Iromycins: A new family of pyridone metabolites from Streptomyces sp. II. Convergent total synthesis

Article abstract of DOI:10.1021/jo070327j

(Chemical Equation Presented) The total synthesis of iromycin A (1a), a microbial metabolite combining a novel structure with an interesting biological activity as a NO synthase inhibitor, was accomplished using a flexible and highly convergent approach. Thus, the ring fragment was prepared as 6-bromomethylpyrone 27 by acylation of the respective β-ketoester 13 and subsequent lactonization of the thus-obtained β,δ-diketoester 11, followed by bromination of the 6-methyl group. In addition, the unsaturated side chain was efficiently prepared as terminal alkyne 34 which was then carboaluminated to furnish the alkenyldimethylalane 35. The assembly of these two fragments was thoroughly studied using nickel, palladium, and copper catalysts yet only succeeded in the absence of any transition metal after formation of the respective lithium alkenyltrialkylalanate. Treatment of the coupled product 41 with liquid ammonia then completed the total synthesis which furnished an 18% overall yield over the nine steps of the longest linear sequence.

Full text of DOI:10.1021/jo070327j

Iromycins: A New Family of Pyridone Metabolites from
Streptomyces sp. II. Convergent Total Synthesis
Heydar Shojaei, Zhen Li-Bo¨hmer, and Paultheo von Zezschwitz*
Institut fu¨r Organische und Biomolekulare Chemie der Georg-August-UniVersita¨t Go¨ttingen,
Tammannstrasse 2, D-37077 Go¨ttingen, Germany
pzezsch@gwdg.de
ReceiVed February 16, 2007
The total synthesis of iromycin A (1a), a microbial metabolite combining a novel structure with an
interesting biological activity as a NO synthase inhibitor, was accomplished using a flexible and highly
convergent approach. Thus, the ring fragment was prepared as 6-bromomethylpyrone 27 by acylation of
the respective â-ketoester 13 and subsequent lactonization of the thus-obtained â,δ-diketoester 11, followed
by bromination of the 6-methyl group. In addition, the unsaturated side chain was efficiently prepared as
terminal alkyne 34 which was then carboaluminated to furnish the alkenyldimethylalane 35. The assembly
of these two fragments was thoroughly studied using nickel, palladium, and copper catalysts yet only
succeeded in the absence of any transition metal after formation of the respective lithium alkenyltri-
alkylalanate. Treatment of the coupled product 41 with liquid ammonia then completed the total synthesis
which furnished an 18% overall yield over the nine steps of the longest linear sequence.
Introduction
side chain but a different type of heterocyclic moiety such as
the ichthyotoxic kalkipyrone,3a the actinopyrones3b (e.g., 2) with
The iromycins (1) are a group of microbial polyketide-derived
metabolites, recently isolated in yields of up to 18 mg/L from
Streptomyces sp.1 Regarding their structure, they are character-
ized by a fully substituted R-pyridone ring carrying an n-propyl
chain at C-5 and a branched, unsaturated eight-membered side
chain at C-6. Thus, they represent a new family of natural
products since they noticeably differ from other pyridone
compounds such as tenellin,2a the antifungal antibiotic ilicicolin
H,2b the protein tyrosine kinase inhibitor pyridovericin,2c and
kirromycin,2d an inhibitor of the elongation factor TU. These
metabolites also possess long unsaturated side chains, yet they
are placed at C-3 of the heterocycle and contain a carbonyl
moiety at C-1′ as opposed to the methylene group in the
iromycins. Moreover, there are natural products with a similar
(1) (a) Surup, F.; Wagner, O.; von Frieling, J.; Schleicher, M.; Oess, S.;
Mu¨ller, P.; Grond, S. J. Org. Chem. 2007, 72, 5085-5090. (b) Sukenaga,
Y.; Yamazaki, T.; Aoyama, T.; Takayasu, Y.; Harada, T. Japan Patent JP10
237044, 1998; Chem. Abstr. 1998, 129, 244203S.
(2) (a) Williams, D. R.; Sit, S.-Y. J. Org. Chem. 1982, 47, 2846-2851.
(b) Williams, D. R.; Bremmer, M. L.; Brown, D. L.; D’Antuono, J. J. Org.
Chem. 1985, 50, 2807-2809. (c) Irlapati, N. R.; Adlington, R. M.; Conte,
A.; Pritchard, G. J.; Marquez, R.; Baldwin, J. E. Tetrahedron 2004, 60,
9307-9317. (d) Hogg, T.; Mesters, J. R.; Hilgenfeld, R. Curr. Protein Pept.
Sci. 2002, 3, 121-131.
a vasodilating activity, and the piericidins3c (e.g., 3), which
exhibit a strong inhibition of the mitochondrial electron transfer
chain protein NADH-ubiquinone reductase as they presumably
mimic the ubiquinones (4) themselves. The iromycins (1) also
bear a highly interesting biological activity since they selectively
10.1021/jo070327j CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/12/2007
J. Org. Chem. 2007, 72, 5091-5097
5091

Shojaei et al.
SCHEME 1. Retrosynthetic Analysis of the Iromycins (1)
inhibit the nitric oxide synthase (NOS) and thus the release of
this crucial second messenger molecule.1 In particular, they are
the first natural products showing a differentiating influence on
the isoforms of NOS and thus might become valuable bio-
chemical tools. Additionally, an apparent structure-activity
relationship was observed since iromycin A (1a) with its
terminal isopropyl group is a stronger inhibitor than the
hydroxylated derivative B (1b) or C (1c) that possesses just a
terminal ethyl group.1a This combination of structural novelty
and promising biological activity makes the total synthesis of
the iromycines and their non-natural derivatives an attractive
aim. Herein, we report on our work toward a general and
efficient synthesis of this family of natural products.
Results and Discussion
Synthetic Considerations. Due to the interest in the synthesis
of a number of derivatives, a convergent and flexible approach
involving the coupling of the side chain and the ring fragment
at a later stage of the sequence was anticipated as this would
allow for a systematic alteration of each half of the molecule.
On a similar basis, a few syntheses of piericidins4 and derivatives
thereof have been performed, and very recently the synthesis
of verticipyrone was accomplished.5 Thus, Boger et al.4a
disconnected compound 3 at the C-1′sC-2′ bond and performed
a Stille-type coupling of the respective 6-bromomethylpyridine
with the side chain as alkenylstannane, which proceeded in good
yield yet required 50 mol % of palladium catalyst. On the
contrary, the C-6sC-1′ bond was formed in Stille-type reactions
of stannylated pyridine or benzene derivatives with an allylic
carbonate or halide in syntheses of piericidin analogues by
Keaton and Phillips4b or Ono, Akita et al.,4c respectively, but
these transformations afforded mixtures of the desired (E)- and
the undesired (Z)-isomers. Finally, Rapoport et al.4d prepared
piericidin analogues by reaction of a lithiated pyridine derivative
with various prenyl bromides.
