Synthesis of Benzothiophene-Containing 10- and 11-Membered Cyclic Phostones

Article abstract of DOI:10.1002/ejoc.201600333

Phosphinate and phosphonate derivatives can serve as useful transition-state analogues of proteases, as substrate mimics of DNA/RNA-processing enzymes, and as inhibitors of enzymes catalyzing the biosynthesis of isoprenoids. Synthetic methodologies for the preparation of medium-sized ring phosphonate-containing compounds (also known as phostones are currently limited to a few examples. A synthetic protocol was developed that is amenable to the parallel synthesis of structurally diverse phostones containing a benzo[b]thiophene core, which enables the profiling of such novel compounds in biological screens of potential therapeutic targets.

Full text of DOI:10.1002/ejoc.201600333

DOI: 10.1002/ejoc.201600333
Full Paper
Macrocyclic Phostones
Synthesis of Benzothiophene-Containing 10- and 11-Membered
Cyclic Phostones
Alexios N. Matralis[a] and Youla S. Tsantrizos*[a,b]
Abstract: Phosphinate and phosphonate derivatives can serve currently limited to a few examples. A synthetic protocol was
as useful transition-state analogues of proteases, as substrate
mimics of DNA/RNA-processing enzymes, and as inhibitors of
enzymes catalyzing the biosynthesis of isoprenoids. Synthetic
methodologies for the preparation of medium-sized ring phos-
phonate-containing compounds (also known as phostones) are
developed that is amenable to the parallel synthesis of structur-
ally diverse phostones containing a benzo[b]thiophene core,
which enables the profiling of such novel compounds in biolog-
ical screens of potential therapeutic targets.
Introduction
Phosphorus-containing ligands have been used as molecular
probes for mechanistic investigations of enzymatic reactions
and as key pharmacophores in the development of human
therapeutics. In particular, phosphinate and phosphonate deriv-
atives have been explored as transition-state analogues and in-
hibitors of therapeutically relevant protease enzymes. Examples
include the antihypertension drug fosinoprilat (1, a potent in-
hibitor of the zinc-metallopeptidase angiotensin-converting en-
zyme; ACE)[1] and preclinical anti-inflammatory agent 2 (an in-
hibitor of the human mast cell chymase).[2] Six-membered ring
phosphinates (known as oxaphosphinanes or phostines) and
phosphonates (known as phostones) have also been previously
explored in drug discovery as bioisosteres of the furanose or
pyranose ring, in which the anomeric carbon atom is replaced
by the phosphinate or phosphonate moiety. Examples of this
type include C-glycoside mimics that block glioma stem cell
proliferation (e.g., compound 3)[3] and conformationally rigidi-
fied nucleotides that are potentially useful in antisense technol-
ogies (e.g., phostone-based dinucleotide 4).[4] Six-membered
ring phostones have also been explored as prodrugs of antiviral
nucleosides, such as cidofovir (5),[5] and dioxaphosphinane 2-
oxide 6 has been identified as an inhibitor of γ-secretase,[6] an
important target associated with the progression of Alzheimer's
disease.
pound 7 (a hapten for raising catalytic antibodies)[7] and anti-
proliferation and migration agent 8 (an inhibitor of focal adhe-
sion kinase; FAK)[8] are two examples of reported macrocyclic
phostones. As part of our program aimed at synthesizing bioac-
tive phosphorus-containing heterocyclic compounds, herein we
describe the synthesis of 10- and 11-membered macrocyclic
phostones 9–11 having a benzo[b]thiophene core structure.
The synthetic protocols developed are amenable to the parallel
synthesis of structurally diverse analogues with general struc-
ture I or II that may be of interest in biological screening. These
molecules are not flat (they possess a plane of asymmetry), a
factor that has been proposed to play an important role in im-
proving clinical success of exploratory therapeutics.[9]
However, far less attention has been devoted to the synthesis
and biological evaluation of large ring systems of phostines,
phostones, and phosphates. Recently, novel macrocyclic phos-
phates and phosphoramidates, with structural similarities to
macrolide polyketides, were reported.[32] Macrocyclic com-
[a] Department of Chemistry, McGill University,
801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada
E-mail: youla.tsantrizos@mcgill.ca
[b] Department of Biochemistry, McGill University,
3649 Promenade Sir William Osler, Montreal, QC, H3G 0B1, Canada
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600333.
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Results and Discussion
Previously, we reported on synthetic methodologies for the
preparation of thieno[2,3-d]pyrimidine-based bisphosphon-
ate[10] and monosphosphonate (ThP-MPs)[11] libraries of com-
pounds with the ability to inhibit isoprenoid biosynthesis. In
parallel, we also investigated the synthesis and biological prop-
erties of other phosphorus-containing heterocyclic compounds,
including pyridopyrimidine-based bisphosphonates as inhibi-
tors of HIV-1 reverse transcriptase.[12] In this repost, we focus
on the synthesis of benzo[b]thiophene-containing macrocyclic
phostones of general structures I and II (the latter will be re-
ferred to as the reversed analogues). As examples, the synthetic
route leading to the preparation of 10-membered ring pho-
stones 9 and 10 and 11-membered ring analogue 11 is de-
scribed.
Scheme 1. Literature examples of benzo[b]thiophene synthesis (SPhos = 2-
dicyclohexylphosphino-2′,6′-dimethoxybiphenyl).
hyde (15), which was first converted into tert-butyl thioether 16
through SNAr displacement of the fluoride with the thiol under
basic conditions (Scheme 2). The aldehyde moiety was then
extended to the gem-dibromovinyl moiety under Ramirez ole-
Testament to the value of the benzo[b]thiophene core in fination conditions,[19] and the thiol was deprotected with p-
drug discovery, as well as materials chemistry, numerous syn- toluenesulfonic acid (TsOH)·H2O under slightly modified condi-
thetic protocols have been reported for the construction of this tions to those previously described[18,20] (Scheme 2). The S-vin-
heterocycle in just the last decade.[13–17] Many of these method- ylation/Suzuki–Miyaura coupled reactions (in the presence of
ologies stem from the initial [3+2] cycloaddition reported by tolylboronic acid)[18] proceeded smoothly to give 18 in 65 %
Malte and Castro (Scheme 1, a).[14] The formation of the thio- yield. Intermediate 18 was selectively converted into the corre-
phene ring from benzenethiol 12 is presumed to proceed sponding 3-carbaldehyde with dichloromethyl methyl ether in
through intermediate acetylide 13a. Various acetylides have the presence of silver trifluoromethanesulfonate, and the 3-
been independently synthesized and cyclized in the presence carbaldehyde was subsequently reduced with NaBH4 to give
of various catalysts, including elemental iodine; intermediates intermediate alcohol 19 in excellent yield.[21] This intermediate
13b (Scheme 1, b)[15] and 13c (Scheme 1, c)[16] represent a few was then treated with allyltributylstannane under Stille cou-
key examples leading to structurally diverse 2,3-disubtituted pling conditions optimal for aryl chlorides[22] to form olefinic
benzo[b]thiophene cores.[17]
intermediate 20. Reaction of the free hydroxy moiety of 20 with
benzyl allylphosphonochloridate under basic conditions pro-
vided desired precursor diene 21 with nearly quantitative con-
version (based on recovered compound 20) but modest yield
(50 %); the low yield is likely due to the chemical instability of
the benzyl allylphosphonochloridate reagent, which needs to
be prepared and used immediately without purification.
