The preparation of α-alkylidene-γ-butyrolactones using a telescoped intramolecular Michael/Olefination (TIMO) sequence: Synthesis of (+)-paeonilactone B

FULL PAPER

DOI: 10.1002/ejoc.200800558

The Preparation of α-Alkylidene-γ-Butyrolactones Using a Telescoped

Intramolecular Michael/Olefination (TIMO) Sequence: Synthesis of

(+)-Paeonilactone B

Michael G. Edwards,^[a]Martin N. Kenworthy,^[a]Russell R. A. Kitson,^[a]Alexis Perry,^[a]

Mark S. Scott,^[a]Adrian C. Whitwood,^[a]and Richard J. K. Taylor*^[a]

Keywords: Tandem reactions / Phosphonates / Michael addition / Horner–Wadsworth–Emmons / Lactones

A novel telescoped intramolecular Michael addition/proton

transfer/HWE olefination sequence has been developed to

provide rapid access to α-alkylidene-γ-butyrolactones. This

methodology has been applied to prepare a range of tetra-

hydrobenzofuran-2,5-diones, and related systems, and also

utilised in an extremely short synthesis of the natural product

(+)-paeonilactone B in enantiomerically pure form. In ad-

dition, preliminary experiments are described that illustrate

a palladium-catalysed variant proceeding by way of a π-allyl

intermediate.

Germany, 2008)

Introduction

The α-alkylidene-γ-butyrolactone motif is found in many

synthetically challenging and biologically interesting natu-

ral products whose diverse properties include herbicidal ac-

tivity, transcription-factor inhibition and anticancer ac-

tivity, amongst others.^[1]Representative examples are illus-

trated in Figure 1, ranging from the relatively simple paeon-

ilactone B (1)^[2]to more complex examples such as the zin-

aflavins [e.g., zinaflavin F, (2)],^[3a]the helenalins (e.g., 3^[3b]

)

and montahibisciolide (4).^[3c]

There are a range of published procedures for the prepa-

ration of α-alkylidene-γ-butyrolactones, commonly involv-

ing lactone construction and subsequent HWE-type

methylenation or hydroxymethylation/dehydration, but the

majority of the routes are lengthy and low yielding.^[1–4]As

part of our growing interest in telescoped processes,^[5]we

devised a streamlined, one-pot approach to α-alkylidene-γ-

butyrolactones, as outlined in Scheme 1.

Figure 1. Representative α-alkylidene-γ-butyrolactone natural

products.

It was envisaged that deprotonation of diethyl phospho-

noacetate 5 would trigger intramolecular Michael ad-

dition^[6–8]to give enolate 6. We anticipated that subsequent

proton transfer (anion exchange) would generate the more

stable phosphonate anion 7, and then addition of an alde-

hyde should initiate an intermolecular Horner–Wadsworth–

Emmons (HWE) olefination^[9]to generate cyclic or bicyclic

dicarbonyl compounds 8 (Scheme 1). Such a conjunctive se-

quence^[10]introduces the annelated lactone portion as two

fragments; the three carbon α-methylene lactone portion (R

= H) would be introduced as 2 C (from the phosphonoace-

tate) + 1 C (from formaldehyde) units, for example. In ad-

dition, we anticipated that the sequence would be stereose-

lective in the formation of a syn-fused tetrahydrobenzofu-

ran-2,5-dione (i.e., in the formation of bicycle 8, n = 1).

The success of this approach has been reported in a pre-

liminary communication.^[11]Herein, we give a full account

of the development and optimisation of this telescoped in-

tramolecular Michael/olefination (TIMO) sequence and

discuss investigations to establish its scope, limitations and

applications. In addition, a novel variant involving a palla-

dium π-allyl trapping–HWE olefination sequence is dis-

cussed. Finally, the application of the TIMO sequence to

prepare (+)-paeonilactone B 1 is described.

[a] Department of Chemistry, University of York,

Heslington, York YO10 5DD, UK

E-mail: rjkt1@york.ac.uk

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Scheme 1.

Proof of Principle Studies and Optimisation

In order to assess the viability of the TIMO approach,

keto–phosphonate 11 was prepared by coupling of readily

available 4-hydroxy-2-cyclohexenone (9)^[12]with commer-

cially available diethyl phosphonoacetic acid (10) using pro-

panephosphonic acid anhydride (T3P^®)^[13]as shown in

Scheme 2.

When keto phosphonate 11 was treated with KOtBu in

THF, the expected Michael adduct 12 was obtained in 50%

yield (Scheme 2). This moderate yield was attributed to pu-

rification difficulties; the reaction appeared to go to com-

pletion by TLC analysis but the highly polar phosphonyl

lactone proved to be very difficult to isolate. Consequently,

optimisation, in terms of reaction conditions, was unre-

warding [although these studies did identify KHMDS and

potassium 3,7-dimethyl-3-octylate (KDMO) as further suit-

Scheme 3.

Gratifyingly, an efficient transformation was achieved by

able bases for this transformation]. With phosphonate 12 in performing a sequential, one-pot process (Scheme 3). Thus,

hand, the key HWE reaction was explored: treatment of treatment of keto–phosphonate 11 with KHMDS

phosphonate 12 with KOtBu in THF, then paraformalde- (0.95 equiv.) in THF and then, after 60 min, cooling to

hyde, gave α-methylene-γ-butyrolactone product 13 in good –78 °C and addition of paraformaldehyde, produced the ex-

yield (Scheme 2). It was soon established that 13 was highly pected α-methylene lactone 13 directly in 54% overall yield.

base sensitive; indeed, 13 was not observed when the HWE

Encouraged by this validation of the TIMO strategy, we

reaction was performed with 1.2 equiv. of base, and expo- sought to optimise this lead result through variation in

sure of 13 to 0.1 equiv. of KOtBu in THF caused rapid de- base, solvent, temperature and formaldehyde source

gradation. Consequently, the use of a substoichiometric (Table 1). It transpired that the choice of base was funda-

quantity of base (0.95 equiv.) was adopted and this pro- mental to the success of the reaction sequence. Potassium

cedure gave product 13 in 83% yield.

[and to a lesser extent, sodium (Entry 5)] alkoxides ef-

Next, one-pot versions were explored (Scheme 3). We ficiently promoted the required reaction (Entries 3 and 6),

first treated keto–phosphonate 11 with KOtBu in THF in whereas LiOtBu and Ba(OH)₂were ineffective. The strong

the presence of paraformaldehyde. This procedure success- phosphazene base, tert-butyliminotris(dimethylamino)-

fully produced α-methylene lactone product 13 but only in phosphorane (P1-tBu), was only moderately effective (En-

20% yield, with the major product being acrylate 14 (50%) try 7) and organic bases such as MTBD and DBU were

resulting from HWE olefination occurring on noncyclised unsuccessful. Notably, the HWE reaction is at its most ef-

phosphonate 11.

ficient with user-friendly paraformaldehyde (Entry 3),

Scheme 2.

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Synthesis of (+)-Paeonilactone B

Table 1. Optimisation of the TIMO conversion of 11 into 13.^[a]

Entry

Solvent

Base

Formaldehyde

source^[b]

Michael^[c]

T [°C] / t [h]

HWE^[d]

T [°C] / t [h]

Yield

[%]

1

2

3

4

5

6

7

8

THF

KHMDS

KOtBu

NaOtC₅H₁₁

KDMO

P1-tBu

KOtBu

A

B

0 / 1

–78 - 0 / 4

0 / 1

–78 to r.t. / 15

–78 to 0 / 1.5

–78 to r.t. / 1.5

–78 to r.t. / 15

–78 to 0 / 1.5

–78 to r.t. / 1.5

54

72

77

65

11

47

39

40

63

46

55

45

–

THF

Et₂O

MeCN

CH₂Cl₂

THF

0 / 1

0 / 24

0 / 1

9

10

11

12

13

C

D

[a] All reactions were conducted at 0.05 . [b] A = paraformaldehyde dried with P₂O₅, B = thermally cracked paraformaldehyde, C =

ethereal solution of monomeric formaldehyde,^[14]D = formaldehyde generated in situ from reaction of N-(hydroxymethyl)phthalimide

and LDA.^[15][c] Completion of Michael reaction was confirmed by TLC analysis prior to formaldehyde addition. [d] Formaldehyde

source was added at –78 °C and after 15 min the reaction was warmed to 0 °C. If no reaction was observed by TLC analysis after 1 h,

the reaction was warmed to r.t.

whereas more elaborate and less convenient methods^[14,15]cess avoided, the overall yield is improved (77%, compared

of formaldehyde generation were less successful (En- with 43% over two steps). Lactone 13 is novel although the

tries 11–13). Consequently, it was possible to obtain 13 in corresponding anti-isomer is known.^[16]To be certain of the

77% yield by exposure of keto–phosphonate 11 to KOtBu syn-arrangement of 13, an X-ray crystal structure was ob-

in THF, followed by addition of paraformaldehyde (En- tained (Figure 2).^[17]

try 3).

This result emphasises the advantages of a one-pot pro-

cess, not only is a complicated workup and purification pro-

Variation of the Aldehyde Trapping Partner

Following the TIMO optimisation studies, we investi-

gated the scope of the procedure, initially in terms of the

aldehyde-trapping component (Table 2). Thus, the use of al-

iphatic aldehydes such as acetaldehyde and hexanal as

HWE partners under the optimised conditions gave lac-

tones 15 and 16, respectively, in moderate yields as 1:1 mix-

ture of E/Z-isomers (Table 2, Entries 1 and 2). The HWE

process does not appear to be compatible with sterically

demanding aldehydes as pivaldehyde was unreactive under

these conditions.

Aromatic aldehydes were next studied as HWE coupling

partners (Entries 3–6). In all of these cases KHMDS was

found to be the base of choice (KOtBu gave lower yields,

possibly due to competing Cannizzaro reactions^[18]) and

heating was found to be necessary to ensure that the HWE

process reached completion. With benzaldehyde (Entry 3),

an unoptimised 31% yield of adduct 17 was obtained. Elec-

tron-deficient aldehydes (e.g., trifluoromethylbenzaldehyde)

were investigated next and, surprisingly, were not successful

partners in the TIMO sequence (again, possibly due to

Cannizzaro processes). However, electron-rich aldehydes

proved more successful (Table 2, Entries 4–6). In the three

examples explored, reasonable, unoptimised yields of ex-

pected adducts 18, 19 and 20 were obtained, exclusively as

the E-isomers. Biphenyl adduct 20 gave crystals suitable for

X-ray analysis^[19]and this confirmed the syn-ring junction

and the E-configuration of the alkene (Figure 2).

Figure 2. X-ray crystal structure of lactones 13 (top) and 20 (bot-

tom), depicted using Mercury 1.4.

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Table 2. Scope of the TIMO reaction – aldehyde coupling part-

Table 3. Scope of the TIMO reaction – hydroxy-enone compo-

ners.^[a]

nents.^[a]

[a] Unless stated, the fist step (Michael addition) was performed

with 0.95 equiv. of KOtBu for 1 h at 0 °C. [b] –78 to 0 °C, 1 h. [c]

–78 to 0 °C, 15 h, then reflux. [d] 1:1 E/Z mixture. [e] KHMDS

(0.95 equiv.) was used in place of KOtBu. [f] Ͼ95:Ͻ5 E/Z. [g] Use

of KOtBu gave considerably lower yields (17, 22%; 18, 23%).

Variation of the γ-Hydroxy Enone Substrate

Studies were also carried out to evaluate the scope of the

γ-hydroxy enone substrate (Table 3). As can be seen, the

ring size was investigated first. Thus (Entry 1), hydroxycy-

cloheptenone 21 was efficiently converted into keto–phos-

[a] Unless stated, Michael addition was performed with 0.95 equiv.

of KOtBu for 1 h at 0 °C. [b] Michael addition performed overnight

at r.t. [c] Michael addition performed at 70 °C, 5 h. [d] –78 °C, 2 h

then r.t. [e] –78 to 0 °C, 1 to 1.5 h. [f] 3:1 anti/syn diastereomers.

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Synthesis of (+)-Paeonilactone B

phonate 22 which, in turn, underwent the TIMO sequence quence on 5,5-dimethyl analogue 27 was investigated (En-

in excellent yield, producing the cycloheptanone-annelated try 3). This proceeded as expected with keto–phosphonate

product 23; once again, the telescoped process was far more 28 giving γ-butyrolactone 29 in 52% unoptimised yield.

efficient than the corresponding two-step sequence (84% vs.

Substitution at the ring positions was studied next (En-

22%). The syn-ring junction assignment was based on tries 4–6). In terms of substituent compatibility at the al-

coupling constant analysis (J = 7.9 Hz; for related sys- kene moiety, the TIMO reaction of α-allylated enone 30 was

tems^[20]the syn-ring junction isomer exhibited J = 8.6 Hz, explored and under standard conditions, phosphonate 31

the anti J = 10.7 Hz).

gave the expected bicycloadduct 32 in good yield as a 3:1

Moving on to the corresponding cyclopentene analogue diastereomeric mixture (Entry 4). However, the correspond-

24 gave a less successful outcome (Entry 2). Adduct 25 was ing β-methylated enone 34 failed to undergo the intramolec-

prepared without problem but unfortunately the TIMO se- ular Michael reaction even under forcing conditions (En-

quence did not produce the expected α-methylene lactone try 5). In view of the literature examples concerning prob-

26. It appeared that the attempted Michael addition step lematic Michael additions to β-methylcyclohexenone,^[22]

failed, possibly due to β-elimination of the acyl substituent this is unsurprising. As shown in Entry 6, substitution is

(this is known to be facile for related 3-acyloxycyclopen- possible at the hydroxy centre, however. Thus, tertiary

tenones under basic conditions^[21]). Support for this hy- alcohol 36 was converted into phosphonate 37 and the

pothesis was obtained when the corresponding TIMO se- TIMO sequence proceeded successfully giving the highly

functionalised bicyclic adduct 38.

