Asymmetric dihydroxylation of β,γ-unsaturated carboxylic esters with trisubstituted C=C bonds - Enantioselective syntheses of trisubstituted γ-butyrolactones

FULL PAPER

DOI: 10.1002/ejoc.200500963

Asymmetric Dihydroxylation of β,γ-Unsaturated Carboxylic Esters

with Trisubstituted C=C Bonds – Enantioselective Syntheses of Trisubstituted

γ-Butyrolactones

Tobias Kapferer^[a]and Reinhard Brückner*^[a]

Keywords: Asymmetric dihydroxylation / Butyrolactones / β,γ-Unsaturated carboxylic esters / Stereoselective synthesis /

Wolff rearrangement

β,γ-Unsaturated esters with stereodefined trisubstitued C=C

double bonds were prepared by the Arndt–Eistert homologa-

tion of α,β-unsaturated carboxyl halides, by two-step meth-

oxycarbonylation of allylbarium reagents, by deconjugation

of α,β-unsaturated esters, and by Horner–Wadsworth–Em-

mons variants of the Stobbe condensation. Sharpless asym-

metric dihydroxylation of the β,γ-unsaturated esters, fol-

lowed by spontaneous cyclization, afforded β-hydroxy-γ-lac-

tones in moderate to good yields and with enantiomeric ex-

cesses of up to 97%. Similarly, tetrahydroxy-γ-lactones were

obtained from diunsaturated esters; these lactones were con-

verted into a bislactone and an unsaturated β-hydroxy γ-lac-

tone.

Germany, 2006)

Introduction

γ-Lactones are a commonly encountered structural motif

in nature^[1]and synthesis (both as targets and synthetic in-

termediates). This is particularly true if these γ-lactones are

enantiomerically pure. Accordingly, a considerable body of

methods for synthesizing such lactones with saturated (“bu-

tanolides”^[2]) or α,β-unsaturated rings (“∆³-butenolides”^[3])

has been developed over the years. They include a straight-

forward asymmetric synthesis by our group, based on

Sharpless’ asymmetric dihydroxylation (“AD reaction”)^[4]

of β,γ-unsaturated carboxylic esters 1 (Scheme 1).^[5]This

approach provides γ-lactones 3 with ees of typically 94–

98%, in good yields and a single step.^[5–7]

Scheme 1. Dihydroxylation strategy for the asymmetric synthesis of

γ-lactones.

In all previous studies by this group^[5b,6,7](with a single

exception;^[8]vide infra) and by others^[5a,9]the AD reaction

has been performed upon β,γ-unsaturated carboxylic esters

1 containing disubstituted C^β=C^γdouble bonds (Scheme 1:

R²= H), resulting in the formation of γ-monoalkyl- or γ-

monoaryl-β-hydroxy-γ-lactones 3 (R²= H). A logical exten-

sion of this concept appeared to be analogous AD reactions

of β,γ-unsaturated carboxylic esters 1 containing trisubsti-

tuted C^β=C^γdouble bonds (Scheme 1: R²϶ H). They

should provide β,γ-dialkyl- and γ,γ-dialkyl-β-hydroxy-γ-lac-

tones 3 (R²϶ H) as well as their aryl-containing congeners.

This paper describes how this concept was put into practice.

A prerequisite for this study was the acquisition of model

esters for the AD reaction as pure stereoisomers with re-

spect to their C^β=C^γdouble bonds; otherwise AD reactions

of these esters would give mixtures of lactone dia-

stereomers. Stereodefined β,γ-unsaturated esters were ob-

tained by the following approaches: Arndt–Eistert homolo-

gation of α,β-unsaturated acids [7–10, (E)- and (Z)-14], car-

boxylation of allyl barium compounds [(E)- and (Z)-18],

Horner–Wadsworth–Emmons reactions (“HWE reactions”)

[(E)-31–34, (Z)-31, (Z)-33 and -34], and deprotonation/re-

protonation of α,β-unsaturated carboxylic esters (24, 25).

Results and Discussion

Preparation of the AD Precursors

[a] Institut für Organische Chemie und Biochemie, Albert-Lud-

wigs-Universität,

The majority of our syntheses of stereochemically pure

β,γ-unsaturated carboxylic esters were achieved by Arndt–

Eistert homologation of analogously substituted α,β-unsat-

Albertstr. 21, 79104 Freiburg, Germany

Fax: +49-761-2036100

E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de

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T. Kapferer, R. Brückner

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urated carboxylic acids.^[10]This approach worked well when

starting from the α,β-dialkylated α,β-unsaturated acids 4a–

d (Scheme 2) and the β,β-dialkylated α,β-unsaturated acids

(E)- and (Z)-11 (Scheme 3). Acids 4a and 4b were obtained

by alkaline hydrolyses of the corresponding (E)-configured

α,β-unsaturated esters (not shown), these in turn being ob-

tained by Wittig reactions.^[11]Acid 4c was synthesized as

described,^[36]whilst acid 4d is commercially available. Acids

(E)- and (Z)-11 were produced through cis-selective carbo-

cuprations of appropriately substituted alkynoic acids.^[12]

Scheme 3.^[8]Arndt–Eistert homologation of β,β-dialkyl α,β-unsatu-

rated carboxylic acid chlorides. Reagents and conditions: (a) SOCl₂

(1.0 equiv.), DMF (cat.), CH₂Cl₂, 0 °C Ǟ room temp., 3 h.

(b) CH₂N₂(2.0 equiv.), iPr₂NEt (1.0 equiv.), Et₂O, 0 °C Ǟ room

temp., 1 h: 55% over the two steps. (c) AgOBz (0.3 equiv.), NEt₃

(4.7 equiv.), MeOH, room temp., 5 h; 88% (E:Z = 100:0). (Z)-14:

Z:E = 100:0.

the desired β,γ-unsaturated methyl esters 7–10, (E)-13, and

(Z)-13, respectively. These were produced with complete re-

tention of the C=C double bond configuration.

Geraniol [(E)-15] and nerol [(Z)-15] were converted into

the analogous chlorides (E)- and (Z)-15, respectively,

through treatment with mesyl chloride and triethylamine^[15]

(Scheme 4). The corresponding barium derivatives – ob-

tained by treatment with Rieke barium (from anhydrous

barium iodide and lithium biphenylide) – were C₁-extended

through addition to carbon dioxide. This afforded the β,γ-

unsaturated carboxylic acids (E)- and (Z)-17 stereospecifi-

cally, as reported by Yamamoto et al.^[16]Methyl ester for-

mation with (trimethylsilyl)diazomethane^[17]in benzene/

methanol gave the desired β,γ-unsaturated esters (E)- and

(Z)-18 in 96% yield and diastereomerically pure within the

Scheme 2. Arndt–Eistert homologation of α,β-dialkyl α,β-unsatu-

rated carboxyl bromides. Reagents and conditions: (a) For 5a–c:

(COBr)₂(1.01 equiv.), no solvent, –15 °C, overnight; for 5d:

1

limits of H NMR detection.

1-bromo-2-(dimethylamino)-2-methyl-1-propene

(1.0 equiv.),

CH₂Cl₂, 0 °C Ǟ room temp., 1 h. (b) CH₂N₂(1.0 equiv.), iPr₂NEt

(1.1 equiv.), Et₂O, 0 °C Ǟ room temp., 2 h; 6a: 28% over the two

steps; 6b: 83% over the two steps; 6c: 81% over the two steps; 6d:

52% over the two steps. (c) AgOBz, NEt₃, MeOH, room temp., 5 h;

7 (E:Z = 100:0): 76%; 8 (E:Z = 100:0): 77%; 9 (E:Z = 100:0): 87%;

10 (E:Z = 100:0): 86%.

It is known that the acylation of diazomethane with acti-

vated α,β-unsaturated carboxylic acids may be ac-

companied by pyrazoline formation through a 1,3-dipolar

cycloaddition of diazomethane to the electron-deficient

C^α=C^βbond.^[13]This competition was detrimental to for-

mation of the desired diazo ketones 6a–d from the acid

chlorides obtained from the α,β-dialkylated α,β-unsaturated

acids 4a–d (Scheme 2). In contrast, pyrazoline formation

was insignificant in diazomethane treatment of acid chlo-

rides (E)- and (Z)-12 [Ǟ diazo ketones (E)- and (Z)-13,

respectively; Scheme 3]. With use of the α,β-unsaturated

acid bromides 5a–d – rather than the analogous chlorides –

as acylating agents, however, diazo ketones 6a–d were also

generated successfully (Scheme 2).

Scheme 4. Methoxycarbonylation of allylbarium reagents. Reagents

and conditions: (a) MeSO₂Cl (1.5 equiv.), pentane, –5 °C, 30 min;

pyridine (2.0 equiv.), pentane, room temp., 14 h; 83% (ref.^[15]74%).

(b) BaI₂(2.2 equiv.), Li biphenylide (4.4 equiv.), THF, –78 °C,

30 min; CO₂(gaseous), 30 min; 61% (ref.^[16]87%). (c) Me₃SiCHN₂

(1.3 equiv.), MeOH/benzene (1:3.6), room temp., 1 h; 96% (E:Z =

100:0). (Z)-18: Z:E = 100:0.

Silver benzoate-induced Wolff rearrangements^[14]of di-

We found the syntheses of ester (E)-18 shown in

azo ketones 6a–d, (E)-13, and (Z)-13 in methanol furnished Scheme 4 superior to carboxymethylation of either allyl

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chloride (E)-16 or the analogous allyl phosphate with CO/

methanol in the presence of Pd₂(dba)₃/NaOMe.^[18]This

kind of reaction was poorly stereoselective in our hands;

chloride (E)-16, for example, gave (E)-18:(Z)-18 = 73:27

(74%).

β,γ-Unsaturated esters 24^[19]and 25^[20]contain endo-

cyclic C^β=C^γbonds: namely, a cyclopentenyl and a cyclo-

hexenyl moiety, respectively (Scheme 5). These compounds

were obtained by deconjugation of the isomeric α,β-unsatu-

rated esters 22^[19]and 23,^[20]respectively, these in turn being

obtained by HWE reactions between the appropriate cyclo-

alkanones and phosphonate 21.^[21]Deconjugation was

achieved by subsequent deprotonation with LDA followed

by reprotonation with aqueous NH₄Cl and glacial acetic

acid, respectively.

Scheme 6. (E)-selective Horner–Wadsworth–Emmons variant of

the Stobbe condensation. Reagents and conditions: (a₁) 26, NaH

(1.0 equiv.), EtOH, 0 °C Ǟ room temp., 30 min; addition of 27

(1.0 equiv.), 1 h (Ǟ 28; not isolated). (a₂) Crude 28, 29 (1.0 equiv.)

or 30 (1.0 equiv.), 4 h [for preparation of (E)-32] or overnight [for

preparation of (E)-34]; (E)-32: 61% (E:Z = 82:18); (E)-34: 48%

(E:Z = 93:7). (b) NaH (2.0 equiv.), MeOH, room temp., 2 d; 87%

(E:Z = 81:19); (c) same as b), 3 d; 81% (E:Z = 92:8).

Scheme 5. Formation and deconjugation of α,β-unsaturated esters.

Reagents and conditions: (a) NaOMe (1.2 equiv.), methanol, room

temp., 12 h, 22: 93% (as a 90:10 mixture with 24), 23: 98%.

(b) LDA (1.1 equiv.), THF, –78 °C, 1 h; NH₄Cl (for 24) or HOAc

(for 25); 24: 76%, 25: 78%.

The second largest number of β,γ-unsaturated ester syn-

theses in this study was obtained by HWE variants of the

Stobbe condensation (Scheme 6, Scheme 7). These reactions

furnished diethyl diesters (E)-32, (E)-34, and (Z)-34 and di-

methyl diesters (Z)-31 and (Z)-33. Subsequent transesterifi-

cations of diethyl diesters (E)-32 and (E)-34 with sodium

methoxide also gave the dimethyl diesters (E)-31 and (E)-

33.

