Synthesis and evaluation of novel analogues of ripostatins

Article abstract of DOI:10.1002/chem.201403176

Ripostatins are polyene macrolactones isolated from the myxobacterium Sorangium cellulosum. They exhibit antibiotic activity by inhibiting bacterial RNA polymerase (RNAP) through a binding site and mechanism that are different from those of current antibacterial drugs. Thus, the ripostatins serve as starting points for the development of new anti-infective agents with a novel mode of action. In this work, several derivatives of ripostatins were produced. 15-Desoxyripostatin A was synthesized by using a one-pot carboalumination/cross-coupling. 5,6-Dihydroripostatin A was constructed by utilizing an intramolecular Suzuki cross-coupling macrolactonization approach. 14,14-Difluororipostatin A and both epimeric 14,14-difluororipostatins B were synthesized by using a Reformatsky type aldol addition of a haloketone, Stille cross-coupling, and ring-closing metathesis. The RNAP-inhibitory and antibacterial activities are presented. Structure-activity relationships indicate that the monocyclic keto-ol form of ripostatin A is the active form of ripostatin A, that the ripostatin C5-C6 unsaturation is important for activity, and that C14 geminal difluorination of ripostatin B results in no loss of activity.

Full text of DOI:10.1002/chem.201403176

DOI: 10.1002/chem.201403176
Full Paper
&
Antibacterial Agents
Synthesis and Evaluation of Novel Analogues of Ripostatins
Wufeng Tang,[a] Shuang Liu,[b] David Degen,[b] Richard H. Ebright,*[b] and Evgeny V. Prusov*[a]
Abstract: Ripostatins are polyene macrolactones isolated
from the myxobacterium Sorangium cellulosum. They exhibit
antibiotic activity by inhibiting bacterial RNA polymerase
(RNAP) through a binding site and mechanism that are dif-
ferent from those of current antibacterial drugs. Thus, the ri-
postatins serve as starting points for the development of
new anti-infective agents with a novel mode of action. In
this work, several derivatives of ripostatins were produced.
15-Desoxyripostatin A was synthesized by using a one-pot
coupling macrolactonization approach. 14,14’-Difluororipos-
tatin A and both epimeric 14,14’-difluororipostatins B were
synthesized by using a Reformatsky type aldol addition of
a haloketone, Stille cross-coupling, and ring-closing metathe-
sis. The RNAP-inhibitory and antibacterial activities are pre-
sented. Structure–activity relationships indicate that the
monocyclic keto-ol form of ripostatin A is the active form of
ripostatin A, that the ripostatin C5–C6 unsaturation is impor-
tant for activity, and that C14 geminal difluorination of ripos-
tatin B results in no loss of activity.
carboalumination/cross-coupling.
5,6-Dihydroripostatin A
was constructed by utilizing an intramolecular Suzuki cross-
Introduction
Resistance of bacterial patho-
gens to current antibacterial
drugs is an urgent problem.[1]
Bacterial RNA polymerase (RNAP)
represents an attractive target
for the development of new an-
tibacterial agents that are effec-
tive against bacterial pathogens
resistant to current antibacterial
drugs.[2] In particular, the RNAP
“switch region SW1/SW2 sub-
region,” a structure element that
mediates opening and closing of
the RNAP active-center cleft, has
Figure 1. Natural products targeting the “switch region” of RNA polymerase.
been shown to be the binding
site for three classes of antibac-
terial natural products: riposta-
tins (Figure 1, 1, 1’, and 2), corallopyronins (Figure 1, 3), and
myxopyronins (Figure 1, 4).[2,3]
In our pursuit of new lead structures for the development of
novel antibacterial agents, we became attracted to the riposta-
tins due to their interesting biological properties and challeng-
ing molecular architecture. Consequently, we developed a con-
vergent approach to the synthesis of the ripostatin scaffold
and accomplished, concurrently with two other groups, the
total synthesis of ripostatin B.[4] We also reported the first total
synthesis of ripostatin A. With a reliable synthetic strategy in
our hands, we next aimed to generate novel analogues of ri-
postatins A and B for the elucidation of the structure–activity
relationship. In this article, we provide a detailed account of
our recent synthetic endeavors in this direction and also pro-
vide data on the RNAP-inhibitory activity and antibacterial ac-
tivity of the analogues.
[a] W. Tang, Dr. E. V. Prusov
Helmholtz-Zentrum fꢀr Infektionsforschung (HZI)
Inhoffenstrasse 7, 38124 Braunschweig (Germany)
Fax: (+49)0531-6181-9499
E-mail: evgeny.prusov@helmholtz-hzi.de
[b] S. Liu, Dr. D. Degen, Prof. Dr. R. H. Ebright
Waksman Institute of Microbiology and
Department of Chemistry and Chemical Biology, Rutgers University
190 Frelinghuysen Road, Piscataway, NJ 08854 (USA)
Fax: (+1)732-445-5735
E-mail: ebright@waksman.rutgers.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403176.
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Results and Discussion
Although the preparation of 15-desoxyripostatin A had already
been reported by us earlier,[4b] the amount of compound pro-
duced was small. Thus, additional material was needed to per-
form a detailed biological evaluation of this analogue.
Therefore, we decided to optimize key steps in the synthesis
and to streamline the overall sequence. In particular, we re-ex-
amined the one-pot carboalumination/cross-coupling reac-
tion[5] of the first triple bond (Scheme 1). Attempts to achieve
this transformation at room temperature failed, but after addi-
tional experimentation, the desired cross-coupling was found
to proceed smoothly upon heating at 508C. Encouraged by
this result, we also investigated one-pot elaboration of the
second triple bond. Gratifyingly, carboalumination of 6 under
standard conditions followed by treatment of the vinylic alumi-
num species with an excess of allylbromide in the presence of
a palladium catalyst yielded directly the desired product 7.
The one-pot functionalization of the second triple bond was
particularly beneficial, because the cross-coupling of allyltribu-
Scheme 2. Synthesis of alkene-terminated acrylate fragments. DMAP: 4-di-
methylaminopyridine; dppf: 1,1’-bis(diphenylphosphino)ferrocene; EDCI: 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide.
The extended carboxylic acid fragment was appended to
acetal 16 by a Mitsunobu esterification,[9] and the resultant
ester was then subjected to hy-
droboration/Suzuki
cross-cou-
pling[10] reaction conditions to
give macrolactone 18, albeit in
moderate yield (Scheme 3). We
also isolated some quantities of
alcohol 19 following oxidative
workup of the reaction.
The relatively low yield of the
product from the intramolecular
cross-coupling reaction prompt-
ed us to evaluate an alternative
macrolactonization-based
ap-
proach (Scheme 4).[11] No prod-
uct was observed in an attempt-
ed cross-coupling reaction with
carboxylic acid 12. An attempted
Scheme 1. Synthesis of desoxyripostatin A through one-pot carboalumination/cross-coupling. Bn: benzyl; Cp: cy-
clopentadienyl; DIAD: diisopropylazodicarboxylate; DMP: Dess–Martin periodinane; Grubbs II: [1,3-bis-(2,4,6-trime-
thylphenyl)-2-imidazolidinylidene]dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium; PPTS: pyridinium
p-toluenesulfonate; TBAF: tetra-n-butylammonium fluoride; TBS: tert-butyldimethylsilyl; TMS: trimethylsilyl.
intermolecular
cross-coupling
with methyl ester 15 gave an ex-
cellent yield of the desired prod-
tyl stannane proceeds significantly faster at the C3 iodoacrylic
ester site than at the C8 terminal vinyl iodide. With our route,
intermediate 7 was converted into the final product, 15-des-
oxyripostatin A (10), in five steps with an overall yield of 50%.
As a next possible modification, we examined the replace-
ment of the C5–C6 double bond with a saturated chain. We
proposed that this modification would not significantly affect
the conformation of the macrolactone ring. The cyclic methyl
acetal 16 from our synthesis of ripostatin A[6] was utilized here
as an advanced intermediate. Suitable alkene-terminated build-
ing blocks were prepared from the iodoacrylic acid 11
(Scheme 2). The best results were achieved by using the
Pd(Ph3P)4-catalyzed Negishi coupling[7] of 11 with an excess of
alkenyl zinc reagent.[8] The corresponding methyl ester 15 was
Scheme 3. Intramolecular Suzuki cross-coupling and synthesis of 18. 9-BBN:
prepared through a esterification/cross-coupling sequence.
9-borabicyclo[3.3.1]nonane.
