Total synthesis of (+)-ileabethoxazole via an iron-mediated pauson-khand [2 + 2 + 1] carbocyclization

Article abstract of DOI:10.1021/ja5043462

Studies describe the total synthesis of (+)-ileabethoxazole (1) using a Stille cross-coupling reaction of propargylic stannanes with 5-iodo-1,3-oxazoles to produce 1,1-disubstituted allenes (11). An iron-mediated [2 + 2 + 1] carbocyclization yields a novel cyclopentenone for elaboration to 1. Site-selective palladium insertion reactions allow for regiocontrolled substitutions of the heterocycle. Asymmetric copper hydride reductions are examined, and strategies for the formation of the central aromatic ring are discussed.

Full text of DOI:10.1021/ja5043462

Article
pubs.acs.org/JACS
Total Synthesis of (+)-Ileabethoxazole via an Iron-Mediated Pauson−
Khand [2 + 2 + 1] Carbocyclization
David R. Williams* and Akshay A. Shah
Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States
S
* Supporting Information
ABSTRACT: Studies describe the total synthesis of (+)-ileabe-
thoxazole (1) using a Stille cross-coupling reaction of propargylic
stannanes with 5-iodo-1,3-oxazoles to produce 1,1-disubstituted
allenes (11). An iron-mediated [2 + 2 + 1] carbocyclization
yields a novel cyclopentenone for elaboration to 1. Site-selective
palladium insertion reactions allow for regiocontrolled sub-
stitutions of the heterocycle. Asymmetric copper hydride
reductions are examined, and strategies for the formation of
the central aromatic ring are discussed.
After extensive two-dimensional NMR studies, it was concluded
that 1 displayed the substituted five-membered ring as
described for ileabethin (4), which was collected from P.
elisabethae at a different location.5 Interestingly, ileabethoxazole
(1) shows strong inhibition (92%) of Mycobacterium tuber-
culosis (H37Rv) (ATCC27294), and this antimycobacterial
activity has also been reported for the benzoxazoles 2 (97%
inhibition) and 3 (80% inhibition). These substances represent
a subset of the family of pseudopterosins, which are widely
recognized for their potent anti-inflammatory and analgesic
effects.6,7 The anti-inflammatory activity is of particular interest
because the release of pro-inflammatory mediators is sup-
pressed without inhibition of the eicosanoid pathway.8 More
than 30 pseudopterosins have been identified as phenolic
diterpenes, which are based on three diastereomeric aglycones
connected to various monosaccharides via an acetal linkage.9
Pseudopterosins A and G are illustrated in Figure 2. Total
syntheses of pseudopterosins A10 and E11 and several synthesis
studies of aglycone diastereomers have been published.12
INTRODUCTION
■
The chemodiversity exhibited by secondary metabolites of the
Caribbean octocoral Pseudopterogorgia elisabethae has been
extensively investigated and has led to the discovery of new
carbon skeletons and unusual structural features. A review of
selected diterpenes of this family was compiled in 2005 by
Heckrodt and Mulzer to summarize the isolation, biosynthesis,
pharmacology, and selected synthesis studies.1 In 2006,
Rodriguez and co-workers described the isolation of
ileabethoxazole (1) (Figure 1) from specimens collected near
Figure 1. Examples of metabolites of P. elisabethae.
the Island of Providencia, Columbia.2 Ileabethoxazole is a rare
example of a marine benzoxazole derived from the serrulatane
diterpenoid skeleton by incorporating a subsequent cyclization
to produce the fused cyclopentane ring. This metabolite is
present in very low concentrations (yield 9.4 × 10−5% based on
dried gorgonian weight), and is structurally similar to
pseudopteroxazole (2)3 and homopseudopteroxazole (3).4
Figure 2. Representative pseudopterosins.
Received: April 30, 2014
© XXXX American Chemical Society
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Our studies have specifically focused on the chemistry of
ileabethoxazole (1) because of its antitubercular activity.
