Asymmetric total synthesis of paecilomycin E, 10′-epi-paecilomycin e and 6′-epi-cochliomycin C

Article abstract of DOI:10.1039/c4ob01400f

The asymmetric total syntheses of naturally occurring resorcylic acid lactone paecilomycin E and two of its structural congeners have been reported in this article. The major highlight of the synthetic venture is the application of the late stage Mitsunob

Full text of DOI:10.1039/c4ob01400f

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Asymmetric total synthesis of paecilomycin
E, 10’-epi-paecilomycin E and 6’-epi-cochliomycin C†
Cite this: DOI: 10.1039/c4ob01400f
Pratik Pal, Nandan Jana and Samik Nanda*
The asymmetric total syntheses of naturally occurring resorcylic acid lactone paecilomycin E and two of
its structural congeners have been reported in this article. The major highlight of the synthetic venture is
the application of the late stage Mitsunobu macrolactonization method (as it is difficult to achieve the
desired products through the standard carboxyl activation method) of a properly functionalized seco-
acid. The macrolactonization precursor was synthesized by applying an “E”-selective Julia–Kocienski
olefination of a highly functionalized aromatic aldehyde and a sulphone, which constitutes all the stereo-
centers (C4’, C5’, C6’ and C10’; 3S,7R,8R,9S) in the target molecule.
Received 5th July 2014,
Accepted 21st August 2014
DOI: 10.1039/c4ob01400f
www.rsc.org/obc
tions whereas paecilomycins C and D possess 6-membered lac-
tones instead of the 14-membered macrolactones seen in
Introduction
Resorcylic acid lactones (RALs) are a class of mycotoxins iso- other RALs. Paecilomycin E showed antiplasmodial activity
lated from various strains of fungi defined by the presence of a against the Plasmodium falciparum line 3D7 with an IC50 value
β-resorcylic acid ring and a 14-membered macrolactone core of 20.0 nM. Paecilomycins E and F showed moderate activity
with a stereochemically pure methyl substituent at the C10′
-
against the P. falciparum line Dd2.
position (Fig. 1) in its structure. Radicicol, the first known
Of late, two new 14-membered resorcylic acid lactones with
molecule in this family, was isolated from Monocillium nordinii a rare natural acetonide group, cochliomycins A and B, and
in 1953,1 followed by zearalenone (Fig. 1) in 1962,2 LL-Z1640-2 one new 5-chlorosubstituted lactone, cochliomycin C, together
in 1978 3 and hypothemycin in 1980.4 Initially, the estrogen with four known analogues, were obtained from the fungus
agonistic property was reported for zearalenone, but this was Cochliobolus lunatus in the South China Sea.8 These lactones
unable to tempt the synthetic organic chemist community were evaluated against the larval settlement of the barnacle
towards the total synthesis of these molecules. Later on, in Balanus amphitrite, and antifouling activity was detected for
early 1990 the first report of kinase inhibition by radicicol the first time in this type of metabolite. Very recently two new
rekindled interest in this molecule and in 1992 the first syn- brominated RALs (5-bromozeaenol and 3,5-dibromozeaenol)
thesis of radicicol was reported by Lett et al.5 Since the first were isolated from the fungus Cochliobolus lunatus by the
isolation of radicicol, nearly 30 naturally occurring RALs have chemical epigenetic manipulation approach.8b
been reported till today. They have been shown to have estro-
Later, structural revision for paecilomycin F and cochlio-
genic, antifungal, cytotoxic, antimalarial, and nematicidal pro- mycin C was reported.9,10 The stereochemistry of the hydroxyl
perties and inhibitory activities against ATPases and kinases. containing C-6′ carbon is inverted in both the molecules in the
RALs have attracted considerable attention from the synthetic corrected form; hence paecilomycin F became paecilomycin E
organic chemist community due to its broad spectrum of which is also a natural product but the other one became a
bioactivity and skeletal diversity as evident from several 6′-epimer of the natural cochliomycin C (Fig. 2).
elegant publications.6
We have already reported the asymmetric total synthesis of
Recently, six new RAL molecules named paecilomycins several RALs such as cochliomycin A, zeaenol,11 and 5′-epi-
A–F7 (Fig. 1) were isolated from the mycelial solid culture of cochliomycins C and F (uncorrected)12 by successful explora-
Paecilomyces sp. SC0924 by Chen and Wei et al., along with tion of several useful transformations, e.g., ME-DKR (metal
other known RALs. Paecilomycin A possesses a 1′,2′-epoxy enzyme combined dynamic kinetic resolution), Keck asym-
linkage with three hydroxyl groups at the 4′, 5′, and 6′-posi- metric allylation, E-selective Julia–Kocienski olefination, RCM
reactions and macrolactonization (Yamaguchi and Mitsunobu)
reactions. Our main aim is to develop a general and flexible
synthetic strategy for the asymmetric total synthesis of several
naturally occurring RALs and their structural analogues.
Department of Chemistry, Indian Institute of Technology, Kharagpur, 721302, India.
E-mail: snanda@chem.iitkgp.ernet.in
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
Recently a few other groups have also successfully completed
c4ob01400f
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Fig. 1 General structural features of RALs with newly isolated paecilomycins and cochliomycins (uncorrected).
Fig. 2 Structural revision of paecilomycins E and F and cochliomycin C.
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the synthesis of cochliomycin A, cochliomycin B, paecilomycin tution pattern in the aromatic ring in cochliomycin C (con-
E and other structurally related RAL molecules.13
tains an extra “Cl” atom at the C5 position). But the structural
revision paper was published midway of our synthetic venture,
so we have decided to continue the remaining part of the syn-
thesis. Eventually, after structural revision, paecilomycin F
became paecilomycin E (another natural product) and cochlio-
The present work
At the beginning we had two target molecules in our mind, mycin C became 6′-epi-cochliomycin C. A close inspection of
the previously reported synthesis of cochliomycins (A and B)
paecilomycin F and cochliomycin C (uncorrected), as both of
them have similar stereochemical features and substitution and paecilomycins (F and its stereoisomers) reveals that
patterns (C1′–C11′), the notable difference being the substi- (Scheme 1) “E” olefinic unsaturation between C1′ and C2′ was
Scheme 1 Retrosynthetic analysis of paecilomycin E and related RALs.
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created by successful exploration of RCM or Suzuki or Stille through SN2 reaction, and subsequent Mo(IV)-catalyzed oxi-
reactions.
dation18 of the sulfide produced the desired sulfone 8 in 85%
The retrosynthetic analysis of the targeted RALs is pre- yield (Scheme 2).
sented in Scheme 1. We have planned to construct a 14-mem-
bered ring by the late stage macrolactonization (carboxylic acid
Synthesis of the aldehyde 10
activation method) reaction from the seco-acid 3. It was envi- For the synthesis of the aldehyde 10 we have started our journey
sioned that as Julia–Kocienski (JK) olefination is known to be from the known alcohol 19.19 TBDPS protection of this alcohol
very efficient in generating E-alkene selectively, the internal with TBDPS-Cl and imidazole afforded compound 20 in 95%
“E” double bond between C1′ and C2′ could be achieved by JK- yield. Dihydroxylation and oxidative cleavage of olefin under
olefination between sulfone 4 and aldehyde 5 to furnish com- Lemieux–Johnson conditions of compound 20 afforded the alde-
pound 3. Aldehyde 5 could be accessed from commercially hyde 10 in a single pot operation with 80% yield (Scheme 3).20
available 3,5-dihydroxy benzoic acid (7). A Wittig reaction or
Synthesis of the sulfone 4
Z-selective JK-olefination between enantiopure aldehydes 10
and 9/8 should lead to the olefinic compound 7 which upon For the “Z”-selective JK-olefination reaction,21 initially 2-pyri-
substrate directed dihydroxylation and acetonide protection dylsulfone 8 was reacted with the aldehyde 10 under different
was thought to produce compound 4. Compound 10 was syn- reaction conditions (different solvents and different bases) but
thesized from 1,3-propanediol by applying a ME-DKR (metal to our utter disappointment the desired “Z” olefinic com-
enzyme combined dynamic kinetic resolution) strategy as pound 21 was isolated in very less yield. In all the cases the
reported earlier by our group. The sulphone 8 and phos- starting sulfone was completely consumed, but the aldehyde
phonium salt 9 were thought to be accessed from 1,5 pentane 10 was isolated as a major component after the usual work-up
diol and its stereocenter could be fixed by enzymatic kinetic procedure. The reason for this unusually low reactivity of alde-
resolution (EKR) coupled with Mitsunobu inversion reaction hyde 10 towards “Z” selective JK olefination is not very clear to
as depicted in Scheme 1.
us, but the presence of a bulky TBDPS group at the α-position
cannot be ruled out, which might block the nucleophilic
attack to the –CHO functionality. The details of this optimi-
zation are provided in Table 1. As the “Z”-selective JK-olefina-
tion reaction did not proceed well, we switched our attention
to the “Z” selective Wittig olefination reaction. For that
purpose the Wittig salt 9 was treated with KHMDS to generate
Results and discussion
Synthesis of the sulphone 8 and phosphonium salt 9 required
for JK and Wittig olefination
The synthesis was initiated from the known racemic hexane- the required anion which was then subsequently reacted with
1,5-diol (11).12a Enzymatic kinetic resolution (EKR) of 11 was the aldehyde 10 to afford the “Z”-olefin 7 in 76% yield as a
performed using vinyl acetate as the active acyl donor and single product.22 The base KHMDS was found to provide the
CAL-B (Candida antarctica lipase) as a biocatalyst in the DIPE best result for this reaction. Dihydroxylation of the cis olefin 7
solvent to afford the corresponding (R)-acetate 12 (yield = 48%, furnished two diastereomeric diols 21 and 22 in 1 : 8 ratio. The
ee = 98%) and (S)-alcohol 13 (yield = 48%, ee > 99%) according origin of this high diastereoselection can be explained by the
to the Kazlauskas empirical rule.14 The unwanted acetate 12 Kishi model which utilizes A1,3-strain as a deciding factor.23
was then hydrolysed with 1% NaOH in MeOH and the result- The diol functionality in compound 22 was then protected as
ing alcohol was inverted by applying the Mitsunobu inversion its acetonide by treatment with 2,2-DMP and PPTS (catalytic
strategy to give the desired compound (S)-13 (overall yield 90% amount) to furnish compound 23 in 94% yield. Subsequent
after three steps with ee = 98%). The free hydroxyl group of 13 removal of the PMB-group was achieved by treating compound
was protected as its TBS (tert-butyl dimethylsilyl) ether by treat- 23 with DDQ to afford compound 24 in 96% yield. Compound
ment with imidazole and TBS-Cl to afford compound 14 in 24 was then transformed into the corresponding 1-phenyl-1H-
95% yield. Deprotection of the PMB group was achieved by tetrazol-5-yl sulfide through a Mitsunobu reaction, and sub-
treating compound 14 with DDQ15 to furnish the primary sequent Mo(IV)-catalyzed oxidation of sulfide produced the
alcohol 15, which was subsequently converted to its corres- desired sulfone 4 in a yield of 82% over two steps (Scheme 4).
ponding methanesulfonate 16 by treatment with Ms-Cl
Synthesis of the highly functionalized aromatic aldehyde 5
and the corresponding “Cl” derivative 6
(methanesulfonyl chloride) and Et3N. Compound 16 was then
converted to the corresponding iodo compound 17 by treat-
ment with NaI in acetone in the presence of NaHCO3 and The synthesis was initiated from the known 3,5-dimethoxybenz-
DIPEA (catalytic) in 92% yield (Scheme 2).16
aldehyde (26). Regioselective electrophilic bromination of 26
The iodo compound 17 was then refluxed with Ph3P in was performed using Br2 in AcOH to afford compound 27 in
toluene along with Hunig’s base (DIPEA) to furnish the Wittig 85% yield as a sole product. The aldehyde functionality of
salt 9 in 91% yield.17 Addition of DIPEA is necessary as it stops compound 27 was protected as its corresponding ketal using
the deprotection of the TBS group under the reaction con- ethylene glycol to furnish compound 28 in 98% yield. Lithium
ditions. Compound 17 was also converted to its corresponding exchange of the bromo compound 28 with n-BuLi and
sulfide 18 by treatment with 2-mercaptopyridine sulfide subsequent reaction of the generated organo-Li species with
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Scheme 2 Synthesis of the sulphone 8 and phosphonium salt 9.
