Asymmetric total synthesis of paecilomycin C through intramolecular nucleophilic ring opening of an epoxide

Article abstract of DOI:10.1039/c9ob01504c

The convergent total synthesis of naturally occurring paecilomycin C is described here for the first time. Asymmetric Brown allylation, E-selective cross metathesis, and a biomimetic carboxylate assisted intramolecular nucleophilic ring opening of an epoxide were employed to access the enantiopure γ-lactone framework of the natural product. Late stage E-selective Julia-Kocienski olefination was then employed to furnish the natural product in an efficient way.

Full text of DOI:10.1039/c9ob01504c

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DOI: 10.1039/C9OB01504C
Asymmetric total synthesis of paecilomycin C through
intramolecular nucleophilic ring opening of an epoxide
Joy Chakraborty and Samik Nanda*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, 721302,
India
ABSTRACT: The convergent total synthesis of naturally occurring paecilomycin C was
described here for the first time. Asymmetric Brown allylation, E-selective cross metathesis,
and a biomimetic carboxylate assisted intramolecular nucleophilic ring opening of epoxide
were employed to access the enantiopure γ-lactone framework of the natural product. Late
stage E-selective Julia-Kocienski olefination was then employed to furnish the natural
product in an efficient way.
INTRODUCTION
1
Resorcylic acid lactones (RALs) are mycotoxins produced by different fungal strains and
come from a family of polyketide derived macrolides. A handful number of members of this
family show a broad spectrum of biological activities including antifungal, antimalarial,
3,4
antitumor, antibacterial, and several more.2 For example, radicicol inhibits HSP90
and
posses antiplasmodial activities.2e RALs containing a cis-enone like hypothemycin, LL-
Z1640-2, and L-783,277 irreversibly inhibits mitogen-activated protein kinases (MAP
6
kinases).5 Six new β-resorcylic acid lactones, named paecilomycins A-F were isolated
recently from the solid mycelial culture of Paecilomyces sp. SC0924 in late 2010 by Chen
and Wei et al. along with other known RALs. Paecilomycin A (1) possesses 1',2'-epoxy
linkage with three hydroxyl groups at 4',5',6'-position whereas paecilomycin C and D (3 & 4)
possesses 5-membered γ-lactones instead of the 14-membered macrolactones seen in other
RALs (Figure 1). Paecilomycin B (2) consists of a unique tetrahydropyran ring connecting
between C1' and C5'. Paecilomycin E exhibited antiplasmodial activity against Plasmodium
1

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falciparum line 3D7 with IC50 values of 20.0 nM. Paecilomycin E and F (5 & 6) showed
DOI: 10.1039/C9OB01504C
moderate activity against the P. falciparum line Dd2. Three new RALs paecilomycins G-I
(Figure 1) were isolated in 2012 from MeOH extract of the solid culture of Paecilomyces sp.
SC0924 showed antifungal activity against Peronophythora litchii, one of the main pathogens
causing Lithi (Litchi chinensis Sonn.) fruit rot.7 Close structural inspection reveals that
paecilomycin H (8) is the acetonide protected aigialomycin D, whereas paecilomycin I (9) is
structurally related to aigialomycin A and contains an extra ethoxy group at C8ʹ position.
Total syntheses of paecilomycin B, E, F, and G have been achieved in recent years.
Paecilomycin B was synthesized by Ohba and co-workers through successful construction of
aryl-β-C-glycosides through Barbier type lithiation and RCM (ring closing metathesis)
reaction.8 Asymmetric total synthesis of paecilomycins E and F was reported by our group
and others through successful exploration of late-stage biomimetic macrolactonization and
RCM reaction.9-10 Paecilomycin G was synthesized by Das and co-workers for the first time
through late-stage RCM reaction.11 In continuation of our efforts towards the synthetic
studies of naturally occurring RALs, we would like to report the total synthesis of
paecilomycin C (γ-lactone containing RAL) for the first time.
2

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DOI: 10.1039/C9OB01504C
OH
O
OH
O
O
O
O
H3CO
OH
H3CO
OH
O
OH
HO
OH
OH
Paecilomycin B (2)
Paecilomycin A (1)
OH
O
OH
O
O
O
OH
H3CO
OH
H3CO
R1
R2
R R
OH OH
OH
2
1
OH
Paecilomycin C
Paecilomycin D
3
4
; R1 = H, R2 = OH;
; R1 = OH, R2 = H;
Paecilomycin E
Paecilomycin F
5
6
; R1 = OH, R2 = H;
; R1 = H, R2 = OH;
OH
O
OH
O
OH
O
O
O
O
OEt
MeO
OH
MeO
MeO
OH
O
O
O
Paecilomycin I (9)
Paecilomycin H (8)
Paecilomycin G (7)
O
OH
OH
Figure 1: Structural features of paecilomycins A-I
Paecilomycin C and D having a unique γ-lactone core (phthalide framework) in their
structure need a different strategical blueprint compared to their other structural congeners
(having 14 membered lactone ring). We intend to explore a novel biomimetic intramolecular
cyclization of a carboxylate anion to an “electrophilic” oxygen center (such as alcohol or
epoxide) to generate the γ-lactone core of paecilomycin C. Such biomimetic pathway for
“phthalide” containing natural product aigialospirol was speculated earlier.12 Biosynthesis of
epoxy-RALs such as hypothemycin and aigialomycin was known.1g As the gene cluster for
RAL biosynthesis in plants are highly conserved, it was thought that once the 14 ring
membered epoxy-RAL (hypothemycin) was formed subsequent ester hydrolysis generated
2
the carboxylate anion, and concomitant cyclization through 5-exo-tet mode (SN inversion)
and subsequent spiroacetal formation lead to aigialospirol. But this was speculation as no
3

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documented evidence was found in the literature. In another alternative route, epoxide
DOI: 10.1039/C9OB01504C
2
hydrolysis at the benzylic carbon (SN inversion) leading to 1,2-diol followed by γ-lactone
formation was also speculated (Scheme-1). In analogy with the aigialospirol biogenesis, we
argued that paecilomycinc C and D could also be viewed as originated from paecilomycins A
and aigialomycin B (both are epoxy-RALs) through a similar sequence of reactions. The
detailed retrosynthetic disconnection for paecilomycin C was outlined in Scheme 1. We
propose a carboxylate assisted intramolecular nucleophilic ring opening (5-exo-tet fashion) of
the properly assembled epoxide appendage as a key reaction for the construction of the γ-
lactone core present in the natural product.
RESULTS AND DISCUSSION
We have considered accessing the C7´-C8´ trans olefinic unsaturation by a late stage Julia-
Kocienski (JK) olefination between aldehyde 10 and known sulfone 11. The aldehyde 10
having the required γ-lactone core was thought to be constructed through an in-situ generated
carboxylate anion triggered intramolecular epoxide ring opening from 12. Epoxide 12 could
be accessed from olefin 13 by a substrate directed epoxidation reaction. Olefin 13 could be
delivered from aromatic substrate 14 and aliphatic olefin moiety 15 by an olefin cross-
metathesis reaction. Whereas, aromatic cross metathesis precursor 14 could be synthesized by
a known protocol from 2,4,6-tri hydroxyl benzoic acid. The aliphatic CM precursor 15 could
be accessed from (+) DET.
4

