Organoboron-based allylation approach to the total synthesis of the medium-ring dilactone (+)-antimycin A1b

Article abstract of DOI:10.1021/jo501134d

The stereoselective synthesis of (+)-antimycin A_1b has been accomplished in 12 linear steps and 18% overall yield from (-)-ethyl lactate. A robust, scalable, and highly diastereoselective montmorillonite K10-promoted allylation reaction between

Full text of DOI:10.1021/jo501134d

Article
pubs.acs.org/joc
Organoboron-Based Allylation Approach to the Total Synthesis of
the Medium-Ring Dilactone (+)-Antimycin A1b
John Janetzko and Robert A. Batey*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6,
Canada
S
* Supporting Information
ABSTRACT: The stereoselective synthesis of (+)-antimycin A1b has been accomplished in 12 linear steps and 18% overall yield
from (−)-ethyl lactate. A robust, scalable, and highly diastereoselective montmorillonite K10-promoted allylation reaction
between an α-silyloxy aldehyde and a substituted potassium allyltrifluoroborate salt provides a general approach to the core
stereochemical triad of the antimycin A family. The requisite (Z)-substituted potassium allyltrifluoroborate salt was synthesized
using a syn-selective hydroboration/protodeboration of an alkynylboronate ester, followed by a Matteson homologation reaction.
The total synthesis leverages an MNBA (Shiina’s reagent)-mediated macrolactonization to generate the 9-membered dilactone
ring and a late-stage PyBOP-mediated amide coupling employing an unprotected 3-formamidosalicylic acid fragment, thereby
shortening the longest linear sequence and, perhaps most notably, generating the antimycin A C7−C8−C9 stereotriad in a single
step using a single chiral pool-derived stereocenter.
action involved mitochondrial membrane hyperpolarization as
evidenced by the accumulation of NAD(P)H. Interestingly, this
gain-of-function cytotoxicity was only observed in cells
overexpressing Bcl-xL.7a
INTRODUCTION
■
Leben and Keitt first described the antimycins in 1948 when
they reported a bioactive preparation obtained from an
unidentified Streptomyces strain.1 At the time of discovery, the
family of 9-membered dilactones was shown to have potent
antifungal activity against Nigrospora sphaerica. As a result,
members of the antimycin family have been studied extensively,
with a wealth of additional bioactivity being revealed. Seminal
studies suggested that antimycin A was able to potently inhibit
mitochondrial respiration2 by binding to the cytochrome bc1
complex at its Qi site.3 More recently, several groups showed
that various members of the antimycin A family and their
derivatives exhibit biological activities including blocking
angiogenesis,4 inhibiting autophagy,5 conferring cardioprotec-
tion,6 and stimulating apoptosis by inhibiting Bcl-xL.7
Hockenbery and co-workers elegantly demonstrated that
antimycin A was able to inhibit the antiapoptotic effects of
Bcl-xL by binding to its Bcl-2 homology domain 3 (BH3)-
binding hydrophobic groove, facilitating the loss of mitochon-
drial membrane fidelity and ultimately leading to the onset of
apoptotic cell death.7b These studies also demonstrated
promise for the use of an antimycin A analogue for the
treatment of neoplastic or other proliferative diseases reliant on
Bcl-2 protein overexpression by showing that, at least in the
context of antimycin A3, methylation of the phenol abolished its
inhibition of cellular respiration while retaining its ability to
stimulate apoptosis in cells with enhanced levels of Bcl-xL (Bcl-
xLhigh).7b More recent findings suggested the mechanism of
To date, there are several dozen known members of the
antimycin A family, each differing in the nature of the alkyl
chain at C7 (R1) or the acyl group at C8 (R2) (Figure 1).8
More recently, Fenical and co-workers described a related
family of anti-inflammatory natural products, the splenocins,9
which differ from the antimycins in that they incorporate an
aryl moiety at either their C7 or C8 side chains. Several related
structures have also been reported, including UK-2A (a
derivative of splenocin B),10 as well as related neoantimycins,
such as JBIR-52,11 prunustatin A,12 kitastatin 1,13 and
respirantin,14 which share the 1,2,3-trisubstituted aryl fragment
with the antimycins and splenocins (Figure 1).
RESULTS AND DISCUSSION
■
Due to the breadth and potency of their biological activities, the
antimycins have garnered significant synthetic attention,8a both
in the synthesis of natural members15−18 and novel analogues.19
The main synthetic challenges associated with antimycin
synthesis are (i) the formation of the nine-membered ring,
(ii) the synthesis of the C7−C8−C9 stereotriad, and (iii) the
attachment of the formamidosalicylate ring. Our goal was to
Received: May 22, 2014
© XXXX American Chemical Society
A
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coupling of the unprotected substituted salicylic acid fragment
2 would then give (+)-1 (Scheme 1). Such an approach would
both address the limitations of some of the previous antimycin
syntheses and showcase the practical utility of recently
developed robust and scalable organotrifluoroborate-based
allylation and crotylation methods.21
The requisite 9,8-anti-8,7-syn stereochemical configuration of
the key intermediate 5 necessary to form the C7−C8−C9
antimycin A stereotriad suggested an approach based on the
use of a (Z)-substituted organoboron reagent. Previous studies,
on the synthesis of (−)-tetrahydrolipstatin, had established that
diastereoselective crotylation of α- and β-silyloxy aldehydes
using (E)- and (Z)-crotyltrifluoroborate salts21 could be
achieved under phase-transfer-catalyzed conditions.21f,g The
stereochemical outcome of addition to α-substituted aldehydes
was rationalized by invoking Cornforth-like transition states A
and B (Scheme 2).21f,h,22 This model is supported by the
Scheme 2. Stereocontrolled Crotylation of α-Silyloxy
Aldehydes
Figure 1. Structures of antimycins and related natural products.
develop a general route to the antimycin family, targeting the
specific example of antimycin A1b (R1 = n-hexyl, R2
=
CH2CH(CH3)2), a major component of the antimycin A
mixture that, at the onset of this work, had not yet been
chemically synthesized.15c We envisaged a retrosynthetic
approach from chiral pool-derived precursors 4 and 7 using a
diastereoselective organotrifluoroborate20-based allylation ap-
proach with the Z-configured reagent 8 to establish the key
C7−C8−C9 stereotriad of antimycin A1b, (+)-1, via 5 (Scheme
1). Sequential esterification of 5 followed by oxidative cleavage
to protected seco-acid 3, macrolactonization, and late-stage
observation that with a (Z)-configured crotylboron reagent
there is a strong preference for the formation of the 1,2-anti-
2,3-syn diastereomer. The preferred 2,3-syn relationship is
controlled by the (Z)-geometry of the crotylboron reagent, and
the 1,2-anti relationship predominates as a result of the
disfavored syn-pentane like interaction present in the 1,2-syn
transition state B. Notably, in Kiyota’s formal synthesis of
antimycin A3b, a chelation-controlled allylstannane addition was
employed to generate the C7−C8−C9 stereotriad. However, in
their case the addition, while quite stereoselective, produced the
incorrect all-syn diastereomer and required a Mitsunobu
inversion at C9 and the use of ethyl (R)-lactate as a starting
material in order to obtain the natural stereotriad config-
uration.15e
Scheme 1. Retrosynthesis of Antimycin A1b
We envisioned the final step in the synthesis of (+)-1 to be
the union of 2 and a macrocyclic amine. However, this route
required the coupling of an unprotected phenol where previous
syntheses bore this functional group in a protected form, as a
benzyl ether.15 Our initial approach to the arene fragment
involved the saponification of the nitrosalicyl ester, 9, followed
by hydrogenolysis of the resulting 3-nitrosalicylic acid.