Scheme 3 Synthesis of the aldehyde 10.
Table 1 “Z” selective JK-olefination of the sulfone 8 with the aldehyde 10
Entry
Sulfone
Aldehyde
Base
Temperature (°C)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
8
8
8
8
8
8
8
8
8
8
10
10
10
10
10
10
10
10
10
10
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
NaHMDS
NaHMDS
LiHMDS
LiHMDS
nBuLi
−78
0
Toluene
THF
∼5
nra
∼8
∼8
∼5
nra
nra
nra
nra
∼5
−78
−78
−78
−78
−78
−78
−78
−78
THF
THF–HMPAb
THF–DMPUc
Toluene
THF
Toluene
THF
10
THF–HMPAb
a nr: no significant reaction was observed. b THF–HMPA (6 : 1) was used as a solvent. c THF–DMPU (8 : 1) was used as a solvent. HMPA:
hexamethylphosphoramide; DMPU: N,N′-dimethylpropyleneurea.
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Scheme 4 Synthesis of the sulphone 4 by “Z”-selective Wittig olefination.
Scheme 5 Synthesis of aldehydes 5 and 6.
ethyl chloroformate furnished the desired compound 5 in a 72% yield to prepare the corresponding chloro aldehyde 6 25 as
satisfactory 80% yield.24 We have installed the chlorine atom a sole regioisomer (Scheme 5). The structure of the aldehyde 6
in the C-3 position (the C5-position in the natural product was confirmed by 1D-nOe analysis (1H-NMR spectrum; see the
cochliomycin C) of the aldehyde 5 using SO2Cl2 in DCM in ESI†).
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Scheme 6 Synthesis of the seco-acid 3.
Fragment assembly for the synthesis of the seco-acid 3
three cases made us doubtful about the success of the acid
activating macrolactonization strategy for our compound. We
anticipate that the presence of the two –OMe groups in the aro-
matic ring substantially deactivates the –CO2H functionality;
hence mixed anhydride formation is inhibited (which is the
prerequisite for all of the above carboxylic activation macrolacto-
nization protocols). So we went for a Mitsunobu macrolacto-
nization (hydroxyl activation method) reaction, and to our
delight, macrolactone 33 was obtained in 65% yield
(with inversion at the C-10 stereocenter as the Mitsunobu reac-
tion is associated with clean SN2 inversion).31 Acetonide pro-
tection in compound 33 was then removed by treatment with
PPTS to furnish the diol 34 in 90% yield. Selective demethyla-
The sulfone (4) was now reacted with the aromatic aldehyde 5
in the presence of KHMDS at −78 °C to afford the trans olefin
29 exclusively in 80% yield. The attempted hydrolysis of the
ester functionality in compound 29 was a bit problematic than
we really expected. After refluxing with LiOH in THF–water
(1 : 1) for 5 days the starting material was recovered completely.
In another reaction, the hydrolysis was attempted with KOH in
refluxing MeOH, which afforded the hydrolyzed product, and
subsequent removal of the TBDPS group also took place. The
t
use of BuOK in THF as an alternate reagent only removes the
TBDPS group in 2 h without affecting the CO2Et functionality
(Scheme 7). We assume that due to the presence of two –OMe
groups in the aromatic ring (o and p to the –CO2Et group), the
electrophilicity of the carbonyl carbon is substantially reduced,
and the ester group becomes inert towards hydrolysis. As an
alternative arrangement, reduction of compound 29 with
DIBAL-H furnished the benzylic alcohol 30 in 95% yield.
Benzylic oxidation was performed with an excess of MnO2 26 to
furnish the aldehyde 31, which on further oxidation under
Pinnick conditions27 furnished the carboxylic acid 32 in 80%
yield. Compound 39 was then treated with PPTS in the pres-
ence of 2,2-DMP and MeCN, which subsequently removed the
TBS group in the presence of acetonide and TBDPS groups to
furnish the seco-acid 3 in 85% yield (Scheme 6).
32
tion with BBr3 afforded compound 35 in 85% yield. Com-
pound 35 was then treated with HF-pyridine33 in THF for 10 h
to furnish the 10′-epi-paecilomycin E in 80% yield (Scheme 7;
the overall yield is 3.5% from 1,5 hexane diol and 13.5% from
compound 19).
Completion of the synthesis of paecilomycin E
From the above discussion it was clear that, if we initiate our
synthetic journey from ent-9, naturally occurring paecilomycin
E can be synthesized by following the above route. We have
started our journey from compound (R)-12, which was earlier
synthesized by our group12a by adopting a ME-DKR (metal
enzyme dynamic kinetic resolution) strategy. By following
similar reaction sequences depicted in Scheme 2, ent-9 was
Macrolactonization and the synthesis of 10′-epi-paecilomycin E
The seco-acid 3 was then subjected to different intramolecular synthesized in good yield. Wittig olefination of the aldehyde
ring closing protocols viz. Yamaguchi macrolactonization,28 10 with ent-9 afforded compound 36 as a single diastereomer.
Shiina macrolactonization,29 and Keck macrolactonization30 to Compound 36 was then synthetically elaborated to the sul-
prepare the anticipated macrolactone 33. But the failure in all phone 42 as depicted in Scheme 8.
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Scheme 7 Synthesis of 10’-epi-paecilomycin E.
Scheme 8 Synthesis of the sulphone 42.
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Scheme 9 Synthesis of the seco-acids 51 and 52.
With the sulphone 42 in our hand, the stage is now ready article, the NMR spectrum (1H and 13C) of paecilomycins E, F
for the crucial JK-olefination reaction with aldehydes 5 and 6. and cochliomycin C was reported in the CDCl3 solvent. We have
Stereoselective JK-olefination with the sulphone 42 and the also recorded the 1H-NMR spectrum of paecilomycin E and
aldehyde 5/6 furnished compounds 43 and 44 in 82% and 6′-epi-cochliomycin C in acetone (d6) as a solvent, and we
78% yield respectively. Reduction of the –CO2Et functionality observe sharp resolution in the corresponding spectrum (see
with DIBAL-H afforded the benzyl alcohols 45 and 46, and sub- the ESI†) when compared to the spectrum obtained in CDCl3.
sequent oxidation with activated MnO2 furnished the corres-
ponding aldehydes 47 and 48. Pinnick oxidation of aldehydes
47 and 48 under similar conditions to those depicted earlier
yielded the corresponding carboxylic acids 49 and 50. Selective
Conclusion
In conclusion we have disclosed the asymmetric total synthesis
of naturally occurring paecilomycin E and two of its close
structural congeners 10′-epi-paecilomycin E and 6′-epi-cochlio-
mycin C. The synthetic strategy involves successful application
of late stage Mitsunobu macrolactonization (through hydroxyl
group activation by SN2 inversion), E-stereoselective JK-olefina-
tion, substrate directed stereoselective dihydroxylation and
Z-selective Wittig olefination. Further studies directed towards
novel and efficient strategies for the total synthesis of several
structurally related RALs are currently under investigation in
our laboratory and will be reported later.
removal of the TBS group afforded the seco-acids 51 and 52 in
85% and 82% yield respectively (Scheme 9).
Completion of the synthesis through the late stage Mitsunobu
macrolactonization method
The seco-acids 51 and 52 were subjected to the Mitsunobu
macrolactonization method as shown in Scheme 10, which
afforded the ring closed products 53 and 54 in 68% and 65%
yield respectively. Acetonide deprotection and selective
demethylation with BBr3 furnished compounds 57 and 58,
which on desilylation with HF-pyridine afforded paecilomycin E
and 6′-epi-cochliomycin C in 80% and 82% yield respectively
(the overall yield for paecilomycin E is 3.2% from 1,5 hexane
General information
diol). The spectral (1H-NMR, 13C-NMR, HSQC, 1H–1H COSY) Unless otherwise stated, materials were obtained from com-
characteristic of our synthesized paecilomycin E matches per- mercial suppliers and used without further purification. THF
fectly with the naturally occurring one (Table 2). In the previous and diethylether were distilled from sodiumbenzophenone
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Scheme 10 Completion of the synthesis for paecilomycin E and 6’-epi-cochliomycin C.
