Enantioselective Synthesis of Cyclohexadienone Containing

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Enantioselective Synthesis of Cyclohexadienone Containing Spiroketals via DyKat Ketalization/oxa-Michael Addition Cascade Reddy Rajasekhar Reddy, Shibaram Panda, and Prasanta Ghorai J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00371 • Publication Date (Web): 18 Mar 2019 Downloaded from http://pubs.acs.org on March 19, 2019

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The Journal of Organic Chemistry

Enantioselective Synthesis of Cyclohexadienone Containing Spiroketals via DyKat Ketalization/oxa-Michael Addition Cascade Reddy Rajasekhar Reddy,†a Shibaram Panda,†a and Prasanta Ghorai*a Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal By-pass Road, Bhauri, Bhopal-462066, India. †

Both the authors contributed equally.

ABSTRACT: An oxidative dearomatization of phenol followed by dynamic kinetic (DyKat) ketalization/oxaMichael addition cascade using cinchona alkaloid based chiral bifunctional aminosquaramide catalysts is reported. A broad array of sterically hindered [5,5]-spiroketals attached to a cyclohexadienone moiety in spiro-fashion is synthesized in enantiopure form. Further, the methodology was optimized and extended to the corresponding benzannulated [5,5]-spiroketals attached to a cyclohexadienone moiety in spiro-fashion. In general, good yields and excellent diastereo- and enantioselectivities (up to 20:1 dr and up to 99% ee) were obtained. INTRODUCTION Aliphatic spiroketal motifs are fundamental subunit found in a broad array of natural products, microbes, fungi, plants, insects and marine organisms.1 Over the years, stereocontrol synthesis of such unstable, fragile, and arduously accessible subunits remained a challenge but attractive endeavor to the synthetic community not only for their structural complexity but also because of their pharmacological importance. Traditionally, to obtain enantiopure spiroketals, the use of enantiopure starting materials2 or chiral auxiliaries3 are used. However, a much more challenging goal is the enantioselective synthesis of stereogenic spiroketal unit from achiral starting materials in a single step. In this regard, a true enantioselective catalytic method for their synthesis was reported in 2012 by List4b followed by Nagorny4c which relies on the chiral Brönsted acid-catalyzed formation of an oxonium intermediate followed by an intramolecular addition of an alcohol. However, the major challenge frequently encountered in the methods mentioned aboves is the stereoselective assembly of the spiroketal unit, which is a stereogenic center, but can easily isomerize under a mild acidic condition. Recently, Matsubara5 as well as our group6 independently reported a bifunctional amino-thiourea catalyzed intramolecular hemiketalization /oxa-Michael addition cascade to the spiroketals where the reactions 1

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proceed under mild reaction conditions and, therefore, in general, the selectivities are very high. Very recently, chiral iridium catalyzed intramolecular hemiketalization/oxa-allylation cascade have also been explored to highly selective spiroketals.4e However, this research area is still in its infancy, and just a few studies have been reported.

Scheme 1. (a) Dearomatization of phenol/enantioselective oxa-Michael reaction to CHD-THF. (b) dearomatization of phenol followed by hemiketalization/oxa-Michael addition cascade to CHD-spirospiroketals.

Figure 1. Natural products possessing a CHD-spiro-spiroketal moiety. Cyclohexadienone connected to a spiroketal moiety in a spiro-fashion (CHD-spiro-spiroketal) is a fascinating skeleton found in natural products, such as aculeatins A-D and new aculeatin analogue (Figure 1).7 Aculeatins A-D is widely used folk herb medicine against fever and malaria by the indigenous people of Papua New Guinea. Preliminary biological studies have shown that aculeatins A-D displayed potent in vitro antiprotozoal activity (IC50 0.18-0.49 µM) and moderate to high cytotoxicity (IC50 0.38-1.70 µM).8 The enantiopure synthesis of the CHD-spiro-spiroketal moiety is achieved by the use of enantiopure starting materials.9 To the best of our knowledge, catalytic enantioselective synthesis of CHD-spiro-spiroketal where chiral spiroketal unit is assembled catalytically from an achiral starting material is still elusive. 2


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In our recent study, we have demonstrated an oxidative dearomatization (OD) of phenols10 to provide hydroxylcyclohexadienone followed by an enantioselective oxa-Michael reaction of tethered enone as a powerful strategy for the synthesis of sterically hindered cyclohexadienone containing tetrahydrofurans (Scheme 1a).11 As a part of our effort to extend the power of a bifunctional amino-thiourea /squaramide catalyzed12,13 intramolecular oxa-Michael addition cascade to provide the spiroketal moiety, we envisaged that the oxidative dearomatization of phenol attached to a tethered ketoenone at 4-position which would provide the alcohol intermediate II, which on enantioselective dynamic kinetic (DyKat) ketalization followed by an asymmetric oxa-Michael reaction would provide an enantioenriched cyclohexadienone connected to spiroketal moiety in a spiro-fashion (CHD-spiro-spiroketal) IV (Scheme 1b). RESULTS AND DISCUSSION To make it successful, first, an OD of 4-substituted phenol 1a was performed using PhI(OAc)2 as an oxidant to prepare the desired 4-hydroxy cyclohexadienone with tethered ketoenone 2a which was further used for hemiketalization followed by asymmetric oxa-Michael addition through the dynamic kinetic (DyKat) in the presence of various organocatalysts as shown in Table 1, entries 1-7. The optimal catalyst C7 provided yield 88% and 97% ee and 13:1 dr (entry 7). Further on the screening of different solvents (Table 1, entry 8-15) revealed that toluene was the best (entry 7). On decreasing the reaction temperature (see, SI table S1 and S2), the selectivity has been reduced. Table 1. Optimization of the Reaction Conditionsa O

