Enantiose/ective Synthesis of Natural Product-Like Benzo ...shodhganga.inflibnet.ac.in/bitstream/10603/14744/12/12_chapter 5.pdf · describes our efforts towards generation of natural

Chapter 5:

Enantiose/ective Synthesis of Natural

Product-Like Benzo-Annulated Oxa-

Heterocycles

174

Section 5A:

jJ-Hydroxy-a-tosyloxy Esters as Chiral

Building Blocks for the Enantioselective

Synthesis of Benzo-annulated Oxa-

Heterocycles: Scope and Limitations

175

Chapter 5. Enantlose/ect/ve Synthesis of Natural Product-Uke Benzo-Annulated OxaHeterocyc/es

5.1.1 Introduction

Over the past several years organic synthesis of natural product-like small

molecules have received significant attention due to the growing use of small

molecule libraries for studies of protein function and discovery of novel drug leads. I

Small-molecule libraries generated from the core scaffolds derived from natural

products are proving to be a valuable source of biologically active compounds that

provide new probes for molecular targets (for more detailed discussion, see: Chapter

1). In this context, new methodologies have to be designed for stereoselective

synthesis of small-molecule libraries with distinct skeletal frameworks via diversity

oriented synthesis (DOS). Following our interest in the field of diversity oriented

synthesis of benzo-annulated heterocycles as privileged structures, we recently

employed naturally occurring a-amino acids as chiral pools that provided an access to

a large array of heterocycles.3-5 As part of our research programme related to DOS, we

became interested in the enantioselective synthesis of natural product-like small

molecules (Figure 5.1.1 tIl containing 2,3-dihydrobenzofuran, I-benzopyran and 1-

benzoxepin frame works.

Xanthoamoll is a natural dihydrofuranocoumarin which was first isolated from

the heartwood of roots of healthy Xanthoxylum arnottianum. 6a The treatment of cell

suspension cultures of Platanusxacerifolia with the GP66 elicitor produced by

Ceratocystis jimbriata f. sp platani germlings also triggered the fast and intense

synthesis of 1.6c Brosimacutins G 3 was isolated from the bark of Brosimum

acutifolium, a Brazilian folk medicine ("Murure,,).8a Compound 3 was tested on

antibacterial assays, and it showed no antibacterial activities against two pathogenic

bacteria Staphylococcus aureus and S. epidermidis.8b Avicenol A 4 is a naphthofuran

isolated from the stem bark of Avicennia alba (Avicenniaceae).9a Compound 4

exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo

two-stage carcinogenesis test.9b (-)-(2R)-Megapodiol 5 is a 2,3-dihydrobenzofuran

isolated from the ground plant Baccharis megapotamica, a Brazilian shrub of the

genus Baccharis that belongs to the family of Asteraceae. lo Compound 5 showed high

activity in vivo against P388 leukemia in mice and high cytotoxicity in vitro against

KB cells. Heliannuol E 6 and heliannuol D 7 are among a promising group of

phenolic allelochemicals isolated from Helianthus annuus that exhibit activity against

dicotyledon plant species. I I

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Chapter 5. Enantioselective Synthesis of Natural Product-Like Benzo-Annulated Oxa-Heterocyc/es

°t:)CQ"tOH j)j""~OH ~b OH

HOy) N0,>,,,,LoH

~\ OH

1, Xanthoarnol6 ° 2, Vaginol?

° OH OH 3, Brosimacutin GB

~H

~····'tOHoyCD--Fo~HHdHHOJCd OMe OH ~-

4, Avicenol A9 5, Megapodiol10 6, Heliannuol E11 7, Heliannuol D11

Figure 5.1.1 Representative examples biologically important natural products (1-7) containing

benzo-annulated oxa-heterocycles.

5.1.2 Basis of the Present Work Since the pioneering report of Sharpless on the regioselective arenesulfonylation

of the a-hydroxy group of syn 2,3-dihydroxy esters,12 the resulting trifunctional P

hydroxy-a-arenesulfonyloxy esters have been extensively used for their conversions

into the corresponding a-azido-p-hydroxy esters I2,13 and glycidic esters. 12,14 The only

other synthetic utility we are aware of is their use in the synthesis of a combinatorial

library of tetrahydroquinoline based polycyclic molecules. ls Thus, despite their easy

accessibility and multifunctionalities, P-hydroxy-a-arenesulfonyloxy esters have not

been largely utilized for benzo-annulated heterocycle synthesis. The present work

describes our efforts towards generation of natural product-like benzo-annulated oxa

heterocycles through phenoxide ion mediated intramolecular SN2 reaction on the

tosyloxy group of P-hydroxy-a-tosyloxy esters and ring opening of syn-glycidic esters

which were derived from P-hydroxy-a-tosyloxy esters (Figure 5.1.2).

Ring nature and ring '..:::::: OB~ _______ .. Diversity of substituents diversity // Cr.') C0

2Et intramolecular

______ n ;TS Ring size ______

diversity 8, Enantiomerically enriched ~-hydroxy-a-tosyloxy ester

n= D, 1 and 2.

ring formation

Confugurational diversity

Figure 5.1.2 Synthetic versatility of f.Jhydroxy-a-tosyloxy esters (8) in our synthetic strategy.

5.1.3 Results and Discussion

Initially, we focused our attention on a stereos elective synthesis of 2,3-dihydro-

3-hydroxy-2-[1-hydroxy-l-(methyl)-ethyl]benzofuran ring system which constitutes

177

Chapter 5. EnantloselectJve Synthesis of Natural Product-Uke Benzo-Annulated OxcHIeterocycles

the core skeleton of a number of biologically important natural products (Figure

5.1.1, compounds 1-4). Despite their long history, these compounds have not been the

subjects of much organic synthesis. The only successful synthetic studies of the

natural products in this family, we are aware of are the recent reports by Snider et al. 16

Our model synthesis to obtain enantiopure 2,3-dihydro-3-hydroxy-2-[I-hydroxy-

1-(methyl)-ethyl]-benzofuran derivative is shown in Scheme 5.1.1. Benzylation of

commercially available 2-hydroxybenzaldehyde 9a with benzyl bromide and

anhydrous K2C03 in dry acetone under reflux condition followed by Wittig

olefination of the resulting 2-benzyloxybenzaldehyde lOa with

(carbethoxymethylene)triphenylphosphorane in dry CH2Ch at room temparature

furnished the corresponding trans-cinnamate ester 11a. The trans-cinnamate ester 11a

was then subjected to Sharpless asymmetric dihydroxylationl7 with AD mix a in

tBuOH-H20 (1:1) at O°C for 28 h furnishing enantiopure dihydroxyl derivatives 12a

in good yield and high enantiomeric excess (92%, ee>99%). Conversion of diol 12a

into f3-hydroxy-a-tosyloxy ester 13a was achieved, by the regioselective a-tosylation

of diol 12a with tosyl chloride (1.05 equiv.) and anhydrous triethyl amine in dry

CH2Ch at OoC for 72 h.12

~OH ~OBn OBn OBn OBn ~ ~ ~ ~ ~VD" ~ rI(--~H ~rY--~TS ~ CHO ~ CHO ~C02Et ~C02Et ~C02Et 9a 10a 11a 12a OH 13a OH

Scheme 5.1.1. Reagents and conditions: (a) BnBr, anhyd. K2C03, dry acetone, reflux, 4h,

85%. (b) Ph3P=CHC02Et, dry CH2CIz, rt, 2h, 78%. (c) AD-mix-a, t-BuOH/H20 (1:1), O°C,

28h, 92%. (d) TsCl, dry Et3N, dry CH2CIz, O°C, 72h, 87%.

All the products were well characterized by NMR and MS studies. The ESI

mass spectrum of diol 12a showed peaks at 339 [M+Nat, 334 [M+NH4t, 299 [M

OHr and 91 [C~5CH2t whereas the same of f3-hydroxy-a-tosyloxy ester 13a

showed peaks at mlz 493 [M+Nat, 488 [M+NH4t and 453 [M-OHr. The IR

spectrum of 13a showed a broad band at 3436 cm,l indicating the presence of

hydroxyl functionality. IH NMR spectrum of 13a showed CH proton (attached to the

a-carbon with re~pect to the ester functionality) at 05.23 (d, 1H, J = 3.6) whereas the

same proton of 12a appeared at 0 4.50 (s, 1H). 13C NMR spectrum of 13a showed a

signal at 0 21.53 for the CH3 carbon of tosy I group.

178

Chapter 5. Enantloselectlve Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocyc/es

Next, in order to achieve the 2,3-dihydrobenzofuran ring fonnation via a

phenoxide ion-mediated intramolecular SN2 reaction of the tosyloxy group, 13a was

subjected to catalytic debenzylation with hydrogen and 10% Pd/C in ethyl acetate and

subsequently the resulting corresponding phenolic derivative was treated with

anhydrous K2C03 in dry acetone. But unfortunately both the steps resulted into a

inseparable and unstable product mixture from which we could not isolated any pure

compound. This might be due to hydrogenolysis of the benzylic-OH group to some

extent and aromatization of the resulting 2-carbethoxy-2,3-dihydrobenzofuran-3-01.

To overcome this problem, we decided to protect the -OH group of 13a by a suitable

protecting group. Towards that objective, hydroxyl group of 13a was protected as its

tert-butyl dimethylsilyl ether by using tert-butyl dimethylsilyl triflate in the presence

of 2,6-lutidine affording 14a with excellent yield (Scheme 5.1.2). Catalytic

debenzylation of 14a with hydrogen and 10% Pd/C in ethyl acetate followed by

cyclization of the resulting debenzylated product in the presence of anhydrous K2C03

in dry acetone afforded 2,3-dihydrobenzofuran derivative 15a in good yield.

Treatment of the ester 15a with an excess of methyl magnesium iodide furnished the

tertiary alcohol 16a. Finally, removal of the TBDMS of 16a with TBAF in dry THF

afforded 17a in 91% yield. IH NMR spectrum of 13a showed protons of the two

methyl groups at 8 1.25 (s, 3H) and l.22 (s, 3H). Similarly, I3C NMR spectrum of 13a

showed two signals at 8 26.94 and 26.77 due to the presence of two methyl groups.

OBn a WOTS b Cr{-Q (r0Q d 13a- 1 - I·" C02Et ~ 1 " OH-~ C0

2Et ~. ~

14a OTBDMS 1Sa OTBDMS 16a OTBDMS

Scheme 5.1.2. Reagents and conditions: (a) TBDMS-OTf, 2,6-1utidine, O°C-rt, 6h, 85%. (b)

(i) H2, 10% Pd-C, EtOAc, 4 h. (ii) Anhyd. K2C03, dry acetone, 6h, 69% (based on two steps).

(c) MeMgI, dry ether, reflux, 4h, 77%. (d) TBAF, dry THF, 0° C, 5h, 91%.

After the enantioselective synthesis of 2,3-dihydrobenzofuran derivative 17a,

our next attention was to synthesize structurally related dihydronaphthofuran

analogue of 17a. Thus, commercially available 2-hydroxy-l-naphthaldehyde 9b was

179

Chapter 5. Enantloselective Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocycles

converted into 17b using the same reaction sequence as that described for the

synthesis of17a (Scheme 5.13).

I a I b I c -:?' I OH d - -::::-..~-- --YOH &OBn ~OBn OBn

I: CHO I: CHO I h CO,Et IU--rCO,EI 9b 10b 11b U 1'H 1~b

OBn

0Xl' OTs e ::::-.. --I C02Et I ~ OH

13b

aO)'''"~OH U bH

17b

OBn

-- I '. C02Et~ C02Et ::::-..

OTs f QX{,Q. OTBDMS I ~ OTBDMS

14b 15b

Scheme s.u.Reagents and conditions: (a) BnBr, anhyd. K2C03, dry acetone, reflux, 4h, 83%.

(b) Ph3P=CHC02Et, dry CH2Cb, rt, 2h, 80%. (c) AD-mix-a, t-BuOH/H20 (1:1), O°C, 28h,

93%. (d) TsCI, dry Et3N, dry CH2Cl2 O°C, 72h, 94%. (e) TBDMS-OTf, 2,6-lutidine, O°C-rt,

6h, 88%. (f) (i) H2, 10% Pd-C, EtOAc, 4 h. (ii) Anhyd. K2C03, dry acetone, 6h, 72% (based

on two steps). (c) (i) MeMgI, dry ether, reflux, 4h. (ii) TBAF, dry THF, O°C, 5h, 74% for two

steps.

The successful synthesis of enantiomerically pure 17a-b encouraged us to

initiate further application of this strategy on homologated analog of 13a for the

synthesis of other 2,3-dihydrobenzofuran and I-benzopyran derivatives. Towards that

direction, aldehyde lOa was converted into olefin 18 by Wittig reaction with

methyltriphenylphosphonium iodide and potassium tert-butoxide in dry THF

(Scheme 5.1.4). Olefin 18 was converted into primary alcohol 19 by hydroboration

with 9-BBN and oxidation with hydrogen peroxide and NaOH. Compound 19 was

oxidized to its corresponding aldehyde 20 by PCC in dry CH2Cb. With aldehyde 20

in hand, next work was the conversion of it into f3-hydroxy-a-tosyloxy ester 23 using

a similar reaction sequence as that described for the synthesis of 13a. The IR

spectrum of23 showed a broad band at 3464 cm·1 indicating the presence of hydroxyl

functionality. IH NMR spectrum of 23 showed CH3 protons of the tosyl group at b

2.40. The ESI mass spectrum of 23 showed peaks at mlz 507 [M+Nat, 502

[M+NH4t and 485 [Mt.

180

Chapter 5. Enantlose/ectlve Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocycles

~OBn CC:oBn CCOBn ~OBn 10a-4.~ ~ I // ~ I // CHO~~C02Et

OH 18 19 20 21

OBn OBn ~--9H f ~--9H ~C02B ~C02Et

22 OH 23 OT5 Scheme 5.1.4. Reagents and conditions: (a) methyltriphenylphosphonium iodide, tert-

BuOK, dry THF, O°C-rt, 2h, 80%. (b) (i) 9-BBN, dry THF, O°C-rt, overnight. (ii)

NaOH/H20 2, reflux, 2h, 96%. (c) PCC, dry CH2Cl2, 2h, O°C-rt, 76%. (d) Ph3P=CHC02Et, dry

CH2Ch, rt, overnight, 75%. (e) AD-mix-a, tert-BuOHlH20 (1:1), O°C, 40h, 89%. (f) TsCI,

dry Et3N, dry CH2Ch, O°C, 72h, 85%.

With the availability of 23, its conversion into 2,3-dihydrobenzofuran

derivative (Scheme 5.1.5) was first attempted. Accordingly, treatment of j3-hydroxy

a-tosyloxy ester 23 with anhydrous K2C03 in absolute ethanol furnished epoxy ester

24 in good yield. Next, debenzylation of 24 under hydrogen atmosphere using 10%

Pd-C as catalyst followed by anhydrous K 2C03 induced phenoxide ion mediated

intramolecular five exo epoxide ring opening produced enantiomerically pure

dihydrobenzofuran based a-hydroxy ester 25 which on methylmagnesium iodide

Grignard reaction furnished 26. To the best of our knowledge, this is the first report of

phenoxide ion mediated intramolecular ring opening of syn-glycidic ester.

9C4. OBn ~O -PH Q5--X0 pH n~1 A ~I ~ ~I . //:- // co Et //

2 OH 24 C02Et 25 ___ 2_6 ____ _

Scheme 5.1.5. Reagents and conditions: (a) Anhyd. K2C03, ethanol, rt, 8h, 75%. (b) (i) H2

,

10% Pd-C, ethyl acetate, 2h (ii) Anhyd. K2C03, dry acetone, rt, 6h, 81% (for two steps). (c)

MeMgI, dry ether, reflux, 4h, 88%.

After the effective utilization of 23 in the synthesis of enantiomerically pure 26,

we' wanted to further utilize it for the synthesis of l-benzopyran derivative involving

phenoxide ion mediated intramolecular SN2 reaction of tosyloxy group. Thus, 23 was

converted into 1-benzopyran derivative 30 using a similar reaction sequence as that

described for the synthesis of 17a (Scheme 5.1.6).

181

Chapter 5. Enantloselective Synthesis of Natural Product-Uke Benzo-Annulated OxcrHeterocyc/es

OBn ocCH

(J(J:0TBDMS C(X0I', C02Et ~ 01"

23~ I 7 COEt-L I ~I ::::,.. _ 2 .& OTBDMS .& OTBDMS

27 e)Ts 28 29

Scheme 5.1.6. Reagents and conditions_- (a) TBDMS-OTf, 2,6-lutidine, O°C-rt, 6h, 89%. (b)

(i) H2, 10% Pd-C, EtOAc, 4 h_ (ii) anhyd_ K2C03, dry acetone, 8h (70%, based on two steps).

(c) MeMgI, dry ether, reflux, 4h, 91%. (d) TBAF, dry THF, O°C, 5h, 87%.

The successful utilization of f3-hydroxy-a-tosyloxy esters in the synthesis of novel

2,3-dihydrobenzofurans and I-benzopyran derivative inspired us to initiate further

application of this strategy for the synthesis of another structurally related 1-

benzopyran and I-benzoxepin derivatives by using a f3-hydroxy-a-tosyloxy ester 36

homologated by one more carbon atom. The synthesis of 36 was achieved from

aldehyde 20 by following the same reaction sequence as that described for 23

(Scheme 5.1.7).