In our approach (Scheme 2), orthogonal functionalization at
C3 and C4 of the benzo[b]thiophene core was required to allow
construction of the desired P-containing macrocyclic ring. We
employed the Pd-catalyzed tandem S-vinylation/Suzuki–Miya-
ura coupled reactions reported by Lautens and co-workers[18]
to convert gem-dibromovinyl benzenethiol 17 into required 4-
chlorobenzo[b]thiophene ring 18. The synthesis of 17 was initi-
A number of previous reports have described the synthesis
ated from commercially available 2-chloro-6-fluorobenzalde- of six-membered ring phostines[23] and phostones[24] through
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Scheme 2. Synthesis of 10-membered ring phostones 9 (DCM = dichloromethane, dba = dibenzylideneacetone).
ring-closing metathesis (RCM) catalyzed by Grubbs first-genera- in ethyl acetate or a solvent mixture of pyridine/methanol re-
tion catalyst 23. However, a limited number of phosphorus-con- sulted in recovery of mainly the starting material or a mixture
taining larger ring systems have been prepared successfully by of 9a/b and 22, respectively. Optimization of this protocol and
RCM. The few reported examples include the conformationally replacement of the benzylic ester will be investigated in the
restricted cyclic phosphates of dinucleotides;[25] in these exam- future and before the synthesis of a compound library (assum-
ples, catalyst 23 did not work and more reactive second-gener- ing our biological screening leads to hits for interesting biologi-
ation Grubbs catalyst 24 was required for successful cyclization cal targets).
in modest yields (47–60 %).[25,26] Similarly, Snieckus and co-
workers observed that RCM of a similar indole-based diene re-
quired 30 mol-% of catalyst 23 to produce the strained 10-
membered ring macrocycle between C3 and C4 of the indole
scaffold in reasonable yields.[27] We were pleased to see that
RCM cyclization of diene 21, using 15 mol-% of catalyst 23, led
to the formation of compound 9a in 70 % yield (Scheme 2).
At the onset of this project, we examined the suitability of
various commonly used protecting groups for phosphonates.
The most commonly used protecting group is the ethyl ester,
which is typically removed with TMSBr, followed by methanoly-
The synthesis of reversed phostones 10 and 11 was initiated
sis of the intermediate trimethylsilyl esters. However, given the from common intermediate 20 (Schemes 2 and 3). Conversion
high strain of this particular 10-membered ring phostone and of the hydroxy moiety into bromide 25 was easily achieved
the likelihood that the bromide anion could attack the Cα atom with PBr3, and this compound was treated with dibenzyl phos-
of the endocyclic P–O–CH2– bond (i.e., the benzylic position), phite in the presence of NaH to give dibenzyl ester 26a, which
we opted to make phosphonate benzyl ester 21, fully aware was subsequently hydrolyzed to monoester 26b by using LiBr
that the deprotection could also be problematic. Not surpris- (Scheme 3). Alkylation of the free hydroxy moiety with an alk-
ingly, Pd-catalyzed (10 % Pd/C) hydrogenation of intermediate enyl bromide under basic conditions provided acyclic dienes 27
9a in methanol under atmospheric pressure at room tempera- and 28, which were cyclized by RCM with the use of 15 mol-%
ture led to the formation of acyclic compound 22 in nearly of catalyst 23 in good yields. Interestingly, whereas diene 27
quantitative yield. Decreasing the amount of the Pd catalyst to cyclized to cis 10-membered ring phostone 29, diene 28
5 % provided desired compound 9b in modest yield, with an formed a mixture of cis/trans 11-membered ring macrocycles
almost equivalent amount of 22 (40 and 45 % yields of 9b and 30 in a 2:1 ratio. The structural identities of compounds 30a
1
22, respectively). However, the use of the same catalyst loading and 30b were confirmed by 1D and 2D H NMR spectroscopy.
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Scheme 3. Synthesis of reversed macrocyclic phostones 10 and 11. DCE = 1,2-dichloroethane.
Although the olefinic H3/H4 protons appeared as multiplets (J reduction of an allyl ether by Marsh and Carbery.[29] In situ for-
coupling could not be easily assigned to a cis or trans double mation of o-nitrobenzenesulfonylhydrizide (NBSH), followed by
bond), the NOESY NMR spectrum of compound 30a indicated reduction of the alkene with diimine provided intermediate 31,
characteristic strong NOEs between H1–H2 and H1–H5, as well which was deprotected to give phostone 10 in good yield by
as between H3–H4 and H3–H5′ (Figure 1). In contrast, the NOESY using standard hydrogenation condition (Figure 1).
NMR spectrum of compound 30b revealed strong NOEs only
between H1–H3 and H4–H6, consistent with the trans geometry
of the double bond (Figure 1).
Conclusions
Phosphinate and phosphonate compounds are of significant in-
terest to medicinal chemists as transition-state analogues of
protease enzymes and as mimics of natural phosphate/pyro-
phosphate substrates. As part of our ongoing interest in bioac-
tive heterocyclic compounds containing phosphorus, we devel-
oped a synthetic route for the preparation of benzo[b]thio-
phene-based, macrocyclic phosphonate ligands with general
structures I and II. Our synthetic strategy is amenable to the
parallel synthesis of analogues with significant structural diver-
sity. For example, a variety of boronic acids or boronate esters
can be introduced in the conversion of intermediate 17 into 18
Figure 1. Characteristic NOE differences observed in the NOESY NMR spectra
for 11-membered ring phostones 30a versus 30b.
On the basis of literature precedence of Pd-catalyzed depro- (Scheme 2) to allow the preparation of a library of analogues
tection of allyl ethers,[28] it was not totally surprising that at- with structural diversity at C2 of the benzo[b]thiophene core.
tempts to remove the benzyl group of compound 29 by Pd- Similarly, the allyltributylstannane reagent can be replaced with
catalyzed hydrogenation led to acyclic side product 32 in nearly longer and/or branched alkene stannanes to provide structural
quantitative yield (Scheme 3). In contrast, deprotection of 11- diversity on the macrocyclic linker (i.e., vary both the sing size
membered ring analogues 30a and 30b under exactly the same and the R4 substituent of general structures I and II). Addition-
conditions afforded the same product, which was desired phos- ally, one can easily imagine replacing the 2-chloro-6-fluoro-
tone 11 in 83 % yield. We were able to overcome the Pd-medi- benzaldehyde starting material (i.e., compound 15) with com-
ated rind opening of 29 by reducing the allyl double bond mercially available and synthetically equivalent building blocks
in a two-step, one-pot reaction, as previously reported for the (>300 analogues are commercially available or reported in the
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(400 MHz, CDCl3): δ = 1.32 (s, 9 H), 7.26 (t, J = 8.3 Hz, 1 H), 7.42 (dd,
J = 8.1, 1.1 Hz, 1 H), 7.48 (s, 1 H), 7.50 (dd, J = 7.7, 1.1 Hz, 1 H) ppm.
literature) to achieve large structural diversity on the core.
Therefore, a permutation library can lead to a very large num-
ber of final compounds of general structures I and II. It should
be mentioned that as a result of the strained ring system, which
prevents flipping of the phosphorus-containing linker from one
side of the aromatic plane to the other, analogues 9–11 are
expected to form as mixtures of atropisomers. Efforts towards
the optimization of our synthetic scheme, crystallization of the
final compounds, and synthesis of enantiomerically enriched
analogues are currently in progress. To the best of our knowl-
edge, such P-containing macrocyclic compounds have not been
previously reported and, consequently, their potential value in
drug discovery is currently unexplored.