Next, variation in the lactone size was explored (En-

try 7). Hence it was shown that alcohol 39 was readily con-

verted into adduct 40 and this, in turn, underwent the

TIMO process giving the six-membered bicyclic lactone 41

in 75% yield, again exclusively as the syn-diastereoisomer.

In this case, the Michael addition was comparatively slow

and more forcing conditions were required. Finally, in this

section, an acyclic example was investigated (Entry 8). Acy-

clic allylic alcohol 42 was converted into keto–phosphonate

43 and this underwent the TIMO sequence to produce

monosubstituted α-methylene lactone 44 in good yield.

Compounds 29^[23]and 41^[24]were crystalline and their

structures were also confirmed by X-ray crystallography

(Figure 3).

Palladium-Catalysed π-Allyl Variant

With the TIMO sequence established, we briefly sought

to demonstrate the wider applicability of this telescoped

chemistry, i.e., by trapping the keto–phosphonate anion

using alternative intramolecular electrophiles, followed by

HWE elaboration.^[25]Given the ready availability of the

cyclisation precursors, we decided to study the process illus-

trated in Scheme 4 involving the intermediacy of a π-allyl

palladium complex 46 generated from the corresponding al-

lylic acetate 45; ring closure to 47 and subsequent HWE

olefination should give rise to α-methylene-γ-butyrolac-

tones 48.

Initial investigation (Scheme 5) focused on acetate 49,

readily derived as a 1:1 mixture from the previously pre-

pared keto–phosphonate 11 by Luche reduction and acety-

lation. Treatment of 49 with KOtBu and 5 mol-% Pd(PPh₃)₄

at reflux in THF, followed by cooling to room temperature

and addition of paraformaldehyde, gave the desired α-meth-

ylene-γ-butyrolactone 51 in just 13% yield as a 3:1 mixture

of diastereoisomers. Both syn-^[26]and anti-^[27]51 have been

described in the literature and comparison of the high-field

proton NMR spectroscopic data of the mixture with those

published indicated that syn-51 predominated. The low

Figure 3. X-ray crystal structure of γ-butyrolactones 29 (top) and

41 (bottom), depicted using Mercury 1.4.

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Scheme 4.

yielding nature of the reaction of 49 was attributed to the rily explain these disappointing results, which are particu-

similar leaving group abilities of the two allylic substituents, larly galling given the success of related cyclisations de-

i.e., the acetate and the phosphonoacetate groups, thereby scribed in the literature.^[29]

allowing palladium-catalysed π-allyl formation at either end

of the molecule (byproduct analysis substantiated this

suggestion). In view of this hypothesis, we went on to pre-

pare the corresponding allylic carbonate 50 (Scheme 5) in

order to increase the scope for catalyst discrimination be-

tween the allylic substituents. Gratifyingly, treatment of 50

under the conditions employed previously gave the mixture

of methylene lactones 51 in a greatly improved (if still mod-

est) 36% yield. With this promising result in hand, we

undertook a thorough study of base, catalyst and tempera-

ture effects upon this one-pot process.^[28]Frustratingly, fur-

ther optimisation was not achieved. However, this prelimi-

nary study does indicate the potential of the palladium pro-

cedure for the preparation of anti-fused lactones.

Use of the TIMO Sequence to Prepare

(+)-Paeonilactone B 1

Following the model studies described, our attention

turned to a natural product target with which to validate

the utility of the TIMO sequence. Paeony root has a long

history of use in Chinese and Japanese medicine for pain

relief and, in 1985, paeonilactones A, B and C were isolated

from the root of Paeonia Albiflora Pallas.^[2](+)-Paeonilac-

tone B (1)^[2]was chosen for our study as it has been pre-

pared in racemic^[30]and optically pure^[31]form but the

lengthy routes attest to the problems associated with the

preparation of such a densely functionalised molecule.

Retrosynthetic analysis (Scheme 6) indicated that the

ideal TIMO precursor for paeonilactone B would be keto–

phosphonate 55, with alcohol 56 as the starting material.

Scheme 5.

In order to completely remove the possibility of competi-

tive π-allyl formation, we prepared cyclisation precursors 52

and 53. Unfortunately, treatment of acetate 52 with KOtBu

and 5 mol-% Pd(PPh₃)₄, followed by addition of paraform-

aldehyde failed to promote the desired transformation with

no lactone 54 being observed (recovered starting material

and the corresponding alcohol were obtained). With car-

bonate 53, however, a very low yield (5%) of desired cyclo-

hexene adduct 54 was obtained. We are unable to satisfacto- Scheme 6.

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Synthesis of (+)-Paeonilactone B

Scheme 7.

However, given that the stereoisomeric alcohol 57 is more of this route to (+)-paeonilactone B (1) [6 steps, 13% overall

accessible (see later), an alternative approach would involve yield from the known^[32]and readily accessible, enantiopure

the Mitsunobu coupling of alcohol 57 and diethyl phospho- starting material (–)-58].

noacetic acid 10 with consequent inversion of stereochemis-

In summary, a novel telescoped intramolecular Michael

try (Scheme 6).

addition/proton transfer/HWE olefination (TIMO) se-

Following the analysis above, diol 57 was obtained in en- quence has been developed to provide rapid access to α-

antiomerically pure form using the route shown in alkylidene-γ-butyrolactones commencing from γ-hydroxy-

Scheme 7. The Novozyme 435 procedure described by Rob- α,β-unsaturated ketones. This methodology has been ap-

erts et al.^[32]was employed to convert racemic alcohol 9 into plied to prepare a range of model tetrahydrobenzofuran-

(–)-58. Kinetic enolate generation followed by methylation 2,5-diones, as well as examples of the corresponding cy-

gave 59 as a mixture of diastereomers (the 55% yield re- clohepta- and cyclopenta-annelated systems and a monocy-

flecting the ease with which aromatisation occurs in these clic example, in addition, preliminary experiments have

systems). Silyl enol ether formation followed by a modified been described which illustrate a palladium-catalysed vari-

substrate-controlled, diastereoselective Rubottom epoxid- ant proceeding by way of a π-allyl intermediate. Finally,

ation (DMDO)^[33]and deprotection gave required anti-diol validation of the TIMO methodology was achieved when

57 in an efficient three-step process. NOE experiments on it was employed as the cornerstone of an extremely short

anti-diol 57 (and its syn-isomer 56) were employed to con- synthesis of the natural product, (+)-paeonilactone B (1),

firm the relative stereochemistry of the diol substituents in enantiomerically pure form. We are currently exploring

and thus confirm the highly stereoselective (dr = 33:1) na- further variants of the basic TIMO methodology^[25]and in-

ture of the sequence; it is noteworthy that the use of vestigating its utility for the preparation of more complex

DMDO is crucial to obtain high diastereoselectivity in the natural product targets.

enol ether epoxidation process (m-CPBA gave a 3:1 ratio at

best).

With anti-diol 57 in hand, we were in a position to ex-

plore the endgame. Mitsunobu coupling of alcohol 57 and

diethyl phosphonoacetic acid (10), in the presence of tri-

phenylphosphane/DIAD, proceeded as predicted with con-

sequent inversion of stereochemistry to give coupled prod-

uct 55 in a respectable yield (notably, in the presence of the

unprotected tertiary alcohol). This appears to be the first

Experimental Section

General Experimental: ¹H, ¹³C and ³¹P NMR spectra were recorded

with a JEOL EXC400 spectrometer operating at 400, 100 and

162 MHz, respectively. All spectroscopic data was acquired at

295 K. Chemical shifts are quoted in parts per million (ppm) using

the residual solvent peak as an internal standard [¹H NMR

7.26 ppm for CHCl₃and ¹³C NMR 77.0 ppm for CDCl₃, ¹H NMR

example of the use of diethyl phosphonoacetic acid (10) in 4.84 (s), 3.31 (quintuplet) and ¹³C NMR 49.05 (septuplet) for

D₃COD]. Coupling constants (J) are reported in Hz. Multiplicity

abbreviations used: s (singlet), d (doublet), t (triplet), q (quartet),

a Mitsunobu coupling reaction. Keto–phosphonate 55 was

then subjected to the TIMO cascade using KOtBu in THF

at 0 °C, then cooled to –78 °C and treated with paraformal-

dehyde. We were delighted to observe that this procedure

delivered (+)-paeonilactone B (1) in 70% yield. Authenticity

was confirmed spectroscopically, by HRMS and by com-

m

(multiplet) and br. (broad). Signal assignments were ac-

complished by analysis of COSY, NOESY, HSQC and HMBC ex-

periments where necessary. Infrared spectra were recorded with a

ThermoNicolet IR100 spectrometer using NaCl plates. Low- and

high-resolution mass spectra were obtained for all novel com-

pounds. Electrospray ionization (ESI) and chemical ionization (CI,

using ammonia gas) were measured with a Micromass Autospec

spectrometer. Melting points were determined using a Gallenkamp

parison of m.p. (86–87 °C, ref.^[2]88–89 °C) and [α]_D

=

[+23.8 (c = 1.04, MeOH), ref.^[2]+23.2]. The value of the

telescoped intramolecular Michael addition/proton trans-

fer/HWE olefination sequence can be gauged by the brevity apparatus and are uncorrected. Thin-layer chromatography (TLC)

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R. J. K. Taylor et al.

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was performed using Merk silica gel 60F₂₅₄pre-coated aluminum-

backed plates. The compounds were visualized using UV light

(254 nm) and KMnO₄or anisaldehyde. Flash chromatography was

performed at medium pressure using slurry packed Fluka silica gel

35–70 µm, 60 Å with the eluant specified. Petroleum ether is the

fraction with b.p. 40–60 °C. Tetrahydrofuran was distilled from so-

dium–benzophenone ketyl immediately before use. Anhydrous tolu-

ene and dichloromethane were obtained from an MBraun SPS sol-

vent purification system. Water refers to deionised water. Except

where specified, all reagents were purchased from commercial

sources and were used without further purification. Paraformalde-

hyde was dried with P₂O₅in a vacuum dessicatior. N,N-Diisopropy-

lethylamine was distilled from calcium hydride and stored over po-

tassium hydroxide. The following cyclisation precursors were pre-

pared following the published procedures (or closely related pro-

cedures) as follows: 9,^[12]21,^[34]24,^[35]30,^[36]33,^[37]36,^[38]39^[39]and

42.^[40]

= 6.8 Hz), 63.0 (d, J_CP= 6.8 Hz), 46.7 (d, J_CP= 138.6 Hz), 41.7

(d, J_CP= 9.6 Hz), 36.0 (d, J_CP= 2.2 Hz), 33.9, 25.8, 16.2 (d, J_CP

= 4.4 Hz), 16.1 (d, J_CP= 4.4 Hz) ppm. ³¹P{¹H}NMR (162 MHz,

CDCl₃): δ = 19.6 ppm. MS (ESI): m/z (%) = 291 (100) [M + H]⁺,

313 (28) [M + Na]⁺. HRMS (EI): calcd. for C₁₂H₂₀O₆P [M + H]⁺

291.0992; found 291.0998 (δ =2.1 ppm error).

General Procedure 2: Preparation of α-Methylene-γ-butyrolactones

by TIMO

syn-3-Methylidenetetrahydrobenzofuran-2,5(3H,4H)-dione (13): Po-

tassium tert-butoxide (3.88  solution in THF, 206 µL,

0.798 mmol) was added dropwise to a stirred solution of 11

(244 mg, 0.841 mmol) in THF (10 mL) at 0 °C under argon. The

resulting solution was stirred for 1 h at 0 °C then cooled to –78 °C.

Paraformaldehyde (252 mg, 8.41 mmol) was added and the reaction

was stirred for 15 min then warmed to 0 °C and stirred for 2 h. The

reaction was quenched with aqueous saturated NH₄Cl (10 mL) and

extracted with EtOAc (2ϫ10 mL). The combined organics were

dried (Na₂SO₄) and concentrated in vacuo. The resulting crude res-

idue was purified by flash column chromatography, eluting with

petrol/EtOAc, 2:3, to afford 13 (108 mg, 77%) as a white solid.

General Procedure 1: Preparation of Phosphonoacetate Esters

4-Oxocyclohex-2-enyl Diethoxyphosphorylacetate (11): T3P^®in tol-

uene (50% w/w, 15.91 g, 25.00 mmol) was added slowly to a stirred

solution of 4-hydroxy-2-cyclohexenone (9;^[12]2.16 g, 19.23 mmol),

diethylphosphonoacetic acid (10; 3.24 mL, 20.19 mmol) and N,N-

diisopropylethylamine (8.71 mL, 49.99 mmol) in toluene (100 mL).

