
and electrostatic repulsions were minimized, and an early
transition state for hydrogen abstraction in which attack occurs
from the least hindered face of the radical is apparently
operative. The “cis-2, 5” selectivity encountered in the â-alkoxy-
acrylate radical cyclization reactions in forming tetrahydrofura-
nyl ring systems and the “threo” selectivity at the exocyclic R
sites were simultaneously demonstrated in an expedient synthesis
of (+)-methyl nonactate (12).21 In the synthesis, the threo ester
10 was obtained stereoselectively from the â-alkoxymethacrylate
9 (Scheme 2).
Scheme 3. Retrosynthetic Analysis of Pamamycin-607
In the retrosynthetic analysis of 1 (Scheme 3), it was decided
to form the more hindered ester bond first, which called for
preparation of the carboxylic acid A and the alcohol E (Scheme
3). The ester bond formation between A and E would set the
stage for the final macrodiolide cyclization required in the
preparation of 1. The acid A may be obtained from the ester D
employing the key radical cyclization reaction converting the
â-alkoxyvinyl ketone C into the tetrahydrofuranyl ester B. The
two tetrahydrofuran rings in E and F were also envisaged to
arise from radical cyclization reactions of the intermediates such
as G. In practice, two separate radical cyclization reactions were
deemed necessary: the first one was reminiscent of the key
reaction employed in the synthesis of 12, and the second radical
cyclization reaction was analogous to the conversion of C to
B. The substrates for radical cyclization were then to be
synthesized from the protected dimethylpentahydroxynonane
derivative H. Intermediates H and D were to be prepared
employing Evans asymmetric aldol reactions.22
(7) (a) Walkup, R. D.; Park, G. Tetrahedron Lett. 1988, 29, 5505-5508. (b)
Walkup, R. D.; Kim, S. W.; Wagy, S. D. J. Org. Chem. 1993, 58, 6486-
6490. (c) Walkup, R. D.; Kim, S. W. J. Org. Chem. 1994, 59, 3433-
3441. (d) Walkup, R. D.; Kim, Y. S. Tetrahedron Lett. 1995, 36, 3091-
3094.
(8) Mavropoulos, L.; Perlmutter, P. Tetrahedron Lett. 1996, 37, 3751-3754.
(9) Arista, L.; Gruttadauria, M.; Thomas, E. J. Synlett 1997, 627-628.
(10) (a) Mandville, G.; Girad, C.; Block, R. Tetrahedron Asymmetry 1997, 8,
3665-3673. (b) Mandville, G.; Block, R. Eur. J. Org. Chem. 1999, 2303-
2307.
(11) (a) Solladie´, G.; Salom-Roig, X. J.; Hanquet, G. Tetrahedron Lett. 2000,
41, 551-554. (b) Solladie´, G.; Salom-Roig, X. J.; Hanquet, G. Tetrahedron
Lett. 2000, 41, 2737-2740.
(12) Calter, M. A.; Bi, F. C. Org. Lett. 2000, 2, 1529-1531.
(13) (a) Bernsmann, H.; Hungerhoff, B.; Fechner, R.; Fro¨hlich, R.; Metz, P.
Tetrahedron Lett. 2000, 41, 1721-1724. (b) Bernsmann, H.; Fro¨hlich, R.;
Metz, P. Tetrahedron Lett. 2000, 41, 4347-4351. (c) Bernsmann, H.;
Gruner, M.; Metz, P. Tetrahedron Lett. 2000, 41, 7629-7633.
(14) Kang, S. H.; Jeong, J. W. Tetrahedron Lett. 2002, 43, 3613-1616.
(15) (a) Lee, E.; Tae, J. S.; Lee, C.; Park, C. M. Tetrahedron Lett. 1993, 34,
4831-4834. (b) Lee, E.; Tae, J. S.; Chong, Y. H.; Park, Y. C.; Yun, M.;
Kim, S. Tetrahedron Lett. 1994, 35, 129-132. (c) Lee, E.; Park, C. M. J.
Chem. Soc. Chem. Commun. 1994, 293-294. (d) Lee, E.; Jeong, J.-w.;
Yu, Y. Tetrahedron Lett. 1997, 38, 7765-7768. (e) Lee, E.; Song, H. Y.;
Kim, H. J. J. Chem. Soc., Perkin I 1999, 3395-3396. (f) Lee, E.; Kim, H.