We tried to establish the C^β=C^γbonds in the described

“Stobbe condensation products” stereoselectively by vary-

ing the phosphonate moieties in the employed HWE rea-

gents: with a (EtO)₂P(=O) moiety in HWE reagent 28

(Scheme 6) as opposed to a (PhO)₂P(=O) moiety in the

HWE reagents 37 and 38^[22]in Scheme 7. The presence of

the (EtO)₂P(=O) moiety in HWE reagent 28 made the ole-

finations of the aliphatic aldehyde 29 and of benzaldehyde

(30) (E)-selective to extents of 82:18 (32) and 93:7 (34), Scheme 7. (Z)-selective Horner–Wadsworth–Emmons variant of

the Stobbe condensation. Reagents and conditions: (a) 35, NaH

respectively (Scheme 6). The (PhO)₂P(=O)-containing

(1.0 equiv.), THF, 0 °C Ǟ room temp., 30 min, addition of 36

HWE reagents 37 and 38^[22]olefinated the same aldehydes

(1.0 equiv.), 3 h; 69% 37; 38.^[22](b) 37 or 38, NaH (1.0 equiv.), 29

with Z:E selectivities between 81:19 (Ǟ34) and 67:33 (Ǟ31;

(1.0 equiv.) or 30 (1.0 equiv.), THF, 0 °C Ǟ room temp., 3 h [for

Scheme 7);^[23]to the best of our knowledge, these last rea-

preparation of (Z)-31 and (Z)-33] or 1 h [for preparation of (Z)-

34]; (Z)-31: 86% (Z:E = 80:20); (Z)-33: 48% (Z:E = 67:33); (Z)-

34: 79% (Z:E = 81:19).

gents have been used for (Z)-selective succinylidenations for

the first time. In all instances, the major unsaturated ester

isomer could be obtained isomerically pure by flash

chromatography^[24]on silica gel.

order to collect a fairly comprehensive set of data, all AD

reactions were performed separately in the presence of the

chiral auxiliaries contained in AD mix^®α [i.e., (DHQ)₂-

PHAL] and AD mix^®β [(DHQD)₂PHAL], routinely using

AD Reactions

Having made the selected β,γ-unsaturated model esters the so-called “improved”^[25]conditions and only occasion-

accessible as single stereoisomers, we proceeded to examine ally oxidant and auxiliary stoichiometries approaching

magnitudes of stereocontrol during their AD reactions. In “standard AD conditions”.^[26]

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All AD results are shown in Table 1, Table 2, and (55%, 56%; Entries 9, 10). This appears to reflect an elec-

Table 3. Table 1 relates to β,γ-disubstituted esters contain- tronic and a steric effect, respectively.

ing (E)-configured R¹–C=C–CH₂–CO₂R³moieties as sub-

An unusual chemoselectivity of two pairs of AD reac-

strates, Table 2 to AD reactions of β,γ-disubstituted esters tions in Table 1 deserves mention (Entries 3–6). β,γ-Dihy-

with (Z)-configured R¹–C=C–CH₂–CO₂R³moieties, and droxy ester 40a (or its enantiomer 40b) obtained from cy-

Table 3 to the behavior of pairs of E,Z-isomeric γ-disubsti- clopentene 24 did not lactonize at all (Entries 3, 4). Simi-

tuted β,γ-unsaturated esters under AD conditions.

larly (Entries 5, 6), only ca. 25% of the β,γ-dihydroxy ester

The AD reactions of β,γ-disubstituted esters with (E)- 42a (or its enantiomer 42b) obtained from cyclohexene 25

configured (cf. footnote [a] of Table 1) R¹–C=C–CH₂– cyclized to give γ-lactone 41a (or its enantiomer 41b). These

CO₂R³moieties were reasonably high-yielding (Table 1), observations contrast with the spontaneous and complete

the yields for 18 reactions averaging 69% and the peak yield lactonization of all β,γ-dihydroxy esters previously obtained

being 87% (Entries 3, 7). The lowest yields, not unexpec- under AD conditions (Scheme 1). The decreased driving

tedly, resulted from AD reactions with benzylidene succi- force for lactonization in the cases under scrutiny must be

nates (Z)-33 and (Z)-34 (38%, 47%, 49%; Entries 15–17) due to the extra strain expected for trans-fused bicyclic γ-

and with ester 9, which contains a tert-butylated C=C bond lactones.

Table 1. AD reactions^[25]of β,γ-unsaturated β,γ-disubstituted esters containing (E)-configured^[a]R¹-C=C–CH²–CO₂R³moieties.

[a] This classification is also true for the substrates of Entries 9–14 although their C=C configurations are “(Z)” by the Cahn–Ingold–

Prelog priority rules. [b] Absolute configurations were not proven but were assigned in accordance with “Sharpless’ mnemonic” (ref.^[4c,4g]).

[c] Determined by chiral GC and HPLC (details: Experimental Part). [d] Determined after transformation into the corresponding aceto-

nide (without formula number; for details see the Exp. Sect.).

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Table 2. AD reactions^[25]of β,γ-unsaturated β,γ-disubstituted esters containing (Z)-configured^[a]R¹-C=C–CH²–CO₂R³moieties.

[a] This classification is true for all substrates of this Table even if their C=C configuration is “(E)” by the Cahn–Ingold–Prelog priority

rules. [b] Absolute configurations were not proven but were assigned in accordance with “Sharpless’ mnemonic” (ref.^[4c,4g]). [c] Determined

by chiral GC and HPLC (for details see the Exp. Sect.).

The enantiomeric excesses in the AD reactions in Table 1 the (DHQD)₂PHAL-mediated AD of benzylidenesuccinate

span a range from 83–85% ee at best (for the γ-phenylated (E)-34.

ester 10; Entries 11, 12) to 23% ee at worst (for the cyclo-

AD reactions of two pairs of E,Z-isomeric γ,γ-disubsti-

hexene-containing ester 25; Entry 5). For most substrates, tuted β,γ-unsaturated esters [(E)- and (Z)-14,^[8](E)- and

(DHQD)₂PHAL is a more efficient chiral auxiliary than (Z)-18] proceeded with yields around 75–90% (Table 3). Es-

(DHQ)₂PHAL (Entries 1–14), as usually observed in AD ters (E)- and (Z)-18 underwent dihydroxylation at both

chemistry.^[4]However, the AD reactions of benzylidene suc- C=C bonds, giving rise to the trihydroxy-γ-lactones 53 and

cinates (Z)-33 and -34 represent exceptions (Entries 15–18). 55.

Also noteworthy is that the AD reaction of cyclopent-annu-

Half of the ees of the AD reactions summarized in

lated ester 24 proceeds with considerably more stereocon- Table 3 were in the nineties (Entries 1, 2, 7, 8), half in the

trol (66% and 79% ees; Entries 3, 4) than that of the cy- eighties (Entries 3–6). Of the monounsaturated substrate

clohex-annulated analogue 25 (23% and 44% ees; Entries 5, isomers (E)- and (Z)-14, the former (Entries 1, 2) reacted

6). The absolute configurations of the products depicted in with higher enantioselectivity than the latter (Entries 5, 6):

Table 1 were not elucidated experimentally but were as- (E)-14 Ǟ 97% ee in the presence of (DHQD)₂PHAL vs.

signed on the basis of Sharpless’ “mnemonic aid”,^[4c,4g](Z)-14 Ǟ 85% ee; (E)-14 Ǟ 91% ee in the presence of

which is believed to predict correctly the C–OH bond orien- (DHQ)₂PHAL vs. (Z)-14 Ǟ 80% ee. For the diunsaturated

tations resulting from the trans-configured R¹-C=C–R²isomeric substrates (E)- and (Z)-18, this order was reversed,

substructure of any AD substrate containing it.

with the (E) isomer (Entries 3, 4) reacting less enantioselec-

The AD reactions of β,γ-disubstituted esters containing tively than the (Z) isomer (Entries 7, 8): (E)-18 Ǟ 82% ee

(Z)-configured (cf. footnote [a], Table 2) R¹–C=C–CH₂– in the presence of (DHQD)₂PHAL vs. (Z)-18 Ǟ 93% ee;

CO₂R³moieties are summarized in Table 2. The configura- (E)-18 Ǟ 83% ee in the presence of (DHQ)₂PHAL vs. (Z)-

tions of the resulting γ-lactones were again not determined 18 Ǟ 90% ee. These juxtapositions imply the following:

experimentally but assigned on the basis of Sharpless’ (i) the Me₂C=CH–CH₂moiety in the di-unsaturated sub-

“mnemonic aid”.^[4c,4g]The yields and ees of the AD prod- strate 18 is dihydroxylated as rapidly as – or even more

ucts in Table 2 were consistently higher than those observed rapidly than – the C^γ=C^βH–CH₂–CO₂Me moiety, and (ii)

on starting from the isomeric substrates (Table 1, En- the resulting Me₂C(OH)–CH(OH)–CH₂moiety exerts some

tries 13–18). As almost always,^[4](DHQD)₂PHAL was substrate control over stereoselectivity during the (remain-

more powerful than (DHQ)₂PHAL as a chiral auxiliary. der) of the dihydroxylation of the C^γ=C^βH–CH₂–CO₂Me

Consistently with this, the highest ee (90%) was observed in moiety, opposing reagent control for the (E)-olefin (“mis-

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Table 3. AD reactions (“compromise stoichiometry” between the quantities of ref.^[26]and ref.^[25]) of β,γ-unsaturated γ-disubstituted esters

[pairs of (E)- and (Z) isomers].

[a] Absolute configurations were assigned by “Sharpless’ mnemonic” (ref.^[4c,4g]); moreover, they are consistent with the independently

assigned absolute configurations of the β-hydroxy-γ-methyl-γ-pentyl-γ-butyrolactone stereoisomers obtained by analogous AD reactions

(ref.^[8]). [b] Determined by chiral GC; for details see Experimental Part. [c] This moiety was also dihydroxylated during the AD reaction.

[d] Twice as much of each reagent was used as indicated in the equation. [e] Determined after transformation into 57a and 57b, respectively

(Scheme 8). [f] Determined after transformation into 59a and 59b, respectively (Scheme 9).

matched case”) and reinforcing it for the (Z)-olefin

(“matched case”).

The monohydroxy lactone 54a (80% ee; Table 3, Entry 5)

and its enantiomer 54b (85% ee, Entry 1) had been em-

ployed previously for elucidation of the 3D structure of a

butenolide from the moss Plagiomnium undulatum by syn-

thesis.^[8]The trihydroxy lactones 53 and 55 were carried on

as summarized in Scheme 8 and Scheme 9, respectively.

These transformations served two purposes: (i) determi-

nation of the stereochemical purity of the lactone moiety,

and (ii) preparation of nonracemic β-hydroxy-γ-lactones

containing an additional functional group in one γ-substit-

uent.

Scheme 8. Bislactone synthesis from butyrolactone 53a and its en-

Trihydroxy lactone 53a and its enantiomer 53b – both

antiomer. Reagents and conditions: (a) NaIO₄(1.1 equiv.), THF,

derived from methyl geranylcarboxylate – were consecu-

H₂O, room temp., 2 h; 64%, dr 79:21. (b) PCC (2.0 equiv.), CH₂Cl₂,

tively subjected to glycol cleavage^[27]and PCC oxidation of

room temp., 12 h; 57%.

the resulting lactols^[28](Scheme 8), affording bislactone 57a

and its enantiomer 57b, respectively. We needed these com-

pounds chiefly for analytical purposes – namely, ee determi-

Trihydroxy lactone 55a and its enantiomer 55b – both

nation (83 and 82%, respectively) – though their syntheses derived from methyl nerylcarboxylate – rendered the lac-

also represent a straightforward enantioselective route to a tone-containing hydroxyaldehydes 58 when subjected to

structural motif that might otherwise be difficult to obtain. glycol cleavage^[27](Scheme 9). Obviously, lactol formation

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Institut für Organische Chemie und Biochemie, University of Frei-

burg. MS: Dr. J. Wörth and C. Warth, Institut für Organische

Chemie und Biochemie, University of Freiburg. IR spectra: Perkin–

Elmer Paragon 1000. Optical rotations were measured with a Per-

kin–Elmer polarimeter 341 at 589 nm and 20 °C and were calcu-

lated by the Drude equation {[α]_D= (α_exp×100)/(c×d)}; rotational

values are the average of five measurements of α_expin a given solu-

tion of the respective sample. Melting points were measured on a

Dr. Tottoli apparatus (Büchi) and are uncorrected. The ee values

were determined by chiral GC with a Carlo Erba Instruments HRC

5160 Mega series apparatus with a Varian CP7502 (β-cyclodextrin/

dimethylpolysiloxane) column (isothermal analysis) or by chiral

HPLC with a Chiralpak AD (Daicel Chemical Ind. Ltd.) column.

(E)-2-Ethylpent-2-enoic Acid (4a):^[31]a) Propionaldehyde (131 mg,

2.25 mmol, 1.3 equiv.) was added to a solution of ethyl 2-(tri-

phenylphosphanylidene)butanoate^[32](636 mg, 1.69 mmol) in ben-

zene (5 mL). After having been heated at 70 °C for 3.5 h, the mix-

ture was allowed to reach room temperature and stirred overnight.

After evaporation in vacuo the residue was purified by flash

chromatography (cyclohexane/EtOAc, 60:1) to afford ethyl (E)-2-

ethylpent-2-enoate^[31](225 mg, 96%, E:Z = 96:4): ¹H NMR

(300 MHz, CDCl₃): δ = 1.00 (t, J_2Ј,1Ј= 7.5 Hz, 2Ј-H₃)*, 1.05 (t, J_5,4

= 7.5 Hz, 5-H₃)*, 1.29 [t, J_vic= 7.1 Hz, CO₂CH₂CH₃; (E) isomer],

superimposed by 1.30 [t, J_vic= 7.2 Hz, CO₂CH₂CH₃; (Z) isomer],

2.19 (dq, J_4,3= J_4,5= 7.5, 4-H₂), 2.31 (q, J_1Ј,2Ј= 7.5 Hz, 1Ј-H₂),

4.19 (q, J_vic= 7.1 Hz, CO₂CH₂CH₃), 5.81 [m_c, 3-H; (Z) isomer],

6.70 [t, J_3,4= 7.5 Hz, 3-H; (E) isomer] ppm; * = assignments inter-

changeable.

Scheme 9. Unsaturated lactone synthesis from butyrolactone 55a

and its enantiomer. Reagents and conditions: (a) NaIO₄

(1.1 equiv.), EtOAc, H₂O, room temp., 30 min; 94%. (b) Ph₃P=CH₂

(1.6 equiv.), THF, –5 °C Ǟ room temp., 1.5 h; 31%.

was hampered by the arising of ring-strain. Wittig methyl-

enation^[11,29]of the aldehyde group furnished the unsatu-

rated γ-lactone 59a (90% ee) and its enantiomer 59b

(93% ee).

