Total synthesis of (±)-nisamycin

Article abstract of DOI:10.1021/jo990413m

We have developed a highly convergent synthesis of the manumycin-type m- C₇N-antibiotic nisamycin that is applicable to other members of this family of antibiotics. The synthesis features a three-step sequence to the epoxyquinol core that serves as a scaffold for the attachment of the polyene side chains. The eastern polyene side chain was constructed via a novel organozirconocene-mediated synthesis. Zirconocene methodology was also applied to the synthesis of the polyene side chains of asukamycin. The southern side chain of nisamycin was introduced via a Stille reaction that employed a vinyl bromo ketone, derived from an acid-sensitive bromo ketal. Pd-mediated coupling of the vinyl bromide with a stannyl TIPS ester gave TIPS-protected nisamycin that was readily converted to the natural product.

Full text of DOI:10.1021/jo990413m

J . Org. Chem. 1999, 64, 5053-5061
5053
Tota l Syn th esis of (()-Nisa m ycin
Peter Wipf* and Philip D. G. Coish1
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
Received March 8, 1999
We have developed a highly convergent synthesis of the manumycin-type m-C7N-antibiotic
nisamycin that is applicable to other members of this family of antibiotics. The synthesis features
a three-step sequence to the epoxyquinol core that serves as a scaffold for the attachment of the
polyene side chains. The eastern polyene side chain was constructed via a novel organozirconocene-
mediated synthesis. Zirconocene methodology was also applied to the synthesis of the polyene side
chains of asukamycin. The southern side chain of nisamycin was introduced via a Stille reaction
that employed a vinyl bromo ketone, derived from an acid-sensitive bromo ketal. Pd-mediated
coupling of the vinyl bromide with a stannyl TIPS ester gave TIPS-protected nisamycin that was
readily converted to the natural product.
Nisamycin (1) is a recently isolated member of the
manumycin family of antibiotics, which includes alisa-
mycin,2 asukamycin,3 and manumycin A (Figure 1).4,5
Nisamycin was discovered in 1993 by Hayashi and co-
workers in the culture broth of Streptomyces sp. K106, a
bacterial strain isolated from a soil sample collected in
Sakai City, J apan.6 Like other members of the manu-
mycin family, nisamycin has a highly functionalized
epoxyquinol core, known as the m-C7N (meta-substituted
aniline) unit.7 This unit is thought to originate from
3-amino-4-hydroxybenzoic acid via a unique biosynthetic
pathway involving a building block from the TCA cycle.7,8
A consequence of this biosynthetic pathway is the syn
orientation of the epoxide and the quinol oxygen, a
feature that is common to most manumycins. Attached
to the core are two polyunsaturated side chains. The
southern side chain consists of a trienyl acyl unit that is
found in manumycin A, alisamycin, and asukamycin.
Similarly, the eastern side chain of nisamycin contains
a dienyl amide moiety that is common to other manu-
mycins. Collectively, the dense functionality of the core
(1) Present address: Bayer Corporation, West Haven, CT 06516
(2) (a) Franco, C. M. M.; Maurya, R.; Vijayakumar, E. K. S.;
Chatterjee, S.; Blumbach, J .; Ganguli, B. N. J . Antibiot. 1991, 44, 1289.
(b) Chatterjee, S.; Vijayakumar, E.; Franco, C.; Blumbach, J .; Ganguli,
B. N. J . Antibiot. 1993, 46, 1027. (c) Hayashi, K.; Nakagawa, M.; Fujita,
T.; Nakayama, M. Biosci. Biotech. Biochem. 1994, 58, 1332.
(3) (a) Omura, S.; Kitao, C.; Tanaka, H.; Oiwa, R.; Takahashi, Y.;
Nakagawa, A.; Shimada, M.; Iwai, Y. J . Antibiot. 1976, 29, 876. (b)
Kakinuma, K.; Ikekawa, N.; Nakagawa, A.; Omura, S. J . Am. Chem.
Soc. 1979, 101, 3402. (c) Cho, H. G.; Sattler, I.; Beale, J . M.; Zeeck, A.;
Floss, H. G. J . Org. Chem. 1993, 58, 7925.
(4) (a) Buzzetti, F.; Ga¨umann, E.; Hu¨tter, R.; Keller-Schierlein, W.;
Neipp, L.; Prelog, V.; Za¨hner, H. Pharm. Acta Helv. 1963, 38, 871. (b)
Thiericke, R.; Stellwaag, M.; Zeeck, A. J . Antibiot. 1987, 40, 1549. (c)
Zeeck, A.; Schro¨der, K.; Frobel, K.; Grote, R.; Thiericke, R. J . Antibiot.
1987, 40, 1530. (d) Zeeck, A.; Frobel, K.; Heusel, C.; Schro¨der, K.;
Thiericke, R. J . Antibiot. 1987, 40, 1541.
(5) For recent reviews on the chemistry of manumycin-type antibiot-
ics, see: (a) Sattler, I.; Thiericke, R.; Zeeck, A. Nat. Prod. Rep. 1998,
15, 221. (b) Floss, H. G. Nat. Prod. Rep. 1997, 14, 433.
(6) (a) Hayashi, K.; Nakagawa, M.; Fujita, T.; Tanimori, S.; Na-
kayama, M. J . Antibiot. 1993, 46, 1904. (b) Hayashi, K.; Nakagawa,
M.; Nakayama, M. J . Antibiot. 1994, 47, 1104. (c) Hayashi, K.;
Nakagawa, M.; Fujita, T.; Tanimori, S.; Nakayama, M. J . Antibiot.
1994, 47, 1110.
(7) (a) Kim, C.-G.; Kirschning, A.; Bergon, P.; Zhou, P.; Su, E.;
Sauerbrei, B.; Ning, S.; Ahn, Y.; Breuer, M.; Leistner, E.; Floss, H. G.
J . Am. Chem. Soc. 1996, 118, 7486. (b) Hu, Y.; Melville, C. R.; Gould,
S. J .; Floss, H. G. J . Am. Chem. Soc. 1997, 119, 4301.
F igu r e 1. Some members of the manumycin family of
antibiotics.
and the chemical sensitivity of the polyene moieties make
nisamycin a challenging synthetic target.9 We have
reported the first successful synthetic route toward the
manumycin m-C7N core structure in 1994 and subse-
quently applied this strategy in an asymmetric total
synthesis of the antitumor antibiotic LL-C10037R.10,11 To
date, there has been only one reported synthesis of
racemic nisamycin by Taylor and co-workers in 1998
using a related strategy for m-C7N synthesis.12,13 In this
(9) For mechanistic studies of the reactivity pattern of epoxyquinols,
see: Wipf, P.; J eger, P.; Kim, Y. Bioorg. Med. Chem. Lett. 1998, 8,
351.
(10) Wipf, P.; Kim, Y. J . Org. Chem. 1994, 59, 3518.
(11) Wipf, P.; Kim, Y.; J ahn, H. Synthesis 1995, 1549.
(12) Taylor, R. J . K.; Alcaraz, L.; Kapfer-Eyer, I.; Macdonald, G.;
Wei, X.; Lewis, N. Synthesis 1998, 775.
(8) Dewick, P. M. Nat. Prod. Rep. 1993, 10, 233.
10.1021/jo990413m CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/24/1999

5054 J . Org. Chem., Vol. 64, No. 14, 1999
Wipf and Coish
Sch em e 1
Sch em e 2
Sch em e 3
paper, we report our approach for the successful conver-
gent assembly of (()-nisamycin.14
Our initial retrosynthetic analysis of nisamycin is
shown in Scheme 1. Disconnection of the amide and
allylic alcohol bonds affords three segments, the ep-
oxyquinol core 5 and the two polyene side chains 6 and
7. We planned to construct the polyunsaturated acid side
chains using Zr-Zn transmetalation methodology,15 which
we had recently employed for the synthesis of the eastern
side chain of manumycin A (vide infra).14a Our approach
to the m-C7N core 5 was closely patterned after previous
work on the synthesis of LL-C10037R in our laborato-
ries.10,11 Further optimization of this strategy resulted
in a three-step sequence to the core from commercially
available 2,5-dimethoxyaniline 8.
compound, presumably a diketal,17 that was decomposing
to the desired monoketal. To simplify the purification and
convert any diketal to monoketal before chromatography,
the crude product was washed with dilute acid. Subse-
quent purification provided 10 in 60-75% yield. Chemose-
lective epoxidation of the dienone employed a combina-
tion of DBU and TBHP to give 5.18 We knew from our
previous work with LL-C10037R that epoxidation occurs
at the electron-poor double bond, and not at the N-
substituted double bond. Concurrent deprotection of the
Alloc group led to the primary amine 5 as a stable solid
in 45-55% yield. Careful chromatography provided pure
material; however, usually a mixture containing 10-15%
of vinylogous amide 11 was isolated. This was not a
concern since 11 was readily removed as an acyl deriva-
tive in the next step.
Before continuing with the synthesis, we conducted a
brief model study in order to test the feasibility of our
retrosynthetic plan (Scheme 3). Acylation of the core 5
with sorbyl chloride using a protocol similar to that of
Taylor12 provided the desired amide 12 in high yield. 1,2-
Addition of commercially available vinyllithium to the
ketone functionality proceeded smoothly at low temper-
ature and gave the tertiary alcohol 13 in 92% yield. The
assignment of the relative stereochemistry of the epoxide
Resu lts a n d Discu ssion
Protection of the aniline nitrogen of 8 provided the
Alloc derivative 9 in excellent yield (Scheme 2). Subse-
quent hypervalent iodine oxidation16 led to the desired
quinone monoketal 10. During isolation of 10 via radial
chromatography (UV detection), we noted a second
(13) For other syntheses of manumycin-type natural products, see:
(a) Kapfer, I.; Lewis, N. J .; Macdonald, G.; Taylor, R. J . K. Tetrahedron
Lett. 1996, 37, 2101. (b) Alcaraz, L.; Macdonald, G.; Kapfer, I.; Lewis,
N. J .; Taylor, R. J . K. Tetrahedron Lett. 1996, 37, 6619. (c) Macdonald,
G.; Lewis, N. J .; Taylor, R. J . K. Chem. Commun. 1996, 2647. (d)
Alcaraz, L.; Taylor, R. J . K. Chem. Commun. 1998, 1157.