OH

O PhI(OAc)2

catalyst

O O HO

1a

Ar = pTol

Ar

O

O

2a

O

H O

O Ar

3a

Ar

Entry

cat

Solvent

Time (h)

Yield drc (%)b

ee (%)d

1 2 3 4 5 6 7 8 9 10 11

C1 C2 C3 C4 C5 C6 C7 C7 C7 C7 C7

Toluene Toluene Toluene Toluene Toluene Toluene Toluene CH2Cl2 CH3CN THF EtOAc

6 15 6 15 15 5 4 7.5 26.5 72 96

90 60 83 70 NR 87 88 87 92 72 69

93 99 94 99 89 97 98 88 79 92

3:1 2.3:1 3.3:1 2.7:1 5.6:1 13:1 4.5:1 2:1 3.7:1 11:1

3



12 13 14 15

C7 C7 C7 C7

C 6 H6 Mse Xylene F3CC6H5

4 48 4 4

92 85 85 88

7.8:1 5.8:1 7:1 4.4:1

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95 90 93 95

a

Reaction conditions: (i) 1a (0.1 mmol, 1 equiv), PhI(OAc)2 (0.12 mmol, 1.2 equiv), MeCN:H2O (9:1), 0 oC for 10 min., 60% yield. (ii) 2a (0.03 mmol, 1 equiv), catalyst (5 mol %) in the solvent (0.3 mL, 0.1 M) at rt. bAll are isolated yields (purified over neutral alumina). cdr was determined by 1H-NMR. dEe (%) was determined by chiral HPLC analysis. eMs = Mesitylene. S Ar

N H

R'

R'

i

i

Pr

O

O

Pr

N N

Ph

N HN

H

N

OMe

O

N

N

O

H

O

C1: R = H; R' = C2H5 C2: R = OMe; R' = C2H3

i

Me

O

R

NH

NH

Ar

HN

O

O

NH

OMe

C3: R' = C2H5 C4: R' = C2H3

C6

Pr

P

O

NH N

C5

i

Pr

NH N

Me

i OH Pr

i

Pr

C7

H OMe

Ar = 3,5-bis-(F3C)C6H3

With the optimized reaction conditions in hand, various 4-substituted phenols were tested to examine the generality of the reaction which is tabulated in Scheme 2. Electron-rich substituents on aryl ring of enone moiety such as p-Me (3a), p- tBu (3b), p-MeO (3c), m,p-di-MeO (3d) and m,p-OCH2O (3e) worked smoothly and resulted the spiroketals with excellent enantioselectivities (85% to 99% ee). In such cases, the diastereoselectivities were moderate to high (7:1 to 13:1) and the yields were good to excellent (70-93%). Scheme 2. Substrate Scope: CHD-spiro-spiroketala-d OH

O

O

PhI(OAc)2

C7 (5 mol %)

O O

1

Me

O

H

O

O

O

H

Ar/R

O

2

Ar/R

O

toluene

O

HO

O

3

Ar/R

3a (R = Me): 3.5 h, 88%, 13:1 dr, 97% ee 3b (R = t Bu): 17 h, 77%, 11:1 dr, 99% ee 3c (R = MeO): 18.5 h, 71%, 11:1 dr, 99% ee 3f (R = H): 15.5 h, 70%, 7:1 dr, 95% ee

3a

3g (R = Ph): 6.5 h, 59%, 6:1 dr, 90% ee

O

3h (R = Cl): 4 h, 93%, 3.4:1 dr, 77% ee 3i (R = Br): 2 h, 98%, 3:1 dr, 77% ee 3j (R = I): 10 h, 87%, 4:1 dr, 82% ee 3k (R = F): 12 h, 73%, 6:1 dr, 90% ee

O

MeO O

O

OMe

O

O

H

3d

O

H

O

O

O

O

O

H

3m

O O

2 h, 91% yield, 4.3:1 dr, 71% ee

O

3n

S

9.5h, 90% yield, 8:1 dr, 92% ee

8 h, 90% yield, 7:1 dr, 85% ee

O

H O

O

7 h, 93% yield, 9.5:1 dr, 99% ee

O

3l

3e

O

O

O

O

O

H

t

O

Bu

O

H

3o 39 h, 71% yield, 4.5:1 dr, 92% ee

SEt O

O

72 h, 67% yield, 10:1 dr, 99% ee

4


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a

Reaction conditions: (i) 1a (0.2 mmol, 1 equiv), PhI(OAc)2 (0.24 mmol, 1.2 equiv), MeCN:H2O (9:1),

0 oC for 10 min. 60-70% yield. (ii) 2a (0.1 mmol, 1 equiv), catalyst (5 mol %) in solvent (2 mL) at rt. b

All are isolated yields (purified over neutral alumina). cdr was determined by 1H-NMR spectroscopy.

dEe (%) was determined by chiral HPLC analysis.