Unfortunately, this chemistry failed to provide practical
quantities of 3-aminosalicylic acid with poor batch-to-batch
reproducibility and challenges in handling the resulting amino
acid. Similarly, reversal of the reduction and saponification steps
proved unsuitable due to the significant aqueous solubility of 3-
aminosalicylic acid. We ultimately opted for a route in which 9
was subjected to hydrogenolysis, followed by metal silanolate-
mediated ester hydrolysis23 and subsequent acidification to
B
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provide the corresponding hydrochloride salt 11 after a simple
filtration (Scheme 3). Lastly, conversion of 11 to 2 was then
Scheme 5. Synthesis of seco-Acid 21
Scheme 3. Synthesis of 3-Formamidosalicylic Acid (2)
achieved as described by Petitt.14 This route enabled rapid and
robust access to multigram quantities of 2 without the need for
1
chromatographic purification steps. Interestingly, the H NMR
spectrum of 2 was complicated by the fact that the formamide
moiety can adopt two distinct rotomeric species, which
interconvert on the NMR-time scale, in about a 4:1 ratio, as
1
shown by H−1H EXSY NMR (NOESY pulse sequence, see
the Supporting Information for details).
For the preparation of the requisite boron reagent 8, we
sought to identify a robust and scalable route that would enable
access to multigram quantities with the highest possible
stereochemical purity. While numerous methods could be
envisioned for the generation of cis-alkenyl boronates, we opted
for a hydroboration/protodeboration route previously de-
scribed by Molander and Ellis.24 Metalation of 12, trapping
of the alkynyllithium with pinacol borane, and subsequent
protonolysis of the borohydride afforded large quantities of the
labile alkynyl boronate 13 (Scheme 4). Subjecting crude 13 to
Scheme 4. Synthesis of Boron Reagent 8
other allylmetal additions, as evidenced by the cryogenic
temperature used for the allylstanne addition in Kiyota’s
synthesis.15e
Optimized conditions were able to remedy the initially
sluggish acylation encountered for the conversion of the
hindered secondary alcohol in 5 to 17. However, desilylation of
17 was complicated by a 1,2-acyl migration when either TBAF
or aqueous HF were used. Fortunately, reports by Trost and
Carreira,28 who had observed similar acyl migrations, led us to
examine buffered HF·pyridine conditions, enabling the smooth
conversion of 17 to 18 without significant observable acyl
transfer. Various conditions for coupling of the threonine
moiety 4 were explored including PyBOP, EDC, HBTU, BOP,
BOP-Cl, and DCC. Ultimately, DCC proved to be the optimal
reagent for the coupling of 4 with 18, affording 19 in nearly
quantitative yield. Terminal olefin oxidation of 19 proved
challenging, with the use of Sudan III29 being essential for
obtaining 3 in good yield30 after subjecting the crude aldehyde
to Pinnick oxidation.29 Removal of the threonine benzyl ether
occurred under surprisingly mild conditions,15b giving access to
multigram quantities of 21.
We next examined various conditions for forming the 9-
membered ring of antimycin A. The use of Shiina’s reagent,
MNBA,31 which was previously found to be optimal in the
synthesis of antimycin A3b,15b again proved optimal in our
hands (Scheme 6) amidst the other macrolactonization
conditions examined. It is noteworthy that MNBA has been
used by many groups for the construction of challenging
medium and large rings.31,32 Macrolactonization occurred to
give 22 in good yield using slow addition techniques. The
hydroboration with dicyclohexylborane followed by selective
protodeboration afforded 14 as a single detectable stereo-
isomer25 on a multigram scale. Matteson homologation to
allylic boronate 15, using in situ generated (chloromethyl)-
lithium,26 was followed by conversion into the corresponding
(Z)-configured potassium trifluoroborate salt 8 which exhibits
superior stability and ease of handling relative to 15.20
Synthesis of the core fragment began with the conversion of
(−)-ethyl lactate to silyl-protected aldehyde 7 (Scheme 5). We
were pleased to find allylation with boron reagent 8 proceeded
smoothly, using our recently described montmorillonite K10
clay-based allylation method,21d to give 5 as the major
diastereomer on multigram scale. The benefits of the
montmorillonite K10-promoted allylation method include low
cost, low toxicity, and facile reaction setup (open-air flask).
Perhaps more notable is the fact that this reaction is fast yet
highly diastereoselective27 at room temperature in contrast to
C
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before use and transferred via syringe using standard Schlenk
techniques. Dichloromethane, toluene, and acetonitrile were distilled
from CaH2 under nitrogen atmosphere. Tetrahydrofuran, diethyl
ether, and benzene were distilled from sodium under nitrogen
atmosphere. All reagents and starting materials, unless otherwise
stated, were used as received from their respective providers.
Anhydrous methanol was used as received. Anhydrous tert-butyl
alcohol was either freshly distilled from sodium under argon and
stored under argon over activated 4 Å molecular sieves or purchased
and used as received. Alkyllithium reagents were titrated according to
the method by Watson and Eastham33 prior to use.
Scheme 6. Synthesis of Antimycin A1b
Infrared spectra were recorded either as neat samples or from thin
films. Strong bands are noted by the abbreviation “str”. NMR spectra
were obtained as a solution in deuterated solvent (CDCl3, CD3CN,
CD3OD, (CD3)2SO), as indicated. Chemical shifts are expressed in
parts per million (ppm) relative to Me4Si (TMS) and referenced by
the residual solvent peak (1H, 13C), BF3·OEt2 (11B), or CFCl3 (19F).
Peak multiplicities are designated by the following abbreviations: m,
multiplet; s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of
doublets; dt, doublet of triplets and so forth. Additional descriptions
include br, broad (this abbreviation is also used for designation of IR
peaks), and app, apparent. Apparent multiplicities are described when
complex splitting is simplified by averaging or coincidental
equivalence. Coupling constants, J, are expressed in hertz (Hz) to
the nearest 0.5 Hz. Mass spectra, low-resolution (LRMS) and high-
resolution (HRMS), were recorded on either a Q-TOF mass
spectrometer (ESI), a GC TOF mass spectrometer (EI), or an
AccuTOF (DART). LRMS analysis includes peaks of significant
relative intensity only with relative intensities given in parentheses (EI
somewhat modest yield for macrolactonization can be
attributed to the competing formation of an 18-member ring
dimer that was observed in the crude reaction mixtures both by
MS and NMR. Removal of the Boc group and subsequent
amide bond coupling with 2 using PyBOP provided synthetic
(+)-antimycin A1b, which exhibited spectral and physical
properties matching those reported for the natural com-
pound.8c
only). Accurate masses were determined in all cases to be within
5
ppm of the calculated high-resolution mass. Stated melting points are
uncorrected. Since 5 and 17 were obtained as diastereomeric mixtures
no optical rotations are reported.
Previous antimycin A syntheses described in the literature,
notably even the most recent reports, rely on the use of chiral
auxiliaries for the generation of the core antimycin A
stereochemical triad. In contrast, we present here an approach
in which the intrinsic properties of the substrates are exploited
with the single chiral center from the ethyl (S)-lactate starting
material being used to set the correct C7−C8−C9 config-
uration with a single practical transformation. We also describe
a streamlined and chromatography-free route to 2, which can
be coupled to the antimycin A core directly, in contrast to
previous uses of a protected derivative.
With a longest linear sequence of 12 steps (19 steps overall)
and 18% overall yield (linear sequence), this constitutes one of
the shortest syntheses of a member of the antimycin A family.
Key steps included a diastereoselective addition of a (Z)-
substituted potassium allyltrifluoroborate salt under clay
catalysis to establish the C7−C8−C9 stereotriad, an MNBA-
promoted macrolactonization, and the use of an unprotected
formamidosalicylic acid for the final coupling step. The absolute
stereochemistry of the stereotriad was established by the use of
the chiral pool reactant ethyl lactate. The synthesis constitutes
the first total synthesis application of the use of a nonstandard
(Z)-substituted potassium allyltrifluoroborate species. Efforts
are currently underway to use this flexible allylboron based
strategy to access novel analogues with the antimycin A core
structure and medicinally interesting neoantimycins and related
natural products.