Step 2: The above dibromide (2.15 g, 5.6 mmol), TsOH·H2O (1.10 g,
5.8 mmol), and toluene (10 mL) were added to a flask adopted with
a Dean–Stark apparatus, and the air was removed from the system
under high vacuum. Argon was added, and the mixture was heated
at reflux (110 °C) under an atmosphere of Ar overnight. [Note: if the
mixture was not degassed, a significant amount of disulfide was
formed as a side product.] The mixture was cooled to room temper-
ature, diluted with Et2O (20 mL), and water (5 mL) was added. The
biphasic mixture was stirred for 5 min (removal of TsOH·H2O), and
the organic phase was separated. Then, a 5 % aqueous solution of
NaOH (50 mL) was added to the organic phase and stirring was
continued for another 10 min (extraction of the sodium salt of the
desired product). The aqueous layer was acidified with 1
N HCl to
pH 4–5, and the product was extracted with Et2O (75 mL). The
organic phase was washed with brine, dried with MgSO4, filtered,
and concentrated to afford thiol 17 as a light yellow oil (1.29 g,
70 % yield). The product was kept under an atmosphere of Ar at
–20 °C. 1H NMR (400 MHz, CDCl3): δ = 3.59 (s, 1 H), 7.14 (t, J =
7.8 Hz, 1 H), 7.21 (d, J = 6.9 Hz, 1 H), 7.25 (d, J = 6.8 Hz, 1 H), 7.31
(s, 1 H) ppm.
Experimental Section
General Methods: All compounds were purified by normal-phase
flash column chromatography on silica gel by using a CombiFlash
instrument and the solvent gradient indicated. The homogeneity of
all final compounds was confirmed to ≥95 % by reverse-phase
HPLC. HPLC analysis was performed by using a Waters ALLIANCE
instrument (e2695 with 2489 UV detector and 3100 mass spectrom-
eter). Final compounds were fully characterized by 1H NMR,
13C NMR, and 31P NMR spectroscopy and HRMS. Chemical shifts (δ)
are reported in ppm relative to the internal deuterated solvent (1H,
13C) or external H3PO4 (δ = 0.00 ppm, 31P), unless indicated other-
wise. High-resolution mass spectra of the final products were re-
corded by using electrospray ionization (ESI+/–) and a Fourier-trans-
form ion cyclotron resonance mass analyzer (FTMS).
4-Chloro-2-(p-tolyl)benzo[b]thiophene (18): gem-Dibromide in-
termediate 17 (0.69 g, 2.1 mmol), 4-methylboronic acid (0.49 g,
3.6 mmol), potassium phosphate (1.36 g, 6.4 mmol), and triethylam-
ine (0.65 g, 6.4 mmol) were dissolved in dry dioxane (25 mL) in a
pressure vessel, and the mixture was degassed with Ar for 15 min.
Then, PdCl2 (11 mg, 0.064 mmol) and SPhos (26 mg, 0.064 mmol)
were added, and the mixture was degassed for another 30 min. The
mixture was then stirred at room temperature for 15 min and at
110 °C for 18 h. The mixture was cooled to room temperature, and
the solids were removed by filtration and washed with EtOAc
(15 mL). The filtrate was concentrated and purified by column chro-
matography (silica gel, hexane) to give desired compound 18 as a
Method (homogeneity analysis using a Waters Atlantis T3 C18
5 μm column): Solvent A: H2O, 0.1 % formic acid; solvent B: CH3CN,
0.1 % formic acid; mobile phase: linear gradient from 95 % A and
5 % B to 0 % A and 100 % B in 13 min.
1
white solid (0.35 g, 65 % yield). H NMR (400 MHz, CDCl3): δ = 2.40
(s, 3 H), 7.20–7.28 (m, 3 H), 7.34 (dd, J = 7.7, 0.6 Hz, 1 H), 7.63 (d,
J = 8.1 Hz, 2 H), 7.66 (s, 1 H), 7.70 (d, J = 8.0 Hz, 1 H) ppm.
2-(tert-Butylthio)-6-chlorobenzaldehyde (16): To a flame-dried
flask, NaH (60 % in mineral oil, 0.25 g, 10.4 mmol) was added in dry
DMF (10 mL). The flask was purged with Ar, and a solution of tert-
butylthiol (0.86 g, 9.5 mmol) in DMF (5 mL) was added dropwise at
0 °C. The mixture was allowed to stir at the same temperature for
2 h and then a solution of 2-chloro-6-fluoro-benzaldehyde (15;
1.51 g, 9.5 mmol) in DMF (5 mL) was added dropwise. The mixture
was stirred at room temperature overnight. The mixture was diluted
with diethyl ether (80 mL), and the organic phase was washed with
10 % aq. HCl (40 mL), water (40 mL), satd. NaHCO3 (40 mL), water
(40 mL), and brine (40 mL); dried with MgSO4; filtered; and concen-
trated. The crude material was purified by column chromatography
(silica gel, 100 % hexanes to 1 % Et2O in hexanes) to afford the
[4-Chloro-2-(p-tolyl)benzo[b]thiophen-3-yl]methanol (19)
Step 1: To an oven-dried flask containing intermediate 18 (0.70 g,
2.7 mmol) and AgOTf (2.1 g, 8.1 mmol) in dry CH2Cl2 (25 mL), a
solution of dichloromethyl methyl ether (0.93 g, 8.1 mmol) in dry
CH2Cl2 (5 mL) was added dropwise at –78 °C under an atmosphere
of Ar (color changed from deep yellow to deep green). The solution
was stirred at –78 °C for 30 min and then at 0 °C for 1 h (color
changed from deep green to black). The reaction was quenched
with the addition of CH2Cl2 (10 mL) and saturated NaHCO3 solution
(20 mL), and the biphasic mixture was stirred at room temperature
for 30 min. The organic phase was separated, the aqueous phase
was washed with EtOAc (2 × 30 mL), and the combined organic
layer was washed with brine (30 mL), dried with anhydrous MgSO4,
filtered, and concentrated under vacuum. The mixture was purified
by column chromatography (silica gel, 100 % hexane to 20 % EtOAc
in hexane), and the desired aldehyde intermediate was isolated as
a white solid (0.71 g, 91 % yield). 1H NMR (500 MHz, CDCl3): δ =
2.45 (s, 3 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.36 (t, J = 7.9 Hz, 1 H), 7.50–
7.54 (m, 3 H), 7.79 (dd, J = 8.0, 1.0 Hz, 1 H), 10.78 (s, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 21.4, 120.8, 125.6, 127.3, 128.5, 129.1,
129.4, 130.2, 130.8, 135.5, 140.0, 140.5, 154.3 ppm. HRMS (ESI+):
calcd. for C16H11ClOS 287.0297 [M + H]+; found 287.0294.