For the synthesis of the iromycins two different strategies
were envisaged, both of them relying on a stereo- and regiose-
lective metalation of an alkyne moiety (Scheme 1). Thus, a
disassembly of the molecule at the C-3′sC-4′ bond would lead
to ring fragment 5 which would be coupled with allyl bromides
6 via hydrozirconation6 of the triple bond with the Schwartz
reagent Cp2Zr(H)Cl and a subsequent transition-metal-catalyzed
cross-coupling reaction (path A). The pyridine 5 in turn would
be prepared from the pyridone 7 by a carbon homologation of
the aldehyde using the Corey-Fuchs protocol.7 Since this
approach promised a particular rapid variation of the terminal
group R in the iromycins (1), it was initially tested yet was
abandoned due to problems in the preparation of aldehyde 7
from â-ketoester 8 (see Supporting Information for details).
A second path comprised a scission of the C-1′sC-2′ bond
(path B), and the CsC coupling was intended to be achieved
by carboalumination8a of enynes 9 with AlMe3 followed by
cross-coupling of the thus obtained alkenyldimethylalanes with
a 6-halomethylheterocycle 10. This procedure has been per-
formed under Ni-catalysis by Lipshutz et al.8b in their efficient
synthesis of the ubiquinones (4). The ring fragment 10 would
now stem from cyclization of â,δ-diketoester 11 to form a
pyrone9 and subsequent transformations including functional-
ization of the methyl substituent at C-6 of the heterocycle.
Preparation of Ring and Side Chain Fragments. For the
synthesis of iromycin A (1a) along path B a number of different
ring fragments 10 were prepared since the cross-coupling with
alkenylalanes later on proved to be quite difficult. At first, the
synthesis of the required â,δ-diketo acid 11 was performed using
the methodology of Weiler et al.10 for the generation and
transformation of the dianions of â-ketoesters (Scheme 2). The
starting material 12 was lithiated and then alkylated to give ethyl
heptanoate 13 in 56% yield using nPrI while nPrBr furnished
the desired product in only 25% yield. Acylations in the
γ-position of â-ketoesters have been performed using esters,11a,b
N-methoxy-N-methylamides (Weinreb amides),11c,d and imidazo-
lides11e,f as acylating agents, yet here the latter reagents furnished
the best results. Under optimized conditions an 83:17 mixture
of â,δ-diketoester 11 and starting material 13 was isolated,
which could only be separated by column chromatography on
silica gel with substantial loss of product. Therefore, crude 11
was directly used in the next step, i.e., the lactonization in the
presence of DBU. This afforded a mixture of pyrone 14 and
ketoester 13 from which the pyrone could easily be separated
(3) (a) Graber, M. A.; Gerwick, W. H. J. Nat. Prod. 1998, 61, 677-
680. (b) Yano, K.; Yokoi, K.; Sato, J.; Oono, J.; Kouda, T.; Ogawa, Y.;
Nakashima, T. J. Antibiot. 1986, 39, 38-43. (c) Takahashi, N.; Suzuki,
A.; Tamura, S. J. Am. Chem. Soc. 1965, 87, 2066-2068.
(4) (a) Schnermann, M. J.; Romero, F. A.; Hwang, I.; Nakamaru-Ogiso,
E.; Yagi, T.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 11799-11807. (b)
Keaton, K. A.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 408-409. (c)
Ono, M.; Yoshida, N.; Akita, H. Chem. Pharm. Bull. 1997, 45, 1745-
1750. (d) Schmidtchen, F. P.; Rapoport, H. J. Am. Chem. Soc. 1977, 99,
7014-7019.
(8) (a) Negishi, E.-i.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc.
1985, 107, 6639-6647. (b) Lipshutz, B. H.; Bulow, G.; Fernandez-Lazaro,
F.; Kim, S.-K.; Lowe, R.; Mollard, P.; Stevens, K. L. J. Am. Chem. Soc.
1999, 121, 11664-11673.
(9) Harris, T. M.; Harris, C. M. Tetrahedron 1969, 25, 2687-2691.
(10) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082-1087.
(11) (a) Spencer, R. W.; Copp, L. J.; Pfister, J. R. J. Med. Chem. 1985,
28, 1828-1832. (b) Kanazawa, T.; Ohkawa, Y.; Kuda, T.; Minobe, Y.;
Tani, T.; Nishizawa, M. Chem. Pharm. Bull. 1997, 45, 1046-1051. (c)
Oster, T. A.; Harris, T. M. Tetrahedron Lett. 1983, 24, 1851-1854. (d)
Wolberg, M.; Ji, A.; Hummel, W.; Mu¨ller, M. Synthesis 2001, 937-942.
(e) Shone, R. L.; Deason, J. R.; Miyano, M. J. Org. Chem. 1986, 51, 268-
270. (f) Ishibashi, Y.; Ohba, S.; Nishiyama, S.; Yamamura, S. Tetrahedron
Lett. 1996, 37, 2997-3000.
(5) Shimamura, H.; Sunazuka, T.; Izuhara, T.; Hirose, T.; Shiomi, K.;
Omura, S. Org. Lett. 2007, 9, 65-67.
(6) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975,
97, 679-680.
(7) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769-3772.
5092 J. Org. Chem., Vol. 72, No. 14, 2007

ConVergent Total Synthesis of Iromycins
SCHEME 2. Synthesis of Different Ring Fragments
by extraction with saturated NaHCO3 solution.12 That way
pyrone 14 was isolated in a high yield of 64% over the two
steps from compound 13. Next, the 4-hydroxy moiety of 14
was benzoylated to give 15 as a prerequisite for the subsequent
functionalization of the methyl substituent at C-6.13,14 In parallel,
pyrone 14 was also transformed into the respective nitrogen
analogue 16.15 This was achieved by heating 14 with aqueous
ammonia in a sealed tube at 120 °C. The same type of reaction
smoothly occurred at 60 °C with the more nucleophilic
hydrazine to intermediately give hydrazone 17 which was
cleaved to N-aminopyridone 18 upon acidic workup. Treatment
of this compound with nitrous acid under mild conditions then
furnished pyridone 16 in 88% overall yield from 14, thus making
this two-step procedure the favorable method. The product was
then either mono-acetylated to give the protected pyridone 19
or bis-acetylated to 21.
SCHEME 3. Improved Functionalization of the 6-Methyl
Substituent
The selective functionalization of alkyl substituents at C-6
in R-pyrones similar to compound 15 has been the subject of
several studies which revealed that halogenation via radical
substitution is possible yet frequently occurs in varying yields.13,16
Indeed, bromination of compounds 15 and 19 using NBS and
dibenzoyl peroxide (DBPO) proceeded rather unselectively thus
furnishing only low yields of the desired products, e.g., 20%
of compound 20. Similarly, chlorination of pyridine 21 using
trichloroisocyanuric acid17 afforded 6-chloromethylpyridine 22
in just 21% yield.