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We then turned our attention
toward fluorinated derivatives of
the ripostatins. We reasoned
that the introduction of a gem-
difluoro substitution at the C14
position of ripostatin A would
stabilize the bicyclic hemiketal
form of ripostatin A relative to
the monocyclic keto-ol form of
ripostatin A (see 1 and 1’ in
Figure 1) and, simultaneously,
would prevent b-acetoxy elimi-
nation, which has been shown
to be the major route of degra-
dation of ripostatin A.[15] By fol-
Scheme 4. Attempted macrolactonization approach.
uct 20; however, the ester resist-
ed subsequent saponification
under numerous conditions.[12]
Reduction of the ester with lithi-
um aluminum hydride to form
21 was possible, but attempts to
convert 21 into the seco-acid 22
or directly into the macrolactone
Scheme 6. Completion of the synthesis of 5,6-dihydroripostatin A (25).
18 through various oxidation methods were fruitless.
Unable to accomplish the ring closure through lactone bond
formation, we next examined intramolecular Suzuki cross-cou-
pling at the iodoacrylic ester terminus. Thus, cyclic acetal 16
was coupled first with an alkenyl zinc reagent to introduce
a four-carbon chain with a terminal double bond (Scheme 5).
Esterification of 23 under Mitsunobu or Yamaguchi condi-
tions[13] yielded ester 24, which failed to provide the macrolac-
tone 18 in even moderate yield under standard conditions.
Scheme 7. Synthesis of the difluoroketone building block.
lowing our general synthetic logic, we synthesized the difluor-
oketone building block 29 by using an organolithium reagent
derived from the side-chain alkyl iodide 28[4b] with the Weinreb
amide of chlorodifluoroacetic acid (Scheme 7). Interestingly, in
the case of the Weinreb amide of bromodifluoroacetic acid,
a reversed halogen–metal exchange was observed in the reac-
tion with the organolithium reagent.
Use of the difluoroketone 29 in the Reformatsky type aldol
addition according to the Ishihara[16] protocol produced the de-
sired product 34 in relatively low yield (Scheme 8). Attempts to
optimize this reaction by varying the reaction temperature
and/or by addition of Lewis acids were unsuccessful.
We reasoned that the vinylic iodide functionality may inter-
fere with the aldol reaction by concomitant formation of a vi-
nylzinc reagent and consequent polymerization of the alde-
hyde. Therefore, we changed the order of steps in our se-
Scheme 5. Alternative intramolecular Suzuki cross-coupling approach. TCBC:
2,4,6-trichlorobenzoyl chloride.
Finally, selective cleavage of the primary TBS ether of 18
(Scheme 3), a sequence of Dess–Martin periodinane and Pin-
nick–Kraus[14] oxidations, and hydrolysis of the methyl acetal
upon purification by reversed-phase HPLC in the presence of
formic acid completed the synthesis of 5,6-dihydroripostatin A
(25; Scheme 6).
Scheme 8. Attempted aldol reaction with aldehyde 33.
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accompanied by migration of the acyl group towards the 11-
OH position and, thus, only the 11-OH ester 40 was isolated
from the reaction mixture. Cleavage of this ester under basic
conditions led to the hemiketal 38, which confirmed the inver-
sion of the absolute configuration at the C13 position. A simi-
lar sequence of steps was performed with acetic acid with the
intention to convert 39 into 38, but the overall yield was only
40%. It turned out that the 13-hydroxy group can be selective-
ly acylated by the activated anhydride of iodoacrylic acid 11 in
relatively good yield by using our modified Yamaguchi proto-
col (Scheme 10).
Subsequent transformations, including Stille cross-cou-
pling[18] and ring-closing metathesis,[19] proceeded with gener-
ally high yields. Finally, deprotection of the primary hydroxy
group followed by a double oxidation gave rise to 14,14’-di-
fluororipostatin A (45). NMR data indicate that, as expected,
this compound exists predominantly in the bicyclic hemiketal
form (as in 1 in Figure 1).
We next attempted to produce difluorinated derivatives of
ripostatin B. First, in line with the earlier work on ripostati-
n A,[15] we investigated a direct reduction of 14,14’-difluorori-
postatin A (45) with NaBH4. However, no reaction was ob-
served under standard conditions. Reasoning that the bicyclic
hemiketal form of 45 was too stable to permit reduction, we
repeated the reaction in the presence of a base, with the aim
of shifting the equilibrium between the bicyclic hemiketal and
monocyclic keto-ol forms in the direction of the monocyclic
keto-ol form to promote reduction. In the presence of a stoi-
chiometric amount of base, the two epimeric 14,14’-difluorori-
postatins B, 14,14’-difluororipostatin B1 (46) and 14,14’-difluor-
oripostatin B2 (47), were obtained by reduction (Scheme 11).
Scheme 9. Synthesis and stereochemical assignment of cyclic hemiketals by
aldol reaction with difluorochloroketone 29. CSA=10-camphorsulfonic acid.
quence and prepared the allyl-
substituted aldehyde 36 from
diol 35 through cross-coupling
and subsequent periodate cleav-
age (Scheme 9). With aldehyde
36, the aldol reaction proceeded
in excellent yield and produced
a 1:1.2 mixture of diastereomeric
adducts. Subsequent treatment
of this mixture with camphorsul-
fonic acid in MeOH in the pres-
ence of trimethyl ortoformate
Scheme 10. Completion of the synthesis of difluororipostatin A.
provided two cyclic hemiketals,
38 and 39, instead of the ex-
pected methylacetal derivatives. The hemiketals were separat-
ed by flash chromatography, and their stereochemistries were
assigned by using the Rychnovsky acetonide method by analy-
sis of the 13C NMR spectra of compounds 41 and 42.[17] In both
cases, the methyl groups and acetal carbon atom of the aceto-
nide moieties exhibited the expected characteristic shift pat-
terns (see the Experimental Section).
The apparent stability of the hemiketal form of the difluoro
derivatives 38 and 39 prompted us to proceed with the syn-
thesis without protecting these intermediates as methyl ace-
tals. Unexpectedly, inversion of the stereocenter at the C13 po-
sition in hemiketal 39 by using Mitsunobu esterification was
Scheme 11. Synthesis of difluroripostatin B and its epimer.
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The stereochemistries of 46 and 47 were tentatively assigned
based on the similarity of the NMR spectra to the NMR spec-
trum of ripostatin B, activity data, and additional information
from the X-ray crystal structure of the difluororipostatin B–
RNAP complex.[20]
form of ripostatin A (1) is inactive and that the monocyclic
form of ripostatin A (1’) is the active form of ripostatin A.
5,6-Dihydroripostatin A (25) exhibited weak but clear RNAP-
inhibitory activity (IC50 value approximately one order of mag-
nitude higher than that for ripostatin A). We infer that the C5–
C6 unsaturation is important for, but not indispensable for, the
interaction of ripostatin with RNAP. 14,14’-Difluororipostatin B1
(46) exhibited RNAP-inhibitory and antibacterial activities com-
parable to those of ripostatins A and B. The epimeric 14,14’-di-
fluororipostatin B2 (47) was significantly less potent than 46 in
both RNAP-inhibitory and antibacterial activities. The high po-
tency and high stability of 14,14’-difluororipostatin B1 (46) al-
lowed a crystal structure of the corresponding RNAP–inhibitor
complex to be determined, which represents the first crystal
structure of an RNAP–ripostatin complex.[21] The excellent bio-
chemical and biological activities of 14,14’-difluororipostatin B1
(46), which exists exclusively in a monocyclic form, support the
conclusion that the monocyclic form of ripostatin A (1’ in
Figure 1) is the active form of ripostatin A.
The RNAP-inhibitory activities and antibacterial activities
were measured as previously described[2b] and are reported in
Table 1 and Table 2, respectively. 15-Desoxyripostatin (10) and
Table 1. RNAP-inhibitory activities.
Compound
IC50 values [mM]
Escherichia Staphylococcus
Mycobacterium
tuberculosis
RNAP
coli
aureus
RNAP
RNAP
ripostatin A (1)
ripostatin B (2)
15-desoxyripostatin A
(10)
5,6-dihydroripostatin A
(25)
14,14’-difluoro-
ripostatin A (45)
14,14’-difluoro-
ripostatin B1 (46)
14,14’-difluoro-
ripostatin B2 (47)
0.026
0.018
>25
0.88
0.081
160
270
300
70
0.11
38
n.t.[a]
65
n.t.[a]
68
Conclusion
0.035
3.1
0.068
45
3000
200
The presented results demonstrate that our synthetic strategy
can be utilized to prepare structurally modified analogues of ri-
postatins A and B. Although difficulties were encountered en
route to 5,6-dihydroripostatin A, the synthesis of the geminal-
difluorinated derivatives of both ripostatin A and ripostatin B
was straightforward.