Flash column chromatography on silica gel (60 Å, 230−400 mesh)
was performed with reagent-grade solvents. Chromatography was
either run manually or using a flash purification system. Analytical
thin-layer chromatography (TLC) was performed on precoated
aluminum-backed silica gel plates (Alugram SIL G/UV254), visualized
with one of more of the following methods: UV lamp (254 nm),
iodine, ninhydrin, potassium permanganate, p-anisaldehyde, phospho-
molybdic acid, vanillin, Hanessian’s stain (cerium molybdate), 2,4-
dinitrophenylhydrazine, or bromocresol green. References following
compound names indicate literature articles where full-character-
ization, including all spectral and physical properties, is reported.
Preparation of Boron Reagents. 4,4,5,5-Tetramethyl-2-(oct-1-
yn-1-yl)-1,3,2-dioxaborolane (13).34 A 250 mL three-neck round-
bottomed flask, equipped with a thermocouple, for internal temper-
ature monitoring, and a large Teflon stir bar, was flame-dried under
vacuum and refilled with dry argon. Anhydrous ether (100 mL) was
added followed by 1-octyne (12, 14.8 mL, 100 mmol). The stirred
solution was then cooled to −78 °C, and n-BuLi (38.0 mL, ca. 2.63 M
in hexanes, 100 mmol) was added dropwise over 1 h to this solution to
form the corresponding lithium acetylide. This solution was then
stirred for 1 h before being transferred via cannula to a 500 mL round-
bottomed flask, dried as described above, and charged with
pinacolborane (14.5 mL, 100 mmol) in 100 mL of anhydrous ether
prechilled to −78 °C. This addition occurs over approximately 1 h,
during which stirring in the recipient flask became labored due to the
gel-like nature of the borohydride complex.35 After the addition, the
mixture was stirred at −78 °C for 1 h and then slowly warmed to room
temperature, at which point stirring became facile. The solution was
then cooled to 0 °C, and hydrogen chloride (100 mL, ca. 1.0 M in
ether) was added dropwise. Over the course of the addition LiCl
precipitated and vigorous gas evolution was observed. The reaction
mixture was then stirred for an additional 30 min before being filtered
through Celite to remove lithium chloride and subsequently
concentrated in vacuo to afford crude 13 (21.4 g) as a colorless oil
which was used without further purification.
EXPERIMENTAL SECTION
■
General Considerations. The following general experimental
considerations apply for all experiments described in this paper. Unless
otherwise stated, all reactions were performed under nitrogen or argon
atmosphere using oven-dried (140 °C) and subsequently flame-dried
glassware. Reaction solvents were distilled under an inert atmosphere
1H NMR (CDCl3, 400 MHz): δ 2.25 (2H, t, J = 7.0 Hz), 1.57−1.48
(2H, m), 1.44−1.20 (21H, m), 0.88 (3H, t, J = 7.0 Hz). 13C NMR
D
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(CDCl3, 100 MHz): (carbon directly bound to boron not observed) δ
84.0, 31.3, 28.5, 28.0, 24.6, 24.5, 22.4, 19.5, 14.0. 11B NMR (CDCl3,
128 MHz): (major) δ 29.7.
diethyl ether (2 × 50 mL) followed by drying on-frit (for at least 30
min) afforded a clumpy, white solid. After transfer to a suitable
container, the solid was allowed to dry overnight under high vacuum
to afford the crude, yet now free-flowing, product. This solid was then
“dissolved” in a minimal quantity of hot anhydrous acetonitrile such
that most of the organic reagent was dissolved but residual inorganic
salts remained suspended. Hot filtration, followed by concentrating the
filtrate in vacuo, afforded 8 as a powdery white solid (11.9 g, 83% over
two steps, ≥ 85% purity as determined by 19F NMR).
(Z)-4,4,5,5-Tetramethyl-2-(oct-1-en-1-yl)-1,3,2-dioxaborolane
(14).36 In a nitrogen-filled glovebox, a 250 mL, round-bottomed flask
equipped with a large Teflon stir bar was charged with dicyclohex-
ylborane37 (19.4 g, 108.9 mmol). The flask was covered with a rubber
septum, removed from the glovebox, and connected to a Schlenk line.
Under an argon atmosphere, diethyl ether (160 mL, anhydrous) was
added via syringe. To the stirring slurry was added 13 (21.4 g, 90.7
mmol) slowly via cannula as a solution in anhydrous ether (50 mL).
The reaction was stirred for 1 h before being cooled to 0 °C. Acetic
acid (glacial, 6.7 mL, 117.8 mmol) was then added dropwise, the
solution was stirred for 20 min before ethanolamine (14.1 mL, 235.7
mmol) was added, and the mixture was allowed to warm to room
temperature. Hexanes (20 mL) was added, and the white precipitate
that formed upon addition of ethanolamine was removed by filtration
through Celite. The filtrate was concentrated in vacuo to afford a crude
residue, which was purified by flash chromatography on silica to afford
14 (15.2 g) as a colorless to pale yellow oil in 70% yield over two steps
and in accordance with spectral data previously reported.
1H NMR (DMSO-d6, 400 MHz): δ 5.58−5.46 (1H, m), 5.11−5.01
(1H, m), 1.97−1.86 (2H, m), 1.32−1.20 (8H, m), 0.90−0.78 (5H, m).
13C NMR (DMSO-d6, 100 MHz): (major) δ 133.2, 123.2, 31.3, 29.6,
28.6, 26.5, 22.1, 22.0−19.0 (br), 14.0. 11B NMR (DMSO-d6, 128
MHz): (major) δ = 4.03; 19F NMR (DMSO-d6, 376 MHz): (major) δ
−135.6 to −136.6 (m). IR (neat): νmax 3002, 2957, 2922, 2853, 1646,
1404, 1229, 1169, 1068, 963, 917, 788, 752, 670 cm−1. LRMS (ESI−):
m/z 425.2, 408.3, 278.1, 193.1, 173.1. HRMS (ESI−): m/z calcd for
C9H17BF3 [M]− 193.1380, found 193.1377.
Preparation or Arene Fragment. Methyl 3-Amino-2-hydrox-
ybenzoate (10). A 250 mL round-bottomed flask, equipped with a
magnetic stir bar, was flame-dried under vacuum and refilled with
argon. To this, degassed, wet methanol (100 mL) was transferred via
cannula or syringe. The methanol was degassed by bubbling argon or
nitrogen through the solution for a minimum of 10 min to remove
dissolved oxygen. To the stirring solvent was added 9 (2.7 g, 13.7
mmol) to afford a pale yellow solution. While an argon atmosphere
was maintained in the reaction vessel, Pd/C (10 wt %, 270 mg, of 10
wt % Pd/C − 1 wt % Pd) was added in one portion to give a black
suspension. At this time, the atmosphere was exchanged to hydrogen
(1 atm) by bubbling hydrogen gas into the solution (with a gas outlet
connected) for at least 5 min. A balloon of hydrogen gas was then used
to maintain the hydrogen atmosphere, and the reaction was allowed to
stir at room temperature for 12 h. After 12 h, the reaction was judged
complete by TLC analysis. The balloon of hydrogen was removed and
dry argon bubbled through the solution for at least 5 min. The vessel
was opened to the air, and the suspension was filtered through a fritted
glass funnel packed to about half its volume with Celite into a round-
bottomed receiving flask. The reaction vessel and filter cake were
washed with methanol to ensure complete transfer of the materials (3
× 60 mL). Care was taken to not let the filter cake dry completely. The
resultant green-yellow filtrate was concentrated in vacuo to afford a
beige solid. This solid was then dissolved in methylene chloride (120
mL), and a magnetic stir bar was added. To the stirring solution was
added activated carbon (4.0 g), and the suspension was allowed to stir
at room temperature under an air atmosphere for 5 h and then filtered
(as above) through a fritted glass funnel packed with Celite into a
preweighed round-bottomed flask. The flask and filter cake were
washed with methylene chloride (3 × 20 mL) to ensure quantitative
transfer, and the resultant yellow-orange filtrate was concentrated in
vacuo to afford 10 (2.13 g, 93%) as a peach-colored solid (after drying
under high vacuum) that was used without further purification.