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DOI: 10.1039/C9OB01504C
OH
O
OH
O
O
OH
JK-olefination
H3CO
P2O
CHO
OP2
PtO2S
O
H3CO
Paecilomycin C
+
OH OH OH
OH
OP4
11
3
10
OP1 OP1
Intramolecular epoxide
ring opening and lactonization
O
O
OH
O
Substrate directed
epoxidation
O
O
OP1 OP2
OP2
O
O
OP1 OP2
OP2
OP3
OP3
MeO
MeO
12
Biomimetic 5-exo-tet
mode of cyclization
O
O
O
OH OP2
OP2
O
O
OH OP2
Cross metathesis
OP3
OP3
MeO
O
+
OP2
13
MeO
15
14
P1 = TBS; P2 = acetonide; P3 = PMB
P4 = TBDPS; JK = Julia-Kocienski
OH
OH
CO2Et
CO2H
OH
EtO2C
OH
HO
(+)-DET
16
17
O
OH
O
Path 1: Hydrolysis of the ester linkage and attack at
benzylic carbon of epoxide through SN mode and
subsequent spiroacetal formation took place
2
O
O
O
MeO
O
OH
2
O
Or path 2: Epoxide cleavage at bezylic carbon with SN
OH
O
Me
Hypothemycin
leading to 1,2-diol followed by -lactonization
HO
OH
Aigialospirol
OH
O
O
Analogy to the earlier hypothesis
H3CO
OH
Paecilomycin C and D
O
R
OH
R = -OH; Paecilomycin A
R = OH, Aigialomycin B

Putative biosynthesis of paecilomycins C & D involves
similar pathway as reported for aigialospirol

12
Scheme 1. Putative biosynthesis of phthalide containing natural product involving ester
hydrolysis/epoxide opening and our proposed retrosynthetic disconnection of paecilomycin C
through a biomimetic nucleophilic ring opening of an epoxide.
The synthesis was initiated from L(+) DET as a chiral pool starting material which was
converted to known compound 18 by a three-step protocol.13 Compound 18 was then
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14
subjected to Swern Oxidation
to furnish aldehyde 19 which was then immediately
DOI: 10.1039/C9OB01504C
subjected to Brown allylation reaction 15 to afford compound 15 as a major diastereomer in
72% yield (dr = 9:1). The absolute configuration of compound 15 was not established at this
stage, it was assumed that the compound would have the predicted absolute configuration at
the newly generated stereocenter based on the previous report.15b The homoallylic alcohol 15
was next subjected to CM reaction with the fully substituted styrene 14 16 in the presence of
HG-II catalyst (6 mol %), but unfortunately, the starting material was recovered without any
detectable amount of the desired product. The outcome for this unsuccessful CM can be
explained by considering the pioneering work of Grubbs and co-workers.17a A general
ranking of several olefins in the CM reaction (based on their steric and electronic
behavior) was proposed in that article. It was argued that the best approach towards
a successful CM reaction should involve, reaction of a fast reacting olefin (type-I;
which undergoes fast homodimerization; styrene compound with small ortho
substitution, compound 14 in our case) with a slow reacting olefin (type-II; slow
homodimerization and the homodimers are sparingly consumed in CM reaction,
compound 15 with free 2° allylic alcohol in our case) or type-III (unable to
homodimerize but can take part with CM with type-I olefin, compound 21 in our
case). Initially, the CM reaction in our case with 14 and 15 did not take place. We
speculate that compound 15 bearing a free 2° allylic alcohol moiety can undergo
6

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DOI: 10.1039/C9OB01504C
slow homodimerization process, and once this homodimer was formed, it hardly
reacts with homodimer of compound 14 (type-I olefin). To overcome this unwanted
homodimerization process, free –OH group in 15 was protected as its –TBS ether by
treatment with imidazole and TBS-Cl to furnish compound 21 in 90% yield (hence a
type-II olefin was converted to a type-III olefin). The attempted CM reaction with
compound 14 and 21 now worked well as shown in Scheme 2 and provided
compound 22 in 72% yield (in the presence of 6 mol% of HG-II catalyst,17b-d exclusively E
isomer was obtained). This simple substrate modification (by suitable protecting group
manipulation) results in enhanced yield in the CM reaction by suppressing the
unwanted homodimerization side reaction. This reaction condition represents the
control of product and stereoselectivity in CM based purely on steric considerations,
which may be adjusted through the careful choice of suitable protecting groups.
The olefin 22 was then treated with TBAF to afford secondary alcohol 13 in 93% yield.
Substrate directed epoxidation of compound 13 with mCPBA was next attempted, and
diastereomeric mixtures of epoxides (3:1) were obtained in 82% yield. At this stage, the
diastereomers were inseparable by column chromatography. Hence mixtures of 23 and 24
were then converted to its corresponding TBS ether by treatment with TBS-Cl and imidazole
to furnish compound 12. The mixtures of epoxy silyl ether were next treated with LiOH for
the proposed carboxylate assisted intramolecular epoxide ring opening reaction. The
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intramolecular lactonization (through the 5-exo-tet mode of cyclization) 18 smoothly furniVsiehweAdrticle Online
DOI: 10.1039/C9OB01504C
lactone 25 (major) in 54% yield and 26 (minor) in 18% yield (72% overall yield in two steps;
based on the recovery of starting material 12). Diastereomeric mixture of epoxide 23 and 24
which was inseparable initially was separated after lactonization by column chromatography
as lactone 25 and 26. The appearance of a strong peak at 1750 cm-1(ν) of compound 25 in its
IR spectrum confirmed the presence of a γ-lactone core (due to C=O stretching frequency of
the carbonyl group of lactone in conjugation with the aromatic ring) is also consistent with
the literature value.12 The formation of the regioisomeric δ-lactone core was nullified as such
system would exhibit a peak at 1640 cm-1(ν) (due to C=O stretching frequency of the
carbonyl group) as reported for aigialomycin F (having a δ-lactone core in conjugation with
the aromatic ring).19 The stereochemical relationship between C2´and C4´ stereocenter was
confirmed by Rychnovsky method.20 Desilylation of compound 25 and 26 with HF-Pyridine
afforded corresponding diols, which was next reacted with 2,2´-DMP to afford the acetonides
13
27 and 28. C-NMR analysis of the corresponding acetonides 27 and 28 confirmed the 1,3-
syn and 1,3-anti-relationship between the two hydroxyl groups (Scheme 2).
8

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P2O
OPMB
P2O
DOI: 10.1039/C9OB01504C
OHC
HO
OPMB
OPMB
OP2
OPMB
b
a
O
O
+
OP2
O
O
OH
15
OH
20
19
18
O
O
O
O
P2O
OPMB
OP2
OP3
O
O
OH
c
O
+
X
MeO
MeO
OH
13
O
14
15
P2 = acetonide
d
O
O
O
O
P2O
OPMB
OP2
OP3
c
O
O
OP1
O
+
MeO
MeO
OP1
21
O
O
14
22
e
O
O
O
O
OP3
O
O
O
OH
OP3
O
O
OH
OP3
+
f
O
OH
MeO
O
MeO
O
O
MeO
O
O
24
23
O
13
1:3
Inseparable mixture
P1 = TBS; P3 = PMB
g
O
O
OH
O
OH
O
OP3
O
OP1
h
O
O
O
O
O
O
MeO
+
MeO
O
MeO
O
O
25
OH OP1
i,j
26
OH OP1
i,j
12
OP3
OP3
OH
O
OH
O
B
)
O
O
O
O
2
O
O
MeO
MeO
(-)-Ipc2B-allyl
27
: 29.5 ppm
O
O
28
O
O
OP3
OP3
: 19.8 ppm
: 98.9 ppm
: 24.9 ppm
: 24.6 ppm
: 100.9 ppm
Scheme 2. Preparation of lactone 25, Reagents and conditions: (a) Oxalyl chloride,
DMSO, Et3N, DCM, -78 °C, 2h (b) (˗)-Ipc2BOMe, allylMgBr, ether, ˗78 °C, 2h, 72% in two
steps (c) HG II, DCM, reflux, 2 days, 72% (d) TBS-Cl, imidazole, DCM, rt, 90% (e) TBAF,
THF, rt, 2h, 93% (f) mCPBA, DCM, rt, 12h, 82% (g) TBS-Cl, imidazole, DCM, rt, 3h (h)
LiOH, THF:H2O (3:1), rt, 12h, 72% in two steps (recovery of starting material 12 is 18%) (i)
HF-pyridine, THF, rt, 2h, 90% (j) 2,2´- DMP, PPTS, DCM, rt, 10h, 90%.
The required lactone 25 then reacted with TBS-Cl and imidazole to afford tri-TBS protected
compound 29 in 85% yield. Treatment of compound 29 with DDQ furnished the primary
9