Table 2 Comparison of 1H and 13C NMR data for paecilomycin E
1H NMR (δ and J in Hz)
13C NMR (δ)
Natural (400 MHz
in CDCl3)
Synthetic (400 MHz
in CDCl3)
Synthetic (600 MHz
in acetone-d6)
Natural (100 MHz
in CDCl3)
Synthetic (100 MHz
in CDCl3)
Position
1
2
3
4
5
6
7
1′
103.9
164.0
100.2
165.9
108.6
143.0
171.3
128.3
134.5
39.0
103.9
164.0
100.1
165.6
108.6
142.9
171.3
128.3
134.5
38.9
6.38 s
6.38 s
6.37 s
6.37 s
6.51 d (2.4)
6.43 d (2.4)
7.20 dd (15.4, 1.6)
5.75 ddd (15.4, 10.6, 3.0)
2.75 dt (14.6, 10.8), 2.63 m
4.17 m
7.19 dd (15.2, 1.2)
5.27 s
2.72 s, 2.64 s
4.16 s
7.24 dd (15.6, 1.2)
5.99 ddd (15, 10.8, 3.6)
2.85–2.84 m, 2.53–2.50 m
4.12 s
2′
3′
4′
77.3
77.3
5′
6′
7′
3.67 br d (3.5)
3.93 dd (10.7, 6.4)
1.71–1.86 m
3.67 br s
3.92 s
1.77–1.73 m
3.74 s
3.97 s
1.79 m
71.3
76.0
33.8
71.3
75.9
33.8
8′
9′
10′
11′
4-OMe
2-OH
1.66 m, 1.42 m
1.71–1.86 m
5.00 m
1.40 d (6.1)
3.79 s
1.67–1.71 m
1.79–1.85 m
5.09–5.06 m
1.44 d (6)
3.98
12.10 br s
21.1
35.8
74.1
20.5
21.1
35.8
74.1
20.4
4.99 s
1.40 s
3.78
12.00 br s
55.4
55.4
12.00 br s
ketyl. Dichloromethane (CH2Cl2), dimethylformamide (DMF) acquired in CDCl3 unless otherwise mentioned. Chemical
and dimethylsulfoxide (DMSO) were distilled from CaH2. Reac- shifts are reported in parts per million (ppm, δ), downfield
tions were monitored by thin-layer chromatography (TLC) from tetramethylsilane (TMS, δ = 0.00 ppm), and are refer-
carried out on 0.25 mm silica gel plates (Merck) with UV light, enced to the residual solvent (CDCl3, δ = 7.26 ppm (1H),
ethanolic anisaldehyde and phosphomolybdic acid/heat as 77.16 ppm (13C) and CD3COCD3, δ = 2.09 ppm (1H)). Coupling
developing agents. Silica gel 100–200 mesh was used for constants (J) are reported in hertz (Hz) and the resonance multi-
column chromatography. Yields refer to chromatographically plicity abbreviations used are s, singlet; d, doublet; t, triplet; q,
and spectroscopically homogeneous materials unless other- quartet; dt, doublet of triplets; dd, doublet of doublets; ddd,
wise stated. Proton nuclear magnetic resonance (1H-NMR) and doublet of doublet of doublets; m, multiplet; comp, overlap-
carbon nuclear magnetic resonance (13C-NMR) spectra were ping multiplets of magnetically non-equivalent protons.
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Optical rotations were measured on a JASCO P1020 digital brine solution (40 mL) and dried over anhydrous MgSO4 and
polarimeter. Mass spectrometric analysis was performed in the concentrated under reduced pressure. Two diastereomeric
CRF, IIT-Kharagpur (TOF analyzer). HPLC analysis was per- diols (compound 21 and compound 22) were purified by flash
formed with the help of a PDA detector (200–800 nm).
column chromatography (EtOAc–hexane = 1 : 20) to afford diol
22 (4.5 g, 6.49 mmol) and diol 21 (563 mg, 0.81 mmol) in 8 : 1
ratio.
(5S,11S,Z)-5-(2-(4-Methoxybenzyloxy)ethyl)-2,2,11,13,13,14,14-
heptamethyl-3,3-diphenyl-4,12-dioxa-3,13-disilapentadec-6-
ene (7)
Rf of 22 = 0.31 (EtOAc–hexane, 1 : 5).
1H NMR of compound 22 (400 MHz, CDCl3): δ: 7.71–7.61
Wittig salt 9 (3.59 g, 5.95 mmol) was dissolved in 30 mL anhy- (m, 4H), 7.44–7.34 (m, 6H), 7.14 (d, J = 8.4 Hz, 2H), 6.84 (d, J =
drous THF and the temperature was brought to −78 °C. A solu- 8.4 Hz, 2H), 4.31 (d, J = 2.8 Hz, 2H), 4.01–3.98 (m, 1H), 3.79
tion of KHMDS (0.5 M in THF, 13.1 mL, 6.54 mmol) was added (s, 3H), 3.75–3.71 (m, 1H), 3.57–3.65 (m, 2H), 3.24 (s, 1H),
to this solution dropwise and the resulting orange red solution 3.20–3.13 (m, 1H), 1.93–1.82 (m, 1H), 1.81–1.71 (m, 1H),
was stirred for 40 minutes. The aldehyde 10 (2.5 g, 5.41 mmol) 1.41–1.23 (m, 6H), 1.09 (d, J = 6 Hz, 3H), 1.05 (s, 9H), 0.88
in 15 mL anhydrous THF was added to this orange red solution (s, 9H), 0.04 (d, J = 2.4 Hz, 6H).
at −78 °C and the temperature was allowed to reach room temp-
13C NMR of compound 22 (50 MHz, CDCl3): δ: 159.3, 135.8,
erature slowly. The reaction is quenched with saturated aq. 133.8, 133.2, 129.8, 129.7, 129.5, 129.4, 127.7, 127.6, 113.7,
NH4Cl solution (35 mL) and further 50 mL diethyl ether was 77.0, 72.8, 72.4, 71.8, 68.7, 66.2, 55.2, 39.9, 32.5, 32.2, 27.0,
added. The organic layer was separated and the aqueous layer 25.9, 23.7, 21.9, 19.3, 18.1, −4.4, −4.7.
was further washed with diethyl ether (2 × 30 mL). The com-
bined organic part was washed with water (40 mL), brine solu-
[α]2D8 = 11.1 (c = 0.8, CHCl3).
HRMS (ESI) for C40H62O6Si2Na [M + Na]+, calculated:
tion (40 mL) and dried over anhydrous MgSO4 and concentrated 717.3982, found: 717.3973.
under reduced pressure. Purification by means of flash column
chromatography (EtOAc–hexane = 1 : 40) furnished the Z-alkene
7 as a colorless oil (2.71 g, 4.1 mmol) in 76% yield.
Rf = 0.65 (EtOAc–hexane, 1 : 20).
Rf of 21 = 0.32 (EtOAc–hexane, 1 : 5).
1H NMR of compound 21 (400 MHz, CDCl3): δ: 7.71–7.66
(m, 4H), 7.46–7.36 (m, 6H), 7.09 (d, J = 8.8 Hz, 2H), 6.82 (d, J =
8.8 Hz, 2H), 4.20 (s, 2H), 4.16–4.13 (m, 1H), 3.79 (s, 3H),
1H NMR (200 MHz, CDCl3): δ: 7.67–7.64 (m, 4H), 7.42–7.31 3.78–3.75 (m, 1H), 3.51–3.49 (m, 1H), 3.37–3.35 (m, 1H),
(m, 6H), 7.16 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 3.28–3.27 (m, 1H), 3.21–3.18 (m, 1H), 2.06–2.00 (m, 2H),
5.42–5.37 (m, 1H), 5.21–5.16 (m, 1H), 4.62–4.60 (m, 1H), 4.29 1.68–1.66 (m, 2H), 1.65–1.64 (m, 2H), 1.49–1.41 (m, 2H), 1.11
(s, 2H), 3.80 (s, 3H), 3.64–3.60 (m, 1H), 1.75–1.60 (m, 1H), (d, J = 6 Hz, 3H), 1.06 (s, 9H), 0.88 (s, 9H), 0.04 (s, 6H).
1.42–1.16 (m, 6H), 1.03 (s, 3H), 1.03 (s, 9H), 0.88 (s, 9H), 0.02
13C NMR of compound 21 (100 MHz, CDCl3): δ: 159.2,
(s, 6H).
136.0, 135.9, 133.6, 132.9, 130.4, 127.2, 130.0, 129.9, 129.3,
13C NMR (50 MHz, CDCl3): δ: 159.2, 136.2, 136.1, 134.5, 127.9, 127.9, 127.7, 113.8, 74.9, 72.4, 72.2, 72.0, 68.6, 66.3,
132.7, 130.9, 130.3, 129.6, 129.5, 129.2, 127.7, 127.5, 113.8, 55.3, 39.7, 33.4, 33.6, 29.7, 27.1, 26.0, 23.7, 21.6, 19.4, 18.2,
72.5, 68.6, 67.4, 66.8, 55.5, 39.5, 38.5, 31.8, 29.9, 27.6, 27.2, −4.3, −4.6.
26.1, 25.8, 23.9, 19.5, 18.4, −4.2, −4.5.
[α]2D8 = 1.3 (c = 0.8, CHCl3).
[α]2D8 = 12.16 (c = 1.16, CHCl3).
HRMS (ESI) for C40H62O6Si2Na [M + Na]+, calculated:
HRMS (ESI) for C40H60O4Si2Na [M + Na]+, calculated: 717.3982, found: 717.3988.
683.3927, found: 683.3920.
(5S,6R,7R,11S)-5-(2-(4-Methoxybenzyloxy)ethyl)-
tert-Butyl((S)-1-((4R,5R)-5-((S)-4-(tert-butyldimethylsilyloxy)-
2,2,11,13,13,14,14-heptamethyl-3,3-diphenyl-4,12-dioxa-3,13-
disilapentadecane-6,7-diol (22) and (5S,6S,7S,11S)-5-(2-(4-
methoxybenzyloxy)ethyl)-2,2,11,13,13,14,14-heptamethyl-3,3-
diphenyl-4,12-dioxa-3,13-disilapentadecane-6,7-diol (21)
pentyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(4 methoxybenzyloxy)-
propoxy)diphenylsilane (23)
To a stirring solution of the desired diol 22 (4.5 g, 6.49 mmol)
in anhydrous acetone (26 mL), 2,2′ DMP (1.6 mL, 12.98 mmol)
Compound 7 (5.42 g, 8.2 mmol) was dissolved in 32 mL THF and a catalytic amount of PPTS were added at room tempera-
and the solution was cooled to 0 °C. To this solution NMO ture and the reaction mixture was stirred for 5 h. The solvent
(1.4 g, 12.3 mmol) and 0.05 M solution of OsO4 in toluene was then evaporated in vacuo and the residue was purified by
(16 mL, 0.82 mmol) were added consecutively and the reaction flash column chromatography (EtOAc–hexane = 1 : 20) to
was protected from light by covering the reaction flask with afford compound 23 (4.47 g, 6.1 mmol) as colorless oil in
black paper. The mixture was stirred for 12 h at the same 94% yield.
temperature. The reaction was quenched by the addition of a
saturated aq. Na2SO3 solution (8 mL) and further stirred for
Rf = 0.25 (EtOAc–hexane, 1 : 20).
1H NMR of compound 23 (400 MHz, CDCl3): δ: 7.69–7.64
1 h at room temperature. Furthermore, 20 mL water and (m, 4H), 7.43–7.32 (m, 6H), 7.15 (d, J = 8.4 Hz, 2H), 6.84 (d, J =
40 mL EtOAc were added to this mixture and the organic layer 8.4 Hz, 2H), 4.26 (s, 2H), 4.07–4.04 (m, 1H), 3.97–3.89 (m, 2H),
was separated. The aqueous part was washed with EtOAc 3.8 (s, 3H), 3.66–3.63 (m, 1H), 3.55–3.48 (m, 2H), 1.97–1.83 (m,
(2 × 50 mL). The combined organic part was washed with 2H), 1.34 (s, 3H), 1.29 (s, 6H), 1.20–1.07 (m, 2H), 1.04 (d, J =
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5.2 Hz, 3H), 1.02 (s, 9H), 0.88–0.87 (m, 2H), 0.87 (s, 9H), (EtOAc–hexane
=
1 : 20) afforded compound 25 (4.3 g,
0.02–0.00 (m, 6H).