3-Amino-2-hydroxybenzoic Acid, Hydrochloride Salt (11). A 250
mL round-bottomed flask, equipped with a magnetic stir bar, was
flame-dried under vacuum and refilled with nitrogen. Anhydrous THF
(120 mL) was then transferred via syringe, and solid 10 was added
under a positive-pressure of nitrogen to afford a yellow-orange
solution. To this solution was added solid KOTMS (90% purity) (5.4
g, 2.5 equiv) portionwise. Upon addition the reaction mixture turned
from yellow-orange to light green up to the addition of the first
equivalent. Addition of subsequent reagent resulted in an orange-red
solution that darkened with time and as additional KOTMS was
added. Upon complete addition of the KOTMS, the reaction was then
stirred at room temperature for 24 h before a solution of hydrogen
chloride in diethyl ether (65 mL, ca. 1.0 M, 4.25 equiv) was added via
syringe at room temperature. The heterogeneous suspension was
stirred for 48 h at room temperature and then sonicated for an
additional 2 h to ensure conversion to a homogeneous brown
suspension. The suspension was then filtered with a Buchner funnel,
and the filter cake was washed with cold Et2O (3 × 20 mL) to remove
any organic byproducts and obtain 11 (5.96 g) as a fine gray solid
1
Rf = 0.44 (10% ethyl acetate in hexanes). H NMR (CDCl3, 400
MHz): δ 6.43 (1H, dt, J = 13.5, 7.5 Hz), 5.32 (1H, dt, J = 13.5, 1.0
Hz), 2.49−2.46 (2H, m), 1.42−1.22 (20H, m), 0.88 (3H, m). 13C
NMR (CDCl3, 100 MHz): (major) δ 155.3, 120.0−116.0 (1C, br),
82.8, 32.2, 31.7, 29.4, 28.7, 24.8, 22.6, 14.1. 11B NMR (CDCl3, 128
MHz): (major) δ 29.7.
(Z)-4,4,5,5-Tetramethyl-2-(non-2-en-1-yl)-1,3,2-dioxaborolane
(15). To a 1 L, three-neck, round-bottomed flask, equipped with a
large Teflon stir bar that had previously been flame-dried under
vacuum, was added 14 (14.4 g, 60.4 mmol) followed by anhydrous
ether (400 mL). Chloroiodomethane (4.84 g, 66.5 mmol), which had
been freshly dried over 3 Å molecular sieves, was then added via
syringe. The system was cooled to −78 °C and protected from light. n-
BuLi (28.0 mL, ca. 2.34 M in hexanes, 66.5 mmol) was then slowly
added dropwise. If the addition rate is too rapid a sudden flash of
yellow color will be observed. After the addition was complete, the
reaction mixture was stirred for an additional 1 h at this temperature
before gradually being warmed to room temperature. Once at room
temperature, the reaction mixture was stirred for an additional 24 h
(LiI precipitated over the course of the addition). The reaction was
quenched by the addition of distilled water (50 mL) (to dissolve salts),
and the two phases were separated. The aqueous phase was washed
once with diethyl ether (100 mL), and the combined organic layers
were dried over anhydrous sodium sulfate, filtered by gravity, and
concentrated in vacuo to afford the crude product (10.8 g). NMR
analysis showed about 95% conversion of the starting alkenylboronate.
In addition to trace quantities of unreacted starting material, residual
butyl iodide (3.18, 1.79, 1.38, 0.91 ppm) was also present. This
mixture was characterized and used in the following step without
further purification.
1H NMR (CDCl3, 400 MHz): δ 5.52−5.32 (2H, m), 1.99 (2H, app
q, J = 7.0 Hz), 1.65 (2H, d, J = 7.5 Hz), 1.46−1.12 (20H, m), 0.86
(3H, t, J = 7.0 Hz). 13C NMR (CDCl3, 100 MHz): (major) δ 130.0,
123.9, 83.1, 31.8, 29.5, 29.0, 27.0, 24.7, 22.6, 14.1. 11B NMR (CDCl3,
128 MHz): (major) δ = 33.0. IR (thin film): νmax 2978, 2957, 2926,
2360, 2341, 1467, 1459, 1388, 1370, 1345, 1325, 1273, 1215, 1165,
1146, 1111, 968, 882, 848 cm−1. LRMS (EI): m/z 195.2 (33.9), 124.1
(13.8), 101.1 (13.7), 95.1 (11.0), 85.1 (25.2), 84.1 (100), 83.1 (32.9),
82.1 (10.5), 81.1 (17.0), 69.1 (17.5), 67.1 (22.6), 57.1 (18.0), 55.1
(20.1), 54.0 (10.2), 44.0 (10.8). HRMS (EI): m/z calcd for
C15H29BO2 [M]+ 252.2261, found 252.2261.
Potassium (Z)-2-(Non-2-en-1-yl)trifluoroborate (8). To a 250 mL
round-bottomed flask, equipped with a large Teflon stir bar, were
added crude 15 (10.8 g), methanol (50 mL), and a saturated aqueous
solution of KHF2 (18 mL, ca. 4.5 M). Almost immediately, an
exothermic reaction took place with appreciable frothing and
formation of a white solid. Stirring was permitted for 2 h after
which the flask was placed on ice for about 1 h prior to filtration.
Vacuum filtration and subsequent washing of the filter cake with cold
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(along with the KCl byproduct of the reaction) after drying under
vacuum and used without further purification.
were washed with NaCl (satd aq) (200 mL), dried over anhydrous
sodium sulfate, filtered by gravity, and concentrated in vacuo to afford
compound 7 as a colorless oil, which was used immediately without
further purification.
3-Formamido-2-hydroxybenzoic Acid (2).14 To a 50 mL round-
bottomed flask, equipped with a magnetic stir bar, under an
atmosphere of air, was added 11 (5 g, mixture of 11·KCl−ca 12.83
mmol). To the solid was added formamide (12 mL). The flask was
fitted with a reflux condenser and placed in an oil bath held at 150 °C.
The reaction was monitored as follows: at a given time, an aliquot
from the reaction mixture was diluted with methanol, filtered through
Celite, and analyzed by ESI-MS (positive-mode). After 1 h, the
reaction was stopped by removing the flask from the oil bath and
allowing it to cool to room temperature. The resultant solution was
dissolved in 6% NaHCO3 (aq) (100 mL), acidified with 1 M KHSO4
(verified by litmus paper), and extracted with ethyl acetate (3 × 100
mL). The combined extracts were washed with 50% satd NaCl (aq) (2
× 25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was then coevaporated with toluene (or benzene) to
afford 2 (2.1 g, 92%) as a fine gray solid whose spectral data were
consistent with those previously described and as an ∼4:1 mixture of
conformers (see the Supporting Information).38
To a solution of 7 (6.58 g, 35.0 mmol) in dichloromethane (98 mL)
were added 8 (10.8 g, 42 mmol), montmorillonite K10 (7 g), and
distilled water (7 mL). The slurry was then stirred at room
temperature for 10 h.40 TLC analysis showed the reaction was
complete, and the reaction mixture was filtered through a pad of
Celite. The reaction vessel was washed with additional dichloro-
methane (ca. 250 mL). This solution was concentrated in vacuo to
afford a crude oil, which was purified directly by flash chromatography
on silica (10% v/v ethyl acetate in hexanes) to afford 5 as a colorless
oil in good analytical purity contaminated only with a minor quantity
of the diastereomeric compounds as impurities (9.9 g, 90% over two
steps).41
1
Rf = 0.34 (10% ethyl acetate in hexanes). H NMR (CDCl3, 400
MHz): (major) δ 5.45 (1H, dt, J = 17.0, 10.0 Hz), 5.08−4.96 (2H, m),
3.89 (1H, qd, J = 6.0, 3.0 Hz), 3.42−3.36 (1H, ddd, J = 9.5, 3.0, 1.5
Hz), 2.43 (1H, d, J = 1.0 Hz), 2.14−1.80 (2H, m), 1.40−1.10 (11H,
m), 1.05 (3H, d, J = 6.0 Hz), 0.91−0.84 (5H, m), 0.88 (9H, s), 0.054
(3H, s), 0.048 (3H, s). 13C NMR (CDCl3, 100 MHz): (major) δ
138.4, 116.5, 77.15, 69.8, 46.9, 31.9, 31.0, 29.4, 26.7, 25.86, 22.7, 18.0,
15.2, 14.1; −4.5, −4.9. IR (thin film) νmax 3576, 3078, 2956, 2929,
2858, 2361, 1642, 1463, 1383, 1362, 1327, 1257, 1123, 1087, 1003,
965, 863, 809, 776, 678 cm−1. LRMS (ESI+) m/z 337.3, 315.3, 297.3,
183.2. HRMS (ESI+) m/z calcd for C18H38O2SiNa [MNa]+ 337.2540,
found 337.2533.