2o~1 ~I ~ cc::oBn C(:;0Bn

~ ~ ~ OH

31 32

e -~oBn f

f OH_

~ C02Et 35 OH

(X:0Bn I ~ ~ CHO

33

~oBn

~COEt 34 2

Scheme 5.1.7. Reagents and conditions: (a) methyltriphenylphosphonium iodide, ter/-

BuOK, dry THF, O°C-rt, 2h, 88%. (b) (i) 9-BBN, dry THF, O°C-rt, overnight. (ii)

NaOH/H20 2, reflux, 2h, 96%_ (c) PCC, dry DCM, 2h, O°C-rt, 72%. (d) Ph3P=CHC02Et, dry

DCM, rt, overnight, 77%. (e) AD-mix-a, t-BuOHIH20 (1:1), OoC, 40h, 87%. (f) TsCI, dry

Et3N, dry DCM, OoC, 72h, 80%

With the availability of 36, attention was first turned to its elaboration into 1-

benzopyran derivative (Scheme 5.1.8). Thus, f3-hydroxy-a -tosyloxy ester 36 was

converted into I-benzopyran derivative 39 using a similar reaction sequence as that

described for the synthesis of 26.

182

Chapter 5. Enantloselectlve Synthesis of Natural Product-Like Benzo-Annulated Oxa-Heterocycles

QH QH

36 --"-- OCJ02Et -L~C02Et -"-- ~OH

37 0 38 39 '-_;';" ___ ..J

Scheme 5.1.8. Reagents and conditions: (a) Anhyd. K2C03, ethanol, 8h, 78%. (b) (i) H2,

10% Pd-C, ethyl acetate, 2h. (ii) Anhyd. K 2C03, dry acetone, 6h, (68%, for two steps). (c)


In an attempt to utilize l3-hydroxy-a-tosyloxy ester 36 for the synthesis of 1-

benzoxepin derivative, 36 was converted into 40, which was first debenzylated and

subsequently treated with anhyd. K2C03 (as described for the synthesis of 15a-b and

28). To our dismay, the reaction did not proceed at all to give 41 and the starting

phenolic derivative remained unchanged (Scheme 5.1.9). Varying the base, solvent,

reaction time and temperature did not give any fruitful result. This is perhaps for the

easy formation of five and six member rings over seven membered ones.

P Bn a I ~ OTs b 36 --=--- _

.h- C02Et 40 OTBDMS

,C02Et o .-'

~~OH 41, not formed

Scheme 5.1.9. Reagents and conditions: (a) TBDMS-OTf, 2,6-lutidine, O°C-rt, 8h, 85%. (b)

(i) H2, 10% Pd-C, ethyl acetate. (ii) Anhyd. K 2C03, dry acetone, reflux, ISh.

5.1.4 Conclusion

In summary, an efficient diversity oriented enantioselective synthesis of "natural

product like" benzo-annulated ox a-heterocycles 2,3-dihydrobenzofuran and 1-

benzopyran is described using l3-hydroxy-a-tosyloxy esters as chiral building blocks

which are easily accessible through regioselective a-tosylation of Sharpless

asymmetric dihydroxylation-derived syn 2,3-dihydroxy esters. However, the

methodology was not feasible to synthesize I-benzoxepine derivatives. The ease of

the reaction sequence, as well as the commercial availability of large array of starting

2-hydroxyaromatic aldehydes, makes this process a practical method for the

preparation of "natural product like" 2,3-dihydrobenzofuran and I-benzopyran

derivatives. In addition, the scope the reaction sequence is much broader, and the

synthesis of various substituted aromatic and heteroaromatic nuclei can be envisioned

from the starting hydroxy aldehydes.

183

Chapter 5. Enantloselective Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocyc/es

5.1.5 Experimental Section

S.1.S.1 General Remarks

All dry reactions were carried out under argon or nitrogen III oven-dried

glassware using standard gas-light syringes, cannulas and septa. All reagents and

solvents were dried prior to use according to the standard methods. Commercial

reagents were used without further purification unless otherwise stated. Reactions

were monitored on silica gel TLC plates (coated with TLC grade silica gel, obtained

from Merck). Detecting agents used (for TLC) were iodine vapors and/or spraying

with an aqueous solution of vanillin in 10% sulfuric acid followed by heating at 150

DC. Column chromatography was performed over silica gel (60-120 mesh) procured

from Qualigens (India) using freshly distilled solvents. Mass spectra were recorded as

electron spray ionization (ESI-MS) or fast atom bombardment spectra (FAB-MS) on a

lEOl SX 102 spectrometer using argon/xenon as the F AB gas. Elemental analyses

were done on Varian EL-Ill C H N analyzer. Melting points were determined on

COMPlAB melting point apparatus and are uncorrected. IR spectra were recorded on

a Perkin-Elmer FT-IR RXI spectrometer. 'H NMR and I3C NMR spectra were

recorded on Brucker DPX-200 (operating at 200 MHz for 'H and 50 MHz for I3C) or

DPX-300 (operating at 300 MHz for 'H and 75 MHz for I3C) spectrometer using

CDCh or d6-acetone as solvent. Tetramethylsilane (0.00 ppm) served as an internal

standard in 'H NMR and CDCh (77.0 ppm) in I3C NMR. All spectra were recorded at

25DC. Coupling constants (J values) are given in hertz (Hz). Chemical shifts are

expressed in parts per million. The enantiomeric excess was determined by Lichro

CART Chiradex column (250x4 mm, 5 11m) using water and methanol as eluent at 25

DC. Optical rotations were measured at the sodium D-line at ambient temperature,

with a Perkin Elmer 141 polarimeter.

S.1.S.2 Synthesis of Compounds

2-Benzyloxybenzaldehyde (lOa):

To a solution of commercially available 2-hydroxybenzaldehyde (10 mL, 95.64

mmol) in dry acetone (200 mL) was added anhydrous K 2C03 (20.0 g, 144.70 mmol)

and benzyl bromide (13.0 mL, 109.52 mmol) and refluxed for 4 h. The mixture was

then filtered through celite and the filter cake was well washed with acetone (200

ml). The filtrate was concentrated and the resulting residue was redissolved in ethyl

acetate (300 mL), washed with water (2xl00 mL) and brine (l00 mL). The organic

184

Chapter 5. Enantloselectlve Synthesis of Natural Product-Uke BenzcrAnnulated Oxa-Heterocycles

layer was dried over anhydrous Na2S04, filtered, and then

concentrated under vacuo. Purification of the crude product by silica (yoBn

~CHO 10a gel column chromatography (4% ethyl acetate in hexane) afforded

lOa (17.25 g, 85%) as a colorless oil. Rf 0.52 (20% ethyl acetate in hexane). IR

(Neat): 2874, 1680, 1597, 1237,991, 755 cm-I. IH NMR (200 MHz, CDCh): 810.55

(s, IH), 7.85 (dd, IH, J j = 2.0, J2 = 7.9), 7.52-7.36 (m, 6H), 7.06-7.02 (m, 2H), 5.17

(s, 2H). l3C NMR (75 MHz, CDCh): 8 189.5, 160.9, 135.9, 135.8, 128.6, 128.2,

128.1, 127.1, 124.9, 120.8, 112.9, 70.2. MS (ESI): mlz 212 [Mt, 91 [C6H5CH2t.

Anal. Calcd for CI4H\202: C, 79.22; H, 5.70. Found: C, 79.37; H, 5.88. The above

spectroscopic data are in consistence with the literature data. 18

2-Benzyloxynaphthalene-l-carbaldehyde (lOb):

Using commercially available 2-hydroxy-1-naphthaldehyde (2.0 g, 11.61

mmol), the title compound was prepared in the same manner as that described for lOa.

Purification of the crude product by silica gel column chromatography (4% ethyl

I ~. CHO

acetate in hexane) afforded lOb (2.52 g, 83%) as a light yellow

solid. Mp: 118-119°C. Rf 0.49 (20% ethyl acetate in hexane). IR

(KBr): 2886, 1660, 1589, 1510, 1347, 1269, 1220, 1147, 1055, G:'::::: OBn

~ 10b 807, 750 cm-I. IH NMR (200 MHz, CDCh): 810.96 (s, 1H), 9.28

(d, IH, J = 8.6), 8.01 (d, 1H, J = 9.1), 7.75 (d, IH, J = 8.0), 7.65-7.57 (m, 1H), 7-43-

7.28 (m, 7H), 5.31 (s,2H). l3C NMR (50 MHz, CDCh): 8192.5, 163.6, 137.9, 136.4,

131.9,130.3,129.2,129.1,128.8,128.6,127.8,125.4,125.3, 117.6, 114.4,71.9. MS

(ESI): mlz 263 [M+ I]+, 91 [C6H5CH2t. Anal. Calcd for C18H1402: C, 82.42; H, 5.38.

Found: C, 82.51; H, 5.49. The above spectroscopic data are in consistence with the

literature data. 19

(2E)-3-(2-Benzyloxyphenyl)acrylic Acid Ethyl Ester (l1a):

To a solution of lOa (1.50 g, 7.06 mmol) in

dichloromethane (20 mL) was added ~OBn

~COEt 11a 2

(carbethoxymethylene)triphenylphosphorane (3.0 g, 8.60

mmol) at room temperature. The reaction mixture was stirred

at room temperature for 2 h. Solvent was removed under reduced pressure and the

residue was purified by silica gel column chromatography (4% ethyl acetate in

hexane) to afford 11a (1.55 g, 78%) as a colorless gum. R(. 0.58 (20% ethyl acetate in

hexane). IR (KBr): 2937, 1715, 1502, 1277, 1179, 1066, 758 cm-I. IH NMR (300

185


MHz, CDCh): 88.08 (d, IH,J= 16.1),7.54 (dd, IH,J! = 1.3,J2= 7.6), 7.44-7.25 (m,

6H), 6.99-6.93 (m, IH), 6.53 (d, IH, J = 16.1),5.17 (s, 2H), 4.24 (q, 2H, J = 7.1),

1.32 (t, 3H, J= 7.1). 13C NMR (75 MHz, CDCh): 8167.4, 157.3, 139.8, 136.6, 131.3,

128.6,128.6,127.9,127.1,123.9,121.0,118.8,112.8,70.3, 60.2,14.3. MS (FAB):

mlz 283 [M+lr, 237 [M-OEtt Anal. Calcd for ClsH1S03: C, 76.57; H, 6.43. Found:

C, 76.46; H, 6.34.

(2E)-3-(2-Benzyloxynaphthalen-I-yl)acrylic Acid Ethyl Ester (l1b).

Using 1.5 g (5.71 mmol) of lOb, the title compound was prepared in the same

manner as that described for 11a. Purification of the crude product by silica gel

column chromatography (4% ethyl acetate in hexane)

I ~ OBn afforded 11b (1.51 g, 80%) as a colorless semi-solid. Rj.

.h- ~ C02Et 0.50 (20% ethyl acetate in hexane). IR (KBr): 2927, 2363,

11b 1707, 1592, 1267, 1165, 1044, 745 cm-!. !H NMR (200

MHz, CDCh): 8 1H NMR (200 MHz, CDCh): 0 8.38 (d, IH, J = 16.1), 8.19 (d, IH, J

= 8.5), 7.79-7.75 (m, 2H), 7.55-7.24 (m, 8H), 6.78 (d, IH,J= 16.1), 5.29 (s, 2H), 4.30

(q, 2H, J = 7.1), 1.35 (t, 3H, J = 7.1). l3C NMR (50 MHz, CDCh): 8168.2, 155.9,

138.1, 137.1, 131.7, 130.0, 129.6, 129.0, 128.4, 127.8, 127.5, 127.0, 124.5, 124.2,

123.9, 118.1, 114.9, 71.6, 60.8, 14.8. MS (ESI): mlz 333 [Mr, 287 [M-OEtt. Anal.

Calcd for C22H2003 : C, 79.50; H, 6.06. Found: C, 79.59; H, 6.18.

(2R,3S)-3-(2-Benzyloxyphenyl)-2,3-dihydroxypropionic Acid Ethyl Ester (12a):

To a stirred solution of tert-butyl alcohol (18 mL) and water (18 mL) were

added AD mix a (5.0 g) and methanesulfonamide (0.34 g, 3.54 mmol) at room

OBn N--~H

~C02Et 12a OH

temperature. The mixture was vigorously stirred at room

temperature until both phases were clear and then cooled to

O°c. A solution of cinnamate ester 11a (1.0 g, 3.54 mmol)

in tert-butyl alcohol (5 mL) was added O°c. The reaction

was stirred at the same temperature for 28 h. The reaction was quenched at O°C.by the

addition of sodium sulfite (5.1 g), warmed to room temperature, and further stirred for

1 h. The reaction mixture was then extracted with ethyl acetate (3x50 mL). The

combined organic layer was washed with aq. 2N KOH solution (50 mL), water (50

mL) and brine (50 mL). The organic layer was dried over anhydrous Na2S04, filtered,

and then concentrated under vacuo. Purification of the crude product by silica gel

column chromatography (25% ethyl acetate in hexane} afforded 12a (1.03 g, 92%) as

186

Chapter 5. Enantloselectlve Synthesis of Natural Product-Uke Benzr>-Annulated OxcHIeterocyc/es

a colorless solid. Mp: 96-97°C. Rf 0.35 (40% ethyl acetate in hexane). [a]25o +8.4 (c

0.9, CHCh). The enantiomeric excess was estimated to be >99% by chiral HPLC

analysis (instrument: HPII00, column: LichroCART Chiradex column 250 mm x 4

mrn, 5 /lm), flow rate: 0.5 mL/min, detection: UV 254 nm, eluent: methanol/H20). IR

(KBr): 3537, 3512,2982, 1722,1601,1496,1456,1386,1290, 1240, 1111, 1049,

760, 736 em-I. IH NMR (300 MHz, CDCh): 87.45-7.24 (m, 7H), 7.03-6.93 (m, 2H),

5.42 (s, 1H), 5.10 (d, 1H,J= 11.8),5.09 (d, 1H,J= 11.8),4.50 (s, 1H), 4.27-4.17 (m,

2H), 3.13 (s, br, 1H), 3.01 (s, br, 1H), 1.22 (t, 3H, J = 7.1). I3C NMR (75 MHz,

CDCh): 8173.0, 155.1, 136.7, 128.8, 128.5, 127.9, 127.2, 127.0, 121.0, 111.5, 73.2,

70.3, 70.0, 61.9, 14.0. MS (ESI): mlz 339 [M+Nar, 334 [M+NH4r, 299 [M-OH]+, 91

[C6H5CH2r. Anal. Calcd for CIsH2005: C, 68.34; H, 6.37. Found: C, 68.29; H, 6.51.

3-(2-Benzyloxynaphthalen-1-yl)-2,3-dihydroxypropionic Acid Ethyl Ester (12b):

Starting from 1.25 g (3.76 mmol) of llb, the title compound was prepared in

the same manner as that described for 12a. Purification of the crude product by silica

gel column chromatography (25% ethyl acetate in hexane) afforded 12b (1.28 g, 93%)

as a colorless gum. Rf 0.37 (40% ethyl acetate in

hexane). [af5o -4.4 (c 1.13, CHCh). The enantiomeric

excess was estimated to be >99% by chiral HPLC

analysis as that described for 12a. IR (KBr): 3509, 1720,

1250, 1125, 1048, 757, 742 em-I. IH NMR (300 MHz, CDCh): 88.04 (d, 1H, J = 8.6), 7.78 (d, 2H, J= 8.8), 7.52-7.29 (m, 8H), 5.82 (d, 1H, J = 4.3),5.25 (s, 2H), 4.88

(s, br, 1H), 4.56 (d, 1H, J = 4.7), 4.13-3.98 (m, 2H), 3.26 (s, br, 1H), 1.01 (t, 3H, J = 7.1). I3C NMR (75 MHz, CDCh): 8172.6, 155.0, 136.1, 131.7, 130.1, 129.5, 128.8,

128.7, 128.4, 127.5, 127.1, 123.9, 122.5, 119.8, 114.9, 74.4, 72.3, 72.1, 61.7, 13.7.

MS (ESI): mlz 389 [M+Nar, 384 [M+NH4r, 349 [M-OHf, 91 [C6H5CH2f. Anal.

CaJcd for C22H220 5: C, 72.12; H, 6.05. Found: C, 72.19; H, 6.18.

(2R,3S)-3-(2-Benzyloxyphenyl)-3-hydroxy-2-(toluene-4-sulfonyloxy)propionic

Acid Ethyl Ester (13a):

187

Chapter 5. Enantlose/ectlve Synthesis of Natural Product-Uke BenzcHtnnulated Oxa-Heterocyc/es

To a solution of diol 12a (1.0 g, 3.16 mmol) in dry CH2Ch (20 mL) at O°C

was added dry triethyl amine (0.75 mL, 5.37 mmol) followed by tosyl chloride

(0.62 g, 3.25 mmol) and kept in the refrigerator for three OBn

(Y--~TS

~C02Et 13a OH

days. The reaction mixture was diluted with H20 (50 mL),

and extracted with CH2Ch (2x50 mL). The combined

organic layers were washed with brine (50 mL) and dried

over anhydrous Na2S04. The solvent was removed under reduced pressure and

purification of the crude product by silica gel column chromatography (18% ethyl

acetate in hexane) afforded 13a (1.30 g, 87%) as a white solid. Mp: 105-106°C. Rj

0.41 (40% ethyl acetate in hexane). [a]25D +62.8 (c 1.5, CHCh). lR (KBr): 3436,

2989,2364,1749,1618,1509,1445,1284,1204,1039,826, 730 cm· l. IH NMR (300

MHz, CDCh): 87.44-7.18 (m, 9H), 7.08 (d, 2H, J = 8.2), 6.91 (d, 1H, J = 7.0),6.77

(d, 1H,J= 8.2), 5.39 (s, 1H), 5.23 (d, 1H,J= 3.6), 5.00 (d, 1H,J= 13.0),4.99 (d, 1H,

J = 13.0),4.13 (q, 2H, J = 7.1),2.82 (s, br, 1H), 2.38 (s, 3H), 1.15 (t, 3H, J = 7.1). \3C

NMR (75 MHz, CDCh): 8167.1, 155.0, 144.4, 136.4, 132.7, 129.4, 129.1, 128.6,

128.0,127.7,127.1,126.0,121.1,111.4,79.3,70.6,70.0, 61.8,21.5,13.8. MS (ES1):

mlz 493 [M+Nat, 488 [M+NH4t, 453 [M-OHt. Anal. Ca1cd for C25H2607S: C,

63.81; H, 5.57. Found: C, 63.98; 5.50.

