Stereoselective synthesis of fully functionalized acyclic core of Tianchimycin A

Article abstract of DOI:10.24820/ark.5550190.p010.287

A highly convergent synthetic approach towards the macrolactone polyketide tianchimycin A is described. Notable features of our synthetic approach include highly stereoselective Myers alkylation, substrate controlled anti aldol reaction, and Masamune-Roush olefination.

Full text of DOI:10.24820/ark.5550190.p010.287

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Arkivoc 2017, part v, 301-313
Organic Chemistry
Stereoselective synthesis of fully functionalized acyclic core of Tianchimycin A
Vanipenta Yamini and Subhash Ghosh*
Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Uppal Road,
Tarnaka, Hyderabad 500007, India
E-mail: subhash@iict.res.in
Received 07-31-2017
Accepted 10-18-2017
Published on line 11-19-2017
Abstract
A highly convergent synthetic approach towards the macrolactone polyketide tianchimycin A is described.
Notable features of our synthetic approach include highly stereoselective Myers alkylation, substrate
controlled anti aldol reaction, and Masamune-Roush olefination.
Keywords: Tianchimycin, Crimmins’s protocol, Paterson’s aldol reaction, Takai olefination, Masamune-Roush
olefination, intramolecular Heck-cyclization
DOI: https://doi.org/10.24820/ark.5550190.p010.287
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Introduction
Actinobacteria are important sources of bioactive secondary metabolites.1 In 2013, Deng and co-workers
isolated two new 16-membered macrolactone type polyketides from the rare actinomycete Saccharothrix
xinjiangensis B-24321 and named them as tianchimycin A and tianchimycin B (Figure 1).2 Structures of
tianchimycins A-B were determined based on detailed NMR and MS spectroscopy. Architecturally tianchimycin
A is quite interesting. It is a macrocyclic lactone adorned with six stereogenic centers and three olefinic
moieties. Out of three double bonds, two are part of 1,4–butadiene system and the third one is a part of α,β-
unsaturated lactone moiety. Initial biological studies revealed that they do not have antibacterial activity.
However modification of the structure might provide good antibacterial lead. Thus with this intention we
initiated a program for the total synthesis of tianchimycin A and its analogs to unveil the full biological
potential. In 2015 Sabitha et al. reported the synthetic study of tianchimycin A. They synthesized the entire
acyclic C1-C16 framework of the molecule. However the macrolactonization under different conditions was
unsuccessful.3 Thus we thought an alternate approach to construct 1 could be intramolecular Heck-cyclization
for the formation of macrocyclic ring.4 Recently the employment of intramolecular Heck reaction for
macrocyclization has flourished in natural product synthesis.4,16,17,18,19 It is interesting to note that this reaction
is applicable to variation depending upon the macrocyclic ring size (16-24 size macrocycles), which requires
optimization of variety of reaction parameters.
Figure 1. Structures of Tianchimycins.
Results and Discussion
Retrosynthetically, we dissected 3 into building blocks 4 and 5 (Scheme 1). Heck coupling of substrate 3 was
envisaged as a key step to close the macrocycle, while connection of the cyclization precursor 3 was planned
to arise from Masamune-Roush olefination of aldehyde 4 and ketophosphonate 5.5,6 The aldehyde 4 would be
acquired from the known compound 77 using Myers asymmetric alkylation and the ketophosphonate 5 might
be synthesized from known compound 98 using Paterson’s anti aldol reaction.
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Scheme 1. Retrosynthetic analysis of tianchimycin A.
From the synthetic perspective, synthesis of 4 (Scheme 2) began with the diastereoselective alkylation of
the known iodide 77 with Myers pseudoephedrine derived auxiliary9.10 to yield amide 10 as a single
diastereomer in 95% yield. Reduction of 10 with BH3.NH3 gave primary alcohol 6 in 90% yield. Compound 6 on
oxidation under Dess-Martin Periodinane conditions provided an aldehyde, to which addition of (Z)-enolate,
generated from 11, using Crimmins’s protocol11 afforded 12 with excellent diastereoselectivity (98:2 dr), which
are separated by standard silica gel column chromatography to obtain the required single isomer 12 in 96%
yield. Reductive removal of the chiral auxiliary with LiBH4 in ether furnished the 1,3-diol compound 13, which
on protection as PMP-acetal followed by TBDPS deprotection with TBAF gave a primary alcohol 15. Oxidation
of 15 with DMP gave an aldehyde which on reaction with vinylmganesium bromide yielded diastereomerically
mixture of alcohols 16, which on TBS protection with TBSOTf in presence of 2,6-lutidine gave globally
protected compound 17. At this stage the p-methoxybenzylidine acetal of 17 was opened regioselectively with
DIBAL-H to give a primary alcohol 4a, which was oxidized with DMP to give required aldehyde 4 in 90% yield.
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Scheme 2. Reagents and conditions: (a) n-BuLi, LiCl, DIPA, (1R, 2R)-(-)-Pseudoephedrine propionamide, THF, -
78 oC- -20 oC, 14 h, 95%; (b) n-BuLi, LiCl, BH3.NH3, THF, 0 oC-rt, 4 h, 90%; (c) i. DMP, NaHCO3, CH2Cl2, 0 oC-rt, 2
h; ii. TiCl4, (-)-sparteine, 0 oC, CH2Cl2, 20 min then 11, 0 oC, 10 min, 96% (over two steps); (d) LiBH4, 0 oC, Et2O,
o
10 min, 96%; (e) PMP-acetal, CSA (cat), CH2Cl2, 0 C-rt, 12 h, 94%; (f) TBAF, THF, 0 oC, 12 h, 91%; (g) i. DMP,
NaHCO3, CH2Cl2, 0 oC-rt, 2 h; ii. vinylmagnesium bromide, THF, 0 oC, 1 h, 84% (over two steps); (h) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 oC-rt, 2 h, 93%; (i) DIBAL-H, CH2Cl2, -40 oC-0 oC, 2 h, 90%; (j) DMP, NaHCO3, CH2Cl2, 0 oC-rt, 2
h.