1
desired compound as a yellow oil, yield = 92 %. H NMR (400 MHz,
CDCl3): δ = 1.30 (s, 9 H), 7.39–7.43 (m, 1 H), 7.48 (dd, J = 8.3, 1.0 Hz,
1 H), 7.53 (dd, J = 7.5, 1.3 Hz, 1 H), 10.66 (s, 1 H) ppm.
3-Chloro-2-(2,2-dibromovinyl)benzenethiol (17)
Step 1: Aldehyde 16 (1.76 g, 7.7 mmol) and carbon tetrabromide
(3.81 g, 11.5 mmol) were dissolved in dichloromethane (50 mL) and
cooled to 0 °C under an Ar atmosphere. A solution of triphenylphos-
phine (6.03 g, 23.0 mmol) in dichloromethane (25 mL) was added
dropwise over 1 h. The mixture was warmed to room temperature
and stirred for 1 h. The solvent was distilled, and the residue was
purified by column chromatography (silica gel, 100 % hexanes to
1 % Et2O in hexanes) to afford tert-butyl[3-chloro-2-(2,2-dibromo-
vinyl)phenyl]sulfane as a colorless oil (2.34 g, 80 % yield). 1H NMR
Step 2: To an oven-dried flask containing the above aldehyde
(0.71 g, 2.5 mmol), MeOH/THF (3:1, 64 mL) was added, and the
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solution was cooled to 0 °C. Then, NaBH4 (0.19 g, 4.9 mmol) was
added, and the mixture was stirred at 0 °C for 30 min. The mixture
was quenched with saturated NH4Cl (50 mL) and extracted with
EtOAc (3 × 50 mL). The combined organic layer was washed with
brine (50 mL), dried with anhydrous MgSO4, filtered, and concen-
trated under vacuum. The residue was purified by column chroma-
tography (silica gel, 100 % hexane to 5 % EtOAc in hexane) to give
desired alcohol intermediate 19 as a white solid (0.64 g, 90 % yield).
1H NMR (500 MHz, CDCl3): δ = 2.46 (s, 3 H), 4.99 (s, 2 H), 7.27–7.33
(m, 3 H), 7.44 (dd, J = 7.7, 0.9 Hz, 1 H), 7.56 (d, J = 8.1 Hz, 2 H), 7.78
(dd, J = 8.0, 0.9 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
21.3, 57.1, 121.3, 124.7, 126.4, 127.8, 129.5, 130.0, 130.3, 130.4, 135.9,
139.0, 141.4, 146.0 ppm. HRMS (ESI+): calcd. for C16H13ClNaOS
311.0268 [M + Na]+; found 311.0266.
5.86 (m, 1 H), 7.31–7.40 (m, 5 H), 8.90 (br. s, 1 H, OH) ppm. 31P NMR
(202 MHz, CDCl3): δ = 30.71 ppm.
Step 3: Benzyl hydrogen allylphosphonate (0.32 g, 1.5 mmol) was
put into a well-dried flask and dissolved in anhydrous CH2Cl2
(15 mL). The solution was cooled to 0 °C under an atmosphere of
Ar, and a small amount of dry DMF (ca. 2 drops) was added followed
by the dropwise addition of oxalyl chloride (0.38 g, 3.0 mmol). The
mixture was then stirred at 0 °C for 1 h and then at room tempera-
ture overnight. The progress of the reaction was monitored by
31P NMR spectroscopy [31P NMR (202 MHz, CDCl3): δ = 30.71 ppm
for the acid and 40.0 ppm for the chloride]. The solvent and the
excess amount of oxalyl chloride were distilled under vacuum, and
the residue was dried for 1 h and then used in the subsequent
reaction without purification (although the yield was assumed to
be quantitative, this reagent is highly unstable). 31P NMR (202 MHz,
CDCl3): δ = 40.00 ppm.
[4-Allyl-2-(p-tolyl)benzo[b]thiophen-3-yl]methanol (20): To an
oven-dried flask, intermediate 19, Pd2(dba)3 (51 mg, 0.06 mmol),
and CsF (1.02 g, 6.7 mmol, dried under high vacuum at 100 °C for
4 h) were added; air was removed under high vacuum, and the
flask was purged with Ar. The ligand P(tBu)3 (0.13 g, 0.6 mmol), dry
degassed dioxane (30 mL), and allyltributyltin (0.92 g, 2.8 mmol)
were added under an atmosphere of Ar, and the mixture was then
stirred at reflux for 48 h. The solvent was distilled off, and the resi-
due was purified by chromatography (K2CO3/silica gel, 1:9 w/w;
100 % hexane to 5 % EtOAc in hexane). Desired compound 20 was
isolated as a white solid (0.51 g, 78 % yield). 1H NMR (500 MHz,
CDCl3): δ = 1.74 (br. s, 1 H), 2.46 (s, 3 H), 4.08 (d, J = 5.5 Hz, 2 H),
4.84 (s, 2 H), 4.93 (dq, J = 17.2, 1.8 Hz, 1 H), 5.15 (dq, J = 10.2, 1.7 Hz,
1 H), 6.23 (m, 1 H), 7.26 (d, J = 6.7 Hz, 1 H), 7.30–7.34 (m, 3 H), 7.51
(d, J = 8.1 Hz, 2 H), 7.76 (dd, J = 7.9, 1.0 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 21.3, 37.3, 57.7, 116.0, 120.6, 124.3, 127.3,
129.4, 129.9, 130.7, 131.1, 135.2, 137.7, 138.3, 138.6, 140.1,
144.8 ppm. HRMS (ESI+): calcd. for C19H18NaOS 317.0971 [M + Na]+;
found 317.0970.
[4-Allyl-2-(p-tolyl)benzo[b]thiophen-3-yl]methyl Benzyl Allyl-
phosphonate (21): Intermediate 20 (0.15 g, 0.5 mmol) was dis-
solved in anhydrous Et2O (15 mL) and dry triethylamine (0.15 g,
1.5 mmol) was added. The mixture was first cooled to 0 °C and
then a solution of freshly prepared benzyl allylphosphonochloridate
(0.35 g, 1.5 mmol) in anhydrous Et2O (25 mL) was added dropwise.
The mixture was subsequently stirred at room temperature for 48 h.
The solvent was evaporated, and the residue was purified by flash
column chromatography (100 % hexane to 33 % EtOAc in hexane).
Desired product 21 was isolated as a colorless semisolid (0.12 g,
1
50 % yield). H NMR (500 MHz, CDCl3): δ = 2.42 (s, 3 H, CH3), 2.62
(dd, J = 21.9, 7.4 Hz, 2 H), 3.95 (d, J = 5.3 Hz, 2 H), 4.89 (dd, J =
17.2, 1.8 Hz, 1 H), 4.96 (dd, J = 11.8, 8.1 Hz, 1 H), 5.06–5.22 (m, 5 H),
5.31 (dd, J = 11.5, 4.7 Hz, 1 H), 5.71–5.81 (m, 1 H), 6.09–6.17 (m, 1
H), 7.24–7.28 (m, 4 H), 7.31–7.34 (m, 5 H), 7.47 (d, J = 8.0 Hz, 2 H),
7.75 (d, J = 7.9 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.3,
32.1 (d), 37.2, 60.4, 67.8, 116.1, 120.2, 120.6, 124.4, 126.0, 127.0,
127.4, 127.9 (2 C), 128.3, 128.5 (2 C), 129.4 (2 C), 130.0 (2 C), 130.4,
135.2, 136.4, 137.6, 138.0, 138.9, 139.8, 147.0 ppm. 31P NMR
(202 MHz, CDCl3): δ = 27.37 ppm. HRMS (ESI+): calcd. for
C29H29NaO3PS [M + Na+]+ 511.1467; found 511.1472.