(2R,3S)-3-(2-Benzyloxynaphthalen-l-yl)-3-hydroxy-2-(toluene-4-sulfonyloxy)

propionic Acid Ethyl Ester (13b):

Starting from 1.0 g (2.72 mmol) of 12b, the title compound was prepared in the

same manner as that described for 13a. Purification of the crude product by silica gel


afforded 13b (1.34 g, 94%) as a colorless solid. Mp: 109-

110°C. Rr: 0.44 (40% ethyl acetate in hexane). [af5D

+54.7 (c 2.3, CHCh). lR (KBr): 3502, 2923, 2363, 1767,

1597, 1367, 1169, 1040, 889, 856, 726 em-I. IH NMR

(300 MHz, CDCI3): 87.81 (d, IH, J = 8.5), 7.70-7.66 (m, 2H), 7.50 (d, IH, J=6.9),

7.44-7.27 (m, 7H), 7.18 (d, IH, J= 9.1), 6.87 (d, IH, J= 8.1), 5.91 (d, IH, J= 5.1),

5.22 (d, 1H, J = 5.1),5.18 (s, 2H), 4.34 (s, br, IH), 3.94 (q, 2H, J = 7.1), 2.22 (s, 3H),

0.94 (t, 3H, J = 7.1). J3C NMR (75 MHz, CDCh): 8166.7, 155.1, 144.3, 135.8, 132.1,

131.0, 130.5, 129.1, 128.7, 128.5, 128.3, 127.6, 127.3, 127.2, 123.8, 121.8, 117.2,

188

Chapter 5. Enantlose/ectlve Synthesis of Natural Product-Uke Benzo-Annu/ated Oxa-Heterocycles

80.5, 71.6, 70.4, 61.6, 21.4, 13.5. MS (BSI): mlz 543 [M+NaJ+, 538 [M+NH4t, 503

[M-OHt Anal. Ca1cd for C29H2807S: C, 66.91; H, 5.42. Found: C, 67.11; H, 5.55.

(2R,3S)-3-(2-Benzyloxyphenyl)-3-(tert-butyldimethylsilanyloxy)-2-(toluene-4

sulfonyloxy)propionic Acid Ethyl Ester (14a):

To a stirring solution of 13a (1.0 g, 2.12 mmol) in dry CH2Cb (30 mL) at 0 DC

were added 2,6-lutidine (0.48 mL, 4.14 mmol) and TBDMSOTf (0.73 mL, 3.l8

mmol), successively. The reaction mixture was then stirred at rt for 6 h. The reaction

OBn was quenched with a saturated aqueous NH4CI solution (20

W~ OTs

mL) and extracted with CH2Ch (3 x25 mL). The combined h- C02Et

14a OTBDMS organic layers were washed with water (50 mL), brine (50

mL) and dried over anhydrous Na2S04. The solvent was

removed under reduced pressure and purification of the crude product by silica gel

column chromatography (6% ethyl acetate in hexane) afforded 14a (1.05 g, 85%) as a

colorless solid. Mp: 75-76DC. Rf 0.52 (20% ethyl acetate in hexane). [aJ25o +45.4 (c

2.34, CHCh). IR (KBr): 2930,2362,1764,1597,1370,1220,1181,1039,901,758

cm· l. IH NMR (300 MHz, CDCh): 57.41-7.31 (m, 8H), 7.l8-7.l2 (m, IH), 7.04 (d,

2H, J = 8.1), 6.89-6.84 (m, IH), 6.69 (d, IH, J = 7.9), 5.62 (d, IH, J = 2.8),5.04 (d,

IH, J = 3.l), 5.01 (d, IH, J I = 12.0),4.98 (d, IH, J1 = 12.0), 4.l9-4.05 (m, 2H), 2.l6

(s, 3H), 1.17 (t, 3H, J = 7.1), 0.84 (s, 9H), -0.04 (s, 3H), -0.19 (s, 3H). 13C NMR (75

MHz, CDCh): 5167.1, 154.2, 143.9, 136.7, 132.9, 129.2, 129.0, 128.7, 128.5, 127.8,

127.6, 127.0, 126.7, 120.6, 110.9,79.8,69.6,69.1,61.5,25.5,21.5,18.0,13.7, -4.9,-

5.6. MS (BS}): mlz 608 [M+Nat, 602 [M+N~t Anal. Ca1cd for C31H4007SSi: C,

63.67; H, 6.89. Found: C, 63.56; H, 7.07.

(2R,3S)-3-(2-Benzyloxynaphthalen-l-yl)-3-(tert-butyldimethylsilanyloxy)-2-

(toluene-4-sulfonyloxy)propionic Acid Ethyl Ester (14b):

Starting from 1.0 g (1.92 mmol) of 13b, the title compound was prepared in the


column chromatography (6% ethyl acetate in hexane) afforded 14b (1.07 g, 88%) as a

OBn OTs

14b

colorless semi-solid. Rr: 0.54 (20% ethyl acetate in

hexane). [a]25o +60.0 (c 1.73, CHCh). IR (KBr): 2932,

2360, 1741, 1460, 1375, 1248, 1180, 1028, 885, 840,

737 em-I. IH NMR (300 MHz, CDCh): 58.61 (d, IH, J

= 8.5), 7.61 (d, 2H, J= 8.6), 7.48-7.22 (m, 9H), 7.08 (d,

189

Chapter 5. Enantloselective Synthesis of Natural Product-Llke Benzo-Annulated Oxa-Heterocycles

IH, J = 9.1),6.87 (d, IH, J = 8.1), 6.27 (d, IH, J = 5.2), 5.22 (d, IH, J = 5.2), 5.13 (s,

2H), 3.96 (q, 2H, J = 7.1), 2.28 (s, 3H), 0.98 (t, 3H, J = 7.1), 0.75 (s, 9H), -0.03 (s,

3H), -0.42 (s, 3H). I3C NMR (75 MHz, CDCh): 5166.8, 152.6, 143.9, 136.8, 133.1,

132.5, 130.3, 129.5, 128.9, 128.6, 127.9, 127.7, 127.3, 127.2, 126.9, 125.8, 123.5,

119.4, 112.9, 81.3, 70.9, 69.3, 61.4, 25.5, 21.4, 17.9, 13.6, -5.4, -5.6. MS (ESI): mlz

658 [M+Nat, 652 [M+NRtt Anal. Calcd for C35H4207SSi: C, 66.22; H, 6.67.

Found: C, 66.10; H, 6.43.

(2S,3S)-3-(tert-Butyldimethylsilanyloxy)-2,3-dihydrobenzofuran-2-carboxylic

Acid Ethyl Ester (lSa):

To a stirred solution of 14a (1.0 g, 1.71 mmol) in ethyl acetate (20 mL) was

added 10% Pd-C (100 mg). After stirring for 4 h at room temperature under pressure

of a hydrogen balloon, the reaction mixture was filtered through a pad of Celite® and

the filtrate was concentrated under reduced pressure to get the corresponding

debenzylated product (0.733 g) as a colorless semi-solid which was used for the next

step without further purification.

To a stirring solution of the above debenzylated product in dry acetone (20

mL), was added anhyd. K2C03 (0.35 g, 2.53 mmol) and the mixture was stirred for 6

h at room temperature. After removing acetone of the raction mixture under reduced

pressure, water (10 mL) was added to the resulting residue and extracted with ethyl

acetate (3 x 20 mL) and washed with brine (1 x 20 mL). The organic layer was dried

over Na2S04, filtered, and concentrated under reduced pressure. Purification of the

Nq;-V-( C02Et

crude product by silica gel column chromatography (4%

ethyl acetate in hexane) afforded lSa (0.384 g, 69%, for

15a OTBDMS two steps) as a colorless semi-solid. [a]25o +62.6 (c 1.31,

CHCb). Rf 0.42 (10% ethyl acetate in hexane). IR (KBr):

2932,2361, 1752, 1471, 1217, 1082,842,758 cm· l. IH NMR (300 MHz, CDCb): 5

7.28-7.24 (m, 2H), 6.97-6.93 (m, 2H), 5.51 (d, 1H, J = 3.1), 4.92 (d, 1H, J = 3.1),

4.29-4.22 (m, 2H), 1.31 (t, 3H, J = 7.1), 0.92 (s, 9H), 0.19 (s, 6H). 13C NMR (75

MHz, CDCb): 5169.8, 159.5, 130.4, 127.1, 125.3, 121.5, 110.7, 87.5, 76.8, 61.7,

25.7, 18.0, 14.1, -4.4, -4.5. MS (ESI): mlz 346 [M+Nat. Anal. Calcd for C17H260 4Si:

C, 63.32; H, 8.13. Found: C, 63.39; H, 8.25.

(1 S,2S)-(1-(tert-Butyldimethylsilanyloxy )-1 ,2-dihydronaphtho (2,1-b ]furan-2-

carboxylic Acid Ethyl Ester (lSb):

190

Chapter 5. Enantloselectlve Synthesis of Natural Product-Llke Benzo.Annulated Oxa-Heterocycles

Starting from 0.85 g (1.34 mmol) of 14b, the title compound was prepared in two

steps in the same manner as that described for 15a. Purification of the crude product

OTBDMS 15b

by silica gel column chromatography (4% ethyl acetate in

hexane) afforded 15b (0.362 g, 72%) as a colorless solid.

Mp: 92-93°C. ~ 0.44 (10% ethyl acetate in hexane).

[a]25D +37.7 (c 1.43, CHCh). IR (KBr): 2932, 2855,

2362,1750,1460,1366,1259,1195,1072,885,840,743

cm-'. 'H NMR (300 MHz, CDCh): 87.87-7.83 (m, 3H), 7.57-7.52 (m, IH), 7.41-7.36

(m, IH), 7.31 (d, IH, J = 8.8), 6.04 (d, IH, J = 2.1), 5.17 (d, IH, J = 2.1), 4.36-4.25

(m,2H), 1.35 (t, 3H, J = 7.1), 0.97 (s, 9H), 0.36 (s, 3H), 0.25 (s, 3H). I3C NMR (75

MHz, CDCh): 8169.8, 158.1, 132.1, 130.7, 130.0, 129.0, 127.2, 123.6, 122.6, 118.6,

112.7,88.2, 77.6, 61.9, 25.8, 18.2, 14.2, -3.9, -4.7. MS (ESI): mlz 395 [M+Nat. Anal.

Ca1cd for C2,H2s04Si: C, 67.71; H, 7.58. Found: C, 67.56; H, 7.66.

2- [(2S,3S)-3-(tert-Butyldimethylsilanyloxy)-2,3-dihydrobenzofuran-2-yl]-propan-

2-01 (16a):

To a freshly prepared, magnetically stirred, ice-cold suspenSIOn of

methylmagnesium iodide [prepared from methyl iodide (0.56 mL, 7.0 mmol) and

magnesium (0.17 g, 7.0 mmol) in 10 mL of dry ether] was added a solution of ester

15a (0.154 g, 0.46 mmol) in dry THF (10 mL). The

~~r-l V-{ ""OH reaction mixture was refluxed for 4 h, cooled, and

quenched with aqueous NH4CI solution (10 mL). The 16a OTBDMS

mixture was extracted with ethyl acetate (2x25 mL),

washed with water (25 mL) and brine (25 mL). The combined organic layer was dried

over Na2S04, filtered and concentrated under reduced pressure. Purification of the

crude product by silica gel column chromatography (8% ethyl acetate in hexane)

afforded 16a (0.112 g, 77%) as a colorless semi-solid. Rr: 0.54 (20% ethyl acetate in

hexane). [a]25D +93.1 (c 2.04, CHCh).IR (KBr): 3462, 3194, 2932, 2362,1598,1477,

1234, 1178, 1047, 750 cm-'. 'H NMR (300 MHz, d6-acetone): 87.33 (d, IH, J = 7.3),

7.20 (t, IH, J = 7.7), 6.88 (t, IH, J = 7.3), 6.78 (d, IH, J = 8.0), 5.53 (d, IH, J = 2.4),

4.26 (d, IH, J = 2.8), 1.29 (s, 3H), 1.10 (s, 3H), 0.88 (s, 9H), 0.20 (s, 6H). J3 C NMR

(75 MHz, d6-acetone): 8161.3, 130.4, 130.1, 126.2, 120.8, 110.3, 97.7, 74.6, 71.1,

27.1, 26.0, 24.6, 18.3, -3.8, -4.2. MS (ESI): mlz 332 [M+Nat. Anal. Ca1cd for

C17H280 3Si: C, 66.19; H, 9.15. Found: C, 66.26; H, 9.31.

191

Chapter 5. Enantlose/ective Synthesis of Natural Product-Uke BenzcrAnnulated Oxa-Heterocyc/es

(2S, 3S)-2-(1-Hydroxy-1-methyJethyJ)-2,3-dihydrobenzofuran-3-oJ (17a):

To an ice-cooled solution of 16a (80.5 mg, 0.26 mmol) in dry THF (5 mL)

was added tetra-n-butylammonium fluoride (TBAF) (1 M in THF, 0.60 mL). After

being stirred at O°C for 5 h, the reaction mixture was diluted with ethyl acetate (25

~~r--L V-{ \ OH

mL), washed with water (25 mL) and brine (25 mL). The

combined organic layer was dried over Na2S04, filtered

and concentrated under reduced pressure. Purification of 17a OH

the crude product by silica gel column chromatography

(30% ethyl acetate in hexane) afforded 17a (46 mg, 91 %) as a colorless solid. Mp: 95-

96°C. Rf 0.55 (60% ethyl acetate in hexane). [a]25o +93.3 (c 0.9, CHCh). IR (KBr):

3462, 3194, 2932, 2362, 1598, 1477, 1234, 1178, 1047, 750 em-I. IH NMR (300

MHz, d6-acetone): 87.33 (d, IH,J= 7.4),7.19-7.13 (m, IH), 6.87-6.82 (m, IH), 6.74

(d, IH, J = 8.0), 5.39 (d, IH, J = 4.5), 4.74 (s, br, IH), 4.24 (d, IH, J = 4.6), 3.74 (s,

br, IH), 1.25 (s, 3H), 1.22 (s, 3H). I3C NMR (75 MHz, d6-acetone): 8162.1, 132.1,

131.3, 127.3, 122.1, 111.4, 98.6, 74.4, 72.2, 26.9, 26.8. MS (ESI): mlz 217 [M+Nat.

Anal. Calcd for CII HI40 3: C, 68.02; H, 7.27. Found: C, 68.16; H, 7.50.

(2S,3S)-2-(1-Hydroxy-1-methylethyl)-1,2-dihydronaphtho(2,1-b ]furan-l-01 (17b):

Starting from 0.205 mg (0.55 mmol) of ISb, the title compound was prepared

in two steps. First step is the Grignard reaction as that described for 16a and the

second step deprotection of TBDMS group as that described for 16a. The

intermediate tertiary alcohol resulting from the Grignard reaction was not much stable

OH

and hence used for the next step (deprotection of

TBDMS group) without purification by silica gel column

chromatography. Purification of the crude product of the

final step by silica gel column chromatography (30%

ethyl acetate in hexane) afforded 17b (113 mg, 74%, for two steps) as a colorless

semi-solid. R( 0.58 (60% ethyl acetate in hexane). [a]25o +46.7 (c 1.97, CHCh). IR

(KBr): 3355, 2925, 2360,1595,1488,1457,1257,1050,757 em-I. em-I. IH NMR

(300 MHz, d6-acetone): 88.03 (d, IH, J= 8.3), 7.85-7.78 (m, 2H), 7.50-7.45 (m, IH),

7.33-7.28 (m, IH), 7.09 (d, IH, J = 8.0),5.85 (d, IH, J = 3.6), 4.68 (s, br, IH), 4.43

(d, IH, J = 3.6), 3.71 (s, br, IH), 1.32 (s, 3H), 1.28 (s, 3H). I3C NMR (75 MHz, d6-

acetone): 8 160.3, 133.3, 132.8, 131.4, 130.5, 128.6, 124.8, 124.7, 122.6, 114.2,

192

Chapter 5. Enantloselective Synthesis of Natural Product-Uke Benzo.Annuiated OxiHIeterocycles

100.0, 74.6, 72.3, 27.1, 26.6. MS (ESI): mlz 267 [M+Nat. Anal. Calcd for C15H1603:

C, 73.75; H, 6.60. Found: C, 73.86; H, 6.73.

2-Benzyloxystyrene (18):

To a suspension of methyltriphenylphosphonium iodide (17.15 g, 42.42 mmol)

in dry THF (100 mL) under a nitrogen atmosphere at 0 DC was added I-BuOK (4.76 g,

42.42 mmol). The reaction mixture was stirred for 15 min at

r(Y0Bn

~ o DC and then warmed to rt while stirring was continued for

45 min. The solution was then recooled to 0 DC, and a solution 18

of aldehyde lOa (6.0 g, 28.27 mmol) in dry THF (50 mL) was

added dropwise. The reaction mixture was then warmed to rt and stirred for an

additional 2 h. The reaction was quenched with saturated aq. NH4Cl solution (50 mL)

and extracted with Et20 (3 x l00 mL). The combined organic extracts were washed

with brine (200 mL), dried (Na2S04), and concentrated in vacuo. The residue was

purified by silica gel column chromatography (2% ethyl acetate in hexane) to give

alkene 18 (4.75 g, 80%) as colorless oil. R;: 0.46 (10% ethyl acetate in hexane). IR

(neat): 3065, 3030, 2360, 1597, 1489, 1452, 1237, 1014, 751 cm-I. IH NMR (300

MHz, CDCh): 87.51-7.30 (m, 6H), 7.22-7.08 (m, 2H), 6.96-6.90 (m, 2H), 5.75 (dd,

IH, JI = 17.7, J2 = 1.4), 5.25 (dd, IH, JI = 11.2, J2 = 1.4),5.08 (s, 2H). 13C NMR (75

MHz, CDCh): 8155.9, 137.1, 131.6, 128.8, 128.5, 127.8, 127.3, 126.5, 121.0, 114.4,

112.5, 70.3. MS (ESI): mlz 211 [M+lt. Anal. Calcd for C I5H I40: C, 85.68; H, 6.71.