Synthesis of phosphonate fragment 5 commenced from known keto compound 98 (Scheme 3), which on
reaction with acetaldehyde under Paterson’s anti-aldol conditions12,13 using dicyclohexylborane chloride
afforded β-keto alcohol 8, in 96% yield with excellent diastereoselectivity which was protected as its TBS ether
to give compound 18 in 92% yield. Reduction of the keto as well as benzoate group in 18 with LiBH4 afforded
diastereomerically mixture of diols 19 in 92% yield.7 Oxidative cleavage of the diol with NaIO4 furnished an
aldehyde, which on Takai olefination gave vinyl iodide 20 (E:Z ratio 19:1) in 80% yield over two steps.14,15 TBS
deprotection from compound 20 furnished a secondary alcohol, which on acylation with diethyl
phosphonoacetic acid under EDCI/DMAP conditions afforded the phosphonate 5 in 85% yield.
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o
o
Scheme 3. Reagents and conditions: (a) c-Hex2BCl, Me2NEt, acetaldehyde, Et2O, -78 C- -20 C, 14 h, 96%; (b)
o
o
o
TBSOTf, 2,6-lutidine, CH2Cl2, 0 C-rt, 2 h, 92%; (c) LiBH4, THF, -78 C-0 C, 21 h, 92%; (d) i. NaIO4, MeOH:H2O
o
(2:1), rt, 30 min; ii. CHI3, CrCl2, THF, rt, 1 h, 80% (over two steps); (e) TBAF, THF, 0 C, 12 h, 91%; (f) Diethyl
phosphonoacetic acid, EDCI, DMAP, CH2Cl2, 0 oC-rt, 4 h, 85%.
Having both the fragments in our hand, the Horner-Wadsworth-Emmons reaction5 under Masamune-
Roush conditions was carried out between aldehyde 4 and the phosphonate 5 in presence of DBU and LiCl in
acetonitrile to give key acyclic precursor 3 (Scheme 4) for intramolecular Heck-cyclization. At this stage the
crucial intramolecular Heck-cyclization under assorted conditions (Table 1) was not successful leaving the total
synthesis still elusive.4,16,17,18,19
Scheme 4. Reagents and conditions: (a) LiCl, DBU, CH3CN, 0 oC-rt, 12 h, 77%.
Table 1. Attempts to Intramolecular Heck cross Coupling for Macrocyclization.
Sl. No
Catalyst
Pd(OAc)2
PdCl2(MeCN)2
Pd(OAc)2
Conditions
Yield (%)
1
2
3
4
Cs2CO3, Et3N, DMF, rt, 48 h
Et3N, HCOOH, MeCN, rt, 1 h
K2CO3, DMF, 80 oC, 24h
Decomposition
Decomposition
Decomposition
Decomposition
Pd(OAc)2
K2CO3, Bu4NCl, DMF, 60 oC, 1 h
Conclusions
The synthesis of acyclic precursor of macrocyclic tianchimycin A was achieved by employing Myers asymmetric
alkylation, Crimmins’s aldol reaction, Paterson’s aldol reaction, Takai olefination and Masamune-Roush
olefination as key steps. Currently we are working to develop a diverse strategy to circumvent the problem of
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macrocyclization, which might help us to achieve the total synthesis of tianchimycin A and its potential analogs
and for biological screening, which will be reported in due course.
Experimental Section
General. All the reactions were performed in oven-dried glass apparatus under nitrogen or argon atmosphere
under magnetic stirring. Standard methods were used to make anhydrous solvents. Unless otherwise noted,
commercially available reagents were used without further purification. Glass columns packed with silica gel
1
(60-120 or 100-200 mesh) were used for column chromatography. H and 13C NMR were recorded on 400
MHz, 500 MHz and 100MHz, 125 MHz spectrometer, respectively, in CDCl3 solvent using TMS as an internal
1
standard. Chemical shifts are measured as ppm values relative to internal CHCl3 δ 7.26 or TMS δ 0.0 for H
1
NMR and CHCl3 δ 77 for 13C NMR. In H NMR multiplicity defined as: s = singlet; d = doublet; t = triplet; q =
quartet; dd = doublet of doublet; ddd = doublet of doublet of doublet; dt = doublet of triplet; m = multiplet;
brs = broad singlet. Horiba sepa 300 polarimeter was used to record optical rotation using a 2 mL cell with a 10
mm path length. Alpha (Bruker) infrared spectrophotometer was used to record FTIR spectra. Either a TOF or a
double focusing spectrometer was used to obtain high resolution mass spectra (HRMS) [ESI]+.
(2S,4R)-5-(tert-Butyldiphenylsilyloxy)-N-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)-N,2,4-trimethylpentan-
amide (10). n-BuLi was added drop wise (29.18 mL of 2.5 M solution in hexanes, 72.96 mmol) to a stirred
solution of flame dried LiCl (3.73 g, 91.2 mmol) and diisopropylamine (11.69 mL, 82.08 mmol) in THF (10 mL)
o
o
o
at 0 C, over 1 h. This mixture was stirred at 0 C for an additional 15 min before being cooled to -78 C. A
solution of (1R, 2R)-(-)-pseudoephedrine propionamide (6.32 g, 38.30 mmol) in THF (20 mL) was then added to
o
the reaction mixture very slowly using syringe pump. After being stirred at -78 C for 30 min the reaction
mixture was warmed to -20 °C and treated with a solution of the iodide 7 (2.0 g, 9.12 mmol) in THF (10 mL).
The reaction mixture was stirred at -20 oC for 24 h and quenched with saturated aqueous solution of NH4Cl (5
mL). The reaction mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed
with water (5 mL), brine (5 mL), dried over Na2SO4, filtered and concentrated under vacuo. The residue was
purified by column chromatography (SiO2, 25% EtOAc/hexane) to afford 10 (2.40 g, 95%) as a colorless liquid.