R-pyrone comprising oxidation with SeO2 to form the respective
secondary alcohol and subsequent treatment with PBr3.13 The
oxidation of pyrone 15 and pyridone 19 generated aldehydes
23 and 24, respectively, which were reduced in an additional
reaction step using NaBH4 (Scheme 3). The bromides 20 and
27 were thus obtained in excellent overall yields, and pyrone
27, after treatment with an excess of NEt4Cl, furnished the
chloride 28. Finally, the rather acidic secondary amide moiety
in 20 was protected by N-silylation with Me3SiCl to furnish
pyridone 30 or by N-methylation with diazomethane in the
presence of silica gel which afforded 29 in a low yield due to
a large amount of O-methylation. Altogether, the building blocks
20, 22, and 27-30 with similar skeletonssyet different
heterocyclic moieties and leaving groupsswere thus efficiently
obtained.
Therefore, we turned to a method developed by Hoffmann
et al. for the bromination of an ethyl substituent at C-6 of an
(12) The acidity of such 4-hydroxypyran-2-ones is comparable to that
of acetic acid: Ferri, D.; Bu¨rgi, T.; Baiker, A. J. Chem. Soc. Perkin Trans.
2 2002, 437-441.
(13) Ko¨ster, G.; Hoffmann, R. W. Liebigs Ann. Chem. 1987, 987-990
and references therein.
(14) Pyrone 14 could also be acetylated in 69% yield (see Supporting
Information), yet this protecting group turned out to be unstable in the
subsequent transformations.
(15) (a) Groutas, W. C.; Stanga, M. A.; Brubaker, M. J.; Huang, T. L.;
Moi, M. K.; Carroll, R. C. J. Med. Chem. 1985, 28, 1106-1109. (b) El-
Kholy, I. E.; Mishrikey, M. M.; Abdoul-Ela, S. L. J. Heterocycl. Chem.
1982, 19, 1329-1334.
(16) (a) Bloomer, J. L.; Zaidi, S. M. H.; Strupczewski, J. T.; Brosz, C.
S.; Gudzyk, L. A. J. Org. Chem. 1974, 39, 3615-3616. (b) Bacardit, R.;
Moreno-Manas, M.; Pleixats, R. J. Heterocycl. Chem. 1982, 19, 157-160.
(17) Jeromin, G. E.; Orth, W.; Rapp, B.; Weiss, W. Chem. Ber. 1987,
120, 649-651.
Unlike the side chains of the piericidins (3) which required
a multistep synthesis,4 the side chain of iromycin A (1a) was
obtained in just five steps from isobutyraldehyde (Scheme 4).
A 1:4 mixture of allyl bromides 31 and 32 was prepared via
J. Org. Chem, Vol. 72, No. 14, 2007 5093

Shojaei et al.
SCHEME 5. Attempted Transition-Metal-Catalyzed
SCHEME 4. Synthesis of the Side Chain Fragment as
Alkenylalane
Coupling of Ring and Side Chain Fragments
vinylation of the aldehyde with vinylmagnesium bromide18a and
subsequent treatment of the alcohol with PBr3.18b Interestingly,
the copper-catalyzed alkynylation of this mixture furnished a
single enyne 33 which was desilylated to afford compound 34.
The carboalumination of this terminal alkyne was performed
according to the general procedure of Negishi et al. using zirco-
nocene dichloride as catalyst and 2 equiv of AlMe3.8a This ex-
cess of AlMe3 caused problems in subsequent cross-coupling
reactions when using in-situ prepared alkenylalane. Therefore,
the AlMe3 was distilled off and the isolated alkenylalane 35 as
solution in hexane could be stored for several weeks at -18 °C.
Attempted Coupling of Ring and Side Chain Fragments
under Transition Metal Catalysis. Since alkenylalanes are
readily and selectively accessible by hydroalumination19 and
carboalumination8a,20 of alkynes, their use in carbon-carbon
bond forming processes has been studied for a long time. As
shown by Negishi et al., 1,3-dienes,21a,b 1,4-dienes,21c,d and
allylarenes21e can be formed when treating these alanes with
alkenyl halides, allylic electrophiles, and benzyl halides, re-
spectively, in the presence of a palladium catalyst. Nickel
catalysts sometimes afford faster conversions,21f but stereo-
chemical scrambling was noted as a problem.21b Lipshutz et al.
demonstrated the higher reactivity of nickel catalysts when
performing coupling reactions with various chloromethylarenes,
-heteroarenes, and -quinones as electrophiles,22 and both Pd and
Ni have been employed in these transformations toward the
synthesis of natural products.8b,23 Therefore, both transition
metals were tried out for the intended coupling of the ring and
side chain fragments of iromycin A (1a), and preliminary tests
were performed using (E)-2-methyl-1-heptenyldimethylalane
(36) as a model substrate (Scheme 5).24 The 6-bromomethylpy-
ridone 20 turned out to be unstable under these conditions, and
complex mixtures of unidentified products were obtained even
when starting from N-protected derivatives 29 or 30. Palladium-
catalyzed transformations of pyrone 27 led to smooth debro-
mination to furnish the 6-methylpyrone 15 as the sole product.
Using in situ prepared [Ni(PPh3)4] as catalyst, 27 underwent a
reductive dimerization to furnish compound 38 together with
39, the product of a homo-coupling of the alkenylalane. The
same result was obtained when decreasing the phosphine-nickel
ratio to 2:1 or when adding LiCl, even though these changes
were reported to favor the formation of cross-coupled as opposed
to homo-coupled products.22 In contrast, minor amounts of the
desired product 37 were obtained when switching to chloride
28 as starting material, but still homo-coupling predominated.
Finally, pyridine 22 turned out to be rather unreactive in the
nickel-catalyzed transformation, and only slow decomposition
was observed. These difficulties are presumably caused by the
very specific character of these heterocyclic ring fragments in
which the C-2sC-6 subunit together with the halomethyl group
at C-6 can be seen as a vinylogous R-haloester and, together
with the acyloxy group at C-4, resembles a vinylogous acid
anhydride. Pyrone 27 might undergo a fast oxidative addition
to the metal(0) complexes, but the organometallic species then
decomposes either by protiodepalladation, i.e., placement of
hydrogen on the pyrone ligand, or under dimerization of the
same in the case of nickel.25
Besides palladium and nickel complexes, copper(I) salts have
rarely been used in cross-coupling reactions of alkenylalanes
with allylic electrophiles to form 1,4-dienes,26a,b even though
alkenylalanes can also undergo oxidative dimerizations with
stoichiometric amounts of CuCl to form symmetrical 1,3-dienes
and metallic copper.26c When treating pyrone 27 with the side
chain model, the in situ prepared alane 36, in the presence of a
catalytic amount of CuBr, a smooth conversion occurred;
however, a methyl group was transferred to yield solely
6-ethylpyrone 40a (Scheme 5). Therefore, a quick survey on
the transferability of different substituents on alanes was
undertaken, for which several alkylvinylalanes were prepared
from the respective alkylaluminum chloride and vinylmagnesium
(18) (a) Kaga, H.; Goto, K.; Takahashi, T.; Hino, M.; Tokuhashi, T.;
Orito, K. Tetrahedron 1996, 52, 8451-8470. (b) Jacoby, D.; Ce´le´rier, J.