Found: C, 85.56; H, 6.79.

2-(2-Benzyloxyphenyl)ethanol (19):

To a stirring solution of 18 (4.0 g, 19.02 mmol) in anhydrous THF (30 mL)

was added a 0.5 M THF solution of 9-BBN (60 mL) dropwise under a nitrogen

atmosphere at 0 DC and the mixture was stirred at room temperature overnight. H20 (5

mL) was added followed by 3 N NaOH solution (40 mL) and r(Y1 ,,-,::V OoBln I ~ 30% aqueous hydrogen peroxide solution (30 mL). The reaction

~ OH mixture was stirred for 2 h at 50 DC. The mixture was extracted 19

with ethyl acetate (2x50 mL), washed with water (150 mL) and

brine (150 mL). The combined organic layer was dried over Na2S04, filtered and

concentrated under reduced pressure. Purification of the crude product by silica gel

column chromatography (8% ethyl acetate in hexane) afforded alcohol 19 (4.15 g,

96%) as a colorless gum. R(. 0.32 (20% ethyl acetate in hexane). IR (Neat): 3429,

193

Chapter 5. Enant/ose/ectlve Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocyc/es

1601, 1462, 1247, 1046,758 cm-I. IH NMR (300 MHz, CDCh): 87.54-7.41 (m,5H),

7.32-7.27 (m, 2H), 7.05-7.00 (m, 2H), 5.14 (s, 2H), 3.92 (t, 3H,J= 6.6),3.05 (t, 3H,J

= 6.6), 2.48 (s, br, IH). I3C NMR (75 MHz, CDCh): 8156.5, l36.9, l30.8, 128.4,

127.7, 127.5, 1272, 127.0, 120.7, 111.6,69.7,62.3,33.9. MS (FAB): mlz 228 [Mt,

211 [M-OHt. Anal. Calcd for ClsH1602: C, 78.92; H, 7.06. Found: C, 79.08; H, 7.14.

(2-Benzyloxyphenyl)acetaldehyde (20):

To a stirring solution of 19 (3.0 g, l3.14 mmol) in anhydrous dichloromethane

(50 mL) was added 4 A molecular sieve (3.85 g) and PCC (3.85 g, 17.86 mmol) at

o DC and the mixture was stirred at room temperature for 2h. After evaporating

r(Y0Bn

~CHO 20

dichloromethane the reaction mixture was diluted with ether (50

mL) and filtered through a small pad of silica gel. Concentration

of the filtrate and purification of the residue by silica gel column

chromatography (4% ethyl acetate in hexane) afforded 20 (2.25

g, 76%) as a colorless gum. Rr: 0.55 (20% ethyl acetate in hexane). IR (Neat): 3035,

2950,2360,1720,1597,1500,1230,758 cm-I. IH NMR (300 MHz, CDC h): 89.81

(t, IH, J = 1.9), 7.50-7.35 (m, 6H), 7.25-727 (m, IH), 7.09-7.05 (m, 2H), 5_14 (s,

2H), 3_79 (d, 2H, J = 1.9). I3C NMR (75 MHz, CDCh): 8199.5, 156.4, l36_5, l31.1,

128_6, 128.3, 127.6, 126.9, 121.3, 120.8, 11l.5, 69.6, 45.2. MS (FAB): mlz 226 [Mt-.

Anal. Calcd for ClsH1402: C, 79.62; H, 6.24_ Found: C, 79.73; H, 6.33.

(2E)-4-(2-Benzyloxyphenyl)but-2-enoic Acid Ethyl Ester (21):

Starting from 2_0 g (8.83 mmol) of 20, the title compound was prepared in the

same manner as that described for lla. Purification of the crude product by silica gel


afforded 21 (1.96 g, 75%) as a colorless gum. R(. 0.58

21 (20% ethyl acetate in hexane). IR (Neat): 2368, 1720,

1502, 1253, 1045, 750 cm- I. IH NMR (300 MHz,

CDCb): 87.40-7.26 (m, 6H), 7.20-7_07 (m, 2H), 6.92-6.87 (m, 2H), 5.77 (d, IH, J =

15.5),5.03 (s, 2H), 4.14 (q, 2H, J = 7.1), 3.55-3_53 (m, 2H), l.24 (t, 3H, J = 7.1). I3C

NMR (75 MHz, CDCh): 816651, 156_32, 147_10, l36.98, l30.20, 128.42, 127.91,

127.75, 127_14, 126.54, 121.88, 120.83, 11l.72, 69.86, 59.98, 32_97, 14.l6_ MS

(ESI): mlz 319 [M+Nat. Anal. Calcd for C19H2003: C, 77_00; H, 6.80_ Found: C,

77_09; H, 6.65_

(2R, 3S)-4-(2-Benzyloxyphenyl)-2,3-dihydroxybutyric Acid Ethyl Ester (22):

194

Chapter 5. Enantlose/ectlve Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocycles

Starting from 1.85 g (6.24 mmol) of 21, the title compound was prepared in the:



afforded 22 (1.83 g, 89%) as a colorless semi-solid. R/

0.41 (40% ethyl acetate in hexane). The enantiomeric

excess was estimated to be >99% by chiral HPLC analysis

as that described for 12a. [a]2sD -15.3 (c 2.4, CHCh). lR (KBr): 3346, 2927, 2362,

1759,1497,1453,1240,122, 749cm- I.

IHNMR(300MHz,CDCh): 87.43-7.27(m,

5H), 7.24-7.15 (m, 2H), 6.93-6.88 (m, 2H), 5.08 (s, 2H), 4.31-4.25 (m, IH), 4.19 (q,

2H,J= 7.1), 4.05 (d, 1H,J= 1.6),3.10-2.91 (m, 2H), 2.56 (s, br, 2H), 1.22 (t, 3H, J=

7.1). 13C NMR (75 MHz, CDCh): 8173.4, 156.6, 136.9, 131.4, 128.5, 127.9, 127.8,

127.1, 126.4, 121.0, 111.8, 72.6, 72.3, 70.0, 61.7, 35.1, 14.0. MS (ES1): mlz 353

[M+Nat, 348, 331, 313, 295. Anal. Calcd for CI9H220 S: C, 69.07; H, 6.71. Found: C,

69.17; H, 6.56.

(2R,3S)-4-(2-Benzyloxyphenyl)-3-hydroxy-2-(toluene-4-sulfonyloxy)butyric Acid

Ethyl Ester (23):

Starting from 1.5 g (4.54 mmol) of 22, the title compound was prepared in the


23 OTs


afforded 23 (1.87 g, 85%) as a colorless semi-solid. R/

0.46 (40% ethyl acetate in hexane). [afsD -10.1 (c 2.1,

CHCb). IR (KBr): 3464, 3022, 2401, 1756, 1599, 1494,

1373, 1217, 1028, 762 cm-I. IH NMR (300 MHz, CDCh): 87.81 (d, 2H, J = 8.3),

7.37-7.28 (m, 7H), 7.20-7.09 (m, 2H), 6.89-6.85 (m, 2H), 5.06 (s, 2H), 4.87 (d, IH, J

= 2.7),4.36-4.35 (m, IH), 4.10-4.02 (m, 2H), 2.92-2.83 (m, 2H), 2.40 (s, 3H), 2.39 (s,

br, IH), 1.12 (t, 3H, J = 7.1). 13C NMR (75 MHz, CDCb): 8167.18, 156.56, 145.09,

136.73, 133.15, 131.41, 129.68, 128.62, 128.29, 128.14, 127.90, 127.06, 125.46,

121.05, 111.77, 79.49, 71.56, 69.97, 61.88, 34.74, 21.63, 13.86. MS (ESI): mlz 507

[M+Nat, 502 [M+NH4t, 485 [Mt. Anal. Calcd for C26H2s07S: C, 64.45; H, 5.82.

Found: C, 64.61; H, 5.90.

(2S, 3S)-3-(2-Benzyloxybenzyl)oxirane-2-carboxylic Acid Ethyl Ester (24):

A solution of tosylate 23 (0.5 g, 1.03 mmol) in dry methanol (25 mL) was

treated with anhyd. K2C03 (0.21 g, 1.52 mmol) and the resulting suspension stirred

195

Chapter 5. Enantlose/ectlve Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocyc/es

vigorously at room temperature for 8 h. After removing acetone of the reaction

mixture under reduced pressure, water (20 mL) was added to the resulting residue and

extracted with ethyl acetate (3 x 20 m) and washed with brine (1 x 30 mL). The

organic layer was dried over Na2S04, filtered, and

concentrated under reduced pressure to give light-yellow

oil. Purification of the crude product by silica gel column

chromatography (10% ethyl acetate in hexane) afforded 24

(0.24 g, 75%) as a colorless gum. R/ 0.54 (20% ethyl acetate in hexane). [a]25o +38.4

(c 1.9, CHCh). IR (KBr): 3020, 2363, 1742, 1495, 1216, 758 em-I. IH NMR (300

MHz, CDCh): 87.43-7.29 (m, 5H), 7.23-7.12 (m, 2H), 6.92-6.87 (m, 2H), 5.09 (s,

2H), 4.29-4.17 (m, 2H), 3.55-3.50 (m, 2H), 3.22-3.15 (m, 1H), 3.01-2.93 (m, 1H),

l.27 (t, 3H, J= 7.1). I3C NMR (75 MHz, CDCh): 8168.3, 156.5, 136.9, 130.6, 128.5,

128.1,127.8,127.1,125.3,120.9, 11l.6, 69.8, 61.4, 56.8, 52.9,28.7,14.1. MS (ESI):

mlz 345 [M+Nat. Anal. Calcd for CJ9H2004: C, 73.06; H, 6.45. Found: C, 72.89; H,

6.3l.

(S)-[(2R)-2,3-Dihydrobenzofuran-2-yIJhydroxyacetic Acid Ethyl Ester (25):

Starting from 0.225 g (0.72 mmol) of 24, the title compound was prepared in


gel column chromatography (10% ethyl acetate in hexane) afforded 25 (0.13 g, 81 %,

for two steps) as a white solid. Mp: 80-81°C. Rj: 0.35 (20%

ethyl acetate in hexane). [aJ25o -76.9 (c l.13, CHCh). IR

(KBr): 3437, 2929, 2364, 1728, 1483, 1233, 1136, 1014,

754 em-I. IH NMR (300 MHz, CDCh): 87.15 (d, 1H, J=

7.1), 7.08 (t, IH, J = 7.6), 6.85-6.80 (m, IH), 6.75 (d, lH, J = 7.9), 5.l1-5.05 (m, IH),

4.33-4.25 (m, 3H), 3.42-3.24 (m, 2H), 2.96 (d, IH, J= 6.9), l.30 (t, 3H, J= 7.1). J3C

NMR (75 MHz, CDCh): 8172.0, 159.5, 127.9, 126.4, 124.7, 120.7, 109.1,82.4, 72.4,

62.1, 3l.3, 14.1. MS (ESI): mlz 245 [M+Nat, 241. Anal. Calcd for C12H I40 4: C,

64.85; H, 6.35. Found: C, 64.76; H, 6.48.

(1S)-I-[ (2R)-2,3-Dihydrobenzofuran-2-yl)-2-methyl-propane-l,2-dio] (26):

~o PH I .'

//

26 OH

Starting from 0.l25 g (0.562 mmol) of 26, the title

compound was prepared in the same manner as that

described for 16a. Purification of the crude product by silica

gel column chromatography (30% ethyl acetate in hexane)

196

Chapter 5. Enantloselectlve Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocycles

afforded 26 (0.103 g, 88%) as a white solid. Mp: 89-90°C. Rf 0.57 (60% ethyl acetate

in hexane). [a]25D -55.9 (c 1.42, CHCh). IR (KBr): 3431, 2925, 2363, 1729, 1634,

1332, 1224, 1163,755, 678 cm· l. IH NMR (300 MHz, CDCh): 8 7.l8 (d, 1H, J =

7.2), 7.10 (t, 1H, J = 7.6), 6.86 (dd, IH, J I = 7.0, J2 = 7.5), 6.76 (d, 1H, J = 7.9), 5.04

(m, 1H), 3.45-3.37 (m, 2H), 3.25-3.16 (m, IH), 2.66 (s, br, 2H), 1.39 (s, 3H), 1.33 (s,

3H). 13C NMR (75 MHz, CDCh): 8158.9, 127.8, 126.8, 124.9, 121.0, 109.2, 82.7,

77.2, 72.8, 32.6, 26.6. MS (ESI): mlz 231 [M+Na]\ 226. Anal. Calcd for C12H1603: C,

69.21; H, 7.74. Found: C, 69.42; H, 7.79.

(2R,3S)-4-(2-Benzyloxyphenyl)-3-(tert-butyldimethylsilanyloxy)-2-(toluene-4-

sulfonyloxy)-butyric Acid Ethyl Ester (27):



column chromatography (8% ethyl acetate in hexane} afforded 27 (0.82 g, 89%) as a

colorless semi-solid. Rj 0.55 (20% ethyl acetate in

hexane). [af5o -7.2 (c 0.92, CHCh). IR (KBr): 2931,

27 OTs 2360, 1745, 1495, 1370, 1216, 1031,758,671 em-I. IH

NMR (300 MHz, CDCh): 87.79 (d, 2H, J = 8.3), 7.45-

7.27 (m, 7H), 7.l9-7.09 (m, 2H), 6.88-6.82 (m, 2H), 5.07 (s, 2H), 4.74 (d, IH, J = 3.4), 4.51-4.48 (m, IH), 4.02-3.95 (m, 2H), 3.02-2.96 (m, IH), 2.83-2.77 (m, IH),

2.41 (s, 3H), 1.12 (t, 3H,J= 7.1), 0.74 (s, 9H), -0.21 (s, 3H), -0.44 (s, 3H). 13C NMR

(75 MHz, CDCh): 8167.5, 156.9, 144.6, 137.0, 133.9, 132.6, 129.5, 128.6, 128.0,

127.9, 127.5, 125.4, 120.7, 111.3, 79.4, 71.2, 69.9, 61.5, 35.2, 25.6, 21.6, 17.8, 13.8, -

5.3. MS (ES!): mlz 621 [M+Nat, 617, 599. Anal. Calcd for C32H4207SSi: C, 64.18;

H, 7.07. Found: C, 64.06; H, 7.20.

(2S, 3S)-3-(tert-Butyldimethylsilanyloxy)chroman-2-carboxylic Acid Ethyl Ester

(28):




afforded 28 (0.195 g, 70%; based on two steps) as a

colorless viscous liquid. Rj: 0.48 (10% ethyl acetate in

hexane). [a]25o +51.2 (c 2.5, CHCh). IR (Neat): 2932,

1751,1250,1197,1119,838,756 em-I. IH NMR (300 MHz, CDCh): 87.16-7.11 (m,

197

Chapter 5. Enantlose/ectlve Synthesis of Natural Product-Uke Benzo.Annulated OXiHleterocyc/es

IH), 7.05-7.03 (m, IH), 6.93-6.88 (m, 2H), 4.43-4.38 (m, 2H), 4.34-4.21 (m, 2H),

3.03-2.84 (m, 2H), 1.33 (t, 3H, J = 7.1), 0.91 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H). J3C

NMR (75 MHz, CDCh): 8 169.6, 152.8, 129.6, 127.5, 121.1 119.3, 116.3, 78.76,

65.62, 61.32, 33.73, 25.51, 17.79, 13.96, -4.50, -5.10. MS (ESI): mlz 360 [M+Nat,

337 [Mt. Anal. Calcd for CIsH2s0 4Si: C, 64.25; H, 8.39. Found: C, 64.36; H, 8.43.

2-[(2S, 3S)-3-(tert-Butyldimethylsilanyloxy)chroman-2-yIJpropan-2-01 (29):



column chromatography (5% ethyl acetate in hexane) afforded 29 (0.132 g, 91%) as a

colorless semi-solid. Rf 0.36 (10% ethyl acetate in

~O",~H hexane). [af5D +94.4 (c 1.56, CHCb). IR (KBr): 3512,

~OTBDMS 2933, 2362, 1586, 1489, 1363, 1248, 1089, 1049, 840,

29 755 em-I. IH NMR (300 MHz, CDCh): 87.16-7.06 (m,

2H), 6.93-6.84 (m, 2H), 4.32-4.24 (m, IH), 4.17 (s, IH), 3.67 (d, IH, J= 9.0), 3.10-

2.91 (m, 2H), 1.41 (s, 3H), 1.39 (s, 3H), 0.98 (s, 9H), 0.26 (s, 3H), 0.25 (s, 3H). J3 C

NMR (75 MHz, CDCb): 8153.9, 129.4, 127.5, 120.78, 120.1, 116.2,82.8, 72.2, 68.5,

36.4,27.0,25.7, 23.7, 17.7, -3.2, -4.8. MS (ESI): mlz 346 [M+Nat, 323 [Mt Anal.

Calcd for CIsH3003Si: C, 67.03; H, 9.38. Found: C, 67.13; H, 9.11.

(2S,3S)-2-(1-Hydroxy-l-methylethyl)chroman-3-01 (30):



ccC°H I ~ 0",

h- OH 30

gel column chromatography (30% ethyl acetate in hexane)

afforded 30 (56 mg, 87%) as a colorless solid. Mp: 115-

116°C. Rf 0.65 (60% ethyl acetate in hexane). [a]25D +85.2

(c 0.95, CHCh). IR (KBr): 3343, 2925, 2361, 1587, 1486,

1457, 1242, 1043, 755 em-I. IH NMR (300 MHz, d6-acetone): 87.07-7.04 (m, 2H),

6.86-6.75 (m, 2H), 5.10 (s, IH), 4.62 (s, IH), 4.16-4.08 (m, IH), 3.57 (d, IH, J= 9.0),

3.06-2.99 (m, IH), 2.83-2.75 (m, IH), 1.38 (s, 3H), 1.32 (s, 3H). J3C NMR (75 MHz,

d6-acetone): 8156.0, 131.4, 129.2, 122.9, 122.5, 117.8, 84.9, 74.6, 67.5, 36.8, 29.4,

25.0. MS (ESI): mlz 231 [M+Nat, 226 [M+NH4t. Anal. Calcd for C12HI603: C,

69.21; H, 7.74. Found: C, 69.29; H, 7.98.