Rf 0.5 (50% EtOAc in hexanes); [α]D25 –42.1 (c 0.96, CHCl3). IR (neat): νmax 3742, 3393, 3065, 2931, 1696, 1620,
1
1464, 1105, 819, 744, 700 cm-1; H NMR (400 MHz, CDCl3): δ 7.67-7.64 (m, 4H), 7.44-7.28 (m, 11H), 4.60 (d, J
7.4 Hz, 1H), 4.34 (brs, 1H), 3.51 (dd, J 9.9, 5.1 Hz, 1H), 3.42 (dd, J 9.9, 5.8 Hz, 1H), 2.78 (s, 3H), 2.68 (m, 1H),
1.76-1.60 (m, 2H), 1.18 (m, 1H), 1.12 (d, J 6.5 Hz, 3H), 1.06 (d, J 6.7 Hz, 3H), 1.05 (m, 1H), 1.05 (s, 9H), 0.87 (d, J
6.5, 3H); 13C NMR (100 MHz, CDCl3): δ 179.08, 142.62, 135.60, 135.58, 133.88, 133.84, 129.54, 128.28, 127.58,
126.20, 77.20, 76.50, 68.75, 37.59, 34.09, 33.24, 26.89, 19.31, 17.69, 17.31, 14.37; HRMS (ESI) m/z [M + Na]+
calcd. for C33H45NO3SiNa 554.3039, found 554.3060.
(2S,4R)-5-(tert-Butyldiphenylsilyloxy)-2,4-dimethylpentan-1-ol (6). To a stirred solution of diisopropylamine
o
(4.81 mL, 33.76 mmol) in THF (20 mL) at 0 C was added n-BuLi (12.54 mL of 2.5 M solution in hexanes, 31.36
o
mmol) drop wise and the solution was stirred at 0 C for an additional 15 min. Then Borane-ammonia complex
o
(90%, 0.96 g, 31.36 mmol) was added to the solution. After stirring for 30 min at 0 C, the solution was
o
warmed to rt and stirred for additional 30 min. Then the reaction mixture was cooled to 0 C and it was
treated with a solution of amide 10 (2.1 g, 3.94 mmol) in 10 mL of THF. After stirring for 4 h at room
temperature, the reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) solution and extracted
with EtOAc (2x50 mL). The combined organic extracts were washed with brine (20 mL) and dried over Na2SO4.
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Evaporation of the solvent under reduced pressure gave crude mass which on purification via silica gel column
chromatography (SiO2, 17% EtOAc/hexanes) afforded 6 (980 mg, 90% yield) as a colourless viscous liquid. Rf
0.6 (25% EtOAc in hexanes); [α]D25 –2.04 (c 1.23, CHCl3). IR (neat): νmax 2956, 2860, 1515, 1466, 1107, 821, 740,
1
613 cm-1; H NMR (500 MHz, CDCl3): δ 7.69-7.66 (m, 4H), 7.45-7.36 (m, 6H), 3.53 (dd, J 9.8, 5.3 Hz, 1H), 3.48
(dd, J 10.6, 5.1 Hz, 1H), 3.44(dd, J 9.8, 6.2 Hz, 1H), 3.35 (dd, J 10.5, 6.6 Hz, 1H), 1.75 (m, 1H), 1.64 (m, 1H), 1.46
(m, 1H), 1.34 (m, 1H), 1.07 (s, 9H), 0.97 (d, J 6.6, 3H), 0.90 (d, J 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ
135.61, 133.95, 129.51, 127.56, 68.70, 68.26, 37.13, 33.14, 26.87, 19.27, 17.88, 17.39; HRMS (ESI) m/z [M +
Na]+ calcd. for C23H34O2SiNa 393.2226, found 393.2221.
(R)-4-Benzyl-3-((2R,3S,4S,6R)-7-(tert-butyldiphenylsilyloxy)-3-hydroxy-2,4,6-trimethylheptanoyl)oxazolidin-
2-one (12). To a stirred solution of 6 (800 mg, 2.08 mmol) in CH2Cl2 (10 mL), NaHCO3 (0.34 g, 4.16 mmol) was
o
added at 0 C, followed by Dess-Martin periodinane (1.32 g, 3.12 mmol) under nitrogen atmosphere and
stirred for 2 h at room temperature. Saturated aqueous NaHCO3 (5 mL) and Na2S2O3 (7 mL) were added to the
reaction mixture and extracted with EtOAc (2x10 mL). The organic phase was washed with water (10 mL),
brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The aldehyde, thus obtained, was used directly,
for the next reaction without any further characterization.
TiCl4 (2.4 mL, 2.32 mmol) was added to the compound 11 (0.53 g, 2.24 mmol) in dry CH2Cl2 (10 mL) at 0 oC and
after 5 min, (-)-sparteine (1.23 mL, 5.3 mmol) was added. After stirring at the same temperature for 20 min, a
solution of crude aldehyde in CH2Cl2 (5mL) was added under nitrogen atmosphere. After 10 min the reaction
mixture was quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2 x 20 mL).
The combined organic layers were washed with 0.5 N HCl (5 mL), water (5 mL), brine (5 mL), dried over Na2SO4
and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 18% EtOAc/hexanes) to
25
afford 12 (1.24 g, 96% yield over two steps) as a colourless viscous liquid. Rf 0.2 (20% EtOAc in hexane); [α]D
1
+15.88 (c 0.86, CHCl3). IR (neat): νmax 2927, 1781, 1694, 1515, 1462, 1384, 1206, 1108, 823, 740, 703 cm-1; H
NMR (400 MHz, CDCl3): δ 7.69-7.65 (m, 4H), 7.44-7.27 (m, 9H), 7.22-7.18 (m, 2H), 4.65 (m, 1H), 4.21-4.14 (m,
2H), 3.97 (m, 1H), 3.68 (t, J 5.5 Hz, 1H), 3.54 (dd, J 9.8, 5.0 Hz, 1H), 3.44 (dd, J 9.8, 6.4 Hz, 1H), 3.24 (dd, J 13.4,
3.4 Hz, 1H), 2.77 (dd, J 13.4, 9.5 Hz, 1H), 2.34 (brs, 1H), 1.78 (m, 1H), 1.69-1.56 (m, 2H), 1.49 (m, 1H), 1.24 (d, J
7.0 Hz, 3H), 1.06 (s, 9H), 0.96, (d, J 6.7 Hz, 3H), 0.90 (d, J 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 177.13,
152.84, 135.68, 135.65, 135.10, 133.97, 129.54, 129.46, 128.98, 127.62, 127.43, 74.93, 68.46, 66.06, 55.16,
40.22, 37.76, 37.11, 33.25, 32.86, 26.93, 19.31, 18.24, 15.23, 12.12; HRMS (ESI) m/z [M + Na]+ calcd. for
C36H47NO5SiNa 624.3109, found 624.3106.