Tuberculosis (TB) continues to be a leading cause of disease-
related deaths worldwide. Statistics provided by the World
Health Organization (WHO) have documented the significance
of the problem.13 It is estimated that more than 1 billion people
are infected. Millions of new cases of TB are diagnosed each
year (5.7 million in 2010), and the evolution of new cases of
multidrug resistant TB (MDR-TB) have risen dramatically
(650 000 in 2010). Drug resistance is a constant threat, and the
conditions that allow MDR-TB to re-emerge from dormancy
are poorly defined. Selective cytotoxicity toward the slow-
growing organism has proven to be a challenging issue.14 The
identification of new lead compounds has been a critical barrier
to advances in this arena. Davidson and Corey have reported a
synthesis pathway leading to pseudopteroxazole beginning with
(S)-limonene, and these efforts have also led to a revision of the
assigned stereochemistry as depicted in 2.15
leading to a tertiary benzylic alcohol for reductive deoxygena-
tion. Alternatively, a cuprate reagent, which incorporates the E-
alkenyl chain, could be used for the displacement of an
appropriate benzylic leaving group. The saturated ketone 7 is
available by α-methylation of the corresponding enolate, and
this transformation is advanced by the conjugate reduction of
the enone 8 with subsequent addition of methyl iodide. Since
we were interested in opportunities that would directly
introduce the oxazole heterocycle, we recognized that 8 could
be assembled via the [2 + 2 + 1] carbocyclization of the allene
11 to produce an unsaturated five-membered cyclopentenone
10. Thus, formation of the fully substituted aromatic ring of 8 is
anticipated from an intramolecular Heck reaction of 9. On the
basis of our prior studies of oxazoles, we expected that the C-2
position (C21 ileabethoxazole numbering) would be reactive,
especially toward hydrogen abstraction or toward nucleophilic
additions.16 This aspect suggested the need to consider a C-2
blocking unit (PG).
In this work, we describe an enantiocontrolled total synthesis
of ileabethoxazole (1). Our studies were designed to achieve
several specific aims in addition to establishing a viable pathway
to the natural product itself. We have sought to provide a
synthesis platform for the generation of tricyclic and tetracyclic
derivatives of 1 toward studies of medicinal chemistry. We have
also explored advancements of synthesis methodology with
broad implications. Thus, these efforts feature our findings of
palladium-catalyzed cross-coupling reactivity for direct incor-
poration of the intact oxazole heterocycle. A general and
effective preparation of 1,1-disubstutited allenes is described as
a prerequisite for the application of a novel iron-mediated [2 +
2 + 1] carbocyclization. Overall, these fundamental advances
offer improved efficiency for the assembly of molecular
complexity.
Initial studies have explored the development of an efficient
method for the preparation of the nonracemic allene 11 of
Scheme 1. These investigations have led to the discovery of a
regioselective Stille cross coupling reaction of 3-tri-n-butyl-
stannyl-1-trimethylsilyl-1-propyne with alkenyl iodides for
direct formation of 1,1-disubstituted allenylsilanes.17 The
scope of the reaction is extended to generally include alkyl-
substituted propargylic stannanes as illustrated in Scheme 2.
The asymmetry at C-1 of ileabethoxazole is introduced by the
Myers alkylation18 of 12, subsequent reduction of 13, and
Dess−Martin oxidation to provide the nonracemic aldehyde 15.
The asymmetric alkylation gave 13 with high diastereoselectiv-
ity (dr ≥ 25:1), and this material was purified by flash silica gel
Scheme 2. Preparation of Nonracemic Allenes 21 and 22
RESULTS AND DISCUSSION
■
An outline of our synthesis strategy is illustrated in Scheme 1.
We envisioned that the E-alkenyl chain (C13C17) of 1 could
be introduced via a nucleophilic addition to the C-12 ketone 7
Scheme 1. Retrosynthetic Analysis for Ileabethoxazole (1)
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chromatography prior to reduction with lithium amidotrihy-
droborate.19 The nonracemic primary alcohol 14 was
confirmed by comparison with published characterization
data,20 and its optical purity was also established by Mosher
ester analysis.21 After oxidation to 15, a small sample of
aldehyde was reduced (NaBH4) for an additional Mosher ester
analysis, establishing the high optical purity (≥25:1) of 15. The
aldehyde was then utilized for an efficient three-step trans-
formation into the propargylic stannane 16 by application of
the Corey−Fuchs procedure, which employed a quench with
paraformaldehyde to obtain the corresponding propargylic
alcohol.22 Treatment of this alcohol with ethyl chloroformate
and pyridine gave the expected carbonate (95%), and a
regioselective, titanium-mediated stannylation exclusively pro-
duced the propargyl stannane 16.23 This transformation
involves a reduction of the starting carbonate by the addition
of titanium tetra-isopropoxide and isopropylmagnesium
chloride in anhydrous ether at −40 °C. The reaction is
quenched by the introduction of tri-n-butyltin chloride at −78
°C, and is thought to proceed via the formation of an
allenyltitanium intermediate. The stannane 16 is highly acid
sensitive and requires flash chromatography using silica gel that
has been pretreated with 3% triethylamine in hexanes.