P.; Petit, H.; Lhommet, G. Synthesis 1990, 301-304.
(19) Zweifel, G.; Miller, J. A. Org. React. 1984, 32, 375-517 and
references therein.
(20) Wipf, P.; Lim, S. Angew. Chem. 1993, 105, 1095-1097; Angew.
Chem. Int. Ed. Engl. 1993, 32, 1068-1071.
(21) (a) Negishi, E.-i.; Okukado, N.; King, A. O.; Van Horn, D. E.;
Spiegel, B. I. J. Am. Chem. Soc. 1978, 100, 2254-2256. (b) Negishi, E.-i.;
Takahashi, T.; Baba, S.; Van Horn, D. E.; Okukado, N. J. Am. Chem. Soc.
1987, 109, 2393-2401. (c) Matsushita, H.; Negishi, E.-i. J. Am. Chem.
Soc. 1981, 103, 2882-2884. (d) Negishi, E.-i.; Chatterjee, S.; Matsushita,
H. Tetrahedron Lett. 1981, 22, 3737-3740. (e) Negishi, E.-i.; Matsushita,
H.; Okukado, N. Tetrahedron Lett. 1981, 22, 2715-2718. (f) Negishi, E.-
i.; Baba, S. J. Chem. Soc., Chem. Commun. 1976, 596-597.
(22) (a) Lipshutz, B. H.; Bu¨low, G.; Lowe, R. F.; Stevens, K. L.
Tetrahedron 1996, 52, 7265-7276. (b) Lipshutz, B. H.; Kim, S.-K.; Mollard,
P.; Blomgren, P. A.; Stevens, K. L. Tetrahedron 1998, 54, 6999-7012.
(23) (a) Lipshutz, B. H.; Kim, S.-K.; Mollard, P.; Stevens, K. L.
Tetrahedron 1998, 54, 1241-1253. (b) Tatsuta, K.; Tamura, T. J. Antibiot.
2000, 53, 418-421. (c) Negishi, E.-i.; Liou, S.-Y.; Xu, C.; Huo, S. Org.
Lett. 2002, 4, 261-264.
(24) Since alkyl groups are not transferred under these conditions,21c crude
alkenyldimethylalane stemming from carboalumination of 1-heptyne with
an excess of AlMe3 was employed.
(25) For a study on the oxidative addition of benzyl halides to Ni(0)
complexes leading to formation of dibenzyl, see: Bartsch, E.; Dinjus, E.;
Fischer, R.; Uhlig, E. Z. Anorg. Allg. Chem. 1977, 433, 5-12. For other
examples of protiodepalladations, see: Voigt, K.; von Zezschwitz, P.;
Rosauer, K.; Lansky, A.; Adams, A.; Reiser, O.; de Meijere, A. Eur. J.
Org. Chem. 1998, 1521-1534.
(26) (a) Lynd, R. A.; Zweifel, G. Synthesis 1974, 658-659. (b)
Flemming, S.; Kabbara, J.; Nickisch, K.; Westermann, J.; Mohr, J. Synlett
1995, 183-185. (c) Zweifel, G.; Miller, R. L. J. Am. Chem. Soc. 1970, 92,
6678-6679.
5094 J. Org. Chem., Vol. 72, No. 14, 2007

ConVergent Total Synthesis of Iromycins
TABLE 1. Study on Copper-Catalyzed Cross-Coupling Reactions
of 27 with Alanes
SCHEME 6. Completion of the Total Synthesis of Iromycin
A (1a) and its Analogue 42
conversionb
[%]
ratio of
entry
alane, (equiv)a
products productsb
1
2
3
4
(CH2dCH)AlEt2, (4)
(CH2dCH)Al(iBu)2, (4)
(CH2dCH)2AlEt, (2)
(CH2dCH)2AlMe, (2)
94
53
34
40d, 40b
40d, 40c
40d, 40b
40d, 40a
51:49
63:37
100:0
100:0
100
a In situ prepared from the respective alkylaluminum chloride and vinyl-
magnesium bromide. b Determined by 1H NMR spectroscopy of the crude
mixture.
byproduct.28c Starting from unprotected pyridone 20 and methyl-
protected 29 complete decomposition of the ring fragment was
observed, and SiMe3-protected 30 was mainly desilylated under
these conditions to furnish 20. Yet, pyrone 27 proved to be a
very suitable substrate. After a short screen of solvents including
toluene, Et2O, and THF in combination with reaction temper-
atures ranging from -30 °C to rt, the desired product 37 was
obtained in 83% isolated yield when treating 27 with the alanate
prepared from 2 equiv of each, alane 36 and nBuLi (Scheme
6). The preparation of 41, the precursor of iromycin A (1a),
succeeded in an even higher yield of 95% when the alanate
was prepared from 3 equiv of alane 35 and 2 equiv of nBuLi.
It is obvious that an excess of the latter with respect to the alane
must be avoided since lithium organyls rapidly react with pyrone
27 under lithium-bromide exchange. With the coupling of both
fragments achieved, the final challenge was to convert the
assembled pyrones 37 and 41 into the respective pyridones 1a
and 42, which was hampered by a pronounced instability of
these compounds.29 Thus, treatment of 41 with hydrazine or
aqueous ammonia under conditions which worked well for the
analogous transformation of pyrone 14 to pyridone 16 (Scheme
2) led to decomposition or debenzoylation. The balance between
a required high reactivity of the nitrogen nucleophile and mild
conditions was found in treating the pyrones with liquid
ammonia in an autoclave at 70 °C. This, in one step, afforded
the desired OsN exchange and the deprotection of the hydroxyl
moiety at C-4 of the pyridone ring to furnish the natural product
iromycin A (1a) and a first non-natural derivative 42. The
properties of synthetic 1a proved identical in all respects to those
of the isolated metabolite.