(2S,3S,4S,6R)-7-(tert-Butyldiphenylsilyloxy)-2,4,6-trimethylheptane-1,3-diol (13). To a stirred solution of
o
compound 12 (1.1 g, 1.76 mmol) in dry ether (25 mL) at 0 C were added one drop of distilled water followed
by LiBH4 (77 mg, 3.53 mmol) in portion wise. The reaction mixture was stirred at the same temperature for 10
min before being quenched with the careful addition of distilled water and extracted with EtOAc (2 x 20 mL),
the combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2SO4 and
concentrated in vacuo. Purification of the residue by column chromatography (SiO2, 25% EtOAc/hexanes)
afforded 13 (680 mg, 96% yield) as a colourless viscous liquid. Rf 0.3 (30% EtOAc in hexane); [α]D25 –3.6 (c 1.01
, CHCl3). IR (neat): νmax 3856, 3618, 3393, 2957, 2859, 1515, 1427, 1386, 1107, 1081, 972, 821, 740, 701 cm-1;
1H NMR (400 MHz, CDCl3): δ 7.68-7.64 (m, 4H), 7.43-7.34 (m, 6H), 3.65 (d, J 4.8 Hz, 2H), 3.52 (dd, J 9.8, 4.9 Hz,
1H), 3.47-3.40 (m, 2H), 2.0 (brs, 1H), 1.84 (m, 1H), 1.73 (m, 1H), 1.60 (m, 1H), 1.46 (m, 1H), 1.05 (s, 9H), 0.95
(d, J 6.8 Hz, 3H), 0.92 (d, J 6.9 Hz, 3H), 0.91 (d, J 6.6 Hz, 3H), 0.85 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 135.64,
135.58, 133.92, 133.87, 129.54, 127.58, 78.11, 68.18, 67.50, 37.18, 36.60, 33.64, 33.14, 26.89, 19.28, 18.43,
15.69, 10.29; HRMS (ESI) m/z [M + H]+ calcd. for C26H41O3Si 429.2821, found 429.2825.
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tert-Butyl((2R,4S)-4-((4S,5S)-2-(4-methoxyphenyl)-5-ethyl-1,3-dioxan-4-yl)-2-methylpentyloxy)diphenyl-
silane (14). Freshly prepared PMP acetal (0.36 mL, 2.09 mmol), followed by CSA (30 mg, 0.14 mmol) were
o
added to the compound 13 (0.6 g, 1.40 mmol) in anhydrous CH2Cl2 (25 mL) at 0 C. The resulting reaction
mixture was stirred for 12 h at ambient temperature. The reaction mixture was quenched with saturated
aqueous NaHCO3 solution (5 mL) and extracted with EtOAc (2 x 15 mL). Combined organic layers were washed
with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by
column chromatography (SiO2, 12% EtOAc/hexanes) to afford 14 (0.72 g, 94% yield) as a colourless liquid. Rf
25
0.7 (30% EtOAc in hexanes); [α]D –8.90 (c 1.94 , CHCl3). IR (neat): νmax 2956, 2853, 1616, 1515, 1387, 1246,
1108, 1004, 822, 740, 701, 613 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.70-7.66 (m, 4H), 7.46-7.36 (m, 8H), 6.90 (d,
J 8.6 Hz, 2H), 5.43 (s, 1H), 4.01 (s, 2H), 3.81 (s, 3H), 3.60 (dd, J 10.0, 4.6 Hz, 1H), 3.46 (dd, J 9.8, 6.3 Hz, 1H), 3.39
(dd, J 9.6, 1.9 Hz, 1H), 1.82 (m, 1H), 1.75-1.66 (m, 2H), 1.48 (m, 1H), 1.10 (d, J 7.0 Hz, 3H), 1.08 (s, 9H), 1.0 (d, J
6.6 Hz, 3H), 0.95 (d, J 6.4 Hz, 3H), 0.79 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 159.73, 135.65, 135.58, 133.91,
133.84, 131.72, 129.54, 129.51, 127.56, 127.21, 113.52, 101.65, 85.06, 67.53, 55.26, 35.13, 32.69, 32.23,
29.99, 19.29, 19.09, 16.24, 11.19; HRMS (ESI) m/z [M + H]+ calcd. for C34H47O4Si 547.3233, found 547.3238.
(2R,4S)-4-((4S,5S)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-4-yl)-2-methylpentan-1-ol (15). TBAF (1M
solution in THF 1.3 mL, 1.3 mmol) was added to a stirred solution of compound 14 (0.65 g, 1.18 mmol) in dry
THF (15 mL), at 0 oC. Reaction mixture was warmed to room temperature and stirred for 12 h. It was quenched
with saturated aqueous NH4Cl solution (5 mL), extracted with EtOAc (2 x 15 mL), washed with brine (5 mL),
dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 16%
EtOAc/hexanes) to afford 15 (333 mg, 91% yield) as a colourless viscous liquid. Rf 0.4 (20% EtOAc in hexanes);
25
1
[α]D –2.81 (c 0.76 , CHCl3). IR (neat): νmax 2969, 2854, 1615, 1516, 1248, 1110, 1034, 826, 739, 703 cm-1; H
NMR (400 MHz, CDCl3): δ 7.42-7.37 (m, 2H), 6.91-6.86 (m, 2H), 5.42 (s, 1H), 4.02 (s, 2H), 3.79 (s, 3H), 3.51-3.38
(m, 3H), 1.81-1.63 (m, 5H), 1.15 (d, J 6.8 Hz, 3H), 0.92 (d, J 6.4 Hz, 3H), 0.86 (d, J 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 159.86, 131.28, 127.23, 113.61, 101.88, 85.06, 73.93, 67.16, 55.22, 37.42, 33.67, 32.38, 30.08,
18.62, 15.63, 10.83; HRMS (ESI) m/z [M + Na]+ calcd. for C18H28O4SiNa 331.1871, found 331.1874.
(4R,6S)-6-((4S,5S)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-4-yl)-4-methylhept-1-en-3-ol (16). To a stirred
o
solution of 15 (0.30 g, 1.94 mmol) in CH2Cl2 (10 mL), NaHCO3 (0.16 g, 1.94 mmol) was added at 0 C, followed
by Dess-Martin periodinane (0.82 g, 1.94 mmol) under nitrogen atmosphere. The reaction mixture was
allowed to come to room temperature and stirred for 2 h before being quenched with saturated Na2S2O3 (5
mL) and NaHCO3 (3 mL) and extracted with EtOAc (2x10 mL). The combined organic layers were washed with
water (5 mL), brine (5 mL), dried over anhydrous Na2SO4. Evaporation of the solvent furnished crude aldehyde,
which was passed through a short pad of silica gel and used as such for the next reaction.