poor conversions only in selected cases. We have detailed a
mechanistic pathway for these iron-mediated [2 + 2 + 1]
reactions which is distinguished from the usual reaction profile
of the PKR by the characterization of a reaction-competent,
three-membered iron metallacycle.33 In fact, these reactions are
quenched by the introduction of a CO atmosphere. On the
basis of these findings, facile carbocyclizations of 21 and 22
occurred in anhydrous THF upon addition of Fe2(CO)9 and N-
methylmorpholine-N-oxide at 22 °C (Scheme 3). Reactions
Scheme 3. [2 + 2 + 1] Carbocyclizations
The Stille cross coupling of 16 using 10 mol % Pd2(dba)3 in
dry DMF at 22 °C with oxazoles 17 and 18 proved to be highly
regioselective.24,25 As anticipated, palladium insertion at C-5
leads to the allenes 19 and 20 without formation of enyne
products.17 These experiments do not proceed via an initial
isomerization of 16 to the corresponding allenylstannane prior
to the cross coupling since substituted allenes are not observed
in the absence of the alkenyl iodide coupling partner. The
terminal alkynes of 21 and 22 are introduced in three steps by
silyl ether hydrolysis, IBX oxidation,26 and application of the
Ohira−Bestmann reagent27 (81% yield and 92% yield,
respectively). In this fashion, Scheme 2 provides a general
pathway to readily available substrates for the proposed
cyclization studies.
The retrosynthetic analysis suggests opportunities to examine
an intramolecular [2 + 2 + 1] carbocyclization to deliver the
cyclopentenone system of 10 (Scheme 1). In fact, the Pauson−
Khand reaction (PKR) is readily identified as an important
process for the synthesis of cyclopentenones via the
precomplexation of dicobalt octacarbonyl with an alkyne in
the presence of alkene and carbon monoxide at elevated
temperatures. Significant contributions by Brummond,28
Cazes,29 Evans,30 and others31 have improved the scope of
the reaction and introduced the use of several transition metal
catalysts. Intramolecular variants of the PKR are particularly
attractive strategies for the synthesis of polycyclic cyclo-
pentenones in natural product synthesis.32 The body of
published results illustrates successful reactions for relatively
unfunctionalized substrates. This aspect raised concerns for our
use of allene 22 at elevated pressures and at temperatures
exceeding 100 °C. Fortunately, our investigations have
uncovered a [2 + 2 + 1] carbocyclization using diiron
nonacarbonyl that proceeds under ambient conditions (−20
to 22 °C).33,34 Studies with 1,1-disubstituted allenylsilanes and
a variety of terminal alkynes have demonstrated stereoselective
cyclizations leading to (E)-4-alkylidene-2-cyclopentenones.
Furthermore, these iron-mediated carbocyclizations proved to
be tolerant of an impressive range of sensitive functionality. We
did not observe reactions with CO2(CO)8 and Mo(CO)6 under
these conditions, and the use of tungsten hexacarbonyl led to
progress to the cyclopentenone products at temperatures as low
at 0 °C. Our intermolecular studies support the initial
formation of the three-membered metallacycle as shown in
23, followed by oxidative decarboxylation to provide an open
coordination site leading to intermediate 24. Subsequent
carbonylation cleanly affords the enones 25 and 26 after
purification by flash silica gel chromatography. We speculate
that the yields of these isolated enones are somewhat
diminished by an accumulation of iron precipitates that may
sequester some oxazole product. Without further optimization,
at this point, we proceeded to explore formation of the fully
substituted aromatic system.