(14) In preliminary communications, we have reported the prepara-
tion of polyene side chains of manumycins using organozirconocene
methodology: (a) Wipf, P.; Xu, W.; Takahashi, H.; J ahn, H.; Coish, P.
D. G. Pure Appl. Chem. 1997, 69, 639. (b) Wipf, P.; Coish, P. D. G.
Tetrahedron Lett. 1997, 38, 5073.
(15) (a) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197. (b) Wipf,
P.; Xu, W. Org. Synth. 1996, 74, 205. (c) Wipf, P.; Ribe, S. J . Org. Chem.
1998, 63, 6454.
(16) (a) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677. (b)
Wipf, P.; Kim, Y. J . Org. Chem. 1993, 58, 1649. (c) Wipf, P.; J ung,
J .-K. J . Org. Chem. 1998, 63, 3530.
(17) 1H NMR analysis (300 MHz, CDCl3) of an impure sample
supported this assumption. Peak listings characteristic for the diket-
al: δ 3.13 (s, 6 H), 3.26 (s, 6 H), 4.54 (d, 2 H, J ) 4.5 Hz), 5.19 (d, 1 H,
J ) 10.5 Hz), 5.23 (d, 1 H, J ) 18 Hz), 5.75 (d, 1 H, J ) 10.5 Hz),
5.8-6.0 (m, 1 H), 6.25 (dd, 1 H, J ) 2.5, 10 Hz), 6.62 (br s, 1 H), 6.74
(br s, 1 H).
(18) Other epoxidation protocols, including enantioselective proce-
dures, were inefficient.

Total Synthesis of (()-Nisamycin
J . Org. Chem., Vol. 64, No. 14, 1999 5055
Sch em e 4
Sch em e 5
Sch em e 6
and tertiary alcohol centers of 13 was based on the
assumption that the vinyllithium approached from the
less-hindered face of the ketone, anti to the electron-
withdrawing epoxide.19 This assignment was confirmed
by an X-ray analysis of an analogue of 13 obtained by
phenyllithium addition to the corresponding N-Alloc-
protected epoxy ketone.20
The final step in our model study was the deprotection
of the ketal, which we thought would be problematic
given the presence of the very acid-sensitive tertiary bis-
allylic alcohol moiety in 13. In fact, ketal hydrolysis in
closely related systems has met with failure.13b However,
treatment of 13 with PPTs/TsOH afforded the desired
ketone 14, albeit in low yield.
acrolein,21 afforded the bis-allylic alcohol 18, which was
readily converted to the desired trienyl TIPS ester 19 in
60% yield. The preparation of 19, in addition to the
earlier approach toward the manumycin A dienonate,14
demonstrates the generality of our protocol for the
preparation of a broad range of conjugated polyenes
present in this family of natural products.
The preparation of the southern side chain segment 7
required access to a metallotriene equivalent. Hydrozir-
conation/transmetalation of TIPS alkynyl ester 15 pro-
vided a vinyl zinc species that was readily added to
â-tributylstannylacrolein14b to give alcohol 20 (Scheme
6). Trifluoroacetylation with the imidazolide followed by
base treatment gave the desired all-trans triene 21 in
good yield. In this sequence, 1-(trifluoroacetyl)imidazole
was used rather than TFAA for the protection step since
the side product, imidazole, is unreactive (compared to
trifluoroacetic acid derived from TFAA) toward the acid-
sensitive vinyl tin moiety.
We next studied the conversion of stannyl ester 21 to
the required trienyllithium reagent. Treatment of the
stannane with 1.05 equiv of n-BuLi in THF at low
temperature (-85 to -78 °C) resulted in complete
decomposition of the starting material. Similarly, the
generation of trienyllithium from the corresponding
bromo- and iodotrienyl ester,22 or the addition of the
dianion obtained from the corresponding acid23 to the core
gave rapid decomposition. Therefore, we decided to
modify our strategy for the introduction of the southern
Encouraged by the success of this model study that
yielded a compound 14 closely related to the nisamycin
target molecule, we proceeded with a synthesis of the
eastern side chain 6. Our approach was based on the
sequential hydrozirconation, Zr-Zn transmetalation, and
1,2-addition reactions demonstrated in our synthesis of
the dienyl side chain of manumycin A.14 Starting with
TIPS 3-butynoate (15),14b derived in two steps from
3-butynol, hydrozirconation of the triple bond followed
by in situ Zr-Zn transmetalation using Me2Zn and
subsequent addition of the generated vinyl zinc to com-
mercially available cyclohexyl carboxaldehyde provided
the allylic alcohol 17 in good yield (Scheme 4). It should
be noted that the TIPS alkynyl ester and its acid
precursor are labile intermediates. Base washing of the
crude product from the J ones oxidation of 3-butynol
resulted in rapid isomerization to the corresponding
allenyl acid. Similarly, silica gel chromatography of the
TIPS ester gave the allenyl ester.
The secondary alcohol 17 was activated toward elimi-
nation by conversion to the trifluoroacetate. In situ
treatment of this trifluoroacetate with diisopropylethy-
lamine gave the all-trans diene 6 as the major product
in 44% yield. Minor side products were observed but not
isolated. Furthermore, the elimination product was con-
taminated by a small amount of a geometric isomer
(possibly the 2Z,4E compound), which was removed
during the next step. The elimination of the trifluoroac-
etate moiety was not as facile as the elimination of the
bis-allylic acetate of 18 (vide infra) and required extended
warming to room temperature in order to consume the
trifluoroacetylated intermediate.
(21) Maeta, H.; Suzuki, K. Tetrahedron Lett. 1993, 23, 3851.
(22) The trienyl bromide was obtained in 82% yield by treating
stannane 21 with 2 equiv of NBS in CH2Cl2 (1H NMR δ 0.85-1.45 (m,
21 H), 5.96 (d, 1 H, J ) 15.0 Hz), 6.34 (dd, 1 H, J ) 10.5, 15.0 Hz),
6.41 (dd, 1 H, J ) 10.5, 15.0 Hz), 6.55 (d, 1 H, J ) 13.5 Hz), 6.81 (dd,
1 H, J ) 10.5, 13.5 Hz), 7.20 (dd, 1 H, J ) 10.5, 15.0 Hz)). The trienyl
iodide was obtained as an approximately 1:1 mixture of presumably
cis and trans isomers in 83% yield by treating stannane 21 with 2
equiv of NIS in CH2Cl2 (1H NMR δ 1.00-1.45 (m, 21 H), 5.99 (d, 1 H,
J ) 15.0 Hz), 6.01 (dd, 1 H, J ) 10.5, 15.0 Hz), 6.33 (dd, 1 H, J ) 10.5,
14.5 Hz), 6.43 (dd, 1 H, J ) 10.5, 15.0 Hz), 6.52-6.75 (m, 4 H), 6.84
(dd, 1 H, J ) 7.5, 10.0 Hz), 7.10-7.48 (m, 3 H)). For a related cis-
trans isomerization during tin-iodine exchange, see: Mapp, A. K.;
Heathcock, C. H. J . Org. Chem. 1999, 64, 23.
The zirconocene strategy was also applied to the
synthesis of the trienyl side chain of asukamycin (Scheme
5). Hydrozirconation of butynoate 15, followed by Zr-
Zn transmetalation and 1,2-addition to 3-cyclohexyl
(23) The iodo trienyl acid was prepared obtained in 84% yield by
treating the TIPS ester with K2CO3 in MeOH/THF/H2O (1H NMR (CD3-
OD) δ 5.96 (d, 1 H, J ) 15.0 Hz), 6.00 (d, 1 H, J ) 13.0 Hz), 6.41 (dd,
1 H, J ) 11.0, 15.0 Hz), 6.54 (dd, 1 H, J ) 11.0, 15.0 Hz), 6.62-6.96
(m, 5 H), 7.12-7.40 (m, 3 H)).
(19) Wipf, P.; Kim, Y. J . Am. Chem. Soc. 1994, 116, 11678.
(20) Wipf, P.; J eger, P. Unpublished results.

5056 J . Org. Chem., Vol. 64, No. 14, 1999
Wipf and Coish
Sch em e 7
Sch em e 8
to the procedure of Farina et al.27 Repeated chromatog-
raphy of the crude product provided the desired coupling
product 28 in 76% yield. However, treatment of 28 with
PPTs in acetone/H2O resulted in decomposition of the
starting material. This negative result was analogous to
that of Taylor et al., who attempted the ketal deprotection
of a fully functionalized precursor of alisamycin.12 Pd-
catalyzed coupling of ketone 25 with stannane 27 did not
provide a viable alternative, since the coupling product
was only obtained in 24% yield after a difficult purifica-
tion.
side chain. From our model study, we knew that vinyl-
lithium added readily to the acylated core 12. Accord-
ingly, we considered the addition of vinylstannyllithium
22,24 which provides a stannylated addition product that
could be elongated via a Stille reaction (Scheme 7). The
vinyl tin linker was successfully employed by Taylor and
co-workers in their synthesis of nisamycin; however, in
their approach, addition to a quinone core structure was
not chemoselective and required separation of regioiso-
mers.12 In our strategy, vinylstannane 23 was subjected
to tin-bromide exchange.25 The presence of the bromide
substituent allowed the deprotection of the ketal moiety
of 24 under acidic conditions to access epoxy ketone 25,
which would then serve as a coupling partner in the Stille
reaction. The tin-bromide exchange reaction represents
an Umpolung of the reactivity of the vinyl linker segment
that was crucial for acetal hydrolysis and thus for a
successful realization of our strategy toward nisamycin.
Nonetheless, the yield for the hydrolysis of the acid-
sensitive dimethyl acetal 24 was modest even after
reaction optimization (47% based on recovered starting
material), and elimination product 26 was isolated in
18%.