To a stirred solution of crude aldehyde in dry THF (10 mL), vinyl magnesium bromide (1M solution in THF 1.94
o
mL, 1.94 mmol) was added at 0 C. Reaction mixture was warmed to room temperature and stirred for 1 h. It
was quenched with saturated aqueous NH4Cl solution (5 mL), extracted with EtOAc (2 x 10 mL). The combined
organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (SiO2, 14% EtOAc/hexanes) to afford 16 (0.27 g, 84% yield) as a colourless
viscous liquid. Rf 0.6 (20% EtOAc in hexanes); [α]D25 –2.85 (c 0.7 , CHCl3). IR (neat): νmax 2856, 1514, 1465, 1248,
1
1035, 621 cm-1; H NMR (500 MHz, CDCl3): δ 7.44-7.41 (m, 2H), 6.90-6.86 (m, 2H), 5.89 (ddd, J 16.0, 10.7, 5.4
Hz, 1H) 5.44 (s, 1H), 5.23 (dt, J 17.3, 1.6 Hz, 1H), 5.15 (dt, J 10.5, 1.6 Hz, 1H), 4.16 (m, 1H), 4.03-4.01 (m, 2H),
3.79 (s, 3H), 3.44 (dd, J 9.6, 2.2 Hz, 1H), 1.87-1.72 (m, 3H), 1.66 (ddd, J 13.3, 9.5, 3.2 Hz, 1H), 1.18 (d, J 7.0 Hz,
3H), 1.01 (d, J 6.4 Hz, 3H) 0.89 (d, J 6.8 Hz, 3H), 0.77 (ddd, J 15.3, 10.9, 4.4 Hz, 1H); 13C NMR (125 MHz, CDCl3):
δ 159.75, 140.43, 131.73, 127.23, 114.58, 113.54, 101.69, 84.96, 73.98, 73.50, 55.27, 34.96, 34.54, 32.25,
30.11, 16.27, 15.09, 11.15; HRMS (ESI) m/z [M + Na]+ calcd. for C20H30O4Na 357.2047, found 357.2051.
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tert-Butyl((4R,6S)-6-((4S,5S)-2-(4-methoxyphenyl)-5-ethyl-1,3-dioxan-4-yl)-4-methylhept-1-en-3-yloxy)
dimethylsilane (17). 2,6-Lutidine (0.26 mL, 2.26 mmol) and TBSOTf (0.14 mL, 0.83 mmol) were added
o
sequentially to a stirred solution of compound 16 (0.25 g, 0.75 mmol) in CH2Cl2 (7 mL) at 0 C. After 2 h,
reaction was quenched with saturated NH4Cl solution (5 mL), the reaction mixture was extracted with EtOAc
(2 x 10 mL). The organic layer was washed with saturated aqueous CuSO4 solution (5 mL), brine (5 mL), dried
over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 3%
EtOAc/hexanes) to afford 17 (0.32 g, 93% yield) as a colourless viscous liquid. Rf 0.8 (10% EtOAc in hexanes);
[α]D25 +5.2 (c 0.52, CHCl3). IR (neat): νmax 2915, 2858, 1515, 1427, 1386, 972, 822, 740, 624 cm-1; 1H NMR (400
MHz, CDCl3): δ 7.42-7.38 (m, 2H), 6.88-6.84 (m, 2H), 5.82 (ddd, J 17.0, 10.4, 6.5 Hz, 1H) 5.43 (s, 1H), 5.16-5.06
(m, 2H), 4.20-4.01 (m, 2H), 3.80 (s, 3H), 3.39 (dd, J 9.6, 2.2 Hz, 1H), 1.83-1.60 (m, 5H), 1.16 (d, J 6.9 Hz, 3H),
1.01 (d, J 6.4 Hz, 3H), 0.91 (d, J 6.7 Hz, 3H), 0.89 (s, 9H), 0.63 (m, 1H) 0.04 (s, 3H), 0.01 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 159.74, 139.68, 131.82, 127.24, 115.05, 113.53, 101.73, 85.30, 77.64, 74.02, 55.28, 37.68,
34.30, 33.36, 30.23, 25.9, 17.18, 16.92, 11.53, -4.05, -4.86; HRMS (ESI) m/z [M + H]+ calcd. for C26H45O4Si
449.3089, found 449.3087.
(3R,4S,6R)-7-(tert-Butyldimethylsilyloxy)-3-(4-methoxybenzyloxy)-4,6-dimethylnon-8-enal (4). To a stirred
o
solution of compound 17 (0.270 g, 0.60 mmol) in dry CH2Cl2 (8 mL) at -40 C, DIBAL-H (1.5 M solution in
toluene, 1.6 mL, 2.4 mmol) was added drop wise under nitrogen atmosphere. After stirring for 0.5 h at the
o
same temperature, the reaction mixture was slowly brought to 0 C and stirred for 2 h. Dry MeOH (3 mL) was
added drop wise at -78 oC to quench the reaction mixture, and stirred for 0.5 h at the same temperature, then
added potassium sodium tartrate, stirred at room temperature for 1 h and extracted with EtOAc (2 x 10 mL).