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alcohol 30 in 90% yield (concomitant removal of –PMB group took place). AlcDoOhIo: 1l0.31003V9iw/eCw9aAOsrtBic0le1O50nl4inCe
then subjected to oxidation with Dess-Martin periodinane to afford the aldehyde 10 in 84%
yield. Aldehyde 10 was then immediately reacted with enantiopure sulfone 1121 in the
presence of KHMDS as a base and 18-crown-6 as an additive to afford the E-olefin 31
exclusively in 80% yield.22 All the silyl groups (three -OTBS and one -OTBDPS) present in
compound 31 was removed by treating with HF-pyridine afforded acetonide protected
compound 32 in 88% yield. Finally, the acetonide group in compound 32 was deprotected
using 2(N) HCl to furnish paecilomycin C in 78% yield. The characteristic spectral value of
13
the synthesized product (1H-NMR, C-NMR, and optical rotation) is in accordance with the
naturally occurring paecilomycin C (see the supporting information for direct comparison).
The 1H-NMR of paecilomycin C (3) was originally reported in pyridine-d5 as a solvent in the
isolation paper, we have recorded the spectrum in CD3OD as well. The spectrum in CD3OD
(water suppression was done at 5.1 ppm) looks sharp and fine splitting pattern for the olefinic
protons were observed (corresponds to C6 and C7). The appearance of peak at δ (ppm) 5.74
(dt, J = 15.6, 7.5 Hz, 1H; corresponds to proton at C7) and δ (ppm) 5.66 (dd, J = 15.6, 7.1
Hz, 1H; corresponds to proton at C6) also confirms the presence of “E”-olefinic unsaturation
due to large coupling constant. Such fine splitting pattern of the olefinic protons was absent
1
in the H-NMR spectrum recorded in pyridine-d5 (isolation paper and synthetic samples in
this article).
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DOI: 10.1039/C9OB01504C
OH
O
OP1
O
O
O
O
O
O
O
TBSCl, Imidazole, DCM, 85%
MeO
MeO
OH OP1
25
OPMB
OP1 OP1
29
OPMB
P1 = TBS
2. DDQ, DCM:H2O, 90%
OP1
O
OP1
O
O
O
Dess-Martin, DCM, 84%
MeO
O
O
O
O
MeO
10
OP1 OP1
OP1 OP1
30
O
OH
TPO2S
OTBDPS
KHMDS, 18-c-6, Toluene, -78 oC, 80%
OP1
O
OH
O
O
O
O
O
O
O
MeO
HF-Py, THF, 88%
MeO
OP1 OP1
OH OH
31
32
OTBDPS
2 (N) HCL,THF:H2O
(3:1), 16h, 78%
OH
OH
O
O
OH
MeO
3
OH OH OH
OH
Literature [ ] 24 = +12.6 (c 0.27, MeOH)6

D
Observed [ ] 25 = +11.9 (c 0.27, MeOH)

D
Paecilomycin C
Overall yield = 6.95%f rom (+)-DET
Scheme 3. Completion of the synthesis of paecilomycin C
CONCLUSION
In conclusion, asymmetric total synthesis of naturally occurring paecilomycin C having a γ-
lactone core was synthesized through a convergent approach for the first time with 9.03%
overall yield from compound 18 (6.95% from DET). Carboxylate anion assisted biomimetic
intramolecular ring opening of an epoxide through 5-exo-tet fashion was employed as a key
reaction for the construction of the γ-lactone framework present in the natural product. Brown
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asymmetric allylation, E-selective cross metathesis, and late-stage Julia-Kocienski olefination
DOI: 10.1039/C9OB01504C
reactions were also employed en-route to the total synthesis of paecilomycin C.
EXPERIMENTAL SECTION
General procedures: All oxygen and/or moisture-sensitive reactions were carried out under
N2 atmosphere in glassware that had been flame-dried under vacuum (ca. 0.5 Torr) and
purged with N2 prior to use. Unless otherwise stated, materials were obtained from
commercial suppliers and used without further purification. THF, diethyl ether were distilled
from sodium benzophenone ketyl. Dichloromethane (DCM), hexane were distilled from
calcium hydride. Reactions were stirred magnetically using Teflon-coated magnetic stirring
bars. Teflon-coated magnetic stirring bars and syringe needles were dried in an oven at 120
°C for at least 12 h prior to use then cooled in a desiccator cabinet over Drierite. Reactions
were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm silica gel plates
with UV light, ethanolic anisaldehyde, and phosphomolybdic acid/heat as developing agents.
Silica gel 100-200 mesh was used for column chromatography. Yields refer to
chromatographically and spectroscopically homogeneous materials unless otherwise stated.
NMR spectra were recorded on 600, 400 MHz spectrometers at 25 °C in CDCl3 using TMS as
the internal standard. Chemical shifts are shown in δ. 13C NMR spectra were recorded with a
complete proton decoupling environment. Coupling constants (J) are reported in hertz (Hz)
and the resonance multiplicity abbreviations used are s, singlet; d, doublet; dd, doublet of
doublet; t, triplet; q, quartet; m, multiplet; overlapping multiplets of magnetically non-
equivalent protons. The mass spectrometric analysis was performed in the CRF, IIT-
Kharagpur (TOF analyzer). HPLC analysis of the final compound was performed on a semi-
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DOI: 10.1039/C9OB01504C
prep chiral column (Chiralpak IA, 10 mm × 250 mm, particle size: 5μM) with a PDA
detector on a Prominence-20AT system.
(S)-1-((4S,5S)-5-((4-Methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-3-en-
1-ol (15):
To a stirred solution of (COCl)2 (3.4 mL, 39 mmol ) in dry CH2Cl2 (70 mL) was added
DMSO (4.14 mL, 58.5 mmol) dropwise at ˗78 °C. After stirring for 15 min, compound 18
(4.9 g, 17.22 mmol) was diluted with CH2Cl2 (20 mL) and added dropwise at the same
temperature. The mixture was then stirred for another 45 min at the same temperature. Et3N
(14.8 mL, 106 mmol) was added to the above mixture, and the reaction solution was slowly
allowed to attain the room temperature. The reaction mixture was then stirred at the room
temperature for 1 h. The reaction mixture was then diluted with CH2Cl2 (50 mL) and the
organic solution was washed with saturated NaHCO3 (2×30 mL), H2O (40 mL), and brine
solution (2×40 mL). The organic layer was then dried over anhydrous MgSO4 and evaporated
in vacuo. The crude aldehyde 19 was then immediately used for the next step.
To a stirred solution of (˗)-ipc2BOMe (9.01 g, 28.4 mmol) in anhydrous Et2O (50 mL), was
added allyl magnesium bromide (22.5 mL of 1.0 M solution in ether, 22.5 mmol) at 0 °C. The
mixture was stirred at room temperature for 1 h and then cooled to ˗78 °C. The aldehyde 19
(4.3 g, 15.5 mmol) was then added to the reaction mixture dropwise at ˗78 °C and stirred for
1 h at the same temperature. The reaction solution was then allowed to warm to room
temperature. The mixture was then treated with an aqueous solution of NaOH (2 M in H2O,
30 mL) and 30% H2O2 solution (14 mL) at 0 °C. The biphasic solution was separated, and the
aqueous layer was extracted with Et2O (3 × 70 mL). The combined organic layer was dried
over MgSO4 and evaporated under reduced pressure to furnish the crude product which was
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then purified by flash column chromatography (EtOAc/hexane = 1:5) to afford compound 15
DOI: 10.1039/C9OB01504C
as colourless liquid (3.6 g, 11.15 mmol) and compound 20 (400 mg, 1.23 mmol) in 72% yield
(in two steps) in 9:1 diastereomeric ratio.
25
Compound 15: Rf = 0.3 (EtOAc/hexane = 1:3). [α]D = +11.4 (c 1.0, CHCl3). IR (neat, ν
cm˗1): 3300 (br), 1513 (s), 1245 (s). 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.1 Hz, 2H),
6.87 (d, J = 8.5 Hz, 2H), 5.87 (ddt, J = 17.1, 10.0, 7.0 Hz, 1H), 5.18 – 5.11 (m, 2H), 4.53 (AB
system, J = 12.0 Hz, 2H), 4.07 (q, J = 5.9 Hz, 1H), 3.80 (s, 3H), 3.69-3.63 (m, 3H), 3.55 (dd,
13
J = 9.7, 5.9 Hz, 1H), 2.49 – 2.39 (m, 1H), 2.19 (dt, J = 14.8, 7.6 Hz, 1H), 1.39 (s, 6H). C
NMR (100 MHz, CDCl3) δ 159.5, 134.5, 129.7, 118.0, 114.0, 109.2, 81.6, 78.2, 73.4, 71.6,
70.5, 55.4, 38.1, 27.1, 27.0. HRMS (ESI) m/z: for C18H26O5 [M + H]+, calculated: 323.1858;
found: 323.1850.
Compound 20: Rf = 0.3 (EtOAc/hexane = 1:3). [α]D25 = ˗4.8 (c 1.0, CHCl3). IR (neat, ν cm-
1): 3300 (br), 1513 (s), 1245 (s). 1H NMR (600 MHz, CDCl3) δ 7.24 (d, J = 8.6 Hz, 2H), 6.87
(d, J = 8.6 Hz, 2H), 5.87 – 5.82 (m, 1H), 5.13 – 5.09 (m, 2H), 4.51 (AB system, J = 12.0 Hz,
2H), 4.16 (dt, J = 8.0, 5.0 Hz, 1H), 3.84 – 3.81 (m, 1H), 3.80 (s, 3H), 3.59 (dd, J = 10.3, 5.3
Hz, 1H), 3.54 (dd, J = 10.3, 4.8 Hz, 1H), 2.33 – 2.27 (m, 2H), 1.42 (s, 3H), 1.41 (s, 3H). 13C
NMR (150 MHz, CDCl3) δ 159.4, 134.5, 130.0, 129.4, 117.8, 113.9, 109.5, 80.8, 76.3, 73.3,
70.2, 69.9, 55.4, 39.1, 27.3, 27.2. HRMS (ESI) m/z: for C18H26O5 [M + H]+, calculated:
323.1858; found: 323.1850.
tert-Butyl((S)-1-((4S,5S)-5-((4-methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)but-3-enyloxy)dimethylsilan (21):
To a stirred solution of alcohol 15 (3.6g, 11.18 mmol) and imidazole (912.3 mg, 13.42 mmol)
CH2Cl2 (30 mL), TBSCl (2.19 g, 14.53 mmol) was added portionwise at 0 °C and the reaction
mixture was stirred at room temperature for 3 h. The reaction mixture quenched with water
(10 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×30
14