Conclusions

We have studied the asymmetric dihydroxylation of β,γ-

unsaturated carboxylic esters with trisubstituted double

bonds. Except in those esters in which the C^γ=C^βbond was

part of a five-membered (namely compound 24) or a six-

b) A solution of LiOH·H₂O (6.64 g, 0.158 mol, 10 equiv.) in H₂O

(40 mL) was added to a solution of ethyl (E)-2-ethylpent-2-enoate

(2.472 g, 15.82 mmol) in MeOH (165 mL). The mixture was heated

membered ring (namely compound 25), each substrate was at 45 °C for 7.5 h and stirred overnight at room temperature. After

removal of MeOH in vacuo, the mixture was acidified with HCl

(2 ) and extracted with EtOAc (3×70 mL). The combined organic

extracts were dried with MgSO₄and the solvents were evaporated

in vacuo. The residue was purified by flash chromatography (cyclo-

hexane/EtOAc, 15:1) to afford the title compound (1.604 g, 79%):

¹H NMR (300 MHz, CDCl₃): δ = 1.03 (t, J_5,4= 7.5 Hz, 5-H₃)*,

1.07 (t, J_2Ј,1Ј= 7.5 Hz, 2Ј-H₃)*, 2.23 (dq, J_4,3= J_4,5= 7.4 Hz, 4-

H₂), partly superimposed by 2.32 (q, J_1Ј,2Ј= 7.4 Hz, 1Ј-H₂), 6.87

(t, J_3,4= 7.5 Hz, 3-H), 11.70 (br.s, CO₂H) ppm; * = assignments

interchangeable.

smoothly converted into the corresponding trisubstituted γ-

lactone (Table 1-Table 3). Lactone yields were good to ex-

cellent (up to 92%, Table 3, Entry 5). Enantiocontrol

strongly depended on the substrate, lactone ee values span-

ning a range from 97% (Table 3, Entry 2) to 23% (Table 1,

Entry 5), though half of our AD reactions proceeded with

ees Ͼ80%. This shows that our strategy for the construc-

tion of enantioenriched γ-lactones through the AD reac-

tions of β,γ-unsaturated carboxylic esters is not limited to

the production of disubstituted γ-lactones but is also useful

for the synthesis of trisubstituted γ-lactones.

(E)-2,4-Dimethylpent-2-enoic Acid (4b):^[33]a) Isobutyraldehyde

(3.732 g, 51.75 mmol, 1.7 equiv.) was added to a solution of ethyl 2-

(triphenylphosphanylidene)propionate^[34](10.84 g, 30.00 mmol) in

benzene (30 mL). After having been heated at 70 °C overnight, the

mixture was allowed to reach room temperature and the solvents

were evaporated in vacuo. The residue was purified by flash

chromatography (cyclohexane/EtOAc, 60:1) to afford ethyl (E)-2,4-

dimethylpent-2-enoate^[35](4.241 g, 90%, E:Z = 96:4): ¹H NMR

(300 MHz, CDCl₃): δ = 0.98 [d, J_4-Me,4= J_5,4= 6.7 Hz, 4-CH₃, 5-

H₃; (Z) isomer], 1.02 [d, J_4-Me,4= J_5,4= 6.6 Hz, 4-CH₃, 5-H₃; (E)

Experimental Section

All reactions were performed in oven-dried (110 °C) glassware un-

der N₂. THF was freshly distilled from K, CH₂Cl₂was distilled

from CaH₂. Diazomethane was prepared as an ethanol-free diethyl

ether solution as described in the literature^[30]with the aid of an

ALDRICH Diazald^®Kit; the diazomethane concentrations were

determined^[30]prior to use. Products were purified by flash

chromatography^[24]on Merck silica gel 60 and were isolated as li-

quids or oils unless stated differently (only for one enantiomer).

Yields refer to analytically pure samples. ¹H [CHCl₃(δ = 7.26 ppm)

as internal standard in CDCl₃. C₆HD₅(δ = 7.15 ppm) as internal

standard in C₆D₆]: Varian Mercury VX 300, Bruker AM 400, and

Bruker DRX 500. Integrals are in accordance with assignments;

isomer], 1.29 (t, J_vic= 7.1 Hz, CO₂CH₂CH₃), 1.83 [d, J_allyl

=

1.2 Hz, 2-CH₃, (E) isomer], 1.87 [d, J_allyl= 1.2 Hz, 2-CH₃, (Z) iso-

mer], 2.63 [dqq, J_4,3= 9.9, J_4,4-Me= J_4,5= 6.6 Hz, 4-H; (E) isomer],

3.20 [m_c, 4-H, (Z) isomer], 4.16 (q, J_vic= 7.1 Hz, CO₂CH₂CH₃),

5.68 [incompletely resolved dq, J_3,4= 9.7, J_allyl= 1.3 Hz, 3-H; (Z)

isomer], 6.56 [incompletely resolved dq, J_3,4= 9.7, J_allyl= 1.3 Hz,

3-H; (E) isomer] ppm.

1

coupling constants are in Hz. The assignments of H NMR reso-

b) The title compound (4b; 1.153 g, 71%, E:Z = 94:6) was prepared

from ethyl (E)-2,4-dimethylpent-2-enoate (1.976 g, 12.65 mmol,

E:Z = 96:4) in a manner analogous to that specified for 4a, part b):

nances refer to the IUPAC nomenclature except within substituents

where primed numbers are used. Combustion analyses: E. Hickl,

Eur. J. Org. Chem. 2006, 2119–2133

www.eurjoc.org

2125

T. Kapferer, R. Brückner

FULL PAPER

¹H NMR (300 MHz, CDCl₃): δ = 0.99 [d, J_4-Me,4= J_5,4= 6.6 Hz, 700 cm^–1; elemental analysis calcd. (%) for C₉H₁₄N₂O (166.2): C

4-CH₃, 5-H₃; (Z) isomer], 1.04 [d, J_4-Me,4= J_5,4= 6.7 Hz, 4-CH₃, 65.03, H 8.49, N 16.85; found: C 64.95, H 8.27, N 16.59.

5-H₃; (E) isomer], 1.85 [d, J_allyl= 1.3 Hz, 2-CH₃; (E) isomer], 1.89

(E)-1-Diazo-3-methyl-4-phenylbut-3-en-2-one (6d):^[10b]This com-

[d, J_allyl= 1.3 Hz, 2-CH₃; (Z) isomer], 2.67 [dqq, J_4,3= 10.0,

pound (127 mg, 52%) was prepared from a crude solution of 5d in

J_4,4-Me= J_4,5= 6.6 Hz, 4-H; (E) isomer], 3.35 [dqq, J_4,3= 9.9,

a manner analogous to that specified for 6a: yellow solid (m.p.

J_4,4-Me= J_4,5= 6.6 Hz, 4-H; (Z) isomer], 5.86 [incompletely

1

85 °C). H NMR (300 MHz, CDCl₃): δ = 2.11 (d, J_allyl= 1.3 Hz,

resolved dq, J_3,4= 9.9, J_allyl= 1.4 Hz, 3-H; (Z) isomer], 6.72 [dq,

3-CH₃), 5.70 (s, 1-H), 7.24 (incompletely resolved q, J_allyl= 1.0 Hz,

J_3,4= 9.8, J_allyl= 1.3 Hz, 3-H; (E) isomer], 12.05 (br.s, CO₂H) ppm.

4-H), 7.29–7.45 (m, 5× Ar-H) ppm; elemental analysis calcd. (%)

(E)-2-Ethylpent-2-enoyl Bromide (5a): Oxalyl bromide (2.96 mL,

for C₁₁H₁₀N₂O (186.2): C 70.95, H 5.41, N 15.04; found C 70.73,

6.80 g, 31.5 mmol, 1.01 equiv.) and DMF (cat.) were added at H 5.69, N 14.78.

–15 °C to (E)-2-ethylpent-2-enoic acid (4a; 4.00 g, 31.2 mmol).

After stirring overnight, the crude product was converted into 6a

without further purification.

Methyl (E)-3-Ethylhex-3-enoate (7): Under exclusion of light, a

solution of silver() benzoate (400 mg, 1.75 mmol, 0.2 equiv.) in tri-

ethylamine (4 mL) was added dropwise to a solution of 6a (1.334 g,

8.771 mmol) in methanol (15 mL). After the mixture had been

stirred for 5 h at room temperature, the solvent was evaporated

in vacuo and the residue was purified by flash chromatography

(petroleum ether/diethyl ether 40:1) to afford the title compound

(E)-2,4-Dimethylpent-2-enoyl Bromide (5b): This compound was

prepared from (E)-2,4-dimethylpent-2-enoic acid (4b; 920 mg,

7.18 mmol) in a manner analogous to that specified for 5a and was

also used without purification.

1

(1.044 g, 76%) as a colorless liquid: H NMR (300 MHz, CDCl₃):

(E)-2,4,4-Trimethylpent-2-enoyl Bromide (5c): This compound was

prepared from (E)-2,4,4-trimethylpent-2-enoic acid (4c;^[36]1.20 g,

8.45 mmol) in a manner analogous to that specified for 5a and was

also used without purification.

δ = 0.96 (t, J_6,5= J_2Ј,1Ј= 7.5 Hz, 6-H₃, 2Ј-H₃), 2.04 (dq, J_5,4= J_5,6

= 7.8 Hz, 5-H₂), superimposed in part by 2.11 (q, J_1Ј,2Ј= 7.8 Hz,

1Ј-H₂), 2.99 (br.s, 2-H₂), 3.67 (s, CO₂CH₃), 5.24 (t, J_4,5= 7.2 Hz,

4-H) ppm. IR (film): ν = 2965, 2935, 2875, 1740, 1560, 1540, 1505,

˜

1460, 1435, 1375, 1335, 1300, 1255, 1195, 1155, 1015 cm^–1. HRMS

(EI = 70 eV) C₉H₁₆O₂: calcd. 156.1150; found 156.1146.

(E)-2-Methyl-3-phenylpropenoyl Bromide (5d): 1-Bromo-2-(dimeth-

ylamino)-2-methylpropene^[37](1.00  in CH₂Cl₂, 1.43 mL,

1.43 mmol, 1.0 equiv.) was added at 0 °C to a solution of α-methyl-

cinnamic acid (211 mg, 1.30 mmol) in CH₂Cl₂(1.5 mL). After

warming to room temperature and stirring for 1 h, the solution was

used directly for the preparation of 6d.

Methyl (E)-3,5-Dimethylhex-3-enoate (8): This compound (497 mg,

77%) was prepared from 6b in a manner analogous to that specified

for 7: ¹H NMR (500 MHz, CDCl₃): δ = 0.93 (d, J_5-Me,5= J_6,5

=

6.7 Hz, 5-CH₃, 6-H₃), 1.67 (d, J_allyl= 1.4 Hz, 3-CH₃), 2.52 (dqq,

J_5,4= 9.1, J_5,5-Me= J_5,6= 6.7 Hz, 5-H), 2.96 (m_c, 2-H₂), 3.67 (s,

(E)-1-Diazo-3-ethylhex-3-en-2-one (6a): The crude acid bromide 5a

was added at 0 °C to a solution of CH₂N₂(0.37  in diethyl ether,

84 mL, 31 mmol, 1.0 equiv.) and iPr₂NEt (5.99 mL, 4.43 g,

34.3 mmol, 1.1 equiv.). The mixture was allowed to reach room

temperature and stirred for 2 h. After filtration and evaporation in

vacuo, the residue was purified by flash chromatography (petro-

leum ether/diethyl ether 20:1 Ǟ 10:1) to afford the title compound

(1.334 g, 28% over two steps) as a yellow oil: ¹H NMR (500 MHz,

CDCl₃): δ = 0.99 (t, J_6,5= 7.5 Hz, 6-H₃)*, 1.05 (t, J_2Ј,1Ј= 7.5 Hz,

2Ј-H₃)*, 2.21 (dq, J_5,4= J_5,6= 7.5 Hz, 5-H₂), 2.32 (q, J_1Ј,2Ј= 7.5 Hz,

1Ј-H₂), 5.54 (s, 1-H)**, 6.16 (t, J_4,5= 7.4 Hz, 4-H)** ppm; * =

assignments interchangeable, ** = distinguishable by a C,H corre-

CO₂CH₃), 5.10 (dm_c, J_4,5= 9.1 Hz, 4-H) ppm. IR (film): ν = 2960,

˜

2870, 1745, 1465, 1435, 1415, 1390, 1360, 1335, 1300, 1260, 1225,

1190, 1160, 1040, 1005 cm^–1; elemental analysis calcd. (%) for

C₉H₁₆O₂(156.2): C 69.25, H 10.25; found: C 69.08, H 10.36.

Methyl (E)-3,5,5-Trimethylhex-3-enoate (9): This compound

(637 mg, 87%) was prepared from 6c in a manner analogous to

that specified for 7: ¹H NMR (500 MHz, CDCl₃): δ = 1.10 (s, 2×5-

CH₃, 6-H₃), 1.78 (d, J_allyl= 1.4 Hz, 3-CH₃), 2.92 (d, J_2,4= 0.9 Hz,

2-H ), 3.66 (s, CO CH ), 5.28–5.29 (m, 4-H) ppm. IR (film): ν =

˜

2

3

2955, 2905, 2870, 1745, 1465, 1435, 1365, 1335, 1285, 1250, 1195,

1150, 1040, 1030, 1010, 890, 845, 820, 760, 710 cm^–1. HRMS (EI

= 70 eV) C₁₀H₁₈O₂: calcd. 170.1307; found 170.1305.

lation spectrum. IR (film): ν = 3125, 3090, 2970, 2935, 2875, 2100,

˜

1640, 1605, 1460, 1390, 1365, 1345, 1300, 1225, 1200, 1155, 1115,

1100, 1065 cm^–1. HRMS (EI = 70 eV) C₈H₁₂N₂O: calcd. 152.0950;

found 152.0949.

Methyl (E)-3-Methyl-4-phenylbut-3-enoate (10):^[10b]The title com-

pound (102 mg, 86%) was prepared from 6d in a manner analogous

1

to that specified for 7: H NMR (500 MHz, CDCl₃): δ = 1.94 (d,

(E)-1-Diazo-3,5-dimethylhex-3-en-2-one (6b): Compound 6b

(126 mg, 83% over two steps) was prepared from crude 5b in a

manner analogous to that specified for 6a: ¹H NMR (500 MHz,

CDCl₃): δ = 1.02 (d, J_5-Me,5= J_6,5= 6.6 Hz, 5-CH₃, 6-H₃), 1.83 (d,

J_allyl= 1.4 Hz, 3-CH₃), 2.66 (dqq, J_5,4= 9.4, J_5,5-Me= J_5,6= 6.7 Hz,

5-H), 5.54 (s, 1-H), 6.07 (dq, J_4,5= 9.4, J_allyl= 1.4 Hz, 4-H) ppm.