J.; Kang, E. J.; Lee, I. S.; Chung, Y. K. Chirality, 2000, 12, 360-361.
(16) Lee, E. In Radicals in Organic Synthesis, Vol. 2: Applications; Renaud,
P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; pp 303-333.
(17) Lee, E.; Park, C. M.; Yun, J. S. J. Am. Chem. Soc. 1995, 117, 8017-8018.
(18) Lee, E.; Yoo, S.-K.; Cho, Y.-S.; Cheon, H.-S.; Chong, Y. H. Tetrahedron
Lett. 1997, 38, 7757-7758.
Synthesis of the carboxylic acid A started with the reaction
of the PMB-protected 3-hydroxypropanal (14) and the (Z)-boron
enolate prepared from the chiral imide 13. The aldol imide 15
was converted into the corresponding methyl ester 16 using
samarium triflate23 in methanol-THF, and the diol ester 17 was
obtained from 16 via PMB-deprotection. Regioselective tosy-
lation of 17 provided the primary tosylate 18. The reaction of
18 with 1, 1-dimethoxyhexan-3-one (19) under acidic conditions
afforded the â-alkoxyvinyl ketone 20.24 Subsequent iodide
substitution of 20 afforded the corresponding iodide 21. Radical
cyclization of 21 in the presence of tributylstannane and AIBN
(19) Lee, E.; Yoo, S.-K.; Choo, H.; Song, H. Y. Tetrahedron Lett. 1998, 39,
317-318.
(22) For an example of asymmetric aldol reactions, see: Evans, D. A.; Kaldor,
S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112,
7001-7031.
(23) Evans, D. A.; Trotter, B. W.; Caˆte´, B.; Colman, P. J.; Dias, L. C.; Tyler,
A. N. Angew. Chem., Int. Ed. Engl. 1997, 36, 2744-2748.
(24) For an example of radical cyclizations of â-aminovinyl ketones, see: Lee,
E.; Kang, T. S.; Chung, C. K. Bull. Kor. Chem. Soc. 1996, 17, 212-214.
(20) (a) Guindon, Y.; Lavalle´e, J.-F.; Boisvert, L.; Chabot, C.; Delorme, D.;
Yoakim, C.; Hall, D.; Lemieux, R.; Simoneau, B. Tetrahedron Lett. 1991,
32, 27-30. (b) Durkin, K.; Liotta, D.; Rancourt, J.; Lavalle´e, J.-F.; Boisvert,
L.; Guindon, Y. J. Am. Chem. Soc. 1992, 114, 4912-4914.
(21) Lee, E.; Choi, S. J. Org. Lett. 1999, 1, 1127-1128.
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Stereoselective Synthesis of Pamamycin-607
A R T I C L E S
Scheme 4
Scheme 6
Scheme 7
Scheme 5
under the standard high-dilution conditions proceeded efficiently
to give the tetrahydrofuranyl ketone product 22 in high yield
(Scheme 4). The acetal ketone 19 and the â-methoxyvinyl
ketone 25 were synthesized from butanal (23) via 1-hexyn-3-
one (24). Column chromatographic separation of 19 and 25 was
tedious, and the mixture of 19 and 25 could be used in place of
pure 19 in the synthesis of the â-alkoxyvinyl ketone 20 with
equal efficiency. Direct preparation of 20 from the reaction of
18 with 24 did not proceed in the presence of N-methylmor-
pholine, sodium hydride, or tri-n-butylphosphine (Scheme 5).
The next problem was the introduction of the stereogenic
center at C8′. A number of reducing agents were tested for the
stereoselective reduction of 22. LS-Selectride and L-Selectride
reduction25 of 22 in THF at low-temperature resulted in the
predominant formation of the wrong epimer 27 (9:1∼6:1).
Sodium borohydride reduction afforded a 3:1 mixture of 27 and
26.7a Eventually, it was found that an acceptable stereoselectivity
(26:27 ) 8.5:1) was obtained when samarium(II) iodide26 was
used as the reducing agent in the presence of methanol (Scheme
6). TBS-protection of the hydroxy group provided the TBS ether
28, which was converted into the carboxylic acid 29 via basic
hydrolysis of the methyl ester moiety.