The resulting solution was stirred for 2 d at room temperature then

diluted with water (100 mL) and extracted with EtOAc

(2ϫ100 mL). The combined organics were washed with 10% aque-

ous HCl (50 mL), saturated aqueous NaHCO₃(50 mL), saturated

brine (50 mL), dried (MgSO₄) and concentrated in vacuo. The re-

sulting crude residue was purified by passing through a pad of

SiO₂, eluting with EtOAc, to afford 11 (4.89 g, 88%) as a yellow

M.p. 107.5–108.5 °C. R = 0.50 (EtOAc/MeOH, 9:1). IR (neat): ν

˜

f

= 2969, 2947, 2908, 1761, 1710, 1660, 1475, 1423, 1266, 1142, 1009,

1

820 cm^–1. H NMR (400 MHz, CDCl₃): δ = 6.34 (d, J = 2.9 Hz, 1

H, =CH), 5.62 (d, J = 2.7 Hz, 1 H, =CH), 5.00 (ddd, J = 8.6, 4.2,

1.6 Hz, 1 H, 7a-H), 3.59 (ddddd, J = 11.9, 8.6, 6.3, 2.9, 2.7 Hz, 1

H, 3a-H), 2.70 (dd, J = 16.4, 6.3 Hz, 1 H, 4-H), 2.57 (dd, J = 16.4,

5.0 Hz, 1 H, 4-H), 2.33–2.16 (m, 4 H, 6- and 7-H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 208.8, 169.8, 137.6, 124.4, 74.4, 41.1, 35.5,

33.2, 25.9 ppm. MS (ESI): m/z (%) = 167 (100) [M + H]⁺, 184 (12)

[M + NH₄]⁺, 189 (58) [M + Na]⁺. HRMS: calcd. for C₉H₁₁O₃[M

+ H]⁺167.0703; found 167.0706 (δ =1.8 ppm error).

oil. R = 0.22 (EtOAc). IR (neat): ν = 2983, 2936, 2910, 1736, 1686,

˜

f

1445, 1388, 1371, 1318, 1267, 1207, 1164, 1114, 1050, 1025, 971,

913, 875, 863, 837, 786 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ =

6.84 (ddd, J = 10.2, 2.8, 1.4 Hz, 1 H, 2-H), 6.10 (ddd, J = 10.3,

1.8, 0.8 Hz, 1 H, 3-H), 5.61 (ddt, J = 6.8, 2.8, 2.0 Hz, 1 H, 1-H),

(3E)- and (3Z)-syn-3-Ethylidenetetrahydrobenzofuran-2,5(3H,4H)-

dione (15): Following general procedure 2, potassium tert-butoxide

(3.88  solution in THF, 34 µL, 0.13 mmol), 11 (40 mg, 0.14 mmol)

and freshly distilled acetaldehyde (12.0 µL, 0.21 mmol) (the alde-

hyde was added by syringe pump over 3 h in order to minimise self-

condensation and the reaction was then stirred at room tempera-

ture overnight) in THF (2.8 mL) gave 15 (14 mg, 60%, 1:1 E/Z) as

4.17 (qd, J = 8.1, J_HP= 6.7 Hz, 4 H, OCH₂), 3.00 (d, J_HP

=

21.6 Hz, 2 H, PCH₂), 2.51 (dt, J = 17.0, 5.0 Hz, 1 H, 5-H), 2.48–

2.33 (m, 2 H, 5- and 6-H), 2.17–2.08 (m, 1 H, 6-H), 1.34 (td, J =

7.1, J_HP= 0.4 Hz, 6 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 198.2, 165.7 (d, J_CP= 6.3 Hz), 147.1, 131.4, 68.7, 62.7 (d, J_CP

a colourless oil. R = 0.50 (EtOAc/MeOH, 9:1). IR (neat): ν = 2958,

˜

f

1746, 1729, 1713, 1674, 1443, 1357, 1216, 1141, 1028, 1009,

940 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.87 [qd, J = 7.3,

2.4 Hz, 1 H, =CH(Z)], 6.16 [qd, J = 7.3, 2.4 Hz, 1 H, =CH(E)],

4.94–4.87 [m, 2 H, 7a-H(E+Z)], 3.63–3.56 [m, 1 H, 3a-H(Z)], 3.55–

3.48 [m, 1 H, 3a-H(E)], 2.67 [ddd, J = 15.8, 6.7, 2.9 Hz, 2 H, 4-

H(E+Z)], 2.53–2.47 [m, 1 H, 4-H(E)], 2.43–2.35 [m, 1 H, 4-H(Z)],

2.33–2.21 [m, 2 H, 6-H(E+Z)], 2.20–2.16 [m, 2 H, 7-H(E+Z)], 1.89

[dd, J = 7.3, 1.6 Hz, 6 H, CH₃(E+Z)] ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 209.6, 209.5, 170.3, 169.7, 141.8, 138.9, 130.2, 128.2,

74.1, 73.7, 41.8, 40.4, 36.9, 34.8, 33.34, 33.33, 26.1, 25.6, 14.8,

13.8 ppm. MS (CI, NH₃): m/z (%) = 180 (100) [M + H]⁺. HRMS:

calcd. for C₁₀H₁₆NO₃[M + NH₄]⁺198.1129; found 198.1130 (δ

=0.8 ppm error).

= 6.4 Hz), 34.5, 34.2 (d, J_CP= 133.5 Hz), 28.2, 16.0 (d, J_CP

=

6.2 Hz) ppm. ³¹P{¹H}NMR (162 MHz, CDCl₃): δ = 19.7 ppm. MS

(CI, NH₃): m/z (%) = 291 (11) [M + H]⁺, 308 (56) [M + NH₄]⁺.

HRMS (EI): calcd. for C₁₂H₂₃NO₆P [M + NH₄]⁺308.1263; found

308.1266 (δ =1.0 ppm error).

Diethyl 2,5-Dioxooctahydrobenzofuran-3-yl-phosphonate (12): Po-

tassium tert-butoxide (3.88  solution in THF, 130 µL, 0.55 mmol)

was added dropwise to a stirred solution of 11 (168 mg, 0.58 mmol)

in THF (10 mL) at 0 °C under argon. The resulting solution was

stirred for 1 h at 0 °C then quenched with aqueous saturated

NH₄Cl (1.5 mL), dried (Na₂SO₄) and concentrated in vacuo. The

resulting crude residue was purified by passing through a pad of

SiO₂, eluting with EtOAc/MeOH, 9:1, to afford 12 (84 mg, 50%)

(3E)- and (3Z)-syn-3-Hexylidenetetrahydrobenzofuran-2,5(3H,4H)-

dione (16): Following general procedure 2, potassium tert-butoxide

(3.88  solution in THF, 126 µL, 0.49 mmol), 11 (141 mg,

as a yellow oil. R = 0.33 (EtOAc/MeOH, 9:1). IR (neat): ν = 2982,

˜

f

2931, 1770, 1718, 1249, 1163, 1021, 973 cm^–1. ¹H NMR (400 MHz,

CDCl₃): δ = 5.00 (ddd, J = 9.9, 7.5, 4.9 Hz, 1 H, 7a-H), 4.22–4.09 0.48 mmol) and freshly distilled hexanal (300 µL, 2.43 mmol) in

(m, 4 H, OCH₂), 3.29 (dddd, J_HP= 22.9 Hz, J = 14.3, 7.7, 4.3 Hz, THF (6.7 mL) gave 16 (36 mg, 35%, 1:1 E/Z) as a colourless oil.

1 H, 3a-H), 2.78 (dd, J_HP= 24.7 Hz, J = 4.3 Hz, 1 H, 3-H), 2.56

R = 0.63 (EtOAc/MeOH, 9:1). IR (neat): ν = 2957, 2929, 2859,

˜

f

(dd, J = 15.8, 6.6 Hz, 1 H, 4-H), 2.43–2.34 (m, 2 H, 6-H), 2.28 (t, 1752, 1720, 1671, 1371, 1344, 1233, 1187, 1138, 1026, 915,

J = 5.9 Hz, 1 H, 4-H), 2.24–2.19 (m, 2 H, 7-H), 1.30 (td, J = 7.1 Hz,

J_HP= 1.5 Hz, 6 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

208.0, 170.4 (d, J_CP= 3.6 Hz), 76.0 (d, J_CP= 3.9 Hz), 63.9 (d, J_CP

733 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.79 [td, J = 7.4,

2.4 Hz, 1 H, hexyl 1-H(Z)], 6.16 [td, J = 7.8, 2.4 Hz, 1 H, hexyl 1-

H(E)], 4.95–4.85 [m, 4 H, 7a-H(E+Z)], 3.58–3.49 [m, 2 H, 3a-

4776

www.eurjoc.org

Eur. J. Org. Chem. 2008, 4769–4783

Synthesis of (+)-Paeonilactone B

H(E+Z)], 2.70 [dddd, J = 15.6, 7.5, 4.0, 2.1 Hz, 2 H, 4-H(E+Z)],

4.98 (ddd, J = 7.5, 5.0, 5.0 Hz, 1 H, 7a-H), 4.05 (ddd, J = 14.5,

2.63 [ddd, J = 15.6, 7.6, 6.1 Hz, 2 H, 4-H(E+Z)], 2.54–2.37 [m, 4 7.5, 2.0 Hz, 1 H, 3a-H), 2.73 (dd, J = 16.0, 7.0 Hz, 1 H, 4-H), 2.52

H, 6-H(E+Z)], 2.35–2.12 [m, 8 H, hexyl 2-H and 7-H(E+Z)], 1.48–

1.23 [m, 12 H, hexyl 3-, 4- and 5-H(E+Z)], 0.89–0.83 [m, 6 H, hexyl

6-H(E+Z)] ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 208.9, 208.8,

170.1, 169.1, 147.0, 143.9, 128.6, 126.9, 74.1, 73.7, 42.0, 41.0, 37.1,

35.2, 33.6, 33.5, 31.4, 31.3, 29.5, 28.5, 28.0, 27.4, 26.4, 25.9, 22.4,

22.3, 13.9, 13.8 ppm. MS (ESI): m/z (%) = 237 (97) [M + H]⁺, 254

(100) [M + NH₄]⁺. HRMS: calcd. for C₁₄H₂₁O₃[M + H]⁺

237.1488; found 237.1485 (δ =1.0 ppm error).

(dd, J = 16.0, 7.5 Hz, 1 H, 4-H), 2.50–2.43 (m, 1 H, 6-H), 2.39 (s,

3 H, CH₃), 2.37–2.27 (m, 3 H, 6- and 7-H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 208.8, 171.3, 141.0, 138.8, 130.3, 130.1,

129.9, 126.2, 76.7, 38.7, 36.3, 33.4, 25.9, 21.5 ppm. MS (CI): m/z

(%) = 274 (100) [M + NH₄]⁺, 257 (15) [M + H]⁺. HRMS: calcd.

for C₁₆H₂₀NO₃[M + NH₄]⁺274.1443; found 274.1440 (δ =1.2 ppm

error).

(3E)-syn-3-(Biphenyl-4-yl-methylidene)tetrahydrobenzofuran-

2,5(3H,4H)-dione (20): Following general procedure 3, KHMDS

(0.5  solution in toluene, 0.38 mL, 0.19 mmol) and 11 (50 mg,

0.17 mmol) in THF (2.4 mL) and 4-phenylbenzaldehyde (170 mg,

0.86 mmol) in THF (1 mL) gave 20 (30 mg, 55%) as a white solid.

General Procedure 3: Preparation of Substituted α-Arylidene-γ-bu-

tyrolactones

(3E)-syn-3-Benzylidenetetrahydrobenzofuran-2,5(3H,4H)-dione (17):

KHMDS (0.5  solution in toluene, 0.66 mL, 0.327 mmol) was

added dropwise to a stirred solution of 11 (100 mg, 0.344 mmol) in

THF (7 mL) at –78 °C under argon. After 10 min the reaction was

warmed to 0 °C and stirred for 1 h. A solution of benzaldehyde

(175 µL, 1.72 mmol) in THF (1 mL) was added and the reaction

was warmed to room temperature overnight then heated to reflux

for 1 h. The mixture was concentrated in vacuo, diluted with water

(10 mL) and extracted with EtOAc (3ϫ20 mL). The combined or-

ganics were dried (Na₂SO₄) and concentrated in vacuo. The re-

sulting crude residue was purified by flash chromatography, eluting

with petrol/EtOAc, 1:1, to afford 17 (26 mg, 31%), as a pale yellow

M.p. 146–148 °C. R = 0.37 (petrol/EtOAc, 1:1). IR (neat): ν =

˜

f

3030, 2957, 2920, 2851, 1743, 1715, 1602, 1485, 1448, 1410, 1344,

1312, 1237, 1180, 1028, 940, 914, 840, 768, 727 cm^–1. ¹H NMR

(400 MHz, CDCl₃): δ = 7.67 (d, J = 8.2 Hz, 2 H, Ar 3- and 5-H),

7.60–7.64 (m, 3 H, =CH and Ar 8- and 12-H), 7.53 (d, J = 8.2 Hz,

2 H, Ar 2- and 6-H), 7.47 (t, J = 7.0 Hz, 2 H, Ar 9- and 11-H),

7.40 (t, J = 7.0 Hz, 1 H, Ar 10-H), 4.94–4.99 (m, 1 H, 7a-H), 4.11

(dddd, J = 7.4, 7.3, 7.0, 2.4 Hz, 1 H, 3a-H), 2.79 (dd, J = 15.9,

6.7 Hz, 1 H, 4-H), 2.58 (dd, J = 15.9, 7.0 Hz, 1 H, 4-H), 2.46–2.54

(m, 1 H, 7-H), 2.32–2.40 (m, 3 H, 6- and 7-H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 208.5, 171.2, 143.0, 139.6, 138.2, 131.9,

130.5, 128.9, 128.0, 127.6, 127.2, 127.0, 74.3, 38.7, 36.3, 33.4,

25.8 ppm. MS (CI): m/z (%) = 336 (45) [M + NH₄]⁺, 319 (100) [M

+ H]⁺. HRMS (CI): calcd. for C₁₀H₁₃O₄[M + NH₄]⁺336.1600,

found 336.1605 (δ =1.6 ppm error).

solid. M.p. 130.5–131 °C. R = 0.5 (EtOAc). IR (neat): ν = 2960,

˜

f

1739, 1710, 1650, 1239, 1188, 1030 cm^–1. ¹H NMR (400 MHz,

CDCl₃): δ = 7.59 (d, J = 2.5 Hz, 1 H, =CH), 7.47–7.40 (m, 5 H,

Ar-H), 5.01–4.95 (m, 1 H, 7a-H), 4.06 (ddd, J = 15.0, 7.0, 2.5 Hz,

1 H, 3a-H), 2.72 (dd, J = 16.0, 7.0 Hz, 1 H, 4-H), 2.50 (dd, J =

16.0, 7.0 Hz, 1 H, 4-H), 2.48–2.41 (m, 1 H, 6-H), 2.36–2.27 (m, 3

H, 6- and 7-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 209.3,

171.1, 138.8, 133.1, 130.4, 129.9, 129.1, 127.5, 74.1, 38.8, 36.3, 33.4,

25.9 ppm. MS (CI): m/z (%) = 260 (100) [M + NH₄]⁺, 243 (95) [M

+ H]⁺. HRMS: calcd. for C₁₅H₁₈NO₃[M + NH₄]⁺260.1287; found

260.1288 (δ =0.4 ppm error).