J_allyl= 1.4 Hz, 3-CH₃), 3.19 (d, J_2,4= 1.1 Hz, 2-H₂), 3.72 (s,

CO₂CH₃), 6.39 (br.s, 4-H), 7.19–7.23 and 7.24–7.27 (C₆H₅) ppm;

elemental analysis calcd. (%) for C₁₂H₁₄O₂(190.2): C 75.76, H 7.42;

found: C 75.52, H 7.51.

Compounds (E)- and (Z)-11, -12, -13, and -14: These compounds

IR (film): ν = 3090, 2965, 2930, 2870, 2360, 2335, 2105, 1740, 1700,

were synthesized as described in ref.^[8]

˜

1645, 1605, 1560, 1540, 1515, 1460, 1395, 1345, 1245, 1155,

1060 cm^–1. HRMS (EI = 70 eV) C₈H₁₂N₂O: calcd. 152.0950; found

152.0949.

Methyl (E)-4,8-Dimethylnona-3,7-dienoate [(E)-18]:^[16](Trimethyl-

silyl)diazomethane (2.0  in hexane, 0.83 mL, 1.66 mmol,

1.3 equiv.) was added to a solution of (E)-4,8-dimethylnona-3,7-

dienoic acid [(E)-17;^[16]235 mg, 1.28 mmol] in methanol (2.5 mL)

and benzene (9 mL). After the mixture had been stirred for 1 h, the

solvent was evaporated in vacuo and the residue was purified by

flash chromatography (cyclohexane/EtOAc, 50:1) to afford the title

(E)-1-Diazo-3,5,5-trimethylhex-3-en-2-one (6c): Compound 6c

(94 mg, 81% over two steps) was prepared from crude 5c in a man-

ner analogous to that specified for 6a: ¹H NMR (500 MHz,

CDCl₃): δ = 1.17 (s, 2×5-CH₃, 6-H₃), 1.94 (d, J_allyl= 1.4 Hz, 3-

CH₃), 5.52 (s, 1-H), 6.23 (q, J_allyl= 1.4 Hz, 4-H) ppm. IR (film): ν

compound (240 mg, 96%) as

(300 MHz, CDCl₃): δ = 1.60, 1.63, and 1.68 (3×s, 4-CH₃, 8-CH₃,

a

colorless liquid: ¹H NMR

˜

= 3090, 2960, 2910, 2870, 2100, 1735, 1635, 1610, 1465, 1405, 1360,

1345, 1230, 1185, 1145, 1100, 1060, 1030, 1005, 990, 925, 855, 720, 9-H₃), 2.01–2.11 (m, 5-H₂, 6-H₂), 3.05 (br.d, J_2,3= 7.2 Hz, 2-H₂),

2126

www.eurjoc.org

Eur. J. Org. Chem. 2006, 2119–2133

Enantioselective Syntheses of Trisubstituted γ-Butyrolactones

FULL PAPER

3.68 (s, CO₂CH₃), 5.09 (m_c, 7-H), 5.33 (br.t, J_3,2= 7.5 Hz, 3-

H) ppm.

3.0 kPa) afforded the title compound (4.443 g, 78%): ¹H NMR

(300 MHz, CDCl₃): δ = 1.53–1.68 (m, 4Ј-H₂, 5Ј-H₂), 2.00–2.05 (m,

3Ј-H₂, 6Ј-H₂), 2.95 (br.s, 2-H₂), 3.68 (s, CO₂CH₃), 5.56 (m_c, 2Ј-

H) ppm.

Methyl (Z)-4,8-Dimethylnona-3,7-dienoate [(Z)-18]:^[16]This com-

pound (244 mg, 96%) was prepared from (Z)-17^[16](239 mg,

Dimethyl (E)-2-(3-Methylbutylidene)succinoate [(E)-31,^[38]81:19

Mixture with (Z)-31]: A solution of (E)-32 (500 mg, 2.06 mmol, E:Z

= 82:18) in methanol (5 mL) was added to NaH (99 mg, 4.1 mmol,

2.0 equiv.) in methanol (5 mL). After the mixture had been stirred

for 2 d at room temperature, aq. NH₄Cl (10 mL) was added. The

mixture was extracted with EtOAc (5×20 mL) and the combined

organic extracts were dried with MgSO₄. After evaporation in

vacuo, the residue was purified by flash chromatography (cyclohex-

ane/EtOAc, 20:1 Ǟ 15:1) to afford 31 (386 mg, 87%, E:Z = 81:19).

Isomerically pure (E)-31 for the next step could be obtained by

more meticulously performed flash chromatography: ¹H NMR

(300 MHz, CDCl₃): δ = 1.77 (qqt, J_3Ј,3Ј-Me= J_3Ј,4Ј= J_3Ј,2Ј= 6.7 Hz,

3Ј-H), 2.07 (t, J_2Ј,1Ј= J_2Ј,3Ј= 7.3 Hz, 2Ј-H₂), 3.35 (s, 3-H₂), 3.67 (s,

⁴CO₂CH₃)*, 3.74 (s, ¹CO₂CH₃)*, 6.99 (t, J_1Ј,2Ј= 7.6 Hz, 1Ј-H) ppm;

* = interchangeable.

Dimethyl (Z)-2-(3-Methylbutylidene)succinoate [(Z)-31,^[39]80:20

Mixture with (E)-31]: A solution of 37 (2.00 g, 5.30 mmol) in THF

(10 mL) was added at 0 °C to a suspension of NaH (127 mg,

5.29 mmol, 1.0 equiv.) in THF (10 mL). The mixture was allowed

to reach room temperature and stirred for 30 min. After the mix-

ture had been cooled to 0 °C, a solution of isovaleraldehyde (29;

456 mg, 5.30 mmol, 1.0 equiv.) in THF (10 mL) was added. The

mixture was allowed to reach room temperature and stirred for 3 h.

After addition of aq. NH₄Cl (55 mL), the mixture was extracted

with EtOAc (4×50 mL) and dried with MgSO₄. Evaporation in

vacuo and flash chromatography (cyclohexane/EtOAc, 25:1) af-

forded 31 (977 mg, 86%, Z:E = 80:20). Isomerically pure (Z)-31

for the next step could be obtained by more meticulously per-

formed flash chromatography: ¹H NMR (300 MHz, CDCl₃): δ =

0.93 (d, J_3Ј-Me,3Ј= J_4Ј,3Ј= 6.6 Hz, 3Ј-CH₃, 4Ј-H₃), 1.72 (qqt,

1

1.30 mmol) in a manner analogous to that specified for (E)-18: H

NMR (300 MHz, CDCl₃): δ = 1.61, 1.68, and 1.74 (3×s, 4-CH₃,

8-CH₃, 9-H₃), 2.04 (m_c, 5-H₂, 6-H₂), 3.04 (dm_c, J_2,3= 7.2 Hz, 2-

H₂), 3.67 (s, CO₂CH₃), 5.06–5.12 (m, 7-H), 5.32 (tm_c, J_3,2= 7.5 Hz,

3-H) ppm.

Methyl Cyclopentylideneacetate [(22),^[19]90:10 Mixture with Methyl

(Cyclopent-1-enyl)acetate (24)]: Methyl (dimethoxyphosphonyl)ace-

tate (21,^[21]10.0 mL, 11.3 g, 61.8 mmol, 1.0 equiv.) was added to

NaH (1.78 g, 74.1 mmol, 1.2 equiv.) in methanol (48 mL). After the

mixture had been stirred for 40 min, cyclopentanone (5.47 mL,

5.20 g, 61.8 mmol) was added and the mixture was stirred over-

night. Aq. NH₄Cl (100 mL) was added and the mixture was ex-

tracted with EtOAc (4×100 mL). The combined organic extracts

were dried with MgSO₄and the solvents were evaporated in vacuo.

The residue was purified by vacuum distillation (140–145 °C/

2.0 kPa) to afford a 90:10 mixture of 22/24 (8.06 g, 93%) as a color-

1

less liquid: H NMR (300 MHz, CDCl₃): δ = 1.66 (dddd, J_4Ј,3Ј-H(1)

= J_4Ј,3Ј-H(2)= J_4Ј,5Ј-H(1)= J_4Ј,5Ј-H(2)= 6.8 Hz, 4Ј-H₂; 22), 1.76 (dddd,

J_3Ј,2Ј-H(1)= J_3Ј,2Ј-H(2)= J_3Ј,4Ј-H(1)= J_3Ј,4Ј-H(2)= 6.8 Hz, 3Ј-H₂; 22),

1.85–1.95 (m, 4Ј-H₂; 24), 2.31–2.37 (m, 3Ј-H₂, 5Ј-H₂; 24), 2.44 (br.t,

J_5Ј,4Ј-H(1)= J_5Ј,4Ј-H(2)= 7.0 Hz, 5Ј-H₂, 22), 2.78 (tm_c, J_2Ј,3Ј-H(1)

=

J_2Ј,3Ј-H(2)= 6.7 Hz, 2Ј-H₂; 22), 3.13 (br.s, 2-H₂; 24), 3.69 (s,

CO₂CH₃; 22, 24), 5.54 (m_c, 2Ј-H; 24), 5.81 (m_c, 2-H; 22) ppm.

Methyl Cyclohexylideneacetate (23):^[20]The title compound

(6.114 g, 98%) was prepared from cyclohexanone (4.20 mL, 3.97 g,

40.5 mmol) in a manner analogous to that specified for 22, but the

purification was carried out by flash chromatography (cyclohexane/

EtOAc, 8:1): ¹H NMR (500 MHz, CDCl₃): δ = 1.56–1.67 (m, 3Ј-

H₂, 4Ј-H₂, 5Ј-H₂), 2.19 (br.t, J_6Ј,5Ј-H(1)= J_6Ј,5Ј-H(2)= 6.2 Hz, 6Ј-

H₂)*, 2.82 (br.t, J_2Ј,3Ј-H(1)= J_2Ј,3Ј-H(2)= 5.8 Hz, 2Ј-H₂)*, 3.68 (s,

CO₂CH₃), 5.60 (m_c, 2-H) ppm; * = assignments interchangeable.

J_3Ј,3Ј-Me= J_3Ј,4Ј= J_3Ј,2Ј= 6.7 Hz, 3Ј-H), 2.47 (br.t, J_2Ј,1Ј= J_2Ј,3Ј

=

7.2 Hz, 2Ј-H₂), 3.68 and 3.73 (2×s, 2 ×CO₂CH₃), 6.08 (br.t,

Methyl (Cyclopent-1-enyl)acetate (24):^[19]n-BuLi (2.6  in hexane,

6.47 mL, 16.8 mmol, 1.1 equiv.) was added at –78 °C to a solution

of diisopropylamine (2.61 mL, 1.87 g, 18.5 mmol, 1.2 equiv.) in

THF (16 mL). After the mixture had been stirred for 1 h, a solution

of 22 (2.14 g, 15.3 mmol; 90:10 mixture with 24) in THF (7 mL)

was added over 1 h and the mixture was stirred for 1 h. Aq. NH₄Cl

(10 mL) was added and the mixture was allowed to reach room

temperature. After extraction with EtOAc (4×40 mL), the com-

bined organic extracts were washed with aq. NaCl (2×40 mL) and

dried with MgSO₄. Evaporation in vacuo followed by flash

chromatography (cyclohexane/EtOAc, 50:1) afforded the title com-

pound (1.637 g, 76%): ¹H NMR (300 MHz, CDCl₃): δ = 1.90

(dddd, J_4Ј,3Ј-H(1)= J_4Ј,3Ј-H(2)= J_4Ј,5Ј-H(1)= J_4Ј,5Ј-H(2)= 7.5 Hz, 4Ј-

H₂), 2.33 (m_c, 3Ј-H₂, 5Ј-H₂), 3.13 (br.s, 2-H₂), 3.69 (s, CO₂Me),

5.54 (m_c, 2Ј-H) ppm.

Methyl (Cyclohex-1-enyl)acetate (25):^[20]n-BuLi (2.07  in hexane,

18.8 mL, 38.9 mmol, 1.05 equiv.) was added at –78 °C to a solution

of diisopropylamine (5.50 mL, 3.94 g, 38.9 mmol, 1.05 equiv.) in

THF (40 mL). After the mixture had been stirred for 1 h, a solution

of 23 (5.71 g, 37.0 mmol) in THF (50 mL) was added and the mix-

ture was stirred for a further 1 h. HOAc (6.4 mL, 6.7 g, 0.11 mol,

3.0 equiv.) was added and the mixture was stirred for 15 min. After

addition of KHSO₄(1.0  in H₂O, 62 mL) the mixture was allowed

to reach room temperature. After extraction with EtOAc

(3×100 mL) the combined organic extracts were washed with aq.

NaHCO₃(2×50 mL) and aq. NaCl (50 mL) and dried with

MgSO₄. Evaporation in vacuo and vacuum distillation (98–102 °C/

J_1Ј,2Ј= 7.5 Hz, 1Ј-H) ppm.

Diethyl (E)-2-(3-Methylbutylidene)succinoate [(E)-32,^[40]82:18 Mix-

ture with (Z)-32]: NaH (168 mg, 7.00 mmol, 1.0 equiv.) was added

at 0 °C to a solution of diethyl phosphite (26; 967 mg, 7.00 mmol)

in EtOH (35 mL). The mixture was allowed to reach room tem-

perature and stirred for 30 min. After addition of diethyl maleate

(27, 1.21 g, 7.00 mmol, 1.0 equiv.) stirring was continued for 1 h.