Synthesis of the Linker Benzyl Allylphosphonochloridate
Step 1:[30] To a stirred solution of dibenzyl phosphite (1.0 g,
3.8 mmol) in dry Et2O (20 mL), a solution of nBuLi (2.5
M in hexanes,
4.2 mmol) was added dropwise at –78 °C. The mixture was stirred
at –78 °C for 1 h and allyl bromide (1.15 g, 9.5 mmol) was added
dropwise. The mixture was stirred at room temperature for 5 h, then
cooled to 0 °C and quenched with H2O (40 mL). The organic layer
was separated, washed with H2O (20 mL) and brine (20 mL), dried
with anhydrous MgSO4, filtered, and concentrated under vacuum.
The residue was purified by chromatography (silica gel, 100 % hex-
ane to 70 % EtOAc in hexane). The dibenzyl allylphosphonate was
isolated as a slightly yellow liquid (0.86 g, 75 % yield). 1H NMR
(500 MHz, CDCl3): δ = 2.65 (dd, J = 22.1, 7.4 Hz, 2 H), 5.05 (ddd, J =
36.4, 11.9, 8.5 Hz, 4 H), 5.16–5.21 (m, 2 H), 5.74–5.84 (m, 1 H), 7.28–
7.39 (m, 10 H) ppm. 31P NMR (202 MHz, CDCl3): δ = 28.12 ppm.
(Z)-10-(Benzyloxy)-1-(p-tolyl)-6,9,10,12-tetrahydro-11-oxa-2-
thia-10-phosphacyclodeca[cd]indene 10-Oxide (9a): Intermedi-
ate 21 (82 mg, 0.17 mmol) was placed in an oven-dried flask, a
magnetic stirrer was added, and air was removed under high vac-
uum. Then, the flask was purged with Ar and catalyst 23 (21 mg,
0.025 mmol) was added to the flask under an atmosphere of Ar,
followed by dry and degassed dichloromethane (67 mL, to bring
the concentration of the solution to 2.5 mM). The mixture was
stirred at 40 °C for 2 h under an atmosphere of Ar and then at room
temperature for 1 h with the flask opened to air. The solvent was
evaporated to dryness, and the residue was purified by flash col-
umn chromatography (silica gel, 100 % hexane to 33 % EtOAc in
hexane). Desired macrocyclic phostone 9a was isolated as a white
solid (54 mg, 70 % yield). 1H NMR (500 MHz, [D6]DMSO): δ = 2.41
(s, 3 H, CH3), 2.64–2.71 (m, 1 H), 3.42–3.58 (m, 1 H), 4.48–4.58 (m, 1
H), 4.81 (dd, J = 25.3, 11.1 Hz, 1 H), 5.00 (dd, J = 11.7, 8.2 Hz, 1 H),
5.07–5.11 (m, 1 H), 5.36–5.44 (m, 1 H), 5.59–5.60 (m, 1 H), 5.73–5.81
Step 2:[31] LiBr (0.32 g, 3.6 mmol) was dissolved in dry acetonitrile
(9 mL) and a solution of dibenzyl allylphosphonate (0.55 g,
1.8 mmol) in dry acetonitrile (3 mL) was added dropwise at room
temperature. The mixture was heated at reflux for 18 h under an
atmosphere of Ar. The white solid precipitate was filtered, washed
with a small amount of cold acetonitrile, dried under high vacuum
for 1 h, transferred into a flask, dissolved in 5 % aq. HCl solution (m, 2 H), 7.35–7.42 (m, 10 H), 7.48 (m, 1 H), 7.90 (d, J = 6.6 Hz, 1 H)
(7 mL), and stirred for 10 min. The aqueous phase was extracted
with EtOAc (3 × 10 mL), and the organic phase was dried with anhy-
ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 21.3, 24.1 (d), 32.5, 60.8,
66.3, 118.0, 118.9, 121.3, 125.3, 127.1, 128.0, 128.6, 128.8, 129.0,
drous MgSO4, filtered, and concentrated under high vacuum to give 129.2, 129.9, 130.1, 130.5, 134.7, 134.8, 136.1, 136.8, 139.3, 139.7,
benzyl hydrogen allylphosphonate as a slight yellow semisolid 145.5 ppm. 31P NMR (202 MHz, [D6]DMSO): δ = 25.80 ppm. MS (ESI):
(0.32 g, 75 % yield). 1H NMR (500 MHz, CDCl3): δ = 2.65 (dd, J =
m/z = 461.2 [M + H]+. HRMS (ESI+): calcd. for C27H25NaO3PS [M +
22.5, 7.3 Hz, 2 H), 5.07 (d, J = 8.0 Hz, 2 H), 5.21–5.27 (m, 2 H), 5.76– Na]+ 483.1154; found 483.1157.
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Full Paper
10-Hydroxy-1-(p-tolyl)-6,7,8,9,10,12-hexahydro-11-oxa-2-thia-
Benzyl Hydrogen {[4-Allyl-2-(p-tolyl)benzo[b]thiophen-3-yl]-
10-phosphacyclodeca[cd]indene 10-Oxide (9b): Hydrogenation methyl}phosphonate (26b): LiBr (34 mg, 0.4 mmol) was dissolved
of intermediate 9a (23 mg, 0.05 mmol) was performed by using H2
at atmospheric pressure in dry MeOH (7 mL) and catalyzed by Pd/
C (5 % w/w, 0.0042 mmol). The mixture was stirred at room temper-
ature for 5 h, then filtered through Celite, washed with MeOH
(10 mL), and concentrated to dryness. The crude product was puri-
in dry acetonitrile (3 mL) and a solution of dibenzyl phosphonate
26a (0.11 g, 0.2 mmol) in dry acetonitrile (2 mL) was added drop-
wise at room temperature. Then, the mixture was heated at reflux
overnight under an atmosphere of Ar. The mixture was concen-
trated under vacuum, and the residue was washed with cold hex-
fied by C18 reverse-phase HPLC by using a solvent gradient from ane (5 mL), dried under high vacuum for 1 h, then dissolved in 5 %
5 % CH3CN in H2O (containing 0.6 % formic acid) to 100 % 5 %
CH3CN (also containing 0.6 % formic acid). After lyophilization of
the aqueous solvent, desired product 9b was isolated as a white
aq. HCl solution (10 mL), and stirred for 10 min. The aqueous phase
was extracted with EtOAc (3 × 10 mL), and the organic phase was
dried with anhydrous MgSO4, filtered, and concentrated under high
solid (7.5 mg, 40 % yield), along with side product 22 (8.4 mg, 45 % vacuum to give desired compound 26b as a yellow oil (85 mg, 97 %
1
1
yield). Data for 9b: H NMR (500 MHz, [D6]DMSO, 90 °C): δ = 1.10– yield). H NMR (500 MHz, CDCl3): δ = 2.37 (s, 3 H, CH3), 3.59 (d, J =
1.25 (m, 1 H), 1.65–1.73 (m, 3 H), 1.80–1.88 (m, 4 H), 2.38 (s, 3 H),
5.09 (s, 2 H), 7.20 (d, J = 7.1 Hz, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.31
(d, J = 7.7 Hz, 2 H), 7.44 (d, J = 7.9 Hz, 2 H), 7.75 (d, J = 7.9 Hz, 1 H)
ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 20.7, 21.2, 21.7, 29.8, 30.5,
21.6 Hz, 2 H), 3.95 (s, 2 H), 4.55 (d, J = 7.0 Hz, 2 H), 4.79 (d, J =
17.2 Hz, 1 H), 5.05 (d, J = 10.2 Hz, 1 H), 6.02 (ddt, J = 15.9, 10.5,
5.5 Hz, 1 H), 7.07 (d, J = 6.1 Hz, 2 H), 7.11–7.13 (m, 3 H), 7.20 (t, J =
7.6 Hz, 1 H), 7.28–7.31 (m, 5 H), 7.60 (d, J = 7.9 Hz, 1 H), 9.98 (br. s,
60.2, 120.7, 124.9, 127.5, 128.2, 130.0 (C1′ and 2 C2′ of the tolyl 1 H, OH) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.3, 27.2 (d), 38.0,
substituent are overlapping), 130.8, 136.8, 138.9, 139.6, 139.7,
144.2 ppm. 31P NMR (202 MHz, [D6]DMSO): δ = 19.00 ppm. HRMS
(ESI–): calcd. for C20H20O3PS 371.0876 [M – H+]–; found 371.0878.