bromide and then added to a pre-cooled suspension of CuBr
and pyrone 27 (Table 1). The results disclosed that the selectivity
of vinyl versus alkyl transfer is rather low when using vinyl-
dialkylalanes (entries 1, 2). In contrast, selective vinyl transfer
took place starting from divinylalkylalanes, and the respective
methylalane was far more reactive than the analogous ethylalane
(entries 3, 4). At first glance, these results were contradictory
with the outcome of the reaction of alane 36 furnishing product
40a of a methyl transfer. Yet, when the isolatedsthus AlMe3-
freesalane 36 was employed, no cross-coupling reaction
occurred at all, and the homo-coupled compounds 38 and 39
were the only identified products. The formation of 6-ethylpy-
rone 40a in the first experiment must therefore be caused by
the remaining AlMe3 in the in situ prepared alane 36, and both
the methyl and the heptenyl groups of the isolated 36 are
obviously transferred so slowly that other reaction pathways
prevail. The preferred transfer of the alkenyl group from the
alanes shown in Table 1 thus seems to be limited to the simple
ethenyl group. Altogether, these observations are noteworthy,
as transfer of an alkenyl group is generally kinetically favored
over an alkyl group exchange in related transformations.27
Coupling of the Fragments via Lithium Alkenylalanates
and Completion of the Total Synthesis. Before the ascent of
transition metal catalysts in carbon-carbon bond forming pro-
cesses, 1,4-dienes and allylarenes are known to be formed by
reaction of the respective halides with lithium alkenyltrialky-
lalanates. However, yields were moderate, and the reported sub-
strate scope is quite narrowsonly covering plain benzyl halides
and simple allyl halides that can give just one product.28 Never-
theless, this method was finally applied in the coupling of ring
and side chain fragments of iromycin A, and again, first experi-
ments were performed with the model substrate 36 stemming
from carboalumination of 1-heptyne. This alane was treated suc-
cessively with nBuLi to form the lithium alanate and afterward
with the respective halide. The reaction with benzyl bromide
as model substrate indeed turned out to proceed sluggishly
and yielded considerable amounts of 1,2-diphenylethane as
Conclusion
In summary, a convergent and efficient total synthesis of
iromycin A (1a) was developed which furnished this potent NOS
inhibitor in a high overall yield of 18% over the nine steps from
â-ketoester 12. Crucial for this achievement was a thorough
study of the key step of the synthesis: the coupling reaction of
6-bromomethylpyrone 27 with alkenylalanes. Remarkably, this
transformation could not be accomplished by any of the
sophisticated transition-metal-catalyzed protocols which either
led to reductive debromination using Pd catalysts, reductive
dimerization of the ring fragment under Ni catalysis, or
preferential alkyl transfer in the case of Cu catalysts. Only the
rather conventional noncatalyzed procedure involving formation
of lithium trialkylalkenyl-alanates resulted in excellent yields
(27) Wipf, P.; Smitrovich, J. H.; Moon, C.-W. J. Org. Chem. 1992, 57,
3178-3186. For an example of a copper-catalyzed 1,4-addition to an enone
in which a slight variation of the substrate completely inverted this
selectivity, see: Lipshutz, B. H.; Dimock, S. H. J. Org. Chem. 1991, 56,
5761-5763.
(28) (a) Eisch, J. J.; Damasevitz, G. A. J. Org. Chem. 1976, 41, 2214-
2215. (b) Uchida, K.; Utimoto, K.; Nozaki, H. J. Org. Chem. 1976, 41,
2215-2217. (c) Baba, S.; Van Horn, D. E.; Negishi, E.-i. Tetrahedron Lett.
1976, 17, 1927-1930.
(29) All these compounds slowly start to decompose even when stored
either neat or in solution at -18 °C.
J. Org. Chem, Vol. 72, No. 14, 2007 5095

Shojaei et al.
benzene (300 mL), and the mixture was refluxed for 6 h, poured
into a saturated NaHCO3 solution (50 mL), and extracted with Et2O
(3 × 200 mL). The combined organic phases were dried over Na2-
SO4, then filtered, and concentrated in vacuo to give 7.552 g of a
fraction partially containing ethyl 2-methyl-3-oxo-heptanoate (13).
The aqueous phase was acidified with concd HCl to pH 2 and
extracted with Et2O (3 × 150 mL). The combined organic phases
were dried over Na2SO4, then filtered, and concentrated in vacuo.
The residue was purified by column chromatography on SiO2
(800 g, hexane/EtOAc 2:1 + 5% MeOH) to furnish 9.71 g (64%
over 2 steps from 13) of pyrone 14 (Rf ) 0.35) as a colorless solid.
Mp: 81 °C. IR (cm-1, KBr): 3205, 2962, 2873, 1669, 1569, 1456,
(up to 95%) of the desired products. On the basis of our
experience, it would in certain instances be valuable to examine
uncatalyzed couplings of compatible partners early in the
screening phase of reaction development in the event a
straightforward solution is available. The thus-completed syn-
thesis of 1a shows the additional advantages of employing cheap
and readily available starting materials and reactants and
allowing for a flexible modification of both parts of the
molecule. With the first non-natural iromycin 42 in hand, work
is now in progress to prepare an array of derivatives in order to
get more insight into the structure-activity relationship of this
family of pyridone metabolites.
1
1223, 1174, 1131, 1056, 945, 761. H NMR (250 MHz, CDCl3):
δ 0.92 (t, 3J ) 7.4 Hz, 3 H), 1.49 (mc, 2 H), 1.99 (s, 3 H), 2.21 (s,
3
3 H), 2.36 (t, J ) 8.0 Hz, 2 H). 13C NMR (62.9 MHz, CDCl3,
Experimental Section
DEPT): δ 8.7 (+), 13.7 (+), 16.9 (+), 22.3 (-), 26.6 (-), 98.4
(Cquat), 112.6 (Cquat), 155.7 (Cquat), 166.4 (Cquat), 167.2 (Cquat). MS
(EI, 70 eV) m/z (%): 182 (16) [M+], 154 (16) [M+ - C2H4], 127
(9) [M+ - C4H7], 125 (18) [M+ - C4H9], 86 (20), 84 (35), 57 (53)
[C3H5O+], 43 (100) [C3H7+].