Isovaleraldehyde (29; 603 mg, 7.00 mmol, 1.0 equiv.) was added

and the mixture was stirred for 4 h. After addition of aq. NH₄Cl

(25 mL), the mixture was extracted with EtOAc (4×30 mL). The

combined organic extracts were dried with MgSO₄. After evapora-

tion in vacuo the residue was purified by flash chromatography

(cyclohexane/EtOAc, 15:1 Ǟ 10:1) to afford 32 (1.034 g, 61%, E:Z

1

= 82:18): H NMR (300 MHz, CDCl₃): δ = 0.93 (d, J_vic= 6.7 Hz,

4

3Ј-CH₃, 4Ј-H₃), 1.24 (t, J_vic= 7.2 Hz, CO₂CH₂CH₃)*, 1.28 (t, J_vic

= 7.1 Hz, ¹CO₂CH₂CH₃)*, 1.72 [qqt, J_3Ј,3Ј-Me= J_3Ј,4Ј= J_3Ј,2Ј

=

6.8 Hz, 3Ј-H; (Z)-32], superimposed in part by 1.78 [qqt, J_3Ј,3Ј-Me

= J_3Ј,4Ј= J_3Ј,2Ј= 6.6 Hz, 3Ј-H; (E)-32], 2.08 [t, J_2Ј,1Ј= J_2Ј,3Ј

=

7.3 Hz, 2Ј-H₂; (E)-32], 2.47 [t, J_2Ј,1Ј= J_2Ј,3Ј= 7.3 Hz, 2Ј-H₂; (Z)-

32], 3.26 [br.s, 3-H₂; (Z)-32], 3.33 [br.s, 3-H₂; (E)-32], 4.15 (q, J_vic

=

7.0 Hz, ⁴CO₂CH₂CH₃)**, 4.20 (q, J_vic

=

7.0 Hz,

¹CO₂CH₂CH₃)**, 6.06 [t, J_1Ј,2Ј= 7.5 Hz, 1Ј-H; (Z)-32], 6.97 [t, J_1Ј,2Ј

= 7.7 Hz, 1Ј-H; (E)-32] ppm; *^,** = interchangeable; elemental

analysis calcd. (%) for C₁₃H₂₂O₄(242.3): C 64.45, H 9.15; found:

C 64.65, H 9.29.

Dimethyl (E)-2-Benzylidenesuccinoate [(E)-33,^[41]92:8 Mixture with

(Z)-33]: A solution of (E)-34 (1.92 g, 7.33 mmol, E:Z = 92:8) in

Eur. J. Org. Chem. 2006, 2119–2133

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2127

T. Kapferer, R. Brückner

CO₂CH₃), 3.82 (ddd, J_2,₃₁= 24.8, J_2,3-H(B)= 11.4, J_2,3-H(A)

FULL PAPER

methanol (20 mL) was added to NaH (352 mg, 14.7 mmol,

2.0 equiv.) in methanol (70 mL). After the mixture had been stirred

for 3 d at room temperature, aq. NH₄Cl (50 mL) was added. The

mixture was extracted with EtOAc (4×50 mL) and the combined

organic extracts were dried with MgSO₄. After evaporation in

vacuo, the residue was purified by flash chromatography (cyclohex-

ane/EtOAc, 5:1 Ǟ 3:1) to afford 33 (1.383 g, 81%, E:Z = 92:8).

Isomerically pure (E)-33 for the next step could be obtained by

more meticulously performed flash chromatography: ¹H NMR

(300 MHz, CDCl₃): δ = 3.54 (s, 3-H₂), 3.73 and 3.83 (2×s,

2×CO₂CH₃), 7.33–7.43 (m, C₆H₅), 7.90 (s, 1Ј-H) ppm.

=

P

3.4 Hz, 2-H), superimposed by 3.81 (s, CO₂CH₃), 7.16–7.21 and

7.30–7.35 (2 m, 2 Ph) ppm. IR (film): ν = 3070, 3005, 2955, 1740,

˜

1590, 1490, 1455, 1440, 1410, 1365, 1325, 1280, 1210, 1185, 1160,

1070, 1025, 1010, 945, 905, 860, 840, 770, 690 cm^–1; elemental

analysis calcd. (%) for C₁₈H₁₉O₇P (378.3): C 57.16, H 5.06; found:

C 57.00, H 5.28.

(4S,5S)-4,5-Diethyl-4-hydroxy-4,5-dihydro-3H-furan-2-one

(39a):

(DHQ)₂PHAL (78 mg, 0.10 mmol, 10 mol-%), K₃Fe(CN)₆

(988 mg, 3.00 mmol, 3.0 equiv.), K₂CO₂(415 mg, 3.00 mmol,

3.0 equiv.), MeSO₂NH₂(95 mg, 1.0 mmol, 1.0 equiv.), and K₂O-

sO₂(OH)₄(7.4 mg, 20 µmol, 2 mol-%) were dissolved in tBuOH

(5 mL) and H₂O (5 mL). After the mixture had been cooled to

0 °C, 7 (156 mg, 1.00 mmol) was added. After the mixture had been

stirred overnight at 0 °C, aq. Na₂SO₃(5 mL) was added, the mix-

ture was stirred for 1 h at room temperature and extracted with

EtOAc (4×20 mL), and the combined organic extracts were dried

Dimethyl (Z)-2-Benzylidenesuccinoate [(Z)-33,^[42]67:33 Mixture

with (E)-33]: The title compound (795 mg, 48%, Z:E = 67:33) was

prepared from benzaldehyde (30; 757 mg, 7.13 mmol, 1.0 equiv.) in

a manner analogous to that specified for (Z)-31. Isomerically pure

(Z)-33 for the next step could be obtained by more meticulously

1

performed flash chromatography: H NMR (300 MHz, CDCl₃): δ

= 3.48 (s, 3-H₂), 3.64 and 3.72 (2 s, 2 CO₂CH₃), 6.88 (s, 1Ј-H), with MgSO₄. After evaporation in vacuo the residue was purified

7.26–7.35 (m, C₆H₅) ppm.

by flash chromatography (cyclohexane/EtOAc, 2:1) to afford the

title compound (103 mg, 65%): [α]_D= –69.6 (c = 0.3 in CHCl₃).

¹H NMR (500 MHz, CDCl₃): δ = 1.01 (t, J_2Ј,1Ј= 7.5 Hz, 2Ј-H₃)*,

1.09 (t, J_2ЈЈ,1ЈЈ= 7.4 Hz, 2ЈЈ-H₃)*, AB signal (δ_A= 1.61, δ_B= 1.73,

J_AB= 14.8, A part additionally split by J_A,2Ј= 7.2, B part addition-

ally split by J_B,2Ј= 7.2 Hz, 1Ј-H₂), superimposed by AB signal (δ_A

Diethyl (E)-2-Benzylidenesuccinate [(E)-34,^[43]93:7 Mixture with (Z)

-34]: NaH (42 mg, 1.8 mmol, 1.0 equiv.) was added at 0 °C to a

solution of diethyl phosphite (26; 242 mg, 1.75 mmol) in EtOH

(9 mL). The mixture was allowed to reach room temperature and

stirred for 30 min. After addition of diethyl maleate (27; 301 mg,

1.75 mmol, 1.0 equiv.) stirring was continued for 3 h. Benzaldehyde

(30; 0.18 mL, 0.19 g, 1.75 mmol, 1.0 equiv.) was added and the mix-

ture was stirred overnight. After addition of aq. NH₄Cl (20 mL),

the mixture was extracted with EtOAc (4×20 mL). The combined

organic extracts were dried with MgSO₄. After evaporation in

vacuo the residue was purified by flash chromatography (cyclohex-

ane/EtOAc, 15:1) to afford 34 (220 mg, 48%, E:Z = 93:7). Isomer-

ically pure (E)-34 for the next step could be obtained by more me-

ticulously performed flash chromatography: ¹H NMR (300 MHz,

CDCl₃): δ = 1.27 (t, J_vic= 7.2 Hz, ⁴CO₂CH₂CH₃)*, 1.34 (t, J_vic

= 1.67, δ_B= 1.79, J_AB= 14.6, A part additionally split by J_A,2ЈЈ

7.1, J_A,5= 3.2, B part additionally split by J_B,5= 9.8, J_B,2ЈЈ

=

7.3 Hz, 1ЈЈ-H₂), 2.12 (br.s, 4-OH), AB signal (δ_A= 2.54, δ_B= 2.60,

J_AB= 17.5 Hz, 3-H₂), 4.11 (dd, J_5,1ЈЈ-H(B)= 9.8, J_5,1ЈЈ-H(A)= 3.2 Hz,

5-H) ppm; * = interchangeable. IR (film): ν = 3445, 2975, 2940,

˜

2885, 1780, 1770, 1760, 1755, 1465, 1405, 1380, 1355, 1310, 1265,

1230, 1170, 1140, 1120, 1085, 1050, 1020, 1000, 970, 935, 825 cm^–1;

t_r(4S,5S) = 29.96 min, t_r(4R,5R) = 25.79 min (n-heptane/propan-2-

ol, 96:4); 68% ee; elemental analysis calcd. (%) for C₈H₁₄O₃

(158.2): C 60.74, H 8.92; found: C 60.94, H 9.12.

= 7.1 Hz, ¹CO₂CH₂CH₃)*, 3.53 (s, 3-H₂), 4.19 (q, J_vic= 7.1 Hz, (4R,5R)-4,5-Diethyl-4-hydroxy-4,5-dihydro-3H-furan-2-one (39b):

⁴CO₂CH₂CH₃)**, 4.28 (q, J_vic= 7.1 Hz, ¹CO₂CH₂CH₃)**, 7.30– This compound (74 mg, 84%) was prepared from 7 (87 mg,

7.43 (m_c, C₆H₅), 7.89 (s, 1Ј-H) ppm; *^,** = interchangeable.

0.56 mmol) in a manner analogous to that specified for 39a but

with (DHQD)₂PHAL as a ligand: [α]_D= +72.2 (c = 0.5 in CHCl₃);

t_r(4R,5R) = 25.28 min, t_r(4S,5S) = 29.37 min (n-heptane/propan-2-

ol, 96:4); 72% ee.

Diethyl (Z)-2-Benzylidenesuccinoate [(Z)-34,^[43]81:19 Mixture with

(E)-34]: The title compound (207 mg, 79%, Z:E = 81:19) was pre-

pared from 38^[22](406 mg, 1.00 mmol) and benzaldehyde (30;

106 mg, 1.00 mmol, 1.0 equiv.) in a manner analogous to that speci-

fied for (Z)-31 but with stirring for only 1 h after the addition of

the aldehyde. Isomerically pure (Z)-34 for the next step could be

obtained by more meticulously performed flash chromatography:

Methyl [(1S,2S)-1,2-Dihydroxycyclopentyl]acetate (40a): This com-

pound (968 mg, 87%) was prepared from 24 (894 mg, 6.38 mmol)

in a manner analogous to that specified for 39a: [α]_D= +1.8 (c =

0.6 in CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.49 (ddddd, J_gem

= 12.4, J_{4Ј-H(1),5Ј-H(1)}= 9.1, J_{4Ј-H(1),5Ј-H(2)}= 8.9, J_{4Ј-H(1),3Ј-H(1)}= 6.9,

¹H NMR (500 MHz, CDCl₃):

δ = 1.09 (t, J_vic= 7.1 Hz,

¹CO₂CH₂CH₃)*, 1.27 (t, J_vic= 7.2 Hz, ⁴CO₂CH₂CH₃)*, 3.46 (d, J_{4Ј-H(1),3Ј-H(2)}= 4.7 Hz, 4Ј-H¹), 1.60 (ddd, J_gem= 13.3, J_{5Ј-H(1),4Ј-H(1)}

4

J_3,1Ј= 1.2 Hz, 3-H₂), 4.11 (q, J_vic= 7.2 Hz, CO₂CH₂CH₃)**, 4.18

= 9.3, J_5Ј-H(1),

= 6.7 Hz, 5Ј-H¹), 1.69 (dddd, J_gem= 13.1,

4Ј-H(2)

(q, J_vic= 7.1 Hz, ¹CO₂CH₂CH₃)**, 6.88 (br.s, 1Ј-H), 7.27–7.33 (m, J_{3Ј-H(1), 4Ј-H(2)}= 9.7, J_{3Ј-H(1),4Ј-H(1)}= J_3Ј-H(1),2Ј= 7.0 Hz, 3Ј-H¹), 1.82

C₆H₅) ppm; *^,** = interchangeable.

(ddddd, J_gem= 12.3, J_{4Ј-H(2),3Ј-H(1)}= 9.6, J_{4Ј-H(2),3Ј-H(2)}= 9.2,

J_{4Ј-H(2),5Ј-H(1)}= 6.7, J_{4Ј-H(2),5Ј-H(2)}= 4.7 Hz, 4Ј-H²), 1.91 (ddd, J_gem

= 13.3, J_{5Ј-H(2),4Ј-H(1)}= 8.8, J_{5Ј-H(2),4Ј-H(2)}= 4.5 Hz, 5Ј-H²), 1.99

(dddd, J_gem= 13.0, J_{3Ј-H(2),4Ј-H(2)}= 8.4, J_3Ј-H(2),2Ј= 7.8, J_{3Ј-H(2),4Ј-H(1)}

= 4.6 Hz, 3Ј-H²), AB signal (δ_A= 2.56, δ_B= 2.65, J_AB= 15.9 Hz, 2-

H₂), 3.16 (m_c, 2Ј-OH), 3.57 (s, 1Ј-OH), 3.71 (s, CO₂CH₃), 3.86 (ddd,

J_2Ј,3Ј-H(1)= J_2Ј,3Ј-H(2)= 7.5, J_2Ј,2Ј-OH= 5.4 Hz, 2Ј-H) ppm. IR (film):

Dimethyl 2-(Diphenoxyphosphonyl)succinate (37): Diphenyl phos-

phite (35; 3.83 mL, 4.68 g, 20.0 mmol) was added at 0 °C to a sus-

pension of NaH (480 mg, 20.0 mmol, 1.0 equiv.) in THF (20 mL).

The mixture was allowed to reach room temperature and stirred

for 30 min. Dimethyl maleate (36, 2.50 mL, 2.88 g, 20.0 mmol,

1.0 equiv.) was added and the mixture was stirred for 3 h. After

addition of H₂O (10 mL), the mixture was extracted with EtOAc

(4×25 mL) and dried with MgSO₄. After evaporation in vacuo, the

residue was purified by flash chromatography (cyclohexane/EtOAc,

7:1) to afford the title compound (5.184 g, 69%): ¹H NMR

ν = 3440, 2955, 2875, 1730, 1440, 1410, 1340, 1285, 1255, 1205,

˜

1170, 1105, 1050, 1010, 975, 920, 855, 785, 725, 665, 585, 555 cm^–1.