Similarly, electron-neutral substitutions such as H (3f) and p-biphenyl (3g) also worked fine and gave excellent enantioselectivities (90-95% ee) of the desired products and with good diastereoselectivities. Electron-deficient substituents such as p-Cl (3h), p-Br (3i) and p-I (3j) gave good enantioselectivities (77-82% ee) and with low diastereoselectivities (3.4:1 to 4:1). But, in contrast, p-F (3k) substitution gave a very good selectivity (90% ee and 6:1 dr) and good yield (73%). Then, the replacement of phenyl ring with heteroaryl groups such as 2-thiophenyl (3l) and 2-furyl (3m) moieties provided the corresponding cascade cyclization products in good yields (90-91%). In case of thiophenyl, high enantioselectivity was observed (92% ee, 8:1 dr), however, a moderate selectivity has been observed (71% ee, 4:1 dr) in case of furyl moiety. Not only aryl and heteroaryls but also aliphatic ketone such as t

Bu ketone (1n) worked well under the similar reaction conditions and provided the corresponding

product 3n with 92% ee and 4.5:1 dr. Notably, the thioester (3o) functionality was also equally effective and gave an excellent enantio- and diastereoselecctivity (99% ee and 10:1) of the product. Encouraged by this results, further investigation of the reactivity and selectivity of corresponding benzannulated (e.g., isobenzofuran based) spiroketal connected to a cyclohexadienone moiety (Scheme 3) was initiated. The abundance and bioactivity of such isobenzofuran based spiroketals was the motivation to this exploration.15 Nevertheless, the enantioselective synthesis of such moieties is very rare.16,6 Unfortunately, the previous optimized reaction conditions were not suitable to provide the best results. Further optimization of solvents was carried out; and, the best results were obtained with acetonitrile as a solvent instead of toluene (for details, see SI table S3 and S4).

5



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Scheme 3. Substrate Scope: CHD-spiro-Furan-spiro-Benzofurana

a

Reaction conditions: same as Scheme 2 except acetonitrile was used as solvent instead of toluene. With this optimized reaction conditions, the selectivities of various 4-substituted phenols were tested which is shown in Scheme 3. First, the model substrate p-Me (4a) was executed, and the corresponding product 5a was formed with an excellent enantio (94% ee) and diastereoselectivity (18:1 dr). Interestingly, electron withdrawing substituents, such as p-I(5b) and p-F3C (5c) provided an excellent enantio (96% and 93% ee) and diastereoselectivities (20:1 and 15:1 dr) respectively. Instead of aryl moiety, heteroaryl such as 2-furyl (5d) moiety also performed well (91% ee, 10:1 dr). Substitution of internalbenzene moiety, e.g., 4,5-di(MeO) even well tolerated in the reaction conditions and provided the desired spiroketal with excellent enantio (97% ee) and diastereoselectivity (18:1 dr). Finally, spiroketal 5b was synthesized in higher scale (0.5 g) with a declining in diastereoselectivity (decreased to 10:1 from 20:1); however, no change in enantioselectivity and yield was observed. The absolute configuration of the spiro-spiroketal (5b) was unambiguously determined by single-crystal X-ray diffraction analysis as shown in Scheme 3. Scheme 4. Synthesis of CHD-spiro-Furan-spiro-Pyran

6


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Scheme 5. Functionalization of CHD-spiro-Furan-spiro-Isobenzofuran Moiety

Once the aliphatic as well as benzannulated [5,5]-spiroketal containing cyclohaxadienones were sucessfully synthesized using this methodology, we became interested to synthesize the aliphatic [5,6]spiroketal which is a core of Aculeatins A-D. As shown in Scheme 4, the above optimized catalyst C7 at 45 oC was effective to provide the desired spiroketal 7 with very good enantioselectivity (90% ee), albeit, the diastereoselectivity was bit low. Finally, a ring expansion of the benzannulated [5,5]-spiro-spiroketal 5b was performed in the presence of a Lewis acid (e.g., BF3.OEt2) as shown in Scheme 5. The expected isochroman, having a similar skeleton of paecilospirone, was obtained with a little loss of enantioselectivity (from 95% to 92% ee, 10:1 to 7:1 dr). CONCLUSIONS In conclusion, a chiral bifunctional organocatalyzed enantioselective intramolecular ketalization/oxaMichael reaction of in situ generated cyclohexadienone alcohol attached to a tethered ketoenone is achieved through a dynamic kinetic (DyKat) ketalization process. This process provides the very first and promising approach for the diastereo and enantioselective synthesis of a broad array of spiroketals, attached to a cyclohexadienone moiety in spiro-fashion, with excellent enantioselectivities and good to excellent diastereoselectivities. Overall, this methodology contributes to the development of the stereoselective synthesis of sterically hindered spiroketals which are ubiquitous in natural products like aculeatin A-D and its‘ analogs. EXPERIMENTAL SECTION General Remarks: All reagents and solvents were used as supplied commercially. Analytical thin-layer chromatography (TLC) was performed on 0.2 mm coated Science silica gel (EM 60-F254) plates. Visualization was accomplished with UV light (254 nm) and exposure to either ethanolicphosphomolybdic acid (PMA), anisaldehyde or KMnO4 solution, CeSO4 + ammonium phosphomolybdate + 10% H2SO4 followed by heating. Melting points are uncorrected. 1H NMR spectra were acquired on a Bruker AVANCE (at 400 MHz or 500 MHz) instrument. Chemical shifts are reported relative to the residual 7