Scheme 8
The aldol imide 35 was obtained from the reaction of 34 with
the (Z)-boron enolate of the imide 13 in high yield. The aldol
imide 35 was converted into the diol 36 via NaBH4 reduction,
and protection of the primary hydroxy group with TBSCl led
to the formation of the secondary alcohol 37. Benzylation of
the secondary hydroxy group provided the protected tetrahy-
droxy intermediate 38. The primary alcohol 39 was obtained
after TBS-deprotection of 38 (Scheme 8). Generation of the four
stereogenic centers in H was thus accomplished in a straight-
forward manner employing two consecutive Evans aldol reac-
tions.
Considerable experimentation was necessary for the genera-
tion of the stereogenic center at C10, and eventually, Lewis
acid-catalyzed allylation of an aldehyde intermediate was
examined.27 Oxidation of 39 with sulfur trioxide-pyridine
complex led to the aldehyde 40. Conditions for stereoselective
allylation of the aldehyde 40 were examined in detail. Reaction
Synthesis of the alcohol E commenced with the reaction of
the aldehyde 14 with the (Z)-boron enolate of the imide 30
(Scheme 7). The Weinreb amide 32 was obtained from the aldol
imide 31 via transamination, and it was transformed into the
BOM-protected derivative 33, which was converted into the
aldehyde 34 via DIBAL reduction.
(25) Arco, M. J.; Trammell, M. H.; White, J. D. J. Org. Chem. 1976, 41, 2075-
2083.
(26) (a) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
2693-2698. (b) Keck, G. E.; Wager, C. A. Org. Lett. 2000, 2, 2307-
2309. (c) Keck, G. E.; Wager, C. A.; Sell, T.; Wager, T. T. J. Org. Chem.
1999, 64, 2172-2173.
(27) Keck, G. E.; Abbott, D. E. Tetrahedron Lett. 1984, 25, 1883-1886.
9
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A R T I C L E S
Jeong et al.
Scheme 9
Figure 2. NOE Analysis of the Lactone 51.
Scheme 11
Scheme 10
Scheme 12
For confirmation of the stereochemistry at C10, the aldehyde
40 was allowed to react with allyltributylstannane (41) in ether
in the presence of zinc chloride. From this reaction, the major
product 42 was obtained in 55% yield, and the epimeric
homoallylic alcohol 43 was obtained in 20% yield. Both were
derivatized to form the O-acetyl (S)-mandelate esters28 52 and
53. From inspection of NMR spectra of 52 and 53, it was clear
that the vinylic protons in 52 gave rise to signals more upfield
compared to those in 53, confirming (10R) configuration for
52 and (10S) for 53 (Scheme 11).
Unsuccessful attempts on the alternative preparation of the
intermediates such as 45 may deserve some comments. The
Weinreb amide 32 was converted into the corresponding TBS
ether and DIBAL reduction afforded the aldehyde 54. Reaction
of the (Z)-boron enolate obtained from 13 and 54 proceeded in
high yield to produce the aldol imide 55. The C-C bond
forming reaction between the Weinreb amide obtained from 55
and allylmagnesium bromide proceeded uneventfully to yield
the hydroxy ketone 56. Tetrabutylammonium triacetoxyboro-
hydride reduction produced the anti/syn diol mixture 57, but
the sample was contaminated with the byproducts from TBS
migration (Scheme 12).
of 40 with allyltributylstannane (41) did not proceed in the
presence of magnesium bromide in THF or dichloromethane.
The reaction in dichloromethane-THF mixture (100:1∼4:1) in
the presence of magnesium bromide yielded a mixture of the
homoallylic alcohols 42 and 43. The allylation reaction pro-
ceeded stereoselectively when 40 and 41 were allowed to react
in dichloromethane-diethyl ether mixture (25:1) in the presence
of magnesium bromide. Highly efficient stereoselective allyla-
tion of 40 was also achieved upon addition of allyltributylstan-
nane (41) in dichloromethane in the presence of magnesium
bromide-diethyl ether complex (Scheme 9). The homoallylic
alcohol 42 thus obtained was converted into the diol 44 via
oxidative cleavage of the double bond and sodium borohydride
reduction, and subsequent benzoylation led to the dibenzoate-
protected pentahydroxy intermediate 45.
At this point, confirmation of the stereochemical assignments
C6∼10 was deemed necessary. The aldol imide 35 was
converted into the corresponding methyl ester 46, which was
converted into the primary alcohol 47 via PMB-deprotection.