2-Benzyloxyallylbenzene (31):

198



same manner as that described for 18. Purification of the crude product by silica gel

cc:oBn

10

column chromatography (2% ethyl acetate in hexane) afforded

31 (3.50 g, 88%) as a colorless oil. Rj 0.46 (10% ethyl acetate

in hexane). IR (Neat): 3069, 2908, 2370, 1597, 1494, 1453, ~ 31

1241, 1022, 749 cm· l. IH NMR (300 MHz, CDCh): 87.44-7.28

(m, 5H), 7.20-7.14 (m, 2H), 6.93-6.89 (m, 2H), 6.08-5.95 (m, 1H), 5.08 (s, 2H), 5.05-

5.02 (m, 2H), 3.45 (d, 2H, J = 6.6). 13C NMR (75 MHz, CDCh): 8156.4, 137.4,

137.0, 129.9, 129.0, 128.5, 127.7, 127.3, 127.1, 120.8, 115.4, 111.7, 69.9, 34.4. MS

(ESI): mlz 225 [M+lt, 91 [C6H5CH2t. Anal. Calcd for CI6HI60: C, 85.68; H, 7.19.

Found: C, 85.76; H, 7.30.

3-(2-Benzyloxyphenyl)propan-1-o1 (32):

Starting from 3.0 g (13.37 mmol) of31, the title compound was prepared in the



colorless gum. Rj 0.32 (20% ethyl acetate in hexane). IR r(Y0Bn ~OH (Neat): 3421,1594,1452,1351,1239, 1040,750 cm· l

. IH

32 NMR (300 MHz, CDCb): 87.41-7.25 (m, 5H), 7.l6-7.l0

(m, 2H), 6.91-6.86 (m, 2H), 5.03 (s, 2H), 3.54 (t, 2H, J = 6.3), 2.74 (t, 2H, J =7.3),

2.01 (s, IH), 1.87-1.78 (m, 2H). BC NMR (75 MHz, CDCh): 8156.5, 137.l, 130.4,

130.1,128.5,127.8,127.1,127.0,120.9,111.7,70.0,61.8, 32.8, 26.1. MS (FAB): mlz

242 [Mr. Anal. Calcd for CI6HIS02: C, 79.31; H, 7.49. Found: C, 79.39; H, 7.61.

3-(2-Benzyloxyphenyl)propionaldehyde (33):




0:::--...:::::: OBn colorless oil. Rj 0.55 (20% ethyl acetate in hexane). IR

(Neat): 3032, 2930,2360, 17l0, 1600,1501,1240,751 cm-I. o CHO 33 IH NMR (200 MHz, CDCl3): 89.77 (t, IH, J = 1.9), 7.41-

7.32 (m, 5H), 7.23-7.15 (m, 2H), 6.93-6.87 (m, 2H), 5.08 (s, 2H), 3.00 (t, 2H,J= 7.3),

2.75 (t, 2H, J = 7.3), 2.01 (s, IH), 1.87-1.78 (m, 2H). 13C NMR (50 MHz, CDCh): 8

202.9,157.0, 137.6, 130.6, 129.4, 129.1, 128.4, 128.1, 127.6, 121.3, 112.1, 70.3, 44.3,

199

Chapter 5. Enantloselectlve Synthesis of Natural Product-LIke BenzcHVInulated Oxa-Heterocycles

24.0. MS (FAB): mlz 240 [Mt. Anal. Calcd for C16H1602: C, 79.97; H, 6.71. Found:

C, 79.93; H, 6.79.

(2E)-5-(2-Benzyloxyphenyl)-pent-2-enoic Acid Ethyl Ester (34):


same manner as that described for 11a. Purification of ~OBn

~COEt 34 2

the crude product by silica gel column chromatography

(5% ethyl acetate in hexane) afforded 34 (2.0 g, 77%)

as a colorless oil. Rf 0.58 (20% ethyl acetate in

hexane). IR (Neat): 2361, 1717, 1495, 1453, 1240, 1039, 749 em-I. IH NMR (200

MHz, CDCh): 57.41-7.21 (m, 5H), 7.16-6.98 (m, 2H), 6.92-6.88 (m, 3H), 5.81 (d,

IH,) = 15.6), 5.07 (s, 2H), 4.l6 (m, 2H), 2.82 (t, 2H,) = 7.9), 2.57-2.46 (m, 2H),

1.26 (t, 3H,)= 7.l). 13C NMR (50 MHz, CDCh): 5167.2, 157.0, 149.3, 137.7, 130.4,

130.0, 129.0, 128.2, 127.9, 127.5, 121.9, 121.2, 112.0, 70.2, 60.6, 32.9, 29.6, 14.7.

MS (ESI): mlz 311 [M+lt. Anal. Calcd for C2oH2203: C, 77.39; H, 7.l4. Found: C,

77.51; H, 7.09.

(2R, 3S)-5-(2-Benzyloxyphenyl)-2,3-dihydroxypentanoic Acid Ethyl Ester (35):




~OBn I OH

// C02Et 35 OH

colorless semi-solid. Rf 0.38 (40% ethyl acetate in

hexane). [a]25D -18.75 (c 1.71, CHCh). The

enantiomeric excess was estimated to be >99% by

chiral HPLC analysis as that described for 12a. IR

(KBr): 3431, 2933, 1731, 1595, 1492, 1449, 1238, 1023,754 em-I. IH NMR (300

MHz, CDCh): 57.44-7.31 (m, 5H), 7.19-7.l4 (m, 2H), 6.93-6.88 (m, 2H), 5.08 (s,

2H), 4.27-4.20 (m, 2H), 4.06 (dd, 1H,}1 = 2.0,}2 = 5.6), 3.04 (d, 1H,) = 5.7), 2.88-

2.79 (m, 2H), 2.14 (d, 1H,)= 8.4),1.95-1.90 (m, 2H), 1.27 (t, 3H,)= 7.1). 13C NMR

(75 MHz, CDCh): 5173.5, 156.5, 137.2, 130.2, 130.2, 128.6, 127.9, 127.2, 127.2,

120.9, 111.8, 73.3, 71.9, 70.0, 61.9, 34.0, 26.4, 14.1. MS (ESI): mlz 367 [M+Nat,

362,345. Anal. Calcd for C2oH2405: C, 69.75; H, 7.02. Found: C, 69.65; H, 7.12.

(2R,3S)-5-(2-Benzyloxyphenyl)-3-hydroxy-2-(toluene-4-suIfonyloxy)pentanoic

Acid Ethyl Ester (36):

200





afforded 36 (1.79 g, 80%) as a colorless gum. R/ 0.41

(40% ethyl acetate in hexane). [a]25D -1.5 (c 1.15,

CHCh). IR (KBr): 3407,2924,2143, 1754, 1593, 1444,

1366, 1231, 1178, 1022, 755 cm-l. lH NMR (300 MHz, CDCh): 87.77 (d, 2H, J = 8.3),7.42-7.24 (m, 7H), 7.18-7.08 (m, 2H), 6.91-6.86 (m, 2H), 5.05 (s, 2H), 4.81 (d,

IH, J = 3.3), 4.08-4.04 (m, 2H), 3.96-3.93 (m, 1H), 2.80-2.70 (m, 2H), 2.39 (s, 3H),

1.82-1.74 (m, 2H), 1.13 (t, 3H, J = 7.1). l3C NMR (75 MHz, CDCh): 8167.2, 156.5,

145.1, 137.0, 133.1, 130.2, 129.7, 129.5, 128.6, 128.1, 127.9, 127.4, 127.2, 120.9,

111.7,80.0, 70.9, 70.0, 61.8, 33.1, 25.9, 21.6, 13.8. MS (ESI): mlz 521 [M+Nat, 516,

499. Anal. Calcd for C27H300 7S: C, 65.04; H, 6.06. Found: C, 65.22; H, 6.14.

(2S, 3S)-3-(2-(2-Benzyloxyphenyl)ethyl]oxirane-2-carboxylic Acid Ethyl Ester

(37):



column chromatography (10% ethyl acetate in hexane) afforded 37 (0.585 g, 78%) as

a colorless semi-solid. Rr: 0.58 (20% ethyl acetate in

hexane). [a]25D +21.87 (c 1.6, CHCh). IR (KBr): 3021,

2366,1744,1218,1028,767 cm-l. lH NMR (300 MHz,

CDCh): 87.44-7.31 (m, 5H), 7.16-7.14 (m, 2H), 6.91-

6.87 (m, 2H), 5.08 (s, 2H), 4.17-4.04 (m, 2H), 3.39 (d, IH, J = 4.5), 3.19-3.17 (m,

IH), 2.89-2.80 (m, 2H), 2.07-1.92 (m, 2H), 1.23 (t, 3H, J= 7.1). l3C NMR (75 MHz,

CDCh): 8168.2, 156.5, 137.2, 130.1, 129.3, 128.5, 127.8, 127.4, 127.1, 120.8, 111.6,

69.8,61.3,57.3,52.9,27.5,26.9,14.1. MS (FAB): mlz 327 [M+lt. Anal. Calcd for

C2oH220 4 : C, 73.60; H, 6.79. Found: C, 73.75; H, 6.53.

(S)-(2R)-Chroman-2-yl]hydroxyacetic Acid Ethyl Ester (38):

OH o -():yC02Et

38

Starting from 0.45 g (1.38 mmol) of 37, the title

compound was prepared in the same manner as that

described for 15a. Purification of the crude product by

silica gel column chromatography (15% ethyl acetate in

hexane) afforded 38 (0.221 g, 68%; based on two steps) as

201


a colorless semi-solid. Rf 0.39 (20% ethyl acetate in hexane). [0.]250 -80.86 (c 1.77,

CHCh). IR (KBr): 3446,2928, 1739, 1487, 1234, 1131,756 em-I. IH NMR (300

MHz, CDCh): 87.09-7.03 (m, 2H), 6.87-6.75 (m, 2H), 4.38-4.24 (m, 4H), 3.04-2.99

(m, IH), 2.95-2.78 (m, 2H), 2.24-2.09 (m, IH), 2.04-1.96 (m, IH), 1.32 (t, 3H,J=7.1).

DC NMR (75 MHz, CDCh): 8172.4, 154.4, 129.3, 127.2, 121.5, 120.4, 116.7, 76.4,

72.9,61.9,24.7,23.5, 14.1. MS (FAB): mlz 237 [M+lt. Anal. Calcd for C13HI604:

C, 66.09; H, 6.83. Found: C, 66.17; H, 6.99.

(1S)-I-[ (2R)-Chroman-2-yl]-2-methylpropane-l,2-diol (39):



gel column chromatography (30% ethyl acetate in hexane) afforded 39 (0.152 g, 83%)

9H as a colorless oil. [a.f50 -93.75 (c 2.04, CHCh). Rf 0.52 o -CC)'fOH

39

(60% ethyl acetate in hexane). IR (Neat): 3555, 3015,

2933,2362,1583,1489,1388,1231,1090,756 em-I. IH

NMR (300 MHz, CDCh): 87.10-7.04 (m, 2H), 6.89-6.75

(m, 2H), 4.32-4.27 (m, IH), 3.33 (d, IH, J = 6.5), 2.91-2.78 (m, 4H), 2.24-2.23 (m,

IH), 1.93-1.86 (m, IH), 1.38 (s, 3H), 1.32 (s, 3H). DC NMR (75 MHz, CDCh): 8

153.9, 129.7, 127.2, 122.1, 120.9, 116.6,77.5, 76.4, 73.1,26.6,26.5,24.8,24.7. MS

(ESI): mlz 246 [M+Nat. Anal. Calcd for C13HI80 3: C, 70.24; H, 8.16. Found: C,

70.11; H, 8.40.

(2R,3S)-S-(2-Benzyloxyphenyl)-3-(tert-butyldimethylsilanyloxy)-2-(toluene-4-

sulfonyloxy)pentanoic Acid Ethyl Ester (40):




G(:0Bn I ~ OTs

/5- C02Et 40 OTBDMS

colorless semi-solid. R/ 0.58 (20% ethyl acetate in

hexane). [0.]25 0 +1.2 (c 2.10, CHCI3). IR (KBr): 3022,

2932,2362,1741, 1599, 1372, 1216,758,699 em-I. IH

NMR (300 MHz, CDCh): 87.77 (d, 2H, J = 8.2), 7.44-

7.24 (m, 7H), 7.17-7.07 (m, 2H), 6.90-6.86 (m, 2H), 5.06 (s, 2H), 4.88 (d, IH, J =

3.9),4.07-3.94 (m, 3H), 2.70-2.65 (m, IH), 2.54-2.50 (m, IH), 2.40 (s, 3H), 1.93-1.90

(m, IH), 1.80-1.68 (m, IH), 1.13 (t, 3H,J= 7.1), 0.79 (s, 9H), -0.07 (s, 3H), 0.076 (s,

3H). I3C NMR (75 MHz, CDCh): 6167.4, 156.4, 144.8, 137.3, 133.5, 129.9, 129.8,

202


129.6, 1285, 128.1, 127.7, 127.2, 120.7, 111.5, 79.4, 72.1, 69.8, 61.5, 33.0, 25.8,

25.6,21.6, 17.9, 13.8, -4.6, -4.9. MS (ESI): mlz 636 [M+Nat, 631, 613. Anal. Calcd

for C33H4407SSi: C, 64.67; H, 7.24. Found: C, 64.81; H, 7.19.

5.1.6 References

1. For recent reviews, see: (a) Weber, L. Curro Opin. Chem. Bioi. 2000, 4, 295.

(b) Wessjohann, L. A. Curro Opin. Chem. Bioi. 2000, 4, 303. (c) Hall, D. G.;

Manku, S.; Wang, F. J Comb. Chem. 2001, 3, 125. (d) Ganesan, A. Pure

Appl. Chem. 2001, 73, 1033. (e) Breinbauer, R.; Vetter, I. R.; Waldmann, H.

Angew. Chem., Int. Ed. 2002,41,2878.

2. (a) Schreiber, S. L. Science 2000, 287, 196. (b) Abel, U.; Koch, c.; Speitling,

M.; Hansske, F. G.; Curro Opin. Chem. BioI. 2002, 6, 453. (c) Liao, Y.; Hu,

Y.; Wu, 1.; Zhu, Q.; Donovan, M.; Fathi, R.; Yang, Z. Curro Med. Chem.

2003, 10, 2285. (d) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed.

2004,43,46. (e) Kim, Y.; Arai, M. A.; Arai, T.; Lamenzo, 1. 0.; Dean, E. F.,

III; Patterson, N.; Clemons, P. A.; Schreiber, S. L. JAm. Chem. Soc. 2004,

126, 14740. (0 Ortholand, 1. Y.; Ganesan, A. Curro Opin. Chem. Bioi. 2004,8,

271. (g) Boldi, A. M. Curro Opin. Chem. Bioi. 2004, 8, 281. (h) Tan, D. S.

Comb. Chem. High Through. Screen. 2004, 7, 631.

3. Mishra, 1. K.; Panda, G. J Comb. Chem. 2007,9,321.

4. Mishra, 1. K.; Panda, G. Synthesis 2005, 1881

5. Mishra, 1. K.; Garg, P.; Dohare, P.; Kumar, A.; Siddiqi, M. I.; Ray, M.;

Panda, G. Bioorg. Med. Chem. Lett. 2007,17, 1326.

6. (a) Ishii, H.; Ishikawa, T.; Sekiguchi, H.; Hosoya, K. Chem. Pharm. Bull.

1973, 21, 2346. (b) Asahara, T.; Sakakibara, 1.; Okuyama, T.; Shibata, S.

Planta Med. 1984,50, 488. (c) Alami, 1.; Clerivet, A.; Naji, M.; Van Munster,

M.; Macheix, 1. 1. Phytochemistry 1999, 51, 733.

7. Rajendran, K.; Mesta, C. K.; Paknikar, S. K.; Bhattacharyya, S. C. Indian J

Chem. 1970,8,200.

203

Chapter 5. Enantiose/ectlve Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocyc/es

8. (a) Takashima, J.; Ohsaki, A. J. Nat. Prod. 2002,65, 1843. (b) Takashima, J.;

Ohsaki, A. 1. Nat. Prod. 2002,65, 1843. (b) Yin, S.; Fan, C.; Wang, Y.; Dong,

L.; Yue, J. Bioorg. Med. Chern. 2004, 12,4387.

9. (a) Ito, c.; Katsuno, S.; Kondo, Y.; Tan, H. T.; Furukawa, H. Chern. Pharrn.

Bull. 2000,48, 339. (b) Itoigawa, M.; Ito, C.; Tan, H. T.; Okuda, M.; Tokuda,

H.; Nishino, H.; Furukawa, H. Cancer Lett. 2001, 174,135.

10. Jarvis, B.B.; Pena, N.B.; Comezoglu, S.N.; Rao, M.M. Phytochernistry 1986,

25,533.

11. (a) Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G.; Fronczek,

F.R. Tetrahedron Lett. 1993,34, 1999. (b) Macias, F. A.; Molinillo, 1. M. G.;

Varela, R. M.; Torres, A.; Fronczek, F. R J. Org. Chern. 1994,59, 8261. (c)

Zhang, 1.; Wang, X.; Wang, W.; Quan, W.; She, X.; Pan, X.; Tetrahedron

2007,63,6990.

12. Fleming, P. R.; Sharpless, K. B.; J. Org. Chern. 1991,56,2869.

13. (a) Chandrasekhar, S.; Sultana, S. S.; Kiranmai, N.; Narsihmulu, C.