solvent peak.

13

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C NMR spectra were acquired on a Bruker AVANCE (at 100 MHz or 125 MHz) and

chemical shifts are reported in ppm relative to the residual solvent peak. Unless noted, NMR spectra were acquired in CDCl3 or DMSO-D6; individual peaks are reported as: multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,), integration, coupling constant in Hz. All IR spectra were obtained as neat films and selected absorbances are reported in cm-1. Low resolution mass spectrometry data were acquired using Agilent 7890A GC with Agilent 5975C MS (EI 70 eV) using DB-5 column. High resolution data were acquired using a Bruker Daltonics MicroTOF-Q-II Mass Spectrometer in MeOH as solvent or using Agilent GCQTOF Mass Spectrometer. Enantiomeric ratio data acquired by using HPLC on chiral stationary phase column. Materials: The thiourea catalysts C1-C2, C10-C11 and squaramide catalysts C3, C4, C6-C9 were prepared according to the reported procedure.11,13 The starting materials S117a and S217b were prepared according to the reported procedure. Wittig olefins (S5)11,13 were prepared according to the reported procedure. The starting materials 4S117c, 4S26 and 6S217d were prepared according to reported procedure. The Scheme for the preparation of starting substrates is given in Supporting Information. Preparation of 1-(4-((Tert-butyldimethylsilyl)oxy)phenyl)-5-(1,3-dioxolan-2-yl)pentan-3-one (S3): To a stirred solution of S1 (500 mg, 1.54 mmol) and freshly distilled THF (5 mL) under atmosphere of nitrogen the Grignard reagent (S2, 2.00 mmol) was added dropwise at 0 °C, then the reaction mixture was shifted to room temperature (rt) and stirred for 3 h. After completion (monitored by TLC), the reaction mixture was quenched by saturated NH4Cl (5 mL) solution and water, the crude product was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4.Then the solvent was removed under reduced pressure and the crude residue was purified by flash column chromatography (EtOAc/n-Hexane) on silica gel to provide S3. Yield: 311 mg, 56%; Rf = 0.55 (30:70 = EtOAc/n-Hexane); colourless liquid; FT-IR (neat): 2954, 2929, 2885, 2858, 2374, 1699, 1508, 1259, 1141, 1095, 1037, 916, 839, 750 cm-1; 1H NMR (400 MHz, CDCl3): δ, 7.00 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 4.87 (t, J = 4.3 Hz, 1H), 3.99 – 3.86 (m, 2H), 3.86 – 3.79 (m, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.69 (t, J= 7.4 Hz, 2H), 2.49 (t, J = 7.4 Hz, 2H), 1.95 (td, J = 7.4, 4.3 Hz, 2H), 0.96 (s, 9H), 0.16 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ, 209.3, 153.9, 133.7, 129.2 (2C), 120.0 (2C), 103.3, 65.0 (2C), 44.53, 36.7, 29.0, 27.6, 25.7, 18.2 (3C), -4.4 (2C); HR-MS (ESI, m/z): [M + H]+ calculated for C20H33O4Si: 365.2143; found: 365.2124. Preparation of 6-(4-Hydroxyphenyl)-4-oxohexanal (S4): To the stirred solution of S3 (536 mg, 1.47 mmol) and THF (5 mL), 4.5 ml 4 (N) HCl was added drop wise at r.t and running for 3 h. After comple8


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tion (monitored by TLC), the reaction mixture was quenched by aq. NaHCO3 (5 mL). The crude product was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4. Then the solvent was removed under reduced pressure and the crude residue was purified by flash column chromatography (EtOAc/n-Hexane) on silica gel to provide S4. Yield: 137 mg, 91% yield; Rf = 0.36 (40:60 = EtOAc/n-Hexane); brown coloured liquid; FT-IR (neat): 3356, 3022, 2906, 2852, 2736, 2362, 2322, 1714, 1516, 1224, 1099, 1062, 831 cm-1; 1H NMR (400 MHz, CDCl3): δ 9.77 (s, 1H), 7.02 (d, J = 8.2 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 6.28 (s, 1H), 2.89 – 2.80 (m, 2H), 2.76 (dd, J = 13.2, 6.0 Hz, 4H), 2.73 – 2.69 (m, 2H);