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Organic & Biomolecular Chemistry
mL). The combined organic layer was washed with brine (5 mL) and dried over MgSO4.ViTewhAerticle Online
DOI: 10.1039/C9OB01504C
organic fraction was evaporated under reduced pressure and the crude product was purified
by flash column chromatography (EtOAc/hexane = 1:20) to furnish compound 21 as
25
colourless liquid (4.39 g, 90%). Rf = 0.5 (EtOAc/hexane = 1:10). [α]D = +10.2 (c 1.0,
CHCl3). IR (neat, ν cm˗1): 1514 (s), 1247 (s). 1H NMR (600 MHz, CDCl3) δ 7.29 (d, J =
8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 5.87 – 5.82 (m, 1H), 5.09 (dd, J = 13.6, 2.0 Hz,
2H), 4.61 – 4.47 (m, 2H), 4.16 (td, J = 7.4, 2.6 Hz, 1H), 3.83-3.81 (m, 1H), 3.82 (s,
3H), 3.74 (t, J = 7.0 Hz, 1H), 3.66 (dd, J = 10.2, 2.6 Hz, 1H), 3.49 (dd, J = 10.3, 6.9
Hz, 1H), 2.40–2.29 (m, 2H), 1.41 (s, 6H), 0.88 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H). 13C
NMR (150 MHz, CDCl3) δ 159.2, 133.9, 130.2, 129.4, 117.6, 113.7, 109.1, 78.7,
78.4, 73.1, 72.9, 71.7, 55.2, 38.8, 27.2, 27.0, 25.9, 18.0, ˗4.2, ˗4.3. HRMS (ESI) m/z:
for C24H40O5SiNa [M + Na]+, calculated: 459.2543; found: 459.2544.
5-((S,E)-4-(tert-Butyldimethylsilyloxy)-4-((4S,5S)-5-((4-methoxybenzyloxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)but-1-enyl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-
4-one (22):
Substituted styrene 14 (4.7 g, 20.12 mmol) and aliphatic olefin 21 (4.39 g, 10.06
mmol) were added in a two necked round bottom flask in dry DCM (20 mL). The
reaction mixture was purged with argon to remove any trace amount of dissolved
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DOI: 10.1039/C9OB01504C
nd
oxygen. Hoveyda-Grubbs 2 Generation catalyst (6 mol%, 378 mg) was added to
the mixture and the reaction mixture was stirred at 60 °C for 24 h. Then the reaction
temperature was elevated to 90 °C and it was stirred for another 24 h until aliphatic
olefin 21 consumed completely. The remaining solvent was then evaporated under
reduced pressure and the crude material was purified through flash column
chromatography (EtOAc/hexane = 1: 10) to afford the E-olefin 22 (4.65 g, 7.24 mmol)
as colourless liquid in 72 % yield with respect to the aliphatic olefin.
Rf = 0.5 (EtOAc/hexane = 1:5). [α]D25 = +3.5 (c 0.5, CHCl3). IR (neat, ν cm˗1): 1725 (s), 1612
(s), 1248 (s). 1H NMR (600 MHz, CDCl3) δ 7.49 (d, J = 15.8 Hz, 1H), 7.25 (d, J = 10.8 Hz,
2H), 6.84 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 2.5 Hz, 1H), 6.34 (d, J = 2.5 Hz, 1H), 6.21 (dt, J =
15.3, 7.3 Hz, 1H), 4.66 – 4.40 (m, 2H), 4.17 (td, J = 7.2, 2.6 Hz, 1H), 3.90 (q, J = 5.7 Hz,
1H), 3.83 (s, 3H), 3.82 – 3.79 (m, 1H), 3.78 (s, 3H), 3.66 (dd, J = 10.3, 2.7 Hz, 1H), 3.51 (dd,
J = 10.3, 6.7 Hz, 1H), 2.62 – 2.48 (m, 2H), 1.69 (s, 6H), 1.41 (s, 3H), 1.40 (s, 3H), 0.86 (s,
13
9H), 0.09 (s, 3H), 0.06 (s, 3H). C NMR (100 MHz, CDCl3) δ 164.7, 160.1, 159.2, 158.7,
143.9, 130.8, 130.3, 130.2, 129.4, 113.7, 109.3, 108.2, 104.9, 103.7, 100.2, 79.1, 78.5, 77.3,
73.3, 73.1, 71.7, 55.6, 55.2, 38.2, 27.3, 27.1, 25.9, 25.7, 25.6, 18.1, ˗4.1, ˗4.2. HRMS (ESI)
m/z: for C35H54NO9Si[M + NH4]+, calculated: 660.3568; found: 660.3574.
5-((S,E)-4-Hydroxy-4-((4S,5S)-5-((4-methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)but-1-enyl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (13):
To a stirred solution of compound 22 (4.65 g, 7.24 mmol) in THF (20 mL) was added tetra
butyl ammonium fluoride (1 M in THF, 8.6 mL) at 0 °C and the reaction mixture was
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allowed to stir at room temperature for 2 h. After completion of the reaction as monitored by
DOI: 10.1039/C9OB01504C
TLC, the solvent was evaporated under reduced pressure. Ethyl acetate (30 mL) and water (7
mL) was added to the crude reaction mixture and the aqueous layer was extracted twice with
ethyl acetate (2×30 mL). The combined organic layer was washed with brine and dried over
MgSO4. The organic part was evaporated under reduced pressure and the crude material was
purified through flash column chromatography (EtOAc/hexane = 1:5) to provide compound
13 (3.55 g, 93%) as colourless gummy oil.
25
Rf = 0.3 (EtOAc/hexane = 1:3). [α]D = +3.7 (c 0.4, CHCl3). IR (neat, ν cm-1): 3324 (br),
1724 (s), 1611 (s). 1H NMR (600 MHz, CDCl3) δ 7.42 (d, J = 15.8 Hz, 1H), 7.25 (d, J = 9.3
Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 2.5 Hz, 1H), 6.34 (d, J = 2.5 Hz, 1H), 6.20 (dt,
J = 15.8, 7.2 Hz, 1H), 4.61 – 4.43 (m, 2H), 4.13 (dt, J = 7.6, 5.3 Hz, 1H), 3.84 (s, 3H), 3.79
(s, 3H), 3.78 – 3.75 (m, 1H), 3.71 (t, J = 7.4 Hz, 1H), 3.69 – 3.60 (m, 2H), 2.66-2.62 (m, 1H),
2.44 – 2.36 (m, 1H), 1.70 (s, 6H), 1.40 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 164.8, 160.3,
159.2, 158.6, 143.9, 131.5, 130.2, 129.6, 129.4, 113.7, 109.1, 108.5, 105.0, 103.5, 100.2,
80.9, 78.5, 73.1, 71.9, 70.6, 55.5, 55.1, 37.2, 26.9, 26.9, 25.5, 25.4. HRMS (ESI) m/z: for
C29H37O9 [M + H]+, calculated: 529.2438; found: 529.2423.
5-((2R/2S,3R/3S)-3-((S)-2-hydroxy-2-((4S,5S)-5-((4-methoxybenzyloxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)ethyl)oxiran-2-yl)-7-methoxy-2,2-dimethyl-4H-
benzo[d][1,3]dioxin-4-one (23/24):
m-CPBA (1.4 g, 8.076 mmol) was added to a stirred solution of 13 (3.55 g, 6.73 mmol) in
CH2Cl2 (18 mL) at 0 °C and the reaction mixture was continued to stir at room temperature
for 10 h until the starting material consumed completely. The reaction mixture was then
quenched with saturated solution of NaHCO3 (5 mL) and CH2Cl2 (30 mL) were added to it.
The aqueous part was extracted with CH2Cl2 (2×30 mL) and the combined organic phase was
washed with brine (10 mL) and dried over MgSO4. The solvent was evaporated under
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reduced pressure and the crude material was purified through flash column chromatography
DOI: 10.1039/C9OB01504C
(EtOAc/hexane = 1: 5) to provide inseparable mixture of compounds 23 and 24 as gummy oil
(3 g, 82%) in a diasteriomeric ratio of 3:1. Rf = 0.35 (EtOAc/hexane = 1:3). IR (neat, ν cm˗1):
1
1727 (s), 1611 (s), 835 (s), 777 (s). H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.2 Hz, 2H),
6.87 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 2.3 Hz, 1H), 6.37 (d, J = 2.6 Hz, 1H), 4.53 (d, J = 2.0
Hz, 2H), 4.44 (d, J = 2.0 Hz, 1H), 4.19 – 4.10 (m, 1H), 3.92 – 3.83 (m, 1H), 3.83 (s, 3H),
3.80 (s, 3H), 3.73 – 3.58 (m, 3H), 2.95 (td, J = 5.9, 2.0 Hz, 1H), 2.29 (ddd, J = 14.4, 5.7, 2.2
Hz, 1H), 1.81 (ddd, J = 14.9, 9.7, 6.2 Hz, 1H), 1.74 (s, 3H), 1.70 (s, 3H), 1.39 (s, 3H), 1.37 (s,
13
3H). C NMR (100 MHz, CDCl3) δ 166.1, 160.7, 159.2, 158.6, 144.4, 129.9, 129.4, 113.8,
109.3, 106.4, 105.8, 104.1, 101.0, 80.9, 79.0, 73.2, 70.8, 70.1, 60.6, 57.2, 55.7, 55.2, 37.2,
27.03, 27.01, 26.6, 24.6. HRMS (ESI) m/z: for C29H36O10Na[M +Na]+, calculated: 567.2206;
found: 567.2214.
(S)-3-((1R,3S)-3-(tert-Butyldimethylsilyloxy)-1-hydroxy-3-((4S,5S)-5-((4-
methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propyl)-7-hydroxy-5-
methoxyisobenzofuran-1(3H)-one (25):
To a stirred solution of a mixture of 23 and 24 (3 g, 5.52 mmol) and imidazole (450 mg, 6.62
mmol) in CH2Cl2 (16 mL) was added TBSCl (1.08 g, 7.2 mmol) portion wise at 0 °C and the
reaction mixture was stirred at room temperature for 3 h. Then the reaction mixture was
quenched with water (4 mL), and the layers were separated. The aqueous layer was extracted
with CH2Cl2 (2×20 mL). The combined organic layer was washed with brine and dried over
MgSO4. The organic fraction was evaporated under reduced pressure and the crude product
12 used without further purification.
To a stirred solution of compound 12 (3.27 g, 4.96 mmol) in THF (15 mL) and H2O (5 mL) at
0 °C was added LiOH (355 mg, 14.9 mmol) and the reaction mixture was allowed to stir at
room temperature for 12 h. The reaction mixture was then quenched by adding a saturated
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solution of NH4Cl (5 ml). Ethyl acetate (40 mL) was added to the reaction mixture and layer
DOI: 10.1039/C9OB01504C
was separated. The aqueous layer was extracted with ethyl acetate (2×40 mL), and the
combined organic phase was then washed with brine (10 mL) and dried over MgSO4. The
organic fraction was evaporated under reduced pressure, and the crude product was purified
by flash column chromatography (EtOAc/hexane = 1:5) to furnish compound 25 (1.79 g,
54%) and compound 26 (599.4 mg, 18%) as colourless oil (72% overall yield in two steps,