[a] n.t.: not tested.
The structure–activity relationships derived from analysis of
the RNAP-inhibitory and antibacterial activities of the resulting
analogues indicate that the bicyclic form of ripostatin A
(Figure 1, 1) is inactive and that the monocyclic form of ripos-
tatin A (Figure 1, 1’) is the active form of ripostatin A. The
structure–activity relationships further indicate that the riposta-
tin C5–C6 unsaturation is important for activity and that stabili-
ty-enhancing geminal difluorination can be introduced at the
C14 position of ripostatin B without loss of activity.
Table 2. Antibacterial activities.
Compound
MIC values [mgmLÀ1
]
Escherichia coli
D21f2tolC
Staphylococcus aureus
ATCC 12600
ripostatin A (1)
ripostatin B (2)
15-desoxyripostatin A
(10)
0.39
0.39
12.5
12.5
6.25
>50
14,14’-difluoro-
ripostatin A (45)
14,14’-difluoro-
ripostatin B1 (46)
14,14’-difluoro-
ripostatin B2 (47)
12.5
0.78
6.25
50
Future work on ripostatin-based inhibitors of RNA poly-
merase will be aimed at the development of more potent
compounds, with support from in silico screening. Efforts will
be focused on analogues of ripostatin A trapped in the mono-
cyclic state (“monocylic-trapped” analogues, including 11-OH-
methylated ripostatin A analogues) and on analogues of ripos-
tatins A and B with modifications of the ripostatin phenylalkyl
side chain. The outcomes of these studies will be reported in
due course.
12.5
>50
14,14’-difluororipostatin A (45) exhibited no or poor RNAP-in-
hibitory activity (half maximal inhibitory concentrations (IC50)
values at least approximately two orders of magnitude higher
than the IC50 value for ripostatin A) and no or poor antibacteri-
al activity (minimum inhibitory concentrations (MICs) at least
approximately an order of magnitude higher that the MIC for
ripostatin A). 15-Desoxyripostatin (10) and 14,14’-difluororipos-
tatin A (45) exist exclusively or predominantly in a bicyclic
form, in contrast to ripostatin A, which exists as an equilibrium
mixture of the bicyclic and monocyclic forms (1 and 1’ in
Figure 1). The poor biochemical and biological activities of
these “bicyclic-trapped” analogues suggests that the bicyclic
Experimental Section
General remarks
Optical rotations were determined on a Perkin–Elmer 241 instru-
ment. NMR spectra were recorded in CDCl3 and D3COD on Bruker
AM 300, AM 400, AMX 500, DMX-600, and AMX 700 spectrometers.
ESI mass spectra were obtained on a Finnigan MAT 95 spectrome-
ter; high-resolution data were acquired by using peak matching
(M/DM=10000, mass resolution according to the 10% valley defi-
nition). Analytical TLC was performed on aluminum sheets coated
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with silica gel 60 F254 (Merck), with mixtures of ethyl acetate/pe-
troleum ether (PE) as the solvent and with detection by UV absorp-
tion at 254 nm and the formation of dark blue spots upon staining
with cerium(IV)sulfate–phosphomolybdic acid in sulfuric acid fol-
lowed by charring. Unless otherwise stated, all reactions were per-
formed under an inert gas blanket. All of the solvents used were
commercial absolute solvents over molecular sieves with a water
content less than 50 ppm (for example, from Acros Organics). Ex-
perimental procedures for compounds 8, 9, 10, 20, 21, 23, 24, 27,
29, 31, 32, 36, 40, 44, and some other intermediates are provided
in the Supporting Information.
5.20 mmol) and iBuOH (48.0 mL, 0.52 mmol) at 08C. While the mix-
ture was stirred at 08C, alkyne 6 (356.9 mg, 0.86 mmol) in CH2Cl2
(3 mL) was added. The mixture was warmed to room temperature
and stirred for 1 day, at which point carboalumination was com-
plete, as determined by TLC. The solvent was removed under re-
duced pressure and replaced with THF (2 mL). In a separate flask,
allyl bromide (112 mL, 1.29 mmol) was added to solution of
Pd(PPh3)4 (60.0 mg, 0.05 mmol) in THF (3 mL). The yellow mixture
was immediately transferred to the vinylalane solution through
a canula, and the reaction was stirred at 608C. After 3 h, the reac-
tion was diluted with diethyl ether (25 mL) and quenched with 1m
HCl (25 mL). The aqueous layer was extracted with diethyl ether
(3ꢁ15 mL), and the combined organic extracts were washed with
saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude
residue was purified by flash chromatography (PE/Et2O, 30:1) to
provide 7 (237.70 mg, 0.51 mmol, 59%) as a colorless oil. Rf =0.31
tert-Butyldimethyl(((2S,4R,6R)-2-((E)-3-methyl-5-phenylpent-
3-en-1-yl)-6-(prop-2-yn-1-yl)tetrahydro-2H-pyran-4-yl)oxy)si-
lane (6)
Zirconocene dichloride (276.4 mg, 0.95 mmol) was added to
a flame-dried argon-purged 25 mL round-bottomed Schlenk flask,
followed by dropwise addition of trimethylaluminum (2.0m solu-
tion in toluene; 3.8 mL, 7.6 mmol) and iBuOH (43.6 mL, 0.47 mmol)
at 08C. While the mixture was being stirred at 08C, alkyne 5
(895.2 mg, 2.36 mmol) in CH2Cl2 (5 mL) was added. The mixture
was warmed to room temperature and stirred overnight, at which
point the carboalumination was complete, as determined by TLC.
In a separate flask, BnBr (0.34 mL, 2.86 mmol) was added to a solu-
tion of Pd(PPh3)4 (90.0 mg, 0.08 mmol) in THF (6 mL). The yellow
mixture was immediately transferred into the vinylalane solution
through a cannula, and the reaction mixture was stirred at 508C.
After 3 h, the mixture was diluted with diethyl ether (60 mL) and
quenched with 1m HCl (60 mL). The aqueous layer was extracted
with diethyl ether (3ꢁ45 mL), and the combined organic extracts
were washed with saturated aqueous NaHCO3 (40 mL) and brine
(50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo to give a yellow oil, which was engaged in the following
step.
1
(PE/Et2O, 30:1); H NMR (500 MHz, CDCl3): d=0.04 (s, 6H), 0.87 (s,
9H), 1.12–1.22 (m, 2H), 1.50–1.57 (m, 1H), 1.61 (s, 3H), 1.63–1.72
(m, 1H), 1.70 (s, 3H), 1.75–1.78 (m, 1H), 2.03–2.19 (m, 4H), 2.26–
2
3
2.30 (dd, J=13.73, J=7.17 Hz, 1H), 2.72–2.75 (m, 2H), 3.16–3.21
(m, 1H), 3.29–3.38 (m, 1H), 3.33–3.35 (d, 3J=7.32 Hz, 2H), 3.67–
3.73 (m, 1H), 4.91–4.94 (d, 3J=10.07 Hz, 1H), 4.98–5.02 (d, 3J=
17.09 Hz, 1H), 5.21 (t, 3J=7.32 Hz, 1H), 5.33 (t, 3J=7.32 Hz, 1H),
5.74–5.82 (m, 1H), 7.15–7.28 ppm (m, 5H); 13C NMR (125 MHz,
CDCl3): d=À4.5, 16.2, 16.5, 18.2, 25.9, 32.3, 34.3, 34.4, 35.6, 41.6,
41.8, 46.1, 69.2, 74.4, 75.0, 114.3, 123.2, 123.8, 125.7, 128.3, 133.4,
136.0, 137.2, 141.8 ppm; [a]D = +2.57 (c=2.61 in CH2Cl2); HRMS
(ESI): m/z calcd for C30H48O2SiNa [M+Na]+: 491.3321; found:
491.3322.