5.55 mmol) as colorless oil in 95% yield.
Rf = 0.45 (EtOAc–hexane, 1 : 10).
13C NMR of compound 21 (100 MHz, CDCl3): δ: 159.3,
136.2, 134.1, 129.8, 129.3, 127.7, 113.9, 107.7, 80.7, 72.6, 69.9,
1H NMR of compound 25 (400 MHz, CDCl3): δ: 7.69–7.66
68.6, 66.6, 55.4, 39.8, 34.9, 30.1, 29.9, 27.9, 27.2, 26.1, 27.8, (m, 4H), 7.60–7.52 (m, 5H), 7.42–7.32 (m, 6H), 4.16–4.13 (m,
23.9, 22.5, 19.6, 18.3, −4.2, −4.2.
1H), 4.04–4.01 (m, 1H), 3.90–3.89 (m, 1H), 3.69–3.67 (m, 1H),
3.51–3.46 (m, 2H), 2.22–2.11 (m, 1H), 2.09–2.01 (m, 1H), 1.37
[α]2D8 = 9.2 (c = 0.6, CHCl3).
HRMS (ESI) for C43H66O6Si2Na [M + Na]+, calculated: (s, 3H), 1.30 (s, 3H), 1.28–1.21 (m, 4H), 1.18–1.14 (m, 2H), 1.08
757.4295, found: 757.4283.
(d, J = 6.8 Hz, 3H), 1.05 (s, 9H), 1.09 (s, 9H), 0.07 (s, 6H).
13C NMR of compound 25 (50 MHz, CDCl3): δ: 154.3, 136.0,
133.9, 133.5, 130.0, 129.8, 127.8, 127.7, 123.8, 107.9, 80.4,
70.73, 68.57, 39.7, 34.2, 30.1, 29.4, 27.9, 27.1, 26.0, 25.7, 23.8,
22.3, 19.4, 18.2, −4.2, −4.5.
(S)-3-((4R,5R)-5-((S)-4-(tert-Butyldimethylsilyloxy)pentyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)-3-(tert-butyldiphenylsilyloxy)-
propan-1-ol (24)
Compound 23 (4.47 g, 6.1 mmol) was dissolved in 24 mL of
CH2Cl2–phosphate buffer (pH = 7; 19 : 1) and the solution was
[α]2D8 = 6.2 (c = 0.3, CHCl3).
HRMS (ESI) for C42H62N4O4SSi2Na [M + Na]+, calculated:
cooled to 0 °C. DDQ (1.38 g, 7.32 mmol) was added portion- 797.3927, found: 797.3935.
wise to it and the mixture was stirred at this temperature for
5-((S)-3-((4R,5R)-5-((S)-4-(tert-Butyldimethylsilyloxy)pentyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)-3-(tert-butyldiphenylsilyloxy)-
propylsulfonyl)-1-phenyl-1H-tetrazole (4)
1 h. Then, the reaction mixture was filtered through a pad of
celite. The residue was washed with 65 mL of CH2Cl2. The
combined organic solution was washed successively with 5%
NaHCO3 solution, water and brine solution. The organic layer To a stirring solution of sulfide 25 (4.3 g, 5.55 mmol) in
was then dried with anhydrous MgSO4 and evaporated ethanol (60 mL) was added a mixture of (NH4)6Mo7O24·4H2O
in vacuo. Purification by flash column chromatography (1.236 g, 1.0 mmol) and 30% H2O2 solution (7.3 mL) at 0 °C.
(EtOAc–hexane
= 1 : 10) afforded compound 24 (3.59 g, The mixture was then stirred at room temperature for 6 h, and
5.85 mmol) as colorless oil in 96% yield.
after that the reaction mixture was poured into 10% Na2S2O3
solution and extracted with ethyl acetate (200 mL). The organic
Rf = 0.20 (EtOAc–hexane, 1 : 10).
1H NMR of compound 24 (400 MHz, CDCl3): δ: 7.69–7.67 layer was washed with saturated NaHCO3 solution and brine,
(m, 4H), 7.46–7.39 (m, 6H), 4.16–4.11 (m, 2H), 3.91–3.89 (m, dried over anhydrous MgSO4 and concentrated in vacuo to
1H), 3.72–3.66 (m, 2H), 3.53–3.47 (m, 4H), 2.31–2.30 (m, 1H), afford the crude sulphone. The crude product was then puri-
1.90–1.87 (m, 2H), 1.44 (s, 3H), 1.41 (s, 3H), 1.39–1.20 (m, 6), fied by flash column chromatography (EtOAc–hexane = 1 : 20)
1.08–1.05 (m, 3H), 0.94 (s, 9H), 0.91 (s, 9H), 0.05–0.02 (m, 6H).
to furnish pure sulphone 4 (3.85 g, 4.77 mmol) as colorless
13C NMR of compound 24 (100 MHz, CDCl3): δ: 136.0, gummy oil in 86% yield.
136.0, 134.0, 133.6, 130.1, 127.8, 108.2, 80.6, 78.4, 70.8, 68.7,
59.2, 39.8, 38.7, 30.1, 28.3, 27.4, 27.2, 26.1, 23.8, 22.2, 19.4,
18.3, −4.2, −4.5.
Rf = 0.45 (EtOAc–hexane, 1 : 10).
1H NMR of compound 4 (400 MHz, CDCl3): δ: 7.68–7.63 (m,
5H), 7.62–7.60 (m, 4H), 7.46–7.38 (m, 6H), 4.09–4.06 (m, 1H),
4.02–3.98 (m, 1H), 3.93–3.83 (m, 3H), 3.68–3.65 (m, 1H),
[α]2D8 = 12.2 (c = 0.7, CHCl3).
HRMS (ESI) for C35H58O5Si2Na [M + Na]+, calculated: 2.26–2.16 (m, 2H), 1.36 (s, 3H), 1.31 (s, 3H), 1.21 (comp. 6H),
637.3720, found: 637.3711.
1.10 (s, 3H), 1.07 (s, 9H), 0.90 (s, 9H), 0.04 (s, 6H).
13C NMR of compound 4 (50 MHz, CDCl3): δ: 153.5, 136.1,
135.9, 133.3, 133.1, 132.9, 131.5, 130.3, 130.2, 129.8, 128.1,
127.9, 125.3, 108.2, 80.5, 69.8, 68.6, 52.6, 39.6, 30.2, 29.8, 29.9,
27.6, 27.1, 26.1, 25.8, 23.8, 22.8, 22.3, 19.4, 18.3, −4.2, −4.5.
[α]2D8 = 9.5 (c = 0.8, CHCl3).
5-((S)-3-((4R,5R)-5-((S)-4-(tert-Butyldimethylsilyloxy)pentyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)-3-(tert-butyldiphenylsilyloxy)-
propylthio)-1-phenyl-1H-tetrazole (25)
To a stirring solution of compound 24 (3.59 g, 5.85 mmol) in
anhydrous THF (20 mL) were added triphenylphosphine
HRMS (ESI) for C42H62N4O6SSi2Na [M + Na]+, calculated:
(2.19 g, 8.37 mmol) and 1-phenyl-5-mercapto-1H-tetrazole 829.3826, found: 829.3815.
[PT-SH] (1.66 g, 9.36 mmol) at −5 °C. After stirring for
Ethyl 2-((S,E)-4-((4R,5R)-5-((S)-4-(tert-butyldimethylsilyloxy)-
pentyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-(tert-
butyldiphenylsilyloxy)but-1-enyl)-4,6-dimethoxybenzoate (29)
15 minutes at this temperature, DIAD (2.3 mL, 11.7 mmol) in
8 mL of anhydrous THF was added dropwise and the reaction
was left to stir for 12 h. Water (60 mL) and 40 mL of EtOAc
were added to this mixture and the organic layer was separ- The sulfone 4 (0.96 g, 1.19 mmol) was dissolved in anhydrous
ated. The aqueous part was then washed with EtOAc (2 × THF (10 mL) and the solution was cooled to −78 °C. To this
50 mL). The combined organic part was washed with saturated solution 0.5 M KHMDS in toluene (2.6 mL) was added drop-
aq. NaHCO3 solution and brine solution (40 mL). The organic wise and stirred for 40 min. The aldehyde 5 (339 mg,
solution was then dried over anhydrous MgSO4 and concen- 1.42 mmol) in anhydrous THF (5 mL) was then added to the
trated under reduced pressure to furnish the crude product, reaction solution at −78 °C and the temperature was allowed
which on purification by flash column chromatography to attain room temperature slowly. The reaction was then
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quenched with saturated NH4Cl and extracted with diethyl
HRMS (ESI) for C45H68O7Si2Na [M + Na]+, calculated:
ether (150 mL). The organic layer was washed with brine solu- 799.4401, found: 799.4393.
tion and dried with anhydrous MgSO4 and concentrated
in vacuo to furnish the crude olefin. The crude product was
then purified by flash column chromatography (EtOAc–
hexane = 1 : 15) to give E-olefin 29 (778 mg, 0.95 mmol) as col-
orless gummy oil in 80% yield.
2-((S,E)-4-((4R,5R)-5-((S)-4-(tert-Butyldimethylsilyloxy)pentyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)-4-(tert-butyldiphenylsilyloxy)-
but-1-enyl)-4,6-dimethoxybenzaldehyde (31)
To a stirring solution of compound 30 (700 mg, 0.90 mmol) in
anhydrous CH2Cl2 (7 mL) was added activated MnO2 (1.95 g,
22.5 mmol) at room temperature and stirred for 48 h. The
mixture was then filtered through celite and the residue was
washed with 100 mL of CH2Cl2. The organic solvent was dried
over anhydrous MgSO4 and concentrated in vacuo. The crude
product was then purified by flash column chromatography
(EtOAc–hexane = 1 : 18) to furnish the aldehyde 31 (640 mg,
0.83 mmol) as colorless oil in 92% yield.
Rf = 0.30 (EtOAc–hexane, 1 : 10).
1H NMR of compound 29 (400 MHz, CDCl3): δ: 7.68–7.43
(m, 4H), 7.41–7.33 (m, 6H), 6.45 (d, J = 2.4 Hz, 1H), 6.34 (d, J =
2 Hz, 1H), 6.29 (d, J = 15.2 Hz, 1H), 6.30–6.15 (m, 1H),
4.35–4.30 (m, 2H), 4.09–4.07 (m, 1H), 4.04–4.00 (m, 1H),
3.95–3.90 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.66–3.65 (m, 1H),
2.46–2.45 (m, 2H), 1.43–1.41 (comp. 6H), 1.35 (s, 3H), 1.30
(s, 3H), 1.29–1.22 (comp. 3H), 1.10 (d, J = 6.4 Hz, 3H), 1.04
(s, 9H), 0.88 (s, 9H), 0.04 (s, 9H).
Rf = 0.25 (EtOAc–hexane, 1 : 10).