based on recovered starting material of compound 12. 0.9 mmol of compound 12 was
recovered after column chromatography).
25
Compound 25: Rf = 0.2 (EtOAc/hexane = 1:3). [α]D = +2.7 (c 0.4, CHCl3). IR (neat, ν
1
cm˗1): 3320 (br), 1750 (s). H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.24 (d, J = 8.3 Hz,
2H), 6.85 (d, J = 7.9 Hz, 2H), 6.63 (s, 1H), 6.45 (s, 1H), 5.22 (d, J = 6.2 Hz, 1H), 4.58 – 4.41
(m, 2H), 4.06 (t, J = 7.8 Hz, 2H), 3.97 (q, J = 6.1 Hz, 1H), 3.85 (s, 3H), 3.82 (d, J = 5.5 Hz,
1H), 3.79 (s, 3H), 3.63 (dd, J = 10.2, 3.0 Hz, 1H), 3.49 (dd, J = 10.2, 6.7 Hz, 1H), 2.01 (ddd,
J = 14.3, 9.8, 3.7 Hz, 1H), 1.84 (dd, J = 14.7, 6.3 Hz, 1H), 1.41 (s, 6H), 0.82 (s, 9H), 0.02 (s,
13
3H), 0.01 (s, 3H). C NMR (100 MHz, CDCl3) δ 171.5, 167.3, 159.4, 157.8, 149.6, 130.1,
129.6, 113.9, 109.9, 104.6, 102.1, 101.3, 84.2, 80.0, 79.8, 73.4, 71.6, 71.4, 69.4, 56.1, 55.4,
37.8, 27.2, 27.1, 25.9, 18.0, ˗4.2, ˗4.3. HRMS (ESI) m/z: for C32H46O10SiNa [M + Na]+,
calculated: 641.2758; found: 641.2753.
25
Compound 26: Rf = 0.18 (EtOAc/hexane = 1:3). [α]D = ˗3.5 (c 0.4, CHCl3). IR (neat, ν
1
cm˗1): 3319 (br), 1748 (s). H NMR (600 MHz, CDCl3) δ 7.68 (s, 1H), 7.27 (d, J = 7.0 Hz,
2H), 6.87 (d, J = 6.8 Hz, 2H), 6.63 (s, 1H), 6.47 (s, 1H), 5.24 (d, J = 5.9 Hz, 1H), 4.77 – 4.38
(m, 2H), 4.13 – 4.07 (m, 1H), 4.07 – 4.02 (m, 1H), 3.90 (dt, J = 9.8, 5.1 Hz, 1H), 3.87 (s,
3H), 3.83 (dd, J = 7.5, 1.3 Hz, 1H), 3.81 (s, 3H), 3.67 – 3.63 (m, 1H), 3.50 (dd, J = 9.5, 7.2
Hz, 1H), 2.01 – 1.94 (m, 1H), 1.86 (ddd, J = 15.8, 9.4, 5.7 Hz, 1H), 1.42 (s, 3H), 1.39 (s, 3H),
13
0.85 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H). C NMR (150 MHz, CDCl3) δ 171.5, 167.2, 159.3,
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157.6, 149.4, 129.8, 129.5, 113.8, 109.8, 104.5, 101.8, 101.2, 84.1, 79.7, 79.4, 73.3, 73.2,
DOI: 10.1039/C9OB01504C
71.2, 70.5, 56.0, 55.2, 37.8, 27.0, 25.8, 17.8, ˗4.4. HRMS (ESI) m/z: for C32H46O10SiNa [M +
Na]+, calculated: 641.2758; found: 641.2756.
(S)-7-Hydroxy-5-methoxy-3-((4R,6S)-6-((4S,5S)-5-((4-methoxybenzyloxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-1,3-dioxan-4-yl)isobenzofuran-1(3H)-one (27):
To a stirred solution of compound 25 (40 mg, 0.066 mmol) in dry THF (1.5 mL) was added
HF-pyridine (300 μL) at 0 °C. The reaction mixture was then stirred for another 2 h at room
temperature. After completion of the reaction it was quenched with a saturated solution of
ammonium chloride (2 mL) and extracted with ethyl acetate (2 × 10 mL). The organic layer
was washed with brine (4 mL), dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude diol was used for the next reaction without further purification.
2,2´-DMP (70 μL, 0.7 mmol) and PPTS (2 mg) were added to a stirred solution of the crude
diol in dry CH2Cl2 (1 mL) at room temperature. The reaction mixture was stirred at the same
temperature for another 10 h. After completion of the reaction the solution was concentrated
under reduced pressure and purified by flash column chromatography (EtOAc/hexane = 1:10)
to furnish compound 27 (22 mg, 80%) as a colorless oil. Rf = 0.5 (EtOAc/hexane = 1:5).
25
1
[α]D = +7.6 (c 1.0, CHCl3). IR (neat, ν cm˗1): 1737 (s), 1612 (s), 1247 (s). H NMR (600
MHz, CDCl3) δ 7.69 (s, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 6.60 (s, 1H),
6.47 (s, 1H), 5.20 (d, J = 6.5 Hz, 1H), 4.66 – 4.44 (m, 2H), 4.15 – 4.04 (m, 1H), 3.98 (dd, J =
11.3, 6.8 Hz, 1H), 3.87 (s, 3H), 3.85-3.82 (m, 1H), 3.82 (s, 3H), 3.66 (ddd, J = 18.1, 12.5, 5.0
Hz, 2H), 3.52 (dd, J = 10.3, 6.8 Hz, 1H), 1.57 (q, J = 12.2 Hz, 2H), 1.43 (s, 3H), 1.40 (s, 3H),
13
1.38 (s, 3H), 1.36 (s, 3H). C NMR (150 MHz, CDCl3) δ 171.3, 167.2, 159.1, 157.6, 149.2,
130.2, 129.3, 113.7, 109.9, 104.1, 102.0, 101.0, 98.9, 82.7, 79.5, 79.4, 73.0, 70.8, 70.6, 70.5,
56.0, 55.2, 29.9, 29.5, 27.1, 27.0, 19.7. HRMS (ESI) m/z: for C29H36O10Na [M +Na]+,
calculated: 567.2206; found: 567.2204.
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(R)-7-Hydroxy-5-methoxy-3-((4S,6S)-6-((4S,5S)-5-((4-methoxybenzyloxy)metDhOyI:l1)0-.210,329-/C9OB01504C
dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-1,3-dioxan-4-yl)isobenzofuran-1(3H)-one (28):
Compound 26 (40 mg, 0.066 mmol) was subjected to the same reaction procedure as
described earlier for compound 25 to furnish compound 28 (23 mg, 0.052 mmol) in 80%
25
yield as a colourless oil. Rf = 0.5 (EtOAc/hexane = 1:5). [α]D = +2.5 (c 1.0, CHCl3). IR
(neat, ν cm˗1): 1737 (s), 1612 (s), 1246 (s). 1H NMR (600 MHz, CDCl3) δ 7.69 (s, 1H), 7.28
(d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.3 Hz, 2H), 6.56 (d, J = 1.8 Hz, 1H), 6.47 (d, J = 1.9 Hz,
1H), 5.35 (d, J = 6.1 Hz, 1H), 4.61 – 4.48 (m, 2H), 4.03 (dt, J = 9.4, 6.1 Hz, 1H), 3.98 (ddd, J
= 9.4, 6.4, 3.3 Hz, 1H), 3.92 (dt, J = 8.8, 6.3 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.76 (t, J =
7.1 Hz, 1H), 3.62 (dd, J = 10.3, 3.4 Hz, 1H), 1.94 (ddd, J = 13.0, 9.4, 6.2 Hz, 1H), 1.85 (ddd,
13
J = 13.3, 8.9, 6.0 Hz, 1H), 1.42 (s, 3H), 1.40 (s, 3H), 1.38 (s, 3H), 1.30 (s, 3H). C NMR
(150 MHz, CDCl3) δ 171.4, 167.3, 159.2, 157.7, 149.1, 130.1, 129.3, 113.7, 110.0, 104.4,
101.4, 101.1, 100.9, 82.5, 79.5, 79.0, 73.0, 70.5, 68.0, 67.9, 56.0, 55.2, 29.7, 27.1, 27.0, 24.9,
24.6. HRMS (ESI) m/z: for C29H36O10Na [M +Na]+, calculated: 567.2206; found: 567.2207.
(S)-7-(tert-Butyldimethylsilyloxy)-5-methoxy-3-((5R,7S)-7-((4S,5S)-5-((4-
methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2,3,3,9,9,10,10-octamethyl-
4,8-dioxa-3,9-disilaundecan-5-yl)isobenzofuran-1(3H)-one (29):
To a stirred solution of compound 25 (360 mg, 0.597 mmol) and imidazole (102 mg, 1.5
mmol) in CH2Cl2 (5 mL) was added TBSCl (252.4 mg, 1.67 mmol) portion wise at 0 °C and
the reaction mixture was stirred at room temperature for 10 h. The reaction mixture was
quenched with water (5 mL), diluted with CH2Cl2 (20 mL) and the layer was separated. The
aqueous layer was extracted twice with DCM (20 mL). The combined organic layer was
washed with brine (5 mL) and dried over MgSO4. The organic fraction was evaporated under
reduced pressure and the crude product was purified by flash column chromatography
(EtOAc/hexane = 1:20) to furnish compound 29 (422 mg, 85%) as a colourless liquid. Rf =
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0.6 (EtOAc/hexane = 1:10). [α]D25 = +8.7 (c 1.0, CHCl3). IR (neat, ν cm˗1): 1766D(Os)I:,1106.110309/(Cs9)O,B01504C
1250 (s), 832 (s). 1H NMR (600 MHz, CDCl3) δ 7.24 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz,
2H), 6.47 (d, J = 1.5 Hz, 1H), 6.34 (d, J = 1.9 Hz, 1H), 5.18 (d, J = 2.4 Hz, 1H), 4.52 – 4.45
(m, 2H), 4.45 (td, J = 5.8, 4.7, 2.4 Hz, 1H), 4.08 (ddd, J = 8.0, 6.3, 3.0 Hz, 1H), 3.98 – 3.93
(m, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.72 (dd, J = 8.0, 5.9 Hz, 1H), 3.62 (dd, J = 10.3, 3.0 Hz,
1H), 3.47 (dd, J = 10.3, 6.3 Hz, 1H), 1.91 (ddd, J = 14.3, 8.1, 4.6 Hz, 1H), 1.43 (s, 3H), 1.38
(s, 3H), 1.04 (s, 9H), 0.83 (s, 9H), 0.79 (s, 9H), 0.26 (s, 3H), 0.26 (s, 3H), 0.08 (s, 6H), 0.06
(s, 3H), 0.04 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 167.9, 165.5, 159.3, 156.2, 150.7, 130.2,
129.6, 113.8, 110.8, 109.2, 106.8, 100.9, 82.5, 80.9, 78.7, 73.4, 71.6, 70.1, 70.0, 55.8, 55.4,
38.8, 27.4, 27.0, 26.0, 25.9, 25.8, 25.7, 18.5, 18.0, ˗3.9, ˗4.0, ˗4.1, ˗4.2, ˗4.3, ˗4.4. HRMS
(ESI) m/z: for C44H74O10Si3Na [M + Na]+, calculated: 869.4487; found: 869.4482.
(S)-7-(tert-Butyldimethylsilyloxy)-3-((5R,7S)-7-((4S,5S)-5-(hydroxymethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-5-
yl)-5-methoxyisobenzofuran-1(3H)-one (30):
Compound 29 (422 mg, 0.507 mmol) was dissolved in CH2Cl2/phosphate buffer (pH = 7.0;
19:1, 4 mL) and the solution was cooled to 0 ºC. DDQ (138 mg, 0.608 mmol) was added
portion wise to the solution and the mixture was stirred at this temperature for 2 h. After
completion, the reaction mixture was passed through a pad of Celite and the residue was then
washed with CH2Cl2 (100 mL). The combined organic fraction was washed with water and
brine solution. The organic layer was then dried over anhydrous MgSO4 and evaporated in
vacuo. Purification by flash column chromatography (EtOAc/hexane = 1:10) afforded
25
compound 30 (298 mg, 90%) as a colorless oil. Rf = 0.35 (EtOAc/hexane = 1:5). [α]D
=
1
+3.4 (c 0.6, CHCl3). IR (neat, ν cm˗1): 3335 (br), 1768 (s),1612 (s), 1248 (s). H NMR (600
MHz, CDCl3) δ 6.50 (s, 1H), 6.35 (s, 1H), 5.27 (d, J = 2.3 Hz, 1H), 4.45 (dd, J = 7.9, 3.7 Hz,
1H), 3.97 (dq, J = 7.5, 3.8 Hz, 2H), 3.84 (s, 3H), 3.81 – 3.76 (m, 2H), 3.53 (dd, J = 11.9, 4.6
22