(E)-3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)hepta-2,6-dienoic
acid (12)
The crude protected alkyne was dissolved in a mixture of THF
(6 mL) and MeOH (5 mL) at 08C, and solid potassium carbonate
(654.0 mg, 4.73 mmol) was added in one portion. The suspension
was stirred at room temperature for 3.5 h. Additional K2CO3
(108.0 mg, 0.78 mmol) was added, and the mixture was stirred for
0.5 h. The precipitate was filtered off, the filter cake was washed
with diethyl ether (10 mL), and the filtrate was concentrated in
vacuo. The residue was purified by column chromatography (PE/
Et2O, 70:1) to give terminal alkyne 6 (520.9 mg, 1.26 mmol, 53%)
as a colorless oil. Rf =0.49 (PE/EtOAc, 25:1); 1H NMR (500 MHz,
CDCl3): d=0.05 (s, 6H), 0.88 (s, 9H), 1.16–1.25 (m, 2H), 1.50–1.57
(m, 1H), 1.67–1.73 (m, 1H), 1.71 (s, 3H), 1.76–1.80 (m, 1H), 1.98–
Zinc dust (1.28 g, 19.58 mmol) was added to a nitrogen-purged
flask, to which dry THF (8 mL) was then added, and the flask was
irradiated in an ultrasonic cleaning bath for 15 min. 1,2-Dibromo-
ethane (76 mL, 0.88 mmol) was then added, and the mixture was
heated to 658C for 3 min. The reaction mixture was cooled to
room temperature and chlorotrimethylsilane (111 mL, 0.88 mmol)
was added. After the mixture had been stirred for 10 min, a solution
of 4-iodobutene (3.20 g, 17.58 mmol) in THF (3 mL) was slowly
added. The reaction mixture was stirred for 20 h at 36–398C and
cooled to room temperature again. The clear and colorless solution
was immediately transferred into a flask containing a solution of
carboxylic acid 11 (1.22 mg, 3.43 mmol) and Pd(PPh3)4 (0.24 g,
0.17 mmol) in Et2O (20 mL) and DMF (10 mL) through a cannula at
08C. The mixture was then stirred at room temperature for 3 h.
The reaction mixture was diluted with diethyl ether (20 mL) and
quenched with saturated aqueous NH4Cl (60 mL). The aqueous
layer was extracted with diethyl ether (4ꢁ30 mL), and the com-
bined organic extracts were washed with brine (50 mL), dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude
residue was purified by flash chromatography (PE/EtOAc, 5:1) to
provide 12 (0.79 g, 2.78 mmol, 81%) as a yellow oil. Rf =0.30 (PE/
2
3
2.02 (m, 2H), 2.06–2.18 (m, 2H), 2.28–2.33 (ddd, J=16.63, J=7.32,
4J=2.75 Hz, 1H), 2.44–2.49 (ddd, 2J=16.63, 3J=5.80, 4J=2.75 Hz,
3
1H), 3.21–3.26 (m, 1H), 3.32–3.39 (m, 1H), 3.35 (d, J=7.17 Hz, 2H),
3.69–3.75 (m, 1H), 5.34–5.38 (m, 1H), 7.15–7.28 ppm (m, 5H);
13C NMR (125 MHz, CDCl3): d=À4.5, 16.2, 18.1, 25.9, 34.2, 34.3,
35.5, 40.8, 41.4, 68.7, 69.9, 73.8, 75.2, 80.9, 123.4, 125.7, 128.3,
128.4, 135.7, 141.8 ppm.
tert-Butyldimethyl(((2S,4R,6R)-2-((E)-3-methyl-5-phenylpent-
3-en-1-yl)-6-((E)-2-methylhexa-2,5-dien-1-yl)tetrahydro-2H-
pyran-4-yl)oxy)silane (7)
1
EtOAc, 5:1); H NMR (500 MHz, CDCl3): d=0.04 (s, 6H), 0.88 (s, 9H),
3
2.20–2.25 (m, 2H), 2.36–2.39 (t, J=6.56 Hz, 2H), 2.40–2.74 (m, 2H),
3
3
3.73–3.76 (t, J=6.56 Hz, 2H), 4.94–4.97 (d, J=10.22 Hz, 1H), 5.00–
5.05 (d, 3J=17.09 Hz, 1H), 5.70 (s, 1H), 5.79–5.87 ppm (m, 1H);
13C NMR (75 MHz, CDCl3): d=À5.3, 18.3, 25.9, 32.0, 32.6, 41.8, 61.4,
115.0, 116.9, 137.9, 163.6, 171.6 ppm; HRMS (ESI): m/z calcd for
C15H28O3SiNa [M+Na]+: 307.1705; found: 307.1706.
Zirconocene dichloride (505.0 mg, 1.73 mmol) and dichlorome-
thane (0.5 mL) were added to a flame-dried argon-purged 25 mL
round-bottomed Schlenk flask, followed by the dropwise addition
of trimethylaluminum (2.0m solution in toluene; 2.6 mL,
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Full Paper
concentrated under reduced pressure, and the residue was imme-
diately purified by flash chromatography (PE/Et2O, 10:1) to provide
ester 17 (117.6 mg, 0.16 mmol, 89%) as a colorless oil. Rf =0.24
Methyl (Z)-5-((tert-butyldimethylsilyl)oxy)-3-iodopent-2-
enoate (14)
1
MeOH (45 mL, 1.11 mmol) and DMAP (8.1 mg, 66 mmol) were added
to a solution of EDC·HCl (139.6 mg, 0.73 mmol) and acid 11
(235.8 g, 0.66 mmol) in CH2Cl2 (2 mL) at 08C. The mixture was
stirred at 08C for 0.5 h, then warmed to room temperature and
stirred for 3 h. The mixture was diluted with CH2Cl2 (2 mL) and
quenched with saturated aqueous NH4Cl (3 mL). The aqueous layer
was extracted with CH2Cl2 (3ꢁ3 mL), and the combined organic ex-
tracts were washed with brine (5 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified by
flash chromatography (PE/Et2O, 14:1) to give 14 (200.6 mg,
(PE/Et2O, 10:1); H NMR (400 MHz, CD3OD): d=0.11 (s, 6H), 0.94 (s,
9H), 1.50–1.88 (m, 5H), 1.78 (s, 3H), 1.95 (s, 3H), 2.03–2.10 (m, 3H),
2.25–2.30 (m, 2H), 2.36–2.49 (m, 4H), 2.71–2.87 (m, 2H), 3.14 (s,
3H), 3.37–3.39 (d, 3J=7.63 Hz, 2H), 3.82–3.85 (t, 3J=6.10 Hz, 2H),
4.04–4.10 (m, 1H), 4.97–5.10 (m, 3H), 5.38–5.42 (m, 1H), 5.78 (s,
1H), 5.83–5.95 (m, 1H), 6.10 (s, 1H), 7.15–7.30 ppm (m, 5H);
13C NMR (75 MHz, CD3OD): d=À5.2, 16.3, 19.1, 25.2, 26.4, 32.6,
33.8, 34.4, 35.1, 35.4, 36.1, 36.4, 42.3, 46.0, 47.9, 62.3, 65.2, 67.7,
77.4, 100.8, 115.3, 119.2, 124.6, 126.7, 129.3, 129.4, 136.9, 139.3,
142.9, 146.2, 161.5, 167.6 ppm; [a]D = +19.6 (c=2.13 in CH2Cl2);
HRMS (ESI): m/z calcd for C37H57IO5SiNa [M+Na]+: 759.2918; found:
759. 1919.
1
0.54 mmol, 82%) as a yellow oil. Rf =0.40 (PE/Et2O, 12:1); H NMR
(400 MHz, CDCl3): d=0.07 (s, 6H), 0.89 (s, 9H), 2.91–2.94 (t, 3J=
3
5.92 Hz, 2H), 3.77 (s, 3H), 3.79–3.82 (t, J=5.92 Hz, 2H), 6.43 ppm
(s, 1H); 13C NMR (100 MHz, CDCl3): d=À5.3, 18.2, 25.8, 51.0, 51.6,
61.3, 117.2, 126.4, 164.8 ppm; HRMS (ESI): m/z calcd for
C12H23IO3SiNa [M+Na]+: 393.0359; found: 393.0366.
(1R,4E,10E,13R,15S)-5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-
15-methoxy-11-methyl-15-((E)-3-methyl-5-phenylpent-3-en-
1-yl)-2,14-dioxabicyclo[11.3.1]heptadeca-4,10-dien-3-one
(18)
Methyl (E)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)hepta-2,6-
dienoate (15)
A solution of iodide 17 (24.6 mg, 33 mmol) in THF (0.6 mL) was
added to a solution of 0.5m 9-BBN (100.0 mL, 50 mmol) at 08C. The
reaction mixture was stirred for 1 h at 08C and for 2.5 h at room
temperature. The colorless mixture was diluted with THF (4 mL)
and added through a cannula to a solution of Pd(PPh3)4 (2.3 mg,
2 mmol), PPh3 (0.8 mg, 3 mmol), and 3mK3PO4 (33 mL, 99 mmol) in
THF (2 mL) in a separate flask over 1.5 h at 498C. After the mixture
had been stirred for 1.5 h, additional Pd(PPh3)4 (2.4 mg, 2 mmol)
was added, and the reaction mixture was stirred at 498C for 2 h.