Tetrahedron Lett. 2007, 48,2773. (b) Pearson, A. J.; Heo, J.-N. Tetrahedron

Lett. 2000,41,5991. (c) Chun, J.; He, L.; Bittman, R. J. Org. Chern. 2000,

65, 7634. (d) Luzzio, F. A.; Thomas, E. M.; Figg, W. D. Tetrahedron Lett.

2000,41, 7151. (e) Boger, D. L.; Schule, G. J. Org. Chern. 1998,63,6421. (f)

Rao, A.V. R.; Chakraborty, T. K.; Reddy, K.L.; Rao, A.; S. Tetrahedron Lett.

1994, 35, 5043.

14. (a) Rao, A. V. R.; Rao, S. P.; Bhanu, M. N. J. Chern. Soc., Chern. Cornrnun.

1992, 859. (b) Ziegler, F. E.; Wang, Y. J. Org. Chern. 1998, 63, 7920. (c)

Gogoi, S.; Barua, N. C.; Kalita, B. Tetrahedron Lett. 2004,45,5577.

15. Khadem, S.; Joseph, R.; Rastegar, M.; Leek, D. M.; Oudatchin, K. A.; Arya,

P. J. Cornb. Chern. 2004, 6, 724.

16. (a) Zou, Y.; Lobera, M.; Snider, B. B. J. Org. Chern. 2005, 70, 1761. (b)

Snider, B. B.; Wu, X. Heterocycles, 2006, 70, 279.

17. Kolb, H. c.; VanNieuwenhze, M. S.; Sharpless, K. B. Chern. Rev. 1994, 94,

2483.

18. Chang, c.-Y.; Kuo, S.-c.; Lin, Y.-L.; Wang, J.-P.; Huang, L.-J. Bioorg. Med.

Chern. Lett. 2004, 14, 2797.

204

Chapter 5. Enantloselective Synthesis of Natural Proc/uct-Uke Benzo-Annulated Oxa-Heterocycles

19. Quideau, S.; Pouysegu, L.; Oxoby, M.; Looney, M. A. Tetrahedron, 20(H, 57,

319.

5.1. 7 Spectra

!glil~~~~~~~~!~!!~~i~~ ~~~; ~l~~~~~~~~~~ '~';';';\'~~~.;, \~ ~

i i i i i i i i i , i i i i i 9":': •.. ... LO ;.1 ;_0 6.S ..• " S.O ... ~ , .. .. H ~ .. :05

'--l~n~( ~'nY('-rl"'( , ,-' _, <:. 1,;; ~, I~I -, ~. 1- -

i i , :.0 " I.'

~l

i i 05 ...

NOB~H ~C02Et

OH 12.

Figure 5.1.3 J H NMR (CDCI3, 300 MHz) spectrum of 12a.

180 160 i

140 12U 100 80 i

60 i

40 10

N "-~ .• => :i.

i o

('yOB~H ~C02Et

OH

12.

Figure 5.1.4 J3C NMR (CDCl3, 75 MHz) spectrum of 12a.

205

Chapter 5. Enantloselectlve Synthesis of Natural Product-Llke Benzo-Annu/ated Oxa-Heterocyc/es

OBn rllr~JTS "-~C02EI

OH

I 7

Id~13)~1

I I

I~\ 1.01

Figure 5.1.5 I H NMR (CDCh 300 MHz) spectrum oj J3a .

........ ". ~ _.,:;..:...: ""': x"':'-

.r.::-,;,: -:00::'" Z"" -? '"' =- 1- .....

13.

~~~;:;;;~~sr-·~~~:;~ ., . ..,. . .,: ... ::'"::-::Ie 7.: ,- ,-....: --

~:!:!:,.~~~~:!~~~=

I I OBn

CQ, "" OTs

// "Co,EI

I i _l .. J

Ii' I I '

I I ,I I !. 1.

1 I I, ,~""""""",,,,,,,,,,_-,-,,_,,,,,,,,,--'w......)........

·~;-·--T-~¥-,--r----:----"""--r-----r----T---.---r---r-·-"""'----,-----,~~

J~O 160 150 J 40 DO no no 100 90 80 Of, 6(' ,,0 40 ~O 20 ppm

Figure 5.1.6 /3C NMR (CDCh 75 MHz) spectrum oj J3a.

OH 13.

206


'3C -.; v • ..,. -= ,-~ r-, ." ." Qf:fi3::;~~;;;::~ ~~;~~~ ,... f""' ,.. ,.. ,..~ =- -=- -=- ~ eo =-"""'.'".,.., • -: ,..: ,-: r-: ,-: ..c ..i; .¢ .i ......

.."...".-T"'T"T-r v V~)

_U~J

::= 1"1"".,.- ,- "" "'"'I-:lIe .... ",,!""1"'!e" • ---c

,....~-.-.-.-,,~~~, ~~"T'. ~""''''~~''--'~'-''~~~I~~-'-''-I ~~

7654 1 o ppm

(~II~( I~r l§( (~1 r~I~1 (~I

Figure 5.1.7 iH NMR (CDCl3, 300 MHz) spectrum o/15a .

~ ~ ....; ...:: .,. ,..~ .r-. ""T r- <: v.1;JC -r - ...:;:: 1-" r .. ;r.;

:! .- ~ :;= "" :t ~ ~ ~ ;t'~ ~~~ ;~t::l ~:! :; "'. =' ==,..:.,.: ~.: '1'. "T C ~ tr:...:::: .-e; v. ~~~~= ~ r::: ~~~ ;..r; ~~ =t~

I I l I I I

I t, \ \ )) I I i I

l } \\! / \¥ Y \r ( \ I

.....---.---,·---.----,--.-T-............... --,----.-I--,---,-~-·-·r~·---~__,-·-.........-__r_ so 160 140 120 100 80 60 40 20 0 -20 I

Figure 5.1.8 i3C NMR (CDCh 75 MHz) spectrum 0/15a.

("'yQ,:.~ C~Et

15a OTBDMS

0} I // '. C~Et

15a OTBOMS

207

Chapter 5. EnantJoselect/ve Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocycles

E~=~M~CC.E~M-=~~~.=.E~M ••• -~.=~"'~ •• -. ~~~~~~~~~~=~3~~.~~~~3~~~~=a&~3~~~~~3~ :.c;: ~ '7i ~ 0': ": or: ": ": ""': ""': "1 "'l -: -: r! e, ~ -: -: "'1 .... ! "1 "1 ""'! "1 ""'! 1': .. '! ... ~ r: : "'1 -: -c: "! ... ! (. ~" to. I_ t-· 1_ ,- ,. 1-, ,-. ,-. I· {,_, _ t-. 1- ..: ..;; v . ..... ...,..." .." ...,. ..,. ..,. -r ..... ...,. .......... - - - e e e

r

jJj r

-' \----, '---

, , , 1J 10 S 6 4 1 0 ppm

(~1~131 ~~) I~I ';"'1 ::; (!'~H~I~ 1:' :: :;:;!

I 'CO;,Et

~q

I ""J OTBDMS 15b

Figure 5.1.9 IH NMR (CDCl3, 300 MHz) spectrum ofI5h.

I I

I I

::-". =-- - e _..,. '="'..,. ~I'---~-="'-"'::

=~a~~s~~~

~~~~:;~~~~ V~II'):;) ~ ,J 1/, ~\ii0(,

hl! H 1

'I I I I I

.----,----, 180 160 140

I \ I

-" --.,------,-'---, 80 60 40 20

I J \i d

I o'-CO;,Et mo

I ~/ OTBDMS l5b

-20 ppm

Figure 5.1.10 /3C NMR (CDCh 75 MHz) spectrum of I5h.

208

Chapter 5. Enantlose/ectlve Synthesis of Natural Procluct-Uke BenzcrAnnulated Oxa-Heterocyc/es

~'" - ~. ".r-, ""1"1

\ I I

~'~~~~~~~~~~~~~~~~~~

8

CC~"'~OH 17. OH

Figure 5.1.11 IH NMR (CD3COCD3, 300 MHz) spectrum o/17a.

QC -:; or,- .' ~; "'''" ..e- -.,. f"tX - '::'<..:;J- Gql '" ~~~~ ..,

3 ~ ~ ~E: g~i~~n3;;~ I "+OH t;~-:~~"'t:-:=:r;

'" :!:2~:: = ~ ;!~ ;::;;:;;:;~~~~~~ .b \ \ I ) ) I I \ I l,~// 17a OH

\ /1 I. I \1

i -'+-}-_ .• ---"-- ·--r-..--.'--.--,--...--"I----.---r'---.---.,-----,-----.-r------

!OO ISO 160 ]40 110 100 30 60 40 20 PI'"

Figure 5.1.12 /3C NMR (CD3COCD3, 75 MHz) spectrum o/17a.

209

Chapter 5. Enantloselectlve Synthesis of Natural Product-Uke Benzo-Annulatecl Oxa-Heterocyc/es

$0 I

I h ) .. 'tOH

I/, OH 17b

!Ie :Ie r- t- r-- ,~ I' r- J' ' ..... f"- ,- ,... t, ... ,... ~. ".

L--~~~~~/,;q:b;;~/-~;~/

, , , 8 • 4 1

I I '-- ~ \ ; "- ) , II~( ~I~ 1=11'" "T lsi ~II~I :'~! !~

Figure 5.1.13 /H NMR (CD3COCD3, 300 MHz) spectrum of17b .

ii, ,c f.

i ~ ,~,

.., ,~ I' 1"- .." ~

_ oe: _ 1-·

~ ~i!!fr;

3g55 -= ~,(\

'\~\

, ... ,.l oj, ..

.' "f"'!"

~::Ie >.,,; r ~. ~ -.c eo. t-- _ ~ __

~ f.:;:: ~:t! ~~~~~:;~~~ ..,. .... 4"'1.,-,., "'I "'.- ;i ~:;:;;~~~~~~A ,1,/ )

"~~~/ Ii- / (( (

"'T--··~l~--T--~-r--'--~-~---'-~----r~ --,-~~,.---

~Ol) I so J61l un 1211 t Of) xn 4(1 zn PI

$1 I ""~OH h \

I h OH 17b

Figure 5.1.14 /3C NMR (CD3COCD3, 75 MHz) spectrum of 17b.

210


~~~'~~~~~~~~~~~~ij~~~~~IJ~i~~~_~~~~I~~i~i~iij~~~~II~i~j~~~~! ~~g#~#~?·~~'7!~1

I ,

I.E- SJl

'" '" ;;t; ~

I

180

I I i I I , j iii I i f

'.J. :.0 u: 6.(1 F.! FA u: 4.0 ~s 3.. !,S :.0 u: l.O O..f

]~Ih;(~( L~( 1~( ]§( \~!I§( 'l!1

Figure 5.1.15 IH NMR (CDCl;, 300 MHz) spectrum 0/24.

~

~

I

I 160

""l<..;X''''t-or,-',.e-'-=~;el"");e,...,:--..,\C

~~~;~~~~~ ~~~~:!~:!~=

\~!))// 0li (

140 I

120 I

100

-...;..:: r- _ ...... x r.~X;1i!:.!:tM '"':: :: "I fA:! ~ r-; =: I·~"""..c::- - I¢ r( r- r- r- ~.,.; .... t"

\JII

I 80

\ \

I 60

I

I 40

,-~ ~

I

I 20

(X0Bn ~ i/y -;

I 24 C02Et

Figure 5.1.16 /3C NMR (CDCh 75 MHz) spectrum 0/24.

211


~"'--""-l·~"""''''r'''''''''''-'''''''''·''--''''''r-·-'''''-''''''''''''''''''''''''''''-'''''''''''''"",,-··''''''~''''''''''''

S 1 6 :!i ... 3 2 I o ppm

'. I (' --' 'I" '~Il~ ';ii, r;;;;;l 'J.I_ l- "'lo-.I

Figure 5.1.17 iH NMR (CDCl3, 300 MHz) spectrum 0/26.

II ~o .PH I .'

N

26 OH

II: I I I I ill . Ii . ! JU~_._ \ , !

......,--.,.....--.-. - 1""""-"-'-' -,-.. ...,......,-,...,...-,-. I I I I [ i

160 l~O J.40 l~'O l.!() UO )00 ~) SO iO 1 .. 0 ~O ... 0 ~o 21) 11) 0

Figure 5.1.18 i3C NMR (CDCh 75 MHz) spectrum 0/26,

212

Chapter 5. Enantloselectlve Synthesis of Natural Product-Uke Benzo-Annulafed Oxa-Heterocycles

~.=""~~W-.~-W=~~W~~~_~.;.~=;-=~~~.G_=~_

~~~~~~~=~~~~=S5~~~~;~~~~~ri=~=~~S~~~~~~~ -: -: -: ~ =: co:. ~ ~ ~ ~ "t ""t "t ""'t "t f'1: "1 "'"! "1 r~ r! f"t .. ~ "! .... ! ""! f"1 ::; ~ ~ ::-:. ~ ;,q -: '1 "1 ';:: -: -: f- f" r-. I~ r·· '" '..:> ~ ~ ~ ,. .., .,. "'!' .., "T .., .., ~ ..,. ..,. .., ""T "'T ...,. ..,. -t ..., "") .... , .. , ........ , - - - 0 .:. -=

7

'--~ r.-1 i5. 1

\, ) \ )

l~\ I~l

Figure 5.1.19 IH NMR (CDC!;, 300 MHz) spectrum 0/28 .

I 160

,. f r; ...

"

HO

.. G ;;

\

.., x

~ " ~ ~ '" " I • ! ; : / \ I

:i

I

110 I

100

" ~ \

~ >i 2 " ~ '" :f.

~: f f ' I I

\;, (/1 II"

I SO

I 60

, .0

-: -.., ~

I

'" ~ ~.

~~ I

I

I 20

::; .., ii, e roCo,EI :' I';:

\ } ~ OTBDMS 28

\! r

Figure 5.1.20 l3C NMR (CDCl3, 75 MHz) spectrum 0/28.

213


I I I 8 7 6 5 4

I~~~( l~rI~rls( 'lsi \"'( i'~ ... (~~

I o

30

Figure 5.1.21 'H NMR (CD3COCD3, 300 MHz) spectrum 0/30 .

........ e .... ::::-~:2~;e~ '"Y-.:;,e .... 7!

~ ~ ~i ~j ~ - - - --

\\\1/

I I i i I '

I ' I I I -· .... -·--·I·-~-··-·-,---·--I--··-·-l--·-.-1---·---r--·"··· "1 "-", ." .~~--. '-'--"'--r----"--I---\" , 100 180 160 140 110 100 80 60 ~o 20 0 P:

IOH ~oX·"'<.: V'-./ OH

30

Figure 5.1.22 /3C NMR (CD3COCD3, 75 MHz) spectrum 0[30.

214


QH

Q)'f-OH

- \ ___ L--

---~T'-""'~' ~""~~~~~I~~~I' T~~~'~~~'''T'-'~-

7 6 4 J 1 0 ppm

Is( I§n~( ~~( I~I

Figure 5.1.23 IH NMR (CDCl3, 300 MHz) spectrum of39.

-= ...... ,." -..Qo ~. _ r~;. _ .... , 1- = 1- - ~ -.:~, =:. a-- v.

39

OH

~5aE~

\\\// -... ,- - d"-r-"......, ........ " -" t-· =--= ...::....,.;,e ...

~~~~ o "I COr-OH

39

--,.---,.-~ 'r-~-'-j' --........,.-------,-- .. , --"-~'--.-~--'--Y-------IH NO IH WO H 60 40 20 0 PI

Figure 5.1.24 /3C NMR (CDCh 75 MHz) spectrum of 39.

215

Section 58:

Enantiose/ective Synthesis of a 2,3-

Disubstitued 1-Benzoxepine Derivative

216

Chapter 5. Enantloselective Synthesis of Natural Product-Like Senzo-Annulated Oxa-Heterocycles

5.2.1 Introduction

Over the past decades, the design and synthesis of medium ring heterocycles

having a ring size in the range of 7 to 11 received a lot of attention in synthetic

organic chemistry as a consequence of wide variety of applications as biologically

active natural products, drug candidates, materials and for catalysis. Among various

benzo-fused oxa-heterocycles, I-benzoxepines are an important class of structural

motifs because of their wide occurrence in natural products! and their biological

activities.!,2 Thus, synthesis of I-benzoxepine derivatives constitutes an important

objective in modem organic synthesis.3 As part of our research programme in this

field, we sought to develop a synthetic route that could provide enantiomerically pure

natural product like small molecules containing I-benzoxepin frame work.

OH ~

~ Ph~OY-1, Radulanin A

HO~ HO~Hm ~O-/ ~01'" OH I '" 0"

2, Heliannuol 8 roH 3, Heliannuol C 4, Heliannuol 0 l';H

~ 0 H0)Cd· 1.&

o ., 5, Heliannuol H FoH

Figure 5.2.1 Selected natural products 1-5 and our designed target molecule 6 containing

I-benzoxepine ring system.

5.2.2 Basis of the Present Work

In the Section A of Chapter 5, we have described the synthesis of natural

product-like enantiomerically pure 2,3-dihydrobenzofuran and I-benzopyran

derivatives via phenoxide ion mediated intramolecular SN2 displacement of tosyloxy

group. However, this strategy was not successful in the asymmetric synthesis of

corresponding I-benzoxepin derivative possibly due to an entropy factor (Scheme

5.2.1).

217

Chapter 5. Enantlose/ectlve Synthesis of Natural Product-Llke Benzo-Annulated Oxa-Heterocyc/es

(yoBn ~TS (i) H2, Pd-C, EtOA~ ~C02Et (ii) Anhyd. K2C03"

7 OTBDMS dry acetone

,C02Et o .,'

~OH 8, not formed

Scheme 5.2.1 The unsuccessful synthesis of 2-substituted-l-benzoxepine derivative.