For the successful completion of the total synthesis of
nisamycin, core enamine 5 was treated with acid chloride
29, prepared in situ by exposure of TIPS ester 6 to oxalyl
chloride in the presence of a catalytic amount of DMF
(Scheme 9). Enone 30 was obtained in 50% yield and
subjected to vinyllithium reagent 22 to afford the 1,2-
addition product in 52% yield. Tin-bromine exchange
proceeded smoothly using conditions previously opti-
mized for the stannane 23; treatment with NBS provided
the vinyl bromide 31 in 88% yield. In the crucial hydroly-
sis step, addition of PPTs to a solution of 31 in acetone/
H2O followed by heating at 40 °C for 4 h provided the
ketone 32 in 39% yield based on recovered starting
material. The elimination product 26 was also isolated
in 23% yield. We then examined the cross coupling of the
vinyl bromide 32 with dienyl stannane 33.28 This Stille-
type reaction was performed using preformed Pd(0)
catalyst, generated by DIBAL-H reduction of PdCl2-
(PPh3)2.29 The pentaene 34 was isolated in good yield
(70% based on recovered starting material). The final step
in the total synthesis of (()-nisamycin was the depro-
tection of the TIPS ester. An initial attempt using
aqueous methanolic K2CO3 provided a mixture of com-
ponents. We next employed methanolic CsF which ef-
fected clean and rapid conversion of the ester to the acid.
Aqueous acidic workup followed by concentration of the
organic layer under high vacuum provided (()-nisamycin
in quantitative yield and high purity by LC-MS analysis.
An analytically pure sample was also obtained by pre-
parative TLC. The spectral data of the synthetic sample
were in full agreement with the natural product.6
In conclusion, we have developed a convergent syn-
thesis of (()-nisamycin that is applicable to other mem-
bers of the manumycin family of antibiotics. The syn-
We decided to study the cross-coupling reaction of the
advanced model 24 with amide 27 (Scheme 8). This
amide was quite similar in structure to the electrophile
required for completion of nisamycin. A degassed solution
of bromo ketal and dienyl stannane 2726 was stirred at
room temperature for 5.5 h with catalytic Pd2(dba)2‚
CHCl3 in the presence of tri(2-furyl)phosphine according
(24) (a) Corey, E. J .; Wollenberg, R. H. J . Org. Chem. 1975, 40, 3788.
(b) Corey, E. J .; Wollenberg, R. H. J . Am. Chem. Soc. 1974, 96, 5581.
(25) Treatment of the vinylstannane with NBS at low temperature
resulted in partial conversion to the vinyl bromide. For example,
stirring the stannane with 1 equiv of NBS at -40 °C for 1 h gave a
44% yield of the vinyl bromide 24 and a 34% yield of recovered starting
material. However, conducting the experiment at higher temperature
(0 °C) resulted in complete consumption of stannane. At this temper-
(27) Farina, V.; Roth, G. P. Adv. Metal-Org. Chem. 1996, 5, 1.
(28) This compound was prepared by Horner-Emmons condensation
of â-tributylstannylacrolein with diethyl(trimethylsilyloxycarbonyl-
methyl)phosphorane, followed by aqueous base workup and reprotec-
tion of the acid function using TIPS-Cl and imidazole (see the
Experimental Section).
ature, the vinyl bromide was obtained in 82% yield as
stereoisomer (see Experimental Section).
a single
(26) This compound was prepared in 51% yield by Horner-Emmons
condensation of â-tributylstannyl acrolein with N-methoxy-N-methyl-
2-(triphenylphosphoranylidene)acetamide (see the Experimental Sec-
tion).
(29) Negishi, E.-I.; King, A. O.; Okukado, N. J . Org. Chem. 1977,
42, 1821.

Total Synthesis of (()-Nisamycin
J . Org. Chem., Vol. 64, No. 14, 1999 5057
(2.2 M in THF) was obtained from Organometallics, Inc. Pd2-
(dba)2‚CHCl3, tri(2-furyl)phosphine, Me2Zn (2 M in toluene),
1-octyne, TBHP (5.0-6.0 M in decane), N-methoxy-N-methyl-
2-(triphenylphosphoranylidene)acetamide, cyclohexyl carbox-
aldehyde, and diethyl(trimethylsilyloxycarbonylmethyl)phos-
phonate were obtained from the Aldrich Chemical Co.
Cp2Zr(H)Cl was prepared according to the procedure of Buch-
wald et al.31 Cp2ZrCl2 was obtained from Boulder Chemicals,
Inc. Other solvents or reagents were used as acquired except
when otherwise noted. 13C and 1H NMR spectra were mea-
sured with 300 and 500 MHz spectrometers using CDCl3 as
the solvent unless stated otherwise. LCMS analysis was
performed with an HP 1100 Series LC/MSD equipped with a
Waters Nova-Pak C18 column and with a Finnigan LCQ
(electrospray detection) equipped with a Phenomenox Luna
C18 column. Column chromatography was performed using
silica gel 60 (particle size 0.040-0.055 mm, 230-400 mesh).
Radial chromatography was carried out on a Chromatotron
using in-house plates coated with silica gel 60 (with CaSO4,
E. Merck, 1, 2, or 4 mm thick).
Sch em e 9
3-Am in o-4,4-d im e t h oxy-5,6-e p oxyc yc loh e x-2-e n -1-
on e (5). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 3.01 mL,
20.14 mmol) was added to a cold (0 °C) approximately 5 M
solution of TBHP (40.25 mmol) in decane (8.05 mL). The
resulting mixture was stirred for 20 min. A solution of ketone
1011 (1.02 g, 4.03 mmol) in 1,2-dichloroethane (10 mL) was
added via cannula, giving a clear, colorless solution. The
reaction mixture was allowed to warm to room temperature
over a period of 5.5 h. The reaction flask was opened to the
atmosphere and treated with Na2SO3 (3.8 g). The resulting
suspension was vigorously stirred for 15 min and filtered
through a pad of Celite (fritted-glass funnel, water aspirator,
and elution with ethyl acetate). The filtrate was thoroughly
concentrated (water aspirator) to give ∼7-8 mL of a yellow-
brown solution that contained decane. The solution was
filtered through a pad of silica gel (fritted-glass funnel, water
aspirator, and elution with hexanes). Subsequently, the silica
pad was washed with ethyl acetate (4×). The ethyl acetate
extracts were concentrated to give crude product that was
purified by column chromatography on SiO2 (ethyl acetate) to
afford 339 mg (45%) of solid epoxide as an approximately 85:
15 mixture of 5 and 11. Careful chromatography gave a pure
sample of 5. A similar procedure using a solution of TBHP in
1,2-dichloroethane32 was also effective and gave a 31% yield
of a 85:15 mixture of epoxide and dienone: mp 155.5-157.9
thesis features a highly functionalized cyclohexyl core 5
that was readily prepared via a three-step sequence from
commercially available material. The core served as a
scaffold for the attachment of the eastern and southern
side chains. One-flask hydrozirconation-Zr-Zn trans-
metalation-1,2-addition, followed by base-mediated elimi-
nation, provided the eastern side chain of (()-nisamycin
stereoselectively. This methodology was also applied to
the preparation of the eastern side chains of manumycin
A and asukamycin. Umpolung of a vinylstannane addi-
tion product to the corresponding vinyl bromide allowed
the crucial acetal hydrolysis to unmask the epoxyketone
moiety. Subsequent Stille reaction with a dienyl stannane
completed the assembly of the carbon skeleton of (()-
nisamycin, and, after TIPS ester deprotection, provided
the natural product. Despite the modest overall yield of
3% for (()-1 due to decomposition of the acid-sensitive
enamide functionality during acetal hydrolysis, the long-
est linear sequence is only nine steps, and thus, this
strategy is well suited to gain rapid synthetic access to
the manumycin class of epoxyquinol natural products.
1
°C; IR (CDCl3) 3511, 3399, 1618, 1415, 1251, 1125 cm-1; H
NMR δ 3.30 (s, 3 H), 3.40 (dd, 1 H, J ) 2.0, 4.0 Hz), 3.57 (s, 3
H), 3.73 (d, 1 H, J ) 4.0 Hz), 4.96 (br s, 2 H), 5.11 (d, 1 H, J
) 2.0 Hz); 13C NMR δ 50.4, 51.5, 51.9, 53.0, 95.8, 96.2, 157.2,
190.8; MS (EI) m/z (rel intensity) 185 (M+, 80), 153 (95), 126
(100); HRMS (EI) m/z calcd for C8H11NO4 185.0688, found
185.0691.
The 1H NMR signals derived from 11 appeared in the
spectrum of the mixture as follows: δ 3.17 (s, 6 H), 4.76 (br s,
2 H), 5.49 (d, 1 H, J ) 2.0 Hz), 6.31 (dd, 1 H, J ) 2.0, 10.0
Hz), 6.37 (d, 1 H, J ) 10.0 Hz).
3-(Hexa -2′E,4′E-d ien a m id o)-4,4-d im eth oxy-5,6-ep oxy-
cycloh ex-2-en -1-on e (12). A 1.6 M solution of BuLi in
hexanes (1.20 mL, 1.90 mmol) was added dropwise to a chilled
(0 °C) solution of t-BuOH (182 µL, 1.90 mmol) in dry THF (2.0
mL). The resulting clear, colorless solution was stirred for 30
min and was then transferred via cannula to a -78 °C solution
of ketone 5 (335 mg, 1.81 mmol) and sorbyl chloride (266 µL,
2.17 mmol) in dry THF (16.4 mL). The reaction mixture
became cloudy, and then clear and yellowish, within minutes
after the addition. The solution was allowed to warm to 0 °C
over 30 min. Saturated aqueous NH4Cl was added, and the
mixture was warmed to room temperature. Water and ethyl
acetate were added, the layers were separated, and the
aqueous layer was extracted with ethyl acetate (3×). The
Exp er im en ta l Section
Gen er a l Meth od s. THF and Et2O were dried by distillation
over Na/benzophenone ketyl. Dry CH2Cl2, DBU, DCE, and
toluene were obtained by distillation from CaH2. DMF and
t-BuOH were dried over 4 Å sieves. BuLi (1.6 M in hexanes)
was obtained from Aldrich Chemical Co. and was standandized
using the procedure of Kofron and Baclawski.30 Vinyllithium
(31) Buchwald, S. l.; LaMarie, S. J .; Nielson, R. B.; Watson, B. T.;
King, S. M. Tetrahedron Lett. 1987, 28, 3895.
(32) Sharpless, K. B.; Verhoeven, T. R. Aldrichim. Acta 1979, 12,
68.