Ethyl 2-Methyl-3-oxo-heptanoate (13). nBuLi (95 mL,
0.22 mmol, 2.27 M in hexane) was slowly added at 0 °C to a
solution of diisopropylamine (30.5 mL, 22.0 g, 0.218 mol) in THF
(380 mL), and the solution was stirred for 30 min. A solution of
ethyl 2-methyl-3-oxo-butanoate (12, 14.12 g, 97.94 mmol) in THF
(5 mL) was added dropwise, and the mixture was stirred for 30
min. Then, n-propyl iodide (10.5 mL, 18.3 g, 0.108 mol) in THF
(5 mL) was added dropwise at 0 °C, and stirring was continued
for 2.5 h. The mixture was treated with concd HCl (12 mL), the
phases were separated, and the aqueous phase was extracted with
Et2O (2 × 50 mL). The combined organic phases were washed
with H2O (2 × 20 mL), and the aqueous phases were re-extracted
with Et2O (50 mL). The combined organic phases were dried over
MgSO4, then filtered, and concentrated in vacuo. The residue was
purified by distillation (90 °C, 8 mbar) to furnish 10.23 g (56%) of
â-ketoester 13 as a colorless liquid. IR (cm-1, film): 2984, 2961,
2875, 1749, 1716, 1653, 1457, 1377, 1327, 1270, 1239, 1198, 1115,
4-Benzoyloxy-3,6-dimethyl-5-propylpyran-2-one (15). A solu-
tion of pyrone 14 (5.17 g, 28.4 mmol) and benzoyl chloride
(3.63 mL, 4.40 g, 31.3 mmol) in pyridine (50 mL) was stirred for
44 h at rt and then poured into a saturated NaHCO3 solution
(50 mL). The aqueous phase was extracted with EtOAc (3 ×
100 mL), and the combined organic phases were dried over Na2-
SO4, then filtered, and concentrated in vacuo. The residue was
purified by column chromatography on SiO2 (550 g, hexane/EtOAc
8:1 + 5% MeOH) to yield 7.21 g (89%) of benzoate 15 (Rf )
0.30) as a colorless oil. IR (cm-1, film): 2965, 1743, 1707, 1577,
1
1387, 1256, 1178, 1114, 1066, 908, 733. H NMR (250 MHz,
3
CDCl3): δ 0.87 (t, J ) 7.4 Hz, 3 H), 1.47 (mc, 2 H), 1.92 (s,
3 H), 2.22 (t, 3J ) 7.4 Hz, 2 H), 2.28 (s, 3 H), 7.54 (mc, 2 H), 7.70
(mc, 1 H), 8.15 (mc, 2 H). 13C NMR (62.9 MHz, CDCl3, DEPT):
δ 10.3 (+), 13.7 (+), 17.2 (+), 22.7 (-), 27.4 (-), 112.8 (Cquat),
113.4 (Cquat), 127.7 (Cquat), 128.9 (+), 130.2 (+), 134.4 (+), 156.3
(Cquat), 159.5 (Cquat), 162.6 (Cquat), 164.5 (Cquat). MS (ESI, MeOH/
NH4OAc): m/z (%) 573 (46) [2M + H]+, 555 (77) [2M - OH]+,
433 (23), 287 (100) [M + H]+. Anal. Calcd (%) for C17H18O4
(286.3): C, 71.31; H, 6.34. Found: C, 71.12; H, 6.02.
1
1069, 1027, 860, 739, 704. H NMR (250 MHz, CDCl3): δ 0.91
3
3
3
(t, J ) 6.4 Hz, 3 H), 1.26 (t, J ) 7.4 Hz, 3 H), 1.32 (d, J )
6.8 Hz, 3 H), 1.34 (mc, 2 H), 1.54 (mc, 2 H), 2.54 (mc, 2 H), 3.50
3
3
(q, J ) 6.8 Hz, 1 H), 4.18 (q, J ) 7.4 Hz, 2 H). 13C NMR
(62.9 MHz, CDCl3, DEPT): δ ) 12.5 (+), 13.6 (+), 13.9 (+),
22.0 (-), 25.4 (-), 40.9 (-), 52.6 (+), 61.0 (-), 170.4 (Cquat),
205.7 (Cquat). MS (EI, 70 eV) m/z (%): 186 (10) [M+], 157 (3)
[M+ - CH2CH3], 141 (8) [M+ - OCH2CH3], 102 (28), 85 (100)
[C5H9O+]. Anal. Calcd (%) for C10H18O3 (186.3): C, 64.49; H 9.74.
Found: C, 64.28; H, 9.49.
4-Benzoyloxy-6-formyl-3-methyl-5-propylpyran-2-one (23). A
mixture of selenium dioxide (6.67 g, 60.1 mmol) and pyrone 15
(9.76 g, 34.1 mmol) in dioxane (200 mL) was heated in a sealed
tube to 130 °C. After 5 and 10 h the same amount of selenium
dioxide was added (20.0 g, 180 mmol in total), and stirring was
continued for another 6 h. The reaction mixture was cooled to rt
and filtered over Na2SO4/Celite, and the solids were washed with
Et2O (200 mL). The filtrate was concentrated in vacuo to give
10.16 g (99%) of aldehyde 23 as a colorless solid, whose purity
was >95%. For analysis a sample was purified by column
chromatography on SiO2 (hexane/EtOAc 4:1, Rf ) 0.32). Mp: 97
°C. IR (cm-1, KBr): 3055, 2969, 1748, 1728, 1636, 1266, 1242,
1193, 1177, 1045, 739, 705. 1H NMR (300 MHz, CDCl3): δ 0.89
(t, 3J ) 7.4 Hz, 3 H), 1.54 (sext, 3J ) 7.4 Hz, 2 H), 2.01 (s, 3 H),
2.68 (bs, 2 H), 7.55 (t, 3J ) 7.8 Hz, 2 H), 7.70 (mc, 1 H), 8.15 (mc,
2 H), 9.78 (s, 1 H). 13C NMR (75.5 MHz, CDCl3, APT): δ 11.5
(+), 13.7 (+), 23.3 (-), 25.2 (-), 123.4 (-), 124.7 (-), 127.1
(-), 129.1 (+), 130.4 (+), 134.9 (+), 147.2 (-), 157.5 (-), 161.4
(-), 162.4 (-), 183.4 (+). MS (EI, 70 eV) m/z (%): 300 (6) [M+],
105 (100), 77 (16). Anal. Calcd (%) for C17H16O5 (300.3): C, 67.99;
H, 5.37. Found: C, 67.70; H, 5.24.
Ethyl 4-Acetyl-2-methyl-3-oxo-heptanoate (11). nBuLi (87 mL,
0.22 mol, 2.5 M in cyclohexane) was slowly added at 0 °C to a
solution of diisopropylamine (30.8 mL, 22.2 g, 0.220 mol) in THF
(500 mL), and the solution was stirred for 30 min. Ketoester 13
(15.60 g, 83.76 mmol) in THF (10 mL) was added dropwise, and
the solution was stirred for 1 h and then cooled to -78 °C. A
solution of N-acetylimidazole (13.84 g, 0.1257 mol) in THF
(150 mL) was added, and stirring was continued for 2 h at -78 °C.
The reaction was quenched with saturated NH4Cl solution and
warmed to rt. The phases were separated, and the aqueous phase
was extracted with EtOAc (2 × 50 mL). The combined organic
phases were washed with H2O (100 mL) and brine (100 mL). The
aqueous phases were extracted with EtOAc (2 × 50 mL), and the
combined organic phases were dried over MgSO4, then filtered,
and concentrated in vacuo to yield 20.84 g of crude diketoester 11
as a brownish oil. Due to partial decomposition on attempted
chromatography, the crude product was directly used in the next
step. IR (cm-1, film): 3057, 2987, 2963, 2875, 1720, 1700, 1653,
1457, 1379, 1266, 737, 704. 1H NMR (250 MHz, CDCl3): δ 0.93
(mc, 3 H), 1.10-1.60 (m, 8 H), 1.68-2.01 (m, 2 H), 2.15 (mc,
3 H), 3.65 (mc, 1 H), 3.80-3.96 (m, 1 H), 4.15 (mc, 2 H). MS
(ESI) m/z (%): 479 (46) [2M + Na]+, 292 (100), 251 (18) [M +
Na]+.