Plans for the synthesis of the central aromatic ring of 1
anticipated the use of a Heck reaction to proceed via palladium
insertion into the C4Br bond in 26. Model studies were
explored as summarized in Scheme 4 by direct α-methylenation
of ketones 25 and 26 to yield the highly unsaturated trienones
27 and 28 using a procedure described by Connell and co-
workers.35 Unfortunately, attempted Heck cyclizations of 28
produce several products upon introduction of the typical
palladium catalysts,36 whereas no reaction of 28 occurs in the
presence of RhCl(PPh3)3 in refluxing toluene.37 We have also
examined the aromatization of 27 as a formal electrocyclization
and dehydrogenation with PdC, which fails to give the
desired benzoxazole 29 as a useful conversion. Mass spectral
analyses in these cases suggest adverse reactivity associated with
the C-2 phenylthio substituent. In fact, studies by Liebeskind,38
Guillaumet,39 and Stambuli40 have described the metal-
catalyzed oxidative insertions in a variety of heteroaromatic
C
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Scheme 4. Attempts for Benzoxazole Formation
Scheme 5. Carbonyl-Condensation Strategy Toward 41
thioethers leading to Stille cross-coupling reactions with aryl
and alkenylstannanes. Subsequent evidence has confirmed our
initial suspicions since the attempts to introduce a methyl
ketone equivalent at C-4 of oxazole 26 via a Stille cross-
coupling reaction with tri-n-butyl(1-ethoxyvinyl)tin using
PdCl2(PPh3)2 in THF at 67 °C exclusively gave 30 (83%
yield). This selective oxidative insertion into the C-2 carbon
sulfur bond in the presence of the C-4 bromide provides a
useful pattern of reactivity for substitution reactions of the
oxazole nucleus. The observed relative rates of palladium
insertion reactions are portrayed in Figure 3.
examined as an opportunity for an intramolecular Michael
reaction, and this exercise rapidly led to decomposition.
The accumulated evidence from these studies led to
alterations of our synthesis plan with two significant adjust-
ments. First, the base-induced aromatization can be most
advantageously accomplished by installation of a methyl ketone
at C-4 of the oxazole heterocycle, and this moiety must be
incorporated at an early stage. Second, the reactivity of the C-2
phenylthio ether toward palladium insertion proved problem-
atic. This aspect can be eliminated by oxidation to the
corresponding sulfone. However, we have previously observed
facile nucleophilic substitution reactions of related 2-sulfonyl-
1,3-oxazoles.42 With this in mind, the trialkylsilyl substituent
was selected as an appropriate C-2 blocking unit. These
changes require validation for the key reactions demonstrating
allene preparation as well as the subsequent [2 + 2 + 1]
cyclization.
An effective pathway for synthesis of the requisite allene is
shown in Scheme 6, beginning with commercially available
ethyl-1,3-oxazole-4-carboxylate via conversion to the Weinreb
amide 43 for addition of methylmagnesium bromide. The
resulting C-4 methyl ketone is transformed into the
corresponding methoxymethyl (MOM) ether 44, and
sequential ring metalations at C-2 and C-5 by regioselective
deprotonations with LDA in THF lead to the desired iodide 45.
The Stille cross coupling of 45 with the propargylic stannane
16 (from Scheme 2) proceeds with allylic transposition to give
the allene 46 in good yield (76%) following purification by flash
chromatography. Removal of silyl protecting groups is
accomplished upon stirring in methanol with pyridinium
tosylate (PPTs) at 22 °C, and the alkyne of 47 is introduced
by oxidation and application of the Ohira−Bestmann
procedure.27 The iron-mediated [2 + 2 + 1] carbocyclization
of 47 (Scheme 7) proceeds in THF upon warming from −50 to
5 °C, and affords the expected dienone 48 (61% yield).
Cyclization and aromatization is efficiently achieved by cleavage
of the MOM acetal of 48, Swern oxidation, and subsequent
treatment with potassium tert-butoxide (2.4 equiv) in dry
toluene at −20 °C to afford desired enone 41 (93% yield) as a
Figure 3. Relative reactivity of cross-coupling reactions.
The results show that insertion for C-5 iodides and bromides
of 34 is considerably faster than the rate of CS bond
insertion of C-2 thioethers 35. Reactions of the C-4 bromides
36 are much slower, albeit feasible.25 Prior efforts of Liebeskind
and Neumann41 suggest that it may be possible to alter this
reactivity pattern by the choice of the palladium catalyst and/or
various additives. On the basis of these observations, a selective
reduction of 26 with sodium formate and PdCl2(PPh3)2 gave
oxazole 31 (73%) which led to α-methylenation affording 32
(68%). However, the proposed intramolecular Heck reaction of
32 to yield 33 also provided a substantial number of
byproducts.