13C NMR of compound 29 (50 MHz, CDCl3): δ: 168.1, 161.4,
158.2, 137.8, 136.2, 136.1, 133.9, 133.7, 129.9, 129.1, 128.1,
127.8, 125.3, 116.0, 107.8, 101.5, 97.7, 79.9, 78.0, 71.9, 68.7,
61.2, 56.1, 55.5, 39.9, 38.6, 32.1, 31.8, 30.4, 29.8, 28.3, 27.2,
26.1, 23.83, 22.8, 22.3, 19.5, 18.3, 14.5, −4.2, −4.5.
[α]2D8 = 25.3 (c = 0.1, CHCl3).
1H NMR of compound 31 (400 MHz, CDCl3): δ: 10.41 (s,
1H), 7.71–7.62 (m, 4H), 7.40–7.33 (m, 6H), 7.23 (d, J = 14 Hz,
1H), 6.45 (s, 1H), 6.34 (s, 1H), 6.16 (td, J = 15.2, 6.8, 1H),
4.12–4.09 (m, 1H), 4.05–4.03 (m, 1H), 3.93–3.91 (m, 1H), 3.87
(s, 1H), 3.82 (s, 1H), 3.66–3.65 (m, 1H), 2.56–2.52 (m, 2H), 1.36
(s, 3H), 1.33 (s, 2H), 1.27 (s, 3H), 1.25–1.21 (m, 4H), 1.09 (s,
3H), 1.08 (s, H), 0.87 (s, 9H), 0.01 (s, 6H).
HRMS (ESI) for C47H70O8Si2Na [M + Na]+, calculated:
841.4506, found: 841.4495.
13C NMR of compound 31 (50 MHz, CDCl3): δ: 190.1, 164.6,
164.4, 143.4, 136.0, 133.7, 130.9, 129.8, 127.7, 115.9, 107.7,
103.9, 96.8, 96.2, 79.9, 77.9, 71.9, 68.6, 55.8, 55.4, 39.7, 38.5,
30.3, 29.7, 28.2, 27.1, 26.0, 23.7, 22.19, 19.48, 18.20, −4.3, −4.5.
[α]2D8 = 31.0 (c = 0.1, CHCl3).
(2-((S,E)-4-((4R,5R)-5-((S)-4-(tert-Butyldimethylsilyloxy)pentyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)-4-(tert-butyldiphenylsilyloxy)-
but-1-enyl)-4,6-dimethoxyphenyl)methanol (30)
HRMS (ESI) for C45H66O7Si2Na [M + Na]+, calculated:
797.4244, found: 797.4249.
To a stirring solution of compound 29 (778 mg, 0.95 mmol) in
anhydrous THF (7 mL) was added 1 M DIBAL solution in THF
(2.37 mL, 2.37 mmol) at −40 °C and the temperature was
slowly increased to 0 °C. The reaction mixture was stirred for
further 3 h at the same temperature and then quenched with a
saturated solution of sodium potassium tartrate. Diethyl ether
2-((S,E)-4-((4R,5R)-5-((S)-4-(tert-Butyldimethylsilyloxy)pentyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)-4-(tert-butyldiphenylsilyloxy)-
but-1-enyl)-4,6-dimethoxybenzoic acid (32)
was added to the reaction mixture and then it was filtered The aldehyde 31 (640 mg, 0.83 mmol) was dissolved in tBuOH
through a pad of celite. The celite bed was washed with (2 mL) and a 2.0 M solution of 2-methyl-2-butene (5.4 mL,
another 80 mL of diethyl ether. The combined organic solvent 10.8 mmol) in THF was added to it. To this mixture was added
was dried over anhydrous MgSO4 and concentrated in vacuo. a solution of NaClO2 (80% purity, 747 mg, 10 mmol) and
The crude product was then purified by flash column chrom- NaH2PO4 (691 mg, 7 mmol) in H2O (2 mL). After two hours the
atography (EtOAc–hexane = 1 : 10) to afford the alcohol 30 yellow biphasic reaction mixture was poured onto H2O (15 mL)
(700 mg, 0.90 mmol) as colorless oil in 95% yield.
and EtOAc (60 mL). The organic layer was separated and the
aqueous part was washed with EtOAc (2 × 50 mL). The com-
Rf = 0.20 (EtOAc–hexane, 1 : 10).
1H NMR of compound 30 (400 MHz, CDCl3): δ: 7.69–7.65 bined organic part was washed with brine solution (40 mL)
(m, 4H), 7.42–7.33 (m, 6H), 6.59 (d, J = 15.6 Hz, 1H), 6.43 (s, and dried over anhydrous MgSO4 and concentrated under
1H), 6.36 (s, 1H), 6.12 (td, J = 15.2, 7.6, 1H), 4.62 (d, J = 3.2 Hz, reduced pressure to afford the crude acid. The crude material
2H), 4.11 (d, J = 6.8 Hz, 1H), 4.56–4.52 (m, 1H), 3.9 (m, 1H), was purified by flash column chromatography (EtOAc–
3.89 (s, 3H), 3.80 (s, 3H), 3.71–3.64 (m, 1H), 2.49 (s, H), 1.37 (s, hexane = 1 : 7) to afford acid 32 (524 mg, 0.66 mmol) in 80%
3H), 1.32 (comp. 3H), 1.29 (s, 3H), 1.19–1.11 (m, 3H), 1.06 yield as colorless oil.
(comp. 3H), 1.03 (s, 9H), 0.87 (s, 9H), 0.02 (s, 6H).
Rf = 0.20 (EtOAc–hexane, 1 : 5).
13C NMR of compound 30 (50 MHz, CDCl3): δ: 160.2, 159.3,
1H NMR of compound 32 (400 MHz, CDCl3): δ: 7.74–7.67
139.5, 136.2, 134.0, 133.7, 130.2, 130.0, 129.6, 127.8, 119.2, (m, 4H), 7.41–7.35 (m, 6H), 6.72 (d, J = 15.6 Hz, 1H), 6.51 (s,
107.8, 102.5, 97.6, 80.0, 78.1, 71.9, 68.8, 55.8, 55.4, 39.9, 38.7, 1H), 6.38 (s, 1H), 6.21–6.17 (m, 1H), 4.13–4.05 (m, 2H),
30.5, 29.9, 28.4, 27.2, 26.1, 23.8, 22.9, 22.3, 19.6, 18.3, 14.3, 3.93–3.91 (m, 1H), 3.87 (s, 3H), 3.79 (s, 3H), 3.70–3.66 (m, 1H),
−4.2, −4.5.
2.5 (s, 2H), 1.36–1.32 (m, 8H), 1.28–1.13 (m, 3H), 1.10 (d, J =
6 Hz, 3H), 1.05 (s, 9H), 0.87 (s, 9H), 0.027 (s, 6H).
[α]2D8 = 31.0 (c = 0.1, CHCl3).
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13C NMR of compound 32 (50 MHz, CDCl3, 77.23):
1H NMR of compound 33 (400 MHz, CDCl3): δ: 7.65–7.63
δ: 169.93, 162.06, 158.90, 140.82, 136.15, 133.89, 133.80, 130.26, (m, 4H), 7.39–7.28 (m, 6H), 6.33 (d, J = 2 Hz, 1H), 6.29 (d, J =
129.95, 127.78, 113.21, 107.84, 103.27, 97.72, 96.30, 79.95, 2 Hz, 1H), 6.18 (s, 2H), 5.04–5.01 (m, 1H), 4.11 (d, J = 7.2 Hz,
78.03, 71.89, 68.83, 56.44, 55.53, 39.83, 38.54, 30.47, 29.85, 1H), 3.91–3.88 (m, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.75–3.74 (m,
28.33, 27.20, 27.11, 23.79, 22.27, 19.57, 18.31, −4.20, −4.47.
1H), 2.54–2.49 (m, 1H), 2.35–2.31 (m, 1H), 1.48–1.47 (m, 4H),
1.27 (s, 3H), 1.25 (s, 3H), 1.23 (s, 2H), 1.13 (s, 2H), 1.07 (s, 9H).
13C NMR of compound 33 (100 MHz, CDCl3): δ: 167.8,
161.2, 157.5, 137.3, 136.1, 135.9, 133.8, 133.5, 131.8, 129.7,
129.6, 127.6, 127.6, 116.3, 107.6, 100.5, 97.7, 82.5, 76.9, 74.4,
72.2, 55.9, 55.4, 38.4, 35.9, 30.0, 27.1, 26.7, 24.7, 20.9, 20.5,
19.3.
[α]2D8 = 29.7 (c = 0.1, CHCl3).
HRMS (ESI) for C45H66O8Si2Na [M + Na]+, calculated:
813.4193, found: 813.4181.
2-((S,E)-4-(tert-Butyldiphenylsilyloxy)-4-((4R,5R)-5-((S)-4-
hydroxypentyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-1-enyl)-4,6-
dimethoxybenzoic acid (3)
[α]2D8 = 11.7 (c = 0.1, CHCl3).
HRMS (ESI) for C39H50O7SiNa [M + Na]+, calculated:
681.3223, found: 681.3218.
To a stirring solution of the acid 32 (524 mg, 0.66 mmol) in
anhydrous acetonitrile (2 mL) and 2,2′ DMP (1.5 mL) was
added pyridinium p-toluenesulfonate (2 g, 8 mmol) and stirred
for 36 h at 45 °C. After completion of the reaction EtOAc
(70 mL) and brine (30 mL) were added to the reaction mixture
and the organic layer was separated. The aqueous part was
(3R,7R,8R,9S,E)-9-(tert-Butyldiphenylsilyloxy)-7,8-dihydroxy-
14,16-dimethoxy-3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-
benzo[c][1]oxacyclotetradecin-1-one (34)
then washed with EtOAc (2 × 50 mL). The combined organic To a stirring solution of macrolide 33 (59 mg, 0.09 mmol) in
part was washed with brine solution (30 mL) and dried over anhydrous CH2Cl2 (2 mL) was added p-toluenesulfonic acid
anhydrous MgSO4 and concentrated under reduced pressure. monohydrate (34 mg, 0.18 mmol) at room temperature and
The crude material was purified by flash column chromato- stirred for 2 h. After completion of the reaction, 20 mg solid
graphy (EtOAc–hexane = 1 : 1) to afford seco-acid 3 (379 mg, NaHCO3 was added to the reaction mixture and the solvent
0.56 mmol) in 85% yield as colorless oil.
was evaporated in vacuo. The residue was then purified by
flash column chromatography (EtOAc–hexane = 1 : 3) to afford
Rf = 0.25 (EtOAc–hexane, 1 : 1).
1H NMR of compound 3 (400 MHz, CDCl3): 7.72–7.67 (m, compound 34 (50 mg, 0.08 mmol) in 90% yield.
4H), 7.38–7.34 (m, 6H), 6.69 (d, J = 15.6 Hz, 1H), 6.50 (s, 1H),
6.37 (s, 1H), 6.23–6.16 (m, 1H), 4.11–4.09 (m, 1H), 4.04–4.02
Rf = 0.30 (EtOAc–hexane, 1 : 3).