The violet mixture was cooled to room temperature and treated
with ethanolamine (10 mL, 166 mmol) for 20 min. The mixture was
then quenched with hexane (6 mL), water (4 mL), and brine (2 mL).
The aqueous layer was extracted with hexane (3ꢁ5 mL), and the
combined organic extracts were washed with brine (7 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo. The crude ma-
terial was purified by flash chromatography (PE/Et2O, 5:1 with
0.1% Et3N) to provide 18 (5.2 mg, 8.5 mmol, 26%) as a colorless oil.
Zinc dust (0.62 g, 9.48 mmol) was added to a nitrogen-purged
flask, to which dry THF (5 mL) was then added, and the flask was
irradiated in an ultrasonic cleaning bath for 15 min. 1,2-Dibromo-
ethane (33 mL, 0.41 mmol) was then added, and the mixture was
heated to 658C for 3 min. The reaction mixture was cooled to
room temperature, and chlorotrimethylsilane (52 mL, 0.41 mmol)
was added. After the reaction mixture had been stirred for 10 min,
a solution of 4-iodobutene (1.50 g, 8.24 mmol) in THF (3 mL) was
slowly added. The reaction mixture was stirred overnight at 388C
and cooled to room temperature again to give a 1m solution of
the alkenyl zinc reagent. The zinc organic solution (1.5 mL,
1.5 mmol) was immediately transferred into a flask containing a so-
lution of 14 (214 mg, 0.58 mmol) and Pd(PPh3)4 (54 mg, 47 mmol)
in Et2O (3.0 mL) and DMF (1.5 mL) through a cannula at 08C, and
the reaction mixture was stirred at room temperature for 1 h. Addi-
tional Pd(dppf)Cl2 (34 mg, 47 mmol) was added. The mixture was
stirred at room temperature for 1 h and then at 508C for 50 min.
The reaction mixture was quenched with saturated aqueous NH4Cl
(5 mL). The aqueous layer was extracted with diethyl ether (2ꢁ
5 mL), and the combined organic extracts were washed with brine
(7 mL), dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The crude residue was purified by flash chromatography
(PE/Et2O, 18:1) to provide alkene 15 (97.8 mg, 0.33 mmol, 57%) as
1
Rf =0.44 (PE/Et2O, 4:1); H NMR (700 MHz, CD3OD): d=0.11 (s, 6H),
0.94 (s, 9H), 1.15–1.21 (m, 1H), 1.27–1.43 (m, 2H), 1.46–1.52 (m,
1H), 1.59–1.64 (m, 1H), 1.67 (s, 3H), 1.79 (s, 3H), 1.77–1.93 (m, 3H),
1.95–1.98 (m, 1H), 2.02–2.16 (m, 6H), 2.23–2.29 (m, 2H), 2.32–2.41
3
(m, 2H), 2.98–3.02 (m, 1H), 3.23 (s, 3H), 3.38–3.39 (d, J=7.53 Hz,
2H), 3.73–3.77 (m, 1H), 3.80–3.83 (m, 2H), 5.03–5.05 (m, 1H), 5.12–
5.14 (m, 1H), 5.40–5.43 (m, 1H), 5.77 (s, 1H), 7.15–7.30 ppm (m,
5H); 13C NMR (125 MHz, CD3OD): d=À5.2, À5.2, 16.3, 18.6, 19.1,
26.4, 28.2, 30.8, 30.8, 32.9, 33.8, 34.4, 35.1, 36.6, 43.8, 45.0, 47.9,
62.2, 66.7, 69.1, 101.5, 119.0, 124.7, 126.7, 128.4, 129.3, 129.4, 133.6,
136.8, 142.8, 158.6, 169.2 ppm; [a]D = +28.1 (c=0.80 in CH2Cl2);
HRMS (ESI): m/z calcd for C37H58O5SiNa [M+Na]+: 633.3951; found:
633. 3953.
1
a colorless oil. Rf =0.34 (PE/Et2O, 18:1); H NMR (500 MHz, CDCl3):
3
d=0.03 (s, 6H), 0.87 (s, 9H), 2.19–2.24 (m, 2H), 2.33–2.36 (td, J=
2
6.56, J=1.07 Hz, 2H), 2.69–2.72 (m, 2H), 3.67 (s, 3H), 3.71–3.74 (t,
3J=6.71 Hz, 2H), 4.94–4.97 (d, J=10.07 Hz, 1H), 5.01–5.05 (d, J=
17.09 Hz, 1H), 5.68 (s, 1H), 5.80–5.88 ppm (m, 1H); 13C NMR
(125 MHz, CDCl3): d=À5.3, 18.3, 25.9, 31.8, 32.6, 41.5, 50.9, 61.5,
114.9, 116.9, 138.0, 160.7, 166.7 ppm; HRMS (ESI): m/z calcd for
C16H30O3SiNa [M+Na]+: 321.1862; found: 321.1866.
3
3
(1R,4E,10E,13R,15S)-5-(2-Hydroxyethyl)-15-methoxy-11-
methyl-15-((E)-3-methyl-5-phenylpent-3-en-1-yl)-2,14-
dioxabicyclo[11.3.1]heptadeca-4,10-dien-3-one
(2S,4R,6R)-6-((E)-3-Iodo-2-methylallyl)-2-methoxy-2-((E)-3-
methyl-5-phenylpent-3-en-1-yl)tetrahydro-2H-pyran-4-yl-(E)-
3-(2-((tert-butyldimethylsilyl)oxy)ethyl)hepta-2,6-dienoate
(17)
20% Et3N·3HF (0.17 mL, 208 mmol) was added to a solution of silyl
ether 18 (12.6 mg, 21 mmol) in dry THF (0.35 mL) at 08C. After
being stirred for 2 days at 08C, the reaction mixture was put into
a solution of NaHCO3 (100 mg) in water (2.5 mL) and EtOAc
(2.5 mL) at 08C. The aqueous layer was washed with EtOAc (3ꢁ
2 mL). The combined organic extracts were washed with brine
(2.5 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
DIAD (77.0 mL, 0.39 mmol) was added to a solution of alcohol 16
(83.2 mg, 0.18 mmol), acid 12 (92.2 mg, 0.32 mmol), and PPh3
(102.0 mg, 0.39 mmol) in dry benzene (1.5 mL) at 08C, and the re-
action was stirred at room temperature for 2 h. The mixture was
Chem. Eur. J. 2014, 20, 1 – 11
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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The residue was purified by flash chromatography (PE/EtOAc,
(2S,4R,6R)-3,3-Difluoro-2-((E)-3-methyl-5-phenylpent-3-en-1-
yl)-6-((E)-2-methylhexa-2,5-dien-1-yl)tetrahydro-2H-pyran-
2,4-diol (38) and (2S,4S,6R)-3,3-difluoro-2-((E)-3-methyl-5-
phenylpent-3-en-1-yl)-6-((E)-2-methylhexa-2,5-dien-1-yl)te-
trahydro-2H-pyran-2,4-diol (39)
1.5:1) to give the primary alcohol (6.3 mg, 13 mmol, 60%) as a color-
1
less oil. Rf =0.20 (PE/EtOAc, 1.5:1); H NMR (700 MHz, CD3OD): d=
1.15–1.22 (m, 1H), 1.29–1.42 (m, 2H), 1.46–1.52 (m, 1H), 1.59–1.64
(m, 1H), 1.67 (s, 3H), 1.79 (s, 3H), 1.82–1.93 (m, 3H), 1.95–1.99 (m,
1H), 2.03–2.15 (m, 6H), 2.22–2.29 (m, 2H), 2.34–2.44 (m, 2H), 2.98–
3
3.02 (m, 1H), 3.23 (s, 3H), 3.38–3.39 (d, J=7.53 Hz, 2H), 3.68–3.76
A solution of CSA (215.0 mg, 0.92 mmol) in MeOH (2 mL) was
added to a solution of silyl ether 37 (760.3 mg, 1.46 mmol) in dry
MeOH (8 mL) at 08C. The reaction was stirred at this temperature
for 4.5 h, before Et3N (150 mL) was added. The mixture was then
quenched with a mixture of pH 7 buffer solution (10 mL), diethyl
ether (50 mL), and water (50 mL). The aqueous layer extracted with
Et2O (3ꢁ50 mL), and the combined organic extracts were washed
with brine (50 mL), dried over anhydrous Na2SO4, and concentrated
in vacuo. The crude material was purified by flash chromatography
(PE/Et2O, 2.5:1 to 1:1) to provide cyclic hemiketals 38 (264.3 mg,
0.65 mmol, 45%) and 39 (326.4 mg, 0.80 mmol, 55%) as a colorless
(m, 3H), 5.04–5.05 (m, 1H), 5.13–5.15 (m, 1H), 5.40–5.42 (m, 1H),
5.79 (s, 1H), 7.16–7.29 ppm (m, 5H); 13C NMR (175 MHz, CD3OD):
d=16.3, 18.5, 28.2, 30.7, 30.9, 32.8, 33.8, 34.4, 35.1, 36.6, 36.6, 43.4,
45.0, 47.8, 60.9, 66.7, 69.2, 101.6, 118.9, 124.7, 126.7, 128.4, 129.3,
129.4, 133.6, 136.8, 142.8, 158.1, 169.2 ppm; [a]D = +31.4 (c=0.44
in CH2Cl2); HRMS (ESI): m/z calcd for C31H44O5Na [M+Na]+:
519.3086; found: 519.3088.