Concomitant with these efforts, our studies of a carbonyl
condensation strategy were initiated toward construction of the
aromatic system. As illustrated in Scheme 5, the reduction of
the C-2 phenylthio ether of 25 gave the expected conjugated
ketone 37. Deprotonation of 37 with LDA (1.0 equiv) in THF
at −78 °C led to C-acylation using acetyl cyanide
(pyruvonitrile). Our studies of the diastereomeric mixture of
1,3-diketones 38 sought a base-promoted equilibration of
enolates featuring the ring-opened tautomers 39 and 40 as
significant intermediates for the internal condensation to
produce 41. In these attempts, our failures were met with the
recovery of the starting 1,3-diketone. However, the base-
induced deprotonation of oxazole 32 (from Scheme 4) was also
D
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hydride conjugate addition occurred with minimal yields of in
situ α-methylation. The stereoselectivity of the 1,4-reduction of
41 has been studied as summarized by the survey of results in
Table 1. In fact, facile reductions take place at 20 °C in the
presence of Ph2SiH2, CuCl (20 mol %), and the nonracemic
(S)-pTol-BINAP ligand (20 mol %) to produce diastereomers
50 and 51 (dr 75:25) in 87% combined yield (entry 1). The
integration of selected signals in the proton NMR spectra of the
reaction products provided isomer ratios which were generally
confirmed by subsequent HPLC analysis. For example, signals
for the oxazole C2H at δ 8.08 (50) and δ 8.07 (51) in
combination with the doublet of the CCH3 at δ 1.54 (50)
and δ 1.34 (51) were measured with consistency. We note that
the observed diastereoselectivity is slightly diminished as the
reaction temperature is decreased (entries 1−3). Furthermore,
the reaction at −55 °C (entry 3), resulting in the production of
50/51 (dr 61:39), is also complicated by carbonyl reduction of
these products leading to poor yields. The use of the DTBM-
(S)-SEGPHOS hydridocopper species44 (entry 4) using
polymethylhydrosiloxane affords slow reactions with consid-
erable formation of the corresponding allylic alcohols by 1,2-
reduction. Interestingly, the generation of the (S)-SEGPHOS
hydridocopper complex using Ph2SiH2 improved the diaster-
eoselectivity and the yield of the reduction (entry 5).
Scheme 6. Preparation of Allene 47
The conversion to 50 is optimized by the use of (S)-H8-
BINAP (20 mol %) and Ph2SiH2 at 20 °C (entry 6). This
modification proceeds with good stereocontrol (dr 86:14) and
avoids the formation of side products. For comparison, the
diastereoselectivity of the catalytic hydrogenation of 41 with 5%
PdC (entry 7) and reduction with lithium 4,4′-di-tert-
butylbiphenyl (LiDBB)45 (entry 8) favored formation of the
undesired 51.
Scheme 7. Formation of the Tetracyclic Benzoxazole 41
Transformation of the purified 50 to the corresponding C-11
methyl ketone 52 via alkylation with methyl iodide is
characterized by poor yields of the expected product (<15%)
and the recovery of starting material. Deprotonation of 50 with
LHMDS (2.2 equiv) in THF at −78 °C followed by a
deuterium quench (D2O) provides evidence of complete
exchange of the C2H of the oxazole ring and minimally
90% incorporation of a single deuterium at the α-methylene.
The lithium enolate derived from 50 is surprisingly unreactive
at low temperatures, in spite of the inclusion of the usual
solvent additives (HMPA and DMPU). This problem is
resolved by α-methylenation using N,N,N′,N′-tetramethyldia-
minomethane46 and acetic anhydride, and subsequent reduc-
tion as described by Lipshutz and co-workers using in situ
(BDP)CuH reagent.47 In this fashion, the α-methyl ketone 52
is produced in 76% yield as a white waxy solid (mp 142−150
°C). The product is isolated as a single diastereomer, and the
relative stereochemistry at C4 and C11 is recognized by NOESY
correlations of the C4H (δ 2.71−2.80 (m)) with the C11-
methyl substituent at δ 1.35 (d) as well as the C1-methyl group
at δ 1.55 (d). These findings mirrored similar correlations
described for the natural product itself. The side chain
component of 1 is readily prepared from 3-methyl-1-butyn-3-
ol via palladium-catalyzed hydrostannation to give the known
(E)-alkenylstannane,48 followed by TBS silyl ether formation.
Initial conversion to the known (E)-iodide 53,49 using iodine in
CH2Cl2 at 0 °C, affords a cleaner transmetalation with n-
butyllithium (Scheme 8), and the corresponding alkenyllithium
species leads to carbonyl addition for synthesis of the C-12
tertiary alcohol 54 (70% yield). However, experiments to
provide for an effective deoxygenation of 54 are characterized
solid (mp 92−94 °C). Isomerization of 41 is observed to
provide the corresponding β,γ-enone upon flash chromatog-
raphy with silica gel that has been pretreated with 3%
triethylamine in hexanes.