(30) Kofron, W. G.; Baclawski, l. M. J . Org. Chem. 1976, 47, 361.

5058 J . Org. Chem., Vol. 64, No. 14, 1999
Wipf and Coish
combined organic extracts were washed with brine, dried (Na2-
SO4), and concentrated. The residue was chromatographed on
SiO2 (CH2Cl2/EtOAc 95:5) to yield 84 mg (18%) of acylated 11
and 349 mg (69%) of the epoxy amide 12 as an oil that
crystallized upon standing: mp 115.5-116.5 °C; IR (CDCl3)
3402, 1693, 1666, 1608, 1236 cm-1; 1H NMR δ 1.81 (d, 3 H, J
) 5.0 Hz), 3.24 (s, 3 H), 3.47 (dd, 1 H, J ) 2.0, 4.0 Hz), 3.61 (s,
3 H), 3.77 (d, 1H, J ) 4.0 Hz), 5.80 (d, 1 H, J ) 15.0 Hz), 6.05-
6.25 (m, 2 H), 7.14-7.30 (m, 2 H), 7.62 (br s, 1 H); 13C NMR δ
18.8, 50.6, 51.3, 51.5, 52.1, 95.4, 108.4, 120.6, 129.4, 140.9,
144.7, 146.1, 165.3, 193.0; MS (EI) m/z (rel intensity) 279 (M+,
3), 95 (100); HRMS (EI) m/z calcd for C14H17NO5 279.1107,
found 279.1099.
and the organic layer was washed with water (2×) and
saturated aqueous NaCl (10 mL), dried (Na2SO4), and concen-
trated to afford 115.3 mg (95%) of 15 as a colorless oil (this
1
material contained a small amount (e5% by H NMR) of the
allenyl ester 16): IR (neat) 3295, 1728, 1274 cm-1; 1H NMR δ
1.09 (d, 18 H, J ) 7.5 Hz), 1.25-1.42 (m, 3 H), 2.19 (t, 1 H, J
) 2.5 Hz), 3.32 (d, 2 H, J ) 2.5 Hz); 13C NMR δ 12.0, 17.8,
27.3, 71.8, 76.4, 167.7; MS (EI) m/z (rel intensity) 197 ([M-
C3H7]+, 100), 153 (81), 111 (69); HRMS (EI) m/z calcd for
C
10H17O2Si (M - C3H7) 197.0998, found 197.0990.
Tr iisop r op ylsilyl 5-Cycloh exylp en ta -2E,4E-d ien oa te
(6). To a cold (0 °C) solution of alkyne 15 (8.715 g, 36.25 mmol)
in dry, degassed CH2Cl2 (121 mL) was added Cp2ZrHCl (10.3
g, 39.9 mmol) in three portions. The ice bath was removed,
and the suspension was allowed to warm to room temperature
over 45 min. The suspension became a clear, orange solution
after approximately 6 min of warming and was subsequently
chilled to -78 °C and treated with a solution of Me2Zn in
toluene (20.8 mL, 41.7 mmol) over 30 min. The -78 °C bath
was replaced with a 0 °C bath, and the mixture was stirred
for 25 min. A solution of cyclohexylcarboxaldehyde (4.88 g, 43.5
mmol) in dry, degassed CH2Cl2 (20 mL) was added dropwise
via cannula. The reaction mixture was stirred at 0 °C for 3 h,
transferred to a flask containing EtOAc and saturated aqueous
NH4Cl, and slowly stirred. After addition of H2O and Et2O,
the aqueous phase was reextracted with Et2O (3×). The
combined organic extracts were washed with brine and dried
(Na2SO4). The opaque solution was filtered through silica (55
g, EtOAc). The filtrate was concentrated, and the resulting
oil was purified by flash chromatography on SiO2 (hexanes/
ethyl acetate 85:15) to afford 5.69 g (44%) of pure, oily 17: IR
(neat) 2929, 1720, 1270 cm-1; 1H NMR δ 0.68-1.40 (m, 24 H),
1.52-1.95 (m, 8 H), 3.04 (d, 2 H, J ) 7.0 Hz), 3.76 (t, 1 H, J )
7.0 Hz), 5.53 (dd, 1 H, J ) 7.0, 15.5 Hz), 5.68 (dt, 1 H, J ) 7.0,
15.5 Hz); 13C NMR δ 12.0, 17.9, 26.2, 26.3, 28.7, 29.0, 39.5,
43.7, 124.5, 135.7, 171.9; MS (EI) m/z (rel intensity) 354 (M+,
10), 311 (100), 293 (95); HRMS (EI) m/z calcd for C20H38O3Si
354.2590, found 354.2597.
3-(Hexa -2′E,4′E-d ien a m id o)-4,4-d im eth oxy-5,6-ep oxy-
1-vin ylcycloh ex-2-en -1-ol (13). A 2.2 M solution of vinyl-
lithium in THF (1.97 mmol, 0.90 mL) was added to a cold (-78
°C) solution of ketone 12 (183.6 mg, 0.657 mmol) in dry THF
(6.6 mL). The mixture was stirred at -78 °C for 45 min.
Saturated aqueous NH4Cl was added, and the mixture was
allowed to warm to room temperature while being vigorously
stirred. Et2O and water were added, and the layers were
separated. The aqueous layer was extracted with Et2O (3×).
The combined organic extracts were dried (Na2SO4) and
concentrated. The resulting oil was purified by flash chroma-
tography on SiO2 (CH2Cl2/EtOAc 8:2) to afford 186.6 mg (92%)
of 13 as a colorless solid: mp 136.0-136.7 °C; IR (CDCl3) 3571,
1
3413, 1684, 1641, 1240 cm-1; H NMR δ 1.80 (d, 3 H, J ) 5.0
Hz), 2.23 (br s, 1 H (disappeared upon addition of D2O)), 3.20
(s, 3 H), 3.32 (dd, 1 H, J ) 2.5, 4.5 Hz), 3.51 (s, 3 H), 3.58 (d,
1 H, J ) 4.5 Hz), 5.23 (dd, 1 H, J ) 1.0, 10.5 Hz), 5.48 (dd, 1
H, J ) 1.0, 17.0 Hz), 5.74 (d, 1 H, J ) 15.0 Hz), 5.84 (dd, 1 H,
J ) 10.5, 17.5 Hz), 6.02-6.22 (m, 2 H), 6.58 (d, 1 H, J ) 2.5
Hz), 7.12-7.35 (m, 2 H); 13C NMR δ 18.6, 50.0, 50.8, 51.9, 55.9,
72.1, 95.4, 116.3, 117.0, 121.7, 128.1, 129.6, 138.3, 138.8, 142.4,
164.7; MS (EI) m/z (rel intensity) 307 (M+, 1), 208 (55), 194
(75), 95 (100); HRMS (EI) m/z calcd for C16H21NO5 307.1420,
found 307.1408.
2-(Hexa -2′E,4′E-d ien a m id o)-4-h yd r oxy-5,6-ep oxy-4-vi-
n ylcycloh ex-2-en -1-on e (14). A solution of ketal 13 (12 mg,
0.039 mmol) in acetone (1.1 mL) and water (137 µL) was
treated at room temperature with PPTs (9.8 mg, 0.039 mmol)
and TsOH‚H2O (2.2 mg, 0.012 mmol). The resulting clear,
colorless solution was stirred at room temperature for 46 h,
concentrated, and purified by radial chromatography on SiO2
(1 mm plate, CH2Cl2/EtOAc, 8:2) followed by flash chroma-
tography on SiO2 (CH2Cl2/EtOAc 9:1) to afford 3.4 mg (33%)
of the vinyl ketone 14 as a white solid: mp 166.3-168.7 °C;
IR (CDCl3) 3691, 3575, 1676, 1638, 1241 cm-1; 1H NMR δ 1.87
(d, 3 H, J ) 5.0 Hz), 2.66 (br s, 1 H), 3.64 (d, 1 H, J ) 4.0 Hz),
3.70 (dd, 1 H, J ) 2.5, 4.0 Hz), 5.38 (d, 1 H, J ) 10.5 Hz), 5.52
(d, 1 H, J ) 17.0 Hz), 5.82 (d, 1 H, J ) 14.5 Hz), 5.90 (dd, 1 H,
J ) 10.5, 17.0 Hz), 6.12-6.30 (m, 2 H), 7.20-7.30 (m, 1 H),
7.43 (d, 1 H, J ) 2.5 Hz), 7.58 (br s, 1 H); 13C NMR (125 MHz)
δ 18.8, 53.0, 57.6, 71.5, 118.2, 120.8, 127.0, 128.2, 129.5, 137.5,
140.0, 143.6, 165.2, 188.9; MS (EI) m/z (rel intensity) 261 (M+,
2), 206 (10), 95 (100); HRMS (EI) m/z calcd for C14H15NO5
261.1001, found 261.0996.
To a cold (-10 °C) solution of alcohol 17 (5.58 g, 15.7 mmol)
in dry THF was added trifluoro-acetyl-imidazole (5.37 mL, 47.2
mmol), followed by dry pyridine (5 mL, 62 mmol). The bath
was allowed to warm to approximately 10 °C over 1 h,
diisopropylethylamine (13.7 mL, 78.7 mmol) was added, and
the reaction mixture was allowed to warm to room tempera-
ture over 5 h. Et2O (400 mL) and H2O (400 mL) were added,
and the organic layer was washed with saturated aqueous
NH4Cl (2×), H2O, and brine and dried (Na2SO4). Flash
chromatography on SiO2 (hexanes/EtOAc 98:2) of the resulting
oil afforded 2.31 g (44%) of diene 6: IR (neat) 1692, 1250 cm-1
;
1H NMR δ 0.90-1.38 (m, 24 H), 1.55-1.75 (m, 7 H), 1.96-
2.12 (m, 1 H), 5.74 (d, 1 H, J ) 15.0 Hz), 5.98 (dd, 1 H, J )
6.5, 15.5 Hz), 6.09 (dd, 1 H, J ) 10.5, 15.5 Hz), 7.15 (dd, 1 H,
J ) 10.5, 15.0 Hz); 13C NMR δ 12.2, 18.0, 26.0, 26.2, 32.5, 41.3,
121.3, 126.1, 146.0, 150.1, 167.1; MS (EI) m/z (rel intensity)
293 ([M - CH(CH3)2]+, 100), 211 (10), 159 (10); HRMS (EI)
m/z calcd for C17H29O2Si (M - CH(CH3)2) 293.1937, found
293.1926.