BOM-deprotection of the corresponding TIPS ether 48 led to
the formation of the diol 49. Formation of the lactone 50 from
49 was accomplished efficiently under acidic conditions, and
subsequent benzoylation led to the benzoate lactone 51 (Scheme
10). NOE analysis of 51 (Figure 2) confirmed the relative
stereochemical assignments at C6∼9.
More stable protecting groups were examined. The TIPS-
protected aldehyde 58 was obtained from 32 via the corre-
(28) For examples of determination of absolute stereochemistry via O-acetyl
(S)-mandelate esters, see: Lee, E.; Lee, Y. R.; Moon, B.; Kwon, O.; Shim,
M. S.; Yun, J. S. J. Org. Chem. 1994, 59, 1444-1456.
9
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Stereoselective Synthesis of Pamamycin-607
A R T I C L E S
Scheme 13
Scheme 14
Figure 3. NOE Analysis of 22, 68, and 73.
Scheme 16
Scheme 15
alcohol 70. The reaction of 70 with 1, 1-dimethoxyhexan-3-
one (19) proceeded uneventfully, and the â-alkoxyvinyl ketone
71 obtained was converted into the iodide 72 via iodide
substitution. Radical cyclization reaction of 72 under the
standard high-dilution conditions in benzene in the presence of
tributylstannane and AIBN afforded the ketone 73 in high yield
as expected (Scheme 16). At this stage, it was possible to obtain
pure samples of the ketone 73 by column chromatographic
removal of the erythro (C2-C3) contaminant originating from
the minor product in the radical cyclization step leading to 68.
Stereoselectivity in the conversion of 72 to 73 was difficult to
determine, as the formation of the minor product epimeric at
C13 was insignificant.
sponding Weinreb amide, but the aldol reaction of 58 with the
boron enolate generated from 13 did not proceed (Scheme 13).
Transamination of 35 and allyl Grignard reaction on the
Weinreb amide led to the ketone 59, but the subsequent
reduction of 59 with tetrabutylammonium triacetoxyborohydride
proceeded to give a random mixture of the anti diol 60 and the
syn diol 61 (Scheme 14).
As the stereochemical integrity of 45 was ascertained,
tetrahydrofuran annulation was at hand in the next stage. The
alcohol 62 was obtained from 45 via PMB-deprotection with
ceric ammonium nitrate. Tosylation of the primary hydroxy
group in 62 led to the intermediate 63, and the secondary alcohol
64 was prepared via BOM-deprotection under acidic conditions.
Reaction of 64 with a mixture (3:2) of methyl 3,3-dimethoxy-
2-methylpropanoate (65) and methyl â-methoxymethacrylate in
the presence of an acid catalyst in chloroform provided the
desired â-alkoxymethacrylate derivative 66, which was con-
verted into the iodide 67 via iodide substitution. Low-temper-
ature radical cyclization reaction of 67 in toluene in the presence
of tributylstannane and triethylborane proceeded efficiently
producing a mixture of the tetrahydrofuranyl products favoring
(10.8:1) the correct threo isomer 68 (Scheme 15).
The stereochemical outcome of radical cyclization reactions
in forming three tetrahydrofuran rings in 22, 68, and 73 was
confirmed by NOE (or NOESY) analysis (Figure 3).
Debenzylation of 73 via hydrogenolysis provided the alcohol
74. Having synthesized the carboxylic acid 29 and the alcohol
74 (A and E in Scheme 3) successfully, attention was next
turned to finding conditions for the efficient esterification
reaction. Use of 1, 3-diisopropylcarbodiimide and 4-pyrrolidi-
nopyridine29 in dichloromethane led to efficient esterification
reaction between 74 and 29, but two epimeric products were
obtained. The major isomer 75 was hydrolyzed to the carboxylic
acid 76 with lithium hydroxide in aqueous methanol, but it was
clear that an epimeric mixture again was obtained (Scheme 17).
The site most vulnerable to epimerization in the hydrolysis
step was thought to be C13, and an early introduction of the
15-amino group was considered to prevent epimerization at C13
via retro-Michael/Michael reaction. Reductive amination30 on
73 and Boc-protection led to a mixture (∼6:1) of the (15R)-
amino derivative 77 and the (15S)-epimer 78, which was
(29) Somers, P. K.; Wandless, T. J.; Schreiber, S. L. J. Am. Chem. Soc. 1991,
113, 8045-8056.