4-Benzoyloxy-6-hydroxymethyl-3-methyl-5-propylpyran-2-
one (25). NaBH4 (85 mg, 2.2 mmol) was added to a solution of
aldehyde 23 (0.562 g, 1.87 mmol) in EtOH (15 mL) at 0 °C, and
the mixture was stirred for 4 h at rt. After addition of saturated
NH4Cl solution (10 mL), the mixture was concentrated in vacuo
and then extracted with EtOAc (5 × 25 mL). The combined organic
phases were dried over Na2SO4, then filtered, and concentrated in
vacuo. The residue was recrystallized from EtOAc to yield
4-Hydroxy-3,6-dimethyl-5-propylpyran-2-one (14). 1,8-Diaza-
bicyclo[5.4.0]undec-7-ene (DBU) (16.1 mL, 16.4 g, 0.108 mol) was
added to a solution of diketoester 11 (20.30 g, 88.92 mmol) in
5096 J. Org. Chem., Vol. 72, No. 14, 2007

ConVergent Total Synthesis of Iromycins
0.513 g (91%) of alcohol 25 as a colorless solid. Mp: 110 °C. IR
1.5 Hz, 1 H). 13C NMR (62.9 MHz, CDCl3, DEPT): δ 21.5 (-),
22.2 (+), 30.7 (+), 69.7 (+), 82.1 (Cquat), 120.4 (+), 139.4 (+).
(E,E)-2,6-Dimethylhepta-1,4-dienyldimethylalane (35). Cp2-
ZrCl2 (0.400 g, 1.37 mmol) was treated at 0 °C with AlMe3
(6.92 mL, 14 mmol, 2.0 M in hexane, caution: pyrophoric!), and
the solvent was removed in vacuo. 1,2-Dichloroethane (5 mL) was
added, and the solution was stirred for 30 min at 0 °C. A solution
of enyne 34 (0.75 g, 6.9 mmol) in 1,2-dichloroethane (10 mL) was
added dropwise, and the mixture was stirred for 2 h at rt. At this
point, GC analysis of a hydrolyzed aliquot showed complete
consumption of the enyne. The solvent and the excess of AlMe3
were removed in vacuo, and hexane (1 mL) was added at 0 °C to
precipitate the zirconium salts. The mixture was filtered through a
frit, and the solids were washed with hexane (1 mL). The filtrate
was concentrated in vacuo to furnish 0.85 g (68%) of alane 35 as
a yellow oil whose purity was >95% as determined by GC analysis
(cm-1, KBr): 3423, 2962, 2874, 1746, 1717, 1582, 1243, 1176,
1
1112, 1046, 1022, 706. H NMR (250 MHz, CDCl3): δ 0.89 (t,
3J ) 7.4 Hz, 3 H), 1.50 (mc, 2 H), 1.97 (s, 3 H), 2.30 (mc, 2 H),
4.52 (s, 2 H), 7.55 (t, 3J ) 7.1 Hz, 2 H), 7.70 (mc, 1 H), 8.15 (mc,
2 H). 13C NMR (75.5 MHz, CDCl3, APT): δ 10.7 (+), 13.7 (+),
23.4 (-), 26.9 (-), 59.0 (-), 114.3 (-), 115.9 (-), 127.6 (-),
129.0 (+), 130.3 (+), 134.6 (+), 155.8 (-), 159.0 (-), 162.5 (-),
163.8 (-). MS (EI, 70 eV) m/z (%): 302 (4) [M+], 105 (100), 77
(16). Anal. Calcd (%) for C17H18O5 (302.3): C, 67.54; H, 6.00.
Found: C, 67.61; H, 6.04.
4-Benzoyloxy-6-bromomethyl-3-methyl-5-propylpyran-2-
one (27). PBr3 (0.58 mL, 1.7 g, 6.2 mmol) was added to a solution
of alcohol 25 (1.688 g, 5.583 mmol) in dioxane (10 mL) at 40 °C.
The mixture was stirred for 30 min at 40 °C and for 15 h at rt,
poured into a saturated NaHCO3 solution (20 mL), and extracted
with EtOAc (3 × 20 mL). The combined organic phases were dried
over MgSO4, then filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography on SiO2 (250 g,
hexane/EtOAc 5:1) to furnish 2.04 g (>99%) of bromide 27 (Rf )
0.30) as a colorless solid. Mp: 84 °C. IR (cm-1, KBr): 3055, 2964,
1
of a hydrolyzed aliquot. H NMR (250 MHz, CDCl3): δ -0.78
(s, 6 H), 0.98 (d, 3J ) 6.6 Hz, 6 H), 2.01 (s, 3 H), 2.30 (mc, 1 H),
3
2.92 (d, J ) 5.0 Hz, 2 H), 5.26-5.54 (m, 3 H).
4-Benzoyloxy-6-[(E,E)-3,7-dimethylocta-2,5-dienyl]-3-methyl-
5-propylpyran-2-one (41). nBuLi (0.39 mL, 0.83 mmol, 2.13 M
in hexane) was added to a solution of alane 35 (1.23 mL, 1.2 mmol,
1.0 M in hexane) in THF (1.0 mL) at 0 °C, and the mixture was
stirred for 30 min. A solution of bromide 27 (150.0 mg,
0.411 mmol) in THF (2.0 mL) was slowly added at 0 °C, and
stirring was continued for 2 h. The reaction mixture was poured
into a saturated NH4Cl solution (3 mL) and extracted with EtOAc
(3 × 15 mL). The combined organic phases were dried over MgSO4,
then filtered, and concentrated in vacuo. The residue was purified
by flash column chromatography on SiO2 (10 g, hexane/EtOAc
6:1) to yield 0.16 g (95%) of pyrone 41 (Rf ) 0.45) as a colorless
oil. IR (cm-1, film): 2963, 1747, 1714, 1576, 1457, 1374, 1243,
1
2874, 1747, 1718, 1576, 1265, 1178, 1066, 1046, 658. H NMR
3
(250 MHz, CDCl3): δ 0.92 (t, J ) 7.4 Hz, 3 H), 1.60 (mc, 2 H),
3
1.97 (s, 3 H), 2.30 (t, J ) 7.4 Hz, 2 H), 4.30 (s, 2 H), 7.58 (t,
3J ) 7.1 Hz, 2 H), 7.72 (mc, 1 H), 8.15 (mc, 2 H). 13C NMR (75.5
MHz, CDCl3, APT): δ 10.9 (+), 14.06 (+), 22.6 (-), 24.6 (-),
27.6 (-), 115.9 (-), 117.3 (-), 127.4 (-), 129.0 (+), 130.3 (+),
134.6 (+), 152.6 (-), 158.5 (-), 162.4 (-), 163.1 (-). MS (DCI,
NH3) m/z (%): 748 (38) [2M + NH4]+, 382 (100) [M + NH4]+.