The enantiomeric excess of 40a was determined after transforma-

tion into its acetonide by the following procedure: pTsOH·H₂O

(cat.) was added to a solution of 40a (159 mg, 0.913 mmol) in 2,2-

dimethoxypropane (10 mL). After the mixture had been stirred for

12 h, aq. NaHCO₃(15 mL) was added. The mixture was extracted

(300 MHz, CDCl₃): δ = AB signal (δ_A= 3.03, δ_B= 3.27, J_AB

17.5, A part additionally split by J_A,₃₁= 10.0, J_A,2= 3.4, B part

additionally split by J_B,2= 11.4, J_B,₃₁= 7.7 Hz, 3-H₂), 3.71 (s,

=

P

2128

www.eurjoc.org

Eur. J. Org. Chem. 2006, 2119–2133

Enantioselective Syntheses of Trisubstituted γ-Butyrolactones

FULL PAPER

with EtOAc (4×50 mL) and dried with MgSO₄. After evaporation

in vacuo the residue was purified by flash chromatography (cyclo-

hexane/EtOAc, 5:1) to afford the acetonide (= methyl {2,2-

dimethyl-4,5,6,6a-tetrahydro-2H-cyclopent[1,3]dioxolan-3a-yl}-

acetate) of compound 40a (177 mg, 90%).

2935, 2880, 1765, 1745, 1480, 1465, 1390, 1370, 1340, 1275, 1240,

1170, 1145, 1120, 1110, 1095, 1010, 985, 950, 810 cm^–1; t_r(4S,5S) =

55.98 min, t_r(4R,5R) = 55.23 min (90 °C, 30 min, 2 °C/min, 140 °C,

100 kPa); 58% ee.

(4R,5R)-4-Hydroxy-5-isopropyl-4-methyl-4,5-dihydro-3H-furan-2-

one (43b): This compound (104 mg, 66 %) was prepared from 8

(156 mg, 1.00 mmol) in a manner analogous to that specified for

39a but with (DHQD)₂PHAL as a ligand: [α]_D= +51.1 (c = 0.4 in

CHCl₃); t_r(4R,5R) = 5.75 min, t_r(4S,5S) = 6.14 min (85 °C,

130 kPa); 69 % ee; elemental analysis calcd. (%) for C₈H₁₄O₃

(158.1): C 60.74, H 8.92; found: C 60.81, H 9.00.

1

(4S,5S)-5-tert-Butyl-4-hydroxy-4-methyl-4,5-dihydro-3H-furan-2-

one (44a): This compound (95 mg, 55 %) was prepared from 9

(170 mg, 1.00 mmol) in a manner analogous to that specified for

39a: [α]_D= –21.6 (c = 1.0 in CHCl₃); t_r(4S,5S) = 18.43 min,

t_r(4R,5R) = 23.46 min (n-heptane/propan-2-ol, 95:5); 59% ee.

[α]_D= +5.4 (c = 0.9 in CHCl₃). H NMR (500 MHz, CDCl₃): δ =

1.35 and 1.43 (2 s, 2× 2ЈЈ-CH₃), 1.53–1.66 and 1.79–1.97 (2 m, 3Ј-

H₂, 4Ј-H₂, 5Ј-H₂), AB signal (δ_A= 2.74, δ_B= 2.87, J_AB= 14.9 Hz,

2-H₂), 3.69 (s, CO₂CH₃), 4.54 (dm_c, J_2Ј,3Ј-H(1)= 4.5 Hz, 2Ј-H) ppm.

IR (film): ν = 2985, 2960, 2940, 2880, 2850, 1740, 1460, 1440, 1380,

˜

1370, 1350, 1305, 1290, 1250, 1210, 1175, 1140, 1100, 1045, 1010,

910, 885, 810, 515 cm^–1; t_r(1ЈS,2ЈS) = 53.75 min, t_r(1ЈR,2ЈR) =

52.38 min (85 °C, 130 kPa); 66% ee; elemental analysis calcd. (%)

for C₁₁H₁₈O₄(214.3): C 61.66, H 8.47; found: C 61.62, H 8.34.

(4R,5R)-5-tert-Butyl-4-hydroxy-4-methyl-4,5-dihydro-3H-furan-2-

one (44b): This compound (96 mg, 56 %) was prepared from 9

(170 mg, 1.00 mmol) in a manner analogous to that specified for

39a but with (DHQD)₂PHAL as a ligand: colorless solid (m.p.

86 °C). [α]_D= +23.2 (c = 1.2 in CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 1.13 (s, 2× 1Ј-CH₃, 2Ј-H₃), 1.55 (s, 4-CH₃), AB signal

(δ_A= 2.61, δ_B= 2.65, J_AB= 17.5 Hz, 3-H₂), 3.90 (s, 5-H) ppm. IR

Methyl [(1R,2R)-1,2-Dihydroxycyclopentyl]acetate (40b): This com-

pound (414 mg, 83%) was prepared from 24 (400 mg, 2.85 mmol)

in a manner analogous to that specified for 39a but with

(DHQD)₂PHAL as a ligand: [α]_D= –2.9 (c = 1.4 in CHCl₃); ele-

mental analysis calcd. (%) for C₈H₁₄O₄(174.2): C 55.16, H 8.10;

found: C 55.08, H 8.15.

(film): ν = 3605, 3445, 3035, 3000, 2965, 2910, 2875, 1770, 1485,

˜

1470, 1410, 1400, 1385, 1365, 1330, 1245, 1195, 1155, 1110, 1040,

1005, 940 cm^–1; t_r(4R,5R) = 22.65 min, t_r(4S,5S) = 18.51 min (n-

heptane/propan-2-ol, 95:5); 65% ee; elemental analysis calcd. (%)

for C₉H₁₆O₃(172.1): C 62.77, H 9.36; found: C 62.54, H 9.37.

The enantiomeric excess was determined after transformation of

40b (150 mg, 0.861 mmol) into its acetonide (174 mg, 94%) by a

procedure analogous to that described for 40a: [α]_D= –5.6 (c = 1.0

in CHCl₃); t_r(1ЈR,2ЈR) = 52.25 min, t_r(1ЈS,2ЈS) = 53.79 min (85 °C,

130 kPa); 79% ee.

(4S,5S)-4-Hydroxy-4-methyl-5-phenyl-4,5-dihydro-3H-furan-2-one

(45a): This compound (52 mg, 75%) was prepared from 10 (69 mg,

0.36 mmol) in a manner analogous to that specified for 39a: [α]_D

= +10.1 (c = 0.8 in CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.22

(3aS,7aS)-3a-Hydroxy-3a,4,5,6,7,7a-hexahydrobenzo4,5-

dihydro-3H-furan-2-one (41a),^[44]as a 24:76 Mixture with [(1S,2S)-

1,2-Dihydroxycyclohexyl]acetate (42a): A mixture (135 mg) of the

title compounds (41a: 28 mg, 18%; 42a: 107 mg, 59%) was pre-

pared from 25 (150 mg, 0.973 mmol) in a manner analogous to that

specified for 39a: 41a: [α]_D= –27.4 (c = 1.0 in CHCl₃); t_r(3aS,7aS)

= 53.66 min, t_r(3aR,7aR) = 53.79 min (120 °C, 100 kPa); 23% ee;

elemental analysis calcd. (%) for C₈H₁₂O₃(156.2): C 61.52, H 7.74;

found: C 61.48, H 7.83.

4

(d, J_4-OH,3-H(A)= 2.0 Hz, 4-OH), 1.45 (s, 4-CH₃), AB signal (δ_A

2.71, δ_B= 2.78, J_AB= 17.1, A part additionally split by J_A,4-OH

=

2.0 Hz, 3-H₂), 5.26 (s, 5-H), 7.36–7.46 (m, C₆H₅) ppm. IR (KBr):

ν = 3520, 3455, 3065, 3035, 2975, 2935, 1790, 1780, 1770, 1760,

˜

1755, 1500, 1455, 1385, 1275, 1235, 1200, 1105, 1015, 955, 945,

910, 875, 820, 750, 700 cm^–1; t_r(4S,5S) = 24.91 min, t_r(4R,5R) =

22.22 min (150 °C, 100 kPa); 83% ee.

(4R,5R)-4-Hydroxy-4-methyl-5-phenyl-4,5-dihydro-3H-furan-2-one

(45b): This compound (28 mg, 69%) was prepared from 10 (40 mg,

0.21 mmol) in a manner analogous to that specified for 39a but

with (DHQD)₂PHAL as a ligand: colorless solid (m.p. 106 °C).

[α]_D= –10.8 (c = 1.0 in CHCl₃); t_r(4R,5R) = 21.66 min, t_r(4S,5S)

= 24.82 min (150 °C, 100 kPa); 85% ee; elemental analysis calcd.

(%) for C₁₁H₁₂O₃(192.2): C 68.75, H 6.29; found: C 68.65, H 6.41.

(3aR,7aR)-3a-Hydroxy-3a,4,5,6,7,7a-hexahydrobenzo4,5-

dihydro-3H-furan-2-one (41b), as a 27:73 Mixture with [(1R,2R)-1,2-

Dihydroxycyclohexyl]acetate (42b): A mixture (150 mg) of the title

compounds (41b: 35 mg, 23%; 42b: 115 mg, 62%) was prepared

from 25 (150 mg, 0.973 mmol) in a manner analogous to that speci-

fied for 39a but with (DHQD)₂PHAL as a ligand: 41b: [α]_D= +40.2

(c = 0.8 in CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.32–1.42 (4S,5S)-4-Hydroxy-5-isobutyl-4-methoxycarbonyl-4,5-dihydro-3H-

and 1.52–1.76 and 1.86–2.01 (3 m, 4-H₂, 5-H₂, 6-H₂, 7-H₂), 2.12 furan-2-one (46a): This compound (74 mg, 73%) was prepared from

(m_c, 3a-OH), AB signal (δ_A= 2.51, δ_B= 2.54, J_AB= 16.4 Hz, 3-

H₂), 4.01 (dd, J_7a,7-H(1)= 11.4, J_7α,7-H(2)= 5.0 Hz, 7a-H) ppm; t_r(3a-

R,7aR) = 51.12 min, t_r(3aS,7aS) = 53.14 min (120 °C, 100 kPa);

44% ee.

(Z)-31 (100 mg, 0.467 mmol) in a manner analogous to that speci-

fied for 39a: [α]_D= –27.9 (c = 1.1 in CHCl₃); t_r(4S,5S) = 40.93 min,

t_r(4R,5R) = 42.18 min (126 °C, 100 kPa); 30% ee; elemental analy-

sis calcd. (%) for C₁₀H₁₆O₅(216.2): C 55.56, H 7.46; found: C

55.31, H 7.35.

(4S,5S)-4-Hydroxy-5-isopropyl-4-methyl-4,5-dihydro-3H-furan-2-

one (43a): This compound (138 mg, 87 %) was prepared from 8

(156 mg, 1.00 mmol) in a manner analogous to that specified for

39a: colorless solid (m.p. 47 °C). [α]_D= –50.7 (c = 0.8 in CHCl₃).

(4R,5R)-4-Hydroxy-5-isobutyl-4-methoxycarbonyl-4,5-dihydro-3H-

furan-2-one (46b): This compound (72 mg, 71%) was prepared from

(Z)-31 (100 mg, 0.467 mmol) in a manner analogous to that speci-

¹H NMR (500 MHz, CDCl₃): δ = 1.05 (d, J_1Ј-Me,1Ј= 6.8 Hz, 1Ј- fied for 39a but with (DHQD)₂PHAL as a ligand: [α]_D= +32.2 (c

CH₃)*, 1.10 (d, J_2Ј,1Ј= 6.6 Hz, 2Ј-H₃)*, 1.50 (s, 4-CH₃), 2.16 (dqq,

= 1.2 in CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.92 (d,

J_1Ј,5= 8.6, J_1Ј,1Ј-Me= J_1Ј,2Ј= 6.7 Hz, 1Ј-H), 2.23 (br.s, 4-OH), AB J_2Ј-Me,2Ј= 6.6 Hz, 2Ј-CH₃)*, 0.94 (d, J_3Ј,2Ј= 6.6 Hz, 3Ј-H₃)*, 1.31–

signal (δ_A= 2.62, δ_B= 2.65, J_AB= 17.5 Hz, 3-H₂), 3.85 (d, J_5,1Ј

=

1.37 (m, 1Ј-H¹), 1.70–1.81 (m, 1Ј-H², 2Ј-H), AB signal (δ_A= 2.69,

δ_B= 3.15, J_AB= 17.4, B part additionally split by ⁴J_B,4-OH= 1.1 Hz,

8.6 Hz, 5-H) ppm; * = interchangeable. IR (film): ν = 3450, 2965,

˜

Eur. J. Org. Chem. 2006, 2119–2133

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2129

T. Kapferer, R. Brückner

FULL PAPER

3-H₂), 3.44 (br.d, J_4-OH,3-H(B)= 1.1 Hz, 4-OH), 3.88 (s, CO₂CH₃),

4

(E)-31 (100 mg, 0.47 mmol) in a manner analogous to that specified

for 39a but with (DHQD)₂PHAL as a ligand: [α]_D= +120.8 (c =

0.9 in CHCl₃); t_r(4S,5R) = 14.15 min, t_r(4R,5S) = 12.71 min

(135 °C, 100 kPa); 78% ee.

4.64 (dd, J_5,1Ј-H(2)= 9.1, J_5,1Ј-H(1)= 4.0 Hz, 5-H) ppm; * = inter-

changeable. IR (film): ν = 3470, 2960, 2875, 1790, 1745, 1470, 1440,

˜

1410, 1390, 1370, 1355, 1300, 1265, 1220, 1195, 1135, 1105, 1065,

1035, 985, 955 cm^–1; t_r(4R,5R) = 42.53 min, t_r(4S,5S) = 41.52 min

(125 °C, 100 kPa); 41% ee.