The above mentioned unsuccessful synthesis of 2-substituted-l-benzoxepine

derivative prompted us to search for their alternative synthetic route. Cyclic sulfates

have been known for a long time, and the use of these compounds has been the

subject of several reviews.4 They are like epoxides but have higher reactivity.s High

reactivity of these compounds as nucleophile acceptors is well known. While several

synthetic utilization of cyclic sulfates are known, their use for the enantioselective

preparation of heterocycles has not been explored in depth. For example, cyclic

sulfates have only been used as intramolecular O-alkylation substrates for the

construction of tetrahydrofuran and tetrahydropyran rings.6 Although it is well known

that the intramolecular cyclisation of tetrahedral system generally proceeds via an

exo-cyclisation pathway,' the pioneering report6e by Sharpless and co-workers

suggested that the relatively unstrained cyclic sulfate could permit endo cyclization in

preference to exo cyclization. Taking into account of all these facts and our interest in

the asymmetric synthesis of benzoannulated heterocycles, we herein describe our

results that illustrate an efficient enantioselective synthetic route of I-benzoxepine

derivatives through phenoxide ion mediated intramolecular 7-endo-tet SN2 ring

opening of syn-2,3-dihydroxy ester-derived cyclic sulfate derivatives.

5.2.3 Results and Discussion

In our model study, commercially available 4-methoxypheol 9 was chosen as

starting material. Our approach commenced with the allylation of9 with allyl bromide

and anhydrous K2C03 in dry acetone under reflux condition followed by Claisen

rearrangement of the resulting allyl ether 10 producing 5-methoxy-2-allylpheno!8 11,

Scheme l. Next, benzylation of 11 with benzyl bromide and anhydrous K2C03

produced the corresponding benzylated product 12 in excellent yield which on

hydroboration with 9-BBN followed by oxidation with NaOH/H20 2 furnished the

primary alcohol 13 in high yield.

218

Chapter 5. Enantlose/ective SynthesIs of Natural Product-Uke Benzo-Annulated Oxa-Heterocycles

D OH DO~ ~OH fX:0Bn I ~ I ~I ~ I

MeO h- MeO h- . MeO h- '-':::: MeO h- '-'::::

9 10 11

~OBn

L I h- OH

MeO 13

12

Scheme 5.2.2. Reagents and conditions: (a) Allyl bromide, anhyd. K2CO}, dry acetone,

reflux, 3h, 98%. (b) 180°C, 6h. 85%. (c) BnBr, anhyd. K2CO}, dry acetone, reflux, 4h, 95%.

(d) (i) 9-BBN, dry THF, OOC-rt, 4h. (ii) NaOHIH20 2, reflux, 2h, 94%.

With the ready availability of 13, attention was turned to its elaboration into

cyclic sulfate derivative (Scheme 5.2.3). Towards that objective, alcohol 13 was

oxidized to aldehyde 14 by PCC in dry CH2Ch. Next, Wittig olefination of 14 with

(carbethoxymethylene) triphenylphosphorane in dry CH2Ch at room temperature

furnished the corresponding trans unsaturated ester 15. Subjection of 15 to Sharpless

asymmetric dihydroxylation9 with AD mix ~ in tBuOH-H20 (1:1) at O°C for 25 h

furnished enantiopure dihydroxyl derivatives 16 in good yield and high enantiomeric

excess (90%, ee >99%; determined by chral HPLC analysis).

Treatment of diol16 with thionyl chloride and triethylamine in CH2Ch gave

cyclic sulfite 17, which was further oxidized using NaI04 and a catalytic amount of

ruthenium trichloride to furnish the corresponding cyclic sulfate 18 in high yield.

£(:OBn ~OBn 13~ I ~ I ~

MeO h- CHO MeO h- // C02Et 14 15

~Bn OBn

I ~ 9H L ~~ C02Et ~ ~

MeO =- C02Et MeO : 0 16 OH 17 O-SO

r(YoBn <;;c ~~2Et MeO : 0

18 0-S02

Scheme 5.2.3. Reagents and conditions: a) PCC, dry CH2Ch, 3h, OOC-rt, 76%. (b)

Ph}P=CHC02Et, dry DCM, rt, overnight, 80%. (c) AD mix ~, MeS02NH2, t-BuOH/H20 I: I,

o °c, 24 h, 95%; (d) SOCh, Et3N, CH 2Ch, 0 °c, 20 min (e) RuCh, NaI04 , MeCN-H20; 1:9,

o °c, 10 h, 90% (for the last two steps).

219

Chapter 5. Enantlose/ective Synthesis of Natural Product-Llke Benzo-Annulated Oxa-Heterocyc/es

With cyclic sulfate 18 in hand, we turned our attention to phenoxide Ion

mediated intramolecular cyclic sulfate ring opening reaction (Scheme 5.2.4).

Accordingly, 18 was first debenzylated under H2/l 0% Pd-C condition to furnish the

corresponding phenolic derivative, which was treated with anhydrous K2C03 in dry

acetone without purification and then subsequently with 20% H2S04 in THF .11 a After

extensive NMR studies eH, I3C, COSY, HMBC, HSQC), we were very delighted to

observe the final cyclic product as I-benzoxepine skeleton 20 rather than 1-

benzopyran ring system 19.

MeO

Scheme 5.2.4. Reagents and conditions: (a) H2, 10%Pd-C, EtOAc, 8 h, 89%. (b) (i) anhyd.

K 2CO}, dry acetone, rt, 8h. (ii) 20% H2S04, THF, rt, overnight, 70% (for two steps). (c)


IH NMR Spectrum of20 showed the presence of two multiplets at 6 2.34-

2.25 and 1.65-1.52 attributable to the protons H-4a and H-4b and another multiplet at 6

2.89-2.65 due to two H-5 protons. H-3 appeared as a mUltiplet at 6 4.l8-4.11 whereas

the proton H-2 showed a doublet at 6 3.85 (J = 9.2). The presence of the -OH group

was indicated by a broad singlet at 6 3.11. The above attribution of various protons

was done by incisive analysis of COSY spectrum of 22. Based on the coupling

observed in the HSQC spectrum of 20, ring carbons appearing at 6 83.9, 71.9, 33.4

and 28.0 were attributed to C-2, C-3, C-4 and C-5, respectively. Similarly, the signals

at 6 61.6, 55.4, and 14.0 were assigned to the -OCH2CH3, -O~.H3 and -OCH2~H3

respectively. Finally, six signals at 6 156.0, 151.9, 135.6, 121.8, 115.0, and 112.1

were assigned to the aromatic carbons C-7, C-I0, C-ll, C-8, C-6 and C-9. In the

HMBC spectrum of 22, H-2 [63.85 (J = 9.2)J showed coupling with ~=O (6 170.7),

C-3 (671.9), C-4 (6 33.4) and C-lO (6 151.9), Figure 2. The long range coupling of

H-2 with C-I0 confirmed our hypothesis of I-benzoxepine ring formation over 1-

benzopyran ring formation as this coupling would not be possible in case of 19.

220

Chapter 5. Enant/ose/ectlve Synthesis of Natural Product-Uke BenzC>-Annulated Oxa-Heterocyc/es

Again, had the cyclic product been 19, the proton [64.18-4.11 (m, lH)] would have

shown long range coupling with the aromatic carbon atom [C-9 (6 151.9) and

carbonyl carbon (6 170.7) in structure 19) which is completely absent in the HMBC

spectrum. Thus, the l-benzoxepine structure 20 was confirmed.

,/~X H OH 8 I \\

~! 0 1/, .' CO Et 2 H 2

3 (64.18-4.11) ....-;:; MeO 6 10

19 20

Figure 5.2.2. Coupling of H-2 in the HMBC spectrum of 17c.

The preferential formation of l-benzoxepine derivatives (via 7 -endo-tet

cyclisation) over l-benzopyran derivative (via 6-exo-tet cyclisation) can be explained

on the basis of the higher reactivity of a-carbon due to the presence ester group. This

is in complete agreement with the well-known fact that in case of a,~-dihydroxy ester

cyclic sulfates, nucleophilic attack occurs at the a-position almost exclusively.4b To

the best of our knowledge this is the first use of a,~-dihydroxy ester cyclic sulfates in

benzo-annulated heterocycle synthesis. Finally, treatment of 20 with an excess of

methylmagnesium iodide furnished the tertiary alcohol 21 in high yield.

5.2.4 Conclusion

In conclusion, we have achieved an asymmetric synthesis of a natural product

like 2-substituted l-benzoxepine derivative. Key steps include Sharpless asymmetric

dihydroxylation reaction on suitable a,~-unsaturated ester and construction of the 1-

benzoxepine nucleus by phenoxide ion-mediated intramolecular ring opening of 7-

endo-tet a,~-dihydroxy ester cyclic sulfate. The ease of the reaction sequence, as well

as high yields of all the steps, makes this process an efficient method for the

preparation of 2-substituted I-benzoxepine derivatives. To the best of our knowledge

this is the first use of a,~-dihydroxy ester cyclic sulfate in benzo-annulated

heterocycle synthesis.

5.2.5 Experimental Section

5.2.5.1 General Remarks

As described in the previous section ofthis chapter.

5.2.5.2 Synthesis of compounds

Compound 11 was synthesized by known method. 8

221


3-Allyl-4-benzyloxyanisole (12):

To a solution of 11 (4.0 g, 24.36 mmol) in dry acetone (50 mL) was added

anhydrous K2C03 (5.0 g, 36.17 mmol) and benzyl bromide (2.9 mL, 24.36 mmol) and

refluxed for 4 h. The mixture was then filtered through celite and the filter cake was

well washed with acetone (100 mL). The filtrate was concentrated and the resulting

residue was redissolved in ethyl acetate (100 mL), washed with water (2x50 mL) and

brine (50 mL). The organic layer was dried over anhydrous Na2S04, filtered, and then

concentrated under vacuo. Purification of the crude product by silica gel column

chromatography (2% ethyl acetate in hexane) afforded 12 (5.88 g, 95%) as a colorless

oil. Rj. 0.52 (5% ethyl acetate in hexane). IR (Neat): 2924, 2362, 1639, 1495, 1558,

1216,1043,731,693 em-I. IH NMR (200 MHz, CDCh): 87.40-7.29 (m, 5H), 6.84-

6.66 (m, 3H), 6.01-5.92 (m, IH), 5.09 (m, 2H), 5.00 (s, 2H), 3.73 (s, 3H), 3.42 (d, 2H,

J = 6.5). I3C NMR (75 MHz, CDCh): 8154.2, 151.0, l38,0, l37.2, l30.8, 128.9,

128.1, 127.6, 116.5, 116.2, 113.5, 111.7, 78.1, 71.2, 56.0, 35.0. MS (ESI): mlz 254

[Mr, 91 [C6H5CH2t. Anal. Calcd for CJ7HIs02: C, 80.28; H, 7.l3. Found: C, 80.35;

H,7.32.

3-(2-Benzyloxy-S-metboxypbenyl)-propan-1-ol (13):

To a stirring solution of 12 (4.0 g, 15.72 mmol) in anhydrous THF (30 mL) was

added a 0.5 M THF solution of 9-BBN (47 mL) dropwise under a nitrogen

atmosphere at 0 °C and the mixture was stirred at room temperature overnight. H20 (5

~OBn mL) was added followed by 3 N NaOH solution

I (40 mL) and 30% aqueous hydrogen peroxide solution MeG a OH

13 (30 mL). The reaction mixture was stirred for 2 hat 50

°C. The mixture was extracted with ethyl acetate (2x50

mL), washed with water (150 mL) and brine (150 mL). The combined organic layer

was dried over Na2S04, filtered and concentrated under reduced pressure. Purification

of the crude product by silica gel column chromatography (8% ethyl acetate in

hexane) afforded alcohol 13 (4.02 g, 94%) as a colorless gum. Rj. 0.32 (20% ethyl

acetate in hexane). IR (Neat): 3431,2929,2361, 1497, 1214, 1042, 756, 698 em-I. IH

NMR (200 MHz, CDCh): 8 7.44-7.34 (m, 5H), 7.85 (d, IH, J = 8.7), 6.76-6.66 (m,

2H), 5.02 (s, 2H), 3.75 (s, 3H), 3.57 (t, 2H,J= 6.3), 2.74 (t, 2H,J= 7.2),1.88-1.70

(m,2H), 1.77 (s, br, IH). l3C NMR (75 MHz, CDCb): 8154.3, 151.3, 137.7, l32.3,

129.0, 128.3, 127.7, 116.8, 113.5, 111.6, 71.5, 62.1, 56.0, 33.4, 26.7. MS (ESI): mlz

222

Chapter 5. Enantlose/ectlve Synthesis of Natural Product-Like Benzo-Annulated Oxa-Heterocyc/es

272 [Mt, 255 [M-OHt, 91 [Ct;H 5CH2t. Anal. Calcd for C17H200 3: C, 74.97; H,

7.40. Found: C, C, 74.88; H, 7.58.

3-(2-Benzyloxy-5-methoxyphenyl)propionaldehyde (14):

To a stirring solution of 13 (3.0 g, 11.01 mmol) in anhydrous dichloromethane

(50 mL) was added 4 A molecular sieve (3.85 g) and PCC (3.20 g, 14.84 mmol) at

o °C and the mixture was stirred at room temperature for 5h. After evaporating

dichloromethane the reaction mixture was diluted with

J)::0Bn ether (50 mL) and filtered through a small pad of silica

I ,'l gel. Concentration of the filtrate and purification of the MeO CHO

14 residue by silica gel coloumn chromatography (4% ethyl

acetate in hexane) afforded 14 (2.26 g, 76%) as a colotless gum. IH NMR (200 MHz,

CDCb): 09.69 (t, IH, J = 1.5), 7.36-7.29 (m, 5H), 6.81-6.64 (m, 3H), 4.96 (s, 2H),

3.68 (s, 3H), 2.93 (t, 2H, J = 7.3), 2.70-2.63 (m, 2H). l3C NMR (50 MHz, CDCb): 0

202.5, 154.2, 151.1, 137.8, 130.8, 129.0, 128.3, 127.6, 117.4, 113.3,112.3, 71.0, 56.0,

44.3,24.0. MS (FAB): mlz 270 [Mr'. Anal. Calcd for C17HI803: C, 75.53; H, 6.71.

Found: C, 75.63; H, 6.88.

(2E)-5-(2-Benzyloxy-5-methoxyphenyl)-pent-2-enoic Acid Ethyl Ester (15):

To a solution of 14 (2.0 g, 7.39 mmol) in dichloromethane (30 mL) was added

(carbethoxymethylene)triphenylphosphorane (3.21 g, 9.21 mmol) at room

temperature. The reaction mixture was stirred at room temperature for overnight.

Solvent was removed under reduced pressure and

the residue was purified by silica gel column

chromatography (4% ethyl acetate in hexane) to

afford 15 (2.01 g, 80%) as a colorless gum. IR

(KBr): 2926, 2359, 1708, 1649, 1496, 1211, 1035,

736 cm· l. IH NMR (300 MHz, CDCh): 57.37-7.22 (m, 5H), 7.04-6.94 (m, IH), 6.77-

6.60 (m, 3H), 5.79 (d, IH, J = 15.6),4.93 (s, 2H), 4.14-4.07 (m, 2H), 3.65 (s, 3H),

2.77-2.72 (m, 2H), 2.48-2.41 (m, 2H), 1.20 (t, 3H, J = 7.1). I3C NMR (75 MHz,

CDCb): 5166.1, 153.4, 150.3, 148.1, 137.2, 130.5, 128.1, 127.3, 126.7, 121.2, 115.9,

112.4,110.9,70.1,59.6,55.0,32.1,28.8, 13.9. MS (FAB): mlz 340 [Mr. Anal. Calcd

for C21H2404: C, 74.09; H, 7.11. Found: C, 74.21; H, 7.03.

(2S,3R)-5-(2-Benzyloxy-5-methoxyphenyl)-2,3-dihydroxypentanoic Acid Ethyl

Ester (16)

223

Chapter 5. Enantloselective Synthesis of Natural Product-Llke Benz(;Annulated Oxa-Heterocycles

To a stirred solution of tert-butyl alcohol (17 mL) and water (22 mL) were added

AD mix ~ (6.2 g) and methanesulfonamide (0.42 g, 4.4 mmol) at room temperature.

The mixture was vigorously stirred at room temperature until both phases were clear

and then cooled to O°c. A solution of cinnamate ester 15 (15 g, 4.4 mmol) in ter/-

butyl alcohol (5 mL) was added O°c. The

reaction was stirred at the same temperature for

28 h. The reaction was quenched at O°C by the

addition of sodium sulfite (6.5 g), warmed to

room temperature, and further stirred for 1 h. The reaction mixture was then extracted

with ethyl acetate (3x50 mL). The combined organic layer was washed with aq. 2 N

KOH solution (50 mL), water and brine. The organic layer was dried over anhydrous

Na2S04, filtered, and then concentrated under vacuo. Purification of the crude product

by silica gel column chromatography (25% ethyl acetate in hexane) furnished 16 as a

colorless gum (1.56 g, 95%). [af5D +25.9 (c 3.91, CHCh). The enantiomeric excess

was estimated to be >99% by chiral HPLC analysis (instrument: HPII00, column:

LichroCART Chiradex column 250 mm x 4 mm, 5 !lm), flow rate: 0.5 mL/min,

detection: UV 254 nm, eluent: methanol/H20). IR (KBr): 3438, 2937, 2362, 1733,

1633,1499,1217,756 em-I. IH NMR (300 MHz, CDCh): 87.41-7.26 (m, 5H), 6.83-

6.76 (m, 2H), 6.69-6.65 (m, 1H), 5.00 (s, 2H), 4.25-4.18 (m, 2H), 4.04 (dd, 1H, J I = 1.80, J2 = 5.5),3.86 (s, br, 1H), 3.73 (s, 3H), 3.21 (d, 1H, J= 6.0), 2.87-2.69 (m, 2H),

2.43 (d, 1H, J = 7.4), 2.01-1.80 (m, 2H), 1.25 (t, 3H, J = 7.1). I3C NMR (75 MHz,

CDCh): 8 173.4, 153.7, 150.6, 137.3, 131.6, 128.4, 127.7, 127.1, 116.2, 113.0, 111.2,

73.2, 71.7, 70.8, 61.7, 55.5, 33.8, 26.4, 14.0. MS (FAB): mlz 374 [Mt. Anal. Calcd

for C21 H260 6: C, 67.36; H, 7.00. Found: C, 67.48; H, 7.l1.