Anal. Calcd (%) for C17H17BrO4 (365.2): C, 55.91; H, 4.69.
Found: C, 56.21; H, 4.40.
(E)-1-Trimethylsilyl-6-methylhept-4-en-1-yne (33). n-Propyl-
magnesium bromide (100 mL, 0.10 mol, 1.0 M in Et2O) was added
dropwise at 0 °C to a solution of trimethylsilylacetylene (13.8 mL,
9.59 g, 97.6 mmol) in THF (80 mL), and the mixture was stirred
for 2 h at rt. The thus-obtained trimethylsilylethynylmagnesium
bromide was transferred by cannula to a precooled (-10 °C)
mixture of 3-bromo-4-methylpent-1-ene (31), (E)-1-bromo-4-me-
thylpent-2-ene (32) (10.60 g, 1:4 ratio, 65.01 mmol), and CuCN
(0.29 g, 3.2 mmol) in THF (100 mL), and the mixture was stirred
for 2.5 h at rt. The reaction mixture was poured into a saturated
NH4Cl solution and extracted with Et2O (3 × 50 mL). The
combined organic phases were dried over MgSO4, then filtered,
and concentrated in vacuo (10 mbar). The residue was purified by
column chromatography on SiO2 (150 g, pentane) to yield 11.72 g
1
1108, 1063, 910, 733. H NMR (250 MHz, CDCl3): δ 0.85 (t,
3J ) 7.4 Hz, 3 H), 0.95 (d, 3J ) 7.1 Hz, 6 H), 1.46 (mc, 2 H), 1.66
(s, 3 H), 1.93 (s, 3 H), 2.23 (mc, 3 H), 2.65 (d, 3J ) 5.3 Hz, 2 H),
3
3
3.27 (d, J ) 7.0 Hz, 2 H), 5.20-5.50 (m, 3 H), 7.56 (t, J )
7.1 Hz, 2 H), 7.70 (mc, 1 H), 8.15 (mc, 2 H). 13C NMR (75.5 MHz,
CDCl3, APT): δ 10.5 (+), 13.9 (+), 16.3 (+), 22.6 (+, 2 C), 23.2
(-), 27.4 (-), 30.3 (-), 31.0 (+), 42.7 (-), 112.6 (-), 113.6 (-),
118.1 (+), 124.2 (+), 127.8 (-), 128.9 (+), 130.3 (+), 134.4 (+),
137.9 (-), 139.8 (+), 158.7 (-), 159.5 (-), 162.6 (-), 164.6 (-).
MS (ESI) m/z (%): 839 (100) [2M + Na]+, 431 (21) [M + Na]+,
409 (1) [M + H+].
4-Hydroxy-6-[(E,E)-3,7-dimethylocta-2,5-dienyl]-3-methyl-5-
propyl-1H-pyridin-2-one (1a). In an autoclave a mixture of pyrone
41 (60.0 mg, 0.147 mmol) and liquid NH3 (15 mL) was stirred for
48 h at 70 °C. After the mixture cooled to rt, the NH3 was carefully
evaporated, and the residue was diluted with KHSO4 solution
(1.0 M, 3 mL) and extracted with Et2O (3 × 20 mL). The combined
organic phases were dried over Na2SO4, then filtered, and concen-
trated in vacuo. The residue was purified by flash column
chromatography on SiO2 (8 g, hexane/EtOAc 2:1 + 1% HOAc) to
yield 28.8 mg (65%) of pyridone 1a (Rf ) 0.38). All analytical
data were consistent with the data of iromycin A (1a) isolated from
Streptomyces sp.1
(99%) of compound 33 (Rf ) 0.46) as a colorless liquid. IR (cm-1
,
film): 3033, 2960, 2177, 1669, 1467, 1420, 1250, 1102, 1050, 1008,
1
910, 845. H NMR (250 MHz, CDCl3): δ 0.18 (s, 9 H), 0.98 (d,
3J ) 6.6 Hz, 6 H), 2.28 (mc, 1 H), 2.94 (d, 3J ) 5.5 Hz, 2 H), 5.31
3
3
3
3
(dt, J ) 15.5, J ) 5.5 Hz, 1 H), 5.65 (ddt, J ) 15.5, J ) 5.5
4
Hz, J ) 1.5 Hz, 1 H). 13C NMR (62.9 MHz, CDCl3, DEPT): δ
0.1 (+), 22.3 (+), 23.0 (-), 30.7 (+), 86.0 (Cquat), 104.7 (Cquat),
120.6 (+), 139.2 (+). MS (EI, 70 eV) m/z (%): 180 (8) [M+], 165
(100) [M+ - CH3], 135 (9) [M+ - 3 CH3], 123 (25), 106 (30), 97
(10), 83 (14).
Acknowledgment. This work was financially supported by
the Deutsche Forschungsgemeinschaft (SFB 416, Project B14).
P.v.Z. is grateful to Prof. Armin de Meijere for his continuing
support.
(E)-6-Methylhept-4-en-1-yne (34). NaOH (96 mL, 96 mmol,
1.0 M in H2O) was added at rt to a solution of compound 33
(10.80 g, 58.77 mmol) in MeOH (200 mL), and the mixture was
stirred for 3.5 h, poured into a saturated NH4Cl solution, and
extracted with pentane (4 × 50 mL). The combined organic phases
were dried over MgSO4, then filtered, and concentrated by careful
distillation at atmospheric pressure using a 20 cm Vigreux column.
The residue was purified by Kugelrohr distillation (90 °C, 200 mbar)
Supporting Information Available: Description of the at-
tempted synthesis of iromycin A along path A; general experimental
methods; experimental procedures and characterization data of
compounds 8, 16, 18-22, 24, 26, 28-30, 36, 37, 42, 44-47, 49,
to yield 6.18 g (95%) of enyne 34 as a colorless liquid. IR (cm-1
film): 3309, 2961, 2872, 2252, 1653, 1559, 1466, 1384, 1254, 1056,
,
1
and 50; H NMR and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
3
847, 735. H NMR (250 MHz, CDCl3): δ 0.99 (d, J ) 6.6 Hz,
6 H), 2.05 (mc, 1 H), 2.30 (mc, 1 H), 2.88 (mc, 2 H), 5.31 (dt, 3J )
15.5, J ) 5.5 Hz, 1 H), 5.65 (ddt, J ) 15.5, J ) 5.5 Hz, J )
3
3
3
4
JO070327J
J. Org. Chem, Vol. 72, No. 14, 2007 5097