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Hz, 1H), 1.92 (ddd, J = 13.4, 8.7, 4.1 Hz, 1H), 1.46 (ddd, J = 14.5, 8.3, 4.1 Hz, 1H), 1.43 (s,
DOI: 10.1039/C9OB01504C
3H), 1.38 (s, 3H), 1.04 (s, 9H), 0.86 (s, 9H), 0.84 (s, 9H), 0.26 (s, 6H), 0.12 (s, 6H), 0.07 (s,
13
6H). C NMR (150 MHz, CDCl3) δ 168.0, 165.8, 156.3, 150.7, 110.5, 108.9, 107.1, 100.6,
82.8, 79.8, 79.5, 70.3, 70.0, 63.1, 55.9, 38.4, 27.4, 27.1, 26.0, 25.9, 25.7, 18.5, 18.1, ˗3.9,
˗4.0, ˗4.1, ˗4.3, ˗4.3. HRMS (ESI) m/z: for C36H66O9Si3Na [M + Na]+, calculated: 749.3912;
found: 749.3911.
(S)-7-(tert-Butyldimethylsilyloxy)-3-((5R,7S)-7-((4S,5S)-5-((S,E)-4-(tert-
butyldiphenylsilyloxy)pent-1-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2,3,3,9,9,10,10-
octamethyl-4,8-dioxa-3,9-disilaundecan-5-yl)-5-methoxyisobenzofuran-1(3H)-one (31):
Alcohol 30 (100 mg, 0.152 mmol) in CH2Cl2 (2 mL) was taken in a single neck round bottom
flask and cooled to 0 °C. NaHCO3 (78 mg, 0.9 mmol) was added to the above mixture
followed by the addition of Dess-Martin periodinane (92 mg, 0.212 mmol) at the same
temperature. The reaction mixture was then stirred for 2 h at room temperature. After
completion of the reaction, it was diluted with CH2Cl2 (30 mL) and the organic part was then
successively washed with saturated Na2S2O3 (5 mL) solution and brine (2 mL) solution. The
organic layer was then dried over anhydrous MgSO4 and evaporated under reduced pressure.
Purification by flash column chromatography (EtOAc /hexane = 1:5) afforded unstable
aldehyde 10 (81 mg, 84%) as colorless oil. Rf = 0.5 (EtOAc/hexane = 1:5).
Sulfone 11 (84 mg, 0.16 mmol) and 18-Crown-6 ether (50 mg, 0.184 mmol) was dissolved in
anhydrous Toluene (2.5 mL) and the solution was cooled to ˗78 ºC. To this solution, KHMDS
in toluene (0.4 mL, 0.5 M) was added drop wise and stirred for 20 min. Aldehyde 10 (80 mg ,
0.123 mmol) in anhydrous THF (1 mL) was then added to the reaction solution at ˗78 ºC and
the temperature was allowed to gain the room temperature slowly. The reaction was then
quenched with saturated NH4Cl (2 mL) solution and diluted with ethyl acetate (15 mL) and
23