(2S,3R)-5-[2-(2-Benzyloxy-5-methoxyphenyl)-ethyIJ-2,2-dioxo-216-

[1,3,2Jdioxathiolane-4-carboxylic Acid Ethyl Ester (18):

To an ice cooled stirring solution of diol16 (l.0 g, 2.67 mmol) in dry CH2Cb (15 mL)

and anhydrous Et3N (l.48 mL, 10.62), was dropwise added thionyl chloride (0.3 mL,

4.12 mmol). The reaction mixture was stirred for

20 min and then quenched by adding water

(10 mL). The phases were separated and aqueous

phase extracted with CH2Cb (3 x 20 mL). The

combined organic phases were dried over Na2S04

224

Chapter 5. Enantlose/ectlve SynthesIs of Natural Product-Like Benzo-Annulated Oxa-Heterocycles

and concentrated. The residue was dissolved in CH3CN (10 mL)-and CCl4 (10 mL)

and resulting solution cooled with an ice-water bath. Next, RuCh'H20 (5 mg,

0.024 mmol) and NaI04 (1.23 g, 5.66 mmol) were added followed by water (10 mL).

The resulting orange mixture was stirred at room temperature for 10 h. The mixture

was then diluted with ether (50 mL), and the two phases separated. The organic layer

was washed with water (30 mL), saturated aq NaHC03 (20 mL), brine, dried over

Na2S04, and concentrated under reduced pressure. Purification of the crude product

by silica gel column chromatography (15% ethyl acetate in hexane) furnished 18 as a

colorless gum (0.97 g, 84%). [a]25D +45.4 (c 2.07, CHCh). IR (KBr): 2928, 2361,

1497,1217, 1040,761 cm-I. IH NMR (300 MHz, CDCh): & 7.40-7.30 (m, 5H), 6.87-

6.84 (m, 1H), 6.74-6.70 (m, 2H), 5.02 (s, 2H), 4.96-4.89 (m, 1H), 4.80 (d, IH, J =

7.0),4.24 (q, 2H,J= 7.1), 3.75 (s, 3H), 2.94-2.72 (m, 2H), 2.38-2.18 (m, 2H), 1.25 (t,

3H, J = 7.1). l3C NMR (75 MHz, CDCb): & 164.7, 153.7, 150.6, 137.l 128.9, 128.6,

127.9, 127.2, 116.4, 112.9, 112.0, 83.4, 79.6, 70.6, 63.1, 55.6, 32.9, 26.2, 13.8. MS

(FAB): mlz 436 [Mt. Anal. Calcd for C21H240gS: C, 57.79; H, 5.54. Found: C, C,

57.71; H, 5.68.

(2R,3R)-3-Hydroxy-7 -methoxy-2,3,4,5-tetrahydro-benzo[b ) oxepine-2-carboxyIic

Acid Ethyl Ester (20):

To a stirred solution of 18 (0.9 g, 2.06 mmol) in ethyl acetate (20 mL) was added

10% Pd-C (50 mg). After stirring for 3 h at room

temperature under pressure of a hydrogen balloon, the

reaction mixture was filtered through a pad of Celite®

and the filtrate was concentrated under reduced

pressure to get the corresponding debenzylated product

(0.64 g) as a colorless semi-solid which was used for the next step without further

purification.

To a stirring solution of the above debenzylated product in dry acetone (20

mL), was added anhyd. K2C03 (0.4 g, 2.89 mmol) and the mixture was stirred for 5 h

at room temperature. After removing acetone of the raction mixture under reduced

pressure, the residue was stirred with 20% aq H2S04 (20 mL) and THF (10 mL) for

16 h. The resultant solution was then neutralised with aq. saturated NaHC03 solution

and extracted with ethyl acetate. The combined orgariic phases were washed with

water, brine dried Na2S04, and concentrated. Purification of the crude product by

225

Chapter 5. Enantloselectlve Synthesis of Natural Product-Like Senzo-Annulated Oxa-Heterocycles

silica gel column chromatography (20% ethyl acetate in hexane) furnished 20 as a

colorless semi-solid (0.384 g, 70%). [a]25D +65.38 (c 4.l1, CHCb). IR (KBr): 3434,

2923, 2358, 1648, 1511, 1218, 768 em-I. IH NMR (300 MHz, CDCI3): 0 7.01-6.98

(m, IH), 6.67-6.64 (m, 2H), 4.30 (q, 2H, J = 7.l), 4.l8-4.l1 (m, 1H), 3.85 (d, IH, J =

9.2), 3.75 (s, 3H), 3.11 (s, br, 1H), 2.89-2.65 (m, 2H), 2.34-2.25 (m, IH), 1.65-1.52

(m, IH), 1.35 (t, 3H, J = 7.1). 13C NMR (75 MHz, CDCb): 0 170.7, 156.0, 151.9,

135.6, 121.8, 115.0, 112.1, 83.9, 71.9, 61.6, 55.4, 33.4, 28.0, 14.0. MS (FAB): mlz

266 [Mt Anal. Calcd for CI4HIS05: C, 63.15; H, 6.81. Found: C, 63.31; H, 6.66.

(2R,3R)-2-(1-Hydroxy-l-methyl-ethyl)-7-methoxy-2,3,4,5-tetrahydro

benzo[b]oxepin-3-ol(21):

To a freshly prepared, magnetically stirred, ice-cold suspenSIOn of

methylmagnesium iodide [prepared from methyl iodide (1.2 mL, 14.0 mmol) and

magnesium (0.34 g, 14.0 mmol) in 10 mL of dry ether] was added a solution of ester

MeO 21

20 (0.25 g, 0.93 mmol) in dry THF (10 mL). The

reaction mixture was refluxed for 4 h, cooled, and

quenched with aqueous NH4Cl solution (10 mL).

The mixture was extracted with ethyl acetate (2x25

mL), washed with water and brine. The combined

orgamc layer was dried over Na2S04, filtered and concentrated under reduced

pressure. Purification of the crude product by silica gel column chromatography (40%

ethyl acetate in hexane) afforded 21 (0.206 g, 88%) as a colorless solid. [a]25D +18.4

(c 1.74, CHCh). IR (KBr): 3403, 3019, 2931, 2360,1496,1216,761 em-I. IH NMR

(300 MHz, CDCh): 0 6.86 (d, IH, J = 8.4), 6.65-6.62 (m, 2H), 4.15-4.07 (m, 1H),

3.75 (s, 3H), 3.17 (d, 1H, J = 9.3), 2.86-2.67 (m, 2H), 2.30-2.17 (m, 1H), 1.68-1.56

(m, 1H), 1.47 (s, 3H), 1.39 (s, 3H). 13C NMR (75 MHz, CDCh): 0 155.5, 152.9,

135.4, 120.9, 115.1, 111.9, 89.0, 74.2, 73.0, 55.5, 34.9, 28.8, 28.3, 23.3. MS (FAB):

mlz 252 [Mr, 235 [M-OHt. Anal. Calcd for C14H2004: C, 66.65; H, 7.99. Found: C,

66.77; H, 8.07.

226

Chapter 5. Enantloselectlve Synthesis of Natural Product-Llke BenzoAnnulated Oxa-Heterocycles

5.2.6 References

1. For selected examples, see: (a) Kim, S.; Chin, Y.-W.; Su, B.-N.; Riswan, S.;

Kardono, L. B. S.; Afriastini, 1. 1.; Chai, H.; Farnsworth, N. R; Cordell, G. A.;

Swanson, S. M.; Kinghorn, A. D. J. Nat. Prod. 2006, 69,1769. (b) Macias, F.

A.; Varela, R. M.; Torres, A.; Molinillo, 1. M. G. J. Nat. Prod. 1999, 62,

1639.(c) Wijnberg, J. B. P. A.; van Veldhuizen, A.; Swarts, H. J.; Frankland, 1.

c.; Field, 1. A. Tetrahedron Lett. 1999, 40, 5767 and references therein. (d)

Macias, F. A.; Molinillo, J. M. G.; Varela, R M.; Torres, A.; Fronczek, F. R.

J. Org. Chem. 1994, 59, 8261.(e) McCormic, S.; Robson, K.; Bohm, B.

Phytochemistry 1986, 25, 1723. (f) Asakawa, Y.; Toyota, M.; Takemoto, T.

Phytochemistry 1978,17,2005.

2. For recent examples, see: (a) Lloyd, D. G.; Hughes, R B.; Zisterer, D. M.;

Williams, D. c.; Fattorusso, c.; Catalanotti, B.; Campiani, G.; Meegan, M. J.

J. Med. Chem. 2004, 47, 5612. (b) Shiraishi, M.; Aramaki, Y.; Seto, M.;

Imoto, H.; Nishikawa, Y.; Kanzaki, N.; Okamoto, M.; Sawada, H.; Nishimura,

0.; Baba, M.; Fujino, M. J. Med. Chem. 2000, 43, 2049. (c) Tandon, V. K.;

Singh, K. A.; Awasthi, A.; K.; Khanna, J. M.; Lal, B.; Anand, N.; 2004, 14,

2867.

3. For selected examples, (a) Guo, R.; Portscheller, 1. L.; Day, V. W.;

Malinakova, H. C.; Organometallics 2007, 26, 3874. (b) Roy, A.; Biswas, B.;

Sen, P. K.; Venkateswaran, R.V. Tetrahedron Lett. 2007, 48, 12026 and

references cited therein. (c) Yamaguchi, S.; Tsuchida, N.; Miyazawa, M.;

Hirai, Y. J. Org. Chem. 2005, 70, 7505. (d) Lin, Y.-L.; Kuo, H.-S.; Wang, Y.

W.; Huang, S. T. Tetrahedron 2003, 59, 1277. (e) Kahnberg, P.; Sterner, O.

Tetrahedron 2001, 57, 7181.(f) Gil, M. Y.; Roman, E.; Serrano, 1. A.

Tetrahedron Lett. 2000, 41, 10201.

4. For reviewes of cyclic sulfates, see: (a) Bonini, c.; Righi, G. Tetrahedron

2002, 58, 4981. (b) Byun, H.-S.; He, L.; Bittman, R. Tetrahedron 2000, 56,

7051. (c) Lohray, B. B. Synthesis 1992, 1035.

5. Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988,110, 7538.

6. (a) Lee, T.; Lee, S.; Kwak, Y. S.; Kim, D.; Kim, S. Org. Lett. 2007,9,429. (b)

Defretin, J.; Gieye, c.; Cortes, D.; Franck, x.; Hocquemiller, R.;Figade're, B.

Lett. Org. Chem. 2004, J, 316. (c) van Delft, F. L.; Vaientijn, A. R P. M.; van

227

Chapter 5. Enantlose/ective Synthesis of Natural Product-Llke Benzo-Annulated Oxa-Heterocyc/es

der Marel, G. A.; van Boom, 1. H. J. Carbohydr.Chern. 1999, 18, 191. (d)

Beauchamp, T. 1.; Powers, 1. P.; Rychnovsky,S. D. J. Arn. Chern. Soc. 1995,

117, 12873. (e) Kalantar, T. H.; Sharpless, K. B. Acta Chern. Scand. 1993,47,

307.

7. Baldwin, 1. E. 1. Chern. Soc., Chern. Cornrnun. 1976, 734.

8. Darling, S. D.; Wills, K. D. J. Org. Chern. 1967,32,2794.

9. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.; Chern. Rev. 1994, 94,

2483.

228

Chapter 5. Enantioselective Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocycles

5.2.7 Spectra

liYoBn

Meo~"""'C02Et 15

10

I

6

I~nsn~( I~(

I J

I~I 1~113.1 l~~~(

I I

\ , 1;:'11 !""i

Figure 5.2.3 J H NMR (CDC!;, 300 MHz) spectrum of 15.

\\\11 I //

Ali· Ii I

I I I I I I I 80 170 160 150 140 IJO 120 110

I

100 90

\v! II \ i

~OBn

MeO~CO~t 15

1 L~ I I I

80 70 60 50 40 30 20 10

Figure 5.2.4 13C NMR (CDCh, 75 MHz) spectrum of 15.

229

Chapter 5. Enantlose/ectlve Synthesis of Natural Product-Llke Benzo-Annulated Oxa-Heterocycles

, I I i I I i I Iii t , I I I I .S ,.0 "!.J 7.1.1 6.~ U U ~ U ~ ,~ 3. ~ ~ U IA ~F

I~( ~~( ~~( ~~(I~usni 1§(,D5( \/ i~1

Figure 5.2.5 IH NMR (CDC!;, 300 MHz) spectrum ofl6.

180 160

\ I \ \\V III

140 I

120 100

- ~ c- ~ -,.., _-.-. ~:.!~:;;?~~~ '""': c:; or: ,..! '"':: ~ I~": f::' J.: I'E;::;:: R::;~:

~If/I

I SO 60

I "0

Figure 5.2.6 13C NMR (CDCI3, 75 MHz) spectrum ofl6.

o

, u

230

Chapter 5. Enantloselectlve Synthesis of Natural Product-Llke 8enzo-Annulated Oxa-Heterocycles

, , , , , , , , , , , , , , B , .. .... ., !'_t ~.O ".F .. ~-( 1.' !J: :.0 1_' u .., ... id 'II <----'

, .~( 13.1

~-. -'--..,...,--' W Isll~ I'! or d .,

Figure 5.2.7 IH NMR (CDCh, 300 MHz) spectrum ofl8.

160 I

140 120 I

100

\\\ I) ) ) I '1i'Y ( { I

I 80

I 60

II I

I 20

Figure 5.2.8 J3C NMR (CDCh, 75 MHz) spectrum of18.

231

Chapter 5. EnantloselectJve Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocycles

~ N

~ ;':

J'- LI f r' . j r (

~J~\,--____ -, j~~_j.lJl ~-+-r····+-,.-·--··,·- --_·-t"- . ---" ....... ....,_._. ~1---·--··t---·.......,-·-·-"'T--·-"l-·---·l-'- ._--, .. - --·""f'···'-"··r--·····.....-··· ~l~(-l~[--' u u u '~l!I~"(~t:~ u l:(~~f~"~( ~ l!f"l!J ~ ~, u .u,

Figure 5.2.9 J H NMR (CDC!;, 300 MHz) spectrum 0/20.

0" 1-=.,..' £; e; ,.; ~:!::

\ I I

160

'" '" ~ .;. :::!

I uo

I

co -r • ...; '" '" oe oe

3.~ "" ...

I I

I \

1~O

I JOO

¢'. IT. ,.., ::ae _ .... , r-~

g:~~;2:;~:; .::-- "'T :::: fr. ::-. ...,; "'T

;j~~~~;:::::;~

\\v/ II II CO,EI

('V°-("'OH Meo~

I SO

I

60 I

40 I

20

20

o Pf

Figure 5.2.10 J3C NMR (CDC!;, 75 MHz) spectrum 0/20.

232

Chapter 5. Enantlose/ective Synthesis of Natural Product-Uke Benzo-Annulated Oxa-Heterocycles

J j

I ~

< J ~

~1

--oJ ~ L-- -

I et-- " -t,- It It 2

ID ;., ,. , ! -I' .. . ,

3

• , ,

_ tJ'1 1'" , m .. too 4

. , 5

.. , 6

·-it' ... •

I ~ ..... \ I

, . 7

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

Figure 5.2.11 COSY spectrum 0/20.

MeO~ I O-,l'CO,E1

~ (Y-~\""OH

r==-==-=~_=_==_==~I~I======~I.~I==~ .. ==~==========~==~ ppm

, I

••

. ;

W· .. .

I I......., .. ~"'''''''''''r'''''''''''''''~'''~~'''rl ~"F""""7'~r""~~~'F"'"'T"~~ 11 10 9 8 7 6 4 -1 -2 -3

Figure 5.2.12 HSQC spectrum 0/20.

20

40

60

80

100

-120

140

ppm

233

Chapter 5. Enantloselectlve Synthesis of Natural Product-Uke Benzo-Annulated Ox&-Heterocycles

I I ",.~M)C:~' r=============~I~I========~I.~I==~.~~~~~~========~======;~~

- • 20

•• . ." -, - 110· . - 40

-- •• + 60 - o •

-=== " ... 000 .. - o • 0 80

100

-== 0'$ : 00 -120 --•• ~D ..

140

-= at ,. cO 160

- t • 180

200

-220

10 6 4 -1 -2 ppm

Figure 5.2.13 HMBC spectrum of20.

~r--l--'----"'-"'- , , , , , , , , , r--i5 i.O 65 6.0 :-.5 5.0 45 •. 0 3.~ 3_0 ~5 1',0 1.5- JJ) 1)5 0.0 , --'-r- 1:1 r~) I~i '-l~( 1:( '- ,) ." I~! i-< - I .. ,

Figure 5.2.14 J H NMR (CDCh 300 MHz) spectrum of 21.

234

Chapter 5. Enantloselective Synthesis of Natural Product-Like Benzo-Annulated Oxa-Heterocycles

M "T , .. '" '" """,::e...::- N = ""I 0") 1-~ .., =: ~ ~

,i. ~ ...,.::: or. ... ,::: ", ::O-:lC""\""\

~:' ~;:: ~ ~ ::: -i~~"'" '" ~,.~,..., ,..,

I I I '-\1 i/ \ V I I ''..J~ I

£(}.:H I "" 0 '''OH

MeO A

21

!

JLl ..... b "."

"'~r·'-"""'r·'·"'·"'l····'-··""'r···"""""'l··""··""·r·""""·""~~I"·"'-' ..... T .... • ..... ·nf·····-.···r···..,. .. ··J ...... • ..... ....., .............. -.I~...-· .. ·"'l' .. ··'T>'· .. 1•· ..... ··.r·· .............. T" ..... , 170 160 150 140 130 120 110 100 90 SO iO 60 50 40 30 20 10 0

Figure 5.2.15 J3 C NMR (CDCl3, 75 MHz) spectrum of 21.

235

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