(30) (a) Narasaka, K.; Ukaji, Y.; Yamazaki, S. Bull. Chem. Soc. Jpn. 1986, 59,
525-533. (b) Haddad, M.; Dorbais, J.; Larcheveˆque, M. Tetrahedron Lett.
1997, 38, 5981-5984.
For generation of the second tetrahydrofuran ring, the
benzoate moieties in 68 were hydrolyzed to give the diol 69,
and tosylation of the primary hydroxyl group provided the
9
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A R T I C L E S
Jeong et al.
Scheme 17
Scheme 19
Scheme 18
Scheme 20
Scheme 21
converted into the mixture of the alcohols 79/80 via hydro-
genolysis. Reaction of the 79/80 mixture with the carboxylic
acid 29 in the presence of 1,3-diisopropylcarbodiimide and
4-pyrrolidinopyridine yielded a mixture of isomers, and the
major product 81 was obtained from column chromatographic
separation. Importantly, reductive amination on 75 was highly
stereoselective, and the same product 81 was obtained after Boc-
protection (Scheme 18).
azodicarboxylate in the presence of triphenylphosphine. Hy-
drogenation of the azide 86 and Boc-protection led to the alcohol
79, confirming the original assignment on C15. The minor diol
87 was converted into the epimer 80 via the corresponding azide
89.
The ester 81 was converted into the alcohol 82 after TBS-
deprotection under acidic conditions, and hydrolysis of 82 by
lithium hydroxide in aqueous methanol proceeded without
epimerization to yield the hydroxy carboxylic acid 83. After
considerable experimentation, a mixture of products was
obtained from 83 under Yamaguchi esterification conditions31
in benzene under reflux, from which a macrodiolide 84 was
separated in low yield. Boc-deprotection of 84 and reductive
amination in the presence of excess formaldehyde32 led to a
dimethylamino macrodiolide 85, but it was clearly different from
1 (Scheme 19).
It was evident that problems arose during the esterification
reactions, but pinpointing the site(s) of epimerization within the
complex esters and macrodiolides proved to be quite difficult.
The more viable alternative would be reductive cleavage of these
intermediates and comparison of partial structures. For this
purpose, the hydroxy ester 26 was reacted with lithium
aluminum hydride, and the resulting diol was converted into
the diacetate 90. Similarly, the hydroxy ester 79 was reduced
with lithium borohydride and the diacetate 91 was obtained after
acetylation (Scheme 21). Fortunately, examination of the NMR
spectra of 90 and 91 revealed a clear difference: the AB signals
of the ABX system arising from the methylene protons at C1′
of 90 were centered at δ 3.90 and 3.99, and the corresponding
signals from the analogous protons at C1 of 91 were more
widely separated at δ 3.96 and 4.21. In other words, the erythro
C2′-C3′ and the threo C2-C3 arrangements could be distin-
guished easily by comparing the C1′ or C1 methylene proton
signals of the appropriate diacetate derivatives.
The product 85 was thought to be a stereoisomer of 1, and it
was decided first to confirm the stereochemical assignment at
C15. Accordingly, the hydroxy ketone 74 was converted into
the major diol 86 and the minor diol 87 via samarium iodide
reduction. The stereochemical outcome in this conversion was
assumed to follow the pattern encountered in the conversion of
22 to 26 and 27 (Scheme 20). The major diol 86 was converted
into the azide intermediate 88 upon Mitsunobu-type azide
substitution using diphenylphosporyl azide33 and diisopropyl
(31) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989-1993.
(32) Brouillette, W. J.; Saeed, A.; Abuelyaman, A.; Hutchison, T. L.; Wolkowicz,
P. E.; McMillin, J. B. J. Org. Chem. 1994, 59, 4297-4303.
(33) Takano, S.; Sugihara, T.; Satoh, S.; Ogasawara, K. J. Am. Chem. Soc. 1988,
110, 6467-6471.
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Stereoselective Synthesis of Pamamycin-607
A R T I C L E S
Scheme 22
Scheme 24
Scheme 23
Scheme 25
Scheme 26
The stereochemical integrity of the intermediate 81 was
immediately tested. Lithium borohydride reduction of 82 and
exhaustive acetylation of the resultant diols yielded the diacetate
91 and a new diacetate 92, which exhibited signals centered at
δ 3.96 and 4.20 (Scheme 22). It was now clear that formation
of the major product 81 from 79/80 and 29 (and the major
product 75 from 74 and 29) in the presence of 1, 3-diisopro-
pylcarbodiimide and 4-pyrrolidinopyridine had been accompa-
nied by the epimerization at C2′.