1H NMR (DMSO-d6, 400 MHz): δ (major conformer) 12.12 (1H,
br s), 9.80 (1H, s), 8.42−8.31 (2H, m), 7.53 (1H, d, J = 7.8 Hz), 6.90
(1H, t, J = 8.0 Hz). 13C NMR (DMSO-d6, 100 MHz): δ (major
conformer) 172.7, 160.8, 151.7, 127.0, 126.2, 125.0, 119.0, 113.1.
LRMS (DART+): m/z 138.1, 164.0, 182.0, 199.1. HRMS (DART+):
m/z calcd for C8H8NO4 [MH+] 182.04533, found 182.04422.
Total Synthesis of Antimycin A1b. (S)-Ethyl 2-((tert-
Butyldimethylsilyl)oxy)propanoate (16.39 To a 500 mL round-
bottomed flask equipped with a magnetic stirring bar was added
(−)-ethyl lactate (6.8 mL, 60 mmol) followed by dichloromethane
(220 mL) and imidazole (8.2 g, 120 mmol). The resultant solution
was then cooled in an ice bath, and TBSCl (11.8 g, 78 mmol) was
subsequently added portionwise with vigorous stirring. Over the
course of the addition a white precipitate formed. The ice bath was
removed, and the reaction mixture was allowed to warm to room
temperature with continuous stirring over 20 h. After this time, the
reaction was filtered (vacuum filtration) to remove the white
precipitate. The solid was washed with dichloromethane (50 mL),
and the filtrate was collected and transferred to a separatory funnel.
The organic layer was washed sequentially with 1.0 M HCl (100 mL),
NaHCO3 (satd aq, 100 mL), and NaCl (satd aq, 100 mL). The
resulting organic phase was collected, dried over anhydrous sodium
sulfate, and filtered by gravity. The filtrate was concentrated in vacuo
to afford a colorless oil, 12 (13.95 g, quant), whose spectral data
matched those previously reported.
(2S,3R,4S)-2-((tert-Butyldimethylsilyl)oxy)-4-vinyldecan-3-yl 3-
methylbutanoate (17). Compound 5 (6.34 g, 29.1 mmol) was
dissolved in anhydrous dichloromethane (100 mL). To the solution
was added dry pyridine (4.0 mL, 5 equiv) followed by DMAP (247
mg, 2.9 mmol). The solution was cooled to 0 °C, and isovaleryl
chloride (17.8 mL, 146 mmol) was added dropwise to the reaction
mixture with vigorous stirring. The flask was then allowed to warm
gradually to room temperature. After being stirred for 20 h, the
reaction, deemed complete by TLC analysis, was quenched by the
addition of NaHCO3 (satd aq, 10 mL). The phases were separated,
and the aqueous phase was extracted with additional dichloromethane
(100 mL). The combined organic extracts were washed with NaCl
(satd aq, 3 × 20 mL), dried over anhydrous sodium sulfate, filtered by
gravity, and concentrated in vacuo to afford the crude residue that was
subsequently purified by flash silica gel chromatography with a
gradient from 100% hexanes to 5% (v/v) ethyl acetate in hexanes. This
afforded the desired compound 17 as colorless oil in 91% yield (7.27
g).42
1H NMR (CDCl3, 400 MHz): δ 4.31 (1H, q, J = 6.5 Hz), 4.24−4.14
(2H, m), 1.40 (3H, d, J = 6.5 Hz), 1.28 (3H, t, J = 7.0 Hz), 0.91 (9H,
s), 0.10 (3H, s), 0.07 (3H, s). 13C NMR (CDCl3, 100 MHz): δ 174.4,
68.7, 61.0, 26.0, 21.6, 18.6, −4.7, −5.0. Optical rotation [α]27D = −21.7
1
Rf = 0.47 (5% ethyl acetate in hexanes). H NMR (CDCl3, 400
MHz): (major) δ 5.51 (1H, dt, J = 17.5, 9.5 Hz), 5.10−4.96 (2H, m),
3.89 (1H, dd, J = 8.5, 3.5 Hz), 3.96−3.86 (1H, m), 2.26−2.03 (4H,
m), 1.48−1.16 (10H, m), 1.09 (3H, d, J = 6.5 Hz), 1.01−0.94 (7H,
m), 0.86−0.83 (4H, m), 0.85 (9H, s), 0.021 (6H, s). 13C NMR
(CDCl3, 100 MHz): (major) δ 172.6, 138.5, 116.7, 78.3, 68.1, 45.6,
43.8, 31.8, 29.8, 29.3, 29.3, 26.8, 25.8, 25.8, 25.7, 22.6, 22.5, 18.0, 17.4,
14.1, −4.6, −5.0. IR (thin film): νmax 3078, 2956, 2932, 2857, 2361,
1821, 1740, 1642, 1466, 1419, 1381, 1373, 1362, 1292, 1256, 1187,
1168, 1111, 1093, 1034, 1004, 975, 947, 873, 835, 810, 775, 689, 667
cm−1. LRMS (ESI+): m/z 421.3, 399.3, 372.2, 337.2, 297.3, 267.2.
HRMS (ESI+): m/z calcd for C23H47O3Si [MH]+ 399.3289, found
399.3307.43
(2S,3R,4S)-2-Hydroxy-4-vinyldecan-3-yl 3-methylbutanoate (18).
In a 500 mL Teflon round-bottomed flask was dissolved compound 17
(7.2 g, 19.6 mmol) in anhydrous THF (100 mL). To the solution was
added dry pyridine (19.5 mL). The solution was cooled to 0 °C, and
with vigorous stirring, pyridine−hydrogen fluoride complex (8 mL, 70
wt % HF) was added dropwise. The reaction was monitored by TLC
until satisfactory conversion was achieved (ca. 10 days for 17 to 18).
At this time, saturated sodium bicarbonate solution was added
dropwise until effervescence ceased. After quenching, water (10 mL)
and ethyl acetate (100 mL) were added. The organic and aqueous
phases were separated, and the aqueous phase was extracted with
(c = 1.17, CHCl3) [lit.39 [α]20 = −32.0 (c = 1.98, CHCl3)].
D
(2S,3R,4S)-2-((tert-Butyldimethylsilyl)oxy)-4-vinyldecan-3-ol (5).
Compound 5 was prepared in two steps from 16 as described
below. To a 500 mL round-bottomed flask was added 16 (10.9, 46.7
mmol). The colorless oil was dried by coevaporation with ca. 100 mL
(2 × 50 mL) of anhydrous benzene. The flask was then evacuated and
refilled with argon three times before anhydrous CH2Cl2 was added
(250 mL) via syringe. A thermocouple was inserted into the flask
through the rubber septum to monitor the internal temperature of the
system. The flask was then cooled to −78 °C, and DIBAL-H (53 mL,
ca. 1.1 equiv, 1.0 M in CH2Cl2) was added dropwise via syringe over
approximately 2 h while maintaining an internal temperature of ∼−75
°C. After the addition was complete, the reaction mixture was stirred
for an additional 1 h at this temperature. Methanol (25 mL) was added
dropwise via syringe prior to allowing the reaction to warm to 0 °C.
Saturated potassium sodium tartrate (100 mL) was added, and the
reaction was allowed to continue warming to room temperature.
Though a gel formed initially, vigorous stirring while warming to room
temperature eventually led to the formation of two distinct phases.