The combined organic extracts were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (SiO2, 25% EtOAc/hexanes) to afford primary alcohol 4a
(220 mg, 90% yield) as a colourless viscous liquid. Rf 0.2 (30% EtOAc in hexane); [α]D25 +4.90 (c 1.03, CHCl3). IR
1
(neat): νmax 2925, 2855, 1699, 1515, 1463, 1248, 1036, 835, 775 cm-1; H NMR (500 MHz, CDCl3): δ 7.28-7.25
(m, 2H), 6.88-6.84 (m, 2H), 5.77 (ddd, J 16.4, 10.4, 6.5 Hz, 1H), 5.11 (dt, J 17.1, 3.1, Hz, 1H), 5.06 (dt, J 10.3, 3.0
Hz, 1H), 4.51 (ABq, J 10.9 Hz, 2H), 3.89 (m, 1H), 3.79 (s, 3H), 3.62 (dd, J 10.6, 7.0 Hz, 1H), 3.53 (dd, J 10.6, 5.8
Hz, 1H), 3.30 (t, J 4.5, 1H), 2.01 (m, 1H), 1.90-1.81 (m, 2H), 1.66-1.58 (m, 2H), 1.00 (d, J 6.8 Hz, 3H), 0.95 (d, J
6.9 Hz, 3H), 0.88 (s, 9H), 0.87 (d, J 6.8 Hz, 3H), 0.02 (s, 3H), 0.00 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 159.08,
139.99, 131.07, 114.81, 113.72, 83.90, 77.88, 73.93, 66.46, 55.24, 37.96, 37.50, 32.97, 25.90, 18.25, 16.41,
15.90, -4.18, -4.86; HRMS (ESI) m/z [M + Na]+ calcd. for C26H46O4SiNa 459.2911, found 459.2914.
To a stirred solution of primary alcohol (0.1 g, 0.22 mmol) in CH2Cl2 (3 mL), NaHCO3 (0.37 mg, 0.44 mmol) was
o
added at 0 C, followed by Dess-Martin periodinane (0.18 mg, 0.44 mmol) under nitrogen atmosphere. The
reaction mixture was allowed to attain room temperature and stirred for 2 h. Saturated Na2S2O3 (10 mL) and
NaHCO3 (2 mL) were added to quench the reaction mixture. After stirring 15 min the reaction mixture was
extracted with EtOAc (2 x 20mL). The organic phase was washed with water (20 mL), brine (20 mL), dried over
Na2SO4 and concentrated in vacuo. The aldehyde 4 thus obtained was directly used, after passing through a
short pad of silica, for the next reaction without any further characterization.
(2S, 4R, 5R)-5-Hydroxy-4-methyl-3-oxohexan-2-yl benzoate (8). To a stirred solution of c-Hex2BCl (14.54 mL,
14.54 mmol) in Et2O (20 mL) at –78 oC was added Me2NEt (1.68 mL, 19.4 mmol), followed by ketone 9 (2 g, 9.7
mmol) in Et2O (10 mL). The reaction mixture was warmed to -10 oC for first 30 min and then to 0 oC for next 1
o
h before being cooled to –78 C. The commercially available acetaldehyde (2.70 mL, 48.48 mmol) was added
and stirred for further 2 h at the same temperature. Then the reaction mixture temperature was raised to –20
o
oC and stirred for 14 h. The reaction was quenched at 0 C by addition of MeOH (10 mL) and pH 7 buffer (10
mL), H2O2 (5 mL, 30%) was then added and the stirring continued for 1 h and extracted with EtOAc (3x50mL).
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The combined organic extracts were washed with water (10 mL), brine (5 mL) and dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column chromatography (SiO2, 8% EtOAc/hexanes) to
afford 8 (2.06 g, 96% yield) as a colourless solid. Rf 0.7 (20% EtOAc in hexanes); [α]D25 +30.0 (c 0.75, CHCl3).
1
IR (neat): νmax 2945, 1720, 1515, 1454, 1262, 1116, 1003, 707 cm-1; H NMR (500 MHz, CDCl3): δ 8.08 (m, 2H),
7.58 (m, 1H), 7.45-7.44 (m, 2H), 5.44 (q, J 7.1 Hz, 1H), 3.98 (dq, J 13.7, 6.4 Hz, 1H), 2.80 (p, J 7.3 Hz, 1H), 2.16
(brs, 1H), 1.57 (d, J 7.1 Hz, 3H), 1.25 (d, J 7.3 Hz, 3H), 1.22 (d, J 6.2 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ
211.72, 165.86, 133.36, 129.77, 129.39, 128.45, 74.48, 69.45, 49.91, 20.84, 15.87, 14.40; HRMS (ESI) m/z [M +
Na]+ calcd. for C14H18O4Na 273.1093, found 273.1097.
(2S,4R,5R)-5-(tert-Butyldimethylsilyloxy)-4-methyl-3-oxohexan-2-yl benzoate (18). To a stirred solution of
o
compound 8 (1.9 g, 7.59 mmol) in CH2Cl2 (30 mL) at 0 C, 2,6-lutidine (2.64 mL, 22.7 mmol) was added
followed by TBSOTf (1.9 mL, 8.35 mmol) and stirred for 15 min. The reaction was quenched with saturated
aqueous NH4Cl solution (20 mL), the reaction mixture was extracted with EtOAc (2 x 30 mL), washed with
saturated aqueous CuSO4 solution (20 mL), brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (SiO2, 5% EtOAc/hexanes) to afford 18 (2.57 g, 92% yield) as a
colourless liquid. Rf 0.8 (20% EtOAc in hexanes); [α]D25 –14.00 (c 0.68, CHCl3). IR (neat): νmax 2975, 1720, 1515,
1454, 1262, 1116, 1003, 771, 707 cm-1; 1H NMR (500 MHz, CDCl3): δ 8.09-8.06 (m, 2H), 7.57 (m, 1H), 7.47-7.43
(m, 2H), 5.41 (q, J 6.8 Hz, 1H), 4.05 (m, 1H), 2.84 (dq, J 8.4, 7.1 Hz, 1H), 1.51 (d, J 7.0 Hz, 3H), 1.14 (d, J 6.2 Hz,
3H), 1.10 (d, J 7.0 Hz, 3H), 0.83 (s, 9H), 0.03 (s, 3H), -0.03 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 209.40, 165.78,
133.19, 129.81, 128.39, 75.08, 70.12, 50.58, 25.81, 21.15, 17.87, 15.24, 13.76, -4.69, -4.84; HRMS (ESI) m/z [M
+ Na]+ calcd. for C20H32O4SiNa 388.2049, found 388.2052.