Attention was now turned to finding esterification conditions
free from epimerization problems. Gratifyingly, the ester 93 was
obtained in high yield from 29 and 74 following the room-
temperature Yamaguchi protocol.34 Reductive amination on 93
proceeded in high stereoselectivity as anticipated, and subse-
quent Boc-protection led to the ester 94. The presence of the
epimeric (at C15) product was not noticed. TBS-deprotection
of 94 then led to the hydroxy ester 95 (Scheme 23). Lithium
borohydride reduction of 95 and acetylation of the diols obtained
produced 90 and 91 confirming the stereochemical integrity.
The seco acid 96 was obtained from lithium hydroxide
hydrolysis of 95. For macrodiolide synthesis, the seco acid 96
was subjected to the Yamaguchi esterification conditions in
benzene under reflux (previously employed for conversion of
83 to 84), and the macrodiolide 97 was obtained as the major
product in low yield. Boc-deprotection of 97 and reductive
amination in the presence of excess formaldehyde resulted in
the formation of the dimethylamino derivative 98, which was
again clearly different from 1 (Scheme 24).
The stereochemical integrity of 97 was then checked by
reduction-acetylation protocol: the macrodiolide 97 was con-
verted into the known diacetate 90 and a new diacetate 99, which
exhibited ABX signals centered at δ 3.94 and 4.04 (Scheme
25). It was now clear that the high-temperature Yamaguchi
esterification had caused epimerization at C2 in the major
product 97 from 96 (and the major product 84 from 83).
The seco acid 96 was converted back to the hydroxy ester
95 via diazomethane treatment confirming that the hydrolysis
step was not the source of the problem. For the safe and efficient
macrodiolide formation, a number of esterification protocols
were examined. For example, use of 2, 2′-dipyridyl disulfide
and triphenylphosphine (with and without silver perchlorate)
in benzene under reflux did not yield any macrodiolide product.
Use of 1-methyl-2-chloropyridinium iodide and triethylamine
in acetonitrile under reflux gave an intractable product mixture.
Room-temperature Yamaguchi esterification did not proceed.
Finally, the macrodiolide 100 was obtained in an acceptable
yield by slow addition of 96 to the hot 1, 2-dichloroethane
solution of 1, 3-dicyclohexylcarbodiimide, pyridine, and pyri-
dinium tosylate35 (Scheme 26). Lithium borohydride reduction
of 100 and acetylation produced the diacetates 90 and 91
confirming the stereochemical integrity. Finally, pamamycin-
607 (1) was prepared by Boc-deprotection of 100 under acidic
conditions and reductive amination in the presence of excess
formaldehyde.
In the present synthesis, the three cis-2, 5-disubstituted
tetrahydrofuran rings in 1 were stereoselectively introduced via
radical cyclization reactions of â-alkoxyvinyl ketone intermedi-
ates and a â-alkoxymethacrylate substrate. In particular, the
difficulty in introducing stereogenic centers at C2, 3, 6, 7, 8, 9,
10, 13, and 15 was solved by first building stereogenic centers
at C6∼10 in a systematic manner and then using two outward
tetrahydrofurn-forming radical cyclization reactions. This syn-
thesis provides another efficacious example of radical-mediated
reactions for construction of complex natural products.
Acknowledgment. The authors thank the Ministry of Science
and Technology, Republic of Korea, and Korea Institute of
(35) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.; Somfai, P.;
Whritenour, D. C.; Masamune, S. J. Am. Chem. Soc. 1990, 112, 7407-
7408.
(34) Burke, S. D.; Zhao, Q. J. Org. Chem. 2000, 65, 1489-1500.
9
J. AM. CHEM. SOC. VOL. 124, NO. 49, 2002 14661

A R T I C L E S
Jeong et al.
Science and Technology Evaluation and Planning for a National
Research Laboratory grant (1999). Brain Korea 21 graduate
fellowship grants to E. J. Jeong and L. T. Sung are gratefully
acknowledged. The authors also thank Prof. M. Natsume of
Tokyo University of Agriculture and Technology for supplying
NMR spectra of natural pamamycin-607.
Supporting Information Available: Full experimental pro-
cedures and spectral data for intermediates and 1 (46 pages,
print/PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA0279646
9
14662 J. AM. CHEM. SOC. VOL. 124, NO. 49, 2002