The two phases were separated, and the aqueous phase was washed
with dichloromethane (2 × 100 mL). The combined organic phases
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additional ethyl acetate (100 mL). The combined organic extracts
were washed with NaCl (satd aq, 3 × 20 mL), dried over anhydrous
sodium sulfate, filtered by gravity, and concentrated in vacuo to afford
the crude residue that was purified using flash silica gel
chromatography using a gradient elution from 2% to 20% (v/v%)
ethyl acetate in hexanes. This afforded the desired compound 18 as a
colorless oil in 61% yield (3.37 g), as a single stereoisomer, after two
iterations of chromatography. In addition, 0.662 g of 18 as a mixture of
diastereomers that could be further separated and 0.235 g of
unconverted 17 that was recycled were obtained affording an overall
yield of 72.3% and 75% based on recovered starting material (brsm).
before being allowed to gradually warm to room temperature and then
quenched by the addition of water (10 mL). The organic and aqueous
phases were separated, and the aqueous phase was extracted with
dichloromethane (10 mL). The combined organic extracts were
washed with NaCl (satd aq, 1 × 10 mL), dried over anhydrous sodium
sulfate, filtered by gravity, and then concentrated in vacuo to afford
crude 20 as a slightly colored oil that was used immediately without
further purification.
To the crude aldehyde 20, dissolved in 3:1 t-BuOH/H2O such that
substrate concentration is 5.5 mM (940 mL t-BuOH; 320 mL H2O),
were added 2-methyl-2-butene (3.0 mL, 27.8 mmol), sodium
dihydrogen phosphate (1.05 g, 7.65 mmol), and sodium chlorite
(2.67 g, 23.6 mmol), sequentially and in the order described. The
reaction was then stirred at room temperature for 20 h after which the
reaction mixture was concentrated to remove as much of the tert-butyl
alcohol as possible. The aqueous layer was then extracted with ethyl
acetate (3 × 200 mL). The combined organic phases were washed
with NaCl (satd aq, 2 × 75 mL), dried over anhydrous sodium sulfate,
and filtered by gravity. Concentration in vacuo afforded the desired
carboxylic acid, 3, which was purified using flash silica gel
chromatography with a gradient elution from 2 to 10% (v/v%)
methanol in dichloromethane. This afforded analytically pure 3 as a
heavy colorless oil in 97% yield (3.89 g).
1
Rf = 0.22 (20% ethyl acetate in hexanes). H NMR (CDCl3, 400
MHz): (major) δ 5.55 (1H, dt, J = 17.0, 9.5 Hz), 5.13−5.02 (2H, m),
4.87 (1H, dd, J = 9.0, 3.5 Hz), 4.01−3.92 (1H, m), 2.29−2.06 (5H,
m), 1.54−1.06 (10H, m), 1.12 (3H, d, J = 6.5 Hz), 0.99 (6H, d, J = 6.5
Hz), 0.87 (3H, t, J = 7.0 Hz). 13C NMR (CDCl3, 100 MHz): (major)
δ 174.0, 138.0, 17.3, 79.2, 68.3, 46.0, 31.7, 30.5, 29.2, 26.5, 25.7, 25.6,
22.6, 22.5, 16.5, 14.0. IR (thin film) νmax 3464 (str, br), 3078, 2955,
2924, 2873, 2858, 1720, 1642, 1466, 1370, 995 cm−1. LRMS (ESI+)
m/z 323.2, 307.2, 165.2. HRMS (ESI+) m/z calcd for C17H33O3
[MH]+ 285.2424, found 285.2412. Optical rotation [α]27 = +4.85 (c
D
= 1.03, CHCl3).
(2S,3R)-(2S,3R,4S)-3-((3-Methylbutanoyl)oxy)-4-vinyldecan-2-yl
3-(Benzyloxy)-2-((tert-butoxycarbonyl)amino)butanoate (19).
Compounds 18 (3.13 g, 11.0 mmol) and 4 (10.2 g, 33.0 mmol)
were combined in a flask under argon. Anhydrous dichloromethane
(160 mL) was then added, and the resulting solution cooled to 0 °C.
Solid DCC (6.81 g, 33 mmol) was then added to the vigorously
stirring solution portionwise under a positive pressure of argon. After
the mixture was stirred for 1 h at this temperature, solid DMAP (403
mg, 3.30 mmol) was added in one portion, and the reaction mixture
was permitted to warm to room temperature slowly. After being stirred
for 23 h, the reaction was deemed complete by TLC and was
quenched by the addition of water (50 mL) and dichloromethane (100
mL). The organic and aqueous phases were separated, and the
aqueous phase was extracted with dichloromethane (100 mL). The
combined organic phases were washed with NaCl (satd aq, 3 × 20
mL), and the combined organic components were dried over sodium
sulfate and concentrated in vacuo to afford the crude product 19. The
crude residue was purified using flash silica gel chromatography with a
gradient elution from 5% to 40% (v/v%) ethyl acetate in hexanes. This
afforded the desired 19 as a viscous pale yellow oil in 99% yield (6.31
g) after two sequential iterations of column chromatography.
Rf = 0.54 (10% MeOH in CH2Cl2, visualized with bromocresol
green stain). H NMR (CDCl3, 400 MHz): δ 7.34−7.22 (5H, m),
1
5.36−5.26 (2H, m), 5.18−5.04 (1H, m), 4.55 (1H, d, J = 11.5 Hz),
4.44 (1H, d, J = 11.5 Hz), 4.32−4.18 (2H, m), 2.59−2.52 (1H, m),
2.24−2.04 (3H, m), 1.46 (9H, s), 1.33−1.14 (15H, m), 0.97 (6H, d, J
= 6.5 Hz), 0.85 (3H, t, J = 7.0 Hz). 13C NMR (CDCl3, 100 MHz): δ
176.1, 171.9, 170.2, 156.7, 138.0, 128.3, 127.7, 127.6, 80.4, 75.1, 73.6,
71.5, 71.3, 58.6, 47.0, 43.3, 31.5, 29.1, 28.3, 28.2, 26.9, 25.6, 22.5,
22.39, 22.38, 16.3, 15.8, 14.0. IR (thin film): νmax 3452, 3100 (br, str),
2957, 2931, 2873, 2860, 2591, 1758, 1689, 1609, 1509, 1164, 992, 736
cm−1. LRMS (ESI+): m/z 623.3, 616.3, 494.3, 360.3, 338.3, 284.3.
HRMS (ESI+): m/z calcd for C32H51NO9Na [MNa]+ 616.3456, found
616.3478. Optical rotation [α]27 = +11.6 (c = 1.0, CHCl3).
D
(R)-2-((6S,9S,10R)-6-((R)-1-Hydroxyethyl)-2,2,9,14-tetramethyl-
4,7,12-trioxo-3,8,11-trioxa-5-azapentadecan-10-yl)octanoic Acid
(21). To a 250 mL, round-bottomed, two-necked flask, equipped
with a magnetic stir bar and fitted with a reflux condenser, was added 3
(3.7 g, 6.23 mmol). Anhydrous ethanol (120 mL) was added under
argon, and the resulting solution was degassed by bubbling a stream of
argon through it for about 5 min. Under a positive pressure of argon,
Pd(OH)2 supported on activated carbon (925 mg, 20 wt % Pd) was
added to the stirred solution. The atmosphere was exchanged with
hydrogen, and the reaction was then warmed to between 45 and 50 °C
with an oil bath. After 12 h, the reaction was complete, as judged by
TLC, and the reaction vessel purged with argon while being cooled to
room temperature. The reaction mixture was filtered through a pad of
Celite and concentrated in vacuo. The resultant residue was purified
by flash silica gel chromatography with a gradient elution from 2 to
10% (v/v%) methanol in dichloromethane to afford seco-acid 21 as a
heavy beige oil (2.7 g, 85%).