1H NMR of compound 34 (400 MHz, CDCl3): δ: 7.70–7.67
(m, 1H), 3.85 (s, 3H), 3.89–3.82 (m, 1H), 3.79 (s, 3H), 3.65–3.64 (m, 4H), 7.47–7.37 (m, 6H), 6.47 (d, J = 15.5 Hz, 1H), 6.36 (s,
(m, 1H), 2.56–2.46 (m, 2H), 1.39 (s, 3H), 1.35–1–32 (m, 2H), 1H), 6.33 (d, J = 1.2 Hz, 1H), 5.71 (ddd, J = 15.6, 11.2, 4 Hz,
1.27 (s, 3H), 1.23 (s, 3H), 1.91 (s, 3H), 1.17–1.6 (m, 2H), 1.11 1H), 5.31–5.28 (m, 1H), 4.10 (dd, J = 6.8, 3.6 Hz, 1H), 3.89–3.86
(d, J = 6 Hz, 3H), 1.04 (s, 9H).
(m, 1H), 3.76 (s, 6H), 3.62–3.00 (m, 1H), 2.90–2.81 (m, 1H),
13C NMR of compound 3 (100 MHz, CDCl3): δ: 176.2, 161.7, 2.30–2.26 (m, 1H), 2.16–2.08 (m, 1H), 1.93–1.81 (m, 2H),
158.5, 148.5, 137.8, 136.3, 136.1, 136.1, 133.8, 133.7, 130.1, 1.79–1.70 (m, 4H), 1.09 (d, J = 6.4 Hz, 3H), 1.08 (s, 9H).
129.9, 129.9, 127.8, 127.8, 107.8, 102.5, 97.7, 79.9, 77.6, 72.2,
68.1, 56.3, 55.5, 38.9, 38.3, 30.1, 28.0, 27.3, 27.2, 27.1, 25.7, 157.8, 136.7, 136.1, 136.1, 133.5, 132.4, 130.4, 130.3, 129.9,
13C NMR of compound 34 (50 MHz, CDCl3): δ: 167.8, 161.4,
23.3, 22.20, 19.5.
128.2, 128.1, 116.9, 101.5, 98.1, 77.7, 74.0, 73.5, 71.9, 56.2,
55.6, 38.5, 32.6, 27.3, 19.8, 19.5, 19.1.
[α]2D8 = 21.7 (c = 0.1, CHCl3).
HRMS (ESI) for C39H52O8SiNa [M + Na]+, calculated:
699.3328, found: 699.3319.
[α]2D8 = 15.7 (c = 0.06, CHCl3).
HRMS (ESI) for C36H46O7SiNa [M + Na]+, calculated:
641.291, found: 641.283.
(3aR,7R,17S,17aR,E)-17-(tert-Butyldiphenylsilyloxy)-10,12-
dimethoxy-2,2,7-trimethyl-4,5,6,7,17,17a-hexahydro-3aH-
(3R,7R,8R,9S,E)-9-(tert-Butyldiphenylsilyloxy)-7,8,16-trihydroxy-
benzo[c][1,3]dioxolo[4,5-i][1]oxacyclotetradecin-9(16H)-one (33) 14-methoxy-3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-benzo[c]-
[1]oxacyclotetradecin-1-one (35)
To a solution of TPP (294 mg, 1.12 mmol) and DIAD (0.22 mL,
1.12 mmol) in 75 mL toluene under a N2 atmosphere at Compound 34 (30 mg, 0.04 mmol) was dissolved in anhydrous
−10 °C was added
a solution of seco-acid 3 (95 mg, CH2Cl2 (1.5 mL), and BBr3 (0.08 mL, 1 M 0.08 mmol, dissolved
0.14 mmol) in 50 ml toluene via a syringe pump over 1 h. The in 1 mL anhydrous CH2Cl2) was added for 5 minutes at 0 °C
resulting mixture was then slowly allowed to attain room temp- under a N2 atmosphere. The reaction mixture was then stirred
erature. After disappearance of the starting material as indi- for 4 h at 0 °C. After that, water (10 mL) and CH2Cl2 (20 mL)
cated by TLC, the reaction mixture was concentrated in vacuo were added and the organic layer was separated. The aqueous
and the crude material was purified by flash chromatography phase was extracted with additional CH2Cl2 (2 × 20 ml).
(EtOAc–hexane = 1 : 7) to furnish the macrolactone 33 (59 mg, The combined organic extracts were dried over anhydrous
0.09 mmol) in 65% yield.
MgSO4 and evaporated to dryness in vacuo. The crude
Rf = 0.40 (EtOAc–hexane, 1 : 5).
material was then purified by flash column chromatography
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(EtOAc–hexane = 1 : 5) to afford compound 35 (20 mg,
0.034 mmol) in 85% yield.
13C NMR of compound 53 (100 MHz, CDCl3): δ: 166.9,
161.4, 158.3, 138.8, 136.1, 136.1, 133.7, 133.8, 131.6, 130.1,
130.0, 129.5, 128.0, 115.8, 107.7, 102.7, 97.7, 82.6, 77.2, 72.4,
Rf = 0.40 (EtOAc–hexane, 1 : 3).
1H NMR of compound 35 (400 MHz, CDCl3): δ: 11.47 (s, 72.1, 56.2, 55.6, 37.1, 34.9, 30.8, 27.2, 26.9, 24.9, 20.1, 19.4.
1H), 7.71–7.67 (m, 4H), 7.48–7.40 (m, 6H), 6.77 (d, J = 15.2 Hz,
1H), 6.36 (s, 1H), 6.75 (s, 1H), 5.80 (td, J = 15.2, 6.4 Hz, 1H),
[α]2D8 = −11.7 (c = 0.01, CHCl3).
HRMS (ESI) for C39H50O7SiNa [M + Na]+, calculated:
5.08–5.06 (m, 1H), 4.20–4.19 (m, 1H), 3.79 (s, 3H), 3.76 681.3223, found: 681.3215.
(comp. 1H), 3.68–3.67 (m, 1H), 2.63–2.57 (m, 2H), 2.50–2.48
(3S,7R,8R,9S,E)-9-(tert-Butyldiphenylsilyloxy)-7,8-dihydroxy-
14,16-dimethoxy-3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-
benzo[c][1]oxacyclotetradecin-1-one (55)
(m, 1H), 2.41–2.39 (m, 1H), 1.97–1.93 (m, 2H), 1.73–1.70 (m,
2H), 1.33 (d, J = 6 Hz, 3H), 1.21 (s, 9H).
13C NMR of compound 35 (100 MHz, CDCl3): δ: 171.3,
164.7, 163.9, 142.2, 136.1, 136.1, 133.5, 133.1, 132.8, 130.4, Compound 53 was converted to 55 in 92% yield by PTSA in
130.3, 128.1, 125.0, 127.5, 108.1, 105.1, 100.1, 73.8, 73.7, 73.7, CH2Cl2 as described previously.
73.7, 55.6, 38.2, 34.8, 34.01, 27.3, 19.8, 19.5, 19.3.
1H NMR of compound 55 (400 MHz, CDCl3): δ: 7.71–7.69
(m, 4H), 7.46–7.39 (m, 6H), 6.46 (d, J = 15.6 Hz, 1H), 6.37 d, J =
[α]2D8 = 16.9 (c = 0.03, CHCl3).
HRMS (ESI) for C35H44O7SiNa [M + Na]+, calculated: 2.0 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 6.02–5.94 (m, 1H),
627.2753, found: 627.2747.
5.19–5.15 (m, 1H), 4.16–4.12 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H),
3.79–3.75 (comp. 1H), 3.64–3.62 (m, 1H), 2.59–2.52 (m, 1H),
2.38–2.33 (m, 1H), 1.76–1.56 (m, 4H), 1.51–1.56 (m, 2H), 1.30
(d, J = 6.4 Hz, 3H), 1.10 (s, 9H).
4,11,12,13-Tetrahydroxy-2-methoxy-7-methyl-
7,8,9,10,11,12,13,14-octahydro-6-oxa-benzocyclotetradecen-
5-one (10′-epi-paecilomycin E)
13C NMR of compound 55 (100 MHz, CDCl3): δ: 167.8,
Compound 35 (20 mg, 0.034 mmol) was dissolved in 1 mL 161.4, 158.2, 138.1, 136.6, 136.6, 133.0, 130.9, 130.3, 130.2,
anhydrous THF in a polyethylene vessel and 200 microliters of 129.9, 128.1, 128.0, 116.2, 103.0, 97.8, 76.4, 75.7, 72.7, 71.7,
HF-Py were added to it at 0 °C. The mixture was then stirred 56.2, 55.4, 37.1, 35.1, 33.5, 27.3, 20.3, 20.1, 19.5.
for 10 h at room temperature followed by addition of 15 mL
EtOAc and 5 mL brine solution. The organic layer was separ-
[α]2D8 = −15.7 (c = 0.06, CHCl3).
HRMS (ESI) for C36H46O7SiNa [M + Na]+, calculated:
ated and the aqueous layer was washed with (2 × 10 mL) of 641.291, found: 641.288.
EtOAc. The combined organic part was washed with brine
(3S,7R,8R,9S,E)-9-(tert-Butyldiphenylsilyl)-7,8,16-trihydroxy-14-
methoxy-3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-benzo[c][1]-
oxacyclotetradecin-1-one (57)
(5 mL) and the solution was dried over anhydrous MgSO4 and
then concentrated in vacuo. The crude material was then puri-
fied by flash column chromatography (EtOAc–hexane = 1 : 1) to
afford 10′-epi-paecilomycin E (9 mg, 0.027 mmol) in 80% yield. Compound 55 was reacted with BBr3 to afford compound 57 as
1H NMR of 10′-epi-paecilomycin E (400 MHz, CDCl3): δ: described earlier in 82% yield.
11.54 (s, 1H), 6.94 (d, J = 16 Hz, 1H), 6.46 (s, 1H), 6.40 (s, 1H),
1H NMR of compound 57 (400 MHz, CDCl3): δ: 12.19 (s,
6.11–6.00 (m, 1H), 5.22–5.18 (m, 1H), 4.2 (s, 1H), 3.97–3.74 (m, 1H), 7.71–7.69 (m, 4H), 7.48–7.38 (m, 6H), 7.08 (d, J = 15.2 Hz,
1H), 3.81 (s, 3H), 3.75–3.74 (m, 1H), 2.80–2.70 (m, 2H), 1H), 6.36 (d, J = 2.8 Hz, 1H), 6.21 (d, J = 2.8 Hz, 1H), 5.47–5.40
2.04–1.98 (m, 2H), 1.81–1.80 (m, 2H), 1.78–1.70 (m, 2H), 1.36 (m, 1H), 5.29–4.99 (m, 1H), 4.18–4.14 (m, 1H), 3.89 (s, 1H),
(d, J = 6 Hz, 3H).
3.78 (s, 3H), 3.70–3.68 (m, 1H), 2.84–2.76 (m, 2H), 2.37–2.17
13C NMR of 10′-epi-paecilomycin E (100 MHz, CDCl3): (m, 2H), 1.84–1.71 (m, 2H), 1.70–1.62 (m, 2H), 1.38 (d, J =
δ: 171.1, 165.0, 164.2, 142.1, 134.2, 127.1, 108.4, 105.0, 100.4, 6.0 Hz, 3H), 1.11 (s, 9H).