(4R,5S)-4-Hydroxy-4-methoxycarbonyl-5-phenyl-4,5-dihydro-3H-

furan-2-one (50a): This compound (71 mg, 70%) was prepared from

(E)-33 (100 mg, 0.427 mmol) in a manner analogous to that speci-

fied for 39a: [α]_D= –52.2 (c = 0.6 in CHCl₃); t_r(4R,5S) = 18.37 min,

t_r(4S,5R) = 17.48 min (160 °C, 100 kPa); 82% ee.

(4S,5S)-4-Hydroxy-4-methoxycarbonyl-5-phenyl-4,5-dihydro-3H-

furan-2-one (47a): This compound (95 mg, 47%) was prepared from

(Z)-33 (200 mg, 0.854 mmol) in a manner analogous to that speci-

fied for 39a: [α]_D= –36.5 (c = 1.0 in CHCl₃). ¹H NMR (500 MHz,

(4S,5R)-4-Hydroxy-4-methoxycarbonyl-5-phenyl-4,5-dihydro-3H-

furan-2-one (50b): This compound (78 mg, 77%) was prepared from

(E)-33 (100 mg, 0.427 mmol) in a manner analogous to that speci-

fied for 39a but with (DHQD)₂PHAL as a ligand: colorless solid

(m.p. 86 °C). [α]_D= +58.7 (c = 1.0 in CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = AB signal (δ_A= 3.02, δ_B= 3.11, J_AB= 17.5 Hz, 3-

H₂), 3.47 (s, CO₂CH₃), 3.90 (s, 4-OH), 5.47 (s, 5-H), 7.30–7.35 (m,

4

CDCl₃): δ = 2.59 (d, J_4-OH,3-H(B)= 2.0 Hz, 4-OH), AB signal (δ_A

= 2.89, δ_B= 3.37, J_AB= 17.3, B part additionally split by J_B,4-OH

= 2.0 Hz, 3-H₂), 3.92 (s, CO₂CH₃), 5.68 (s, 5-H), 7.23–7.27 and

7.39–7.43 (2 × m, C H ) ppm. IR (KBr): ν = 3480, 3065, 3015,

˜

6

5

2955, 1795, 1725, 1455, 1435, 1410, 1330, 1320, 1295, 1260, 1220,

1195, 1155, 1110, 1085, 1015, 770, 700, 500 cm^–1; t_r(4S,5S) =

25.33 min, t_r(4R,5R) = 23.89 min (160 °C, 100 kPa); 72% ee; ele-

mental analysis calcd. (%) for C₁₂H₁₂O₅(236.2): C 61.01, H 5.12;

found C 60.88, H 5.28.

C H ) ppm. IR (CHCl ): ν = 3505, 3395, 3005, 2955, 2930, 1795,

˜

6

5

3

1750, 1495, 1455, 1440, 1275, 1240, 1225, 1215, 1175, 1150, 1080,

1040, 1025, 975, 860, 750, 700, 630, 550 cm^–1; t_r(4S,5R) =

17.50 min, t_r(4R,5S) = 18.45 min (160 °C, 100 kPa); 87% ee; ele-

mental analysis calcd. (%) for C₁₂H₁₂O₅(236.2): C 61.01, H 5.12;

found: C 60.87, H 5.18.

(4R,5R)-4-Hydroxy-4-methoxycarbonyl-5-phenyl-4,5-dihydro-3H-

furan-2-one (47b): This compound (77 mg, 38%; mp. 79 °C) was

prepared from (Z)-33 (200 mg, 0.854 mmol) in a manner analogous

to that specified for 39a but with (DHQD)₂PHAL as a ligand: col-

orless solid (m.p. 79 °C). [α]_D= +16.3 (c = 1.0 in CHCl₃); t_r(4R,5R)

= 23.93 min, t_r(4S,5S) = 25.40 min (160 °C, 100 kPa); 61% ee.

(4R,5S)-4-Ethoxycarbonyl-4-hydroxy-5-phenyl-4,5-dihydro-3H-

furan-2-one (51a): This compound (72 mg, 76%) was prepared from

(E)-34 (100 mg, 0.38 mmol) in a manner analogous to that specified

for 39a: colorless solid (m.p. 108 °C). [α]_D= –40.3 (c = 1.1 in

(4S,5S)-4-Ethoxycarbonyl-4-hydroxy-5-phenyl-4,5-dihydro-3H-

furan-2-one (48a): This compound (46 mg, 49%) was prepared from

(Z)-34 (98 mg, 0.37 mmol) in a manner analogous to that specified

for 39a: [α]_D= –25.4 (c = 0.8 in CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 1.38 (tm_c, J_vic= 7.2 Hz, CO₂CH₂CH₃), AB signal (δ_A

= 2.88, δ_B= 3.37, J_AB= 17.2 Hz, 3-H₂), 4.37 (m_c, CO₂CH₂CH₃),

5.67 (s, 5-H), 7.24–7.27 and 7.38–7.43 (2 m, C₆H₅) ppm. IR

1

CHCl₃). H NMR (400 MHz, CDCl₃): δ = 1.02 (t, J_vic= 7.2 Hz,

CO₂CH₂CH₃), AB signal (δ_A= 3.01, δ_B= 3.10, J_AB= 17.3 Hz, 3-

H₂), 3.81 (dq, J_gem= 10.6 Hz, J_vic= 7.2 Hz, 1Ј-H¹), 3.96 (dq, J_gem

= 10.7 Hz, J_vic= 7.1 Hz, 1Ј-H²), superimposed by 3.97 (s, 4-OH),

5.49 (s, 5-H), 7.32–7.37 (m, Ph-H) ppm. IR (KBr): ν = 3570, 3515,

˜

3090, 3065, 3035, 3025, 3020, 3010, 2985, 2940, 2910, 1800, 1735,

1455, 1415, 1320, 1270, 1240, 1165, 1135, 1040, 1025, 860,

780 cm^–1; t_r(4R,5S) = 32.83 min, t_r(4S,5R) = 31.97 min (150 °C,

100 kPa); 84 % ee; elemental analysis calcd. (%) for C₁₃H₁₄O₅

(250.2): C 62.41, H 5.64; found: C 62.20, H 5.64.

(CHCl ): ν = 3545, 3035, 3030, 3015, 2990, 2940, 1795, 1740, 1455,

˜

3

1405, 1370, 1316, 1270, 1220, 1180, 1105, 1085, 1035, 1020, 875,

860, 795 cm^–1; t_r(4S,5S) = 48.35 min, t_r(4R,5R) = 46.04 min

(160 °C, 100 kPa); 50 % ee; elemental analysis calcd. (%) for

C₁₃H₁₄O₅(250.2): C 62.39, H 5.64; found: C 62.33, H 5.74.

(4S,5R)-4-Ethoxycarbonyl-4-hydroxy-5-phenyl-4,5-dihydro-3H-

furan-2-one (51b): This compound (79 mg, 83%) was prepared from

(E)-34 (100 mg, 0.38 mmol) in a manner analogous to that specified

for 39a but with (DHQD)₂PHAL as a ligand: [α]_D= +43.9 (c = 1.0

in CHCl₃); t_r(4S,5R) = 30.98 min, t_r(4R,5S) = 32.58 min (150 °C,

100 kPa); 90% ee.

(4R,5R)-4-Ethoxycarbonyl-4-hydroxy-5-phenyl-4,5-dihydro-3H-

furan-2-one (48b): This compound (39 mg, 66%; mp. 79 °C) was

prepared from (Z)-34 (62 mg, 0.24 mmol) in a manner analogous

to that specified for 39a but with (DHQD)₂PHAL as a ligand: col-

orless solid (m.p. 79 °C). [α]_D= +16.3 (c = 1.0 in CHCl₃); t_r(4R,5R)

= 45.73 min, t_r(4S,5S) = 48.17 min (150 °C, 100 kPa); 44% ee.

Compounds 52a and 52b: These compounds were obtained as de-

scribed in ref.^[8]

(4R,5S)-4-Hydroxy-5-isobutyl-4-methoxycarbonyl-4,5-dihydro-3H-

furan-2-one (49a): This compound (81 mg, 89%) was prepared from

(E)-31 (90 mg, 0.42 mmol) in a manner analogous to that specified

for 39a: colorless solid (m.p. 62 °C). [α]_D= –93.9 (c = 1.0 in

(4S,5S)-5-[(3S)-3,4-Dihydroxy-4-methylpentyl]-4-hydroxy-5-

methyl-4,5-dihydro-3H-furan-2-one (53a): This compound (146 mg,

62%) was prepared from (E)-18 (200 mg, 1.02 mmol) in a manner

analogous to that specified for 39a, but twice as much of each rea-

CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.93 (d, J_2Ј-Me,2Ј

6.6 Hz 2Ј-CH₃)*, 0.95 (d, J_3Ј,2Ј= 6.6 Hz, 3Ј-H₃)*, AB signal (δ_A

1.30, δ_B= 1.38, J_AB= 14.1 Hz, A part additionally split by J_A,2Ј

8.6, J_A,5= 3.0, B part additionally split by J_B,5= 10.2, J_B,2Ј

=

1

gent was used: H NMR (300 MHz, D₂O): δ = 1.24 (s, 4Ј-CH₃, 5Ј-

H₃), 1.37–1.51 (m, 2Ј-H¹)*, superimposed by 1.44 (s, 5-CH₃), 1.76–

1.88 (m, 1Ј-H¹, 2Ј-H²)*, 2.10–2.20 (m, 1Ј-H²)*, 2.61 (dd, J_gem

=

18.5 Hz, J_3-H(1),4= 2.1 Hz, 3-H¹), 3.30 (dd, J_gem= 18.5 Hz,

J_3-H(2),4= 6.2 Hz, 3-H²), 3.43 (dd, J_3Ј,2Ј-H(1)= 10.6 Hz, J_3Ј,2Ј-H(2)

1.6 Hz, 3Ј-H), 4.41 (dd, J_4,3-H(2)= 6.2 Hz, J_4,3-H(1)= 2.2 Hz, 4-

5.4 Hz, 1Ј-H₂), 1.82 (m_c, 2Ј-H), AB signal (δ_A= 2.84, δ_B= 2.95,

J_AB= 17.4 Hz, 3-H₂), 3.65 (s, 4-OH), 3.87 (s, CO₂CH₃), 4.40 (dd,

J_5,1Ј-H(B)= 10.5 Hz, J_5,1Ј-H(A)= 3.1 Hz, 5-H) ppm; * = interchange-

=

able. IR (CHCl ): ν = 3530, 3355, 3035, 3010, 2960, 2940, 2910,

˜

H) ppm; * = assignments interchangeable. IR (KBr): ν = 3410,

˜

3

2875, 1785, 1740, 1470, 1440, 1415, 1295, 1245, 1175, 1140, 1100,

990 cm^–1; t_r(4R,5S) = 12.94 min, t_r(4S,5R) = 14.60 min (135 °C,

100 kPa); 63 % ee, elemental analysis calcd. (%) for C₁₀H₁₆O₅

(216.2): C 55.56, H 7.46; found: C 55.53, H 7.59.

2980, 2940, 2880, 1775, 1740, 1460, 1450, 1440, 1415, 1390, 1295,

1215, 1185, 1165, 1090, 1070, 1020, 995, 950, 885, 795 cm^–1. This

solid was too sparingly soluble for accurate determination of [α]_D.

(4R,5R)-5-[(3R)-3,4-Dihydroxy-4-methylpentyl]-4-hydroxy-5-

methyl-4,5-dihydro-3H-furan-2-one (53b): This compound (135 mg,

75%) was prepared from (E)-18 (152 mg, 0.774 mmol) in a manner

(4S,5R)-4-Hydroxy-5-isobutyl-4-methoxycarbonyl-4,5-dihydro-3H-

furan-2-one (49b): This compound (89 mg, 88%) was prepared from

2130

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Eur. J. Org. Chem. 2006, 2119–2133

Enantioselective Syntheses of Trisubstituted γ-Butyrolactones

FULL PAPER

analogous to that specified for 39a, but twice as much of each rea-

gent and (DHQD)₂PHAL as a ligand was used: colorless solid

(3aR,7aR)-5-Hydroxy-7a-methyl-3,3a,5,6,7,7a-hexahydrofuro[3,2-b]-

pyran-2-one (56b): This compound (120 mg, 72%; dr 79:21) was

(m.p. 128 °C); elemental analysis calcd. (%) for C₁₁H₂₀O₅(232.2): prepared from 53b (224 mg, 0.964 mmol) in a manner analogous

C 56.89, H 8.68; found: C 56.70, H 8.76. This solid was too spar-

to that specified for 56a: [α]_D= +90.6 (c = 1.1 in CHCl₃).

ingly soluble for accurate determination of [α]_D.