Fortunately, this double-bond migration is completely
avoided under the usual conditions of flash chromatography,
and this observation simplified subsequent plans for reduction
and methylation of ketone 41. We sought to achieve facial
stereoselectivity via a reagent-controlled reduction of the
conjugated enone by employing a chiral hydridocopper species.
Initial experiments examined a one-pot protocol of Buchwald
and co-workers,43 and found that the anticipated copper
E
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Table 1. Conjugate Reductions of Enone 41
entry
conditions
dr (50/51)
% yield
a
1
2
3
4
5
6
7
8
conditions at 20 °C (3 h) (S)-pTol-BINAP (20 mol %)
75:25
67:33
61:39
87
a
conditions at −30 °C (3 h) (S)-pTol-BINAP (20 mol %)
78
a
c
conditions at −55 °C (3 h) (S)-pTol-BINAP (20 mol %)
≤40
≤30
b
e
d
conditions at −30 to 0 °C (24 h) (S)-DTBM-SEGPHOS (20 mol %)
ND
a
conditions at 20 °C (3 h) (S)-SEGPHOS (20 mol %)
78:22
86:14
33:67
25:75
85
79
93
61
a
conditions at 20 °C (3 h) (S)-H8-BINAP (20 mol %)
H2 (1 atm); 5% Pd−C
LiDBB (10 equiv); THF bis(methoxyethyl)amine (1.3 equiv) at −78 to −30 °C
a
b
CuCl (20 mol %); NaOtBu (20 mol %); Ph2SiH2 (0.53 equiv); ligand in toluene. CuCl (20 mol %); NaOtBu (20 mol %); PMHS (1.2 equiv);
c
d
ligand in toluene. Varying amounts of isomeric α/β-alcohols from 50/51 are also obtained. Rapid CO reduction gives mixtures of allylic alcohols
e
and 50/51 with modest conversions; Not determined.
Scheme 8. Introduction of C11 and C12 Substitution in
Ketone 50
Scheme 9. Completion of the Synthesis of
(+)-Ileabethoxazole (1)
by poor yields in the attempts to transform the hindered
alcohol into a preferred derivative for nBu3SnH reduction.
Furthermore, subsequent attempts for Barton deoxygenation of
small amounts of thione derivatives also led to unexpected
complications, as evidenced by the isolation of products arising
from reduction of the CC moiety and loss of the OTBS
substituent.
Finally, the total synthesis of (+)-ileabethoxazole (1) is
completed in three efficient operations, as illustrated in Scheme
9. Treatment of 52 with methylenedimethylsulfurane at −20 °C
yields an intermediate epoxide which undergoes facile
rearrangement in the presence of anhydrous InCl3.50 The
aldehyde 55 is produced as a single isomer as a result of
epimerization at C-12, and application of the Horner−Emmons
reaction51 results in formation of the stable α,β-unsaturated
ethyl ester 56. The subsequent addition of methyllithium (3
equiv) leads to synthetic (+)-ileabethoxazole (1), which has
been shown to be identical in all respects, including optical
rotation (α22D + 9.3° (c 1.50, CHCl3), with characterization
data provided for the natural product.2
In summary, the first synthesis of (+)-ileabethoxazole (1), a
novel inhibitor of Mycobacterium tuberculosis, has been
described. Key features of our investigation include the effective
preparation of 1,1-disubstituted allenes via a Stille cross
coupling of propargylic stannanes. Our studies have reported
useful aspects of the relative reactivity for cross-coupling
processes at the C2, C4, and C5 positions of the oxazole nucleus.
An exceptionally mild, iron-mediated [2 + 2 + 1] carbocycliza-
tion has been documented. Our intramolecular PKR variant
using inexpensive Fe2(CO)9 tolerates a wide variety of
functionality, notably including the heterocyclic amine. These
reactions proceed via the reactivity of a previously unexplored
three-membered iron metallacycle. A slight modification that
introduces the use of the chiral H8-BINAP ligand in the
preparation of hydridocopper reagent for 1,4-conjugate
reductions promises improved stereoselectivity in the asym-
metric reductions of indenones. Finally, our studies of
F
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ileabethoxazole have described a pathway well suited for
advancements of medicinal chemistry, the generation of
focused libraries, and continuing studies to explore the
antitubercular activity of these marine natural products.
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete experimental description of reactions and character-
izations of all new compounds, proton and carbon NMR
spectra, as well as comparison data of synthetic and natural
ileabethoxazole. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
williamd@indiana.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors acknowledge the support of the National Science
Foundation (CHE-1055441).
■
REFERENCES
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