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the layer was separated. The aqueous layer was extracted twice with ethyl acetate (15 mL).
DOI: 10.1039/C9OB01504C
The combined organic layer was washed with brine (4 mL) and dried over anhydrous
MgSO4. The organic fraction was evaporated under reduced pressure and the crude product
was purified by flash column chromatography (EtOAc/hexane = 1:15) to give E-olefin 31 (92
25
mg, 80%) as a colorless gummy oil. Rf = 0.7 (EtOAc/hexane = 1:5). [α]D = +8.2 (c 0.5,
1
CHCl3). IR (neat, ν cm˗1): 1745 (s),1613 (s), 1227 (s). H NMR (600 MHz, CDCl3) δ 7.67 –
7.65 (m, 4H), 7.42 – 7.37 (m, 6H), 6.48 (s, 1H), 6.35 (s, 1H), 5.73 (dt, J = 14.9, 7.2 Hz, 1H),
5.40 (ddd, J = 15.5, 7.1, 1.6 Hz, 1H), 5.17 (d, J = 2.8 Hz, 1H), 4.32 (t, J = 7.3 Hz, 2H), 4.07
(dt, J = 6.2, 3.3 Hz, 1H), 3.91 – 3.86 (m, 1H), 3.81 (s, 3H), 3.71 – 3.66 (m, 1H), 2.22 (td, J =
8.4, 3.9 Hz, 1H), 2.18 – 2.12 (m, 1H), 1.92 (ddd, J = 13.6, 7.6, 5.8 Hz, 1H), 1.65 (dt, J = 13.1,
6.4 Hz, 1H), 1.43 (s, 3H), 1.36 (s, 3H), 1.08 (s, 12H), 1.05 (s, 9H), 0.88 (s, 9H), 0.78 (s, 9H),
13
0.27 (d, J = 5.3 Hz, 6H), 0.08 (s, 9H), 0.06 (s, 3H). C NMR (150 MHz, CDCl3) δ 167.8,
165.5, 156.3, 150.7, 135.9, 135.3, 134.9, 131.1, 130.9, 129.8, 127.8, 127.6, 127.5, 110.8,
108.5, 106.6, 101.1, 83.6, 82.2, 78.4, 70.1, 69.1, 68.7, 55.8, 42.5, 38.6, 27.1, 26.9, 26.7, 26.1,
25.9, 25.7, 23.0, 19.1, 18.5, 18.1, 18.0, ˗4.02, ˗4.05, ˗4.2, ˗4.36, ˗4.37, ˗4.4. HRMS (ESI) m/z:
for C56H94NO9Si4 [M +NH4]+, calculated: 1036.6006; found: 1036.6015.
(S)-3-((1R,3S)-1,3-Dihydroxy-3-((4S,5S)-5-((S,E)-4-hydroxypent-1-enyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)propyl)-7-hydroxy-5-methoxyisobenzofuran-1(3H)-one (32):
Compound 31 (35 mg, 0.037 mmol) was dissolved in anhydrous THF (2 mL) in a
polyethylene vessel and HF-pyridine (500 μL )was added to it at 0 ºC. The mixture was then
stirred for 10 h at room temperature followed by addition of CH2Cl2 (15 mL) and brine
solution (5 mL). The organic layer was separated and the aqueous layer was twice washed
with (10 mL) of CH2Cl2. The combined organic part was washed with brine (5 mL) and the
solution was dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was
then purified by flash column chromatography (MeOH/ CH2Cl2 = 1:20) to afford 32 (14.1
24