13

C{1H} NMR (100 MHz, CDCl3): δ, 208.7, 201.1, 154.3,

132.5, 129.4 (2C), 115.4 (2C), 44.5, 37.4, 34.9, 28.9; HR-MS (ESI, m/z): [M + H]

+

calculated for

C12H15O3: 207.1016; found: 207.1015. The general procedure for the synthesis of 4-substituted phenolic compounds 1(a-o): To a stirred solution of aldehyde S4 (1 equiv) and Wittig olefin (1.2 equiv) in CHCl3 (10 mL), were running at reflux condition for 12 hours. After consumption of starting material (monitored by TLC analysis), the solvent was removed under reduced pressure. The crude residue was purified by flash column chromatography (EtOAc/n-Hexane) on silica gel to provide 1 (a-o). (E)-8-(4-Hydroxyphenyl)-1-(p-tolyl)oct-2-ene-1,6-dione (1a): 187 mg, 60% yield; Rf = 0.34 (30:70 = EtOAc/n-Hexane); yellow coloured solid; mp: 86-88 ºC; FT-IR (neat): 3375, 3028, 2927, 1704, 1664, 1609, 1515, 1362, 1230, 1103, 974, 820 cm-1; 1H NMR (400 MHz, CDCl3): δ, 7.85 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 7.04 (d, J = 8.2 Hz, 2H), 6.95 (t, J = 5.4 Hz, 1H), 6.90 (d, J = 15.5 Hz, 1H), 6.77 (d, J = 8.2 Hz, 2H), 5.58 (s, 1H), 2.86 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 2.63 – 2.54 (m, 4H), 2.44 (s, 3H);

13

C{1H} NMR (100 MHz, CDCl3): δ, 208.7, 190.5, 154.2, 147.3, 143.8, 135.1,

132.7, 129.4 (2C), 129.3 (2C), 128.8 (2C), 126.6, 115.5 (2C), 44.6, 41.1, 29.0, 26.5, 21.7; HR-MS (ESI, m/z): [M + Na]+ calculated for C21H22O3Na: 345.1461; found: 345.1469. (E)-1-(4-(Tert-butyl)phenyl)-8-(4-hydroxyphenyl)oct-2-ene-1,6-dione (1b): 115 mg, 50% yield; Rf = 0.73 (40:60 = EtOAc/n-Hexane); yellow liquid; FT-IR (neat): 3462, 2974, 2378, 2310, 1843, 1697, 1521, 1259, 1020, 835, 750cm-1; 1H NMR (400 MHz, CDCl3): δ, 7.86 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H), 6.91 (dt, J = 23.3, 12.8 Hz, 2H), 6.75 (d, J = 8.3 Hz, 2H), 5.87 (s, 1H), 2.82 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.64 – 2.46 (m, 4H), 1.34 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3): δ, 208.8, 190.6, 156.7, 154.3, 147.4, 135.0, 132.5, 129.4 (2C), 128.64 (2C), 126.6, 125.6 (2C), 115.5 (2C), 44.6, 41.1, 35.1, 31.1 (3C), 29.0, 26.5; HR-MS (ESI, m/z): [M+H]+ calculated for C24H29O3: 365.2111; found: 365.2110. 9



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(E)-8-(4-Hydroxyphenyl)-1-(4-methoxyphenyl)oct-2-ene-1,6-dione (1c): 158 mg, 74% yield; Rf = 0.42 (40:60 = EtOAc/n-Hexane); yellow solid; mp: 123 ºC; FT-IR (neat): 3373, 2933, 2374, 2310, 1699, 1595, 1456, 1259, 1172,1024, 983, 949, 829cm-1; 1H NMR (400 MHz, CDCl3): δ, 7.92 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 6.92 (dd, J = 12.6, 7.7 Hz, 4H), 6.75 (d, J = 8.3 Hz, 2H), 6.03 (s, 1H), 3.86 (s, 3H), 2.82 (t, J = 7.3 Hz, 2H), 2.69 (t, J = 7.3 Hz, 2H), 2.59 – 2.49 (m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 208.9, 189.3, 163.5, 154.4, 146.9, 132.5, 131.0 (2C), 130.5, 129.4 (2C), 126.3, 115.5 (2C), 113.8 (2C), 55.5, 44.6, 41.1, 29.0, 26.5; HR-MS (ESI, m/z): [M + Na]+calculated for C21H22O4Na: 361.1410; found: 361.1412. (E)-1-(3,4-Dimethoxyphenyl)-8-(4-hydroxyphenyl)oct-2-ene-1,6-dione (1d): 142 mg, 40% yield; Rf = 0.32 (30:70 = EtOAc/n-Hexane); yellow coloured solid; mp: 91-93 ºC; FT-IR (neat): 3402, 3019, 2914, 2839, 1763, 1710, 1660, 1592, 1517, 1353, 1263, 1022, 829 cm-1; 1H NMR (500 MHz, CDCl3): δ, 7.58 (dd, J = 8.3, 2.0 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.99 – 6.90 (m, 3H), 6.77 (d, J = 8.5 Hz, 2H), 5.90 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 2.85 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.4 Hz, 2H), 2.63 – 2.56 (m, 4H);