(2S,4S,5R)-5-(tert-Butyldimethylsilyloxy)-4-methylhexane-2,3-diol (19). To a stirred solution of the protected
o
aldol product 18 (6.3 mmol) in THF (25 mL) at –78 C was added LiBH4 (2.74 g, 126.18 mmol). The reaction
mixture was warmed slowly to room temperature and stirred for 21 h. Then the reaction mixture was cooled
to 0 oC and quenched with the careful addition of H2O. The mixture was extracted with EtOAc (2 x 25 mL) and
the combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (SiO2, 18% EtOAc/hexanes) to afford 19 (1.52 g, 92%
25
yield) as a colourless viscous liquid. Rf 0.3 (20% EtOAc in hexanes); [α]D –11.27 (c 1.1, CHCl3). IR (neat): νmax
1
3360, 2958, 2893, 1612, 1465, 1251, 1062, 838, 775, 688 cm-1; H NMR (400 MHz, CDCl3): δ 3.89 (p, J 6.2 Hz,
1H), 3.80 (m 1H), 3.58 (dd, J =8.2, 3.9 Hz, 1H), 3.42 (s, 1H), 2.64 (brs, 1H), 1.64 (m, 1H), 1.58 (m, 1H), 1.20 (d, J
6.2 Hz, 3H), 1.16 (d, J 6.3 Hz, 3H), 0.90 (s, 9H), 0.81 (d, J 6.9 Hz, 3H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 73.17, 67.97, 42.98, 25.79, 21.40, 17.93, 16.24, 12.27, -4.22, -4.87; HRMS (ESI) m/z [M + H]+
calcd. for C13H31O3Si 263.2048, found 263.2045.
tert-Butyl((2R,3S,E)-5-iodo-3-methylpent-4-en-2-yloxy)dimethylsilane (20). To a stirred solution of 1,2-diol 19
o
(5.33 mmol) in MeOH (10 mL) and H2O (5 mL) at 0 C was added NaIO4 (3.42 g, 15.99 mmol). The reaction
mixture was stirred at room temperature for 30 min. Then it was diluted with H2O (15 mL) and extracted with
EtOAc (2 x 20 mL). The combined organic extracts were dried over Na2SO4, concentrated in vacuo. The
aldehyde (Rf 0.5, 3% EtOAc in petroleum ether), thus obtained, was directly used, after flash chromatography,
for the next reaction without any further characterization.
To a stirred solution of anhydrous CrCI2 (1.9 g, 31.98 mmol) in THF (20 mL) under argon atmosphere was
o
added a solution of crude aldehyde and iodoform (4.19 g, 10.66 mmol) in THF (15 mL) at 0 C and the reaction
mixture was stirred at 0 °C for 1 h before being quenched with water (15 mL). The reaction mixture was
extracted with EtOAc (2x20 mL). The combined organic extracts were washed with water (10 mL), brine (10
mL) and dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography
(SiO2, hexanes) to afford 20 (1.45 g, 80% yield) as a colourless viscous liquid. Rf 0.9 (5% EtOAc in hexanes);
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[α]D25 –16.91 (c 1.2, CHCl3). IR (neat): νmax 2957, 2931, 2853, 1463, 1373, 1254, 1110, 954, 836, 774, 671 cm-1;
1H NMR (400 MHz, CDCl3): δ 6.47 (dd, J 14.4, 8.6 Hz, 1H), 5.97 (dd, J 14.4, 0.9 Hz, 1H), 3.64 (dq, J 6.1, 4.8 Hz,
1H), 2.16 (m, 1H), 1.07 (d, J 6.1 Hz, 3H), 0.89 (d, J 7.0 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H); 13C NMR (100 MHz,
CDCl3): δ 149.01, 74.73, 71.19, 48.35, 25.83, 21.23, 18.04, 15.70, -4.38, -4.81; HRMS (ESI) m/z [M + Na]+ calcd.
for C12H25IOSiNa 363.0612, found 363.0616.
(2R,3S,E)-5-Iodo-3-methylpent-4-en-2-ol (21). To a stirred solution of compound 20 (1.2 g, 3.52 mmol) in dry
o
THF (25 mL), TBAF (1M solution in THF 3.87 mL, 3.87 mmol) was added at 0 C. Reaction mixture was warmed
to room temperature and stirred for 12 h. saturated aqueous NH4Cl solution (15 mL) was used to quench the
reaction mixture, and extracted with EtOAc (2 x 20 mL), washed with brine (15 mL), dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column chromatography (SiO2, 8% EtOAc/hexanes) to
25
afford 21 (0.725 g, 91% yield) as a colourless viscous liquid. Rf 0.2 (10% EtOAc in hexanes); [α]D +10.00 (c
0.25, CHCl3). IR (neat): νmax 3403, 2956, 2857, 1253, 1095, 837, 776 cm-1; 1H NMR (500 MHz, CDCl3): δ 6.49 (dd,
J 14.4, 8.7 Hz, 1H), 6.12 (dd, J 14.4, 0.6 Hz, 1H), 3.62 (p, J 6.1 Hz, 1H), 2.19 (m, 1H), 1.17 (d, J 6.3 Hz, 3H), 1.03
(d, J 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 148.09, 76.17, 70.52, 48.32, 20.48, 15.63; HRMS (ESI) m/z [M +
H]+ calcd. for C6H12IO 226.9928, found 226.9924.
(2R,3S,E)-5-Iodo-3-methylpent-4-en-2-yl 2-(diethoxyphosphoryl)acetate (5). Diethyl phosphonoacetic acid
(1.06 mL, 6.63 mmol) and DMAP (0.05 g, 0.44 mmol) were added sequentially to a stirred solution of 21 (0.500
o
g, 2.21 mmol) which was previously azeotroped with benzene, in dry CH2Cl2 (10 mL) at 0 C under argon
o
atmosphere. After stirring for 10 min at 0 C, EDCI (1.27g, 6.63 mmol) was added to it and stirred at rt for
another 4 h. Then reaction mixture was quenched with water and extracted with EtOAc (2 x 20 mL). The
combined organic extracts were washed with brine (5 mL) and dried over Na2SO4 and concentrated under
vacuo. The residue was purified by column chromatography (SiO2, 30% EtOAc/hexanes) to afford 5 (0.84 g,
25
85%) as a yellow oil. Rf 0.2 (40% EtOAc /hexanes); [α]D +0.8 (c 1.25, CHCl3). IR (neat): νmax 2938, 2861, 1739,
1470, 1395, 1260, 1105, 1055, 1027, 971, 839, 778, 669 cm-1; 1H NMR (400 MHz, CDCl3): δ 6.46 (dd, J 14.4, 8.6
Hz, 1H), 6.09 (dd, J 14.4, 0.9 Hz, 1H), 4.87 (m, 1H), 4.22-4.11 (m, 4H), 2.96 (d, J 21.6 Hz, 2H), 2.37 (m, 1H), 1.36-
1.31 (m, 6H), 1.17 (d, J 6.4 Hz, 3H), 1.03 (d, J 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.29, 146.56, 76.45,
74.04, 62.62, 62.56, 45.17, 35.15, 33.82, 17.20, 16.36, 15.39; HRMS (ESI) m/z [M + Na]+ calcd. for C12H22IO5PNa
427.0141, found 427.0145.