4-Oxocyclohept-2-enyl 2-(Diethoxyphosphoryl)acetate (22): Follow-

ing general procedure 1, T3P^®in toluene (50 % w/w, 1.97 g,

3.09 mmol), 4-hydroxycyclohept-2-enone (21;^[34]300 mg,

2.38 mmol), diethylphosphonoacetic acid (10; 0.40 mL, 2.50 mmol)

and N,N-diisopropylethylamine (1.08 mL, 6.19 mmol) in toluene

(7 mL) gave 22 (690 mg, 95%) as a yellow oil. R_f= 0.38 (EtOAc/

MeOH, 9:1). IR (neat): ν = 2984, 2938, 1735, 1672, 1395, 1266,

˜

(3E)-syn-3-(3,4,5-Trimethoxybenzylidene)tetrahydrobenzofuran-

2,5(3H,4H)-dione (18): Following general procedure 3, KHMDS

(0.5  solution in toluene, 0.38 mL, 0.19 mmol) and 11 (50 mg,

0.17 mmol) in THF (2.4 mL) and 3,4,5-trimethoxybenzaldehyde

(169 mg, 0.86 mmol) in THF (1 mL) gave 18 (34 mg, 60%) as a

1112, 1023, 973 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.44 (ddd,

J = 12.6, 3.3, 1.2 Hz, 1 H, 2-H), 6.04 (ddd, J = 12.6, 2.1, 0.6 Hz,

1 H, 3-H), 5.64 (ddt, J = 6.8, 3.3, 2.1 Hz, 1 H, 1-H), 4.18 (dq, J_HP

= 8.3 Hz, J = 7.1 Hz, 4 H, OCH₂), 3.00 (d, J_HP= 21.7 Hz, 2 H,

PCH₂), 2.69–2.56 (m, 2 H, 5-H), 2.25–2.18 (m, 1 H, 6-H), 1.97–

1.84 (m, 3 H, 6- and 7-H), 1.34 (dt, J = 7.1 Hz, J_HP= 0.3 Hz, 6 H,

CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 202.3, 165.0 (d, J_CP

= 6.5 Hz), 143.5, 131.7, 73.2, 62.8 (d, J_CP= 6.1 Hz), 42.8, 34.4, (d,

J_CP= 133.3 Hz), 31.5, 18.0, 16.4 (d, J_CP= 6.2 Hz) ppm.

³¹P{¹H}NMR (162 MHz, CDCl₃): δ = 19.9 ppm. MS (ESI): m/z

(%) = 305 (100) [M + H]⁺, 327 (31) [M + Na]⁺. HRMS: calcd. for

C₁₃H₂₂O₆P [M + H]⁺305.1155; found 305.1149 (δ =2.1 ppm error).

yellow oil. R = 0.51 (EtOAc/MeOH, 9:1). IR (neat): ν = 3057,

˜

f

2962, 2940, 2841, 1747, 1714, 1652, 1580, 1505, 1419, 1334, 1242,

1130, 737 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.48 (d, J =

2.4 Hz, 1 H, =CH), 6.66 (s, 2 H, Ar-H), 5.48 (ddd, J = 9.6, 7.4,

2.4 Hz, 1 H, 7a-H), 4.01 (dtd, J = 14.8, 6.80, 2.4 Hz, 1 H, 3a-H),

3.88 (s, 3 H, OMe), 3.85 (s, 6 H, OMe), 2.74 (dd, J = 15.8, 6.8 Hz,

1 H, 4-H), 2.59 (dd, J = 15.8, 6.8 Hz, 1 H, 4-H), 2.49–2.41 (m, 1

H, 6-H), 2.35–2.29 (m, 3 H, 6- and 7-H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 209.0, 171.6, 153.8, 140.4, 139.2, 128.7,

126.4, 107.7, 74.2, 60.9, 56.1, 38.6, 36.1, 33.0, 25.5 ppm. MS (ESI):

m/z (%) = 333 (100) [M + H]⁺, 355 (17) [M + Na]⁺. HRMS: calcd.

for C₁₈H₂₁O₆[M + H]⁺333.1333; found 333.1335 (δ =0.7 ppm er-

ror).

syn-3-Methylidenehexahydro-2H-cycloheptafuran-2,5(3H)-dione

(23): Following general procedure 2, potassium tert-butoxide

(3.88  solution in THF, 38 µL, 0.147 mmol), 22 (64 mg,

0.211 mmol) and paraformaldehyde (63 mg, 2.10 mmol) in THF

gave 23 (32 mg, 84%) as a colourless oil. R_f= 0.52 (EtOAc/MeOH,

(3E)-syn-3-(4-Methylbenzylidene)tetrahydrobenzofuran-2,5(3H,4H)- 9:1). IR (neat): ν = 2948, 2872, 1758, 1705, 1661, 1272, 1164, 1003,

˜

1

dione (19): Following general procedure 3, KHMDS (0.5  solution

in toluene, 0.38 mL, 0.19 mmol) and 11 (50 mg, 0.17 mmol) in

THF (2.4 mL) and 4-methylbenzaldehyde (103 mg, 0.86 mmol) in

THF (1 mL) gave 19 (21 mg, 48%) as a white solid. M.p. 123.5–

947 cm^–1. H NMR (400 MHz, CDCl₃): δ = 6.36 (d, J = 2.7 Hz, 1

H, =CH), 5.70 (d, J = 2.4 Hz, 1 H, =CH), 4.71 (ddd, J = 9.5, 7.9,

3.8 Hz, 1 H, 8a-H), 3.37 (ddddd, J = 11.6, 7.9, 4.5, 2.7, 2.4 Hz, 1

H, 3a-H), 2.82 (dd, J = 13.0, 11.6 Hz, 1 H, 4-H), 2.56 (dd, J =

13.0, 4.5 Hz, 1 H, 4-H), 2.51 (t, J = 7.5 Hz, 2 H, 6-H), 2.21 (dddd,

124.5 °C. R = 0.24 (petrol/EtOAc, 1:1). IR (neat): ν = 2921, 1746,

˜

f

1716, 1648, 1607, 1346, 1236, 1178 cm^{–1 1}H NMR (400 MHz, J = 16.9, 7.5, 3.8, 2.1 Hz, 1 H, 7-H), 2.08–1.92 (m, 2 H, 7- and 8-

.

CDCl₃): δ = 7.55 (d, J = 2.0 Hz, 1 H, =CH), 7.34 (d, J = 8.0 Hz,

2 H, Ar 2- and 6-H), 7.22 (d, J = 8.0 Hz, 2 H, Ar 3- and 5-H),

H), 1.65–1.54 (m, 1 H, 8-H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 209.1, 138.1, 123.9, 99.0, 79.8, 44.5, 43.9, 38.6, 29.9, 18.1 ppm.

Eur. J. Org. Chem. 2008, 4769–4783

www.eurjoc.org

4777

R. J. K. Taylor et al.

FULL PAPER

MS (ESI): m/z (%) = 181 (100) [M + H]⁺, 203 (9) [M + Na]⁺. R = 0.56 (EtOAc/MeOH, 9:1). IR (neat): ν = 2960, 2871, 1762,

˜

f

HRMS: calcd. for C₁₀H₁₃O₃[M + H]⁺181.0859; found 181.0859

(δ =0.1 ppm error).

1741, 1662, 1274, 1117, 994 cm^–1. H NMR (400 MHz, CDCl₃): δ

= 6.31 (d, J = 1.9 Hz, 1 H, =CH), 5.75 (d, J = 1.7 Hz, 1 H, =CH),

4.63 (d, J = 6.3 Hz, 1 H, 6a-H), 3.71 (ddddd, J = 10.9, 6.3, 6.0,

1.9, 1.7 Hz, 1 H, 3a-H), 3.00 (dd, J = 19.6, 10.9 Hz, 1 H, 4-H),

2.21 (dd, J = 19.6, 6.0 Hz, 1 H, 4-H), 1.18 (s, 3 H, 5-CH₃), 1.11 (s,

3 H, 5-CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 217.6, 169.9,

139.7, 123.6, 86.8, 49.6, 41.1, 36.2, 22.8, 17.3 ppm. MS (ESI): m/z

(%) = 181 (100) [M + H]⁺. HRMS: calcd. for C₁₀H₁₃O₃[M + H]⁺

181.0859; found 181.0861 (δ =1.2 ppm error).

1

4-Oxocyclopent-2-enyl 2-(Diethoxyphosphoryl)acetate (25): Follow-

ing general procedure 1, T3P^®in toluene (50 % w/w, 4.34 g,

13.64 mmol), 4-hydroxycyclopent-2-enone (24;^[35]1.03 g,

10.49 mmol), diethylphosphonoacetic acid (10; 1.77 mL,

11.02 mmol) and N,N-diisopropylethylamine (4.75 mL,

27.29 mmol) in THF (20 mL) gave 25 (2.11 g, 73%) as a yellow oil.

R = 0.19 (EtOAc). IR (neat): ν = 2985, 1723, 1401, 1268, 1112,

˜

f

1024, 972, 791 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.56 (ddd,

1

3-Allyl-4-oxocyclohex-2-enyl 2-(Diethoxyphosphoryl)acetate (31):

Following general procedure 1, T3P^®in toluene (50% w/w, 148 mg,

0.23 mmol), 2-allyl-4-hydroxycyclohex-2-enone (30;^[36]28 mg,

0.18 mmol), diethylphosphonoacetic acid (10; 30 µL, 0.19 mmol),

N,N-diisopropylethylamine (81 µL, 0.47 mmol) in toluene (6 mL)

gave 31 (54 mg, 90%) as a colourless oil. R_f= 0.33 (EtOAc). IR

J = 5.7, 2.4, 1.5 Hz, 1 H, 2-H), 6.35–6.33 (m, 1 H, 3-H), 5.89 (ddd,

J = 8.5, 3.7, 2.2 Hz, 1 H, 1-H), 4.19–4.10 (m, 4 H, OCH₂), 3.00

(dd, J_HP= 21.7 Hz, J = 1.5 Hz, 2 H, PCH₂), 2.82 (ddd, J = 18.8,

6.4, 1.7 Hz, 1 H, 5-H), 2.34 (ddd, J = 18.8, 3.9, 2.2 Hz, 1 H, 5-H),

1.34 (ttd, J = 7.1, 2.1 Hz, J_HP= 0.5 Hz, 6 H, CH₃) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 204.4, 165.4 (d, J_CP= 6.4 Hz), 158.2, 137.3,

72.9, 62.81 (d, J_CP= 3.9 Hz), 62.79 (d, J_CP= 3.9 Hz), 40.7, 34.2

(d, J_CP= 133.6 Hz), 16.3 (d, J_CP= 6.2 Hz) ppm. ³¹P{¹H}NMR

(162 MHz, CDCl₃): δ = 19.4 ppm. MS (ESI): m/z (%) = 277 (100)

[M + H]⁺, 299 (15) [M + Na]⁺. HRMS: calcd. for C₁₁H₁₈O₆P [M

+ H]⁺277.0836; found 277.0839 (δ =1.4 ppm error).

(neat): ν = 2982, 2933, 1739, 1681, 1444, 1370, 1266, 1167, 1114,

˜

1025, 972 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.55 (dd, J =

2.9, 1.4 Hz, 1 H, 2-H), 5.56 (ddt, J = 17.2, 10.4, 6.8 Hz, 1 H, allyl

2-H), 5.61–5.56 (m, 1 H, 1-H), 5.06–5.01 (m, 2 H, allyl 3-H), 4.14

(qd, J = 7.1 Hz, J_HP= 0.6 Hz, 4 H, OCH₂), 2.98 (d, J_HP= 21.6 Hz,

2 H, PCH₂), 2.92 (ddd, J = 6.8, 1.3, 1.3 Hz, 1 H, allyl 1-H), 2.62

(ddd, J = 16.9, 5.8, 5.0 Hz, 1 H, 5-H), 2.40 (ddd, J = 16.3, 11.4,

4.8 Hz, 1 H, 5-H), 2.35–2.27 (m, 1 H, 6-H), 2.06 (dddd, J = 19.8,

11.3, 8.4, 4.5 Hz, 1 H, 6-H), 1.30 (t, J = 7.1 Hz, 6 H, CH₃) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 197.7, 165.7 (d, J_CP= 6.3 Hz),

142.0, 140.4, 134.7, 117.6, 69.3, 62.6 (d, J_CP= 5.4 Hz), 34.7, 34.6

(d, J_CP= 133.6 Hz), 32.7, 28.3, 16.0 (d, J_CP= 6.2 Hz) ppm.

³¹P{¹H}NMR (162 MHz, CDCl₃): δ = 19.8 ppm. MS (ESI): m/z

(%) = 353 (100) [M + H]⁺. HRMS: (ESI) calcd. for C₁₅H₂₃NaO₆P

[M + H]⁺353.1124; found 353.1131 (δ =1.9 ppm error).