13

C{1H} NMR (126 MHz, CDCl3): δ, 208.8, 189.1, 154.3, 153.3, 149.2,

146.8, 132.6, 130.7, 129.4 (2C), 126.1, 123.3, 115.5 (2C), 110.8, 110.0, 56.1, 56.0, 44.6, 41.2, 29.0, 26.5; HR-MS (ESI, m/z): [M + H]+ calculated for C22H25O5: 369.1697; found: 369.1682. (E)-1-(Benzo[d][1,3]dioxol-5-yl)-8-(4-hydroxyphenyl)oct-2-ene-1,6-dione (1e): 187 mg, 55% yield; Rf = 0.40 (30:70 = EtOAc/n-Hexane); light yellow coloured liquid; FT-IR (neat): 3393, 2923, 2852, 1712, 1662, 1596, 1513, 1441, 1366, 1254, 1101, 1035, 812 cm-1; 1H NMR (400 MHz, CDCl3): δ, 7.54 (d, J = 8.1 Hz, 1H), 7.44 (s, 1H), 6.99 (dd, J = 22.0, 7.0 Hz, 2H), 6.93 (dd, J = 11.0, 4.8 Hz, 1H), 6.89 – 6.83 (m, 2H), 6.83 – 6.65 (m, 2H), 6.29 (s, 1H), 6.05 (s, 2H), 2.84 (t, J = 7.3 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.65 – 2.49 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ, 208.9, 188.8, 154.4, 151.8, 148.2, 147.1, 132.3, 129.4 (2C), 126.2 (2C), 125.0, 115.5 (2C), 108.5, 107.9, 101.9, 44.6, 41.1, 29.0, 26.5; HRMS (ESI, m/z): [M + Na]+ calculated for C21H20O5Na: 375.1203; found: 375.1200. (E)-8-(4-Hydroxyphenyl)-1-phenyloct-2-ene-1,6-dione (1f): 164 mg, 55% yield; Rf = 0.32 (30:70 = EtOAc/n-Hexane); light yellow coloured solid; mp:74-76 ºC; FT-IR (neat): 3389, 3063, 2914, 1710, 1671, 1614, 1513, 1449, 1261, 1101, 983, 750 cm-1; 1H NMR (400 MHz, CDCl3): δ, 7.99 – 7.88 (m, 2H), 7.62 – 7.53 (m, 1H), 7.53 – 7.44 (m, 2H), 7.02 (dd, J= 10.2, 3.6 Hz, 2H), 7.00 – 6.93 (m, 1H), 6.94 – 6.86 (m, 1H), 6.85 – 6.68 (m, 2H), 6.26 (s, 1H), 2.85 (t, J = 7.3 Hz, 2H), 2.73 (t, J = 7.1 Hz, 2H), 2.64 – 2.54 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ, 208.9, 191.2, 154.4, 148.0, 137.6, 132.9, 132.4, 10


Page 11 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


129.4 (2C), 128.6 (4C), 126.6, 115.5 (2C), 44.6, 41.0, 29.0, 26.5; HR-MS (ESI, m/z): [M + Na]+ calculated for C20H20O3Na: 331.1305; found: 331.1289. (E)-1-([1,1'-Biphenyl]-4-yl)-8-(4-hydroxyphenyl)oct-2-ene-1,6-dione (1g): 204 mg, 55% yield; Rf = 0.29 (30:70 = EtOAc/n-Hexane); white coloured solid; mp: 131-133 ºC; FT-IR (neat): 3384, 3006, 2909, 1693, 1660, 1603, 1509, 1265, 1094, 985, 757 cm-1; 1H NMR (400 MHz, CDCl3): δ, 8.02 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 7.3 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H), 7.02 – 6.90 (m, 2H), 6.77 (d, J= 8.4 Hz, 2H), 5.20 (s, 1H), 2.90 – 2.85 (m, 2H), 2.77 – 2.73 (m, 2H), 2.69 – 2.56 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ, 208.6, 190.3, 154.1, 147.6, 145.6, 129.4 (2C), 129.2 (2C), 129.0 (3C), 128.2, 127.3 (4C), 127.2 (2C), 126.6, 115.4 (2C), 44.6, 41.1, 29.0, 26.6; HR-MS (ESI, m/z): [M + Na]+ calculated for C26H24O3Na: 407.1618; found: 407.1594. (E)-1-(4-Chlorophenyl)-8-(4-hydroxyphenyl)oct-2-ene-1,6-dione (1h): 218 mg, 66% yield; Rf = 0.275 (20:80 = EtOAc/n-Hexane); yellowish red coloured solid; mp: 58-60 ºC; FT-IR (neat): 3406, 2918, 2857, 1708, 1664, 1616, 1585, 1401, 1217, 1090, 1007, 820 cm-1; 1H NMR (500 MHz, CDCl3): δ, 7.88 – 7.86 (m, 2H), 7.48 – 7.45 (m, 2H), 7.07 – 7.03 (m, 2H), 6.99 (dt, J = 15.3, 6.6 Hz, 1H), 6.86 (d, J = 15.4 Hz, 1H), 6.77 (dd, J = 8.6, 2.2 Hz, 2H), 5.56 (s, 1H), 2.86 (t, J = 7.4 Hz, 2H), 2.74 (t, J = 7.3 Hz, 2H), 2.65 – 2.54 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3): δ, 208.6, 189.6, 148.4, 139.3, 136.0, 130.0 (2C), 129.4 (2C), 128.9 (3C), 126.2 (2C), 115.4 (2C), 44.6, 41.0, 29.0, 26.5; HR-MS (ESI, m/z): [M + Na]+ calculated for C20H19ClO3Na: 365.0915; found: 365.0915. (E)-1-(4-Bromophenyl)-8-(4-hydroxyphenyl)oct-2-ene-1,6-dione (1i): 232 mg, 62% yield; Rf = 0.18 (20:80 = EtOAc/n-Hexane); white coloured solid; mp: 61-63 ºC; FT-IR (neat): 3384, 3015, 2923, 1710, 1664, 1620, 1517, 1228, 1070, 1009, 829 cm-1;1H NMR (500 MHz, CDCl3): δ, 7.79 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.3 Hz, 2H), 7.01 – 6.95 (m, 1H), 6.90 – 6.82 (m, 1H), 6.77 (d, J = 8.5 Hz, 2H), 5.48 (s, 1H), 2.86 (t, J = 7.4 Hz, 2H), 2.74 (t, J = 7.4 Hz, 2H), 2.66 – 2.56 (m, 4H); 13