1
Rf = 0.47 (20% ethyl acetate in hexanes). H NMR (CDCl3, 400
MHz): δ 7.37−7.22 (5H, m), 5.42−5.24 (2H, m), 5.16−4.98 (3H, m),
4.89 (1H, dd, J = 10.0, 2.5 Hz), 4.58 (1H, d, J = 11.5 Hz), 4.45 (1H, d,
J = 11.5 Hz), 4.22 (1H, dd, J = 10.0, 3.5 Hz), 4.20−4.10 (1H, m),
2.31−2.06 (4H, m), 1.45 (9H, s), 1.30−1.10 (13H, m), 0.98 (6H, d, J
= 6.5 Hz), 0.86 (3H, t, J = 6.5 Hz). 13C NMR (CDCl3, 100 MHz): δ
172.4, 170.2, 156.1, 138.5, 137.1, 128.2, 127.4, 127.3, 117.9, 79.7, 75.3,
75.1, 71.8, 71.1, 58.3, 45.8, 43.6, 31.7, 30.3, 29.1, 28.3, 26.4, 25.8, 22.6,
22.40, 22.36, 16.3, 14.0, 13.1. IR (thin film): νmax 3455, 3066, 3032,
2959, 2932, 2872, 2854, 2359, 2341, 1730, 1720, 1499, 1455, 1370,
1292, 1251, 1167, 1096, 989, 920, 735, 696 cm−1. LRMS (ESI+): m/z
598.4, 520.3, 476.3, 267.2. HRMS (ESI+): m/z calcd for
C33H53NO7Na [MNa]+ 598.3714, found 598.3719. Optical rotation
Rf = 0.26 (10% MeOH in CH2Cl2, visualized with bromocresol
green). 1H NMR (CDCl3, 400 MHz): δ 5.45 (1H, d, J = 9.5 Hz), 5.34
(1H, dd, J = 9.5, 3.5 Hz), 5.12 (1H, dd, J = 6.0, 4.0 Hz), 4.32−4.14
(2H, m), 2.56 (1H, dt, J = 10.0, 3.5 Hz), 2.30−2.20 (2H, m), 2.13
(1H, app nonet, J = 7.0 Hz), 1.61 (1H, br s), 1.45 (9H, s), 1.98−1.32
(16H, m), 0.99 (6H, d, J = 6.5 Hz), 0.87 (3H, t, J = 7.0 Hz). 13C NMR
(CDCl3, 100 MHz): δ 176.3, 173.2, 170.4, 156.4, 80.0, 73.5, 71.6, 67.1,
59.0, 47.2, 43.4, 31.5, 29.0, 28.6, 28.3, 26.8, 25.6, 22.5, 22.4, 22.3, 19.5,
14.3, 14.0. IR (thin film): νmax 3455, 3364 (br, str), 2960, 2930, 1737
(str), 1688 (str), 1522, 1462, 1368, 1252, 1161, 993, 880, 734 cm−1.
LRMS (DART+): m/z 521.2, 504.2, 460.2, 448.2, 404.2, 302.2, 285.2,
164.0. HRMS (DART+): m/z calcd for C25H46NO9 [MH]+ 504.3173,
[α]26 = +8.45 (c = 1.1, CHCl3).
D
(R)-2-((6S,9S,10R)-6-((R)-1-(Benzyloxy)ethyl)-2,2,9,14-tetrameth-
yl-4,7,12-trioxo-3,8,11-trioxa-5-azapentadecan-10-yl)octanoic Acid
(3). To a 50 mL round-bottomed flask under argon, equipped with a
magnetic stir bar, was added 19 (4.13, 6.95 mmol). Compound 19 was
dissolved in anhydrous dichloromethane (10 mL), and sufficient
Sudan III was added to obtain a visibly colored solution (ca. < 1 mg).
The solution was cooled to −78 °C, and a stream of ozone was
bubbled through the open solution at this temperature until the
solution became colorless. At this point, the ozone stream was stopped
and a stream of argon was blown through the solution to remove
excess ozone. The solution, now again under argon, was stirred at this
temperature while dimethyl sulfide (1.8 mL, 24.5 mmol) was added to
the solution dropwise. The mixture was stirred for an additional 1 h
found 504.3175. Optical rotation [α]29 = −3.49 (c = 0.63, CHCl3).
D
(2R,3S,6S,7R,8R)-3-((tert-Butoxycarbonyl)amino)-8-hexyl-2,6-di-
methyl-4,9-dioxo-1,5-dioxonan-7-yl 3-Methylbutanoate (22). A 100
mL, round-bottomed, two-necked flask, equipped with a magnetic stir
bar, was oven and flame-dried under vacuum prior to the addition of
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activated powdered 4 Å molecular sieves (100 mg). DMAP (46 mg,
0.376 mmol) and MNBA (32 mg, 94 μmol) were added under a
positive pressure of argon after the flask had cooled. In a vial under
argon, 21 (31.6 mg, 0.063 mmol) was dissolved in anhydrous toluene
(20 mL) and transferred to a plastic syringe. The remaining reaction
components were suspended in anhydrous toluene (10 mL) and were
stirred vigorously at room temperature. Using a syringe pump, the
solution of 21 was added dropwise over the course of 8 h to the stirred
solution of DMAP and MNBA. After the addition was complete, the
reaction was stirred for an additional 34 h before being diluted with
ethyl acetate (40 mL) and gravity filtered into a separatory funnel. The
organic phase was washed with NaHCO3 (satd aq, 25 mL), water (25
mL), and NaCl (satd aq, 25 mL). The organic phase was dried over
anhydrous sodium sulfate, filtered by gravity, and concentrated in
vacuo to afford crude 22 which was subsequently purified by flash silica
gel chromatography with a gradient from 100% hexanes to 20% (v/v
%) ethyl acetate in hexanes to afford 22 as a clear oil with some minor
impurities (18.9 mg, 62%).44
residue was then purified by flash column chromatography on silica gel
with a gradient of 40% to 60% (v/v%) ethyl acetate in hexanes to give
purified 1 (3.9 mg, 71%). In order to obtain analytically pure material,
the product was further purified by semipreparative reversed-phase
HPLC (see the Supporting Information) to afford synthetic antimycin
A1b, which was characterized fully and was found to be in good
accordance with the physical and spectral properties previously
described for the natural material.8c
Rf = 0.42 (40% ethyl acetate in hexanes). Mp = 126−127 °C (from
CDCl3). 1H NMR (CDCl3, 500 MHz): (major rotamer) δ 12.62 (1H,
s); 8.55 (1H, dd, J = 8.0, 1.5 Hz), 8.50 (1H, d, J = 1.5 Hz), 7.92 (1H,
br s), 7.24 (1H, dd, J = 8.0, 1.0 Hz), 7.07 (1H, d, J = 7.5 Hz), 6.92
(1H, t, J = 8.0 Hz), 5.73 (1H, app pentet, J = 6.5 Hz), 5.29 (1H, app t,
J = 7.5 Hz), 5.09 (1H, app t, J = 10.0 Hz), 5.02−4.94 (1H, m), 2.50
(1H, app td, J = 11.0, 3.0 Hz), 2.17−2.10 (1H, m), 2.27−2.23 (2H,
m), 1.35−1.20 (16H, m), 0.99 (6H, dd, J = 7.0, 1.0 Hz), 0.86 (3H, t, J
= 7.0 Hz). 13C NMR (CDCl3, 125 MHz): δ 172.9, 171.7, 170.1, 169.4,
158.9, 150.6, 127.5, 124.5, 120.1, 119.0, 112.5, 75.5, 74.9, 70.9, 53.7,
50.2, 43.2, 31.5, 29.0, 28.5, 27.0, 25.5, 22.5, 22.4, 17.9, 15.0, 14.0. IR
(thin film): νmax 3410, 3348 (br), 2959, 2924, 2853, 1738 (str), 1636
(str), 1609, 1583, 1374, 1285, 1249, 1207, 1167, 1119, 1018, 870, 756
cm−1. LRMS (ESI+): m/z 223.1, 265.1, 282.3, 295.2, 304.3, 549.3,
571.3. HRMS (ESI+): m/z calcd for C28H41N2O9 [MH]+ 549.2806,
Rf = 0.16 (10% ethyl acetate in hexanes). Mp = 90−91 °C (from
1
CHCl3). H NMR (CDCl3, 400 MHz): δ 5.62−5.45 (1H, m), 5.29−
5.18 (1H, m), 5.04 (1H, t, J = 9.5 Hz), 4.80−4.96 (2H, m), 2.45 (1H,
t, J = 10.0 Hz), 2.27−2.20 (2H, m), 2.12 (1H, app nonet, J = 6.5 Hz),
1.45 (9H, s), 1.34−1.15 (22H, m), 0.85 (3H, t, J = 6.5 Hz). 13C NMR
(CDCl3, 100 MHz): δ 173.1, 171.8, 170.7, 155.0, 80.5, 75.8, 74.3, 71.5,
62.3, 54.7, 50.3, 43.4, 31.6, 29.8, 29.1, 28.6, 28.4, 27.2, 25.6, 22.63,
22.58, 18.0, 14.1. IR (thin film) νmax 3354, 2959, 2929, 2872, 2857,
1738 (str), 1696 (str), 1526, 1368, 1350, 1342, 1252, 1161, 1118, 1023
cm−1. LRMS (ESI+) m/z 146.0, 183.1, 285.2, 430.2, 486.3, 508.3,
570.3. HRMS (ESI+): m/z calcd for C25H43NO8Na [MNa]+ 508.2880,
found 549.2800. Optical rotation [α]24 = +58.7 (c = 0.13, CHCl3)
D
[lit.15c [α]23 +70.4 (c = 0.21, CHCl3)].