1
oil. 38: Rf =0.40 (PE/Et2O, 2:1); H NMR (500 MHz, CDCl3): d=1.62
2-((1R,4E,10E,13R,15S)-15-Hydroxy-11-methyl-15-((E)-3-
methyl-5-phenylpent-3-en-1-yl)-3-oxo-2,14-dioxabicyclo-
[11.3.1]heptadeca-4,10-dien-5-yl)acetic acid (25)
(s, 3H), 1.76 (s, 3H), 1.80–2.00 (m, 4H), 2.10–2.14 (m, 1H), 2.18–2.24
3
(m, 1H), 2.27–2.34 (m, 2H), 2.72–2.75 (m, 2H), 3.35 (d, J=7.17 Hz,
2H), 4.11–4.15 (m, 1H), 4.22–4.27 (m, 1H), 4.93 (d, 3J=10.07 Hz,
1H), 5.00 (d, 3J=17.09 Hz, 1H), 5.24 (t, 3J=7.17 Hz, 1H), 5.43 (t,
3J=7.32 Hz, 1H), 5.73–5.81 (m, 1H), 7.15–7.29 ppm (m, 5H);
13C NMR (125 MHz, CDCl3): d=16.2, 16.4, 30.9, 31.1, 32.3, 34.3,
35.9, 44.8, 62.6, 68.5, 68.7, 68.8, 69.0, 97.8, 98.0, 98.2, 112.1, 114.1,
114.2, 114.5, 116.1, 124.1, 124.6, 125.9, 128.3, 128.5, 132.5, 136.6,
137.0, 141.4 ppm; [a]D = +22.9 (c=3.85 in CH2Cl2); HRMS (ESI): m/z
calcd for C24H32O3F2Na [M+Na]+: 429.2217; found: 429.2214. 39:
Dess–Martin periodinane (10.9 mg, 26 mmol) was added to a solu-
tion of the previous alcohol (6.0 mg, 12 mmol) in THF (0.6 mL) at
08C. The reaction mixture was stirred at room temperature for
15 min. 2,3-Dimethyl-2-butene (0.2 mL) and tert-BuOH (0.6 mL)
were then added at 08C, followed by a solution NaClO2 (4.6 mg,
51 mmol) and NaH2PO4·H2O (9.0 mg, 65 mmol) in water (0.4 mL). The
mixture was stirred at room temperature for 20 min, before satu-
rated aqueous NH4Cl (3 mL) and EtOAc (3 mL) were added. The
phases were separated and the aqueous phase was extracted with
EtOAc (3ꢁ2 mL). The combined organic layers were washed with
brine (2 mL), dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was purified by HPLC (VarioPrep 21ꢁ250 mm
Nucleodur 5m C-18 (Machery-Nagel) column; eluent A: 5% CH3CN
with 1% formic acid in H2O; eluent B: CH3CN; linear gradient 20–
1
Rf =0.16 (PE/Et2O, 2:1); H NMR (700 MHz, CDCl3): d=1.50–1.56 (m,
1H), 1.57 (s, 3H), 1.78 (s, 3H), 1.92–2.03 (m, 3H), 2.11 (dd, 2J=
3
2
3
13.77, J=5.81 Hz, 1H), 2.18–2.22 (m, 1H), 2.27 (dd, J=13.77, J=
3
7.53 Hz, 1H), 2.32–2.36 (m, 1H), 2.71 (t, J=6.67 Hz, 2H), 3.34–3.35
(d, J=7.31 Hz, 2H), 4.06–4.09 (m, 1H), 4.21–4.26 (m, 1H), 4.92 (d,
3J=10.11 Hz, 1H), 4.98 (d, 3J=16.99 Hz, 1H), 5.21–5.23 (m, 1H),
3
3
5.47 (t, J=7.31 Hz, 1H), 5.72–5.78 (m, 1H), 7.13–7.28 ppm (m, 5H);
13C NMR (125 MHz, CDCl3): d=16.0, 16.4, 29.7, 31.7, 32.3, 34.4,
37.4, 45.0, 66.3, 66.5, 66.6, 66.7, 97.5, 97.7, 97.7, 97.9, 114.5, 115.6,
117.5, 117.6, 119.6, 124.8, 125.4, 126.0, 128.3, 128.6, 132.4, 136.7,
137.0, 141.1 ppm; [a]D = +24.0 (c=4.07 in CH2Cl2); HRMS (ESI): m/z
calcd for C24H32O3F2Na [M+Na]+: 429.2217; found: 429.2215.
85%
B in 30 min, then 85–95% B in 20 min; flow rate:
10 mLminÀ1; tR =36.0 min) to give the final product 25 (3.1 mg,
6.2 mmol, 52%) as a mixture of tautomers (hemiacetal/keto form,
1:1.5) as a colorless oil. Rf =0.29 (CH2Cl2/MeOH, 11:1); HRMS (ESI):
m/z calcd for C30H40O6Na [M+Na]+: 519.2723; found: 519.2729.
(E)-1-((4R,6R)-2,2-Dimethyl-6-((E)-2-methylhexa-2,5-dien-1-
yl)-1,3-dioxan-4-yl)-1,1-difluoro-5-methyl-7-phenylhept-5-en-
2-one (41)
(2E,10R,12E)-10-((tert-Butyldimethylsilyl)oxy)-7,7-difluoro-8-
hydroxy-3,12-dimethyl-1-phenylhexadeca-2,12,15-trien-6-
one (37)
2,2-Dimethoxypropane (150 mL, 1.22 mmol) was added to a solution
of cyclic hemiketal 38 (25.4 mg, 62 mmol) in CH2Cl2 (0.7 mL), fol-
lowed by addition of CSA (4.0 mg, 17 mmol), at 08C. The reaction
was warmed to room temperature und stirred for 18 h. After Et3N
(6 mL) was added, the reaction mixture was quenched with a mix-
ture of pH 7 buffer solution (0.5 mL), CH2Cl2 (2 mL), and water
(2 mL). The aqueous layer was extracted with CH2Cl2 (2ꢁ3 mL), and
the combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. The crude material was purified by
flash chromatography (PE/Et2O, 25:1) to provide acetonide 41
(23.6 mg, 53 mmol, 85%) as a colorless oil. Rf =0.28 (PE/Et2O, 22:1);
1H NMR (500 MHz, CD3OD): d=1.31 (s, 3H), 1.39–1.46 (m, 1H), 1.41
(s, 3H), 1.58–1.61 (dt, J=12.82, J=2.59 Hz, 1H), 1.68 (s, 3H), 1.77
(s, 3H), 2.13–2.17 (m, 1H), 2.25–2.29 (m, 1H), 2.35–3.38 (t, 3J=
7.32 Hz, 2H), 2.79–2.81 (m, 2H), 2.85–2.89 (m, 2H), 3.38–3.39 (d,
3J=7.32 Hz, 2H), 4.10–4.15 (m, 1H), 4.44–4.52 (m, 1H), 4.95–4.98
(m, 1H), 5.03–5.07 (m, 1H), 5.26–5.29 (m, 1H), 5.38–5.42 (m, 1H),
5.80–5.88 (m, 1H), 7.15–7.29 ppm (m, 5H); 13C NMR (125 MHz,
Acid-washed zinc dust (230.0 mg, 3.52 mmol) and CuCl (34.8 mg,
0.35 mmol) were added to a nitrogen-purged flask, to which dry
THF (1 mL) was then added, and the flask was irradiated in an ul-
trasonic cleaning bath for 0.5 h. Solutions of ketone (243.0 mg,
0.89 mmol) in THF (1 mL) and aldehyde (299 mg, 1.06 mmol) in
THF (1 mL) were then added through a cannula. This was followed
by addition of TMSCl (10 mL, 0.08 mmol). After the mixture had
been stirred at 608C for 1 h, TMSCl (12 mL, 0.09 mmol) was added
again, and the reaction was stirred at this temperature overnight.