Data for {4-[3-methyl-2-(p-tolyl)benzo[b]thiophen-4-yl]butyl}-
phosphonic acid (22): 1H NMR (500 MHz, MeOD): δ = 1.66–1.72 (m,
2 H), 1.78–1.79 (m, 4 H), 2.42 (s, 3 H), 2.60 (s, 3 H), 3.18 (t, J = 6.6 Hz,
2 H), 7.17–7.23 (m, 2 H), 7.30 (d, J = 7.9 Hz, 2 H), 7.38 (d, J = 8.0 Hz,
2 H), 7.65 (d, J = 7.5 Hz, 1 H) ppm. 31P NMR (202 MHz, MeOD): δ =
26.17 ppm. HRMS (ESI–): calcd. for C20H22O3PS [M – H+]– 373.1033;
found 373.1032.
66.2, 116.1, 120.7, 121.2, 124.0, 127.5, 127.8, 128.1, 128.3, 129.1,
130.2, 131.3, 135.4, 136.0, 137.5, 138.0, 138.1, 139.9, 142.5 ppm. 31P
NMR (202 MHz, CDCl3): δ = 29.33 ppm. HRMS (ESI–): calcd. for
C
26H24O3PS [M – H+]– 447.1189; found 447.1194.
Allyl Benzyl {[4-Allyl-2-(p-tolyl)benzo[b]thiophen-3-yl]methyl}-
phosphonate (27): In a high-pressure vessel, intermediate 26b
(96 mg, 0.2 mmol), allyl bromide (51 mg, 0.4 mmol), and CsCO3
(0.4 mmol) were dissolved in dry acetonitrile (5 mL), and the mix-
ture was heated at 80–90 °C for 2.5–3 h. The solid was filtered, and
the filtrate was purified by flash column chromatography (silica gel,
100 % hexane to 30 % EtOAc in hexanes) to obtain 27 as a yellow
4-Allyl-3-(bromomethyl)-2-(p-tolyl)benzo[b]thiophene (25): To a
solution of [4-allyl-2-(p-tolyl)benzo[b]thiophen-3-yl]methanol (20;
0.29 g, 1 mmol) in dry dichloroethane (5 mL), a solution of PBr3
(0.41 g, 1.5 mmol) in dichloroethane (2 mL) was added dropwise at
0 °C and under an atmosphere of Ar. When the addition was com-
pleted, the mixture was stirred at room temperature overnight.
CH2Cl2 (10 mL) was added, the mixture was washed with water
(5 mL), and the organic phase was dried (MgSO4), filtered, and con-
centrated to afford the desired compound as a yellow oil, which
was used directly in the next step because of its instability.
1
thick oil (78 mg, 75 %). H NMR (500 MHz, CDCl3): δ = 2.42 (s, 3 H,
CH3), 3.76 (d, J = 21.3 Hz, 2 H), 4.02–4.07 (m, 2 H), 4.10–4.15 (m, 1
H), 4.20–4.26 (m, 1 H), 4.67 (dd, J = 11.8, 8.3 Hz, 1 H), 4.82–4.85 (m,
2 H), 5.06–5.11 (m, 3 H), 5.66 (ddd, J = 15.7, 10.9, 5.6 Hz, 1 H), 6.10
(ddd, J = 22.7, 10.6, 5.5 Hz, 1 H), 7.11 (dd, J = 6.4, 2.8 Hz, 2 H), 7.18
(d, J = 7.2 Hz, 1 H), 7.24 (d, J = 7.9 Hz, 2 H), 7.27–7.29 (m, 4 H), 7.44
(d, J = 8.0 Hz, 2 H), 7.73 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 21.3, 27.4 (d), 38.1, 66.3, 67.2, 116.2, 117.7, 120.7, 121.4,
124.2, 127.6, 127.7, 128.1, 128.4, 129.3, 130.2, 131.4, 132.8, 135.4,
136.3, 137.7, 138.0, 138.1, 139.9, 142.1 ppm. 31P NMR (202 MHz,
CDCl3): δ = 26.32 ppm. HRMS (ESI+): calcd. for C29H30O3PS [M +
H+]+ 489.1648; found 489.1641.
Dibenzyl {[4-Allyl-2-(p-tolyl)benzo[b]thiophen-3-yl]methyl}-
phosphonate (26a): To a suspension of NaH (60 % mineral oil,
14 mg, 0.6 mmol) in dry THF (3 mL), a solution of dibenzyl phos-
phite (0.14 g, 0.5 mmol) in THF (1 mL) was added dropwise at room
temperature. The mixture was then stirred at room temperature for
2.75 h and at 60 °C for 15 min. After cooling the mixture to room
temperature, a solution of intermediate 25 (0.11 g, 0.3 mmol) in
THF (3 mL) was added dropwise, and the mixture was stirred over-
night. THF was distilled off, EtOAc (25 mL) was added, and the or-
ganic phase was washed with brine (2 × 10 mL), dried with anhy-
drous MgSO4, filtered, and concentrated under vacuum. The residue
was purified by flash column chromatography (silica gel, 100 % hex-
ane to 33 % EtOAc in hexane) to afford dibenzyl phosphonate 26a
Benzyl But-3-en-1-yl {[4-Allyl-2-(p-tolyl)benzo[b]thiophen-3-
yl]methyl}phosphonate (28): Intermediate 28 was prepared by
following the same protocol as that for the synthesis of 27 above,
with the exception that 4-bromo-1-butene (85 mg, 0.6 mmol) was
used to install the olefin moiety on the phosphonate. The com-
pound was isolated as a yellow thick oil (75 mg, 70 % yield). 1H
NMR (500 MHz, CDCl3): δ = 2.11–2.20 (m, 2 H), 2.42 (s, 3 H), 3.61–
3.67 (m, 1 H), 3.71–3.77 (m, 3 H), 4.05 (s, 2 H), 4.64 (dd, J = 11.8,
8.4 Hz, 1 H), 4.81–4.87 (m, 2 H), 4.93–4.98 (m, 2 H), 5.09–5.12 (m, 1
H), 5.54 (ddt, J = 17.1, 10.4, 6.7 Hz, 1 H), 6.10 (ddd, J = 22.7, 10.6,
5.5 Hz, 1 H), 7.11 (dd, J = 6.4, 3.1 Hz, 2 H), 7.18 (d, J = 7.0 Hz, 1 H),
7.24 (d, J = 7.8 Hz, 2 H), 7.27–7.29 (m, 4 H), 7.46 (d, J = 8.0 Hz, 2 H),
7.73 (dd, J = 7.9, 0.9 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
21.3, 27.3 (d), 34.6, 38.1, 64.9, 67.3, 116.2, 117.3, 120.7, 121.5, 121.6,
124.1, 127.6, 128.1, 128.4, 129.3, 130.1, 131.5, 133.4, 135.4, 136.29,
136.34, 137.7, 138.0, 138.1, 139.9, 141.9 ppm. 31P NMR (202 MHz,
CDCl3): δ = 26.01 ppm. HRMS (ESI+): calcd. for C30H31O3NaPS
525.1624 [M + Na+]+; found 525.1621.