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DOI: 10.1039/C9OB01504C
25
mg, 88%) as a colourless oil. Rf = 0.5 (MeOH/DCM = 1:15). [α]D = +13.7 (c 0.4, CHCl3).
IR (neat, ν cm˗1): 3375 (br), 1744 (s), 1628 (s). 1H NMR (600 MHz, CDCl3) δ 6.67 (d, J = 1.9
Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 5.96 (dt, J = 14.9, 7.3 Hz, 1H), 5.58 (dd, J = 15.4, 8.1 Hz,
1H), 5.25 (d, J = 6.2 Hz, 1H), 4.47 (t, J = 8.1 Hz, 1H), 4.19 – 4.11 (m, 1H), 4.02 (ddd, J =
10.2, 6.4, 2.0 Hz, 1H), 3.92 – 3.89 (m, 1H), 3.88 (s, 3H), 3.69 (dd, J = 8.1, 4.2 Hz, 1H), 2.30
– 2.21 (m, 2H), 1.88 – 1.83 (m, 1H), 1.76 (dt, J = 14.5, 10.3 Hz, 1H), 1.43 (s, 6H), 1.23 (d, J
= 6.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 171.5, 167.3, 157.6, 132.9, 130.8, 127.9,
108.9, 104.3, 101.9, 101.3, 83.6, 82.3, 77.7, 73.7, 71.5, 67.2, 56.0, 41.7, 34.4, 27.0, 26.9,
23.0. HRMS (ESI) m/z: for C22H31O9 [M +H]+, calculated: 439.1968; found: 439.1961.
(S)-7-Hydroxy-5-methoxy-3-((1R,3S,4S,5S,9S,E)-1,3,4,5,9-pentahydroxydec-6-
enyl)isobenzofuran-1(3H)-one (3):
Compound 32 (4 mg, 0.009 mmol) was dissolved in THF (0.6 mL) and H2O (0.2 mL)
in a single neck round bottom flask. The reaction mixture was allowed to cool to 0 ºC
and 2 (N) HCl (30 μL) was added dropwise. The mixture was then stirred for 24 h at
room temperature. After completion, the reaction mixture was quenched with
saturated NaHCO3 (200 μL) solution. Then THF and water have been evaporated
under reduced pressure and the crude product was purified by preparative thin layer
chromatography to afford a white solid. The white fluffy solid was then lyophilized
overnight to afford compound 3 (2.8 mg). This was further purified by passing
through a semi-prep chiral column (Chiralpak IA, 10 mm × 250 mm, particle size:
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DOI: 10.1039/C9OB01504C
5μM, mobile phase: 6:4; hexane:2-propanol with a flow rate 1ml/min). The compound
having retention time 6.091 min was manually collected and evaporated to dryness
to provide final compound 3 (2.7 mg, 78%) of white solid of pure paecilomycin C.
25
Rf = 0.3 (MeOH/ CH2Cl2 = 1:10). mp: 180-182 °C (uncorrected); [α]D = +11.9 (c 0.27,
1
MeOH). IR (KBr, ν cm˗1): 3384 (br), 1735 (s), 1613 (s). H NMR (600 MHz, Pyridine d5) δ
7.0 (s, 1H), 6.69 (s, 1H), 6.23 – 6.16 (m, 2H), 5.72 (d, J = 4.6 Hz, 1H), 5.03 (br s, 1H), 4.82
(dd, J = 8.8, 4.3 Hz, 1H), 4.74 (td, J = 8.1, 3.1 Hz, 1H), 4.10 – 4.02 (m, 2H), 3.64 (s, 3H),
1
2.85 – 2.80 (m, 1H), 2.53 – 2.48 (m, 2H), 2.39 – 2.36 (m, 1H), 1.30 (d, J = 6.1 Hz, 3H). H
NMR (600 MHz, CD3OD) δ 6.71 (s, 1H), 6.44 (s, 1H), 5.74 (dt, J = 15.6, 7.5 Hz, 1H), 5.66 (dd, J =
15.6, 7.1 Hz, 1H), 5.39 (d, J = 4.6 Hz, 1H), 4.24 – 4.20 (m, 3H), 3.94 – 3.89 (m, 1H), 3.88 (s, 3H),
3.80 (dd, J = 13.0, 6.5 Hz, 1H), 2.24-2.17 (m, 2H), 1.98 (dt, J = 15.3, 4.2 Hz, 1H), 1.76 (dt, J = 15.0,
9.0 Hz, 1H), 1.18 (d, J = 6.6 Hz, 3H).
13C NMR (150 MHz, Pyridine d5) δ 169.8, 166.6, 159.3, 152.3, 134.7, 128.8, 107.3,
103.0, 101.0, 83.4, 78.2, 72.7, 72.2, 71.7, 67.2, 55.7, 43.4, 37.0, 23.7. HRMS (ESI)
m/z: for C19H26O9Na [M +Na]+, calculated: 421.1475; found: 421.1476.
Conflicts of Interest
There are no conflicts to declare
ACKNOWLEDGMENTS
26

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Organic & Biomolecular Chemistry
Financial support from CSIR (Grant no: 02(0244)/15/EMR-II), India waDsOI:g1r0a.1t0e3Vf9iu/eCwl9lAOyrtBic0le1O50nl4inCe
acknowledged. One of the authors, JC, is thankful to DST-India for a research fellowship.
DST-India is thanked for 500 MHz NMR machine (Grant no: SR/FST/CSII-026/2013) at
Department of Chemistry, IIT-KGP.
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OPMB
O
O
OH
O
O
OPMB
O
O
OH
O
OH
O
MeO
O
MeO
OH
O
OH OH OH
OH
Paecilomycin C
29