After completion of the reaction, the precipitate was filtered off
and the filter cake was washed with diethyl ether (20 mL). The fil-
trate was washed with brine (20 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo. The residue was purified by flash chro-
matography (PE/Et2O, 13:1) to provide 37 as a 1:1.2 mixture
(442.7 mg, 0.81 mmol, 92%) of two diasteromers as a colorless oil.
Rf =0.41 (PE/Et2O, 8:1); HRMS (ESI): m/z calcd for C30H46O3F2SiNa
[M+Na]+: 543.3082; found: 543.3084.
2
4
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CD3OD): d=16.5, 16.6, 19.8, 29.3, 30.2, 33.2, 33.2, 35.1, 38.2, 47.6,
68.2, 71.0, 71.2, 71.3, 71.5, 100.7, 114.8, 114.9, 116.8, 116.8, 118.8,
125.3, 125.8, 126.9, 129.4, 129.5, 133.7, 135.7, 138.2, 142.7, 202.0,
202.2, 202.3, 202.5 ppm; [a]D = +16.3 (c=2.19 in CH2Cl2); HRMS
(ESI): m/z calcd for C27H36O3F2Na [M+Na]+: 464.2530; found:
464.2530.
31.7, 32.3, 33.8, 34.3, 44.6, 51.3, 61.0, 63.2, 68.5, 68.7, 68.9, 69.0,
96.9, 97.1, 97.3, 111.5, 113.4, 113.6, 114.5, 115.5, 120.4, 123.9, 124.8,
125.7, 125.8, 128.3, 128.4, 132.3, 136.4, 136.9, 141.5, 162.2 ppm;
[a]D =À17.8 (c=3.15 in CH2Cl2); HRMS (ESI): m/z calcd for
C35H51O5F2ISiNa [M+Na]+: 767.2416; found: 767.2413.
2-((1R,4E,7E,10E,13R,15S)-16,16-Difluoro-15-hydroxy-11-
methyl-15-((E)-3-methyl-5-phenylpent-3-en-1-yl)-3-oxo-2,14-
dioxabicyclo[11.3.1]heptadeca-4,7,10-trien-5-yl)acetic acid
(45)
(E)-1-((4S,6R)-2,2-Dimethyl-6-((E)-2-methylhexa-2,5-dien-1-
yl)-1,3-dioxan-4-yl)-1,1-difluoro-5-methyl-7-phenylhept-5-en-
2-one (42)
Dess–Martin periodinane (123.6 mg, 291.4 mmol) was added to a so-
lution of alcohol (33.0 mg, 63.9 mmol) in THF (1.5 mL) at 08C. The
reaction mixture was stirred at room temperature for 80 min. 2,3-
Dimethyl-2-butene (0.5 mL) and tert-BuOH (1.5 mL) were added at
08C, followed by a solution NaClO2 (28.8 mg, 318.4 mmol) and
NaH2PO4·H2O (56.4 mg, 408.7 mmol) in water (1.2 mL). The mixure
was stirred at room temperature for 40 min before saturated aque-
ous NH4Cl (10 mL) and EtOAc (10 mL) were added. The phases
were separated, and the aqueous phase was extracted with EtOAc
(3ꢁ10 mL). The combined organic layers were washed with brine
(10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified by HPLC (VarioPrep 21ꢁ250 mm Nucleo-
dur 5m C-18 (Machery-Nagel) column; eluent A: 5% CH3CN with
1% formic acid in H2O; eluent B: CH3CN; linear gradient 20–85% B
in 30 min, then 85–95% B in 20 min; flow rate: 10 mLminÀ1; tR =
23.3 min) to give carboxylic acid 45 (9.4 mg, 17.7 mmol, 28%) as
2,2-Dimethoxypropane (86 mL, 700 mmol) was added to a solution
of cyclic hemiketal 39 (8.4 mg, 21 mmol) in CH2Cl2 (0.5 mL), fol-
lowed by addition of a solution of CSA (0.55 mg, 2.3 mmol) in
CH2Cl2 (0.1 mL), at 08C. The reaction was warmed to room temper-
ature and stirred for 22 h. After Et3N (5 mL) was added, the reaction
mixture was quenched with a mixture of pH 7 buffer solution
(0.5 mL), CH2Cl2 (2 mL), and water (2 mL). The aqueous layer ex-
tracted with CH2Cl2 (2ꢁ2 mL), and the combined organic extracts
were washed with brine (7 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude material was purified by flash
chromatography (PE/Et2O, 20:1) to provide acetonide 42 (4.8 mg,
11 mmol, 51%) as a colorless oil. Rf =0.48 (PE/Et2O, 9:1); 1H NMR
(700 MHz, CD3OD): d=1.28 (s, 3H), 1.30 (s, 3H), 1.64–1.69 (m, 1H),
1.67 (s, 3H), 1.77 (s, 3H), 2.05–2.09 (m, 1H), 2.18–2.20 (m, 1H),
3
2.27–2.30 (m, 1H), 2.36–2.38 (m, 2H), 2.79–2.81 (t, J=6.67 Hz, 2H),
2.87–2.89 (m, 2H), 3.38–3.39 (d, 3J=7.53 Hz, 2H), 3.98–4.02 (m,
1H), 4.31–4.37 (m, 1H), 4.96–4.98 (m, 1H), 5.03–5.06 (m, 1H), 5.26–
5.29 (m, 1H), 5.39–5.42 (m, 1H), 5.81–5.86 (m, 1H), 7.15–7.29 ppm
(m, 5H); 13C NMR (175 MHz, CD3OD): d=16.4, 16.5, 24.9, 24.9, 31.1,
33.2, 35.1, 37.9, 46.7, 66.7, 68.0, 68.2, 68.2, 68.4, 102.5, 114.8, 115.8,
117.2, 117.2, 118.7, 125.4, 125.6, 126.9, 129.4, 129.5, 134.0, 135.6,
138.2, 142.7, 202.0, 202.2, 202.2, 202.3 ppm; [a]D = +31.4 (c=0.44
in CH2Cl2); HRMS (ESI): m/z calcd for C27H36O3F2Na [M+Na]+:
464.2530; found: 464.2531.
1
a colorless oil. Rf =0.39 (CH2Cl2 /MeOH=10:1); H NMR (700 MHz,
CD3OD): d=1.56–1.61 (m, 4H), 1.73 (s, 3H), 1.76–1.84 (m, 2H),
1.88–1.92 (m, 1H), 2.19–2.27 (m, 2H), 2.34–2.37 (m, 2H), 2.51–2.58
(m, 2H), 2.63–2.68 (m, 1H), 3.13–3.20 (m, 2H), 3.34–3.35 (d, 3J=
7.53 Hz, 2H), 3.92–3.95 (dd, 3J=13.34, 3J=6.02 Hz, 1H), 4.06–4.10
(m, 1H), 4.90–4.93 (m, 1H), 5.14–5.20 (m, 2H), 5.34–5.41 (m, 2H),
5,93 (s, 1H), 7.11–7.24 ppm (m, 5H); 13C NMR (125 MHz, CD3OD):
d=16.5, 18.5, 31.3, 32.8, 33.2, 35.2, 35.3, 35.6, 43.2, 45.3, 67.1, 71.4,
71.6, 71.7, 71.9, 98.5, 98.7, 98.7, 98.9, 114.3, 116.3, 116.5, 118.4,
120.5, 124.6, 126.5, 126.9, 127.8, 129.4, 129.5, 129.9, 133.9, 137.2,
143.0, 154.2, 167.0, 173.6 ppm; [a]D =À33.7 (c=0.92 in CH2Cl2);
HRMS (ESI): m/z calcd for C30H36O6F2Na [M+Na]+: 553.2378; found:
553.2379.