C{1H} NMR (125 MHz, CDCl3): δ, 208.6, 189.8, 154.2, 148.5, 136.4, 132.7, 131.9 (2C), 130.1 (2C),

129.4 (2C), 128.0, 126.2, 115.4 (2C), 44.6, 41.0, 29.0, 26.5; HR-MS (ESI, m/z): [M + Na]+ calculated for C20H19BrO3Na: 409.0410; found: 409.0409. (E)-8-(4-Hydroxyphenyl)-1-(4-iodophenyl)oct-2-ene-1,6-dione (1j): 166 mg, 69% yield; Rf = 0.61 (40:60 = EtOAc/n-Hexane); White coloured solid; mp: 106 ºC; FT-IR (neat): 3378, 2925, 2861, 1706, 1664, 1615, 1579, 1511, 1223, 1094, 1000, 824cm-1; 1H NMR (400 MHz, CDCl3): δ, 7.82 (d, J = 8.5 11



Page 12 of 33

Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.95 (dt, J = 15.2, 6.5 Hz, 1H), 6.79 (d, J = 15.4 Hz, 1H), 6.72 (d, J = 8.5 Hz, 2H), 4.84 (s, 1H), 2.83 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.60 – 2.51 (m, 4H);

13

C{1H} NMR (100 MHz, CDCl3): δ, 208.4, 189.9, 154.0, 148.3, 137.9 (2C),

137.0, 132.9, 130.0 (2C), 129.5 (2C), 126.1, 115.4 (2C), 100.6, 44.6, 41.0, 29.0, 26.5; HR-MS (ESI, m/z): [M + Na]+ calculated for C20H19IO3Na: 457.0271; found: 457.0296. (E)-1-(4-Fluorophenyl)-8-(4-hydroxyphenyl)oct-2-ene-1,6-dione (1k): 215 mg, 68% yield; Rf = 0.32 (30:70 = EtOAc/n-Hexane); light brown coloured solid; mp: 93-95 ºC; FT-IR (neat): 3402, 3054, 2923, 1710, 1669, 1614, 1511, 1267, 1158, 1096, 989, 827, 739 cm-1; 1H NMR (400 MHz, CDCl3): δ, 8.01 – 7.93 (m, 2H), 7.20 – 7.10 (m, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.99 – 6.92 (m, 1H), 6.87 (d, J = 15.4 Hz, 1H), 6.81 – 6.74 (m, 2H), 6.19 (s, 1H), 2.84 (dd, J = 9.0, 5.6 Hz, 2H), 2.73 (t, J = 7.1 Hz, 2H), 2.63 – 2.55 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ, 208.9, 189.4, 166.9, 164.4, 154.4, 148.2, 133.9 (d, J = 2.9 Hz), 132.5, 131.3 (d, J = 9.3 Hz, 2C), 129.4 (2C), 126.2, 115.9, 115.6 , 115.5 (2C), 44.6, 41.0, 29.0, 26.5; HR-MS (ESI, m/z): [M + Na]+ calculated for C20H19FO3Na: 349.1210; found: 349.1212. (E)-8-(4-Hydroxyphenyl)-1-(thiophen-2-yl)oct-2-ene-1,6-dione (1l): 194 mg, 60% yield; Rf = 0.17 (40:60 = EtOAc/n-Hexane); brown coloured viscous liquid; FT-IR (neat): 3380, 3024, 2923, 1708, 1655, 1605, 1517, 1408, 1357, 1239, 980, 823, 735 cm-1; 1H NMR (400 MHz, CDCl3): δ, 7.76 (dd, J = 3.8, 1.0 Hz, 1H), 7.66 (dd, J = 4.9, 1.0 Hz, 1H), 7.15 (dd, J = 4.9, 3.8 Hz, 1H), 7.06 – 6.97 (m, 3H), 6.86 – 6.76 (m, 3H), 6.72 (s, 1H), 2.83 (t, J = 7.3 Hz, 2H), 2.71 (t, J = 7.1 Hz, 2H), 2.60 – 2.51 (m, 4H); 13