3-Bu tyn oic Acid .33 To a cold (0 °C) solution of concentrated
H2SO4 (9.6 mL) and CrO3 (1.39 g, 13.9 mmol) in distilled water
(36 mL) was added a solution of 3-butyn-1-ol (0.5 g, 7.1 mmol)
and acetone (7 mL) over a period of 1 h. After 3.5 h at 0 °C,
the mixture was transferred to a separatory funnel and
extracted with Et2O (6×). The combined organic layers were
washed with H2O (2×), dried (Na2SO4), and concentrated to
afford 270 mg (45%) of 3-butynoic acid as an off-white solid:
1H NMR δ 2.25 (t, 1 H, J ) 2.5 Hz), 3.38 (d, 2 H, J ) 2.5 Hz).34
Tr iisop r op ylsilyl 3-Bu tyn oa te (15). To a solution of
3-butynoic acid (42.6 mg, 0.507 mmol) and TIPS-Cl (97.7 mg,
0.507 mmol) in CH2Cl2 (2.5 mL) was added imidazole (34.5
mg, 0.507 mmol). The mixture was stirred for 45 min and was
then diluted with H2O and CH2Cl2. The layers were separated,
Tr iisop r op ylsilyl 7-Cycloh exylh ep ta -3E,6E-d ien oa te
(18). A solution of freshly distilled 15 (534 mg, 2.22 mmol) in
dry, degassed CH2Cl2 (22 mL) was added to a suspension of
Cp2ZrHCl (548 mg, 2.13 mmol) in CH2Cl2 (10 mL) while the
reaction temperature was maintained near 20 °C. After 10
min, the homogeneous, orange solution was cooled to -78 °C,
and a solution of Me2Zn (2.13 mmol, 2.0 M) in toluene was
added. After 5 min, the -78 °C bath was replaced with a 0 °C
bath, and the reaction mixture was stirred for a further 25
min. A solution of freshly distilled (E)-3-cyclohexyl-2-propen-
1-al35 (267 mg, 1.93 mmol) in CH2Cl2 (6.4 mL) was added, and
the mixture was stirred at 0 °C for 2 h and then at room
temperature for 1.5 h. The mixture was cooled to 0 °C, and
saturated aqueous NH4Cl solution was added followed by, after
20 min, 2 g of MgSO4. The suspension was stirred for 20 min
(33) Holland, B. C.; Gilman, N. W. Synth. Commun. 1974, 4, 203.
(34) Snider, B. B.; Spindell, D. K. J . Org. Chem. 1980, 45, 5017.
(35) Maeta, H.; Suzuki, K. Tetrahedron Lett. 1993, 34, 341.

Total Synthesis of (()-Nisamycin
J . Org. Chem., Vol. 64, No. 14, 1999 5059
and then filtered through Celite (CH2Cl2). Concentration of
the filtrate, followed by dilution with 85:15 hexanes/EtOAc,
gave a suspension that was filtered through Celite (hexanes/
EtOAc 85:15). Concentration of the filtrate, followed by flash
chromatography on SiO2 (hexanes/EtOAc 85:15), afforded 443
mg (60%) of the dienyl alcohol 18 as an oil: IR (CDCl3) 3511
chromatography on SiO2 (hexanes/EtOAc 96:4) afforded 310
mg (75%) of 21 as a yellow-brown oil: IR (C6D6) 1685, 1267
1
cm-1; H NMR (C6D6) δ 0.75-1.05 (m, 15 H), 1.17 (d, 18 H, J
) 7.5 Hz), 1.25-1.75 (m, 15 H), 5.90-6.05 (m, 2 H), 6.25 (dd,
1 H, J ) 10, 15 Hz), 6.46 (d, 1 H, J ) 18.5 Hz), 6.66 (dd, 1 H,
J ) 10, 18.5 Hz), 7.51 (dd, 1 H, J ) 11.5, 15 Hz); 13C NMR
(C6D6) δ 10.2, 12.8, 14.3, 18.5, 28.0, 29.9, 124.1, 129.6, 141.3,
143.1, 145.6, 147.0, 166.6; MS (EI) m/z (rel intensity) 513 ([M
- C4H9]+, 100), 511 (75); HRMS (EI) m/z calcd for C24H45O2-
Si120Sn (M - C4H9) 513.2211, found 513.2226.
(br), 3330, 1708, 1464, 1342, 1189, 1072, 972, 764 cm-1 1H
;
NMR δ 0.94-1.40 (m, 27 H), 1.57-1.78 (m, 5 H), 1.87-2.04
(m, 1 H), 3.12 (d, 2 H, J ) 7 Hz), 4.57 (t, 1 H, J ) 6 Hz), 5.44
(dd, 1 H, J ) 6.5, 16 Hz), 5.58-5.71 (m, 2 H), 5.73-5.87 (m, 1
H); 13C NMR δ 12.1, 18.0, 26.1, 26.2, 32.9, 39.5, 40.5, 73.6,
123.9, 128.6, 135.7, 138.8, 171.8; MS (EI) m/z (rel intensity)
380 (M+, 10), 337 (55); HRMS (EI) m/z calcd for C19H33O3Si
(M - CH(CH3)2) 337.2199, found 337.2188.
3-(Hexa-2′E,4′E-dien am ido)-1-(2′′E-tr ibu tylstan n yleth e-
n yl)-4,4-d im eth oxy-5,6-ep oxycycloh ex-2-en -1-ol (23). A
solution of BuLi in hexanes (201 µL, 0.322 mmol) was added
dropwise over 5 min to a cold (-78 °C) solution of 1,2-di-
(tributylstannyl)ethene24 (250 mg, 0.413 mmol) in dry THF (3.3
mL). The reaction mixture was stirred at -78 °C for 30 min
and was then allowed to warm to 0 °C over 1 h. The solution
was rechilled to -78 °C, and a solution of ketone 12 (30.0 mg,
0.107 mmol) in dry THF (1.1 mL) was added via cannula. The
resulting dark mixture was stirred at -78 °C for 45 min and
quenched by addition of saturated aqueous NH4Cl solution
followed by H2O. Ethyl acetate was added, and the aqueous
phase was re-extracted with EtOAc. The combined organic
extracts were washed with brine, dried (Na2SO4), concentrated,
and purified by radial chromatography on SiO2 (1 mm plate,
CH2Cl2/EtOAc 9:1) to afford 35.1 mg (55%) of 23 as an off-
white solid: mp 87.7-88.6 °C; IR (CDCl3) 3577, 3415, 1791,
1677, 1246 cm-1; 1H NMR (C6D6) δ 0.80-1.10 (m, 15 H), 1.25-
1.75 (m, 15 H), 2.32 (s, 1 H), 3.10 (s, 3 H), 3.20 (s, 3 H), 3.25-
3.35 (m, 2 H), 5.25 (d, 1 H, J ) 14.5 Hz), 5.50-5.66 (m, 1 H),
5.86 (dd, 1 H, J ) 10.5, 14.5 Hz), 6.31 (d, 1 H, J ) 19.0 Hz),
6.85 (d, 1 H, J ) 19.0 Hz), 7.23 (br s, 1 H), 7.44 (d, 1 H, J )
10.5, 14.5 Hz); 13C NMR δ 9.7, 13.9, 18.9, 27.5, 29.2, 50.2, 51.1,
52.3, 56.3, 73.8, 95.8, 116.7, 121.9, 128.3, 129.7, 130.8, 139.1,
142.6, 146.4, 164.7; MS (EI) m/z (rel intensity) 540 ([M -
C4H9]+, 8), 95 (100); HRMS (EI) m/z calcd for C24H38NO5120Sn
(M+ - C4H9) 540.1772, found 540.1802.
3-(Hexa -2′E,4′E-d ien a m id o)-1-(2′′E-br om oeth en yl)-4,4-
d im eth oxy-5,6-ep oxycycloh ex-2-en -1-ol (24). Solid N-bro-
mosuccinimide (139.6 mg, 0.785 mmol) was added in one
portion to a cold (0 °C) solution of stannane 23 (445.6 mg, 0.747
mmol) in dry, degassed CH2Cl2 (7.5 mL). The reaction mixture
was stirred for 1 h and quenched with saturated aqueous
Na2S2O3 and saturated aqueous NaHCO3 solution. CH2Cl2 was
added, and the aqueous layer was extracted with CH2Cl2 (3×).
The combined organic layers were dried (Na2SO4), concen-
trated, and purified by radial chromatography on SiO2 (2 mm
plate, followed by a 1 mm plate for impure fractions, CH2Cl2/
EtOAc 9:1) to afford 236.5 mg (82%) of the vinyl bromide 24
as an off-white solid: mp 110-113 °C dec; IR (CDCl3) 3579,
3409, 1791, 1677, 1240 cm-1; 1H NMR (C6D6) δ 1.43 (d, 3 H, J
) 6.5 Hz), 2.04 (s, 1 H, exchanges with D2O), 2.75 (s, 3 H),
2.95-3.02 (m, 1 H), 3.05-3.11 (m, 4 H), 5.20 (d, 1 H, J ) 14.5
Hz), 5.54-5.70 (m, 1 H), 5.87 (dd, 1 H, J ) 10.5, 14.5 Hz),
6.25 (d, 1 H, J ) 13.5 Hz), 6.68 (d, 1 H, J ) 13.5 Hz), 7.06 (d,
1 H, J ) 2.0 Hz), 7.47 (dd, 1 H, J ) 10.5, 14.5 Hz); 13C NMR
δ 18.9, 50.2, 51.0, 51.9, 55.3, 73.2, 95.5, 109.8, 115.1, 121.6,
129.2, 129.6, 137.1, 139.5, 143.0, 164.9; MS (EI) m/z (rel
intensity) 385 (M+, 1), 208 (50), 95 (100); HRMS (EI) m/z calcd
for C16H20NO5Br 385.0525, found 385.0509.