4-Hydroxy-5,5-dimethylcyclopent-2-enone (27): A solution of 3-hy-

droxy-3-methyl-2-ethylfuran^[41](800 mg, 6.34 mmol) in deionised

water (675 mL) was stirred vigorously and sparged with argon for

1 h before being heated to reflux for 48 h. After cooling to r.t.,

the water was removed in vacuo and azeotroped with diethyl ether

(2ϫ50 mL) to afford 27^[42](430 mg, 54%) as a viscous colourless

oil. R = 0.41 (Et O). IR (Neat): ν = 3415, 2973, 2932, 2872, 1697,

˜

f

2

1465, 1338, 1132, 1099, 1050, 1008, 861 cm^–1. ¹H NMR (400 MHz,

CDCl₃): δ = 7.34 (dd, J = 5.9, 2.3 Hz, 1 H, 3-H), 6.09 (dd, J = 5.9,

1.5 Hz, 1 H, 2-H), 4.47 (ddd, J = 7.7, 2.3, 1.5 Hz, 1 H, 4-H), 1.76

(d, J = 7.7 Hz, 1 H, OH), 1.05 (s, 3 H, CH₃), 0.96 (s, 3 H, CH₃)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 212.7, 161.6, 132.1, 79.4,

48.3, 22.5, 20.1 ppm. MS (CI, NH₃): m/z (%) = 127 (50) [M +

H]⁺, 144 (100) [M + NH₄]⁺. HRMS: calcd. for C₇H₁₄NO₂[M +

NH₄]⁺144.1020, found 144.1025 (δ =3.3 ppm error).

anti- and syn-4-Allyl-3-methylidenetetrahydrobenzofuran-

2,5(3H,4H)-dione (32): Following general procedure 2 (but with

heating overnight at reflux), potassium tert-butoxide (3.88  solu-

tion in THF, 31 µL, 0.121 mmol), 31 (42 mg, 0.13 mmol) and para-

formaldehyde (38 mg, 1.27 mmol) in THF (2.5 mL) gave anti-32

(16 mg, 64%) as a colourless oil. R = 0.74 (EtOAc). IR (neat): ν

˜

f

= 2919, 2851, 1761, 1714, 1642, 1436, 1409, 1344, 1264, 1141 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.35 (d, J = 2.4 Hz, 1 H, =CH),

5.77 (dddd, J = 13.9, 10.3, 7.1, 6.8 Hz, 1 H, allyl 2-H), 5.69 (d, J

= 2.1 Hz, 1 H, =CH), 5.13–5.08 (m, 2 H, allyl 3-H), 4.80 (dt, J =

7.5, 5.5 Hz, 1 H, 7a-H), 3.27 (dddd, J = 8.0, 7.5, 2.4, 2.1 Hz, 1 H,

3a-H), 2.57–2.51 (m, 1 H, 4-H), 2.50–2.34 (m, 3 H, allyl 1-H and

6-H), 2.32–2.25 [m, 3 H, H₂C (allyl 1-H and 7-H)] ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 209.6, 170.0, 138.3, 134.8, 124.0, 118.6,

74.6, 49.2, 41.4, 34.1, 31.8, 26.5 ppm. MS (ESI): m/z (%) = 207

(100, 229 ([M + Na]⁺, 83) [M + H]⁺). HRMS: calcd. for C₁₀H₁₃O₃

[M + H]⁺207.1016; found 207.1016 (δ =0.1 ppm error). Also iso-

lated was syn-32 (5 mg, 20%) as a colourless oil. R_f= 0.65 (EtOAc).

5,5-Dimethyl-4-oxocyclopent-2-enyl 2-(Diethoxyphosphoryl)acetate

(28): Following general procedure 1, T3P^®in toluene (50% w/w,

2.61 g, 4.10 mmol), 4-hydroxy-5,5-dimethyl-2-cyclopentenone

(27;^[41]400 mg, 3.15 mmol), diethylphosphonoacetic acid (10;

0.53 mL, 3.31 mmol) and N,N-diisopropylethylamine (1.43 mL,

8.20 mmol) in toluene (8 mL) gave 28 (900 mg, 93%) as a yellow

oil. R = 0.51 (EtOAc/MeOH, 9:1). IR (neat): ν = 2980, 2934, 2874,

˜

f

1720, 1466, 1388, 1333, 1267, 1114, 1086, 1024, 824 cm^–1. ¹H NMR

(400 MHz, CDCl₃): δ = 6.44 (dd, J = 5.9, 2.3 Hz, 1 H, 2-H), 6.04

(dd, J = 5.9, 1.4 Hz, 1 H, 3-H), 5.62 (dd, J = 2.3, 1.4 Hz, 1 H, 1-

H), 4.18 (qd, J = 7.1 Hz, J_HP= 2.7 Hz, 4 H, OCH₂), 3.03 (d, J_HP

= 21.7 Hz, 2 H, PCH₂), 1.34 (td, J = 7.1 Hz, J_HP= 0.5 Hz, 6 H,

CH₂CH₃), 1.22 (s, 3 H, 5-CH₃), 1.05 (s, 3 H, 5-CH₃) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 210.2, 165.5 (d, J_CP= 6.2 Hz), 156.3,

134.5, 81.5, 62.82 (d, J_CP= 6.1 Hz), 62.80 (d, J_CP= 6.1 Hz), 47.1,

34.1 (d, J_CP= 134.4 Hz), 23.2, 20.0, 16.4 (d, J_CP= 6.2 Hz) ppm.

³¹P{¹H}NMR (162 MHz, CDCl₃): δ = 19.6 ppm. MS (ESI): m/z

(%) = 305 (100) [M + H]⁺, 322 (11) [M + NH₄]⁺. HRMS: calcd.

for C₁₃H₂₂O₆P [M + NH₄]⁺305.1149; found 305.1150 (δ =0.5 ppm

error).

IR (neat): ν = 2919, 2851, 1761, 1714, 1642, 1436, 1409, 1344, 1264,

˜

1

1141 cm^–1. H NMR (400 MHz, CDCl₃): δ = 6.37 (d, J = 2.8 Hz,

1 H, =CH), 5.81 (dddd, J = 17.1, 10.2, 8.4, 5.5 Hz, 1 H, allyl 2-H),

5.75 (d, J = 2.4 Hz, 1 H, =CH), 5.19–5.07 (m, 3 H, allyl 3-H and

7a-H), 3.74 (dddd, J = 9.0, 5.4, 2.8, 2.4 Hz, 1 H, 3a-H), 2.84 (ddd,

J = 8.0, 6.4, 6.3 Hz, 1 H, 6-H), 2.74–2.66 (m, 1 H, 4-H), 2.42–2.16

(m, 3 H, allyl 1-H and 6-H), 2.32–2.25 (m, 2 H, 7-H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 209.4, 169.9, 135.4, 134.4, 126.4,

118.0, 75.2, 48.7, 39.3, 32.9, 28.9, 25.3 ppm. MS (ESI): m/z (%) =

207 (100) [M + H]⁺, 229 (83) [M + Na]⁺. HRMS: calcd. for

C₁₀H₁₃O₃[M + H]⁺207.1016; found 207.1016 (δ =0.1 ppm error).

syn-6,6-Dimethyl-3-methylidenetetrahydro-2H-cyclopentafuran-

2,5(3H)-dione (29): Following general procedure 2, potassium tert-

butoxide (3.88  solution in THF, 25 µL, 0.097 mmol), 28 (31 mg,

0.10 mmol) and paraformaldehyde (30 mg, 1.02 mmol) in THF

(2.5 mL) gave 29 (9 mg, 52%) as a white solid. M.p. 86.0–87.0 °C.

2-Methyl-4-oxocyclohex-2-enyl (Diethoxyphosphoryl)acetate (34):

Following general procedure 1, T3P^®in toluene (50% w/w, 177 mg,

4778

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Eur. J. Org. Chem. 2008, 4769–4783

Synthesis of (+)-Paeonilactone B

0.278 mmol), 2-methyl-4-oxocyclohex-2-en-1-ol (33;^[37]27 mg,

0.5 Hz, 1 H, 3-H), 4.16 (dq, J = 7.5, 7.0 Hz, 4 H, OCH₂), 3.18

0.214 mmol), diethylphosphonoacetic acid (10; 46 mg, (dddd, J = 11.5, 4.5, 2.5, 2.5 Hz, 1 H, 1-H), 2.92 (d, J_HP= 21.5 Hz,

0.235 mmol), N,N-diisopropylethylamine (97 µL, 0.556 mmol) in

THF (2.0 mL) gave 34 (29 mg, 45%) as a colourless oil. R_f= 0.17

2 H, PCH₂), 2.54 (dt, J = 16.5, 3.0 Hz, 1 H, 5-H), 2.38 (ddd, J =

16.5, 14.5, 5.0 Hz, 5-H), 2.17–2.09 (m, 1 H, 6-H), 1.83–1.70 (m, 1

H, 6-H), 1.55 (s, 3 H, Me), 1.46 (s, 3 H, Me), 1.34 (t, J = 7.0 Hz,

6 H, CH₂CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 199.2,

(petrol/EtOAc, 1:4). IR (neat): ν = 2984, 2920, 1737, 1674, 1433,

˜

1385, 1262, 1204, 1163, 1114, 1023, 972 cm^–1. ¹H NMR (400 MHz,

CDCl₃): δ = 5.93 (br. s, 1 H, 3-H), 5.57 (dd, J = 7.3, 4.9 Hz, 1 H, 164.8 (d, J_CP= 6.0 Hz), 150.1, 130.4, 85.2, 62.5 (d, J_CP= 6.0 Hz),

1-H), 4.16 (qd, J = 7.0 Hz, J_HP= 0.5 Hz, 2 H, OCH₂), 4.14 (qd, J 45.0, 37.3, 35.6 (d, J_CP= 134.0 Hz), 24.3, 23.7, 22.9, 16.3 (d, J_CP

= 7.0 Hz, J_HP= 0.5 Hz, 2 H, OCH₂), 3.00 (d, J_HP= 21.7 Hz, 2 H,

PCH₂), 2.56 (ddd, J = 16.8, 7.3, 4.9 Hz, 1 H, 5-H), 2.38 (ddd, J =

16.8, 9.5, 4.9 Hz, 1 H, 5-H), 2.27 (dddd, J = 14.3, 7.3, 4.9, 4.9 Hz,

1 H, 6-H), 2.11 (dddd, J = 14.3, 9.5, 7.3, 4.9 Hz, 1 H, 6-H), 1.97

(s, 3 H, 2-CH₃), 1.34 (t, J = 7.0 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 197.7, 165.3 (d, J_CP= 6.1 Hz), 157.4, 129.0,

= 7.0 Hz) ppm. MS (ESI): m/z (%) = 355 (100) [M + Na]⁺. HRMS

(ESI): calcd. for C₁₅H₂₅NaO₆P [M + Na]⁺355.1281; found

355.1275 (δ =1.6 ppm error).

syn-1,1-Dimethyl-4-methylidenetetrahydro-1H-isochromene-

3,6(4H,5H)-dione (41): Potassium tert-butoxide (3.88  solution in

THF, 42 µL, 0.163 mmol) was added dropwise to a stirred solution

of 40 (57 mg, 0.172 mmol) in THF (3.5 mL) under argon. The re-

sulting solution was heated to reflux for 5 h then cooled to –78 °C.

Paraformaldehyde (252 mg, 8.41 mmol) was added and the reaction

was stirred for 15 min, then warmed to 0 °C and stirred for 1 h.

The reaction was quenched with aqueous saturated NH₄Cl (5 mL)

70.9, 62.8 (d, J_CP= 6.1 Hz), 62.7 (d, J_CP= 6.1 Hz), 34.4 (d, J_CP

=

132.0 Hz), 34.0, 28.1, 20.6, 16.3, 16.2 ppm. ³¹P{¹H} NMR

(162 MHz, CDCl₃): δ = 19.8 ppm. MS (ESI): m/z (%) = 327 (100)

[M + Na]⁺. HRMS (ESI): calcd. for C₁₃H₂₁NaO₆P [M + Na]⁺

327.0968; found 327.0969 (δ =0.2 ppm error).

1-Methyl-4-oxocyclohexa-2,5-dienyl (Diethoxyphosphoryl)acetate and extracted with EtOAc (2ϫ5 mL). The combined organics were

(37): Following general procedure 1, T3P^®in toluene (50% w/w,

dried (Na₂SO₄) and concentrated in vacuo. The resulting crude res-

770 mg, 0.121 mmol), 4-hydroxy-4-methylcyclohexa-2,5-dienone idue was purified by flash column chromatography, eluting with

(36;^[38]100 mg, 0.806 mmol), diethylphosphonoacetic acid (10;

petrol/EtOAc, 3:7, to afford 41 (27 mg, 75%) as a white solid. M.p.

205 mg, 1.05 mmol), N,N-diisopropylethylamine (420 µL, 126–127 °C. R = 0.60 (EtOAc). IR (neat): ν = 2956, 1710, 1624,

˜

f

1

2.42 mmol) in THF (8.0 mL) gave 37 (96 mg, 30%) as a cream

solid. M.p. 82–84 °C. R_f= 0.36 (CH₂Cl₂/Me₂CO, 4:1). IR

1295, 1124, 964 cm^–1. H NMR (400 MHz, CDCl₃): δ = 6.67 (d, J

= 2.5 Hz, 1 H, =CH), 5.74 (d, J = 2.5 Hz, 1 H, =CH), 3.59–3.53

(m, 1 H, 4a-H), 2.82 (dt, J = 15.0, 2.5 Hz, 1 H, 5-H), 2.64 (ddd, J

= 15.0, 5.5, 0.5 Hz, 1 H, 5-H), 2.46–2.38 (m, 1 H, 7-H), 2.38–2.28

(m, 1 H, 7-H), 2.20–2.11 (m, 2 H, 8- and 8a-H), 1.75–1.66 (m, 1

H, 8-H), 1.56 (s, 3 H, Me), 1.44 (s, 3 H, Me) ppm. ¹³C NMR

(CH Cl ): ν = 2985, 2933, 1743, 1668, 1629, 1445, 1393, 1266, 1176,

˜

2

1096, 1046, 1023, 971, 859, 796 cm^–1. ¹H NMR (400 MHz, CDCl₃):

δ = 6.87 [2- and 6-H, J = 10.0 Hz, 2 H, br. d (AAЈBBЈ)], 6.20 [br.

d (AAЈBBЈ), J = 10.0 Hz, 2 H, 3- and 5-H], 4.13 (q, J = 7.0 Hz, 2

H, OCH₂), 4.11 (q, J = 7.0 Hz, 2 H, OCH₂), 2.91 (d, J_HP= 21.7 Hz, (100 MHz, CDCl₃): δ = 208.1, 162.1, 133.7, 130.5, 81.5, 42.7, 41.6,

2 H, PCH₂), 1.54 (s, 3 H, 1-CH₃), 1.31 (t, J = 7.0 Hz, 6 H,

CH₂CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 185.3, 164.6 (d,

J_CP= 6.1 Hz), 148.7, 128.5, 75.2, 62.6 (d, J_CP= 6.1 Hz), 34.6 (d,

J_CP= 132.0 Hz), 25.8, 16.0, 15.9 ppm. ³¹P{¹H} NMR (162 MHz,

CDCl₃): δ = 19.7 ppm. MS (ESI): m/z (%) = 325 (100) [M + Na]⁺.