75.9, 75.7, 73.7, 73.5, 55.7, 38.7, 34.8, 34.5, 19.9, 19.8.
13C NMR of compound 57 (100 MHz, CDCl3): δ: 171.8,
[α]2D6 = 19.9 (c = 0.01, CHCl3).
165.9, 164.1, 143.0, 136.1, 136.1, 134.0, 133.5, 132.7, 130.4,
HRMS (ESI) for C19H26O7Na [M
389.1576, found: 389.1572.
+
Na]+, calculated: 130.3, 129.2, 128.1, 128.0, 108.5, 103.9, 100.3, 77.9, 74.6, 73.3,
73.1, 55.6, 38.6, 35.7, 32.7, 27.3, 20.8, 20.6, 19.5.
[α]2D8 = −36.9 (c = 0.03, CHCl3).
(3aR,7S,17S,17aR,E)-17-(tert-Butyldiphenylsilyloxy)-10,12-
dimethoxy-2,2,7-trimethyl-4,5,6,7,17,17a-hexahydro-3aH-
benzo[c][1,3]dioxolo[4,5-i][1]oxacyclotetradecin-9(16H)-one (53)
HRMS (ESI) for C35H44O7SiNa [M + Na]+, calculated:
627.2753, found: 627.2747.
(3S,7R,8R,9S,E)-7,8,9,16-Tetrahydroxy-14-methoxy-3-methyl-
3,4,5,6,7,8,9,10-octahydro-1H-benzo[c][1]oxacyclotetradecin-
1-one (paecilomycin E)
Seco-acid 51 was cyclized to compound 53 via Mitsunobu
macrolactonization in 68% yield as presented earlier.
1H NMR of compound 53 (400 MHz, CDCl3): δ: 7.70–7.62
(m, 4H), 7.45–7.37 (m, 6H), 6.34–6.32 (m, 2H), 6.20 (d, J = The TBDPS group in compound 57 was reacted with HF-Py in
16.0 Hz, 1H), 6.04–5.97 (m, 1H), 4.96–4.92 (m, 1H), 4.15 (dd, THF as stated earlier to furnish natural paecilomycin E in 80%
J = 6.8, 3.2 Hz, 1H), 3.94–3.93 (m, 2H), 3.78 (s, 6H), 2.59–2.51 yield.
(m, 2H), 1.42 (s, 3H), 1.29 (comp. 2H), 1.25 (s, 3H), 1.24 (d, J =
6.4 Hz, 3H), 1.21–1.16 (comp. 4H), 1.04 (s, 9H).
1H NMR of paecilomycin E (400 MHz, CDCl3): δ: 12.00 (s,
1H), 7.19 (dd, J = 15.2, 1.2 Hz, 1H), 6.37 (s, 1H), 6.37 (s, 1H),
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5.27 (s, 1H), 4.97 (s, 1H), 4.16 (s, 1H), 3.92 (s, 1H), 3.78 (s, 1H), (3S,7R,8R,9S,E)-9-(tert-Butyldiphenylsilyloxy)-13-chloro-7,8,16-
3.67 (s, 2H), 2.72 (s, 1H), 2.64 (s, 1H), 1.77–1.73 (m, 6H), 1.40 trihydroxy-14-methoxy-3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-
(s, 3H).
1H NMR of paecilomycin E (600 MHz, acetone-d6, 2.09):
benzo[c][1]oxacyclotetradecin-1-one (58)
Selective demethylation of compound 56 was performed as
stated earlier to afford compound 58 in 85% yield.
1H NMR of compound 58 (400 MHz, CDCl3): δ: 11.99 (s,
1H), 7.69–7.68 (m, 4H), 7.45–7.38 (m, 6H), 6.52 (d, J = 17.6 Hz,
1H), 6.43 (s, 1H), 5.34–5.27 (m, 1H), 5.07 (s, 1H), 4.11–4.08 (m,
1H), 3.89 (s, 3H), 3.89 (comp. 1H), 3.59–3.58 (m, 1H),
2.73–2.69 (m, 1H), 2.60–2.58 (m, 1H), 2.46–2.42 (m, 1H),
1.70–1.68 (m, 1H), 1.57–1.55 (m, 3H), 1.32 (d, J = 6.0 Hz, 3H),
1.31–1.29 (m, 1H), 1.10 (s, 9H).
δ: 12.10 (s, 1H), 7.24 (dd, J = 15.6, 1.2 Hz, 1H), 6.51 (d, J = 2.4
Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 5.99 (ddd, J = 15.0, 10.8, 3.6
Hz, 1H), 5.09–5.06 (m, 1H), 4.40 (s, 1H), 4.12–4.11 (m, 1H),
3.97 (s, 1H), 3.89 (s, 3H), 3.77 (s, 1H), 3.74 (s, 1H), 2.85–2.84
(m, 1H), 2.53–2.50 (m, 1H), 2.08–2.00 (m, 1H), 1.85–1.79 (m,
2H), 1.79 (m, 2H), 1.71–1.67 (m, 1H), 1.44 (d, J = 6.0 Hz, 3H).
13C NMR of paecilomycin E (100 MHz, CDCl3, 77.00):
δ: 171.34, 165.57, 164.03, 142.97, 134.53, 128.33, 108.60,
103.88, 100.18, 77.30, 75.99, 74.07, 71.37, 55.42, 53.40, 38.96,
35.40, 33.80, 21.19, 20.46.
13C NMR of compound 58 (100 MHz, CDCl3): δ: 171.1,
163.5, 160.2, 140.1, 136.1, 136.0, 133.3, 132.7, 132.6, 130.4,
130.3, 128.3, 128.1, 128.0, 114.3, 105.9, 99.8, 79.1, 79.1, 74.6,
72.4, 56.6, 37.9, 35.8, 33.4, 27.3, 21.2, 20.8, 19.5.
[α]2D6 = −83.97 (c = 0.08, CHCl3).
HRMS (ESI) for C19H26O7Na [M + H]+, calculated: 367.1757,
found: 367.1743.
[α]2D8 = −36.9 (c = 0.03, CHCl3).
HRMS (ESI) for C35H43ClO7SiNa [M + Na]+, calculated:
661.2364, found: 661.2363.
(3aR,7S,17S,17aR,E)-17-(tert-Butyldiphenylsilyloxy)-13-chloro-
10,12-dimethoxy-2,2,7-trimethyl-4,5,6,7,17,17a-hexahydro-3aH-
benzo[c][1,3]dioxolo[4,5-i][1]oxacyclotetradecin-9(16H)-one (54)
(3S,7R,8R,9S,E)-13-Chloro-7,8,9,16-tetrahydroxy-14-methoxy-
3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-benzo[c][1]
oxacyclotetradecin-1-one (6′-epi-cochliomycin C)
Seco-acid 52 was converted to 54 via Mitsunobu macrolactoni-
zation in 65% yield as stated earlier.
1H NMR of compound 54 (400 MHz, CDCl3): δ: 7.76–7.70
(m, 4H), 7.43–7.41 (m, 6H), 6.41 (s, 1H), 6.30 (d, J = 16.0 Hz,
1H), 5.99–5.91 (m, 1H), 4.67–4.64 (m, 1H), 4.14 (dd, J = 7.2,
2 Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.82 (comp. 1H), 3.71 (s,
1H), 2.76–2.69 (m, 1H), 2.58–2.52 (m, 1H), 1.49 (s, 3H),
1.50–1.41 (m, 3H), 1.37–1.33 (m, 3H), 1.31 (s, 3H), 1.21 (d, J =
6.4 Hz, 3H), 1.04 (s, 9H).
Removal of the TBDPS group was achieved when compound 58
was reacted with HF-Py to form 6′-epi-cochliomycin C in 82%
yield as described earlier.
1H NMR of 6′-epi-cochliomycin C (400 MHz, CDCl3):
δ: 11.72 (s, 1H), 6.72 (d, J = 14.0 Hz, 1H), 6.47 (s, 1H), 5.62 (s,
1H), 5.10 (s, 1H), 4.09–4.03 (m, 1H), 3.91 (s, 3H), 3.78–3.64 (m,
2H), 2.76 (m, 2H), 1.69–1.67 (comp. 6H), 1.36 (d, J = 5.2 Hz, 3H).
1H NMR of 6′-epi-cochliomycin C (600 MHz, acetone-d6):
δ: 11.38 (s, 1H), 6.72 (d, J = 16.2 Hz, 1H), 6.63 (s, 1H), 5.85–5.80
(m, 1H), 5.21–5.16 (m, 1H), 4.40 (s, 1H), 3.97 (s, 3H), 3.97
(comp. 1H), 3.80–3.90 (m, 1H), 3.71 (s, 1H), 2.81 (m, 1H), 2.63
(m, 1H), 1.86–1.85 (m, 2H), 1.75–1.72 (m, 2H), 1.68–1.65 (m,
2H), 1.39 (d, J = 6.0 Hz, 3H).
13C NMR of compound 54 (50 MHz, CDCl3): δ: 166.9, 156.4,
155.9, 136.4, 136.1, 135.3, 134.6, 133.6, 129.9, 129.7, 128.2,
127.8, 127.2, 118.2, 113.7, 107.7, 95.5, 82.6, 77.8, 73.2, 72.9,
56.6, 56.5, 38.7, 34.8, 29.7, 27.3, 26.7, 24.9, 22.3, 21.3, 19.5.
[α]2D8 = −11.7 (c = 0.01, CHCl3).
HRMS (ESI) for C39H49ClO7SiNa [M + Na]+, calculated:
715.2833, found: 715.2825.
13C NMR of 6′-epi-cochliomycin C (100 MHz, CDCl3):
δ: 170.8, 163.1, 160.3, 140.3, 129.3, 114.5, 106.2, 99.9, 77.5,
77.2, 76.9, 74.3, 56.6, 38.4, 36.1, 32.1, 21.5, 20.8.
(3S,7R,8R,9S,E)-9-(tert-Butyldiphenylsilyloxy)-13-chloro-7,8-
dihydroxy-14,16-dimethoxy-3-methyl-3,4,5,6,7,8,9,10-
octahydro-1H-benzo[c][1]oxacyclotetradecin-1-one (56)
[α]2D6 = −30.5 (c = 0.02, CHCl3).
HRMS (ESI) for C19H25ClO7Na [M
+
H]+, calculated:
Deprotection of the acetonide group in compound 54 was per-
formed as stated earlier to furnish compound 56 in 95% yield.