Tr iisopr opylsilyl 7-Cycloh exylh epta-2E,4E,6E-tr ien oate
(19). To a cooled (-10 °C) solution of 18 (37.7 mg, 0.099 mmol)
in dry THF (1 mL) was added TFAA (41.6 mg, 0.198 mmol),
followed by pyridine (15.7 mg, 0.20 mmol). The reaction
mixture was allowed to warm to 5 °C over 1 h. Diisopropyl-
ethylamine (76.8 mg, 0.594 mmol) was added, and the solution
was allowed to warm to room temperature over a 2.5 h period.
The reaction mixture was concentrated to approximately half
of the original volume and purified by chromatography on a 1
mm SiO2 chromatotron plate (hexanes/EtOAc 98:2) to yield
21.4 mg (60%) of 19 as a yellow-brown oil: IR (CDCl3) 1679,
1
1275 cm-1; H NMR δ 1.00-1.42 (m, 27 H), 1.60-1.82 (m, 4
H), 2.00-2.15 (m, 1 H), 5.78-5.95 (m, 2 H), 6.11 (dd, 1 H, J )
10.5, 15 Hz), 6.23 (dd, 1 H, J ) 11.5, 15 Hz), 6.52 (dd, 1 H, J
) 10.5, 15 Hz), 7.26 (dd, 1 H, J ) 11.5, 15 Hz); 13C NMR δ
12.3, 18.1, 26.1, 26.3, 32.7, 41.3, 121.9, 127.5, 128.1, 141.8,
145.6, 146.3, 167.1; MS (EI) m/z (rel intensity) 362 (M+, 51),
319 (100); HRMS (EI) m/z calcd for C19H31O2Si (M - CH(CH3)2)
319.2093, found 319.2108.
Tr iisop r op ylsilyl 7-(Tr ibu tylsta n n yl)h ep ta -3E,6E-d i-
en oa te (20). To a suspension of Cp2ZrHCl (1.56 g, 6.05 mmol)
in dry, degassed CH2Cl2 (37 mL) was added at 0 °C a solution
of freshly distilled 15 (1.60 g, 6.66 mmol) in CH2Cl2 (24 mL).
After 20 min, the homogeneous orange solution was cooled to
-78 °C, and a solution of Me2Zn (6.0 mmol, 2.0 M) in toluene
was added. After 5 min, the -78 °C bath was replaced with a
0 °C bath, and the reaction mixture was stirred for another
30 min. A solution of (E)-3-tributylstannyl-2-propen-1-al36 (1.89
g, 5.48 mmol) in CH2Cl2 (27 mL) was added, and the reaction
mixture was stirred at 0 °C for 3 h. After addition of saturated
aqueous NH4Cl, the mixture was allowed to warm to room
temperature over 15 min and treated with Na2SO4 (2 g). After
10 min, the suspension was filtered through approximately 5
g of Celite (CH2Cl2). Concentration of the filtrate was followed
by dilution with hexanes to give a suspension that was filtered
through Celite (hexanes/EtOAc 80:20). Concentration of the
filtrate followed by flash chromatography on SiO2 (hexanes/
EtOAc 93:7) afforded 2.35 g (73%) of the dienyl alcohol 20 as
1
an oil: IR (neat) 3419 (br), 1724, 1265 cm-1; H NMR (C6D6)
δ 0.85-1.75 (m, 49 H), 2.91 (d, 2 H, J ) 7 Hz), 4.42-4.52 (m,
1 H), 5.53 (dd, 1 H, J ) 6, 15.5 Hz), 5.79-5.92 (m, 1 H), 6.17
(dd, 1 H, J ) 5, 19 Hz), 6.34 (d, 1 H, J ) 19 Hz); 13C NMR
(C6D6) δ 10.1, 12.6, 14.3, 18.4, 28.1, 29.8, 39.5, 76.0, 123.8,
127.7, 136.6, 150.4, 171.9; MS (EI) m/z (rel intensity) 531 ([M
- C4H9]+, 36), 529 (31); HRMS (EI) m/z calcd for C24H47O3-
Si120Sn (M - C4H9) 531.2316, found 531.2326.
Tr iisop r op ylsilyl 7-(Tr ibu tylsta n n yl)h ep ta -2E,4E,6E-
tr ien oa te (21). To a cooled (-10 °C) solution of 20 (426 mg,
0.725 mmol) in dry THF was added CF3CO-imidazole (357 mg,
2.18 mmol), followed by pyridine (201 mg, 2.54 mmol). The
reaction mixture was allowed to warm to 5 °C over 1 h.
Diisopropylethylamine (469 mg, 3.63 mmol) was added, and
the reaction mixture was allowed to warm to 15 °C over a 2.5
h period. After addition of H2O and Et2O, the organic layer
was washed sequentially with saturated aqueous NH4Cl (2×),
H2O, and brine. The organic layer was dried (Na2SO4) and
concentrated. Purification of the crude residue by column
2-(H exa -2′E,4′E-d ien a m id o)-4-(2′′E-b r om oet h en yl)-4-
h yd r oxy-5,6-ep oxycycloh ex-2-en -1-on e (25). A solution of
ketal 24 (33.4 mg, 0.086 mmol) and PPTS (54.3 mg, 0.216
mmol) in acetone (247 µL) and H2O (117 µL) was heated at 40
°C for 4 h. The clear, yellow-brown solution was concentrated
and subjected to radial chromatography on SiO2 (1 mm plate,
CH2Cl2/EtOAc 9:1) to yield 10.7 mg (36%, 47% based on
recovered starting material) of the vinyl bromide 25 as a white
solid: mp 85 °C dec; IR (CDCl3) 3688, 3570, 1678, 1240 cm-1
;
1H NMR (C6D6) δ 1.44 (d, 3 H, J ) 6.0 Hz), 2.7 (s, 1 H), 2.88-
2.95 (m, 1 H), 3.02 (d, 1 H, J ) 3.5 Hz), 5.00 (d, 1 H, J ) 14.5
Hz), 5.54-5.74 (m, 1 H), 5.68 (d, 1 H, J ) 13.5 Hz), 5.76-5.90
(m, 1 H), 6.50 (d, 1 H, J ) 13.5 Hz), 7.29 (br s, 1 H), 7.39 (dd,
1 H, J ) 10.5, 14.5 Hz), 7.55 (d, 1 H, J ) 2.5 Hz); 13C NMR δ
18.9, 52.9, 57.1, 72.3, 111.7, 120.7, 125.9, 128.4, 129.6, 136.5,
(36) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.

5060 J . Org. Chem., Vol. 64, No. 14, 1999
Wipf and Coish
140.5, 144.1, 165.6, 188.6; MS (EI) m/z (rel intensity) 341 (0.5),
339 (M+, 0.5), 260 (1), 243 (1), 163 (15), 135 (15), 95 (100), 67
(35); HRMS (EI) calcd for C14H14NO4Br 339.0106, found
339.0112. Also isolated was 4.4 mg (18%) of the elimination
product 26 as a yellow solid: mp 74.7-77.4 °C; IR (CDCl3)
(dd, 1 H, J ) 10.5, 15.5 Hz), 7.35 (dd, 1 H, J ) 10.5, 14.5 Hz),
7.95 (d, 1 H, J ) 2.0 Hz); 13C NMR δ 25.9, 26.1, 32.3, 41.3,
50.9, 51.5, 51.6, 52.3, 95.6, 108.9, 120.9, 125.6, 145.4, 145.8,
151,9, 165.2, 193.0; MS (EI) m/z (rel intensity) 347 (M+, 10),
225 (40), 135 (100); HRMS (EI) m/z calcd for C19H25NO5
347.1733, found 347.1718.
1
1681, 1173 cm-1; H NMR δ 3.22 (s, 3 H), 3.51 (s, 3 H), 3.66
(dd, 1 H, J ) 2.0, 4.0 Hz), 3.80 (d, 1 H, J ) 4.0 Hz), 5.89 (d, 1
H, J ) 2.0 Hz), 6.93 (d, 1 H, J ) 14.0 Hz) 7.13 (d, 1 H, J )
14.0 Hz); 13C NMR δ 47.0, 50.2, 50.8, 53.7, 94.0, 116.4, 126.5,
136.3, 149.2, 188.6; MS (EI) m/z (rel intensity) 274 (M+, 0.5),
217 (25), 215 (25), 195 (20), 167 (80); HRMS (EI) m/z calcd for
3-(5-Cycloh exylp en ta -2E,4E-d ien a m id o)-1-(2′′E-br om o-
eth en yl)-4,4-d im eth oxy-5,6-ep oxycycloh ex-2-en -1-ol (31).
A solution of BuLi in hexanes (0.78 mL, 1.18 mmol) was added
dropwise via syringe pump over 5 min to a cold (-78 °C)
solution of di(tributylstannyl)ethene24 (953 mg, 1.573 mmol)
in dry THF (10.5 mL). After 30 min, the solution was stirred
for 90 min at -10 °C bath and then rechilled to -78 °C. A
solution of ketone 30 (136.6 mg, 0.393 mmol) in dry THF (3.9
mL) was added dropwise via syringe pump over 5 min. The
reaction mixture was stirred at -78 °C for 70 min, quenched
with saturated aqueous NH4Cl, and allowed to warm to room
temperature. After addition of H2O and EtOAc, the aqueous
layer was extracted with EtOAc (3×), and the combined
organic layers were washed with brine, dried (Na2SO4), and
concentrated. The resulting liquid was filtered through a short
pad of SiO2 in (hexanes/EtOAc 95:5, followed by EtOAc). The
EtOAc filtrate was concentrated, and the resulting oil was
purified by flash chromatography on SiO2 (CH2Cl2/EtOAc 98:
2, followed by CH2Cl2/EtOAc 95:5) to afford 135 mg (52%, 57%
based on recovered starting material) of the vinyl stannane
intermediate as a white solid: mp 78.2-81.0 °C; IR (CDCl3)
3695, 3577, 3415, 1678 cm-1; 1H NMR δ 0.70-1.75 (m, 37 H),
1.92-2.10 (m, 1 H), 2.62 (s, 1 H), 3.15 (s, 3 H), 3.26 (dd, 1 H,
J ) 2.5, 4.5 Hz), 3.47 (s, 3 H), 3.51 (d, 1 H, J ) 4.5 Hz) 5.75
(d, 1 H, J ) 15.0 Hz), 5.90 (d, 1 H, J ) 19.5 Hz), 5.95-6.12
(m, 2 H), 6.40 (d, 1 H, J ) 19.5 Hz), 6.58 (br s, 1 H), 7.12 (dd,
1 H, J ) 10.0, 15.0 Hz), 7.25 (br s, 1 H); 13C NMR δ 9.7, 13.8,
26.0, 26.2, 27.4, 29.0, 32.4, 41.2, 50.2, 51.0, 52.2, 56.2, 73.7,
95.8, 116.9, 122.2, 125.8, 128.2, 130.5, 142.9, 146.5, 149.7,
164.7; MS (EI) m/z (rel intensity) 638 ([M-C4H9]+, 2), 251 (25);
HRMS (EI) m/z calcd for C29H46NO5120Sn (M - C4H9) 608.2398,
found 608.2394.