HRMS (ESI): calcd. for C₁₃H₁₉NaO₆P [M + Na]⁺325.0811; found

325.0809 (δ =0.9 ppm error).

39.7, 36.0, 28.8, 27.0, 22.6 ppm. MS (ESI): m/z (%) = 231 (100) [M

+ Na]⁺. HRMS (ESI): calcd. for C₁₂H₁₆NaO₃[M + Na]⁺231.0922;

found 231.0933 (δ =0.4 ppm error).

Methyl (2E)-4-{[(Diethoxyphosphoryl)acetyl]oxy}but-2-enoate (43):

Following general procedure 1, T3P^®in toluene (50% w/w, 4.31 g,

6.77 mmol), 42^[40](604 mg, 5.21 mmol), diethylphosphonoacetic

acid (10; 1.07 g, 5.47 mmol), N,N-diisopropylethylamine (1.8 mL,

(3aR*,7aR*)-7a-Methyl-3-methylidene-3a,7a-dihydro-3H,4H-benzo- 10.4 mmol) in THF (40 mL) gave 43 (1.31 g, 86%) as a colourless

furan-2,5-dione (38): Following general procedure 2, potassium tert-

butoxide (3.88  solution in THF, 54 µL, 0.210 mmol), 37 (67 mg,

oil. R = 0.40 (EtOAc). IR (neat): ν = 2986, 1734, 1726, 1438, 1268,

˜

f

1024 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.93 (dt, J = 15.5,

0.221 mmol) and paraformaldehyde (69 mg, 2.21 mmol) in THF 4.5 Hz, 1 H, 3-H), 6.12 (dt, J = 15.5, 2.0 Hz, 1 H, 2-H), 4.81 (dd,

(6 mL) gave 38 (28 mg, 71%) as a colourless solid. M.p. 148–150 °C

(dec.). R = 0.41 (petrol/EtOAc, 1:1). IR (CH Cl ): ν = 2982, 2904,

J = 4.5, 2.0 Hz, 2 H, 4-H), 4.18 (dq, J = 7.5, 7.0 Hz, 4 H, CH₂CH₃),

3.74 (s, 3 H, MeO), 3.02 (d, J_HP= 21.5 Hz, 2 H, PCH₂), 1.34 (t, J

= 7.0 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

˜

f

2

1759, 1679, 1423, 1393, 1352, 1306, 1254, 1238, 1164, 1117, 1071,

1036, 1001, 944, 914, 870, 804, 718 cm^–^{1 1}H NMR (400 MHz,

CDCl₃): δ = 6.59 (dd, J = 10.4, 1.8 Hz, 1 H, 7-H), 6.30 (d, J =

.

166.2, 165.1 (d, J_CP= 6.0 Hz), 140.7, 122.0, 63.4, 62.8 (d, J_CP

=

6.0 Hz), 51.7, 34.2 (d, J_CP= 134.0 Hz), 16.3 (d, J_CP= 6.0 Hz) ppm.

3.4 Hz, 1 H, =CH), 5.98 (d, J = 10.4 Hz, 1 H, 6-H), 5.58 (d, J = MS (ESI): m/z (%) = 317 (100) [M + Na]⁺. HRMS (ESI): calcd.

2.8 Hz, 1 H, =CH), 3.32–3.38 (m, 1 H, 3a-H), 2.83–2.86 (m, 2 H, for C₁₁H₁₉NaO₇P [M + Na]⁺317.0761; found 317.0755 (δ

4-H), 1.74 (s, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

194.9, 168.6, 147.0, 137.7, 129.1, 122.7, 80.0, 44.8, 35.7, 23.5 ppm.

MS (CI): m/z (%) = 196 (100) [M + NH₄]⁺. HRMS (CI): calcd. for

C₁₀H₁₄NO₃[M + NH₄]⁺196.0974; found 196.0977 (δ =1.6 ppm

error).

=1.7 ppm error).

Methyl (4-Methylidene-5-oxotetrahydrofuran-3-yl)acetate (44): Fol-

lowing general procedure 2, potassium tert-butoxide (3.88  solu-

tion in THF, 83 µL, 0.323 mmol), 43 (100 mg, 0.340 mmol) and

paraformaldehyde (102 mg, 3.40 mmol) in THF (7 mL) gave 44

2-(4-Oxocyclohex-2-en-1-yl)propan-2-yl (Diethoxyphosphoryl)ace-

tate (40): Following general procedure 1, T3P^®in toluene (50%

w/w, 3.38 g, 5.30 mmol), 39^[39](628 mg, 4.08 mmol), diethylphos-

phonoacetic acid (10; 839 mg, 4.28 mmol), N,N-diisopropylethyl-

(42 mg, 73%) as a colourless oil. R = 0.80 (EtOAc). IR (neat): ν

˜

f

= 2917, 1766, 1731, 1436, 1174, 1117 cm^–1. ¹H NMR (400 MHz,

CDCl₃): δ = 6.30 (d, J = 2.5 Hz, 1 H, =CH), 5.65 (d, J = 2.5 Hz,

1 H, =CH), 4.61 (t, J = 9.0 Hz, 1 H, CH₂CO), 4.04 (dd, J = 9.0,

amine (1.4 mL, 8.16 mmol) in THF (30 mL) gave 40 (816 mg, 60%) 6.0 Hz, 1 H, CH₂CO), 3.70 (s, 3 H, OMe), 3.54–3.43 (m, 1 H, 3-

as a colourless oil. R = 0.30 (EtOAc). IR (neat): ν = 2983, 1730,

H), 2.74 (dd, J = 17.0, 5.5 Hz, 1 H, 2-H), 2.56 (dd, J = 17.0, 9.5 Hz,

1 H, 2-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.2, 169.9,

136.9, 122.8, 70.8, 52.0, 37.9, 34.9 ppm. MS (ESI): m/z (%) = 171

˜

f

1680, 1391, 1276, 1114, 1025 cm^–1. ¹H NMR (400 MHz, CDCl₃):

δ = 7.05 (dd, J = 10.5, 2.0 Hz, 1 H, 2-H), 6.08 (ddd, J = 10.5, 2.5,

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R. J. K. Taylor et al.

FULL PAPER

(100) [M + H]⁺. HRMS (ESI): calcd. for C₈H₁₁O₄[M + H]⁺

171.0652; found 171.0653 (δ =0.3 ppm error).

59 µL, 0.228 mmol) was added to a stirred solution of 50 (84 mg,

0.240 mmol) and tetrakis(triphenylphosphane)palladium(0)

(14 mg, 0.012 mmol) in THF (5 mL) under argon. The resulting

solution was heated to reflux for 4 h then cooled to r.t. Paraformal-

dehyde (72 mg, 2.40 mmol) was added and the reaction was stirred

for 18 h. The reaction was quenched with aqueous saturated

NH₄Cl (5 mL) and extracted with EtOAc (2ϫ10 mL). The com-

bined organics were dried (Na₂SO₄) and concentrated in vacuo.

The resulting crude residue was purified by flash column

chromatography, eluting with petrol/EtOAc, 1:1, to afford 51

(13 mg, 36%; 3:1 syn:anti) as a colourless oil. R_f= 0.60 (petrol/

General Procedure 4: Preparation of Allylic Esters and Carbonates

syn- and anti-4-(Acetyloxy)cyclohex-2-en-1-yl (Diethoxyphosphoryl)-

acetate (49): Cerium trichloride heptahydrate (0.4  solution in

MeOH, 4.8 mL, 1.91 mmol) was added to a stirred solution of the

enone 11 (555 mg, 1.91 mmol) in dichloromethane (15 mL) at

–78 °C. After 0.5 h, sodium borohydride (108 mg, 2.87 mmol) was

added and the reaction was slowly warmed to room temperature.

After 3 h, the reaction was quenched with water (20 mL), the layers

were separated and the aqueous phase was extracted with dichloro-

methane (3ϫ10 mL). The combined organics were dried (MgSO₄)

and concentrated in vacuo to give a crude product. Purification by

flash chromatography, eluting with MeOH/EtOAc, 5:95, gave an

intermediate alcohol. A stirred solution of the alcohol in pyridine

(4.5 mL) was treated with acetic anhydride (1.5 mL). After 16 h,

the reaction was concentrated in vacuo to give a crude residue.

Purification by flash chromatography, eluting with EtOAc, gave 49

EtOAc, 1:1). IR (neat): ν = 2919, 1761, 1264, 1136 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃; apostrophe denotes anti-isomer): δ = 6.27 (d, J

= 2.5 Hz, 1 H, =CH₂Ј), 6.22 (d, J = 2.0 Hz, 1 H, =CH₂), 6.12–6.05

(m, 1 H, 4Ј-H), 5.94–5.85 (m, 1 H, 4-H), 5.61 (d, J = 2.5 Hz, 1 H,

=CH₂Ј), 5.61 (d, J = 2.5 Hz, 1 H, =CH₂), 5.58–5.54 (m, 2 H, 5Ј-H

and 5-H), 4.92–4.87 (m, 1 H, 7aЈ-H), 4.77 (ddd, J = 6.0, 6.0, 3.0 Hz,

1 H, 7a-H), 3.52 (dddd, J = 8.5, 4.5, 2.0, 2.0 Hz, 1 H, 3a-H), 3.22–

3.14 (m, 1 H, 3aЈ-H), 2.22–2.08 (m, 2 H, 6- and 6Ј-H), 2.08–1.93

(m, 4 H, 6-, 6Ј-, 7- and 7Ј-H), 1.90–1.80 (m, 2 H, 7- and 7Ј-H)

ppm. MS (ESI): m/z (%) = 151 (100) [M + H]⁺. HRMS (ESI):

calcd. for C₉H₁₁O₂[M + H]⁺151.0754; found 151.0754 (δ

=0.3 ppm error).

(327 mg, 51%; 1:1 syn:anti) as a colourless oil. R_f= 0.30 (EtOAc/

1

MeOH, 8:2). IR (neat): ν = 2984, 1731, 1672, 1242, 1025 cm^–1. H

˜

NMR (400 MHz, CDCl₃; apostrophe denotes syn isomer): δ =

5.91–5.88 (m, 4 H, 2-, 2Ј-, 3- and 3Ј-H), 5.39–5.21 (m, 4 H, 1-,

1Ј-, 4-, and 4Ј-H), 4.17 (dq, J = 7.5, 7.0 Hz, 4 H, OCH₂), 4.16 (dq,

J = 7.5, 7.0 Hz, 4 H, OCH₂Ј), 2.96 (d, J_HP= 21.5 Hz, 2 H, PCH₂),

2.95 (d, J_HP= 21.5 Hz, 2 H, PCH₂Ј), 2.14–2.10 (m, 2 H, 6- and 6Ј-

H), 2.05 (s, 3 H, Me), 2.04 (s, 3 H, MeЈ), 1.94–1.83 (m, 4 H, 5-,

5Ј-, 6- and 6Ј-H), 1.79–1.66 (m, 2 H, 5- and 5Ј-H), 1.34 (t, J =

7.0 Hz, 3 H, CH₂CH₃), 1.34 (t, J = 7.0 Hz, 3 H, CH₂CH₃Ј) ppm.

syn-2-[4-(Acetyloxy)cyclohex-2-en-1-yl]propan-2-yl (Diethoxyphos-

phoryl)acetate (52): Following general procedure 4, cerium trichlo-

ride heptahydrate (0.4  solution in MeOH, 4.0 mL, 1.60 mmol),

enone 40 (530 mg, 1.60 mmol) and sodium borohydride (91 mg,

2.40 mmol) in dichloromethane (20 mL); then acetic anhydride

(1 mL) in pyridine (3 mL) gave syn-52 (421 mg, 70%) as a colour-

¹³C NMR (100 MHz, CDCl₃): δ = 170.63, 170.60, 165.4 (d, J_CP

7.0 Hz), 165.3 (d, J_CP= 6.0 Hz), 130.9, 130.7, 129.6, 129.4, 68.7,

68.4, 68.3, 67.30, 67.28, 62.73 (d, J_CP= 6.0 Hz), 62.66 (d, J_CP

=

less oil. R = 0.50 (EtOAc). IR (neat): ν = 2984, 1729, 1371, 1244,

˜

f

=

1028 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.77 (dd, J = 10.5,

6.0 Hz), 34.42 (d, J_CP= 133.5 Hz), 34.40 (d, J_CP= 133.5 Hz), 25.5,

25.4, 24.7, 24.6, 21.24, 21.23, 16.31 (d, J_CP= 6.0 Hz), 16.30 (d, J_CP

= 6.0 Hz) ppm. MS (ESI): m/z (%) = 357 (100) [M + Na]⁺. HRMS:

calcd. for C₁₄H₂₃NaO₇P [M + Na]⁺357.1074; found 357.1085 (δ

=2.6 ppm error).