1H NMR of compound 56 (400 MHz, CDCl3): δ: 7.70–7.69
(m, 4H), 7.44–7.38 (m, 6H), 6.40 (s, 1H), 6.30 m (d, J = 16.0 Hz,
1H), 5.82–5.75 (m, 1H), 5.07–5.02 (m, 1H), 4.03 (d, J = 9.2 Hz,
1H), 3.93 (s, 3H), 3.86–3.84 (m, 1H), 3.80 (s, 3H), 3.60–3.59 (m,
1H), 2.80–2.75 (m, 2H), 2.35–2.25 (m, 1H), 1.54–1.52 (m, 2H),
1.49–143 (m, 3H), 1.27 (d, J = 6.0 Hz, 3H), 1.04 (s, 9H).
13C NMR of compound 56 (100 MHz, CDCl3): δ: 167.4,
156.2, 155.8, 136.3, 135.8, 135.8, 134.1, 133.3, 132.9, 129.9,
128.4, 127.8, 127.8, 127.2, 117.6, 113.5, 110.2, 95.2, 75.9, 72.2,
70.8, 70.8, 6.4, 56.4, 37.9, 34.7, 30.4, 27.1, 20.7, 19.3, 19.2.
[α]2D8 = −17.7 (c = 0.05, CHCl3).
401.1367, found: 401.1360.
Acknowledgements
Financial support from CSIR-India is gratefully acknowledged
(grant 02(0020)/11/EMR-II). We are also thankful to DST-India
(IRPHA) for the NMR instrument. Two of the authors, PP and NJ,
are thankful to CSIR-India for providing a research fellowship.
References
HRMS (ESI) for C36H45ClO7SiNa [M + Na]+, calculated:
675.2520, found: 675.2527.
1 P. Delmotte and J. Delmotte-Plaquee, Nature, 1953, 171,
344–345.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
2 M. Stob, R. S. Baldwin, J. Tuite, F. N. Andrews and
K. G. Gillette, Nature, 1962, 196, 1318–1318.
3 G. A. Ellestad, F. M. Lovell, N. A. Perkinson,
R. T. Hargreaves and W. J. McGahren, J. Org. Chem., 1978,
43, 2339–2343.
and Y.-C. Lin, J. Nat. Prod., 2011, 74, 629–633;
(b) W. Zhang, C. Shao, M. Chen, Q.-A. Liu and
C.-Y. Wang, Tetrahedron Lett., 2014, 55, 4888–
4891.
9 C.-L. Shao, H.-X. Wu, Ch.-Y. Wang, Q.-A. Liu, Y. Xu,
M.-Y. Wei, P.-Y. Qian, Y.-C. Gu, C.-J. Zheng, Z.-G. She and
Y.-C. Lin, J. Nat. Prod., 2013, 76, 302–302.
4 M. S. R. Nair and S. T. Carey, Tetrahedron Lett., 1980, 21,
2011–2012.
5 (a) M. Lampilas and R. Lett, Tetrahedron Lett., 1992, 33, 10 L. Xu, Z. He, J. Xue, X. Chen and X. Wei, J. Nat. Prod., 2012,
773–776; (b) M. Lampilas and R. Lett, Tetrahedron Lett.,
1992, 33, 777–780.
75, 1006–1006.
11 N. Jana and S. Nanda, Eur. J. Org. Chem., 2012, 4313–
6 (a) I. Navarro, J. F. Basset, S. Hebbe, S. M. Major,
4320.
T. Werner, C. Howsham, J. Brackow and A. G. M. Barett, 12 (a) N. Jana and S. Nanda, Tetrahedron: Asymmetry, 2012, 23,
J. Am. Chem. Soc., 2008, 130, 10293–10298; (b) F. Calo,
J. Richardson and A. G. M. Barett, Org. Lett., 2009, 11,
802–808; (b) N. Jana, D. Das and S. Nanda, Tetrahedron,
2013, 69, 2900–2908.
4910–4913; (c) S. Sugiyama, S. Fuse and T. Takahasi, Tetra- 13 (a) D. K. Mohapatra, D. S. Reddy, N. A. Mallampudi and
hedron, 2011, 67, 6654–6658; (d) V. Navickas and
M. E. Maier, Tetrahedron, 2010, 66, 94–101; (e) T. Hofmann
and K. H. Altmann, C. R. Chim., 2008, 11, 1318–1335;
(f) N. Winssinger, J. C. Fontaine and S. Barluenga, Curr.
Top. Med. Chem., 2009, 9, 1419–1435; (g) R. Jogireddy,
P. Y. Dakas, G. Valot, S. Barluenga and N. Winssinger,
J. S. Yadav, Eur. J. Org. Chem., 2014, 5023–5032;
(b) P. Srihari, B. Mahankali and K. Rajendraprasad, Tetra-
hedron Lett., 2012, 53, 56–58; (c) Y. Gao, J. Liu, L. Wang,
M. Xiao and Y. Du, Eur. J. Org. Chem., 2014, 2092–2098;
(d) L. Wang, Y. Gao, J. Liu, C. Cai and Y. Du, Tetrahedron,
2014, 70, 2616–2620.
Chem. – Eur. J., 2009, 15, 11498–11506; (h) R. M. Garbaccio, 14 U. T. Bornscheuer and R. J. Kazlauskas, in Hydrolases in
S. J. Stachel, D. K. Baeschlin and S. J. Danishefsky, J. Am.
Chem. Soc., 2001, 123, 10903–10908; (i) T. Hofmann and
K. H. Altmarm, Synlett, 2008, 1500–1504; ( j) L. J. Baird,
Organic Synthesis: Regio- and Stereoselective Biotransform-
ations, Wiley-Blackwell, 2nd edn, 2006, ISBN: 978-3-527-
60712-9.
M. S. Timmer, P. H. Teesdale-Spittle and J. E. Harvey, 15 K. Horita, T. Yoshioka, Y. Tanaka, Y. Oikawa and
J. Org. Chem., 2009, 74, 2271–2277; (k) S. Barluenga, O. Yonemitsu, Tetrahedron, 1986, 42, 3021–3028.
J. G. Fontaine, C. H. Wang, K. Aoudi, R. H. Chen, K. Beebe, 16 D. A. Evans, R. L. Dow, T. L. Shih, J. M. Takacs and
L. Neckers and N. Winssinger, ChemBioChem, 2009, 10, R. Zahler, J. Am. Chem. Soc., 1990, 112, 5290–5313.
2753–2759; (l) J. E. H. Day, A. J. Blake and C. J. Moody, 17 C. D. Hopkins, J. C. Schmitz, E. Chu and P. Wipf, Org. Lett.,
Synlett, 2009, 1567–1570; (m) T. Takahashi, H. Ikeda and 2011, 13, 4088–4091.
J. Tsuji, Tetrahedron Lett., 1980, 21, 3885–3888; 18 K. Ishigami, H. Watanabe and T. Kitahara, Tetrahedron,
(n) C. Napolitano, P. McArdle and P. V. Murphy, J. Org. 2005, 61, 7546–7553.
Chem., 2010, 75, 7404–7407; (o) Z. Yang, X. Geng, D. Solit, 19 T. Das, R. Bhuniya and S. Nanda, Tetrahedron: Asymmetry,
C. A. Pratilas, N. Rosen and S. J. Danishefsky, J. Am. Chem. 2010, 21, 2206–2211.
Soc., 2004, 126, 7881–7889; (p) S. Barluenga, P. Y. Dakas, 20 R. Pappo, D. S. Allen, R. U. Lemieux and W. S. Johnson,
Y. Ferandin, L. Meijer and N. Winssinger, Angew. Chem., J. Org. Chem., 1956, 21, 478–479.
Int. Ed., 2006, 45, 3951–3954; (q) X. Geng and 21 C. Aissa, Eur. J. Org. Chem., 2009, 1831–1844.
S. J. Danishefsky, Org. Lett., 2004, 6, 413–416; 22 C. Nilewski, N. R. Deprez, T. C. Fessard, D. B. Li,
(r) C. C. Chrovian, B. Knapp-Reed and J. Montgomery, Org.
Lett., 2008, 10, 811–814; (s) C. A. LeClair, M. B. Boxer,
R. W. Geisser and E. M. Carreira, Angew. Chem., Int. Ed.,
2011, 50, 7940–7943.
C. J. Thomas and D. J. Maloney, Tetrahedron Lett., 2010, 51, 23 J. K. Cha, W. C. Christ and Y. Kishi, Tetrahedron, 1984, 40,
6852–6855; (t) H. Miyatake-Ondozabal and A. G. M. Barett, 2247–2255.
Org. Lett., 2010, 12, 5573–5575; (u) D. Martinez-Solorio, 24 X.-R. Huang, X.-H. Pan, G.-H. Lee and C. Chen, Adv. Synth.
K. A. Belmore and M. P. Jennings, J. Org. Chem., 2011, 76, Catal., 2011, 353, 1949–1954.
3898–3908; (v) P. Y. Dakas, R. Jogireddy, G. Valot, 25 M. V. R. Reddy, B. Akula, S. C. Cosenza, C. M. Lee,
S. Barluenga and N. Winssinger, Chem. – Eur. J., 2009, 15,
11490–11497; (w) P. Y. Dakas, S. Barluenga, F. Totzke,
U. Zirrgiebel and N. Winssinger, Angew. Chem., Int. Ed.,
M. R. Mallireddigari, V. R. Pallela, D. R. C. V. Subbaiah,
A. Udofa and E. P. Reddy, J. Med. Chem., 2012, 55, 5174–
5187.
2007, 46, 6899–6902; (x) S. Barluenga, P. Y. Dakas, 26 R. J. K. Taylor, M. Reid, J. Foot and S. A. Raw, Acc. Chem.
M. Boulifa, E. Moulin and N. Winssinger, C. R. Chim.,
2008, 11, 1306–1317.
7 L. Xu, Z. He, J. Xue, X. Chen and X. Wei, J. Nat. Prod., 2010,
73, 885–889.
8 (a) C.-L. Shao, H.-X. Wu, C.-Y. Wang, Q.-A. Liu, Y. Xu,
M.-Y. Wei, P.-Y. Qian, Y.-C. Gu, C.-J. Zheng, Z.-G. She
Res., 2005, 38, 851–869.
27 B. S. Bal, W. E. Childers and H. W. Pinnick, Tetrahedron,
1981, 37, 2091–2096.
28 J. Inanaga, K. Hirata, H. Saeki, T. Katsuki and
M. Yamaguchi, Bull. Chem. Soc. Jpn., 1979, 52, 1989–
1993.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
29 I. Shiina, M. Kubota, H. Oshiumi and M. Hashizume, 32 (a) J. M. Lansinger and R. Ronald, Synth. Commun., 1979,
J. Org. Chem., 2004, 69, 1822–1830.
30 E. P. Boden and G. E. Keck, J. Org. Chem., 1985, 50, 2394–
9, 341–349; (b) G. N. Varseev and M. E. Maier, Angew.
Chem., Int. Ed., 2006, 45, 4767–4771; (c) M. Pittelkow,
U. Boas and J. B. Christensen, Org. Lett., 2006, 8, 5817–
5820.
2395.
31 D. R. Williams and K. G. Meyer, J. Am. Chem. Soc., 2001,
123, 765–766.
33 R. D. Crouch, Tetrahedron, 2004, 60, 5833–5871.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2014