To a cold (0 °C) solution of this stannane in dry, degassed
CH2Cl2 (1.4 mL) was added solid N-bromosuccinimide (26.1
mg, 0.147 mmol) in one portion. The reaction mixture was
stirred for 1 h and quenched with saturated aqueous Na2S2O3,
saturated aqueous NaHCO3, and CH2Cl2. The aqueous layer
was extracted with CH2Cl2 (3×). The combined organic layers
were dried (Na2SO4) and purified by radial chromatography
on SiO2 (1 mm plate, CH2Cl2/EtOAc 9:1) to afford 55.9 mg
(88%) of the vinyl bromide 31 as a white solid: mp 78-83 °C
dec; IR (CDCl3) 3578, 3413, 1679, 1246 cm-1; 1H NMR δ 0.95-
1.32 (m, 5 H), 1.54-1.75 (m, 5 H), 1.90-2.1 (m, 1 H), 3.18 (s,
3 H), 3.28 (dd, 1 H, J ) 2.5, 4.5 Hz), 3.40 (br s, 1 H), 3.47 (s,
3 H), 3.52 (d, 1 H, J ) 4.5 Hz), 5.76 (d, 1 H, J ) 14.5 Hz),
6.00-6.06 (m, 2 H), 6.11 (d, 1 H, J ) 13.5 Hz), 6.54 (d, 1 H, J
) 13.5 Hz), 6.55 (d, 1 H, J ) 2.5 Hz), 7.06-7.20 (m, 1 H), 7.31
(br s, 1 H); 13C NMR δ 26.0, 26.2, 32.4, 41.3, 50.1, 50.9, 51.7,
55.2, 73.2, 95.5, 109.7, 115.3, 121.7, 125.7, 129.0, 137.3, 143.5,
150.2, 164.9; MS (EI) m/z (rel intensity) 453 (M+, 2), 276 (85),
262 (85); HRMS (EI) m/z calcd for C21H28NO5Br 453.1151,
found 453.1173.
C
10H11O4Br 273.9841, found 273.9854.
N-Met h oxy-N-m et h yl-5-t r ib u t ylst a n n yl-p en t a -2E,4E-
d ien a m id e (27). N-Methoxy-N-methyl-2-(triphenylphospho-
ranylidene)acetamide (212.4 mg, 0.585 mmol) was added in
one portion at room temperature to a solution of (E)-3-
tributylstannyl-2-propen-1-al (183.4 mg, 0.531 mmol) in dry
THF (5.3 mL). After 5 h, the clear, colorless solution was
concentrated and subjected to radial chromatography on SiO2
(1 mm plate, hexanes/EtOAc 8:2) to give 87 mg of starting
material and 104.6 mg (46%, 87% based recovered starting
material) of dienyl amide 27 as an oil: IR (neat) 1654 cm-1
;
1H NMR (C6D6) δ 0.80-1.10 (m, 15 H), 1.25-1.70 (m, 12 H),
2.96 (s, 3 H), 3.03 (s, 3 H), 6.60 (d, 1 H, J ) 15.0 Hz), 6.69 (d,
1 H, J ) 18.5 Hz), 6.91 (dd, 1 H, J ) 10.5, 18.5 Hz), 7.78 (dd,
1 H, J ) 10.5, 15.0 Hz); 13C NMR δ 9.8, 13.9, 27.4, 29.3, 32.7,
62.0, 117.8, 144.9, 145.5, 146.2, 167.7; MS (EI) m/z (rel
intensity) 374 (M+, 100); HRMS (EI) m/z calcd for C15H28
-
NO2120Sn 374.1142, found 374.1145.
3-(H exa -2′E,4′E-d ien a m id o)-1-(N-m et h oxy-N-m et h yl-
h ep t a -1′′E,3′′E,5′′E-t r ien yla m id o)-4,4-d im et h oxy-5,6-ep -
oxycycloh ex-2-en -1-ol (28). To a solution of vinyl bromide
24 (30 mg, 0.078 mmol), dienyl stannane 27 (35.1 mg, 0.0817
mmol), and tri(2-furyl)phosphine (3.6 mg, 0.016 mmol) in dry,
degassed DMF (390 µL) was added at room temperature Pd2-
(dba)2‚CHCl3 (8.0 mg, 0.0078 mmol). After 5.5 h, the solvent
was removed under reduced pressure, and the resulting oil
was purified by radial chromatography on SiO2 (2 × 1 mm
plate, EtOAc/pentane 2:8) to afford 26.5 mg (76%) of ketal 28:
mp 80 °C dec; IR (C6D6) 3411, 3232, 1652 cm-1; 1H NMR (C6D6)
δ 1.43 (d, 3 H, J ) 6.5 Hz), 2.36 (s, 1 H), 2.96 (s, 3 H), 2.98 (s,
3 H), 3.07 (s, 3 H), 3.12-3.28 (m, 5 H), 5.27 (d, 1 H, J ) 15.0
Hz), 5.52-5.62 (m, 1 H), 5.75 (d, 1 H, J ) 15.0 Hz), 5.85 (dd,
1 H, J ) 10.5, 15 Hz), 6.10-6.28 (m, 2 H), 6.50 (d, 1 H, J ) 15
Hz), 6.71 (dd, 1 H, J ) 10.0, 15.0 Hz), 7.0-7.2 (m, 1 H), 7.24
(br s, 1 H), 7.48 (dd, 1 H, J ) 10.5, 15.0 Hz), 7.71 (dd, 1 H, J
) 10.5, 15.0 Hz); 13C NMR (C6D6) δ 18.8, 32.6, 50.0, 50.8, 52.2,
56.3, 61.5, 72.6, 96.5, 117.3, 120.4, 122.7, 129.2, 130.3, 131.0,
132.2, 137.8, 138.6, 139.8, 142.9, 143.7, 164.6, 167.5; MS (FAB)
m/z (rel intensity) 469 ([M + Na]+, 100); HRMS (FAB) m/z
calcd for C23H30N2O7Na (M + Na) 469.1951, found 469.1933.
3-(5-Cycloh exylpen ta-2E,4E-dien am ido)-4,4-dim eth oxy-
5,6-ep oxycycloh ex-2-en -1-on e (30). Dry DMF (10 µL) was
added to a cold (0 °C) solution of TIPS ester 6 (1.089 g, 3.236
mmol) and oxalyl chloride (564 µL, 6.47 mmol) in dry CH2Cl2
(3.2 mL). The clear, colorless solution was stirred at 0 °C for
1.5 h and allowed to warm to room temperature over 30 min.
The solvent was removed under reduced pressure, and after
addition of dry toluene, the mixture was concentrated in vacuo.
Dry THF (11 mL) was added, and the solution was cannulated
under Ar to a flask containing dry epoxide 5 (509 mg, 2.75
mmol). The reaction mixture was cooled to -78 °C, and a
mixture of DMAP (39.5 mg, 0.324 mmol), diisopropylethyl-
amine (672 µL, 3.88 mmol), and dry THF (693 µL) was added.
The solution was allowed to warm to room temperature over
1.5 h and diluted with EtOAc, and saturated aqueous NH4Cl
was added. The organic layer was extracted with saturated
aqueous NH4Cl (2×), H2O, and brine, dried (Na2SO4), and
purified by radial chromatography on SiO2 (4 mm plate, CH2-
Cl2/EtOAc 98:2) to afford 0.48 g (50%) of the amide 30 as an
off-white solid: mp 137.3-137.7 °C; IR (CDCl3) 3400, 1730,
1668, 1246 cm-1; 1H NMR (C6D6) δ 0.85-1.24 (m, 5 H), 1.50-
1.68 (m, 5 H), 1.75-1.90 (m, 1 H), 2.74 (s, 3 H), 3.08 (d, 1 H,
J ) 4.0 Hz), 3.15 (s, 3 H), 3.29 (dd, 1 H, J ) 2.0, 4.0 Hz), 5.05
(d, 1 H, J ) 14.5 Hz), 5.65 (dd, 1 H, J ) 6.5, 15.5 Hz), 5.81
3-(2-Cycloh exylp en ta -2E,4E-d ien a m id o)-4-(2′′-br om o-
eth en yl)-4-h yd r oxy-5,6-ep oxycycloh ex-2-en -1-on e (32). A
solution of ketal 31 (114 mg, 0.251 mmol) and PPTS (158 mg,
0.627 mmol) in acetone (0.72 mL) and H2O (0.34 mL) was
heated at 40 °C for 4 h. The clear, yellow-brown solution was
concentrated and subjected to radial chromatography on SiO2
(4 mm plate, CH2Cl2/EtOAc 95:5) to afford 15.6 mg (23%) of
the elimination product 26 and 32.8 mg (35%, 39% based on
recovered starting material) of the bromo ketone 32 as a yellow
solid: IR (CDCl3) 3692, 3575, 3388, 1676, 1242 cm-1; 1H NMR
δ 1.00-1.35 (m, 5 H), 1.55-1.80 (m, 5 H), 2.0-2.12 (m, 1 H),
3.58 (d, 1 H, J ) 4.0 Hz), 3.62-3.70 (m, 1 H), 5.79 (d, 1 H, J
) 15 Hz), 6.00-6.15 (m, 2 H), 6.12 (d, 1 H, J ) 13.5 Hz), 6.64
(d, 1 H, J ) 13.5 Hz), 7.12-7.25 (m, 1 H), 7.33 (d, 1 H, J ) 2.5
Hz), 7.53 (br s, 1 H); 13C NMR δ 26.0, 26.2, 32.4, 41.4, 52.9,
57.1, 72.4, 111.6, 120.9, 125.7, 126.0, 128.3, 136.6, 144.7, 151.3,
165.6, 188.7; MS (EI) m/z (rel intensity) 407 (M+, 2), 274 (55),

Total Synthesis of (()-Nisamycin
J . Org. Chem., Vol. 64, No. 14, 1999 5061
231 (50), 203 (100); HRMS (EI) m/z calcd for C19H22NO4Br
407.0732, found 407.0726.