D
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra, a comparison of synthetic and natural antimycin
A1b, and final HPLC purification conditions. This material is
available free of charge via the Internet at http://pubs.acs.org.
found 508.2891. Optical rotation [α]27 = +8.0 (c = 0.46, CHCl3).
D
Antimycin A1b: (2R,3S,6S,7R,8R)-3-(3-Formamido-2-hydroxyben-
zamido)-8-hexyl-2,6-dimethyl-4,9-dioxo-1,5-dioxonan-7-yl 3-Meth-
ylbutanoate (1). Compound 22 (5 mg, 1 μmol) was placed in a 20
mL scintillation vial equipped with a magnetic stir bar and covered by
an inverted rubber septum. The vial was purged with argon prior to
running the reaction. The residue was dissolved in anhydrous
dichloromethane (0.5 mL), and with stirring, TFA (150 μL, 1.96
μmol) was added dropwise. The reaction mixture was stirred at room
temperature and monitored by TLC. Additional dichloromethane (0.5
mL) was added after 6 h to compensate for absorption by the septum.
After 18 h, the reaction mixture was diluted with wet dichloromethane
(1 mL) and transferred to a separatory funnel. The organic phase was
washed with NaHCO3 (satd aq, 2 × 5 mL), dried over anhydrous
sodium sulfate, filtered by gravity, and concentrated in vacuo to afford
the free base of 23. This material was used immediately without
further purification.
A 5 mL microwave vial equipped with a magnetic stir bar and
stoppered with a rubber septum was flame-dried under vacuum and
refilled with nitrogen. To this, 2 (2.2 mg, 12.3 μmol) and PyBOP (6.4
mg, 12.3 μmol) were added as solids under a positive pressure of
nitrogen. Anhydrous DMF (150 μL) was added to afford a red
solution. In a separate vial the crude free-base of 23 (3.8 mg, 10.0
μmol), under an atmosphere of nitrogen, was dissolved in anhydrous
DMF (100 μL). The solution of amine was added via syringe to the
stirred solution of carboxylic acid and coupling reagent at room
temperature (total volume of DMF after combining the components
should result in a 0.05 M reaction mixture). Upon addition of the
amine, the reaction mixture turned from red to yellow. Immediately
following complete transfer of the amine, DIEA (2.2 μL, 12.3 μmol)
was added to the reaction, and the mixture was allowed to stir for 20 h
with routine monitoring of the reaction progress by TLC (50% ethyl
acetate in hexanes, CAM staining to detect product and ninhydrin
staining to detect the disappearance of amine). After 20 h, phosphate
buffer (pH 5.5, 0.1 M, 2 mL) and ethyl acetate (3 mL) were added to
quench the reaction. After the mixture was stirred for several minutes
at room temperature, the organic layer was separated and washed five
times with NH4Cl (satd aq, 2 mL), NaHCO3 (satd aq, 2 mL),
NaHCO3 (50% saturated, aq, 2 mL), and NaCl (50% satd aq, 3 × 2
mL). The combined organic layers were dried over anhydrous sodium
sulfate, filtered by gravity, and concentrated in vacuo. The crude
AUTHOR INFORMATION
Corresponding Author
*E-mail: rbatey@chem.utoronto.ca.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The National Science and Engineering Research Council
(NSERC) of Canada funded this research. J.J. was an
NSERC USRA recipient. J.J. thanks Mr. Jordan Goodreid for
assistance with characterization of (+)-1 and Dr. Farhad
Nowrouzi for both helpful discussions and providing potassium
(Z)-crotyltrifluoroborate used in early studies. We thank Dr.
Matthew Forbes for MS analysis and Mr. Dmitry Pichugin and
Dr. Timothy Burrow for NMR assistance.
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NOTE ADDED AFTER ASAP PUBLICATION
This paper was published ASAP on July 25, 2014. Figure 1 was
updated. The revised paper was reposted on July 29, 2014.
■
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(35) Stirring stopped at times. The operator should attempt to regain
stirring by swirling the flask within the cooling bath by hand
(carefully). While mechanical stirring should in principle improve the
efficiency of this step, we were unable to obtain superior results when
mechanical stirring was used.
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(38) In the 13C spectrum, the peak at 163.3 ppm was assigned as
residual formamide. To verify this, formamide was dissolved in
DMSO-d6. The reference solution displayed a single carbon resonance
at 163.3 ppm (150.8 MHz). Further evidence of residual formamide
can be seen in the 1H spectrum at 7.93−7.96 ppm and at 7.14 and 7.41
ppm.
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(40) This reaction was performed in open air without the use of
anhydrous manipulations. The reaction time was longer than the 1 h
reaction time reported (see ref 21d) as it was run overnight and to
ensure full conversion was achieved given the quantity of suspended
solids for this large-scale reaction. Smaller scale test reactions reached
full conversion in the time previously described.
(41) The diastereoselectivity for the crotylation was determined by
integration of the 1H NMR spectrum and using the methine hydrogen
bound to the hydroxyl-bearing carbon. In the case of 5, the peak at
3.37 ppm was assigned as the major diastereomer (9,8-anti-8,7-syn)
and 3.03 ppm as the minor diastereomer (9,8-syn-8,7-syn). The 8,7-
anti stereoisomers are difficult to observe, and only what is believed to
be the major diastereomer (9,8-anti-8,7-anti) at 3.21 ppm is even
discernible and only in a miniscule quantity. The relative stereo-
chemistry of the major species was assigned based on the J3 values that
were consistent with one syn and one anti coupling. Similarly, as
outlined in ref 27, the ratio was determined by the relative integrations
of the protons at 3.30 ppm (1,2-anti-2,3-syn; major) and 3.02 ppm
(1,2-syn-2,3-syn; minor), with a peak at 3.10 ppm being assigned by
analogy to the 1,2-anti-2,3-anti diastereomer.
(42) Compound 17 was characterized with contamination from the
minor diastereomers formed during the allylation step. At this point,
the compound could not be purified to a single diastereomer but was
used in the subsequent step as obtained. Upon removal of the silyl
ether the resulting product, 18, was purified to essentially a single
stereoisomer by flash chromatography.
(43) This compound was originally not detected during HRMS
analysis and could only be observed in ESI+ following a methanol wash
after the initial MS injection.
(44) This reaction was highly dependent on scale. An effort to use
the more recently described DMAPO (see ref 31h) was met with a
very modest 22% yield, even at 0.6 mmol scale (about 10× that
reported above). Conditions used were as described above, but with
the following alterations: MNBA (417 mg, 1.21 mmol) and DMAPO
(167.2 mg, 1.21 mmol), in anhydrous dichloromethane (50 mL), were
stirred at room temperature. To the stirred solution was added 21
(290 mg, 0.576 mmol) as a solution in dichloromethane (320 mL)
over the course of 18 h. The reaction was stirred an additional 10 h
prior to workup and purified as described above.
J
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