1
as a yellow oil (0.11 g, 73 % yield). H NMR (500 MHz, CDCl3): δ =
2.42 (s, 3 H, CH3), 3.77 (d, J = 21.2 Hz, 2 H), 4.04 (d, J = 5.3 Hz, 2 H),
4.64 (dd, J = 11.8, 8.6 Hz, 2 H), 4.73–4.78 (m, 2 H), 4.81 (dd, J = 17.2,
1.7 Hz, 1 H), 5.04–5.10 (m, 1 H), 6.07 (ddd, J = 22.7, 10.6, 5.5 Hz, 1
H), 7.06–7.07 (m, 4 H), 7.16 (d, J = 7.2 Hz, 1 H), 7.20 (d, J = 7.9 Hz,
2 H), 7.25–7.30 (m, 7 H), 7.40 (d, J = 7.9 Hz, 2 H), 7.73 (d, J = 7.9 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.3, 27.5 (d), 38.1, 65.2,
67.3, 116.2, 120.7, 121.4, 121.5, 124.2, 127.0, 127.5, 127.6, 127.8,
128.2, 128.4, 128.5, 129.3, 130.2, 131.4, 135.5, 136.2, 137.7, 138.0,
138.1, 139.9, 141.2, 142.1, 142.2 ppm. 31P NMR (202 MHz, CDCl3):
δ = 26.45 ppm. HRMS (ESI+): calcd. C33H32O3PS [M + H]+ 539.1804;
found 539.1805.
(Z)-11-(Benzyloxy)-1-(p-tolyl)-6,9,11,12-tetrahydro-10-oxa-2-
thia-11-phosphacyclodeca[cd]indene 11-Oxide (29): Into an
oven-dried flask, intermediate 27 (54 mg, 0.13 mmol) and a mag-
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Full Paper
netic stirrer were added, and air was removed under high vacuum.
The flask was purged with Ar and catalyst 23 (14 mg, 0.02 mmol)
was added to the flask under an atmosphere of Ar followed by dry
and degassed dichloromethane (53 mL) to bring the concentration
ca. 0.034 mmol) and Pd/C (10 % w/w, 0.0034 mmol) were added to
a flask, followed by dry MeOH (5 mL). The mixture was stirred at
room temperature under H2 for 2 h at atmospheric pressure. The
mixture was filtered through Celite, washed with MeOH (10 mL),
and concentrated to dryness under vacuum. The mixture was puri-
fied by C18 reverse-phase pre-HPLC to isolate desired compound
10 as a white solid (9 mg, 72 % yield). 1H NMR (500 MHz, [D6]DMSO,
90 °C): δ = 1.25–1.33 (m, 3 H), 1.97–2.07 (m, 2 H), 2.33 (s, 3 H), 3.19
of the solution to 2.5 m
M with respect to the diene. The mixture
was stirred at 40 °C for 3–4 h under an atmosphere of Ar. The flask
was opened to the air, and the mixture was stirred for 2 h. The
solvent was removed under vacuum, and the residue was purified
by flash column chromatography (100 % hexanes to 33 % EtOAc in (m overlapped by DMSO water peak, 3 H), 3.92 (m, 2 H), 7.19–7.24
hexanes) to give 29 as a white solid (35 mg, 69 % yield). 1H NMR
(500 MHz, C6D6, 70 °C): δ = 2.06 (s, 3 H), 3.54 (dd, J = 20.4, 16.0 Hz,
1 H), 3.67 (dd, J = 21.8, 16.8 Hz, 2 H), 3.92–3.98 (m, 2 H), 4.70–4.79
(m, 2 H), 4.93–4.98 (m, 1 H), 5.11–5.15 (m, 1 H), 5.80–5.86 (m, 1 H),
6.89 (d, J = 7.8 Hz, 2 H), 6.98–7.04 (m, 5 H), 7.06–7.07 (m, 2 H), 7.38
(dd, J = 6.8, 2.2 Hz, 1 H), 7.50 (br. d, 2 H) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 21.2, 28.1 (d), 30.1, 63.1, 66.1, 120.8, 122.8, 123.9,
(m, 4 H), 7.63 (d, J = 7.4 Hz, 1 H), 7.96 (m, 2 H) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 21.3, 26.0, 27.8, 29.8, 40.9, 64.0, 119.8,
123.8 (C5 and C6 of the thiophene core are overlapping), 125.4,
129.2, 129.9 (quaternary carbon of the thiophene core and C1′ of
the tolyl substituent attached to the C2 of the thiophene core are
overlapping), 131.2, 132.5, 137.3, 139.1, 139.3 ppm. 31P NMR
(202 MHz, C6D6): δ = 13.24 ppm. MS (ESI): m/z = 373.2 [M + H]+,
124.6, 128.1, 128.5, 128.8, 129.6, 130.4, 131.2, 135.3, 136.7, 138.5, 371.2 [M – H]–. HRMS (ESI–): calcd. for C20H20O3PS [M – H+]–
139.7 ppm. 31P NMR (202 MHz, [D6]DMSO): δ = 25.60 ppm. HRMS
(ESI+): calcd. for C27H25NaO3PS [M + Na+]+ 483.1154; found
483.1151.
371.0876; found 371.0888.
{[4-Butyl-2-(p-tolyl)benzo[b]thiophen-3-yl]methyl}phosphonic
Acid (32): Intermediate 29 (16 mg, 0.035 mmol) and Pd/C (10 % w/
w, 0.0034 mmol) were added to a flask, followed by dry MeOH
(5 mL). The mixture was stirred at room temperature under H2 for
1 h at atmospheric pressure. The mixture was filtered through Cel-
ite, washed with MeOH (10 mL), concentrated, and dried to afford
(Z)- and (E)-12-(Benzyloxy)-1-(p-tolyl)-9,10,12,13-tetrahydro-
6H-11-oxa-2-thia-12-phosphacycloundeca[cd]indene 12-Oxide
(30a and 30b): Macrocyclization of diene 28 was achieved follow-
ing the same protocol as that described above for the RCM reaction
of diene 27. The mixture was purified by flash column chromatogra-
phy (silica gel, 100 % hexanes to 33 % EtOAc in hexanes) to give
the pure cis and trans endocyclic double bond products, 30a and
30b, respectively, in a 2:1 ratio. Data for 30a: white solid (22 mg,
1
ring-opening product 32 as a white solid (12.8 mg, 98 % yield). H
NMR (500 MHz, [D6]DMSO): δ = 0.92 (t, J = 7.3 Hz, 3 H), 1.35–1.42
(m, 2 H), 1.46–1.52 (m, 2 H), 3.28–3.32 (m, 4 H), 7.12 (d, J = 7.1 Hz,
1 H), 7.22 (t, J = 7.6 Hz, 1 H), 7.26 (d, J = 7.9 Hz, 2 H), 7.57 (d, J =
7.8 Hz, 2 H), 7.72 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 14.4, 21.3, 22.39, 22.42, 33.8, 35.2, 120.01, 120.03,
123.8, 126.8, 129.2, 130.80, 130.83, 132.36, 132.38, 137.36, 137.37,
139.3 ppm. 31P NMR (202 MHz, [D6]DMSO): δ = 19.71 ppm. MS (ESI):
m/z = 375.3 [M + H]+, 373.2 [M – H]–. HRMS (ESI–): calcd. for
C20H22O3PS [M – H+]– 373.1033; found 373.1034.