(Z)-((2S,4R,6R)-3,3-Difluoro-2-hydroxy-2-((E)-3-methyl-5-phe-
nylpent-3-en-1-yl)-6-((E)-2-methylhexa-2,5-dien-1-yl)tetrahy-
dro-2H-pyran-4-yl) 5-((tert-butyldimethylsilyl)oxy)-3-iodo-
pent-2-enoate (43)
2-((3E,6E,9E,12R,14R)-14-((R,E)-1,1-Difluoro-2-hydroxy-5-
methyl-7-phenylhept-5-en-1-yl)-12-hydroxy-10-methyl-2-ox-
ooxacyclotetradeca-3,6,9-trien-4-yl)acetic acid (46) and 2-
((3E,6E,9E,12R,14R)-14-((S,E)-1,1-difluoro-2-hydroxy-5-
methyl-7-phenylhept-5-en-1-yl)-12-hydroxy-10-methyl-2-ox-
ooxacyclotetradeca-3,6,9-trien-4-yl)acetic acid (47)
NEt3 (254.0 mL, 1.82 mmol) was added to a solution of vinyl carbox-
ylic acid 11 (540.2 mg, 1.52 mmol) in toluene (5 mL), followed by
2,4,6-trichlorobenzoyl chloride (284.0 mL, 1.82 mmol), at 08C. After
the mixture had been stirred, for 2 h, a solution of alcohol 38
(228.3 mg, 0.56 mmol) and DMAP (22.5 mg, 0.18 mmol) in toluene
(2.5 mL) was added. After the reaction mixture had stirred for 1 h,
additional DMAP (22.8 mg, 0.19 mmol) was added, and the reac-
tion was stirred at 08C for 2 h. The mixture was quenched with
a solution of diethyl ether (5 mL) and 3% aqueous NaHCO3 (5 mL),
then with pH 7 buffer solution (10 mL) and diethyl ether (10 mL).
The phases were separated, and the aqueous phase was extracted
with diethyl ether (3ꢁ15 mL). The combined organic extracts were
washed with brine (25 mL), dried over anhydrous Na2SO4, and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy (PE/Et2O, 7:1 with 0.5% Et3N) to give ester 43 (313.6 mg,
A solution of 45 (6.80 mg, 13 mmol) in THF (200 mL) was added to
a suspension of NaBH4 (2.00 mg, 52 mmol) and K2CO3 (1.60 mg,
12 mmol) in EtOH (200 mL) and H2O (100 mL) at 08C. After the mix-
ture had been stirred at 08C for 4.5 h, additional NaBH4 (2.00 mg,
52 mmol) was added. The reaction was warmed to room tempera-
ture and stirred for 1 h. The mixture was diluted with water (1 mL)
and acidified with 0.1m HCl to reach pH 6. The mixture was then
extracted with EtOAc (3ꢁ3 mL). The combined organic layers were
washed with brine (2 mL), dried over anhydrous Na2SO4, and con-
centrated in vacuo. The residue was purified by HPLC (VarioPrep
21ꢁ250 mm Nucleodur 5m C-18 (Machery-Nagel) column; eluent A:
5% CH3CN with 1% formic acid in H2O; eluent B: CH3CN; 60% B in
5 min, then linear gradient 60–80% B in 35 min; flow rate:
10 mLminÀ1; tR =27.1 and 32.7 min) to give carboxylic acids 46
(1.76 mg, 3.3 mmol, 25%) and 47 (0.85 mg, 1.6 mmol, 12%) as a col-
1
0.42 mmol, 75%) as a colorless oil. Rf =0.35 (PE/Et2O, 7:1); H NMR
(500 MHz, CDCl3): d=0.05 (s, 6H), 0.86 (s, 9H), 1.61 (s, 3H), 1.75 (s,
3H), 1.80–1.97 (m, 4H), 2.08–2.33 (m, 4H), 2.71–2.78 (m, 2H), 2.88–
2.94 (m, 2H), 3.35 (d, 3J=6.87 Hz, 2H), 3.79 (t, 3J=6.10 Hz, 2H),
4.21–4.26 (m, 1H), 4.91–5.01 (m, 2H), 5.21–5.24 (m, 1H), 5.36–5.43
(m, 2H), 5.72–5.80 (m, 1H), 6.49 (s, 1H), 7.15–7.28 ppm (m, 5H);
13C NMR (125 MHz, CDCl3): d=À5.3, 16.2, 16.5, 18.2, 25.9, 31.3,
Chem. Eur. J. 2014, 20, 1 – 11
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orless oil. 47: Rf =0.33 (CH2Cl2 /MeOH, 7:1); 1H NMR (700 MHz,
CD3OD): d=1.60–1.62 (m, 1H), 1.61 (s, 3H), 1.77 (s, 3H), 1.71–1.86
(m, 2H), 2.03–2.07 (m, 2H), 2.13–2.15 (m, 2H), 2.32–2.34 (m, 1H),
2.57–2.61 (m, 1H), 2.70–2.75 (m, 2H), 3.19–3.25 (m, 2H), 3.39–3.40
(d, 3J=7.31 Hz, 2H), 3.89–3.92 (m, 1H), 3.99–4.02 (m, 1H), 4.07–
4.12 (m, 1H), 5.13–5.18 (m, 1H), 5.24–5.26 (t, 3J=7.31 Hz, 1H),
Sevostyanova, J. R. Appleman, A. X. Xiang, R. Lira, S. E. Webber, S.
Klyuyev, E. Nudler, I. Artsimovitch, D. G. Vassylyev, Nature 2009, 457,
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3
5.37–5.41 (m, 1H), 5.42–5.44 (t, J=7.31 Hz, 1H), 5.49–5.53 (m, 1H),
5,85 (s, 1H), 7.17–7.30 ppm (m, 5H); HRMS (ESI): m/z calcd for
C30H38O6F2Na [M+Na]+: 555.2534; found: 555.2536. 46: Rf =0.25
(CH2Cl2/MeOH, 7:1); 1H NMR (700 MHz, CD3OD): d=1.56 (s, 3H),
1.63–1.68 (m, 1H), 1.78–1.81 (m, 1H), 1.79 (s, 3H), 1.86–1.91 (m,
1H), 2.01–2.05 (m, 1H), 2.14–2.26 (m, 3H), 2.32–2.36 (m, 1H), 2.52–
2.54 (m, 1H), 2.61–2.65 (m, 1H), 2.65–2.69 (m, 1H), 3.18–3.28 (m,
2H), 3.38–3.43 (m, 2H), 3.82–3.86 (m, 1H), 3.94–3.97 (m, 1H), 3.99–
4.03 (m, 1H), 5.34–5.46 (m, 5H), 5.77 (s, 1H), 7.16–7.29 ppm (m,
5H); 13C NMR (125 MHz, CD3OD): d=16.2, 16.8, 28.6, 32.1, 34.4,
35.1, 35.6, 36.4, 49.5, 50.9, 65.3, 68.7, 68.9, 69.0, 69.1, 69.8, 69.9,
70.1, 119.7, 121.8, 123.3, 124.7, 125.2, 126.4, 126.8, 129.3, 129.4,
130.7, 135.6, 136.5, 142.9, 158.0, 165.5, 190.7 ppm; HRMS (ESI): m/z
calcd for C30H38O6F2Na [M+Na]+: 555.2534; found: 555.2537.
Acknowledgements
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[12] The complete list of conditions tested is provided in the Supporting In-
formation.
We thank Prof. Dr. M. Kalesse for many insightful discussions
and much valuable advice. We are also indebted to C. Ko-
koshke for performing some special NMR measurements. Fi-
nancial support of this work from the Deutsche Forschungsge-
meinschaft (grant no. PR1328/1-1 to E.V.P.) and from the NIH
(grant no. GM 041376 to R.H.E.) is gratefully acknowledged.
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Keywords: antibacterial agents
products polymerase inhibitors
relationships
·
antibiotics
·
natural
·
·
structure–activity
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[20] The confirmation of the stereochemistry of compounds 46 and 47 by
using Mosher ester analysis is currently under way.
[21] Y. Feng, W. Tang, E. V. Prusov, R. H. Ebright, manuscript in preparation.
Received: April 20, 2014
Published online on && &&, 0000
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FULL PAPER
&
Antibacterial Agents
W. Tang, S. Liu, D. Degen, R. H. Ebright,*
E. V. Prusov*
&& – &&
Synthesis and Evaluation of Novel
Analogues of Ripostatins
F makes the difference: The introduc-
tion of a gem-difluorine substitution
into the antibiotic ripostatin B produced
an analogue with full activity and in-
creased stability (see structures; IC50:
half maximal inhibitory concentration).
The synthesis features the application of
a double Stille cross-coupling/ring-clos-
ing metathesis strategy. Several other ri-
postatin analogues also were prepared
and evaluated.
Chem. Eur. J. 2014, 20, 1 – 11
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11
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