1.5 Hz, 1 H, 2-H), 5.64 (d, J = 10.5 Hz, 1 H, 3-H), 5.27–5.18 (m,

1 H, 4-H), 4.09 (dq, J = 7.5, 7.0 Hz, 4 H, OCH₂), 2.83 (d, J_HP

=

21.5 Hz, 2 H, PCH₂), 2.83–2.77 (m, 1 H, 1-H), 2.12–2.01 (m, 1 H,

5-H), 1.95 (s, 3 H, Ac), 1.82–1.74 (m, 1 H, 5-H), 1.50–1.25 (m, 2

H, 6-H), 1.38 (s, 3 H, CH₃), 1.34 (s, 3 H, CH₃), 1.28 (t, J = 7.0 Hz,

6 H, CH₂CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 170.7,

syn- and anti-4-[(Methoxycarbonyl)oxy]cyclohex-2-en-1-yl (Di-

ethoxyphosphoryl)acetate (50): Following general procedure 4, ce-

rium trichloride heptahydrate (0.4  solution in MeOH, 5.2 mL,

2.07 mmol), enone 11 (600 mg, 2.07 mmol) and sodium borohyd-

ride (116 mg, 3.11 mmol) in dichloromethane (20 mL); then methyl

chloroformate (1.5 mL) in pyridine (6 mL) gave 50 (326 mg, 45%;

164.6 (d, J_CP= 7.0 Hz), 130.4, 128.9, 86.0, 69.8, 62.3 (d, J_CP

=

6.0 Hz), 43.9, 35.3 (d, J_CP= 134.0 Hz), 28.0, 23.0, 22.4, 22.1, 21.2,

16.2 (d, J_CP= 7.0 Hz) ppm. MS (ESI): m/z (%) = 399 (70) [M +

Na]⁺. HRMS (ESI): calcd. for C₁₇H₂₉NaO₇P [M + Na]⁺399.1543;

found 399.1539 (δ =1.0 ppm error).

1:1 syn:anti) as a colourless oil. R = 0.30 (EtOAc). IR (neat): ν =

˜

f

2983, 1742, 1444, 1263, 1023 cm^–1. ¹H NMR (400 MHz, CDCl₃;

apostrophe denotes syn isomer): δ = 5.98 (d, J = 10.5 Hz, 1 H, 3-

H), 5.97 (d, J = 10.5 Hz, 1 H, 3Ј-H), 5.92 (d, J = 10.5 Hz, 2 H, 2-

and 2Ј-H), 5.39–5.34 (m, 1 H, 4-H), 5.30–5.25 (m, 1 H, 4Ј-H), 5.20–

5.16 (m, 1 H, 1-H), 5.12–5.07 (m, 1 H, 1Ј-H), 4.16 (dq, J = 7.5,

7.0 Hz, 4 H, OCH₂), 4.15 (dq, J = 7.5, 7.0 Hz, 4 H, OCH₂Ј), 3.79

(s, 3 H, OMe), 3.79 (s, 3 H, OMeЈ), 2.97 (d, J_HP= 21.5 Hz, 2 H,

PCH₂), 2.96 (d, J_HP= 21.5 Hz, 2 H, PCH₂Ј), 2.22–2.10 (m, 2 H,

6- and 6Ј-H), 1.99–1.88 (m, 4 H, 5-, 5Ј-, 6- and 6Ј-H), 1.84–1.70

(m, 2 H, 5- and 5Ј-H), 1.34 (t, J = 7.0 Hz, 12 H, CH₂CH₃and

CH₂CH₃Ј) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 165.32 (d, J_CP

= 3.0 Hz), 165.30 (d, J_CP= 3.0 Hz), 155.29, 155.27, 130.11, 130.10,

130.04, 130.00, 71.0, 70.9, 68.4, 68.3, 62.68 (d, J_CP= 6.0 Hz), 62.66

(d, J_CP= 6.0 Hz), 54.78, 54.76, 34.42 (d, J_CP= 133.0 Hz), 34.40 (d,

J_CP= 133.0 Hz), 25.3, 25.2, 24.7, 24.5, 16.31 (d, J_CP= 6.0 Hz),

16.30 (d, J_CP= 6.0 Hz) ppm. MS (ESI): m/z (%) = 373 (100) [M +

Na]⁺. HRMS (ESI): calcd. for C₁₄H₂₃NaO₈P [M + Na]⁺373.1023;

found 373.1025 (δ =0.17 ppm error).

syn-2-{4-[(Ethoxycarbonyl)oxy]cyclohex-2-en-1-yl}propan-2-yl (Di-

ethoxyphosphoryl)acetate (53): Following general procedure 4, ce-

rium trichloride heptahydrate (0.4  solution in MeOH, 0.47 mL,

0.189 mmol), enone 40 (63 mg, 0.189 mmol) and sodium borohyd-

ride (11 mg, 0.284 mmol) in dichloromethane (5 mL); then ethyl

chloroformate (0.5 mL) in pyridine (1.5 mL) gave syn-53 (63 mg,

82%) as a colourless oil. R = 0.50 (EtOAc). IR (neat): ν = 2983,

˜

f

1729, 1371, 1262, 1114, 1025 cm^–1. ¹H NMR (400 MHz, CDCl₃):

δ = 5.96–5.90 (m, 1 H, 2-H), 5.88 (dd, J = 10.5, 1.0 Hz, 1 H, 3-H),

4.60–4.55 (m, 1 H, 4-H), 4.15 (dq, J = 7.5, 7.0 Hz, 4 H, POCH₂),

4.14 (q, J = 7.0 Hz, 2 H, OCH₂), 2.88 (d, J_HP= 21.5 Hz, 2 H,

PCH₂), 2.89–2.83 (m, 1 H, 1-H), 2.17–2.10 (m, 1 H, 5-H), 2.00–

1.86 (m, 1 H, 5-H), 1.70 (dt, J = 9.0, 3.5 Hz, 2 H, 6-H), 1.48 (s, 3

H, CH₃), 1.41 (s, 3 H, CH₃), 1.32 (t, J = 7.0 Hz, 9 H, CH₂CH₃)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 164.8 (d, J_CP= 6.0 Hz),

149.8, 131.1, 128.8, 86.2, 73.4, 62.44 (d, J_CP= 6.0 Hz), 62.41, 54.3,

44.1, 35.4 (d, J_CP= 133.0 Hz), 31.2, 23.5, 22.6, 18.3, 16.2 (d, J_CP

= 7.0 Hz) ppm. MS (ESI): m/z (%) = 429 (40) [M + Na]⁺. HRMS

syn-^[26]and anti-3-Methylidene-3a,6,7,7a-tetrahydro-1-benzofuran- (ESI): calcd. for C₁₈H₃₁NaO₈P [M + Na]⁺429.1649; found

2(3H)-one (51):^[27]Potassium tert-butoxide (3.88  solution in THF,

429.1659 (δ =2.0 ppm error).

4780

www.eurjoc.org

Eur. J. Org. Chem. 2008, 4769–4783

Synthesis of (+)-Paeonilactone B

syn-1,1-Dimethyl-4-methylidene-1,4,4a,7,8,8a-hexahydro-3H-iso- der argon. After 30 min the reaction was cooled to –78 °C and a

chromen-3-one (54): Potassium tert-butoxide (3.88  solution in

THF, 36 µL, 0.141 mmol) was added to a stirred solution of 53

(60 mg, 0.148 mmol) and tetrakis(triphenylphosphane)palla-

dium(0) (9 mg, 0.0074 mmol) in THF (3 mL) under argon. The re-

sulting solution was heated to reflux for 16 h then cooled to r.t.

Paraformaldehyde (44 mg, 1.48 mmol) was added and the reaction

was stirred for 18 h. The reaction was quenched with aqueous satu-

rated NH₄Cl (5 mL) and extracted with EtOAc (2ϫ10 mL). The

combined organics were dried (Na₂SO₄) and concentrated in vacuo.

The resulting crude residue was purified by flash column

chromatography, eluting with petrol/EtOAc, 7:3, to afford 51

solution of 59 (794 mg, 3.30 mmol) in THF (5 mL) was added

dropwise. The resulting solution was stirred for 1 h at –78 °C, then

TESCl (1.39 mL, 8.26 mmol) was added dropwise. After 1 h, the

mixture was warmed to room temperature, stirred for 1 h and

quenched with aqueous saturated NH₄Cl (30 mL). Pentane

(150 mL) was added and the layers were separated. The organic

extract was washed with H₂O (100 mL), aqueous saturated CuSO₄

(100 mL) and saturated brine (100 mL), dried (Na₂SO₄) and con-

centrated in vacuo. The crude material was purified by flash

chromatography, eluting with pentane/Et₂O, 50:1, to give 60

(890 mg, 76%) as a colourless oil. [α]²_D^1.5= –141.9 (c = 1.00,

(1.4 mg, 5%) as a colourless oil. R_f= 0.30 (petrol/EtOAc, 7:3).

CHCl ). R = 0.36 (pentane/Et O, 50:1). IR (neat): ν = 3045, 2955,

˜

3 f 2

2929, 2879, 2856, 1665, 1600, 1461, 1398, 1251, 1195, 1122, 1070,

1

IR (neat): ν = 2921, 2851, 1734, 1463, 1375, 1260 cm^–1. H NMR

˜

(400 MHz, CDCl₃): δ = 6.60 (d, J = 2.5 Hz, 1 H, =CH₂), 5.95–5.89 1006, 910, 836, 775, 743 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ =

(m, 1 H, 5-H), 5.84–5.78 (m, 1 H, 6-H), 5.71 (dd, J = 2.5, 1.0 Hz, 5.70 (d, J = 10.1 Hz, 1 H, 3-H), 5.63 (dd, J = 10.1, 3.4 Hz, 1 H, 4-

1 H, =CH₂), 3.51–3.44 (m, 1 H, 4a-H), 2.20–2.12 (m, 1 H, 8a-H), H), 4.36–4.42 (m, 1 H, 5-H), 2.19–2.35 (m, 2 H, 6-H), 1.69 (s, 3 H,

2.11–2.00 (m, 2 H, 7-H), 1.95–1.88 (m, 1 H, 8-H), 1.78 (ddd, J = 1-CH₃), 0.98 (t, J = 7.6 Hz, 9 H, CH₂CH₃), 0.87 (s, 9 H, tBu), 0.67

12.5, 6.0, 2.5 Hz, 1 H, 8-H), 1.47 (s, 3 H, CH₃), 1.43 (s, 3 H, CH₃) (q, J = 7.6 Hz, 6 H, SiCH₂), 0.06 (s, 3 H, SiCH₃), 0.05 (s, 3 H,

ppm. HRMS (ESI): calcd. for C₁₂H₁₇O₂[M + H]⁺193.1223; found

193.1223 (δ =0.2 ppm error).

SiCH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 141.6, 129.2,

126.8, 111.5, 66.2, 38.5, 25.5, 17.8, 15.8, 6.3, 4.9, –5.0, –5.1 ppm.

MS (CI, NH₃): m/z (%) = 355 (38) [M + H]⁺, 354 (30), 297 (18),

223 (100), 132 (15), 115 (15), 104 (17), 75 (26). HRMS (CI): calcd.

for C₁₉H₃₉O₂Si₂[M + H]⁺355.2489; found 355.2483 (δ =1.7 ppm

error).

(4S,6R)- and (4S,6S)-4-tert-Butyldimethylsilyloxy-6-methylcy-

clohex-2-en-1-one (59): nButyllithium (2.5  solution in hexanes,

3.50 mL, 8.75 mmol) was added dropwise to a stirred solution of

diisopropylamine (1.33 mL, 9.48 mmol) in THF (40 mL) at 0 °C

under argon. After 30 min the reaction was cooled to –78 °C and

(4S,6S)- and (4S,6R)-(–)-4-tert-Butyldimethylsilanyloxy-6-hydroxy-

a solution of (S)-(–)-58 (1.65 g, 7.29 mmol) in THF (15 mL) was 6-methylcyclohex-2-en-1-one (61): DMDO (0.0556  solution in

added dropwise. The resulting solution was stirred for 30 min at

–78 °C, then iodomethane (2.27 mL, 36.5 mmol) was added and

after 5 min, the solution was warmed to –20 °C. After 1 h, the reac-

tion was quenched with aqueous 3  NH₄OH (25 mL) and vigor-

ously stirred. EtOAc (150 mL) and water (50 mL) were added and

the layers were separated. The aqueous layer was extracted with

EtOAc (2ϫ30 mL) and the combined organic extracts were washed

with aqueous saturated CuSO₄(100 mL) and saturated brine

(150 mL), dried (Na₂SO₄) and concentrated in vacuo. The crude

material was purified by flash column chromatography, eluting

with petrol/EtOAc, 19:1, to give 59 (972 mg, 55%; 52:48 mixture

of diastereoisomers) as a pale yellow liquid. R_f= 0.45 (petrol/

Me₂CO, 34 mL, 2.00 mmol; in contrast to the previous work of

Adam and coworkers,^[33]the DMDO solution was NOT predried

with 4 Å mol. sieves) was added over 30 min to a stirred solution of

60 (546 mg, 1.54 mmol) in CH₂Cl₂(5 mL) at –50 °C. The resulting

suspension was stirred for 50 min then carefully concentrated in

vacuo. The residue was taken up in CH₂Cl₂(100 mL), dried

(Na₂SO₄) and concentrated in vacuo. The crude material was puri-

fied by flash chromatography, eluting with petrol/EtOAc, 9:1, to

give (4S,6S)-(–)-61 (326 mg, 83%). [α]²_D^1.5–150.8 (c = 1.00, CHCl₃).

M.p. 42–43.5 °C. R = 0.19 (petrol/EtOAc, 9:1). IR (neat): ν = 3402,

˜

f

2930, 2857, 1677, 1465, 1409, 1378, 1251, 1214, 1166, 1106, 1064,

1

862, 836, 774 cm^–1. H NMR (400 MHz, CDCl₃): δ = 6.75 (ddd, J

EtOAc, 9:1). IR (neat): ν = 2954, 2930, 2857, 1686, 1471, 1462,

= 10.1, 4.0, 1.0 Hz, 1 H, 3-H), 5.98 (dd, J = 10.1, 1.0 Hz, 1 H, 2-

˜

1380, 1254, 1213, 1110, 1048, 1011 cm^–^{1 1}H NMR (400 MHz, H), 4.59 (dddd, J = 5.1, 4.2, 4.0, 1.0 Hz, 1 H, 4-H), 3.05 (s, 1 H,

.