1
40 % yield). H NMR (500 MHz, C6D6): δ = 1.60–1.67 (m, 1 H), 2.07
(s, 3 H), 2.29–2.35 (m, 1 H), 3.35 (dd, J = 22.1, 11.2 Hz, 1 H), 3.68
(dd, J = 20.5, 16.0 Hz, 1 H), 3.77–3.89 (m, 2 H), 4.01 (dd, J = 15.7,
8.7 Hz, 1 H), 4.28–4.34 (m, 1 H), 4.63 (dd, J = 11.7, 9.5 Hz, 1 H), 4.73
(dd, J = 11.9, 7.9 Hz, 1 H), 5.30–5.35 (m, 1 H), 5.89–5.93 (m, 1 H),
6.93 (d, J = 7.9 Hz, 2 H), 7.02–7.06 (m, 5 H), 7.15–7.17 (m, 2 H), 7.43
(d, J = 7.8 Hz, 1 H), 7.56 (d, J = 7.8 Hz, 2 H) ppm. 31P NMR (202 MHz,
C6D6): δ = 25.39 ppm. HRMS (ESI+): calcd. for C28H28O3PS 475.1491
[M + H+]+; found 475.1484. Data for 30b: white solid (12 mg, 20 %
yield). 1H NMR (500 MHz, C6D6): δ = 1.28–1.35 (m, 1 H), 1.63–1.69
(m, 1 H), 2.06 (s, 3 H), 3.30 (br. m, 1 H), 3.48 (br. m, 1 H), 3.62 (br.
m, 1 H), 3.76–3.91 (m, 2 H), 4.29 (br. m, 1 H), 4.48 (br. m, 1 H), 4.56
(dd, J = 12.0, 6.8 Hz, 1 H), 5.14–5.16 (m, 1 H), 5.76 (br. m, 1 H), 6.95
(d, J = 7.0 Hz, 2 H), 7.01–7.05 (m, 3 H), 7.07–7.11 (m, 2 H), 7.11–7.15
(m, 3 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.58 (d, J = 7.8 Hz, 2 H) ppm.
31P NMR (202 MHz, C6D6): δ = 29.77 ppm. HRMS (ESI+): calcd. for
C28H28O3PS 475.1491 [M + H+]+; found 475.1487.
12-Hydroxy-1-(p-tolyl)-7,8,9,10,12,13-hexahydro-6H-11-oxa-2-
thia-12-phosphacycloundeca[cd]indene 12-Oxide (11): In a flask
containing a mixture of 30a and 30b (15.5 mg, 0.034 mmol), Pd/C
(10 % w/w, 0.0034 mmol) was added followed by dry MeOH (5 mL).
The mixture was stirred at room temperature under H2 for 2 h at
atmospheric pressure. The mixture was filtered through Celite,
washed with MeOH (10 mL), concentrated, and dried. The mixture
was purified by C18 reverse-phase pre-HPLC to isolate desired com-
1
pound 11 as a white solid (9.3 mg, 72 % yield). H NMR (500 MHz,
[D6]DMSO, 90 °C): δ = 1.50–1.55 (m, 2 H), 1.59–1.64 (m, 2 H), 1.93–
1.98 (m, 2 H), 2.34 (s, 3 H), 3.14 (d, J = 19.7 Hz, 2 H), 3.23–3.37 (m,
2 H), 3.80 (dd, J = 8.5, 4.1 Hz, 2 H), 7.18–7.23 (m, 4 H), 7.62 (d, J =
7.5 Hz, 1 H), 7.91 (d, J = 7.6 Hz, 2 H) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 21.3, 24.8, 29.1, 29.9, 31.1, 31.8, 63.7, 119.9, 123.8,
125.1, 129.1, 129.3, 131.2, 132.6, 137.4, 138.2, 138.4, 139.4,
139.6 ppm. 31P NMR (202 MHz, [D6]DMSO): δ = 13.95 ppm. HRMS
(ESI–): calcd. for C21H22O3PS 385.1033 [M – H+]–; found 385.1029.
11-(Benzyloxy)-1-(p-tolyl)-6,7,8,9,11,12-hexahydro-10-oxa-2-
thia-11-phosphacyclodeca[cd]indene 11-Oxide (10): To a cooled
(0 °C) and vigorously stirring solution of 2-nitrobenzenesulfonyl
chloride (65 mg, 0.3 mmol) and intermediate 27 (27 mg, 0.06 mmol)
in dry CH3CN (5 mL), hydrazine monohydrate (0.15 g, 2.9 mmol)
was added dropwise over a period of 1 min. The resulting white
suspension (hydrochloride salt of hydrazine hydrate) was allowed
to slowly warm to room temperature, stirring vigorously for 4 d.
The solvent was evaporated under high vacuum, EtOAc (15 mL) was
added, and the organic phase was washed with aqueous saturated
NaHCO3 (3 × 5 mL), dried with anhydrous MgSO4, filtered, and con-
centrated to dryness under vacuum. The residue was purified by
flash column chromatography (silica gel, 100 % hexanes to 25 %
EtOAc in hexanes) to give desired compound 31 (18.6 mg) contami-
nated with approximately 10 % of unreacted starting material (9:1
ratio according to LC–MS and 31P NMR spectroscopy). The mixture
was used directly in the next step without further purification. 31P
NMR (202 MHz, [D6]DMSO): δ = 25.36 ppm. Intermediate 31 (16 mg,
Acknowledgments
Financial support for this work was provided by the Natural
Sciences and Engineering Research Council of Canada (NSERC)
and the Canadian Institute of Health Research (CIHR) to Y. S. T.
Keywords: Sulfur heterocycles · Phosphorus heterocycles ·
Macrocycles · Phosphonates · Transition-state mimics
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Received: March 17, 2016
Published Online: ■
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Full Paper
Macrocyclic Phostones
Phostones are useful transition-state
analogues of proteases and substrate
mimics of DNA/RNA-processing en-
zymes. Methodologies for the prepara-
tion of medium-sized ring phostones
are developed that are amenable to
the parallel synthesis of structurally di-
verse derivatives containing a benzo-
[b]thiophene core, which thus enables
profiling of such molecules in biologi-
cal screens.
A. N. Matralis, Y. S. Tsantrizos* ... 1–10
Synthesis of Benzothiophene-Con-
taining 10- and 11-Membered Cyclic
Phostones
DOI: 10.1002/ejoc.201600333
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