Compounds 54a and 54b: These compounds were obtained as de-

scribed in ref.^[8]

(4S,5R)-5-[(3S)-3,4-Dihydroxy-4-methylpentyl]-4-hydroxy-5-

methyl-4,5-dihydro-3H-furan-2-one (55a): This compound (556 mg,

77%) was prepared from (Z)-18 (609 mg, 3.10 mmol) in a manner

analogous to that specified for 39a, but twice as much of each rea-

gent was used: ¹H NMR [500 MHz, D₂O, (CD₃)₂CO]: δ = 1.22 and

1.23 (2 s, 4Ј-CH₃, 5Ј-H₃), 1.43–1.51 (m, 2Ј-H¹)*, superimposed by

1.46 (s, 5-CH₃), 1.76–1.79 (m, 1Ј-H¹, 2Ј-H²), 1.92–1.99 (m, 1Ј-

H²)**, 2.63 (dd, J_gem= 18.5 Hz, J_3-H(1),4= 3.4 Hz, 3-H¹), 3.22 (dd,

(3aS,7aS)-7a-Methyl-3a,6,7,7a-tetrahydrofuro[3,2-b]pyran-2,5-(3H)-

dione (57a): Pyridinium chlorochromate (571 mg, 2.65 mmol,

2.0 equiv.) was added to a solution of 56a (228 mg, 1.32 mmol) in

CH₂Cl₂(10 mL). After stirring overnight, the mixture was filtered

through Celite, evaporated in vacuo, and purified by flash

chromatography (cyclohexane/EtOAc, 1:2) to afford the title com-

pound (129 mg, 57%): colorless solid (m.p. 129 °C). [α]_D= –19.2

J_gem= 18.5 Hz, J_3-H(2),4= 6.7 Hz, 3-H²), 3.38 (dd, J_3Ј,2Ј-H(1)

=

10.6 Hz, J_3Ј,2Ј-H(2)= 1.4 Hz, 3Ј-H), 4.41 (dd, J_4,3-H(2)= 6.7 Hz, J_4,3-

= 3.3 Hz, 4-H) ppm; *^,** = assignable by a C,H correlation

H(1)

spectrum. IR (KBr): ν = 3415, 2985, 2965, 2945, 2910, 2875, 2530,

˜

1

(c = 1.1 in CHCl₃). H NMR (500 MHz, CDCl₃): δ = 1.51 (s, 7a-

2505, 2475, 1750, 1450, 1385, 1295, 1255, 1180, 1150, 1105, 1065,

1030, 1020, 945, 895, 810, 720, 630 cm^–1. This solid was too spar-

ingly soluble for accurate determination of [α]_D.

CH₃), AB signal (δ_A= 2.17, δ_B= 2.30, J_AB= 14.5 Hz, A part

additionally split by J_A,6-H(B)= 9.8 Hz, J_A,6-H(A)= 4.8 Hz, B part

additionally split by J_B,6-H(A)= 7.3, J_B,6-H(B)= 5.0 Hz, 7-H₂), AB

signal (δ_A= 2.49, δ_B= 2.65, J_AB= 17.2, A part additionally split

by J_A,7-H(B)= 7.3 Hz, J_A,7-H(A)= 4.8 Hz, B part additionally split

(4R,5S)-5-[(3R)-3,4-Dihydroxy-4-methylpentyl]-4-hydroxy-5-

methyl-4,5-dihydro-3H-furan-2-one (55b): This compound (300 mg,

84%) was prepared from (Z)-18 (300 mg, 1.53 mmol) in a manner

analogous to that specified for 39a, but twice as much of each rea-

gent and (DHQD)₂PHAL as a ligand were used: colorless solid

(m.p. 133 °C); elemental analysis calcd. (%) for C₁₁H₂₀O₅(232.2):

C 56.88, H 8.68; found: C 56.83, H 8.52. This solid was too spar-

ingly soluble for accurate determination of [α]_D.

by J_B,7-H(A)= 9.8 Hz, J_B,7-H(B)= 4.9 Hz, 6-H₂), AB signal (δ_A

2.82, δ_B= 3.09, J_AB= 18.9 Hz, B part additionally split by J_B,3a

=

6.4 Hz, 3-H₂), 4.79 (dd, J_3a,3-H(B)= 6.5 Hz, J_3a,3-H(A)= 0.6 Hz, 3a-

H) ppm. IR (film): ν = 2980, 2945, 2885, 1780, 1760, 1750, 1455,

˜

1435, 1410, 1385, 1315, 1285, 1240, 1225, 1185, 1155, 1100, 1050,

985, 950, 880, 805, 695, 625, 565, 535 cm^–1; t_r(3aS,7aS) =

15.19 min, t_r(3aR,7aR) = 14.19 min (150 °C, 100 kPa); 83% ee; ele-

mental analysis calcd. (%) for C₈H₁₀O₄(170.2): C 56.47, H 5.92;

found: C 56.53, H 5.79.

(3aR,7aR)-7a-Methyl-3a,6,7,7a-tetrahydrofuro[3,2-b]pyran-2,5-

(3H)-dione (57b): This compound (63 mg, 63%) was prepared from

56b (102 mg, 0.592 mmol) in a manner analogous to that specified

for 57a: [α]_D= +20.1 (c = 0.7 in CHCl₃); t_r(3aR,7aR) = 13.66 min,

t_r(3aS,7aS) = 14.76 min (150 °C, 100 kPa); 82% ee.

(3aS,7aS)-5-Hydroxy-7a-methyl-3,3a,5,6,7,7a-hexahydrofuro[3,2-b]-

pyran-2-one (56a): NaIO₄(370 mg, 1.73 mmol, 1.1 equiv.) was

added to a solution of 53a (365 mg, 1.57 mmol) in H₂O (18 mL)

and THF (1.8 mL). After the mixture had been stirred for 2 h, aq.

NH₄Cl (10 mL) was added. The mixture was extracted with

CH₂Cl₂(5×15 mL) and the combined organic extracts were dried

with MgSO₄. Evaporation in vacuo and flash chromatography (cy-

clohexane/EtOAc, 1:3) afforded the title compound [174 mg, 64%;

(4S,5R)-4-Hydroxy-5-methyl-5-(3-oxopropionyl)-4,5-dihydro-3H-

furan-2-one (58a): H₂O (0.3 mL) was added to a suspension of 55a

(72 mg, 0.31 mmol), EtOAc (6 mL), and NaIO₄(73 mg, 0.34 mmol,

1.1 equiv.). After 30 min, EtOAc (20 mL) was added. The mixture

was dried with MgSO₄, evaporated in vacuo, and purified by flash

chromatography (EtOAc) to afford the title compound (50 mg,

94%): [α]_D= +8.0 (c = 1.0 in CHCl₃).

dr 79:21 (Dia-A:Dia-B)]: colorless solid (m.p. 132 °C). [α]_D= –94.5 (4R,5S)-4-Hydroxy-5-methyl-5-(3-oxopropionyl)-4,5-dihydro-3H-

1

(c = 1.0 in CHCl₃). H NMR (500 MHz, CDCl₃): δ = 1.30 (s, 7a- furan-2-one (58b): This compound (197 mg, 91 %) was prepared

CH₃; Dia-B), 1.32 (s, 7a-CH₃; Dia-A), 1.56–1.81, 1.88–1.95, 2.00– from 55b (292 mg, 1.26 mmol) in a manner analogous to that speci-

1

2.07, and 2.27–2.30 (4 m, 6-H₂and 7-H₂; Dia-A and Dia-B), AB

signal (δ_A= 2.43, δ_B= 2.88, J_AB= 17.7, B part additionally split

fied for 58a: [α]_D= –8.8 (c = 1.0 in CHCl₃). H NMR (500 MHz,

CDCl₃): δ = 1.38 (s, 5-CH₃), AB signal (δ_A= 1.93, δ_B= 1.98, J_AB

by J_B,3a= 4.8 Hz, 3-H₂; Dia-A), AB signal (δ_A= 2.57, δ_B= 2.88, = 14.7 Hz, A part additionally split by J_A,2Ј-H(B)= 8.4 Hz, J_A,2Ј-

J_AB= 17.6 Hz, B part additionally split by J_B,3a= 4.5 Hz, 3-H₂;

Dia-B), 3.03 (m_c, 5-OH; Dia-A), 3.34 (br.d, J_5-OH,5= 7.4 Hz, 5-

OH; Dia-B), 4.18 (d, J_3a,3-H(B)= 4.5 Hz, 3a-H; Dia-B), 4.32 (d,

= 6.4 Hz, B part additionally split by J_B,2Ј-H(A)= 8.3 Hz, J_B,2Ј-

= 6.4 Hz, 1Ј-H₂), 2.29 (br.s, 4-OH), AB signal (δ_A= 2.58, δ_B

= 2.93, J_AB= 18.0 Hz, A part additionally split by J_A,4= 4.8 Hz,

H(A)

H(B)

J_3a,3-H(B)= 4.8 Hz; Dia-A), 4.76 (m_c, presumably interpretable as B part additionally split by J_B,4= 6.9 Hz, 3-H₂), AB signal (δ_A

=

ddd, J_5,6-H(1)= 8.9 Hz, J_5,5-OH= 7.2 Hz, J_5,6-H(2)= 1.8 Hz, 5-H;

Dia-B), 5.25 (q, J_5,5-OH= J_5,6-H(1)= J_5,6-H(2)= 3.2 Hz, 5-H; Dia-

2.66, δ_B= 2.70, J_AB= 18.7 Hz, A part additionally split by J_A,1Ј-

= 8.3 Hz, J_A,1Ј-H(A)= 6.5 Hz, J_A,3Ј= 0.9 Hz, B part addition-

H(B)

A) ppm. IR (film): ν = 3425, 2990, 2970, 2965, 2950, 1745, 1725,

ally split by J_B,1Ј-H(A)= 8.3 Hz, J_B,1Ј-H(B)= 6.4 Hz, J_B,3Ј= 0.8 Hz,

2Ј-H₂), 4.25 (br.dd, J_4,3-H(B)= 6.8 Hz, J_4,3-H(A)= 4.8 Hz, 4-H), 9.82

˜

1445, 1430, 1385, 1340, 1320, 1275, 1195, 1120, 1090, 1045, 1000,

955, 940, 825, 790, 595 cm^–1; elemental analysis calcd. (%) for

C₈H₁₂O₄(172.1): C 55.81, H 7.03; found: C 55.70, H 6.92.

(m , 3Ј-H) ppm. IR (film): ν = 3430, 2985, 2940, 2845, 2735, 1770,

˜

c

1725, 1440, 1415, 1385, 1300, 1260, 1195, 1170, 1110, 1095, 1075,

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T. Kapferer, R. Brückner

FULL PAPER

1045, 945, 800 cm^–1; elemental analysis calcd. (%) for C₈H₁₂O₄

(172.1): C 55.81, H 7.02; found: C 55.69, H 7.04.

4210; f) C. M. Rodríguez, J. L. Ravelo, V. S. Martín, Org. Lett.

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l) K. Kiegiel, T. Balakier, P. Kwiatkowski, J. Jurczak, Tetrahe-

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G.-Q. Lin, J. Org. Chem. 2005, 70, 529–532; n) M. He, A. Lei,

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(4S,5R)-5-But-3-enyl-4-hydroxy-5-methyl-4,5-dihydro-3H-furan-2-

one (59a): n-BuLi (2.3  hexane, 0.28 mL, 0.64 mmol, 1.4 equiv.)

was added at –5 °C to a suspension of triphenylmethylphospho-

nium bromide (266 mg, 0.744 mmol, 1.6 equiv.) in THF (2 mL).

The mixture was allowed to reach room temperature. After stirring

for 1 h, the mixture was cooled to –5 °C and a solution of 58a

(80 mg, 0.47 mmol) in THF (2 mL) was added. The mixture was

allowed to reach room temperature and stirred for 1.5 h. Aq.

NH₄Cl (10 mL) was added and the mixture was extracted with

EtOAc (4×20 mL) and dried with MgSO₄. Evaporation in vacuo

and purification by flash chromatography (cyclohexane/EtOAc,

2:1) afforded the title compound (25 mg, 31%): [α]_D= +1.1 (c =

1

0.6 in CHCl₃). H NMR (500 MHz, CDCl₃): δ = 1.40 (s, 5-CH₃),

1.65–1.77 (m, 1Ј-H₂)*, 2.11–2.24 (m, 2Ј-H₂)*, AB signal (δ_A= 2.56,

δ_B= 2.91, J_AB= 18.0 , A part additionally split by J_A,4= 4.3 , B

part additionally split by J_B,4= 7.0 Hz, 3-H₂), A part superimposed

2.56 (br.s, 4-OH), 4.27 (dd, J_4,3-H(B)= 6.9 , J_4,3-H(A)= 4.3 Hz, 4-

H), 4.99 (dm_c, 4Ј-H¹), 5.05 (dm_c, 4Ј-H²), 5.79 (dddd, J_trans= 17.0 ,

J_cis= 10.4 , J_3Ј,2Ј-H(1)= J_3Ј,2Ј-H(2)= 6.6 Hz, 3Ј-H) ppm; * = assign-

Recent syntheses of enantiomerically pure ∆³-butenolides in-

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Reviews: a) B. B. Lohray, Tetrahedron: Asymmetry 1992, 3,

1317–1349; b) R. A. Johnson, K. B. Sharpless, Asymmetric Ca-

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[3]

able by a C,H correlation spectrum. IR (film): ν = 3440, 3080,

˜

2980, 2940, 2860, 1755, 1640, 1450, 1415, 1385, 1300, 1260, 1200,

1175, 1065, 1000, 950, 920, 795 cm^–1; t_r(4S,5R) = 13.25 min,

t_r(4R,5S) = 14.32 min (135 °C, 100 kPa); 90% ee; elemental analy-

sis calcd. (%) for C₉H₁₄O₃(232.2): C 63.51, H 8.29; found: C 63.23,

H 8.42.

[4]

(4R,5S)-5-(But-3-enyl)-4-hydroxy-5-methyl-4,5-dihydro-3H-furan-2-

one (59b): This compound (49 mg, 36%) was prepared from 58b

(139 mg, 0.807 mmol) in a manner analogous to that specified for

59a: [α]_D= –1.2 (c = 1.1 in CHCl₃); t_r(4R,5S) = 14.16 min,

t_r(4S,5R) = 13.28 min (150 °C, 100 kPa); 93% ee.

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Acknowledgments

This work was financially supported by the Fonds der Chemischen

Industrie. We express our gratitude to Valentina Morgel for her

skilful technical assistance.

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Enantioselective Syntheses of Trisubstituted γ-Butyrolactones

FULL PAPER

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Received: December 8, 2005

Published Online: March 8, 2006

Eur. J. Org. Chem. 2006, 2119–2133

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2133

Article Doi

Asymmetric dihydroxylation of β,γ-unsaturated carboxylic esters with trisubstituted C=C bonds - Enantioselective syntheses of trisubstituted γ-butyrolactones

DOI: 10.1002/ejoc.200500963

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