34 as a viscous, yellow oil: IR (CDCl3) 3572, 3391, 1678 cm-1
1H NMR δ 0.96-1.40 (m, 26 H), 1.55-1.80 (m, 5 H), 2.00-
2.15 (m, 1 H), 2.83 (br s, 1 H), 3.59 (d, 1 H, J ) 4.0 Hz), 3.66
(dd, 1 H, J ) 2.5, 4.0 Hz), 5.77 (d, 1 H, J ) 14.0 Hz), 5.80 (d,
1 H, J ) 15.0 Hz), 5.88 (d, 1 H, J ) 15.0 Hz), 6.00-6.20 (m, 2
H), 6.3-6.6 (m, 3 H), 7.11-7.26 (m, 2 H), 7.36 (d, 1 H, J ) 2.5
Hz), 7.52 (br s, 1 H); 13C NMR δ 12.2, 18.0, 26.0, 26.2, 32.5,
41.4, 53.1, 57.7, 71.4, 121.1, 124.4, 125.7, 126.9, 128.2, 131.9,
132.5, 135.8, 138.6, 144.3, 144.4, 151.1, 165.5, 166.7, 188.9;
MS (EI) m/z (rel intensity) 581 (M+, 8), 538 ([M - CH(CH3)2]+,
100); HRMS (EI) m/z calcd for C30H40NO6Si (M - CH(CH3)2)
538.2625, found 538.2628.
(()-Nisa m ycin (1). A solution of CsF (12.2 mg, 0.0804
mmol) in MeOH (2.0 mL) was added at room temperature to
a solution of the TIPS ester 34 (23.4 mg, 0.0402 mmol) in
benzene (2.5 mL). The resulting slighly yellow solution was
stirred for 15 min and treated with CH2Cl2 followed by a 0.1
M aqueous KH2PO4 solution and H2O. The aqueous layer was
extracted with CH2Cl2 (3×). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated to afford
a quantitative yield of (()-nisamycin as a yellowish solid.
LCMS analysis of this material was in agreement with high-
purity nisamycin. An analytically pure sample was obtained
by preparative TLC (CH2Cl2/MeOH, 95:5): IR (CDCl3) 3692,
3640, 1722, 1678, 1240 cm-1; 1H NMR (500 MHz) δ 1.05-1.20
(m, 3 H, 7′ax, 9′ax, 11′ax), 1.20-1.32 (m, 2 H, 8′ax, 10′ax),
1.60-1.67 (m, 1 H, 9′eq), 1.67-1.78 (m, 4 H, 7′eq, 8′eq, 10′eq,
11′eq), 2.01-2.12 (m, 1 H, 6′), 3.3 (br s, 1 H, OH), 3.62 (d, 1 H,
J ) 4.0 Hz, H6), 3.69 (dd, 1 H, J ) 2.5, 4.0 Hz, H4), 5.81 (d,
1 H, J ) 15.0 Hz, H2′), 5.84 (d, 1 H, J ) 14.5 Hz, H7), 5.90 (d,
1 H, J ) 15.0 Hz, H12), 6.10-6.15 (m, 2 H, H4′, H5′), 6.35-
6.45 (m, 1 H, H10), 6.50-6.62 (m, 2 H, H8, H9), 7.17-7.25
(m, 1 H, H3′), 7.32 (dd, 1 H, J ) 11.0, 15.0 Hz, H11), 7.38 (d,
1 H, J ) 2.5 Hz, H3), 7.55 (s, 1 H, NH); 13C NMR (125 MHz)
δ 25.79 (C8′, 10′), 25.97 (C9′), 32.21 (C7′, 11′), 41.14 (C6′), 52.89
(C6), 57.36 (C5), 71.17 (C4), 120.81 (C2′), 121.21 (C12), 125.46
(C4′), 126.42 (C3), 128.00 (C2), 131.57 (C8), 131.94 (C10),
136.30 (C7), 139.47 (C9), 144.32 (C3′), 145.82 (C11), 150.92
(C5′), 165.26 (C1′), 170.91 (C13), 188.61 (C1) (13C and 1H
assignments were based in part on COSY, HMQC, and HMBC
data); FAB HRMS m/z calcd for C24H28NO6 (M + H) 426.1917,
found 426.1934.
;
Tr iisop r op ylsilyl 5-(Tr ibu tylsta n n yl)p en ta -2E,4E-d i-
en oa t e (33). A solution of BuLi in hexanes (290 µL, 0.463
mmol) was added dropwise to a solution of diethyl(trimethyl-
silyloxycarbonylmethyl)phosphonate (124.3 mg, 0.463 mmol)
in THF (4 mL). The reaction mixture was stirred at room
temperature for 0.5 h. To the resulting clear, colorless solution
was cannulated a solution of (E)-3-tributylstannyl-2-propen-
1-al (143.9 mg, 0.417 mmol) in THF (154 µL). The mixture,
which became slightly yellow within minutes, was stirred at
room temperature for 1.5 h and quenched with saturated
aqueous NaHCO3, H2O, and EtOAc. The aqueous layer was
extracted with EtOAc (2×). The combined organic layers were
dried (Na2SO4) and purified by radial chromatography on SiO2
(1 mm plate, hexanes/EtOAc 75:25, followed by hexanes/EtOAc
50:50, EtOAc, and MeOH) to afford 114.6 mg (71%) of dienyl
acid as a slightly yellow oil: IR (neat) 2969, 1691, 1231 cm-1
;
1H NMR δ 0.76-1.10 (m, 15 H), 1.20-1.65 (m, 12 H), 5.75 (d,
1 H, J ) 15.5 Hz), 6.64 (dd, 1 H, J ) 10.5, 18.5 Hz), 6.86 (d,
1 H, J ) 18.5 Hz), 7.22 (dd, 1 H, J ) 10.0, 15.5 Hz), 11.5 (br
s, 1 H); 13C NMR δ 9.8 (1J Sn-C ) 338 Hz), 13.9, 27.5 (2J Sn-C
)
55 Hz), 29.3 (3J Sn-C ) 21 Hz), 119.2, 144.2, 148.7 (J Sn-C ) 70
Hz), 149.6, 173.4; MS (EI) m/z (rel intensity) 331 (M+, 15), 275
(100), 219 (80); HRMS (EI) m/z calcd for
C
13H23O2120Sn
331.0720, found 331.0719.
Imidazole (58.4 mg, 0.858 mmol) was added to a room-
temperature solution of dienyl acid (332.1 mg, 0.858 mmol)
and TIPS-Cl (165.4 mg, 0.858 mmol) in dry CH2Cl2 (2.8 mL).
The resulting white suspension was stirred for 1 h and
quenched with H2O and CH2Cl2, and the organic layer was
washed with H2O (2×) and brine, dried (Na2SO4), and con-
centrated. Flash chromatography on SiO2 (hexanes/EtOAc 97:
3) gave 425 mg (91%) of ester 33 as a clear, colorless oil: IR
(neat) 2958, 1694 cm-1; 1H NMR δ 0.80-0.95 (m, 15 H), 1.0-
1.1 (m, 18 H), 1.20-1.62 (m, 15 H), 5.77 (d, 1 H, J ) 15.5 Hz),
6.62 (dd, 1 H, J ) 10.0, 18.5 Hz), 6.76 (d, 1 H, J ) 18.5 Hz),
7.10 (dd, 1 H, J ) 10.0, 15.5 Hz); 13C NMR δ 9.8 (J Sn-C ) 330
Hz), 12.2, 13.9, 18.1, 27.5 (J Sn-C ) 54 Hz), 29.3 (J Sn-C ) 21
Hz), 122.0, 144.6, 146.9, 147.3, 167.3; MS (EI) m/z (rel
intensity) 501 ([M - CH(CH3)2]+, 25), 487 ([M - C4H9]+, 100),
211 (70); HRMS (EI) m/z calcd for C22H43O2Si120Sn (M - C4H9)
487.2054, found 487.2051.
2-(Hexa -2′E,4′E-d ien a m id o)-4-(tr iisop r op ylsilylh ep ta -
1′′E,3′′E,5′′E-t r ien oa t e)-4-h yd r oxy-5,6-ep oxycycloh ex-2-
en -1-on e (34). A solution of DIBAL-H in hexanes (114 µL,
0.114 mmol) was added to a solution of PdCl2(PPh3)2 (38 mg,
0.054 mmol) in dry degassed THF (3.8 mL). The resulting dark
brown mixture was stirred at room temperature for 20 min.
A portion of this mixture (1.7 mL) was added to a degassed
solution of stannane 33 (99 mg, 0.182 mmol) and bromide 32
(49.4 mg, 0.121 mmol) in dry DMF (1.2 mL). The mixture was
stirred at room temperature for 14.5 h and quenched with
EtOAc, H2O, and brine. The organic layer was washed with a
3:1 mixture of H2O/brine (3×), dried (Na2SO4), and concen-
trated. Radial chromatography on SiO2 (1 mm plate, CH2Cl2/
EtOAc 95:5, followed by CH2Cl2/EtOAc 9:1) afforded 40.8 mg
(58%, 70% based on recovered starting material) of keto ester
Ack n ow led gm en t. This work was supported by the
National Science Foundation. We thank Tony Paiva
(LCMS analysis) and La´szlo´ Musza (1H and 13C NMR
analysis) of Bayer Corp. for their assistance with the
spectral analysis of (()-nisamycin. We also thank Dr.
R. J . K. Taylor (University of York) for a copy of the
FAB MS of synthetic nisamycin.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all synthetic intermediates and 1H and 13C NMR
and LC-MS spectra for nisamycin. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O990413M