CDCl₃, minor diastereomer is indicated by the use of an apostro-

phe): δ = 6.77 (ddd, J = 10.1, 2.0, 2.0 Hz, 1 H, 3-H), 6.74 (ddd, J

= 10.1, 4.0, 1.0 Hz, 1 H, 3Ј-H), 5.91 (dd, J = 10.1, 2.0 Hz, 1 H, 2-

H), 5.89 (dd, J = 10.1, 1.0 Hz, 1 H, 2Ј-H), 4.59 (dddd, J = 10.3,

5.1, 2.0, 2.0 Hz, 1 H, 4-H), 4.47 (dddd, J = 5.6, 4.2, 4.0, 1.0 Hz, 1

OH), 2.25 (dd, J = 14.0, 5.1 Hz, 1 H, 5-H), 2.11 (ddd, J = 14.0,

4.2, 1.0 Hz, 1 H, 5-H), 1.46 (s, 3 H, 6-CH₃), 0.90 (s, 9 H, tBu), 0.12

(s, 3 H, SiCH₃), 0.11 (s, 3 H, SiCH₃) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 202.4, 150.6, 125.9, 72.5, 64.3, 43.4, 27.0, 25.4, 17.6,

–5.2, –5.3 ppm. MS (ESI): m/z (%) = 279 (100) [M + Na]⁺, 257

H, 4Ј-H), 2.80 (dqd, J = 8.6, 7.2, 4.9 Hz, 1 H, 6Ј-H), 2.36 (dqd, J (20) [M + H]⁺. HRMS (ESI): calcd. for C₁₃H₂₄NaO₃Si [M +

= 13.8, 6.7, 4.4 Hz, 1 H, 6-H), 2.20 (dddd, J = 12.5, 5.1, 4.4, 2.0 Hz,

Na]⁺279.1387; found 279.1397 (δ =3.8 ppm error). Also isolated

1 H, 5-H), 2.06 (dddd, J = 13.4, 5.6, 4.9, 1.0 Hz, 1 H, 5Ј-H), 1.94 was (4S,6R)-61 (10 mg, 2.5%) as a cream solid. M.p. 52–54 °C. R_f

(ddd, J = 13.4, 8.6, 4.2 Hz, 1 H, 5Ј-H), 1.76 (ddd, J = 13.8, 12.5,

10.3 Hz, 1 H, 5-H), 1.15 (d, J = 7.2 Hz, 3 H, 6Ј-CH₃), 1.14 (d, J =

6.7 Hz, 3 H, 6-CH₃), 0.90 (s, 9 H, tBu), 0.88 (s, 9 H, tBuЈ), 0.11 (s,

3 H, SiCH₃), 0.10 (s, 3 H, SiCH₃), 0.09 (s, 3 H, SiCH₃), 0.09 (s, 3

H, SiCH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 203.0, 201.8,

154.5, 149.6, 128.7, 128.5, 68.0, 63.8, 41.2, 40.0, 39.2, 37.5, 25.4,

25.4, 17.8, 17.8, 14.9, 14.7, –5.0, –5.1, –5.19, –5.17 ppm. MS (CI,

NH₃): m/z (%) = 241 (100) [M + H]⁺, 183 (35). HRMS (CI): calcd.

= 0.24 (petrol/EtOAc, 9:1). IR (neat): ν = 3479, 2954, 2930, 2857,

˜

1688, 1462, 1380, 1257, 1161, 1134, 1078, 864, 838, 776 cm^–1. ¹H

NMR (400 MHz, CDCl₃): δ = 6.82 (ddd, J = 10.2, 2.0, 2.0 Hz, 1

H, 3-H), 6.00 (dd, J = 10.2, 2.2 Hz, 1 H, 2-H), 4.55 (dddd, J = 9.8,

5.3, 2.2, 2.0 Hz, 1 H, 4-H), 3.66 (s, 1 H, OH), 2.41 (ddd, J = 12.6,

5.3, 2.0 Hz, 1 H, 5-H), 2.06 (dd, J = 12.6, 9.8 Hz, 1 H, 5-H), 1.29

(s, 3 H, 6-CH₃), 0.90 (s, 9 H, tBu), 0.12 (s, 3 H, SiMe₃), 0.11 (s, 3

H, SiMe₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 202.6, 154.5,

for C₁₃H₂₅O₂Si [M + H]⁺241.1623; found 241.1627 (δ =1.4 ppm 125.3, 73.1, 66.9, 46.4, 25.4, 24.9, 17.7, –5.0, –5.3 ppm. MS (ESI):

error).

m/z (%) = 279 (100) [M + Na]⁺. HRMS (ESI): calcd. for

C₁₃H₂₄NaO₃Si [M + Na]⁺279.1387; found 279.1397 (δ =3.7 ppm

error).

(S)-(–)-5-tert-Butyldimethylsilanyloxy-1-methyl-2-(triethylsilanyloxy)-

cyclohexa-1,3-diene (60): nButyllithium (2.5  solution in hexanes,

1.6 mL, 3.96 mmol) was added dropwise to a stirred solution of

diisopropylamine (601 µL, 4.39 mmol) in THF (55 mL) at 0 °C un-

(4S,6S)-(–)-4,6-Dihydroxy-6-methylcyclohex-2-en-1-one (57): Gla-

cial acetic acid (18 mL) was added to a stirred solution of (4S,6S)-

Eur. J. Org. Chem. 2008, 4769–4783

www.eurjoc.org

4781

R. J. K. Taylor et al.

FULL PAPER

(–)-61 (309 mg, 1.21 mmol) in THF/water (1:1, 12 mL). The re-

sulting suspension was stirred vigorously and heated to 50 °C for

13 h. The reaction was cooled to room temperature, diluted with

EtOAc (150 mL), dried (Na₂SO₄) and concentrated in vacuo. The

crude material was purified by flash chromatography, eluting with

petrol/EtOAc, 1:2, to give (4S,6S)-(–)-57 (134 mg, 79%) as a cream

solid. [α]²_D^1.5= –116.8 (c = 0.895, MeOH). M.p. 95–97 °C. R_f= 0.26

(ESI): calcd. for C₁₀H₁₃O₄[M + H]⁺197.0808; found 197.0807 (δ

= 0.9 ppm error).

CCDC-658935 (for 13), -659261 (for 20), -658922 (for 29), -686541

(for 41) contain the supplementary crystallographic data for this

paper. These data can be obtained free of charge from The Cam-

bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/

data_request/cif.

(petrol/EtOAc, 1:2). IR (neat): ν = 3365, 2978, 2923, 2853, 1680,

˜

1453, 1375, 1252, 1216, 1159, 1125, 1104, 1037, 947, 864, 824 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.91 (ddd, J = 10.1, 1.0, 1.0 Hz,

1 H, 3-H), 6.04 (dd, J = 10.1, 1.4 Hz, 1 H, 2-H), 4.73 (br. s, 1 H,

4-H), 2.87 (s, 1 H, 6-OH), 2.39 (dd, J = 14.0, 5.0 Hz, 1 H, 5-H),

2.12 (dd, J = 14.0, 5.3 Hz, 1 H, 5-H), 1.98 (br. s, 1 H, 4-OH), 1.45

Acknowledgments

We thank Elsevier Science for postdoctoral funding (M.G.E.,

M.N.K. and M.S.S.) and the Engineering and Physical Sciences

Research Council for studentship (R.R.A.K.) and fellowship (A.P.)

support. We are also grateful to Dr. T. Dransfield (University of

York, mass spectrometry) for technical assistance, Archimica for a

gift of T3P^®, BASF for a gift of KDMO in heptanes and GlaxoS-

mithKline for additional support.

1

(s, 3 H, CH₃) ppm. H NMR (400 MHz, CD₃OD): δ = 6.95 (ddd,

J = 10.3, 2.0, 1.8 Hz, 1 H, 3-H), 5.91 (dd, J = 10.3, 2.0 Hz, 1 H,

2-H), 4.66 (ddd, J = 7.4, 4.8, 2.0 Hz, 1 H, 4-H), 2.39 (ddd, J =

13.5, 5.1, 1.7 Hz, 1 H, 5-H), 1.87 (dd, J = 13.5, 8.5 Hz, 1 H, 5-H),

1.30 (s, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CD₃OD): δ = 200.8,

155.3, 127.5, 73.0, 65.2, 46.8, 24.8 ppm. MS (CI): m/z (%) = 160

(100) [M + NH₄]⁺. HRMS (CI): calcd. for C₇H₁₄NO₃[M +

NH₄]⁺160.0972; found 160.0973 (δ =0.7 ppm error).

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ences cited therein.

(1R,5S)-(+)-5-Hydroxy-5-methyl-4-oxocyclohex-2-enyl Diethoxy-

phosphorylacetate (55): Triphenylphosphane (251 mg, 0.956 mmol)

then DIAD (188 µL, 0.956 mmol) were added to a stirred solution

of (4S,6S)-(–)-57 (69 mg, 0.478 mmol) and diethyl phosphonoacetic

acid (10; 141 mg, 0.718 mmol) in THF (12 mL) at 0 °C under ar-

gon. After 0.5 h the cool bath was removed and the reaction was

stirred for 0.5 h as the reaction warmed to room temperature. The

resulting solution was concentrated in vacuo and the crude material

was purified by flash chromatography (it is extremely important to

remove all traces of Ph₃PO prior to the next reaction), eluting with

CH₂Cl₂/EtOAc (1:1)ǞEtOAc, to give (1R,5S)-(+)-55 (99 mg,

64%) as a colourless oil. [α]²_D^1.5= +134.1 (c = 1.10, CHCl₃). R_f=

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0.21 (EtOAc). IR (neat): ν = 3443, 2983, 2934, 1739, 1693, 1391,

˜

1

1371, 1264, 1165, 1108, 1023, 979, 818 cm^–1. H NMR (400 MHz,

CDCl₃): δ = 6.78 (ddd, J = 10.3, 2.0, 2.0 Hz, 1 H, 2-H), 6.09 (dd,

J = 10.3, 2.3 Hz, 1 H, 3-H), 5.66 (dddd, J = 10.1, 5.5, 2.3, 2.0 Hz,

1 H, 1-H), 4.17–4.08 (m, 4 H, OCH₂), 3.77 (br. s, 1 H, OH), 2.98

(d, J_HP= 21.7 Hz, 2 H, PCH₂), 2.51 (ddd, J = 12.3, 5.5, 2.0 Hz, 1

H, 6-H), 2.10 (dd, J = 12.3, 10.1 Hz, 1 H, 6-H), 1.33 (s, 3 H, 6-

CH₃), 1.32–1.26 (m, 6 H, CH₂CH₃) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 201.8, 165.5 (d, J_CP= 6.5 Hz), 148.2, 127.5, 73.0, 69.0,

62.8 (d, J_CP= 6.1 Hz), 62.7 (d, J_CP= 6.3 Hz), 41.8, 34.0 (d, J_CP

=

133.3 Hz), 24.7, 16.0, 15.9 ppm. ³¹P{¹H} NMR (162 MHz,

CDCl₃): δ = 19.5 ppm. MS (CI): m/z (%) = 338 (42) [M + NH₄]⁺,

321 (100) [M + H]⁺. HRMS (CI): calcd. for C₁₃H₂₂O₇P [M + H]⁺

321.1101; found 321.1103 (δ =0.7 ppm error).

(+)-Paeonilactone (1):^[2]Following general procedure 2, potassium

tert-butoxide (3.88  solution in THF, 47 µL, 0.184 mmol),

(1R,5S)-(+)-55 (62 mg, 0.193 mmol) and paraformaldehyde (58 mg,

1.93 mmol) in THF (4.5 mL) gave 1 (26 mg, 70%) as a colourless

solid. [α]²_D^0.5= +23.8 (c = 1.04, MeOH) [ref.^[2]+23.2]. M.p. 86–

87 °C [ref.^[2]88–89 °C]. R = 0.42 (EtOAc). IR (neat): ν = 3442,

˜

f

2970, 2927, 2849, 1757, 1722, 1660, 1409, 1339, 1271, 1237, 1159,

1

1101, 1029, 993, 948 cm^–1. H NMR (400 MHz, CDCl₃): δ = 6.34

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(d, J = 3.0 Hz, 1 H, =CH), 5.66 (d, J = 2.7 Hz, 1 H, =CH), 4.98

(ddd, J = 8.9, 8.2, 5.8 Hz, 1 H, 7a-H), 3.67 (ddddd, J = 8.9, 7.6,

4.3, 3.0, 2.7 Hz, 1 H, 3a-H), 3.42 (s, 1 H, OH), 2.94 (dd, J = 16.1,

7.6 Hz, 1 H, 4-H), 2.77 (dd, J = 16.1, 4.3 Hz, 1 H, 4-H), 2.50 (dd,

J = 14.0, 5.8 Hz, 1 H, 7-H), 1.96 (dd, J = 14.0, 8.9 Hz, 1 H, 7-H),

1.39 (s, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 209.8,

168.8, 136.4, 123.1, 73.8, 73.1, 41.4, 39.2, 36.7, 24.9 ppm. MS

(ESI): m/z (%) = 214 (11) [M + NH₄]⁺, 197 (100) [M + H]⁺. HRMS

4782

www.eurjoc.org

Eur. J. Org. Chem. 2008, 4769–4783

Synthesis of (+)-Paeonilactone B

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Published Online: August 28, 2008

Eur. J. Org. Chem. 2008, 4769–4783

www.eurjoc.org

4783

Article Doi

The preparation of α-alkylidene-γ-butyrolactones using a telescoped intramolecular Michael/Olefination (TIMO) sequence: Synthesis of (+)-paeonilactone B

DOI: 10.1002/ejoc.200800558

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