C{1H} NMR (100 MHz, CDCl3): δ, 209.1, 182.6, 154.6, 147.3, 144.7, 134.3, 132.5, 132.3, 129.4

(2C), 128.8, 126.1, 115.5 (2C), 44.6, 41.0, 29.0, 26.4; HR-MS (ESI, m/z): [M + Na]+ calculated for C18H18O3SNa: 337.0869; found: 337.0882. (E)-1-(Furan-2-yl)-8-(4-hydroxyphenyl)oct-2-ene-1,6-dione (1m): 172 mg, 59% yield; Rf = 0.23 (30:70 = EtOAc/n-Hexane); colourless liquid; FT-IR (neat): 3371, 3024, 2931, 1710, 1684, 1658, 1569, 1460, 1270, 1226, 1099, 829 cm-1; 1H NMR (400 MHz, CDCl3): δ, 7.65 – 7.62 (m, 1H), 7.26 (dd, J = 3.6, 0.6 Hz, 1H), 7.11 – 7.00 (m, 3H), 6.82 – 6.72 (m, 3H), 6.57 (dd, J = 3.6, 1.7 Hz, 1H), 6.22 (s, 1H), 2.84 (dd, J = 8.8, 5.7 Hz, 2H), 2.72 (dd, J = 11.1, 4.3 Hz, 2H), 2.63 – 2.54 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ, 208.9, 178.2, 154.4, 153.1, 147.3, 146.9, 132.4, 129.4(2C), 125.6, 118.2, 115.5, 115.4, 112.5, 44.6, 41.0, 29.0, 26.4; HR-MS (ESI, m/z): [M + Na]+ calculated for C18H18O4Na: 321.1097; found: 321.1098. (E)-10-(4-Hydroxyphenyl)-2,2-dimethyldec-4-ene-3,8-dione (1n): 122 mg, 60% yield; Rf = 0.40 (40:60 = EtOAc/n-Hexane); colourless liquid; FT-IR (neat): 3334, 3178, 3014, 2445, 1683, 1516, 12


Page 13 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1265, 1224, 1087, 987,939 cm-1; 1H NMR (400 MHz, CDCl3): δ,7.00 (d, J = 8.3 Hz, 2H), 6.81 (dt, J = 15.0, 6.7 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 6.49 (d, J = 15.2 Hz, 1H), 5.62 (s, 1H), 2.81 (t, J = 7.4 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H), 2.51 (dd, J = 10.9, 4.2 Hz, 2H), 2.44 (dd, J = 13.6, 6.9 Hz, 2H), 1.13 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3): δ, 208.8, 204.7, 154.22, 145.6, 132.6, 129.4 (2C), 125.0, 115.4 (2C), 44.6, 42.9, 41.1, 28.9, 26.3, 26.1 (3C); HR-MS (ESI, m/z): [M + Na]+ calculated for C18H24O3Na: 311.1618; found: 311.1635. S-Ethyl (E)-8-(4-hydroxyphenyl)-6-oxooct-2-enethioate (1o): 175 mg, 62% yield; Rf= 0.25 (20:80 = EtOAc/n-Hexane); colourless liquid; FT-IR (neat): 3397, 3024, 2936, 1710, 1662, 1623, 1513, 1443, 1368, 1263, 1224, 1086, 967, 829 cm-1; 1H NMR (500 MHz, CDCl3): δ, 7.03 (d, J = 8.5 Hz, 2H), 6.83 (dt, J = 15.5, 6.8 Hz, 1H), 6.79 – 6.76 (m, 2H), 6.19 (s, 1H), 6.10 (dt, J = 15.5, 1.5 Hz, 1H), 2.95 (q, J = 7.4 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.54 (t, J = 7.1 Hz, 2H), 2.44 (q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.4 Hz, 3H);

13

C{1H} NMR (125 MHz, CDCl3): δ, 209.0, 190.8, 154.4, 143.3,

132.4, 129.4 (2C), 129.3, 115.5 (2C), 44.6, 40.9, 29.0, 25.9, 23.2, 14.7; HR-MS (ESI, m/z): [M + Na]+calculated for C16H20O3SNa: 315.1025; found: 315.1030.

Representative synthetic procedure for CHD-spiro-spirokrtal (3a-3o): (Diacetoxyiodo) benzene (1.2 equiv, 0.24 mmol) was added to a solution of phenol 1 (a-o) (0.2 mmol, 1.0 equiv) in MeCN-H2O (9:1) (2 mL) at 0 ˚C. The resulting solution was stirred for 10 min. After completion of starting material (monitored by TLC), solvents were evaporated under vacuum and immediately purified by column chromatography over silica (chromatography solvent evaporated under vacuum at lower temperatures (

Enantioselective Synthesis of Cyclohexadienone Containing

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