(4S,5S,6S,8R,E)-((2R,3S,E)-5-Iodo-3-methylpent-4-en-2-yl)-9-(tert-butyldimethylsilyloxy)-5-(4-
methoxybenzyloxy)-4,6,8-trimethylundeca-2,10-dienoate (3). To a stirred solution of compound 5 (0.100 g,
o
0.22 mmol) and LiCl (0.02 g, 0.44 mmol) in MeCN (6 mL) at 0 C, was added DBU (0.16 mL, 0.22 mmol) under
o
argon atmosphere. After stirring at room temperature for 15 min, the mixture was again cooled to 0 C. Then
a solution of aldehyde 4 in MeCN (5 mL) was added dropwise. After stirring at room temperature for 12 h, the
reaction mixture was quenched by addition of water and extracted with EtOAc (2 x 20 mL). The combined
organic extracts were washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuo. The
residue was purified by column chromatography (SiO2, 60-120 mesh, 6% EtOAc/hexanes) to afford 3 (0.119 g,
77% two steps) as a colorless oil. Rf 0.5 (10% EtOAc /hexanes); [α]D25 –5.10 (c 0.75, CHCl3). IR (neat): νmax 2924,
2855, 1713, 1649, 1513, 1458, 1248, 1179, 1071, 1036, 989, 821, 583 cm-1; 1H NMR (500 MHz, CDCl3) mixture
of two diastereomers at C9 center: δ 7.26 (d, J 7.39 Hz, 2H), 6.94-6.85 (m, 3H), 6.47 (ddd, J 15.4, 9.5, 1.0 Hz,
1H), 6.09 (dt, J 14.4, 1.1 Hz, 1H), 5.84-5.71 (m, 2H), 5.15-5.04 (m, 2H), 4.91 (m, 1H), 4.55-4.46 (m, 2H), 3.90 (m,
1H), 3.80 (s, 3H), 3.17 (tt, J 7.5, 2.9 Hz, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 1.76-1.68 (m, 2H), 1.61 (m, 1H), 1.27
and 1.25 (two d, J 7 and 7.1 Hz, 3H), 1.19 (d, J 6.3 Hz, 3H), 1.15 and 1.13 (two d, J 7.0 and 7.4 Hz, 3H), 1.02 (d, J
6.9, 3H), 0.97-0.89 (m, 4H), 0.89 and 0.88 ( two s, 9H), 0.84 (d, J 6.8 Hz, 3H), 0.02 and 0.01 (two s, 3H), -0.002
and -0.009 (two s, 3H); 13C NMR (125 MHz, CDCl3) mixture of two diastereomers at C9 center: δ 165.99,
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159.10, 152.10, 152.02, 147.05, 140.11, 139.07, 130.97, 130.88, 129.19, 129.15, 120.70, 115.17, 114.82,
113.72, 84.81, 77.79, 77.11, 76.11, 74.69, 74.62, 72.36, 55.26, 45.49, 40.30, 40.08, 37.67, 37.12, 36.97, 33.48,
33.34, 25.92, 25.88, 18.26, 18.20, 17.36, 16.38, 15.97, 15.57, 15.43, 15.28, 15.04, -4.17, -4.35, -4.82; HRMS
(ESI) m/z [M + Na]+ calcd. for C34H55IO5SiNa 721.2753, found 721.2755.
Experimental procedure for the attempted Heck cyclization reaction (22)
1. To
a
stirred solution of
3
(0.02 g, 0.028 mmol) in DMF (5 mL) were added
Cs2CO3 (0.016 g, 0.05 mmol), Et3N (0.005 mL, 0.033 mmol) and Pd(OAc)2 (0.01 g, 0.045 mmol) sequentially at rt
under argon atmosphere. After stirring for 48 h at rt, the reaction mixture was quenched with water and
extracted with EtOAc (2 x 10 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4 and
concentrated under vacuo.
2. To a stirred solution of 3 (0.02 g, 0.028 mmol) in MeCN (5 mL) was added Et3N (0.03 mL, 0.221 mmol),
followed by PdCl2(MeCN)2 (0.001 g, 0.46mmol) and formic acid (0.001 mL, 0.027 mmol) at rt under argon
atmosphere. After stirring for 1 h at rt, the reaction mixture was quenched by the addition of water (5 mL) and
extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (5 mL) and dried over
Na2SO4 and concentrated under vacuo.
3. To a stirred solution of 3 (0.02 g, 0.028 mmol) in DMF (5 mL) were added Pd(OAc)2 (0.008 g, 0.035 mmol)
and dry K2CO3 (0.032 g, 0.233 mmol) sequentially at rt under argon atmosphere. The resulting mixture was
stirred at 80 °C for 2 h before being quenched by the addition of water (5 mL) and extracted with EtOAc (2 ×
10 mL). The combined organic layers were washed with brine (5 mL) and dried over Na2SO4. Evaporation of
the solvent under reduced pressure gave crude mass.
4. To a stirred and degassed solution of 3 (0.02 g, 0.028 mmol) in DMF (5 mL) were added Pd(OAc)2 (0.006 g,
0.028 mmol), dry K2CO3 (0.038 g, 0.28 mmol), and Bu4NCl (0.023 g, 0.084 mmol) and the mixture was once
again degassed. The solution was stirred under argon atmosphere and heated to 60 °C for 50 min. After
cooling to room temperature, diethyl ether (5 mL) was added, and the solution was washed with water (5 mL)
and extracted with EtOAc (2x10 mL). The combined organic extracts were washed with brine (5 mL) and dried
over Na2SO4 and concentrated under vacuo.
Acknowledgements
Yamini. V is thankful to the CSIR, New Delhi for research fellowship.
Supplementary Material
1H & 13C NMR spectra of compound 3, 4a, 5, 6, 8, 10, 12-21.
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